30 - General Problems in Infectious Diseases

Editors: McPhee, Stephen J.; Papadakis, Maxine A.; Tierney, Lawrence M.

Title: Current Medical Diagnosis & Treatment, 46th Edition

Copyright ©2007 McGraw-Hill

> Table of Contents > 33 - Infectious Diseases: Bacterial & Chlamydial

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33

Infectious Diseases: Bacterial & Chlamydial

Henry F. Chambers MD

Infections Caused by Gram-Positive Bacteria

Streptococcal Infections

1. Pharyngitis

Essentials of Diagnosis

  • Abrupt onset of sore throat, fever, malaise, nausea, and headache.

  • Throat red and edematous, with or without exudate; cervical nodes tender.

  • Diagnosis confirmed by culture of throat.

General Considerations

Group A β-hemolytic streptococci (Streptococcus pyogenes) are the most common bacterial cause of pharyngitis. Transmission occurs by droplets of infected secretions. Group A streptococci producing erythrogenic toxin may cause scarlet fever in susceptible persons.

Clinical Findings

A. Symptoms and Signs

“Strep throat” is characterized by a sudden onset of fever, sore throat, pain on swallowing, tender cervical adenopathy, malaise, and nausea. The pharynx, soft palate, and tonsils are red and edematous. There may be a purulent exudate. The Centor clinical criteria for the diagnosis of streptococcal pharyngitis are temperature > 38°C, tender anterior cervical adenopathy, lack of a cough, and pharyngotonsillar exudate.

The rash of scarlet fever is diffusely erythematous, resembling a sunburn, with superimposed fine red papules, and is most intense in the groin and axillas. It blanches on pressure, may become petechial, and fades in 2–5 days, leaving a fine desquamation. The face is flushed, with circumoral pallor, and the tongue is coated with enlarged red papillae (strawberry tongue).

B. Laboratory Findings

Leukocytosis with neutrophil predominance is common. Throat culture onto a single blood agar plate has a sensitivity of 80–90%. Rapid diagnostic tests based on detection of streptococcal antigen are slightly less sensitive than culture.

Complications

Suppurative complications include sinusitis, otitis media, mastoiditis, peritonsillar abscess, and suppuration of cervical lymph nodes.

Nonsuppurative complications are rheumatic fever and glomerulonephritis. Rheumatic fever may follow recurrent episodes of pharyngitis beginning 1–4 weeks after the onset of symptoms. Glomerulonephritis follows a single infection with a nephritogenic strain of streptococcus group A (eg, types 4, 12, 2, 49, and 60), more commonly on the skin than in the throat, and begins 1–3 weeks after the onset of the infection.

Differential Diagnosis

Streptococcal sore throat resembles (and cannot be reliably distinguished clinically from) pharyngitis caused by adenoviruses, Epstein-Barr virus, Arcanobacterium haemolyticus (which also may cause a rash), and other agents. Pharyngitis and lymphadenopathy are common findings in primary HIV infection. Generalized lymphadenopathy, splenomegaly, atypical lymphocytosis, and a positive serologic test distinguish mononucleosis from streptococcal pharyngitis. Diphtheria is characterized by a pseudomembrane; candidiasis shows white patches of exudate and less erythema; and necrotizing ulcerative gingivostomatitis (Vincent's fusospirochetal disease) presents with shallow ulcers in the mouth. Retropharyngeal abscess or bacterial epiglottitis should be considered when odynophagia and difficulty in handling secretions are present and when the severity of symptoms is disproportionate to findings on examination of the pharynx.

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Treatment

Antimicrobial therapy has a modest effect on resolution of symptoms and primarily is administered for prevention of complications. Antibiotic therapy can be safely delayed until the diagnosis is established on the basis of a positive antigen test or culture. Empiric therapy usually is not a cost-effective approach to the management of most adults with pharyngitis because in typical clinical settings, the prevalence of streptococcal pharyngitis is likely to be no more than 10–20% and the positive predictive value of clinical criteria is low. Clinical criteria, such as the Centor criteria, are useful for identifying patients in whom a rapid antigen test or throat culture is indicated. Patients who meet two or more of these criteria merit further testing. When three of the four are present, laboratory sensitivity of rapid antigen testing exceeds 90%. When only one criterion is present, streptococcal pharyngitis is unlikely. In high-prevalence settings or if clinical suspicion for streptococcal pharyngitis is high, a negative antigen test or culture should be confirmed by a follow-up culture.

Gerber MA et al: Rapid diagnosis of pharyngitis caused by group A streptococci. Clin Microbiol Rev 2004;17:571.

McIsaac WJ et al: Empirical validation of guidelines for the management of pharyngitis in children and adults. JAMA 2004;291:1587.

A. Benzathine Penicillin G

Benzathine penicillin G, 1.2 million units intramuscularly as a single dose, is optimal therapy.

B. Penicillin VK

Penicillin VK, 500 mg orally four times a day (or amoxicillin, 750 mg orally twice daily), is effective, but compliance may be poor after the patient becomes asymptomatic in 2–4 days.

C. Macrolides

Erythromycin, 500 mg orally four times a day, or azithromycin, 500 mg orally once daily for 3 days, is an alternative for the penicillin-allergic patient. Macrolides are less effective than penicillins and are considered second-line agents. Macrolide-resistant strains almost always are susceptible to clindamycin, an alternative for serious infections; a 10-day course of 300 mg orally three times a day should be effective.

Prevention of Recurrent Rheumatic Fever

Effectively controlling rheumatic fever depends on identification and treatment of primary streptococcal infection and secondary prevention of recurrences. Patients who have had rheumatic fever should be treated with a continuous course of antimicrobial prophylaxis for at least 5 years. Effective regimens are erythromycin, 250 mg orally twice daily, or penicillin G, 500 mg orally daily.

Neuner J et al: Diagnosis and management of adults with pharyngitis. A cost-effectiveness analysis. Ann Intern Med 2003;139:113.

2. Streptococcal Skin Infections

Group A β-hemolytic streptococci are not normal skin flora. Streptococcal skin infections result from colonization of normal skin by contact with other infected individuals or by preceding streptococcal respiratory infection.

Clinical Findings

A. Symptoms and Signs

Impetigo is a focal, vesicular, pustular lesion with a thick, amber-colored crust with a “stuck-on” appearance.

Erysipelas is a painful superficial cellulitis that frequently involves the face. It is well demarcated from the surrounding normal skin. It affects skin with impaired lymphatic drainage, such as edematous lower extremities or wounds.

B. Laboratory Findings

Cultures obtained from a wound or pustule are likely to grow group A streptococci. Blood cultures are occasionally positive.

Treatment

Parenteral antibiotics are indicated for patients with facial erysipelas or evidence of systemic infection. Penicillin, 2 million units intravenously every 4 hours, is the drug of choice. However, staphylococci infections may at times be difficult to differentiate from streptococcal infections. In practice, initial therapy for patients with risk factors for Staphylococcus aureus (eg, injection drug use, diabetes, wound infection) should cover this organism. Nafcillin, 1.5 g every 6 hours intravenously, and cefazolin, 1 g intravenously or intramuscularly every 8 hours, are reasonable choices. In the patient with a serious penicillin allergy (ie, anaphylaxis), vancomycin, 1000 mg intravenously every 12 hours, should be used.

Patients who do not require parenteral therapy may be treated with amoxicillin, 750 mg twice daily for 7–10 days. A first-generation oral cephalosporin, eg, cephalexin, 500 mg four times daily, or clindamycin, 300 mg orally three times daily, is an alternative to amoxicillin.

3. Other Group A Streptococcal Infections

Arthritis, pneumonia, empyema, endocarditis, and necrotizing fasciitis are relatively uncommon infections that may be caused by group A streptococci. Toxic shock-like syndrome also occurs.

Arthritis generally occurs in association with cellulitis. In addition to intravenous therapy with penicillin G, 2 million units every 4 hours (or cefazolin or vancomycin in doses recommended above for penicillin-allergic

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patients), frequent percutaneous needle aspiration should be performed to remove joint effusions. Open surgical drainage may be necessary when the hip or shoulder is infected.

Pneumonia and empyema often are characterized by extensive tissue destruction and an aggressive, rapidly progressive clinical course associated with significant morbidity and mortality. High-dose penicillin and chest tube drainage are indicated for treatment of empyema. Vancomycin is an acceptable substitute in penicillin-allergic patients.

Group A streptococci can cause endocarditis. Endocarditis should be treated with 4 million units of penicillin G intravenously every 4 hours for 4–6 weeks. Vancomycin, 1 g intravenously every 12 hours, is recommended for persons allergic to penicillin.

Necrotizing fasciitis is a rapidly spreading infection involving the fascia of deep muscle. The clinical findings at presentation may be those of severe cellulitis, but the presence of systemic toxicity and severe pain, which may be followed by anesthesia of the involved area due to destruction of nerves as infection advances through the fascial planes, is a clue to the diagnosis. Surgical exploration is mandatory when the diagnosis is suspected. Early and extensive debridement is essential for survival.

Any streptococcal infection—and necrotizing fasciitis in particular—can be associated with streptococcal toxic shock syndrome, typified by invasion of skin or soft tissues, acute respiratory distress syndrome, and renal failure. The very young, the elderly, and those with underlying medical conditions are at particularly high risk for invasive disease. Bacteremia occurs in most cases. Skin rash and desquamation may not be present. Mortality rates can be up to 80%. The syndrome is due to elaboration of pyrogenic erythrotoxin (which also causes scarlet fever), a superantigen that stimulates massive release of inflammatory cytokines believed to mediate the shock. A β-lactam remains the drug of choice for treatment of serious streptococcal infections, but clindamycin, which is a potent inhibitor of toxin production, should also be administered at a dose of 600 mg every 8 hours intravenously for invasive disease, especially in the presence of shock. Intravenous immune globulin has also been recommended for streptococcal toxic shock syndrome for presumed, although unproven, therapeutic benefit from specific antibody to streptococcal exotoxins in immune globulin preparations. Two dosage regimens have been used: 450 mg/kg once daily for 5 days or a single dose of 2 g/kg with a repeat dose at 48 hours if the patient remains unstable.

Outbreaks of invasive disease have been associated with colonization by invasive clones that can be transmitted to close contacts who, though asymptomatic, may be a reservoir for disease. Tracing contacts of patients with invasive disease is controversial.

Stevens DL et al: Practice guidelines for the diagnosis and management of skin and soft-tissue infections. Clin Infect Dis 2005;41:1373.

Vinh DC et al: Rapidly progressive soft tissue infections. Lancet Infect Dis 2005;5:501.

4. Non-Group A Streptococcal Infections

Non-group A hemolytic streptococci (eg, groups B, C, and G) produce a spectrum of disease similar to that of group A streptococci. The treatment of infections caused by these strains is the same as for group A streptococci.

Group B streptococci are an important cause of sepsis, bacteremia, and meningitis in the neonate. Antepartum screening to identify carriers and peripartum antimicrobial prophylaxis are recommended in pregnancy. This organism, part of the normal vaginal flora, may cause septic abortion, endometritis, or peripartum infections and, less commonly, cellulitis, bacteremia, and endocarditis in adults. Treatment of infections caused by group B streptococci is with either penicillin or vancomycin in doses recommended for group A streptococci. Because of in vitro synergism, some experts recommend the addition of low-dose gentamicin, 1 mg/kg every 8 hours.

Viridans streptococci, which are nonhemolytic or α-hemolytic (ie, producing a green zone of hemolysis on blood agar), are part of the normal oral flora. Although these strains may produce focal pyogenic infection, they are most notable as the leading cause of native valve endocarditis (see below).

Group D streptococci include Streptococcus bovis and the enterococci. S bovis is a cause of endocarditis in association with bowel neoplasia or cirrhosis and is treated like viridans streptococci.

Enterococcal Infections

Two species, Enterococcus faecalis and Enterococcus faecium, are responsible for most human enterococcal infections. Enterococci cause wound infections, urinary tract infections, bacteremia, and endocarditis. Infections caused by penicillin-susceptible strains should be treated with penicillin 3–4 million units every 4 hours; ampicillin 3 g every 6 hours; or if the patient is penicillin-allergic, vancomycin 15 mg/kg every 12 hours intravenously. If the patient has endocarditis, meningitis, or osteomyelitis, gentamicin 1 mg/kg every 8 hours intravenously should be added to the regimen in order to achieve the bactericidal activity that is required to cure these infections.

Resistance to vancomycin, penicillin, and gentamicin is common among enterococcal isolates, especially E faecium; it is essential to determine antimicrobial susceptibility of isolates. Infection control measures that may be indicated to limit their spread include isolation, barrier precautions, and avoidance of overuse of vancomycin and gentamicin. Consultation with an infectious diseases specialist is strongly advised when treating infections caused by resistant strains of enterococci. Quinupristin/dalfopristin and linezolid are approved by the US Food and Drug Administration

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(FDA) for treatment of infections caused by vancomycin-resistant strains of enterococci. Quinupristin/dalfopristin is not active against strains of E faecalis and should be used only for infections caused by E faecium. The dose is 7.5 mg/kg intravenously every 8–12 hours. Phlebitis and irritation at the infusion site (often requiring a central line) and an arthralgia-myalgia syndrome are relatively common side effects. Quinupristin/dalfopristin is an inhibitor of cytochrome P450 enzyme 3A4 and has numerous, important drug interactions. Linezolid, an oxazolidinone, is active against both E faecalis and E faecium. The dose is 600 mg twice daily, and both intravenous and oral preparations are available. Its two principal side effects are thrombocytopenia and bone marrow suppression. Emergence of resistance has occurred during therapy with either quinupristin/dalfopristin or linezolid.

McDonald JR et al: Enterococcal endocarditis: 107 cases from the international collaboration on endocarditis merged database. Am J Med 2005;118:759.

Raad I et al: Prospective, randomized study comparing quinupristin-dalfopristin with linezolid in the treatment of vancomycin-resistant Enterococcus faecium infections. J Antimicrob Chemother 2004;53:646.

Pneumococcal Infections

1. Pneumococcal Pneumonia

Essentials of Diagnosis

  • Productive cough, fever, rigors, dyspnea, early pleuritic chest pain.

  • Consolidating lobar pneumonia on chest radiograph.

  • Gram-positive diplococci on Gram stain of sputum.

General Considerations

The pneumococcus is the most common cause of community-acquired pyogenic bacterial pneumonia. Alcoholism, asthma, HIV infection, sickle cell disease, splenectomy, and hematologic disorders are predisposing factors. The mortality rate remains high in the setting of advanced age, multilobar disease, severe hypoxemia, extrapulmonary complications, and bacteremia.

Clinical Findings

A. Symptoms and Signs

Presenting symptoms and signs include high fever, productive cough, occasionally hemoptysis, and pleuritic chest pain. Rigors occur within the first few hours of infection but are uncommon thereafter. Bronchial breath sounds are an early sign.

B. Laboratory Findings

Pneumococcal pneumonia classically is a lobar pneumonia with radiographic findings of consolidation and occasionally effusion. However, differentiating it from other pneumonias is not possible radiographically or clinically because of significant overlap in presentations. Diagnosis requires isolation of the organism in culture, although the Gram stain appearance of sputum can be suggestive. Sputum and blood cultures, positive in 60% and 25% of cases of pneumococcal pneumonia, respectively, should be obtained prior to initiation of antimicrobial therapy in patients who are admitted to the hospital. A good-quality sputum sample (less than 10 epithelial cells and more than 25 polymorphonuclear leukocytes per high-power field) shows gram-positive diplococci in 80–90% of cases.

Complications

Parapneumonic (sympathetic) effusion is common and may cause recurrence or persistence of fever. These sterile fluid accumulations need no specific therapy. Empyema occurs in 5% or less of cases and is differentiated from sympathetic effusion by the presence of organisms on Gram-stained fluid or positive pleural fluid cultures.

Pneumococcal pericarditis is a rare complication that can cause tamponade. Pneumococcal arthritis also is uncommon. Pneumococcal endocarditis usually involves the aortic valve and often occurs in association with meningitis and pneumonia (sometimes referred to as Austrian's or Osler's triad). Early heart failure and multiple embolic events are typical.

Treatment

A. Specific Measures

Initial antimicrobial therapy for pneumonia is empiric (see Chapter 9 for specific recommendations) pending isolation and identification of the causative agent. Once the pneumonia is determined to be caused by Streptococcus pneumoniae, any of several antimicrobial agents may be used depending on the clinical setting, community patterns of penicillin resistance, and susceptibility of the particular isolate. Uncomplicated pneumococcal pneumonia (ie, arterial Po2 > 60 mm Hg, no coexisting medical problems, and single-lobe disease without signs of extrapulmonary infection) caused by penicillin-susceptible strains of pneumococcus may be treated on an outpatient basis with amoxicillin, 750 mg orally twice daily for 7–10 days. For penicillin-allergic patients, alternatives are azithromycin, one 500-mg dose orally on the first day and 250 mg for the next 4 days; clarithromycin, 500 mg orally twice daily for 10 days; doxycycline, 100 mg orally twice daily for 10 days; or levofloxacin, 750 mg orally for 5 days. Patients should be monitored for clinical response (eg, less cough, defervescence within 2–3 days) because pneumococci have become increasingly resistant to penicillin and the second-line agents.

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Parenteral therapy is generally recommended for the hospitalized patient at least until there has been clinical improvement. Aqueous penicillin G, 2 million units intravenously every 4 hours, or ceftriaxone, 1 g intravenously every 24 hours, is effective for strains that are not highly penicillin-resistant (ie, strains for which the minimum inhibitory concentration [MIC] of penicillin is ≤ 1 mcg/mL). For serious penicillin allergy or infection caused by a highly penicillin-resistant strain, vancomycin, 1 g intravenously every 12 hours, is effective. Alternatively, a fluoroquinolone (eg, levofloxacin, 500 mg, or a comparable dose of any one of several newer fluoroquinolones now on the market, orally or intravenously) can be used. The total duration of therapy is not well defined but 10–14 days is standard.

B. Treatment of Complications

Pleural effusions developing after initiation of antimicrobial therapy usually are sterile, and thoracentesis need not be performed if the patient is otherwise improving. Thoracentesis is indicated for an effusion present prior to initiation of therapy and in the patient who has not responded to antibiotics after 3–4 days. Chest tube drainage may be required if pneumococci are identified by culture or Gram stain, especially if aspiration of the fluid is difficult.

Echocardiography should be done if pericardial effusion is suspected. Patients with pericardial effusion who are responding to therapy and have no signs of tamponade may be monitored and treated with indomethacin, 50 mg orally three times daily, for pain. In patients with increasing effusion, unsatisfactory clinical response, or evidence of tamponade, pericardiocentesis will determine whether the pericardial space is infected. Infected fluid must be drained either percutaneously (by tube placement or needle aspiration), by placement of a pericardial window, or by pericardiectomy. Pericardiectomy eventually may be required to prevent or treat constrictive pericarditis, a common sequela of bacterial pericarditis.

Endocarditis should be treated for 4 weeks with 3–4 million units of penicillin G every 4 hours intravenously; ceftriaxone, 2 g once daily intravenously; or vancomycin, 15 mg/kg every 12 hours intravenously. Mild heart failure may respond to medical therapy, but moderate to severe heart failure is an indication for prosthetic valve implantation, as are systemic emboli or large friable vegetations as determined by echocardiography.

C. Penicillin-Resistant Pneumococci

The prevalence of penicillin-resistant pneumococci (MIC > 0.1 mcg/mL) in the United States is approximately 20%, although there is considerable regional variability. All blood and cerebrospinal fluid isolates should now be tested for resistance to penicillin. Pneumonia caused by intermediately resistant strains (penicillin MIC > 0.1 mcg/mL but ≤ 1 mcg/mL) generally will respond to high-dose penicillin therapy. High-dose penicillin is likely to be effective for infections other than meningitis caused by highly penicillin-resistant strains (MIC > 1 mcg/mL). However, ceftriaxone, 1 g intravenously once daily, or vancomycin, 1 g intravenously every 12 hours, results in a more favorable ratio between serum drug concentration and MIC and may be preferred, especially for immunocompromised patients. Fluoroquinolones with enhanced gram-positive activity (eg, levofloxacin 500 mg once daily or moxifloxacin 400 mg once daily) are effective oral alternatives. Penicillin-resistant strains of pneumococci often are resistant to multiple antibiotics, including macrolides, trimethoprim-sulfamethoxazole, and chloramphenicol, and susceptibility must be documented prior to their use.

Aspa J et al; Pneumococcal Pneumonia in Spain Study Group: Drug-resistant pneumococcal pneumonia: clinical relevance and related factors. Clin Infect Dis 2004;38:787.

Lexau CA et al; Active Bacterial Core Surveillance Team: Changing epidemiology of invasive pneumococcal disease among older adults in the era of pediatric pneumococcal conjugate vaccine. JAMA 2005;294:2043.

Talbot TR et al: Asthma as a risk factor for invasive pneumococcal disease. N Engl J Med 2005;352:2082.

2. Pneumococcal Meningitis

Essentials of Diagnosis

  • Fever, headache, altered mental status.

  • Meningismus.

  • Gram-positive diplococci on Gram stain of cerebrospinal fluid.

General Considerations

S pneumoniae is the most common cause of meningitis in adults. Head trauma, with cerebrospinal fluid leaks, sinusitis, and pneumonia may precede it.

Clinical Findings

A. Symptoms and Signs

The onset is rapid, with fever, headache, meningismus, and altered mentation. Pneumonia may be present. Compared with meningitis caused by the meningococcus, pneumococcal meningitis lacks a rash, and focal neurologic deficits, cranial nerve palsies, and obtundation are more prominent features.

B. Laboratory Findings

The cerebrospinal fluid typically has more than 1000 white blood cells per microliter, over 60% of which

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are polymorphonuclear leukocytes; the glucose concentration is less than 40 mg/dL, or less than 50% of the simultaneous serum concentration; and the protein usually exceeds 150 mg/dL. Not all cases of meningitis will have these typical findings, and alterations in cerebrospinal fluid cell counts and chemistries may be surprisingly minimal, overlapping with those of aseptic meningitis.

Gram stain of cerebrospinal fluid shows gram-positive cocci in 80–90% of cases, and in untreated cases, blood or cerebrospinal fluid cultures are almost always positive.

Treatment

Antibiotics should be given as soon as the diagnosis is suspected. If lumbar puncture must be delayed (eg, while awaiting results of an imaging study to exclude a mass lesion), the patient should be treated empirically for presumed meningitis with intravenous ceftriaxone, 2 g, plus vancomycin, 15 mg/kg, plus dexamethasone, 0.15 mg/kg administered concomitantly after blood cultures (positive in 50% of cases) have been obtained. Once susceptibility to penicillin has been confirmed, penicillin, 24 million units intravenously daily in six divided doses, or ceftriaxone, 2 g every 12 hours intravenously, is continued for 10–14 days in documented cases.

The best therapy for penicillin-resistant strains is not known. Penicillin-resistant strains often are cross-resistant to the third-generation cephalosporins as well as other antibiotics. Susceptibility testing is essential to proper management of this infection. Treatment failures have been reported with ceftriaxone or cefotaxime for meningitis caused by strains with penicillin MICs ≥ 2 mcg/mL. If the MIC of ceftriaxone or cefotaxime is ≤ 0.5 mcg/mL, single-drug therapy with either of these cephalosporins is likely to be effective; when the MIC is ≥ 1 mcg/mL, treatment with a combination of ceftriaxone, 2 g intravenously every 12 hours, plus vancomycin, 30 mg/kg/d intravenously in two or three divided doses, is recommended. If a patient with a penicillin-resistant organism is slow to respond clinically, repeat lumbar puncture may be indicated to assess bacteriologic response.

Dexamethasone administered with antibiotic to adults has been associated with a 60% reduction in mortality and a 50% reduction in unfavorable outcomes. It is recommended that adults with acute bacterial meningitis be given 10 mg of dexamethasone intravenously immediately prior to or concomitantly with the first dose of appropriate antibiotic and every 6 hours thereafter for a total of 4 days. The effect of dexamethasone on outcome of meningitis caused by penicillin-resistant organisms is not known. Because its anti-inflammatory activity could impair penetration of some drugs into the cerebrospinal fluid, patients infected with highly penicillin-resistant organisms may be a risk for treatment failure.

van de Beek D et al: Clinical features and prognostic factors in adults with bacterial meningitis. N Engl J Med 2004;351:1849.

van de Beek D et al: Steroids in adults with acute bacterial meningitis: a systematic review. Lancet Infect Dis 2004;4:139.

Staphylococcus Aureus Infections

1. Skin & Soft Tissue Infections

Essentials of Diagnosis

  • Localized erythema with induration.

  • Tendency toward abscess formation.

  • Folliculitis commonly observed.

  • Gram stain of pus with gram-positive cocci in clusters; cultures usually positive.

General Considerations

Approximately one-quarter of people are asymptomatic nasal carriers of S aureus, which is spread by direct contact. Carriage often precedes infection, which occurs as a consequence of disruption of the cutaneous barrier or impairment of host defenses. S aureus tends to cause more localized skin infections than streptococci, and abscess formation is common. The prevalence of methicillin-resistant strains in community settings is increasing, and these strains have been associated with recurrent and severe skin and soft tissue infections, including necrotizing fasciitis.

Clinical Findings

A. Symptoms and Signs

S aureus skin infections may begin around one or more hair follicles, causing folliculitis; may become localized to form boils (or furuncles); or may spread to adjacent skin and deeper subcutaneous tissue (ie, a carbuncle). Deep abscesses involving muscle or fascia may occur, often in association with a deep wound or other inoculation or injection. Necrotizing fasciitis, a rare form of S aureus skin and soft tissues infection, has been reported with community strains of methicillin-resistant S aureus.

B. Laboratory Findings

Cultures of the wound or abscess material will almost always yield the organism. In patients with systemic signs of infection, blood cultures should be obtained because of potential endocarditis, osteomyelitis, or metastatic seeding of other sites. Patients who are bacteremic should have blood cultures taken early during therapy to exclude persistent bacteremia, an indicator of severe or complicated infection.

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Treatment

Proper drainage of abscess fluid or other focal infections is the mainstay of therapy. Incision and drainage alone may be sufficient for cutaneous abscess. For uncomplicated skin infections, oral antimicrobial therapy is satisfactory. Until recently, an oral penicillinase-resistant penicillin or cephalosporin, such as dicloxacillin or cephalexin, 500 mg four times a day for 7–10 days, has been the drug of choice for empiric therapy. Increasing prevalence of methicillin-resistant strains of S aureus among community isolates may necessitate use of other oral agents to which the isolate is susceptible in vitro, such as clindamycin, 300 mg three times daily; doxycycline, 100 mg twice daily; or trimethoprim-sulfamethoxazole, given in two or three divided doses based on 5–10 mg/kg/d of the trimethoprim component. Unfortunately, the efficacy of these agents is not well defined and not evidence based. Because of the high prevalence of macrolide resistance among S aureus strains, these agents should not be used unless susceptibility is documented.

For more complicated infections with extensive cutaneous or deep tissue involvement or fever, parenteral therapy is indicated initially. A penicillinase-resistant penicillin such as nafcillin or oxacillin in a dosage of 1.5 g every 6 hours intravenously or cefazolin 1 g intravenously or intramuscularly is preferred for infections caused by methicillin-susceptible isolates. In patients with a serious allergy to β-lactam antibiotics or if the strain is methicillin-resistant, vancomycin, 1 g intravenously every 12 hours, is the drug of choice. If the local prevalence of methicillin-resistance is high (eg, 10% or more), and particularly if the patient is seriously ill, vancomycin is indicated pending strain isolation and determination of susceptibility.

Linezolid is FDA-approved for treatment of skin and skin-structure infections as well as nosocomial pneumonia caused by methicillin-resistant strains of S aureus and is as effective as vancomycin according to clinical trial results. The dose is 600 mg orally (bioavailability of 100%) or intravenously twice a day for 10–14 days. Its considerable cost makes it an unattractive choice for most routine outpatient infections, and its safety in treatment courses lasting longer than 2–3 weeks is not well characterized; nevertheless, it is the only proven effective oral alternative to vancomycin.

King MD et al: Emergence of community-acquired methicillin-resistant staphylococcus aureus USA 300 clone as the predominant cause of skin and soft-tissue Infections. Ann Intern Med 2006;144:309.

Miller LG et al: Necrotizing fasciitis caused by community-associated methicillin-resistant Staphylococcus aureus in Los Angeles. N Engl J Med 2005;352:1445.

Zetola N et al: Community-acquired methicillin-resistant Staphylococcus aureus: an emerging threat. Lancet Infect Dis 2005;5:275.

2. Osteomyelitis

S aureus causes of approximately 60% of all cases of osteomyelitis. Osteomyelitis may be caused by direct inoculation, eg, from an open fracture or as a result of surgery; by extension from a contiguous focus of infection or open wound; or by hematogenous spread. Long bones and vertebrae are the usual sites. Epidural abscess is a common complication of vertebral osteomyelitis and should be suspected if fever and severe back or neck pain are accompanied by radicular pain or symptoms or signs indicative of spinal cord compression (eg, incontinence, extremity weakness, pathologic reflexes).

Clinical Findings

A. Symptoms and Signs

The infection may be acute, with abrupt development of local symptoms and systemic toxicity, or indolent, with insidious onset of vague pain over the site of infection, progressing to local tenderness. Fever is absent in one-third or more of cases. Abscess formation is a late and unusual manifestation. Draining sinus tracts occur in chronic infections or infections of foreign body implants.

B. Laboratory Findings

The diagnosis is established by isolation of S aureus from the blood, bone, or a contiguous focus of a patient with signs and symptoms of focal bone infection. Blood culture will be positive in approximately 60% of untreated cases. Bone biopsy and culture are indicated if blood cultures are sterile.

C. Imaging

Bone scan and gallium scan, each with a sensitivity of approximately 95% and a specificity of 60–70%, are useful in identifying or confirming the site of bone infection. Plain bone films early in the course of infection are often normal but will become abnormal in most cases even with effective therapy. Spinal infection (unlike malignancy) traverses the disk space to involve the contiguous vertebral body. CT is more sensitive than plain films and helps localize associated abscesses. MRI is slightly less sensitive than bone scan but has a specificity of 90%. It is indicated when epidural abscess is suspected in association with vertebral osteomyelitis.

Treatment

Prolonged therapy is required to cure staphylococcal osteomyelitis. Durations of 4–6 weeks or longer are recommended. Although oral regimens can be effective, parenteral therapy is preferred, particularly during the acute phase of the infection for patients with systemic toxicity. Nafcillin or oxacillin, 9–12 g/d in six divided doses, is the drug of choice. Cefazolin, 1 g every 6–8 hours, also is effective. Vancomycin, 1 g every 12 hours, may be used for the penicillin-allergic patient, although the risk of relapse is higher than with β-lactam regimens. Addition of rifampin, 300 mg

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twice daily, to the regimen may prevent late relapse and should be strongly considered.

3. Staphylococcal Bacteremia

S aureus readily invades the bloodstream and infects sites distant from the primary site of infection, which may be relatively minor or even inapparent. Whenever S aureus is recovered from blood cultures, the possibility of endocarditis, osteomyelitis, or other metastatic deep infection must be considered. Bacteremia that persists for more than 48 to 96 hours after initiation of therapy is strongly predictive of worse outcome and complicated infection. The appropriate duration of therapy for uncomplicated bacteremia arising from a removable source (eg, intravenous device) or drainable focus (eg, skin abscess) has not been well defined, but a 10- to 14-day course of therapy appears to be the minimum. However, 5% or more of patients may relapse, usually with endocarditis or osteomyelitis, even if treated for 2 weeks.

Nafcillin or oxacillin, 1.5 g intravenously every 4–6 hours; cefazolin, 1 g every 8 hours; or vancomycin, 1 g every 12 hours, is recommended for uncomplicated staphylococcal bacteremia. Vancomycin as definitive therapy should be reserved for patients with serious penicillin allergy or with infections caused by methicillin-resistant strains because it is less active than β-lactam antibiotics and treatment failures are more common than with β-lactams. Transesophageal echocardiography (TEE) is a sensitive and cost-effective method for excluding underlying endocarditis. It is considered for patients for whom the pretest probability of endocarditis is 5% or higher—and for all patients with unexplained S aureus bacteremia.

Vancomycin treatment failures are relatively common, particularly for complicated bacteremia, in foreign body infection, or when the MIC of the isolate is > 2 mcg/mL. Consultation should be sought with an infectious diseases specialist when vancomycin treatment failure is encountered. Cases of vancomycin treatment failures in which the staphylococcal isolate exhibits a vancomycin MIC ≥ 4 mcg/mL should be reported to the Centers for Disease Control and Prevention (CDC) to help track this potentially serious and emerging problem of vancomycin resistance.

Empiric therapy of suspected staphylococcal infection, whether of community or hospital onset, depends on the severity of the infection and the likelihood that it is caused by methicillin-resistant strains. If the prevalence exceeds 5–10% for more seriously ill patients, initial therapy should include vancomycin, 1 g intravenously every 12 hours, until results of susceptibility tests are known. Resistance to vancomycin fortunately remains rare and should not affect the choice of empiric therapy; although with continuing use, emergence of staphylococci resistant to this drug and its relatively high rate of treatment failure merits concern.

Fowler VG Jr et al: Risk factors for hematogenous complications of intravascular catheter-associated Staphylococcus aureus bacteremia. Clin Infect Dis 2005;40:695.

Kuehnert MJ et al: Methicillin-resistant-Staphylococcus aureus hospitalizations, United States. Emerg Infect Dis 2005;11:868.

4. Toxic Shock Syndrome

S aureus produces toxins that cause three important entities: “scalded skin syndrome” in children, toxic shock syndrome in adults, and enterotoxin food poisoning. Toxic shock syndrome is characterized by abrupt onset of high fever, vomiting, and watery diarrhea. Sore throat, myalgias, and headache are common. Hypotension with renal and cardiac failure is associated with a poor outcome. A diffuse macular erythematous rash and nonpurulent conjunctivitis are common, and desquamation, especially of palms and soles, is typical during recovery. Fatality rates may be as high as 15%. Although originally associated with tampon use, any focus (eg, nasopharynx, bone, vagina, rectum, abscess, or wound) harboring a toxin-producing S aureus strain can cause toxic shock syndrome and nonmenstrual cases of toxic shock syndrome are common. Classically, blood cultures are negative because symptoms are due to the effects of the toxin and not systemic infection.

Important aspects of treatment include rapid rehydration, antistaphylococcal drugs, management of renal or cardiac failure, and addressing sources of toxin, eg, removal of tampon or drainage of abscess.

5. Infections Caused by Coagulase-Negative Staphylococci

Coagulase-negative staphylococci are an important cause of infections of intravascular and prosthetic devices and of wound infection following cardiothoracic surgery. These organisms may infrequently cause infections such as osteomyelitis and endocarditis in the absence of a prosthesis. Most human infections are caused by Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus warnerii, Staphylococcus saprophyticus, Staphylococcus saccharolyticus, and Staphylococcus cohnii. These common nosocomial pathogens are less virulent than S aureus, and infections caused by them tend to be more indolent.

Because coagulase-negative staphylococci are normal inhabitants of human skin, it is difficult to distinguish infection from contamination, the latter perhaps accounting for three-fourths of blood culture isolates. Infection is more likely if the patient has a foreign body (eg, sternal wires, prosthetic joint, prosthetic cardiac valve, pacemaker, intracranial pressure monitor, cerebrospinal fluid shunt, peritoneal dialysis catheter) or an intravascular device in place. Purulent or serosanguineous drainage, erythema, pain, or tenderness at the site of the foreign body or device suggests infection. Instability and pain are signs of prosthetic joint infection. Fever, a new murmur, instability of the prosthesis, or signs of systemic embolization are evidence of prosthetic valve endocarditis. Immunosuppression and recent antimicrobial therapy are risk factors.

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Infection is also more likely if the same strain is consistently isolated from two or more blood cultures (particularly if samples were obtained at different times) and from the foreign body site. Contamination is more likely when a single blood culture is positive or if more than one strain is isolated from blood cultures. The antimicrobial susceptibility pattern and speciation are used to determine whether one or more strains have been isolated. More sophisticated typing methods, eg, pulse-field gel electrophoresis of restriction enzyme digested chromosomal DNA, may be required to identify distinct strains.

Whenever possible, the intravascular device or foreign body suspected of being infected by coagulase-negative staphylococci should be removed. However, removal and replacement of some devices (eg, prosthetic joint, prosthetic valve, cerebrospinal fluid shunt) can be a difficult or risky procedure, and it may sometimes be preferable to treat with antibiotics alone with the understanding that the probability of cure is reduced and that surgical management may eventually be necessary.

Coagulase-negative staphylococci are commonly resistant to β-lactams and multiple other antibiotics. For patients with normal renal function, vancomycin, 1 g intravenously every 12 hours, is the treatment of choice for suspected or confirmed infection caused by these organisms until susceptibility to penicillinase-resistant penicillins or other agents has been confirmed. Duration of therapy has not been established for relatively uncomplicated infections, such as those secondary to intravenous devices, which may be eliminated by simply removing the infected device. Infection involving bone or a prosthetic valve should be treated for 6 weeks. A combination regimen of vancomycin plus rifampin, 300 mg orally twice daily, and gentamicin, 1 mg/kg intravenously every 8 hours, is recommended for treatment of prosthetic valve endocarditis caused by methicillin-resistant strains.

Tokars JI: Predictive value of blood cultures positive for coagulase-negative staphylococci: implications for patient care and health care quality assurance. Clin Infect Dis 2004;39:333.

Wisplinghoff H et al: Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study. Clin Infect Dis 2004;39:309.

Clostridial Diseases

1. Clostridial Myonecrosis (Gas Gangrene)

Essentials of Diagnosis

  • Sudden onset of pain and edema in an area of wound contamination.

  • Prostration and systemic toxicity.

  • Brown to blood-tinged watery exudate, with skin discoloration of surrounding area.

  • Gas in the tissue by palpation or radiograph.

  • Gram-positive rods in culture or smear of exudate.

General Considerations

Gas gangrene or clostridial myonecrosis is produced by any one of several clostridia (Clostridium perfringens, Clostridium ramosum, Clostridium bifermentans, Clostridium histolyticum, Clostridium novyi, etc). Trauma and injection drug use are common predisposing conditions. Toxins produced in devitalized tissues under anaerobic conditions result in shock, hemolysis, and myonecrosis.

Clinical Findings

A. Symptoms and Signs

The onset is usually sudden, with rapidly increasing pain in the affected area, hypotension, and tachycardia. Fever is present but is not proportionate to the severity of the infection. In the last stages of the disease, severe prostration, stupor, delirium, and coma occur.

The wound becomes swollen, and the surrounding skin is pale. There is a foul-smelling brown, blood-tinged serous discharge. As the disease advances, the surrounding tissue changes from pale to dusky and finally becomes deeply discolored, with coalescent, red, fluid-filled vesicles. Gas may be palpable in the tissues.

B. Laboratory Findings

Gas gangrene is a clinical diagnosis, and empiric therapy is indicated if the diagnosis is suspected. Radiographic studies may show gas within the soft tissues, but this finding is not specific. The smear shows absence of neutrophils and the presence of gram-positive rods. Anaerobic culture confirms the diagnosis.

Differential Diagnosis

Other bacteria can produce gas in infected tissue, eg, enteric gram-negative organisms, or anaerobes.

Treatment

Penicillin, 2 million units every 3 hours intravenously, is effective. Other agents (eg, tetracycline, clindamycin, metronidazole, chloramphenicol, cefoxitin) are active against Clostridium species in vitro and probably in vivo as well. Adequate surgical debridement and exposure of infected areas are essential, with radical surgical excision often necessary. Hyperbaric oxygen therapy has been used empirically but must be used in conjunction with administration of an appropriate antibiotic and surgical debridement.

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2. Clostridium sordellii Toxic Shock Syndrome

Essentials of Diagnosis

  • Sudden onset after medical abortion.

  • Abdominal pain.

  • Absence of fever.

  • Tachycardia, severe hypotension, capillary leak syndrome with edema.

  • Profound leukocytosis, hemoconcentration.

General Considerations & Clinical Findings

C sordellii is a rare cause of endometritis and toxic shock syndrome following childbirth. Four cases, all fatal, of uterine infection following medically induced abortion with mefipristone have been recently reported. Onset of illness was within 4–5 days of ingestion of mefipristone and the clinical course fulminant. Infection appeared to be limited to the uterus, which showed necrosis, edema, hemorrhage, and acute inflammatory changes.

Treatment

Early recognition, aggressive resuscitation from shock, immediate surgical debridement with hysterectomy, and administration of an antimicrobial that is active against C sordellii are essential to survival. Based on in vitro susceptibility data, any of several agents should be active, including penicillin, ampicillin, a macrolide, clindamycin, a tetracycline, or metronidazole. Whether a protein synthesis inhibitor to block further toxin production offers any advantage over a β-lactam is unknown.

Fischer M et al: Fatal toxic shock syndrome associated with Clostridium sordellii after medical abortion. N Engl J Med 2005;353:2352.

3. Tetanus

Essentials of Diagnosis

  • History of wound and possible contamination.

  • Jaw stiffness followed by spasms of jaw muscles (trismus).

  • Stiffness of the neck and other muscles, dysphagia, irritability, hyperreflexia.

  • Finally, painful convulsions precipitated by minimal stimuli.

General Considerations

Tetanus is caused by the neurotoxin tetanospasmin, elaborated by Clostridium tetani. Spores of this organism are ubiquitous in soil and may germinate when introduced into a wound. The vegetative bacteria produce tetanospasmin, a zinc metalloprotease that cleaves synaptobrevin, a protein essential for neurotransmitter release. Tetanospasmin interferes with neurotransmission at spinal synapses of inhibitory neurons. As a result, minor stimuli result in uncontrolled spasms, and reflexes are exaggerated. The incubation period is 5 days to 15 weeks, with the average being 8–12 days.

Most cases occur in unvaccinated individuals. Persons at risk are the elderly, migrant workers, newborns, and injection drug users. While puncture wounds are particularly prone to causing tetanus, any wound, including bites or decubiti, may become colonized and infected by C tetani.

Clinical Findings

A. Symptoms and Signs

The first symptom may be pain and tingling at the site of inoculation, followed by spasticity of the muscles nearby. Stiffness of the jaw, neck stiffness, dysphagia, and irritability are other early signs. Hyperreflexia develops later, with spasms of the jaw muscles (trismus) or facial muscles and rigidity and spasm of the muscles of the abdomen, neck, and back. Painful tonic convulsions precipitated by minor stimuli are common. Spasms of the glottis and respiratory muscles may cause acute asphyxia. The patient is awake and alert throughout the illness. The sensory examination is normal. The temperature is normal or only slightly elevated.

B. Laboratory Findings

The diagnosis of tetanus is made clinically.

Differential Diagnosis

Tetanus must be differentiated from various acute central nervous system infections such as meningitis. Trismus may occasionally develop with the use of phenothiazines. Strychnine poisoning should also be considered.

Complications

Airway obstruction is common. Urinary retention and constipation may result from spasm of the sphincters. Respiratory arrest and cardiac failure are late, life-threatening events.

Table 33-1. Guide to tetanus prophylaxis in wound management.

History of Absorbed Tetanus Toxoid Clean, Minor Wounds All Other Wounds1
Tdap or Td2 TIG3 Tdap or Td2 TIG3
Unknown or < 3 doses Yes No Yes Yes
3 or more doses No4 No No5 No
1Such as, but not limited to, wounds contaminated with dirt, feces, soil, saliva, etc; puncture wounds; avulsions; and wounds resulting from missiles, crushing, burns, and frostbite.
2Td indicates tetanus toxoid and diphtheria toxoid, adult form. Tdap indicates tetanous toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine, which may be substituted as a single dose for Td. Unvaccinated individuals should receive a complete series of three doses, once of which is Tdap.
3Human tetanus immune globulin, 250 units intramuscularly.
4Yes if more than 10 years have elapsed since last dose.
5Yes if more than 5 years have elapsed since last dose. (More frequent boosters are not needed and can enhance side effects.) Tdap has been safely administered within 2 years of Td vaccination, although local reactions to the vaccine may be increased.

Prevention

Tetanus is completely preventable by active immunization. Immunizations for children include tetanus toxoid, usually as DTP (see Table 30-4 for schedule). For primary immunization of adults, tetanus toxoid is administered as two doses 4–6 weeks apart, with

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a third dose 6–12 months later. Booster doses are given every 10 years or at the time of major injury if it occurs more than 5 years after a dose.

Passive immunization should be used in nonimmunized individuals and those whose immunization status is uncertain whenever a wound is contaminated or likely to have devitalized tissue. Tetanus immune globulin, 250 units, is given intramuscularly. Active immunization with tetanus toxoid is started concurrently. Table 33-1 provides a guide to prophylactic management.

Treatment

A. Specific Measures

Human tetanus immune globulin, 500 units, should be administered intramuscularly within the first 24 hours of presentation. Whether intrathecal administration has any additional benefit is controversial. A recent, but unblinded, randomized trial comparing intramuscular tetanus immune globulin to intramuscular plus intrathecal tetanus immune globulin found more rapid resolution of spasms, fewer days of ventilatory support, and a shorter hospital stay in the intrathecal group. However, the exact immunoglobulin preparation that was used was not specified and the total dose was 4000 units. Tetanus does not produce natural immunity, and a full course of immunization with tetanus toxoid should be administered once the patient has recovered.

B. General Measures

Minimal stimuli can provoke spasms, so the patient should be placed at bed rest and monitored under the quietest conditions possible. Sedation, paralysis with curare-like agents, and mechanical ventilation are often necessary to control tetanic spasms. Penicillin, 20 million units intravenously daily, is given to all patients—even those with mild illness—to eradicate toxin-producing organisms.

Prognosis

High mortality rates are associated with a short incubation period, early onset of convulsions, and delay in treatment. Contaminated lesions about the head and face are more dangerous than wounds on other parts of the body.

Attygalle D et al: New trends in the management of tetanus. Expert Rev Anti Infect Ther 2004;2:73.

Miranda-Filho Dde B et al: Randomised controlled trial of tetanus treatment with antitetanus immunoglobulin by the intrathecal or intramuscular route. BMJ 2004;328:615.

4. Botulism

Essentials of Diagnosis

  • History of recent ingestion of home-canned or smoked foods or of injection drug use and demonstration of toxin in serum or food.

  • Sudden onset of diplopia, dry mouth, dysphagia, dysphonia, and muscle weakness progressing to respiratory paralysis.

  • Pupils are fixed and dilated in most cases.

General Considerations

Botulism is a paralytic disease caused by botulinum toxin, which is produced by Clostridium botulinum, a ubiquitous, strictly anaerobic, spore-forming bacillus found in soil. Four toxin types—A, B, E, and F—cause human disease. Botulinum toxin is a zinc metalloprotease that cleaves a specific component of the synaptic vesicle membrane docking and fusion complex at the neuromuscular junction blocking release of the neurotransmitter acetylcholine. Botulinum toxin is extremely potent and is classified by the CDC as a high-priority agent because of its potential for use as an agent of bioterrorism. Naturally occurring botulism occurs in one of three forms: food-borne botulism, infant botulism, or wound botulism. Food-borne botulism is caused by ingestion of preformed toxin present in canned, smoked, or vacuum-packed foods such as home-canned vegetables, smoked meats, and vacuum-packed fish. Commercial foods have also been associated with outbreaks of botulism. Infant botulism (associated with ingestion of honey) and wound botulism (which typically occurs in association with injection drug use) result from organisms present in the gut or wound that elaborate toxin in vivo.

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Clinical Findings

A. Symptoms and Signs

Twelve to 36 hours after ingestion of the toxin, visual disturbances appear, particularly diplopia and loss of accommodation. Ptosis, cranial nerve palsies with impairment of extraocular muscles, and fixed dilated pupils are characteristic signs. The sensory examination is normal. Other symptoms are dry mouth, dysphagia, and dysphonia. Nausea and vomiting may be present, particularly with type E toxin. The sensorium remains clear and the temperature normal. Paralysis progressing to respiratory failure and death may occur unless mechanical assistance is provided.

B. Laboratory Findings

Toxin in patients' serum and in suspected foods can be demonstrated by mouse inoculation and identified with specific antiserum.

Differential Diagnosis

Cranial nerve involvement may be seen with vertebrobasilar insufficiency, the C. Miller Fisher variant of Guillain-Barré syndrome, myasthenia gravis, or any basilar meningitis (infectious or carcinomatous). Intestinal obstruction or other types of food poisoning are considered when nausea and vomiting are present.

Treatment

If botulism is suspected, the practitioner should contact the state health authorities or the CDC for advice and help with procurement of botulinus antitoxin and for assistance in obtaining assays for toxin in serum, stool, or food.

Respiratory failure is managed with intubation and mechanical ventilation. Parenteral fluids or alimentation should be given while swallowing difficulty persists.

The removal of unabsorbed toxin from the gut may be attempted. Any remnants of suspected foods should be assayed for toxin. Persons who might have eaten the suspected food must be located and observed.

Sobel J et al: Foodborne botulism in the United States, 1990–2000. Emerg Infect Dis 2004;10:1606.

Anthrax

Essentials of Diagnosis

  • Appropriate epidemiologic setting, eg, exposure to animals or animal hides, or potential exposure resulting from an act of bioterrorism.

  • A painless cutaneous black eschar on exposed areas of the skin, with marked surrounding edema and vesicles.

  • Nonspecific flu-like symptoms that rapidly progress to extreme dyspnea and shock in association with mediastinal widening and pleural effusions on chest radiograph.

General Considerations

The death of a Florida photo editor from inhalational anthrax acquired from a letter deliberately contaminated with spores of Bacillus anthracis thrust this extremely rare infection into the public awareness. Between September 18 and November 21 of 2001, there were 13 cases of cutaneous anthrax and 11 cases of inhalational anthrax associated with exposure to anthrax spores in contaminated mail.

Naturally occurring anthrax is a disease of sheep, cattle, horses, goats, and swine. B anthracis is a gram-positive spore-forming aerobic rod. Spores—not vegetative bacteria—are the infectious form of the organism. These are transmitted to humans from contact with contaminated animals, animal products, or animal hides, or from soil by inoculation of broken skin or mucous membranes; by inhalation of aerosolized spores; or, rarely, by ingestion resulting in cutaneous, inhalational, or gastrointestinal forms of anthrax, respectively. Spores germinate into vegetative bacteria that multiply locally in cutaneous and gastrointestinal anthrax but may also disseminate to cause systemic infection. Inhaled spores are ingested by pulmonary macrophages and carried via lymphatics to regional lymph nodes, where they germinate. The bacteria rapidly multiply within the lymphatics, causing a hemorrhagic lymphadenitis. Invasion of the bloodstream leads to overwhelming sepsis, killing the host. Virulence is determined by two plasmids, pXO1 and pXO2, which encode, respectively, genes for two toxins, lethal toxin and edema toxin, and genes for capsule production. Loss of either plasmid attenuates strain virulence. Edema toxin impairs neutrophil function and probably is responsible for the striking edema present in cutaneous anthrax. Lethal factor provokes a cytokine-mediated shock syndrome. The capsule allows the bacteria to evade host immune defenses.

Clinical Findings

A. Symptoms and Signs

1. Cutaneous anthrax

This occurs within 2 weeks after exposure to spores; there is no latency period for cutaneous disease. The initial lesion is an erythematous papule, often on an exposed area of skin that vesiculates and then ulcerates and undergoes necrosis, ultimately progressing to a purple to black eschar. The eschar typically is painless; pain indicates secondary staphylococcal or streptococcal infection. The surrounding area is edematous and vesicular but not purulent. Regional adenopathy, fever, malaise, headache, and nausea and vomiting may be present. The

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infection is self-limited in most cases, but hematogenous spread with sepsis or meningitis may occur.

2. Inhalational anthrax

Illness occurs in two stages, beginning on average 10 days after exposure, but may begin up to 6 weeks after exposure. Nonspecific viral-like symptoms such as fever, malaise, headache, dyspnea, cough, and congestion of the nose, throat, and larynx are characteristic of the initial stage. Anterior chest pain is an early symptom of mediastinitis. Within hours to a few days, progression to the fulminant stage of infection occurs in which signs and symptoms of overwhelming sepsis predominate. Delirium, obtundation, or findings of meningeal irritation suggest an accompanying hemorrhagic meningitis.

3. Gastrointestinal anthrax

This form has not been reported in the United States. Fever, diffuse abdominal pain, rebound abdominal tenderness, vomiting, constipation, and diarrhea occur 2–5 days after ingestion of meat contaminated with anthrax spores. The primary lesion is ulcerative, producing emesis that may be blood-tinged or coffee-grounds and stool that may be blood-tinged or melenic. Bowel perforation can occur. The oropharyngeal form of the disease is characterized by local lymphadenopathy, cervical edema, dysphagia, and upper respiratory tract obstruction.

B. Laboratory Findings

Laboratory findings are nonspecific. The white blood cell count initially may be normal or modestly elevated, with polymorphonuclear predominance and an increase in early forms. Pleural fluid from patients with inhalational anthrax is typically hemorrhagic with few white cells. Cerebrospinal fluid from meningitis cases is also hemorrhagic. Gram stain of pleural fluid, cerebrospinal fluid, unspun blood, blood culture, or fluid from a cutaneous lesion may show the characteristic boxcar-shaped encapsulated rods in chains.

The diagnosis is established by isolation of the organism from culture of the skin lesion (or fluid expressed from it), blood, or pleural fluid—or cerebrospinal fluid in cases of meningitis. In the absence of prior antimicrobial therapy, cultures are invariably positive. Cultures obtained after initiation of antimicrobial therapy may be negative. If anthrax is suspected on clinical or epidemiologic grounds, immunohistochemical tests (eg, to detect capsular antigen), polymerase chain reaction assays, and serologic tests (useful for documenting past cutaneous infection) are available through the CDC and should be used to establish the diagnosis. Any suspected case of anthrax should be immediately reported to the CDC so that a complete investigation can be conducted.

C. Imaging Studies

The chest radiograph is the most sensitive test for inhalational disease, being abnormal (though the findings can be subtle) initially in every case of bioterrorism-associated disease. Mediastinal widening due to hemorrhagic lymphadenitis, a hallmark feature of the disease, has been present in 70% of the bioterrorism-related cases. Pleural effusions were present initially or occurred over the course of illness in all cases, and approximately three-fourths had pulmonary infiltrates or signs of consolidation.

Differential Diagnosis

Cutaneous anthrax, despite its characteristic appearance, can be confused with a variety of other also uncommon or rare conditions such as ecthyma gangrenosum, rat-bite fever, ulceroglandular tularemia, plague, glanders, rickettsialpox, orf (parapoxvirus infection), or cutaneous mycobacterial infection. Inhalational anthrax must be differentiated from mediastinitis due to other bacterial causes, fibrous mediastinitis due to histoplasmosis, coccidioidomycosis, atypical or viral pneumonia, silicosis, sarcoidosis, and other causes of mediastinal widening (eg, superior vena cava syndrome or aortic aneurysm or dissection). Gastrointestinal anthrax shares clinical features with a variety of common intra-abdominal disorders, including bowel obstruction, perforated viscus, peritonitis, gastroenteritis, and peptic ulcer disease.

Treatment

Strains of B anthracis (including the strain isolated in the bioterrorism cases) are susceptible in vitro to penicillin, amoxicillin, chloramphenicol, clindamycin, imipenem, doxycycline, ciprofloxacin (as well as other fluoroquinolones), macrolides, rifampin, and vancomycin. Susceptibility to cephalosporins is variable. B anthracis may express β-lactamases that confer resistance to cephalosporins and penicillins. For this reason, penicillin or amoxicillin is no longer recommended for use as a single agent in treatment of disseminated disease. Based on results of animal experiments and because of concern for engineered drug resistance in strains of B anthracis used in bioterrorism or weaponized, ciprofloxacin is considered the drug of choice (Table 33-2) for treatment and for prophylaxis following exposure to anthrax spores. Other fluoroquinolones activity against gram-positive bacteria (eg, levofloxacin, moxifloxacin) are likely to be just as effective as ciprofloxacin. Doxycycline is an alternative first-line agent. Combination therapy with at least one additional agent is recommended for inhalational or disseminated disease and in cutaneous infection involving the face, head, and neck or associated with extensive local edema or systemic signs of infection, eg, fever, tachycardia and elevated white blood cell count. Anecdotally, four of the six survivors of the 2001 inhalational cases were treated with combinations that included both a fluoroquinolone and rifampin. Single-drug therapy is recommended for prophylaxis following exposure to spores.

Table 33-2. Antimicrobial agents for treatment of or for prophylaxis against anthrax.

First-line agents and recommended doses
   Ciprofloxacin, 500 mg twice daily orally or 400 mg every 12 hours intravenously
   Doxycycline, 100 mg every 12 hours orally or intravenously
Second-line agents and recommended doses
   Amoxicillin, 500 mg three times daily orally
   Penicillin G, 2 mU every 4 hours intravenously
Alternative agents with in vitro activity and suggested doses
   Rifampin, 10 mg/kg/d orally or intravenously
   Clindamycin, 450-600 mg every 8 hours orally or intravenously
   Clarithromycin, 500 mg orally twice daily
   Erythromycin, 500 mg every 6 hours intravenously
   Vancomycin, 1 g every 12 hours intravenously
   Imipenem, 500 mg every 6 hours intravenously

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The required duration of therapy is poorly defined. In naturally occurring disease, treatment for 7–10 days for cutaneous disease and for at least 2 weeks following clinical response for disseminated, inhalational, or gastrointestinal infection have been standard recommendations. Because of concern about relapse from latent spores acquired by inhalation of aerosol in bioterrorism-associated cases, the initial recommendation was treatment for 60 days. In 2001, the CDC offered one of two options for postal workers receiving prophylaxis for exposure to contaminated mail: (1) antibiotics for 100 days (fearing that even with 60 days of treatment late relapses might occur) or (2) vaccination with an investigative agent (three doses administered over a 1-month period) in conjunction with 40 days of antibiotic administration to cover the time required for a protective antibody response to develop. Insufficient information exists to favor one recommendation over the other.

There is also an FDA-approved vaccine for persons at high risk for exposure to anthrax spores. The vaccine is cell-free antigen prepared from an attenuated strain of B anthracis. Multiple injections over 18 months and an annual booster dose are required to achieve and maintain protection. Existing supplies have been reserved for vaccination of military personnel.

The prognosis in cutaneous infection is excellent. Death is unlikely if the infection has remained localized, and lesions heal without complications in most cases. The reported mortality rate for gastrointestinal and inhalational infections is up to 85%. The experience with bioterrorism-associated inhalational cases in which six of eleven victims survived suggests a somewhat better outcome with modern supportive care and antibiotics provided that treatment is initiated before the patient has progressed to the fulminant stage of disease. No cases of anthrax have occurred among the several thousand individuals receiving antimicrobial prophylaxis following exposure to spores.

Fennelly KP et al: Airborne infection with Bacillus anthracis—from mills to mail. Emerg Infect Dis 2004;10:996.

Holty JE et al: Systematic Review: A century of inhalational anthrax cases from 1900 to 2005. Ann Intern Med 2006;144:270.

Diphtheria

Essentials of Diagnosis

  • Tenacious gray membrane at portal of entry in pharynx.

  • Sore throat, nasal discharge, hoarseness, malaise, fever.

  • Myocarditis, neuropathy.

  • Culture confirms the diagnosis.

General Considerations

Diphtheria is an acute infection caused by Corynebacterium diphtheriae that usually attacks the respiratory tract but may involve any mucous membrane or skin wound. The organism is spread chiefly by respiratory secretions. Exotoxin produced by the organism is responsible for myocarditis and neuropathy. This exotoxin inhibits elongation factor, which is required for protein synthesis.

Clinical Findings

A. Symptoms and Signs

Nasal, laryngeal, pharyngeal, and cutaneous forms of diphtheria occur. Nasal infection produces few symptoms other than a nasal discharge. Laryngeal infection may lead to upper airway and bronchial obstruction. In pharyngeal diphtheria, the most common form, a tenacious gray membrane covers the tonsils and pharynx. Mild sore throat, fever, and malaise are followed by toxemia and prostration.

Myocarditis and neuropathy are the most common and most serious complications. Myocarditis causes cardiac arrhythmias, heart block, and heart failure. The neuropathy usually involves the cranial nerves first, producing diplopia, slurred speech, and difficulty in swallowing.

B. Laboratory Findings

The diagnosis is made clinically but can be confirmed by culture of the organism.

Differential Diagnosis

Diphtheria must be differentiated from streptococcal pharyngitis, infectious mononucleosis, adenovirus or herpes simplex infection, Vincent's angina, pharyngitis due to Arcanobacterium haemolyticum, and candidiasis. A presumptive diagnosis of diphtheria should be made on clinical grounds without waiting for laboratory verification, since emergency treatment is needed.

Prevention

Active immunization with diphtheria toxoid is part of routine childhood immunization with appropriate

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booster injections. The immunization schedule for adults is the same as for tetanus.

Susceptible persons exposed to diphtheria should receive a booster dose of diphtheria toxoid (or a complete series if previously unimmunized), as well as a course of penicillin or erythromycin.

Treatment

Antitoxin, which is prepared from horse serum, must be given in all cases when diphtheria is suspected. For mild early pharyngeal or laryngeal disease, the dose is 20,000–40,000 units; for moderate nasopharyngeal disease, 40,000–60,000 units; for severe, extensive, or late (3 days or more) disease, 80,000–100,000 units. Diphtheria equine antitoxin can be obtained from the CDC.

Removal of membrane by direct laryngoscopy or bronchoscopy may be necessary to prevent or alleviate airway obstruction.

Either penicillin, 250 mg orally four times daily, or erythromycin, 500 mg orally four times daily, for 14 days is effective therapy, although erythromycin is slightly more effective in eliminating the carrier state. Azithromycin or clarithromycin is probably as effective as erythromycin. The patient should be isolated until three consecutive cultures at the completion of therapy have documented elimination of the organism from the oropharynx. Contacts to a case should receive erythromycin, 500 mg orally four times daily for 7 days, to eradicate carriage.

Centers for Disease Control and Prevention (CDC): Fatal respiratory diphtheria in a U.S. traveler to Haiti—Pennsylvania, 2003. MMWR Morb Mortal Wkly Rep 2004;52:1285.

Listeriosis

Listeria monocytogenes is a facultative, motile, gram-positive rod that is capable of invading several cell types and causes intracellular infection. Most cases of infection caused by L monocytogenes are sporadic, but outbreaks have been traced to eating contaminated food, including unpasteurized dairy products, hot dogs, and delicatessen meats. Five types of infection are recognized:

  • Infection during pregnancy, usually in the last trimester, is a mild febrile illness without an apparent primary focus. This relatively benign disease for both mother and fetus may resolve without specific therapy.

  • Granulomatosis infantisepticum is a neonatal infection acquired in utero, characterized by disseminated abscesses, granulomas, and a high mortality rate.

  • Bacteremia with or without sepsis syndrome is an infection of neonates or immunocompromised adults. The presentation is of a febrile illness without a recognized source.

  • Meningitis caused by L monocytogenes affects infants under 2 months of age as well as older adults, ranking third after the meningococcus and pneumococcus among the common causes of bacterial meningitis. Cerebrospinal fluid shows a neutrophilic pleocytosis. Adults with meningitis are often immunocompromised, and cases have been associated with HIV infection and therapy with tumor necrosis factor-α (TNF-α) inhibitors such as infliximab.

  • Finally, focal infections, including adenitis, brain abscess, endocarditis, osteomyelitis, and arthritis, occur rarely.

Ampicillin, 8–12 g/d intravenously in four to six divided doses (the higher dose for meningitis) is considered the treatment of choice. It penetrates well into cerebrospinal fluid, and clinical response is better than with penicillin, erythromycin, or chloramphenicol. Gentamicin is synergistic with ampicillin against Listeria in vitro and in animal models, and the use of combination therapy may be considered during the first few days of treatment to enhance eradication of organisms. Mortality and morbidity rates still are high, and relapses occur, perhaps related to poor intracellular penetration of ampicillin. Trimethoprim-sulfamethoxazole with its excellent intracellular and cerebrospinal fluid penetration may be more efficacious. The dose is 10–20 mg/kg/d intravenously of the trimethoprim component. Therapy should be administered for at least 2–3 weeks. Longer durations—between 3 and 6 weeks—have been recommended for treatment of meningitis, especially in immunocompromised persons.

Drevets DA et al: Invasion of the central nervous system by intracellular bacteria. Clin Microbiol Rev 2004;17:323.

Gerner-Smidt P et al: Invasive listeriosis in Denmark 1994–2003: a review of 299 cases with special emphasis on risk factors for mortality. Clin Microbiol Infect 2005;11:618.

Infective Endocarditis

Essentials of Diagnosis

  • Fever

  • Preexisting organic heart lesion.

  • Positive blood cultures.

  • Evidence of vegetation on echocardiography.

  • New or changing heart murmur.

  • Evidence of systemic emboli.

General Considerations

Endocarditis is a bacterial or fungal infection of the valvular or endocardial surface of the heart.

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The clinical presentation depends on the infecting organism and the valve or valves that are infected. More virulent organisms—S aureus in particular—tend to produce a more rapidly progressive and destructive infection. Endocarditis caused by more virulent organisms often presents as an acute febrile illnesses and is complicated by early embolization, acute valvular regurgitation, and myocardial abscess formation. Viridans strains of streptococci, enterococci, other bacteria, yeasts, and fungi tend to cause a more subacute picture.

Underlying valvular disease, less common than in the past, is present in about 50% of cases. Valvular disease alters blood flow and produces jet effects that disrupt the endothelial surface, providing a nidus for attachment and infection of microorganisms that enter the bloodstream. Predisposing valvular abnormalities include rheumatic involvement of any valve, bicuspid aortic valves, calcific or sclerotic aortic valves, hypertrophic subaortic stenosis, mitral valve prolapse, and a variety of congenital disorders such as ventricular septal defect, tetralogy of Fallot, coarctation of the aorta, or patent ductus arteriosus. Rheumatic disease is no longer the major predisposing factor in developed countries. Regurgitation lesions are more susceptible than stenotic ones.

The initiating event in native valve endocarditis is colonization of the valve by bacteria or yeast that gain access to the bloodstream. Transient bacteremia is common during dental, upper respiratory, urologic, and lower gastrointestinal diagnostic and surgical procedures. It is less common during upper gastrointestinal and gynecologic procedures. Intravascular devices are increasingly implicated as a portal of access of microorganisms into the bloodstream. A large proportion of cases of S aureus endocarditis is attributable to healthcare-associated bacteremia.

Native valve endocarditis is usually caused by viridans streptococci, group D streptococci, S aureus, enterococci, or HACEK organisms (an acronym for Haemophilus aphrophilus, Haemophilus parainfluenzae, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae). Streptococcal species formerly accounted for the majority of native valve endocarditis cases, but the proportion of cases caused by S aureus has been increasing, and this organism is now the leading cause. Gram-negative organisms and fungi account for a small percentage.

In injection drug users, S aureus accounts for over 60% of all endocarditis cases and for 80–90% of cases in which the tricuspid valve is infected. Enterococci and streptococci comprise the balance in about equal proportions. Gram-negative aerobic bacilli, fungi, and unusual organisms may cause endocarditis in injection drug users.

The microbiology of prosthetic valve endocarditis also is distinctive. Early infections (ie, those occurring within 2 months after valve implantation) are commonly caused by staphylococci—both coagulase-positive and coagulase-negative—gram-negative organisms, and fungi. In late prosthetic valve endocarditis, streptococci are commonly identified, although coagulase-negative and coagulase-positive staphylococci still cause many cases.

Clinical Findings

A. Symptoms and Signs

Virtually all patients have fever at some point in the illness, although it may be very low grade (less than 38°C) in elderly individuals and in patients with heart failure or renal failure. Rarely, there may be no fever at all.

The duration of illness typically is a few days to a few weeks. Nonspecific symptoms are common. The initial symptoms and signs of endocarditis may be caused by direct arterial, valvular, or cardiac damage. Although a changing regurgitant murmur is significant diagnostically, it is the exception rather than the rule. Symptoms also may occur as a result of embolization, metastatic infection or immunologically mediated phenomena. These include cough; dyspnea; arthralgias or arthritis; diarrhea; and abdominal, back, or flank pain.

The characteristic peripheral lesions—petechiae (on the palate or conjunctiva or beneath the fingernails), subungual (“splinter”) hemorrhages, Osler nodes (painful, violaceous raised lesions of the fingers, toes, or feet), Janeway lesions (painless erythematous lesions of the palms or soles), and Roth spots (exudative lesions in the retina)—occur in about 25% of patients. Strokes and major systemic embolic events are present in about 25% of patients, and tend to occur before or within the first week of antimicrobial therapy. Hematuria and proteinuria may result from emboli or immunologically mediated glomerulonephritis, which can cause renal dysfunction.

B. Diagnostic Studies

Blood cultures establish the diagnosis. Three sets of blood cultures at least 1 hour apart before starting antibiotics are recommended to maximize the opportunity for a microbiologic diagnosis. Approximately 5% of cases will be culture-negative, usually attributable to administration of antimicrobials prior to obtaining cultures. If antimicrobial therapy has been administered prior to obtaining cultures and the patient is clinically stable, it is reasonable to withhold further antimicrobial therapy for 2–3 days so that appropriate cultures can be obtained. Culture-negative endocarditis may also be due to a fungus, organisms that require special media for growth (eg, Legionella, Bartonella, Abiotrophia species, formerly referred to as nutritionally deficient streptococci), organisms that do not grow on artificial media (Tropheryma whippelii, or pathogens of Q fever or psittacosis), or those that are slow-growing and may require prolonged incubation (eg, Brucella, anaerobes, HACEK). Bartonella quintana has emerged as an important cause of culture-negative endocarditis.

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Chest radiograph may show evidence for the underlying cardiac abnormality and, in right-sided endocarditis, pulmonary infiltrates. The electrocardiogram is nondiagnostic, but new conduction abnormalities suggest myocardial abscess formation. Echocardiography is useful in identifying vegetations and other characteristic features suspicious for endocarditis and may provide adjunctive information about the specific valve or valves that are infected. The sensitivity of transthoracic echocardiography is between 55% and 65%; it cannot reliably rule out endocarditis but may confirm a clinical suspicion. TEE is 90% sensitive in detecting vegetations and is particularly useful for identifying valve ring abscesses as well as prosthetic valve endocarditis.

Clinical criteria, referred to as the Modified Duke criteria, for the diagnosis of endocarditis have been proposed. Major criteria include (1) two positive blood cultures for a microorganism that typically causes infective endocarditis or persistent bacteremia, (2) evidence of endocardial involvement documented by echocardiography (eg, definite vegetation, myocardial abscess, or new partial dehiscence of a prosthetic valve), or (3) development of a new regurgitant murmur. Minor criteria include the presence of a predisposing condition; fever ≥ 38°C; vascular phenomena, such as cutaneous hemorrhages, aneurysm, systemic emboli, pulmonary infarction; immunologic phenomena, such as glomerulonephritis, Osler nodes, Roth spots, rheumatoid factor; and positive blood cultures not meeting the major criteria or serologic evidence of an active infection. A definite diagnosis can be made with 80% accuracy if two major criteria, one major criterion and three minor criteria, or five minor criteria are fulfilled. A possible diagnosis of endocarditis is made if one major and one minor criterion or three minor criteria are met. If fewer criteria are found, or a sound alternative explanation for illness is identified, or the endocarditis syndrome has resolved and the patient has defervesced within 4 days, endocarditis is unlikely.

Complications

The course of infective endocarditis is determined by the degree of damage to the heart, by the site of infection (right- versus left-sided, aortic versus mitral valve), by the presence of metastatic foci of infection, by the occurrence of embolization, and by immunologically mediated processes. Destruction of infected heart valves is especially common and precipitous with S aureus but can occur with any organism and can progress even after bacteriologic cure. The infection can also extend into the myocardium, resulting in abscesses leading to conduction disturbances, and involving the wall of the aorta, creating sinus of Valsalva aneurysms.

Peripheral embolization to the brain and myocardium may result in infarctions. Embolization to the spleen and kidneys is also common. Peripheral emboli may initiate metastatic infections or may become established in vessel walls, leading to mycotic aneurysms. Right-sided endocarditis, which usually involves the tricuspid valve, causes septic pulmonary emboli, occasionally with infarction and lung abscesses.

Prevention

Some cases of endocarditis occur after dental procedures or operations involving the upper respiratory, genitourinary, or intestinal tract. Prophylactic antibiotics are given to patients with predisposing congenital or valvular anomalies who are to have any of these procedures (Tables 33-3 and 33-4). Current recommendations are given in Table 33-5.

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Table 33-3. Risk of bacterial endocarditis with underlying cardiac conditions.1

High Risk
   Prosthetic cardiac valves, mechanical, bioprosthetic, or homograft
   Previous bacterial endocarditis
   Complex cyanotic congenital heart disease (eg, single ventricle states, transposition of the great arteries, tetralogy of Fallot)
   Surgically constructed systemic pulmonary shunts or conduits
Moderate Risk
   Most congenital cardiac malformations (other than those listed above and below)
   Rheumatic heart disease
   Hypertrophic cardiomyopathy
   Mitral valve prolapse with valvular regurgitation2
Negligible Risk3
   Isolated secundum septal defect
   Surgical repair of atrial septal defect, ventricular septal defect, or patent ductus arteriosus (without residua beyond 6 months)
   Previous coronary artery bypass graft surgery
   Mitral valve prolapse without valvular regurgitation
   Physiologic, functional, or innocent heart murmurs
   Previous Kawasaki disease without valvular dysfunction
   Rheumatic fever without valvular dysfunction
   Cardiac pacemakers (intravascular and epicardial) and implanted defibrillators
1This table lists selected conditions and is not meant to be all-inclusive.
2Mitral regurgitation determined by the presence of a murmur or by echo-Doppler. Men older than 45 years may warrant prophylaxis even without a consistent systolic murmur. Mitral valve prolapse associated with thickening or redundancy of the valve leaflets may be associated with an increased risk for bacterial endocarditis.
3Risk no greater than in the general population; endocarditis prophylaxis not recommended.

Table 33-4. Recommendations for administration of bacterial endocarditis prophylaxis for high and moderate risk patients according to type of procedure.1

Prophylaxis recommended
  1. Dental procedures
       Dental extractions
       Periodontal procedures
       Dental implantation
       Endodontic (root canal) instrumentation or surgery beyond the apex
       Subgingival placement of antibiotic fibers or strips
       Initial placement of orthodontic bands but not brackets
       Intraligamentary local anesthetic injections
       Cleaning of teeth or implants where bleeding is anticipated
  2. Respiratory tract procedures
       Tonsillectomy, adenoidectomy
       Surgical operations of intestinal or respiratory mucosa
       Rigid bronchoscopy
  3. Gastrointestinal tract procedures4
       Sclerotherapy for esophageal varices
       Esophageal stricture dilation
       Endoscopic retrograde cholangiography with biliary obstruction
       Biliary tract surgery
       Surgical operations that involve intestinal mucosa
  4. Genitourinary tract
       Prostatic surgery
       Cystoscopy
       Urethral dilation
Prophylaxis not recommended
  1. Dental procedures
       Restorative dentistry (filling cavities, operative and prosthodontic) with or without retraction cord2
       Nonintraligamentary local anesthetic injections
       Intracanal endodontic treatment; post placement and buildup
       Placement of rubber dams, removable prosthodontic, or orthodontic appliances
       Postoperative suture removal
       Taking of oral impression
       Fluoride treatments
       Orthodontic appliance adjustment
  2. Respiratory tract procedures
       Endotracheal intubation
       Flexible bronchoscopy, with or without biopsy3
       Tympanostomy (insertion)
  3. Gastrointestinal tract procedures
       Vaginal hysterectomy3
       Transesophageal echocardiography3
       Endoscopy with or without gastrointestinal biopsy3
  4. Genitourinary tract
       Vaginal delivery3
       Cesarean section
       In the absence of infection: urethral catheterization, uterine dilation and curettage, therapeutic abortion, sterilization procedures, insertion or removal of intrauterine devices
  5. Other
       Cardiac catheterization, including balloon angioplasty; implanting cardiac pacemakers or defibrillators and coronary stents; incision or biopsy of surgically scrubbed skin; circumcision
1Based on recommendations by the American Heart Association. JAMA 1997;277:1794. The procedures listed are not meant to be all-inclusive.
2Clinical judgement may indicate antibiotic use in selected circumstances that may create significant bleeding.
3Prophylaxis is optional for high-risk patients, not recommended for moderate-risk patients.
4Prophylaxis is recommended for high-risk patients, optional for moderate-risk patients.

Treatment

Empiric regimens for endocarditis while culture results are pending should include agents active against staphylococci, streptococci, and enterococci. Vancomycin 1 g every 12 hours intravenously plus ceftriaxone 2 g every 24 hours provides appropriate coverage pending definitive diagnosis.

A. Viridans Streptococci

For penicillin-susceptible viridans streptococcal endocarditis (ie, MIC ≤ 0.1 mcg/mL), penicillin G, 2–3 million units intravenously

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every 4 hours for 4 weeks, is recommended. The duration of therapy can be shortened to 2 weeks if gentamicin, 1 mg/kg intravenously every 8 hours, is used with penicillin. Ceftriaxone, 2 g once daily intravenously or intramuscularly for 4 weeks, is also effective therapy for penicillin-susceptible strains and is a convenient regimen for home therapy. For the penicillin-allergic patient, vancomycin, 15 mg/kg intravenously every 12 hours for 4 weeks, is given. The 2-week regimen is not recommended for patients with symptoms of more than 3 months' duration or with complications such as myocardial abscess or extracardiac infection. Prosthetic valve endocarditis is treated with a 6-week course of penicillin with at least 2 weeks of gentamicin.

Table 33-5. American Heart Association recommendations for endocarditis prophylaxis in high- and moderate-risk patients.1

DENTAL, RESPIRATORY, OR ESOPHAGEAL PROCEDURES
Oral Amoxicillin 2 g 1 hour before procedure
   Penicillin allergy Clindamycin 600 mg 1 hour before procedure
or  
Cephalexin or cefadroxil 2 g 1 hour before procedure (contraindicated if there is history of a β-lactam immediate hypersensitivity reaction)
or  
Azithromycin or clarithromycin 500 mg 1 hour before procedure
Parenteral Ampicillin 2 g IM or IV 30 minutes before procedure
   Penicillin allergy Clindamycin 600 mg IV 1 hour before procedure
or  
Cefazolin 1 g IM or IV 30 minutes before procedure (contraindicated if there is history of a β-lactam immediate hypersensitivity reaction)
GASTROINTESTINAL (EXCEPT ESOPHAGEAL) OR GENITOURINARY PROCEDURES
High-risk patient (Table 33-3) Ampicillin plus gentamicin or vancomycin plus gentamicin (for penicillin allergy) Ampicillin, 2 g IM or IV, plus gentamicin, 1.5 mg/kg IV or IM (120 mg maximum) 30 minutes before procedure; 6 hours later, ampicillin, 1 g IM or IV, or amoxicillin, 1 g orally
For the penicillin-allergic patient, instead of ampicillin, use a single dose of vancomycin, 1 g IV over 1-2 hours with completion of infusion 30 minutes before procedure
Moderate-risk patient Amoxicillin or ampicillin or vancomycin (for penicillin allergy) Amoxicillin, 2 g orally 1 hour before procedure, or ampicillin, 2 g IM or IV 30 minutes before starting procedure
For the penicillin allergic patient instead of ampicillin use vancomycin, 1 g IV over 1-2 hours with completion of infusion 30 minutes before procedure; complete infusion 30 minutes before procedure
1See JAMA 1997;277:1794 for details.

Viridans streptococci relatively resistant to penicillin (ie, MIC > 0.1 mcg/mL but ≤ 0.5 mcg/mL) should be treated for 4 weeks. Penicillin G, 3 million units intravenously every 4 hours, is combined with gentamicin, 1 mg/kg intravenously every 8 hours for the first 2 weeks. In the patient with IgE-mediated allergy to penicillin, vancomycin alone, 15 mg/kg intravenously every 12 hours for 4 weeks, should be administered.

Endocarditis caused by viridans streptococci with an MIC > 0.5 mcg/mL or by nutritionally deficient streptococci should be treated the same as enterococcal endocarditis (see below).

B. Other Streptococci

Endocarditis caused by S pneumoniae, S pyogenes (group A streptococcus), or groups B, C, and G streptococci is unusual. S pneumoniae sensitive to penicillin (MIC < 0.1 mcg/mL) can be treated with penicillin alone, 2–3 million units intravenously every 4 hours for 4–6 weeks. Vancomycin should be effective for endocarditis caused by strains resistant to penicillin. Group A streptococcal infection can be treated with penicillin, ceftriaxone, or vancomycin for 4–6 weeks. Groups B, C, and G streptococci tend to be more resistant to penicillin than group A streptococci, and some have recommended adding gentamicin, 1 mg/kg intravenously every 8 hours, to penicillin for the first 2 weeks of a 4- to 6-week course. Endocarditis caused by S bovis is associated with liver disease and gastrointestinal abnormalities, especially colon cancer. Colonoscopy should be performed to exclude the latter.

C. Enterococci

For enterococcal endocarditis, penicillin alone is inadequate; either streptomycin or gentamicin must be included in the regimen. Because aminoglycoside resistance occurs in enterococci, susceptibility should be documented. Gentamicin is the aminoglycoside of choice, because streptomycin resistance is more common and the nephrotoxicity of gentamicin is generally more easily managed than the vestibular toxicity of streptomycin. Ampicillin, 2 g intravenously every 4 hours, or penicillin G, 3–4 million units intravenously every 4 hours (or, in the penicillin-allergic patient, vancomycin, 15 mg/kg intravenously every 12 hours), plus gentamicin, 1 mg/kg intravenously every 8 hours, are recommended. The recommended duration of combination therapy is 4–6 weeks (the longer duration for patients with symptoms for more than 3

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months, relapse, or prosthetic valve endocarditis), although a study from Sweden found that discontinuing the aminoglycoside before 4 weeks did not reduce efficacy. Experience is more extensive with penicillin and ampicillin than with vancomycin for treatment of enterococcal endocarditis, and penicillin and ampicillin are superior to vancomycin in vitro. Thus, whenever possible, either ampicillin or penicillin should be used.

Endocarditis caused by strains resistant to penicillin, vancomycin, or aminoglycosides is particularly difficult to treat. Such cases should be treated according to recent American Heart Association guidelines (see reference below) and managed in consultation with an infectious diseases specialist.

D. Staphylococci

For methicillin-susceptible S aureus, nafcillin or oxacillin, 1.5–2 g intravenously every 4 hours for 6 weeks, is the preferred therapy. Uncomplicated tricuspid valve endocarditis probably can be treated for 2 weeks with nafcillin or oxacillin alone. For penicillin-allergic patients, cefazolin, 2 g intravenously every 8 hours, or vancomycin, 15 mg/kg intravenously every 12 hours, may be used. For methicillin-resistant strains, vancomycin remains the preferred agent. Aminoglycoside combination regimens are probably of no benefit and in general should be avoided. The effect of rifampin with antistaphylococcal drugs is variable, and its routine use is not recommended.

Because coagulase-negative staphylococci—a common cause of prosthetic valve endocarditis—are routinely resistant to methicillin, β-lactam antibiotics should not be used for this infection unless the isolate is demonstrated to be susceptible. A combination of vancomycin 1 g intravenously every 12 hours for 6 weeks, rifampin, 300 mg every 8 hours for 6 weeks, and gentamicin, 1 mg/kg intravenously every 8 hours for the first 2 weeks, is recommended for prosthetic valve infection. If the organism is sensitive to methicillin, either nafcillin or oxacillin or cefazolin can be used in combination with rifampin and gentamicin. Combination therapy with nafcillin or oxacillin (vancomycin for methicillin-resistant strains or patients allergic to β-lactams), rifampin, and gentamicin is also recommended for treatment of S aureus prosthetic valve infection.

E. HACEK Organisms

HACEK organisms are slow-growing, fastidious gram-negative coccobacilli or bacilli that are normal oral flora and cause less than 5% of all cases of endocarditis. They may produce β-lactamase, and thus the treatment of choice is ceftriaxone (or some other third-generation cephalosporin), 2 g intravenously once daily for 4 weeks. Prosthetic valve endocarditis should be treated for 6 weeks. In the penicillin-allergic patient, experience is limited, but trimethoprim-sulfamethoxazole, quinolones, and aztreonam have in vitro activity and should be considered; desensitization may be preferable.

F. Role of Surgery

While many cases can be successfully treated medically, operative management is frequently required. Acute heart failure unresponsive to medical therapy is an indication for valve replacement even if active infection is present, especially for aortic valve infection. Infections unresponsive to appropriate antimicrobial therapy after 7–10 days (ie, persistent fevers, positive blood cultures despite therapy) are more likely to be eradicated if the valve is replaced. Surgery is nearly always required for cure of fungal endocarditis and is more often necessary with gram-negative bacilli. It is also indicated when the infection involves the sinus of Valsalva or produces septal abscesses. Recurrent infection with the same organism prompts an operative approach, especially with infected prosthetic valves. Continuing embolization presents a difficult problem when the infection is otherwise responding; surgery may be the proper approach. Particularly challenging is a large and fragile vegetation demonstrated by echo in the absence of embolization. Most clinicians favor an operative approach, vegetectomy with valve repair if the patient is a good candidate. Embolization after bacteriologic cure does not necessarily imply recurrence of endocarditis.

G. Role of Anticoagulation

Anticoagulation is contraindicated in native valve endocarditis because of an increased risk of intracerebral hemorrhage. The role of anticoagulant therapy during active prosthetic valve endocarditis is more controversial. Reversal of anticoagulation may result in thrombosis of the mechanical prosthesis, particularly in the mitral position. On the other hand, anticoagulation during active prosthetic valve endocarditis caused by S aureus has been associated with fatal intracerebral hemorrhage. One approach is to discontinue anticoagulation during the septic phase of S aureus prosthetic valve endocarditis. In patients with S aureus prosthetic valve endocarditis complicated by a central nervous system embolic event, anticoagulation should be discontinued for the first 2 weeks of therapy. Indications for anticoagulation following prosthetic valve implantation for endocarditis are the same as for patients with prosthetic valves without endocarditis (eg, nonporcine mechanical valves and valves in the mitral position).

Response to Therapy

If infection is caused by viridans streptococci, enterococci, or coagulase-negative staphylococci, defervescence occurs in 3–4 days on average; with S aureus or Pseudomonas aeruginosa, fever commonly persists for 9–12 days. Blood cultures should be obtained to document sterilization of the blood. Other causes of persistent fever are myocardial or metastatic abscess, sterile embolization, superimposed nosocomial infection, and drug reaction. Most relapses occur within 1–2 months after completion of therapy. Obtaining one or two blood cultures during this period is prudent.

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Baddour LM et al: Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications: a statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association: endorsed by the Infectious Diseases Society of America. Circulation 2005;111:e394.

Fowler VG Jr et al: Staphylococcus aureus endocarditis: a consequence of medical progress. JAMA 2005;293:3012.

Le T et al: Combination antibiotic therapy for infective endocarditis. Clin Infect Dis 2003;36:615.

Infections Caused by Gram-Negative Bacteria

Bordetella Pertussis Infection (Whooping Cough)

Essentials of Diagnosis

  • Predominantly in infants under age 2 years. Adolescents and adults are an important reservoir of infection.

  • Two-week prodromal catarrhal stage of malaise, cough, coryza, and anorexia.

  • Paroxysmal cough ending in a high-pitched inspiratory “whoop.”

  • Absolute lymphocytosis, often striking; culture confirms diagnosis.

General Considerations

Pertussis is an acute infection of the respiratory tract caused by B pertussis that is transmitted by respiratory droplets. The incubation period is 7–17 days. Half of all cases occur before age 2 years. Neither immunization nor disease confers lasting immunity to pertussis. Consequently, adults are an important reservoir of the disease.

Clinical Findings

The symptoms of classic pertussis last about 6 weeks and are divided into three consecutive stages. The catarrhal stage is characterized by its insidious onset, with lacrimation, sneezing, and coryza, anorexia and malaise, and a hacking night cough that becomes diurnal. The paroxysmal stage is characterized by bursts of rapid, consecutive coughs followed by a deep, high-pitched inspiration (whoop). The convalescent stage begins 4 weeks after onset of the illness with a decrease in the frequency and severity of paroxysms of cough. The diagnosis often is not considered in adults, who may not have a typical presentation. Cough persisting more than 2 weeks is suggestive. Infection may also be asymptomatic.

The white blood cell count is usually 15,000–20,000/mcL (rarely, as high as 50,000/mcL or more), 60–80% of which are lymphocytes. The diagnosis is established by isolating the organism from nasopharyngeal culture. A special medium (eg, Bordet-Gengou agar) must be requested. Polymerase chain reaction assays for diagnosis of pertussis may be available in some clinical or health department laboratories.

Prevention

Acellular pertussis vaccine is recommended for all infants, combined with diphtheria and tetanus toxoids (DTaP). Infants and susceptible adults with significant exposure should receive prophylaxis with an oral macrolide (see below). In recognition of their importance as a reservoir of disease, vaccination of adolescents and adults against pertussis is now recommended. The FDA licensed two tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine (Tdap) products (BOOSTRIX, GlaxoSmithKline and ADACEL, Sanofi Pasteur) in 2005. Adolescents aged 11–18 years who have completed the DTP or DTaP vaccination series should receive a single dose of either Tdap product instead of Td (tetanus and diphtheria toxoids vaccine) for booster immunization against tetanus, diphtheria, and pertussis. Either vaccine may be used in place of Td for prophylaxis of tetanus in wound management. The ADACEL vaccine is indicated as a one-time dose for booster immunization for pertussis in children and adults (ages 11 through 64 years). It may be used as a replacement dose for one of the Td doses when completing a primary immunization series or in place of Td for tetanus wound prophylaxis. Postpartum women and adults who have not been previously vaccinated with Tdap and who have close contact to an infant younger than 12 months should receive a single dose of Tdap. Women of childbearing age are also candidates for one dose of Tdap.

Treatment

Erythromycin, 500 mg four times a day orally for 7 days, shortens the duration of carriage. It also may diminish the severity of coughing paroxysms. Azithromycin, 500 mg orally on day 1 and 250 mg for 4 more days; or clarithromycin, 500 mg orally twice daily for 7 days, is probably as effective as erythromycin and likely to be better tolerated. Trimethoprim-sulfamethoxazole 160 mg-800 mg orally twice a day for 7 days also is effective. These same regimens are indicated for prophylaxis of contacts to an active case of pertussis who are exposed within 3 weeks of the onset of cough in the index case.

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Broder KR et al; Advisory Committee on Immunization (ACIP): Preventing tetanus, diphtheria, and pertussis among adolescents: use of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccines recommendations of the Advisory Committee on Immunization (ACIP). MMWR Recomm Rep 2006;55(RR-3):1.

Hewlett EL et al: Clinical Practice. Pertussis—Not just for kids. N Engl J Med 2005;352:1215.

Mitka M: Age range widens for pertussis vaccine: boosters advised for adolescents and adults. JAMA 2006;295:871.

Other Bordetella Infections

Bordetella bronchiseptica is a pleomorphic gram-negative coccobacillus causing kennel cough in dogs. On occasion it causes upper and lower respiratory infection in humans, principally HIV-infected patients. Infection has been associated with contact with dogs and cats, suggesting animal-to-human transmission. Treatment of B bronchiseptica infection is guided by results of in vitro susceptibility tests.

Meningococcal Meningitis

Essentials of Diagnosis

  • Fever, headache, vomiting, confusion, delirium, convulsions.

  • Petechial rash of skin and mucous membranes in many.

  • Neck and back stiffness with positive Kernig and Brudzinski signs is characteristic.

  • Purulent spinal fluid with gram-negative intracellular and extracellular diplococci.

  • Culture of cerebrospinal fluid, blood, or petechial aspiration confirms the diagnosis.

General Considerations

Meningococcal meningitis is caused by Neisseria meningitidis of groups A, B, C, Y, and W-135, among others. Meningitis due to serogroup A is uncommon in the United States. Serogroup B generally causes sporadic cases. The frequency of outbreaks of meningitis caused by group C meningococcus has increased, and this serotype is the most common cause of epidemic disease in the United States. Up to 40% of persons are nasopharyngeal carriers of meningococci, but disease develops in relatively few of these persons. Infection is transmitted by droplets. The clinical illness may take the form of meningococcemia (a fulminant form of septicemia without meningitis), meningococcemia with meningitis, or meningitis. Recurrent meningococcemia with fever, rash, and arthritis is seen rarely in patients with certain terminal complement deficiencies.

Clinical Findings

A. Symptoms and Signs

High fever, chills, and headache; back, abdominal, and extremity pains; and nausea and vomiting are typical. Rapidly developing confusion, delirium, seizures, and coma occur in some.

On examination, nuchal and back rigidity are typical, with positive Kernig and Brudzinski signs. (Kernig's sign is pain in the hamstrings upon extension of the knee with the hip at 90-degree flexion; Brudzinski's sign is flexion of the knee in response to flexion of the neck.) A petechial rash appearing in the lower extremities and at pressure points is found in most cases. Petechiae may vary in size from pinpoint lesions to large ecchymoses or even skin gangrene that may later slough if the patient survives.

B. Laboratory Findings

Lumbar puncture typically reveals a cloudy or purulent cerebrospinal fluid, with elevated pressure, increased protein, and decreased glucose content. The fluid usually contains more than 1000 cells/mcL, with polymorphonuclear cells predominating and containing gram-negative intracellular diplococci. The absence of organisms in a Gram-stained smear of the cerebrospinal fluid sediment does not rule out the diagnosis. The capsular polysaccharide can be demonstrated in cerebrospinal fluid or urine by latex agglutination; this is useful in partially treated patients, though sensitivity is 60–80%. The organism is usually demonstrated by smear and culture of the cerebrospinal fluid, oropharynx, blood, or aspirated petechiae.

Disseminated intravascular coagulation is an important complication of meningococcal infection and is typically present in toxic patients with ecchymotic skin lesions.

Differential Diagnosis

Meningococcal meningitis must be differentiated from other meningitides. In small infants and in the elderly, fever or stiff neck is often missing, and altered mental status may dominate the picture.

Rickettsial, echovirus and, rarely, other bacterial infections (eg, staphylococcal infections, scarlet fever) also cause petechial rash.

Prevention

Two vaccines, meningococcal polysaccharide vaccine (MPSV4, indicated for vaccination of persons aged 2–10 years and over age 55) and a conjugate vaccine (MCV4, indicated for persons aged 11–55 years) are effective for meningococcal groups A, C, Y, and W-135. The Advisory Committee on Immunization Practices recommends immunization with a single dose of MCV4 for preadolescents ages 11–12, and for those not previously vaccinated, upon entry into high school. MCV4 is also recommended for college freshmen—particularly those living in dormitories (see Tables 30-4 and 30-5). Vaccine is also recommended for military recruits, asplenic individuals, those with deficiencies in terminal component of complement, and exposed persons during outbreaks.

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Eliminating nasopharyngeal carriage of meningococci is an effective prevention strategy in closed populations and to prevent secondary cases in household or otherwise close contacts. Rifampin, 600 mg orally twice a day for 2 days, ciprofloxacin, 500 mg orally, or one intramuscular 250-mg dose of ceftriaxone is effective. School and work contacts ordinarily need not be treated. Hospital contacts receive therapy only if intense exposure has occurred (eg, mouth-to-mouth resuscitation). Accidentally discovered carriers without known close contact with meningococcal disease do not require prophylactic antimicrobials.

Treatment

Blood cultures must be obtained and intravenous antimicrobial therapy started immediately. This may be done prior to lumbar puncture in patients in whom the diagnosis is not straightforward and for those in whom MR or CT imaging is indicated to exclude mass lesions. Aqueous penicillin G is the antibiotic of choice (24 million units/24 h intravenously in divided doses every 4 hours). The prevalence of strains of N meningitidis with intermediate resistance to penicillin in vitro (MICs 0.1 to 1 mcg/mL) is increasing, particularly in Europe. At what level of resistance penicillin treatment failure can occur is not known. Penicillin-intermediate strains thus far remain fully susceptible to ceftriaxone and other third-generation cephalosporins used to treat meninigitis, and these should be effective alternatives to penicillin. In penicillin-allergic patients or those in whom Haemophilus influenzae or gram-negative meningitis is a consideration, ceftriaxone, 2 g intravenously every 12 hours, should be used. Treatment should be continued in full doses by the intravenous route until the patient is afebrile for 5 days. Shorter courses—as few as 4 days if ceftriaxone is used—are also effective.

Kimmel SR: Prevention of meningococcal diseases. Am Fam Physician 2005;72:2049.

Van de Beek D et al: Clinical features and prognostic factors in adults with bacterial meningitis. N Engl J Med 2004;351:1849.

Van de Beek D et al: Current concepts: community-acquired bacterial meningitis in adults. N Engl J Med 2006;354:44.

Infections Caused by Haemophilus Species

H influenzae and other Haemophilus species may cause sinusitis, otitis, bronchitis, epiglottitis, pneumonitis, cellulitis, arthritis, meningitis, and endocarditis. Nontypeable strains are responsible for most disease in adults. Alcoholism, smoking, chronic lung disease, advanced age, and HIV infection are risk factors. Haemophilus species colonize the upper respiratory tract in patients with chronic obstructive pulmonary disease and frequently cause purulent bronchitis.

β-Lactamase-producing strains are less common in adults than in children. For adults with sinusitis, otitis, or respiratory tract infection, oral amoxicillin, 750 mg twice daily for 10–14 days, is adequate. For β-lactamase-producing strains, use of the oral fixed drug combination of amoxicillin, 875 mg, with clavulanate, 125 mg, is indicated. For the penicillin-allergic patient, oral cefuroxime axetil, 250 mg twice daily, or trimethoprim-sulfamethoxazole, 800/160 mg orally twice daily, for 10 days is effective. Azithromycin and clarithromycin are less effective.

In the more seriously ill patient (eg, the toxic patient with multilobar pneumonia) ceftriaxone, 1 g/d intravenously is recommended pending determination of whether the infecting strain is a β-lactamase producer. Trimethoprim-sulfamethoxazole administered intravenously based on a dose of 10 mg/kg/d of trimethoprim, can be used for the penicillin-allergic patient. A 10- to 14-day course of therapy is adequate for most cases.

Epiglottitis is characterized by an abrupt onset of high fever, drooling, and inability to handle secretions. An important clue to the diagnosis is complaint of a severe sore throat despite an unimpressive examination of the pharynx. Stridor and respiratory distress result from laryngeal obstruction. The diagnosis is best made by direct visualization of the cherry-red, swollen epiglottis at laryngoscopy. Because laryngoscopy may provoke laryngospasm and obstruction, especially in children, it should be performed in an intensive care unit or similar setting, and only at a time when intubation can be performed promptly. Ceftriaxone, 1 g intravenously every 24 hours for 7–10 days, is the drug of choice. Trimethoprim-sulfamethoxazole (see above for dosage) may be used in the patient with serious penicillin allergy.

Meningitis, rare in adults, is a consideration in the patient who has meningitis associated with sinusitis or otitis. Initial therapy for suspected H influenzae meningitis should be with ceftriaxone, 4 g/d two divided doses, until the strain is proved not to produce β-lactamase. Meningitis is treated for 10–14 days. Dexamethasone, 0.15 mg/kg intravenously every 6 hours may reduce the incidence of long-term sequelae, principally hearing loss.

Infections Caused by Moraxella Catarrhalis

M catarrhalis is a gram-negative aerobic coccus morphologically and biochemically similar to Neisseria. It causes sinusitis, bronchitis, and pneumonia. Bacteremia and meningitis have also been reported in immunocompromised patients. The organism frequently colonizes the respiratory tract, making differentiation of colonization from infection difficult. If M catarrhalis is the predominant isolate, therapy is directed against it. M catarrhalis typically produces β-lactamase and therefore is usually resistant to ampicillin and amoxicillin. It is susceptible to amoxicillin-clavulanate, ampicillin-sulbactam, trimethoprim-sulfamethoxazole, ciprofloxacin, and second- and third-generation cephalosporins.

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Murphy TF et al: Moraxella catarrhalis in chronic obstructive pulmonary disease: burden of disease and immune response. Am J Respir Crit Care Med 2005;172:195.

Legionnaire's Disease

Essentials of Diagnosis

  • Patients are often immunocompromised, smokers, or have chronic lung disease.

  • Scant sputum production, pleuritic chest pain, toxic appearance.

  • Chest radiograph shows focal patchy infiltrates or consolidation.

  • Gram stain of sputum shows polymorphonuclear leukocytes and no organisms.

General Considerations

Legionella infection ranks among the three or four most common causes of community-acquired pneumonia and is considered whenever the etiology of a pneumonia is in question. Legionnaire's disease is more common in immunocompromised persons, in smokers, and in those with chronic lung disease. Outbreaks have been associated with contaminated water sources, such as shower heads and faucets in patient rooms and air conditioning cooling towers.

Clinical Findings

A. Symptoms and Signs

Legionnaire's disease is one of the atypical pneumonias, so called because a Gram-stained smear of sputum does not show organisms. However, many features of Legionnaire's disease are more like typical pneumonia, with high fevers, a toxic patient, pleurisy, and grossly purulent sputum. Classically, this pneumonia is caused by Legionella pneumophila, though other species can cause identical disease.

B. Laboratory Findings

Culture onto charcoal-yeast extract agar or similar enriched medium is the most sensitive method (80–90% sensitivity) for diagnosis and permits identification of infections caused by species and serotypes other than L pneumophila serotype 1. Dieterle's silver staining of tissue, pleural fluid, or other infected material is also a reliable method for detecting Legionella species. Direct fluorescent antibody stains and serologic testing are less sensitive because these will detect only L pneumophila serotype 1. In addition, making a serologic diagnosis requires that the host respond with sufficient specific antibody production. Urinary antigen tests, which are targeted for detection of L pneumophila serotype 1, are also less sensitive than culture.

Treatment

Azithromycin (500 mg orally once daily), clarithromycin (500 mg orally twice daily), or a fluoroquinolone (eg, levofloxacin 500 mg orally once daily), and not erythromycin, is the drug of choice for treatment of legionellosis because of their excellent intracellular penetration and in vitro activity, as well as desirable pharmacokinetic properties that permit oral administration and once or twice daily dosing. Duration of therapy is 10–14 days, although a 21-day course of therapy is recommended for immunocompromised patients.

Plouffe JF et al: Azithromycin in the treatment of Legionella pneumonia requiring hospitalization. Clin Infect Dis 2003;37:1475. Epub 2003 Oct 29.

Sabria M et al: Fluoroquinolones vs macrolides in the treatment of Legionnaires' disease. Chest 2005;128:1401.

Gram-Negative Bacteremia & Sepsis

Gram-negative bacteremia can originate in a number of sites, the most common being the genitourinary system, hepatobiliary tract, gastrointestinal tract, and lungs. Less common sources include intravenous lines, infusion fluids, surgical wounds, drains, and decubitus ulcers.

Patients with potentially fatal underlying conditions in the short term such as neutropenia or immunoparesis have a mortality rate of 40–60%; those with serious underlying diseases likely to be fatal in 5 years, such as solid tumors, cirrhosis, and aplastic anemia, die in 15–20% of cases; and individuals with no underlying diseases have a mortality rate of 5% or less.

Clinical Findings

A. Symptoms and Signs

Most patients have fevers and chills, often with abrupt onset. However, 15% of patients are hypothermic (temperature ≤ 36.4°C) at presentation, and 5% never develop a temperature above 37.5°C. Hyperventilation with respiratory alkalosis and changes in mental status are important early manifestations. Hypotension and shock, which occur in 20–50% of patients, are unfavorable prognostic signs.

B. Laboratory Findings

Neutropenia or neutrophilia, often with increased numbers of immature forms of polymorphonuclear leukocytes, is the most common laboratory abnormality in septic patients. Thrombocytopenia occurs in 50% of patients, laboratory evidence of coagulation abnormalities in 10%, and overt disseminated intravascular coagulation in 2–3%. Both clinical manifestations and the laboratory abnormalities are nonspecific and insensitive, which accounts for the relatively low rate of blood culture positivity (approximately 20–40%). If possible, three blood cultures from separate sites should be obtained in rapid succession before

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starting antimicrobial therapy. The chance of recovering the organism in at least one of the three blood cultures is greater than 95%. The false-negative rate for a single culture of 5–10 mL of blood is 30%. This may be reduced to 5–10% (albeit with a slight false-positive rate due to isolation of contaminants) if a single volume of 30 mL is inoculated into several blood culture bottles. Because blood cultures may be falsely negative, when a patient with presumed septic shock, negative blood cultures, and inadequate explanation for the clinical course responds to antimicrobials, therapy should be continued for 10–14 days.

Treatment

Several factors are important in the management of patients with sepsis.

A. Removal of Predisposing Factors

This usually means decreasing or stopping immunosuppressive medications and in certain circumstances (eg, positive blood cultures) giving granulocyte colony-stimulating factor (filgrastim; G-CSF) to the neutropenic patient.

B. Identifying the Source of Bacteremia

By simply finding the source of bacteremia and removing it (intravenous line) or draining it (abscess), a fatal disease becomes easily treatable.

C. Supportive Measures

The use of fluids and pressors for maintaining blood pressure is discussed in Chapter 12; management of disseminated intravascular coagulation is discussed in Chapter 13.

D. Antibiotics

Antibiotics are given as soon as the diagnosis is suspected, since delays in therapy have been associated with increased mortality rates. In general, bactericidal antibiotics should be used and given intravenously to ensure therapeutic serum levels. Penetration of antibiotics into the site of primary infection is critical for successful therapy—ie, if the infection originates in the central nervous system, antibiotics that penetrate the blood-brain barrier should be used—eg, penicillin, ampicillin, chloramphenicol, and third-generation cephalosporins—but not first-generation cephalosporins or aminoglycosides, which penetrate poorly. Sepsis caused by gram-positive organisms cannot be differentiated on clinical grounds from that due to gram-negative bacteria. Therefore, initial therapy should include antibiotics active against both types of organisms.

The number of antibiotics necessary remains controversial and depends on the cause. Table 37-2 provides a guide for empiric therapy. Most authorities believe that for patients with rapidly fatal underlying diseases, a synergistic combination of antibiotics, including an aminoglycoside, should be used. For patients with nonfatal or ultimately fatal diseases and who are not in shock, a single-drug regimen with any of several broad-spectrum antibiotics (eg, a third-generation cephalosporin, ticarcillin-clavulanate, imipenem) is adequate. Therapy can be altered once results of culture and sensitivity are known.

E. Corticosteroids

The role of corticosteroids in treatment of septic shock is still quite controversial. Clinical data have suggested an association between mortality in patients with septic shock and poor adrenal reserve to cosyntropin (Cortrosyn) stimulation testing. Administration of “stress doses” of hydrocortisone, for example 100 mg intravenously three times a day for 5 days followed by a 6-day tapering-dose regimen, to patients with relative adrenal insufficiency and pressor-dependent septic shock may reduce mortality. However, the usefulness of cosyntropin stimulation testing and use of stress-dose hydrocortisone in patients with septic shock are not so well defined as to be standard of care.

F. Adjunctive Therapy

Expanded knowledge of the pathophysiology of sepsis and septic shock and recognition that cytokines play a critical role suggest novel approaches to therapy. Strategies include blocking the effects of endotoxin with anti-endotoxin monoclonal antibodies; blockade of TNF-α, a potent cytokine mediator of septic shock, with anti-TNF monoclonal antibody or soluble TNF receptor; use of IL-1 receptor antagonists to inhibit the proinflammatory effects of IL-1 binding to its receptor; use of corticosteroids; and blocking platelet or thrombin activation. None of these strategies have been met with improved survival. However, a single randomized placebo-controlled trial showed that recombinant human activated protein C (drotrecogin alfa) reduced mortality septic patients with APACHE II scores ≥ 25. This drug should be used cautiously because of the risk of bleeding. Drotrecogin alfa is not beneficial for patients with severe sepsis and low risk of death (eg, APACHE score < 25 or single organ failure), and it is associated with serious bleeding complications; it should not be used in these patients. Patients considered to have an infectious cause of severe sepsis (defined as three or more signs of systemic inflammation—eg, fever or hypothermia, tachycardia, tachypnea—plus sepsis-induced dysfunction of at least one organ system) of less than 24 hours' duration are the best candidates. Platelet counts less than 30,000/mcL, conditions associated with an increased risk of bleeding (eg, recent trauma, surgery, or bleeding episode; anticoagulation), or hypercoagulable states have not been investigated. These criteria should be followed when selecting candidates for treatment with drotrecogin alfa (activated). The agent is administered intravenously by constant infusion at a dosage of 24 mcg/kg/h for 96 hours.

Abraham E et al; Administration of Drotrecogin Alfa (Activated) in Early Stage Severe Sepsis (ADDRESS) Study Group. Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. N Engl J Med 2005;353:1332.

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Annane D et al: Septic shock. Lancet 2005;365:63.

Minneci PC et al: Meta-analysis: the effect of steroids on survival and shock during sepsis depends on the dose. Ann Intern Med 2004;141:47.

Salmonellosis

Salmonellosis includes infection by any of approximately 2000 serotypes of salmonellae. The taxonomy of Salmonella species has been confusing. All salmonella serotypes are members of a single species, Salmonella enterica. Human infections are caused almost exclusively by S enterica subsp enterica, of which three serotypes—typhi, typhimurium, and choleraesuis—are predominantly isolated. Three clinical patterns of infection are recognized: (1) enteric fever, the best example of which is typhoid fever, due to serotype typhi; (2) acute enterocolitis, caused by serotype typhimurium, among others; and (3) the “septicemic” type, characterized by bacteremia and focal lesions, exemplified by infection with serotype choleraesuis. All types are transmitted by ingestion of the organism, usually from contaminated food or drink.

1. Enteric Fever (Typhoid Fever)

Essentials of Diagnosis

  • Gradual onset of malaise, headache, nausea, vomiting, abdominal pain.

  • Rose spots, relative bradycardia, splenomegaly, and abdominal distention and tenderness.

  • Slow (stepladder) rise of fever to maximum and then slow return to normal.

  • Leukopenia; blood, stool, and urine culture positive for salmonella.

General Considerations

Enteric fever is a clinical syndrome characterized by constitutional and gastrointestinal symptoms and by headache. It can be caused by any Salmonella species. The term “typhoid fever” applies when serotype typhi is the cause. Infection is transmitted by consumption of contaminated food or drink. The incubation period is 5–14 days. Salmonella is an intracellular pathogen. Infection begins when organisms breach the mucosal epithelium of the intestines by transcytosis, an organism-mediated transport process through the cell via an endocytic vesicle. Having crossed the epithelial barrier, organisms invade and replicate in macrophages in Peyer's patches, mesenteric lymph nodes, and the spleen. Serotypes other than typhi usually do not cause invasive disease, presumably because they lack the necessary human-specific virulence factors. Bacteremia occurs, and the infection then localizes principally in the lymphoid tissue of the small intestine (particularly within 60 cm of the ileocecal valve). Peyer's patches become inflamed and may ulcerate, with involvement greatest during the third week of disease. The organism may disseminate to the lungs, gallbladder, kidneys, or central nervous system.

Clinical Findings

A. Symptoms and Signs

During the prodromal stage, there is increasing malaise, headache, cough, and sore throat, often with abdominal pain and constipation, while the fever ascends in a stepwise fashion. After about 7–10 days, it reaches a plateau and the patient is much more ill, appearing exhausted and often prostrated. There may be marked constipation, especially early, or “pea soup” diarrhea; marked abdominal distention occurs as well. If there are no complications, the patient's condition will gradually improve over 7–10 days. However, relapse may occur for up to 2 weeks after defervescence.

During the early prodrome, physical findings are few. Later, splenomegaly, abdominal distention and tenderness, relative bradycardia, and occasionally meningismus appear. The rash (rose spots) commonly appears during the second week of disease. The individual spot, found principally on the trunk, is a pink papule 2–3 mm in diameter that fades on pressure. It disappears in 3–4 days.

B. Laboratory Findings

Typhoid fever is best diagnosed by blood culture, which is positive in the first week of illness in 80% of patients who have not taken antimicrobials. The rate of positivity declines thereafter, but one-fourth or more of patients still have positive blood cultures in the third week. Cultures of bone marrow occasionally are positive when blood cultures are not. Stool culture is unreliable because it may be positive in gastroenteritis without typhoid fever. Relative bradycardia and leukopenia are typical.

Differential Diagnosis

Enteric fever must be distinguished from other gastrointestinal illnesses and from other infections that have few localizing findings. Examples include tuberculosis, infective endocarditis, brucellosis, lymphoma, and Q fever. Often there is a history of recent travel to endemic areas, and viral hepatitis, malaria, or amebiasis may be in the differential as well.

Complications

Complications occur in about 30% of untreated cases and account for 75% of deaths. Intestinal hemorrhage, manifested by a sudden drop in temperature and signs of shock followed by dark or fresh blood in the stool,

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or intestinal perforation, accompanied by abdominal pain and tenderness, is most likely to occur during the third week. Appearance of leukocytosis and tachycardia should suggest these complications. Urinary retention, pneumonia, thrombophlebitis, myocarditis, psychosis, cholecystitis, nephritis, osteomyelitis, and meningitis are less often observed.

Prevention

Immunization is not always effective but should be considered for household contacts of a typhoid carrier, for travelers to endemic areas, and during epidemic outbreaks. A multiple-dose oral vaccine and a single-dose parenteral vaccine are available. Their efficacies are similar, but oral vaccine causes fewer side effects. Boosters, when indicated, should be given every 5 years and 3 years for oral and parenteral preparations, respectively.

Adequate waste disposal and protection of food and water supplies from contamination are important public health measures to prevent salmonellosis. Carriers cannot work as food handlers.

Treatment

A. Specific Measures

Several antibiotics, including ampicillin, azithromycin, chloramphenicol, third-generation cephalosporins, and trimethoprim-sulfamethoxazole all are effective for treatment of enteric fever caused by drug-susceptible strains. These drugs can be given orally or intravenously depending on the patient's condition. Because many salmonella strains are resistant to ampicillin, chloramphenicol, and trimethoprim-sulfamethoxazole, a fluoroquinolone—such as ciprofloxacin 750 mg orally twice daily or levofloxacin 500 mg orally once daily, 5–7 days for uncomplicated enteric fever and 10–14 days for severe infection—is the agent of choice for treatment of salmonella infections. Ceftriaxone 2 g intravenously for 7 days is also effective. Resistance to fluoroquinolones or cephalosporins occurs rarely. Infection caused by a drug-resistant strain is treated by using an antibiotic to which the isolate is susceptible (eg, azithromycin), or in severe cases by increasing the dose of ceftriaxone to 4 g/d and treating for 10–14 days.

B. Treatment of Carriers

Chemotherapy often is unsuccessful in eradicating the carrier state. While treatment of carriage with ampicillin, trimethoprim-sulfamethoxazole, or chloramphenicol may be successful, ciprofloxacin, 750 mg orally twice a day for 4 weeks, has proved to be highly effective. Cholecystectomy may also achieve this goal.

Prognosis

The mortality rate of typhoid fever is about 2% in treated cases. Elderly or debilitated persons are likely to do poorly. With complications, the prognosis is poor. Relapses occur in up to 15% of cases. A residual carrier state frequently persists in spite of chemotherapy.

Bhan MK et al: Typhoid and paratyphoid fever. Lancet 2005;366:749.

Steinberg EB et al: Typhoid fever in travelers: who should be targeted for prevention? Clin Infect Dis 2004;39:186.

2. Salmonella Gastroenteritis

By far the most common form of salmonellosis is acute enterocolitis caused by numerous salmonella serotypes. The incubation period is 8–48 hours after ingestion of contaminated food or liquid.

Symptoms and signs consist of fever (often with chills), nausea and vomiting, cramping abdominal pain, and diarrhea, which may be grossly bloody, lasting 3–5 days. Differentiation must be made from viral gastroenteritis, food poisoning, shigellosis, amebic dysentery, and acute ulcerative colitis. The diagnosis is made by culturing the organism from the stool.

The disease is usually self-limited, but bacteremia with localization in joints or bones may occur, especially in patients with sickle cell disease.

Treatment of uncomplicated enterocolitis is symptomatic only. Malnourished or severely ill patients, those with sickle cell disease, and those with suspected bacteremia should be treated for 3–5 days with trimethoprim-sulfamethoxazole (one double-strength tablet twice a day), ampicillin (100 mg/kg intravenously or orally), or ciprofloxacin (750 mg orally twice a day).

Patrick ME et al: Salmonella enteritidis infections, United States, 1985–1999. Emerg Infect Dis 2004;10:1.

3. Salmonella Bacteremia

Salmonella infection may be manifested by prolonged or recurrent fevers accompanied by bacteremia and local infection in bone, joints, pleura, pericardium, lungs, or other sites. Mycotic abdominal aortic aneurysms may also occur. Serotypes other than typhi usually are isolated. This complication tends to occur in immunocompromised persons and is seen in HIV-infected individuals, who typically have bacteremia without an obvious source. Treatment is the same as for typhoid fever, plus drainage of any abscesses. In HIV-infected patients, relapse is common, and lifelong suppressive therapy may be needed. Ciprofloxacin, 750 mg orally twice a day, is effective both for therapy of acute infection and for suppression of recurrence. Incidence of infections caused by drug-resistant strains may be on the rise.

Varma JK et al: Antimicrobial-resistant nontyphoidal Salmonella is associated with excess bloodstream infections and hospitalizations. J Infect Dis 2005;191:554.

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Shigellosis

Essentials of Diagnosis

  • Diarrhea, often with blood and mucus.

  • Crampy abdominal pain and systemic toxicity.

  • White blood cells in stools; organism isolated on stool culture.

General Considerations

Shigella dysentery is a common disease, often self-limited and mild but occasionally serious. Shigella sonnei is the leading cause in the United States, followed by Shigella flexneri. Shigella dysenteriae causes the most serious form of the illness. Shigellae are invasive organisms. The infective dose is 102-103 organisms. There has been a rise in strains resistant to multiple antibiotics.

Clinical Findings

A. Symptoms and Signs

The illness usually starts abruptly, with diarrhea, lower abdominal cramps, and tenesmus. The diarrheal stool often is mixed with blood and mucus. Systemic symptoms are fever, chills, anorexia and malaise, and headache. The abdomen is tender. Sigmoidoscopic examination reveals an inflamed, engorged mucosa with punctate and sometimes large areas of ulceration.

B. Laboratory Findings

The stool shows many leukocytes and red cells. Stool culture is positive for shigellae in most cases, but blood cultures grow the organism in less than 5% of cases.

Differential Diagnosis

Bacillary dysentery must be distinguished from salmonella enterocolitis and from disease due to enterotoxigenic Escherichia coli, Campylobacter, and Yersinia enterocolitica. Amebic dysentery may be similar clinically and is diagnosed by finding amebas in the fresh stool specimen. Ulcerative colitis is also an important cause of bloody diarrhea.

Complications

Temporary disaccharidase deficiency may follow the diarrhea. Reactive arthritis is an uncommon complication, usually occurring in HLA-B27 individuals infected by Shigella.

Treatment

Treatment of dehydration and hypotension is lifesaving in severe cases. The antimicrobial treatments of choice are trimethoprim-sulfamethoxazole, one double-strength tablet twice a day for 7–10 days, or a fluoroquinolone (ciprofloxacin 750 mg orally twice daily for 7–10 days, or levofloxacin, 500 mg orally once daily) for 3 days. Fluoroquinolones are contraindicated in pregnancy. Shigellae resistant to ampicillin are common, but if the isolate is susceptible, a dose of 500 mg orally four times a day is also effective. Amoxicillin, which is less effective, should not be used.

Gupta A et al: Laboratory-confirmed shigellosis in the United States, 1989–2002: epidemiologic trends and patterns. Clin Infect Dis 2004;38:1372.

Thielman NM et al: Clinical practice. Acute infectious diarrhea. N Engl J Med 2004;350:38.

Gastroenteritis Caused by Escherichia Coli

E coli causes gastroenteritis by a variety of mechanisms. Enterotoxigenic E coli (ETEC) elaborates either a heat-stable or heat-labile toxin that mediates the disease. ETEC is an important cause of traveler's diarrhea. Enteroinvasive E coli (EIEC) differs from other E coli bowel pathogens in that these strains invade cells, causing bloody diarrhea and dysentery similar to infection with Shigella species. EIEC is uncommon in the United States. Neither ETEC nor EIEC strains are routinely isolated and identified from stool cultures because there is no selective medium. Antimicrobial therapy directed against Salmonella and Shigella shortens the clinical course, but the disease is self-limited.

Enterohemorrhagic E coli (EHEC) produces two shiga-like toxins that mediate the clinical manifestations, which include an asymptomatic carriage stage, nonbloody diarrhea, hemorrhagic colitis, hemolytic-uremic syndrome, and thrombotic thrombocytopenic purpura. Although there are several serotypes of EHEC, O157:H7 is responsible for most cases in the United States. E coli O157:H7 has caused several outbreaks of diarrhea and hemolytic-uremic syndrome related to consumption of undercooked hamburger and unpasteurized apple juice. Older individuals and young children are most affected, with hemolytic-uremic syndrome being more common in the latter group. E coli O157:H7 is not identified by routine stool cultures. Isolation requires identification of sorbitol-negative colonies of E coli on sorbitol-MacConkey agar followed by serologic testing to confirm the serotype. Antimicrobial therapy does not alter the course of the disease, and may increase the risk of hemolytic-uremic syndrome. Treatment is primarily supportive. Hemolytic-uremic syndrome or thrombotic thrombocytopenic purpura occurring in association with a diarrheal illness suggests the diagnosis and should prompt evaluation for EHEC. Confirmed infections should be reported to public health officials.

Thielman NM et al: Clinical practice. Acute infectious diarrhea. N Engl J Med 2004;350:38.

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Cholera

Essentials of Diagnosis

  • History of travel in endemic area or contact with infected person.

  • Voluminous diarrhea.

  • Stool is liquid, gray, turbid, and without fecal odor, blood, or pus (“rice water stool”).

  • Rapid development of marked dehydration.

  • Positive stool cultures and agglutination of vibrios with specific sera.

General Considerations

Cholera is an acute diarrheal illness caused by certain serotypes of Vibrio cholerae. The disease is toxin-mediated, and fever is unusual. The toxin activates adenylyl cyclase in intestinal epithelial cells of the small intestines, producing hypersecretion of water and chloride ion and a massive diarrhea of up to 15 L/d. Death results from profound hypovolemia.

Cholera occurs in epidemics under conditions of crowding, war, and famine (eg, in refugee camps) and where sanitation is inadequate. Infection is acquired by ingestion of contaminated food or water. Cholera was rarely seen in the United States until 1991, when epidemic cholera returned to the Western Hemisphere, originating as an outbreak in coastal cities of Peru. The epidemic spread to involve several countries in South and Central America as well as Mexico, and cases have been imported into the United States. Cholera should be considered in the differential diagnosis of severe watery diarrhea, especially in those who have traveled to affected countries.

Clinical Findings

Cholera is characterized by a sudden onset of severe, frequent watery diarrhea (up to 1 L/h). The liquid stool is gray; turbid; and without fecal odor, blood, or pus (“rice water stool”). Dehydration and hypotension develop rapidly. Stool cultures are positive, and agglutination of vibrios with specific sera can be demonstrated.

Prevention

A vaccine is available that confers short-lived, limited protection and may be required for entry into or reentry after travel to some countries. It is administered in two doses 1–4 weeks apart. A booster dose every 6 months is recommended for persons remaining in areas where cholera is a hazard.

Vaccination programs are expensive and not particularly effective in managing outbreaks of cholera. When outbreaks occur, efforts should be directed toward establishing clean water and food sources and proper waste disposal.

Treatment

Treatment is by replacement of fluids. In mild or moderate illness, oral rehydration usually is adequate. A simple oral replacement fluid can be made from 1 teaspoon of table salt and 4 heaping teaspoons of sugar added to 1 L of water. Intravenous fluids are indicated for persons with signs of severe hypovolemia and those who cannot take adequate fluids orally. Lactated Ringer's infusion is satisfactory.

Antimicrobial therapy will shorten the course of illness. Several antimicrobials are active against V cholerae, including tetracycline, ampicillin, chloramphenicol, trimethoprim-sulfamethoxazole, and fluoroquinolones. Multiple antibiotic resistance does occur, so susceptibility testing, if available, is advisable.

Sack DA et al: Cholera. Lancet 2004;363:223.

Infections Caused by Other vibrio Species

Vibrios other than V cholerae that cause human disease are Vibrio parahaemolyticus, Vibrio vulnificus, and Vibrio alginolyticus. All are halophilic marine organisms. Infection is acquired by exposure to organisms in contaminated, undercooked, or raw crustaceans or shellfish and warm (> 20°C) ocean waters and estuaries. Infections are more common during the summer months from regions along the Atlantic coast and the Gulf of Mexico in the United States and from tropical waters around the world. Oysters are implicated in up to 90% of food-related cases. V parahaemolyticus causes an acute watery diarrhea with crampy abdominal pain and fever, typically occurring within 24 hours after ingestion of contaminated shellfish. The disease is self-limited, and antimicrobial therapy is usually not necessary. V parahaemolyticus may also cause cellulitis and sepsis, though these findings are more characteristic of V vulnificus infection.

V vulnificus and V alginolyticus—neither of which is associated with diarrheal illness—are important causes of cellulitis and primary bacteremia following ingestion of contaminated shellfish or exposure to sea water. Cellulitis with or without sepsis may be accompanied by bulla formation and necrosis with extensive soft tissue destruction, at times requiring debridement and amputation. The infection can be rapidly progressive and is particularly severe in immunocompromised individuals—especially those with cirrhosis—with death rates as high as 50%. Patients with chronic liver disease and those who are immunocompromised should be cautioned to avoid eating raw oysters.

Tetracycline at a dose of 500 mg orally four times a day for 7–10 days is the drug of choice for treatment of suspected or documented primary bacteremia or cellulitis caused by Vibrio species. V vulnificus is susceptible in vitro to penicillin, ampicillin, cephalosporins,

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chloramphenicol, aminoglycosides, and fluoroquinolones, and these agents may also be effective. V parahaemolyticus and V alginolyticus produce β-lactamase and therefore are resistant to penicillin and ampicillin, but susceptibilities otherwise are similar to those listed for V vulnificus.

Centers for Disease Control and Prevention: Vibrio illnesses after Hurricane Katrina—multiple states, August-September 2005. MMWR 2005;54:928.

Infections Caused by Campylobacter Species

Campylobacters are microaerophilic, motile, gram-negative rods. Two species infect humans: Campylobacter jejuni, an important cause of diarrheal disease, and Campylobacter fetus subsp fetus, which typically causes systemic infection and not diarrhea. Dairy cattle and poultry are an important reservoir for campylobacters. Outbreaks of enteritis have been associated with consumption of raw milk. Campylobacter gastroenteritis is associated with fever, abdominal pain, and diarrhea characterized by loose, watery, or bloody stools. The differential diagnosis includes shigellosis, salmonella gastroenteritis, and enteritis caused by Yersinia enterocolitica or invasive E coli. The disease is self-limited, but its duration can be shortened with antimicrobial therapy. Both erythromycin, 250–500 mg orally four times daily for 5–7 days, and ciprofloxacin, 500 mg orally twice daily for 3 days, are effective regimens. Pending identification of the causative agent of suspected bacterial gastroenteritis, ciprofloxacin is a rational choice for empiric therapy, although the prevalence of fluoroquinolone-resistant Campylobacter has been increasing with approximately 20% resistance reported for US isolates in 2001.

C fetus causes systemic infections that can be fatal, including primary bacteremia, endocarditis, meningitis, and focal abscesses. It infrequently causes gastroenteritis. Patients infected with C fetus are often older, debilitated, or immunocompromised. Closely related species, collectively termed “campylobacter-like organisms,” cause bacteremia in HIV-infected individuals. Systemic infections respond to therapy with gentamicin, chloramphenicol, ceftriaxone, or ciprofloxacin. Ceftriaxone or chloramphenicol should be used to treat infections of the central nervous system because of their ability to penetrate the blood-brain barrier.

Lecuit M et al: Immunoproliferative small intestinal disease associated with Campylobacter jejuni. N Engl J Med 2004;350:239.

Brucellosis

Essentials of Diagnosis

  • History of animal exposure, ingestion of unpasteurized milk or cheese.

  • Insidious onset: easy fatigability, headache, arthralgia, anorexia, sweating, irritability.

  • Intermittent and persistent fever.

  • Cervical and axillary lymphadenopathy; hepatosplenomegaly.

  • Lymphocytosis, positive blood culture, positive serologic test.

General Considerations

The infection is transmitted from animals to humans. Brucella abortus (cattle), Brucella suis (hogs), and Brucella melitensis (goats) are the main agents. Transmission to humans occurs by contact with infected meat (slaughterhouse workers), placentae of infected animals (farmers, veterinarians), or ingestion of infected unpasteurized milk or cheese. The incubation period varies from a few days to several weeks. Brucellosis is a systemic infection that may become chronic. In the United States, brucellosis is very rare. Almost all US cases are imported from countries where brucellosis is endemic (eg, Mexico, Mediterranean Europe, Spain, South American countries).

Clinical Findings

A. Symptoms and Signs

The onset may be acute, with fever, chills, and sweats, but more often is insidious with symptoms of weakness, weight loss, low-grade fevers, sweats, and exhaustion upon minimal activity. Headache, abdominal or back pain with anorexia and constipation, and arthralgias are also common. The chronic form may assume an undulant nature, with periods of normal temperature between acute attacks; symptoms may persist for years, either continuously or intermittently.

Fever, hepatosplenomegaly, and lymphadenopathy are the most common physical findings. Infection may present with or be complicated by specific organ involvement with signs of endocarditis, meningitis, epididymitis, orchitis, arthritis (especially sacroilitis), spondylitis, or osteomyelitis.

B. Laboratory Findings

The organism can be recovered from cultures of blood, cerebrospinal fluid, urine, bone marrow, or other sites. Modern automated systems have shortened the time to detection of the organism in blood culture. Cultures are more likely to be negative in chronic cases. The diagnosis often is made by serologic testing. Rising serologic titers or an absolute agglutination titer of greater than 1:160 supports the diagnosis.

Differential Diagnosis

Brucellosis must be differentiated from any other acute febrile disease, especially influenza, tularemia, Q fever,

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mononucleosis, and enteric fever. In its chronic form it resembles Hodgkin's disease, tuberculosis, HIV infection, malaria, and disseminated fungal infections such as histoplasmosis and coccidioidomycosis.

Complications

The most frequent complications are bone and joint lesions such as spondylitis and suppurative arthritis (usually of a single joint), endocarditis, and meningoencephalitis. Less common complications are pneumonitis with pleural effusion, hepatitis, and cholecystitis.

Treatment

Single-drug regimens are not recommended because the relapse rate may be as high as 50%. Combination regimens of two or three drugs are most effective. Regimens of doxycycline (200 mg/d orally for 6 weeks) plus rifampin (600 mg/d orally for 6 weeks) or streptomycin (1 g/d intramuscularly for 2–3 weeks) or gentamicin (240 mg intramuscularly once daily for 7 days) have the lowest recurrence rates. Longer courses of therapy may be required to prevent relapse of meningitis, osteomyelitis, or endocarditis.

Pappas G et al: New approaches to the antibiotic treatment of brucellosis. Int J Antimicrob Agents 2005;26:101.

Troy SB et al: Brucellosis in San Diego: epidemiology and species-related differences in acute clinical presentations. Medicine (Baltimore) 2005;84:1747.

Tularemia

Essentials of Diagnosis

  • History of contact with rabbits, other rodents, and biting arthropods (eg, ticks in summer) in endemic area.

  • Fever, headache, nausea, and prostration.

  • Papule progressing to ulcer at site of inoculation.

  • Enlarged regional lymph nodes.

  • Serologic tests or culture of ulcer, lymph node aspirate, or blood confirm the diagnosis.

General Considerations

Tularemia is a zoonotic infection of wild rodents and rabbits caused by Francisella tularensis. Humans usually acquire the infection by contact with animal tissues (eg, trapping muskrats, skinning rabbits) or from a tick or insect bite. Hamsters and prairie dogs also may carry the organism. An investigation of an outbreak of pneumonic tularemia on Martha's Vineyard in Massachusetts implicated lawn-mowing and brush-cutting as risk factors for infection, underscoring the potential for probable aerosol transmission of the organism. F tularensis has been classified as a high-priority agent for potential bioterrorism use because of its virulence and relative ease of dissemination. Infection in humans often produces a local lesion and widespread organ involvement but may be entirely asymptomatic. The incubation period is 2–10 days.

Clinical Findings

A. Symptoms and Signs

Fever, headache, and nausea begin suddenly, and a local lesion—a papule at the site of inoculation—develops and soon ulcerates. Regional lymph nodes may become enlarged and tender and may suppurate. The local lesion may be on the skin of an extremity or in the eye. Pneumonia may develop from hematogenous spread of the organism or may be primary after inhalation of infected aerosols, which are responsible for human-to-human transmission. Following ingestion of infected meat or water, an enteric form may be manifested by gastrointestinal symptoms, stupor, and delirium. In any type of involvement, the spleen may be enlarged and tender and there may be nonspecific rashes, myalgias, and prostration.

B. Laboratory Findings

Culturing the organism from blood or infected tissue requires special media. For this reason and because cultures of F tularensis may be hazardous to laboratory personnel, the diagnosis is usually made serologically. A positive agglutination test (> 1:80) develops in the second week after infection and may persist for several years.

Differential Diagnosis

Tularemia must be differentiated from rickettsial and meningococcal infections, cat-scratch disease, infectious mononucleosis, and various bacterial and fungal diseases.

Complications

Hematogenous spread may produce meningitis, perisplenitis, pericarditis, pneumonia, and osteomyelitis.

Treatment

Streptomycin is drug of choice for treatment of tularemia. The recommended dose is 7.5 mg/kg intramuscularly every 12 hours for 7–14 days. Doxycycline (200 mg/d orally) is also effective but has a higher relapse rate. A variety of other agents (eg, fluoroquinolones) are active in vitro but their clinical effectiveness is less well established.

Centers for Disease Control and Prevention (CDC): Tularemia associated with a hamster bite—Colorado, 2004. MMWR Morb Mortal Wkly Rep 2005;53:1202.

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Plague

Essentials of Diagnosis

  • History of exposure to rodents in endemic area.

  • Sudden onset of high fever, malaise, muscular pains, and prostration.

  • Axillary or inguinal lymphadenitis (bubo).

  • Bacteremia, pneumonitis, and meningitis may occur.

  • Positive smear and culture from bubo and positive blood culture.

General Considerations

Plague is an infection of wild rodents with Yersinia pestis, a small bipolar-staining gram-negative rod. It is endemic in California, Arizona, Nevada, and New Mexico. It is transmitted among rodents and to humans by the bites of fleas or from contact with infected animals. Following a fleabite, the organisms spread through the lymphatics to the lymph nodes, which become greatly enlarged (bubo). They may then reach the bloodstream to involve all organs. When pneumonia or meningitis develops, the outcome is often fatal. The patient with pneumonia can transmit the infection to other individuals by droplets. The incubation period is 2–10 days. Because of its extreme virulence, its potential for dissemination and person-to-person transmission, and efforts to develop the organism as an agent of biowarfare, plague bacillus is considered a high-priority agent for bioterrorism.

Clinical Findings

A. Symptoms and Signs

The onset is sudden, with high fever, malaise, tachycardia, intense headache, delirium, and severe myalgias. The patient appears profoundly ill. If pneumonia develops, tachypnea, productive cough, blood-tinged sputum, and cyanosis also occur. There may be signs of meningitis. A pustule or ulcer at the site of inoculation and lymphangitis may be observed. Axillary, inguinal, or cervical lymph nodes become enlarged and tender and may suppurate and drain. With hematogenous spread, the patient may rapidly become toxic and comatose, with purpuric spots (black plague) appearing on the skin.

Primary plague pneumonia is a fulminant pneumonitis with bloody, frothy sputum and sepsis. It is usually fatal unless treatment is started within a few hours after onset.

B. Laboratory Findings

The plague bacillus may be found in smears from aspirates of buboes examined with Gram stain. Cultures from bubo aspirate or pus and blood are positive but may grow slowly. In convalescing patients, an antibody titer rise may be demonstrated by agglutination tests.

Differential Diagnosis

The lymphadenitis of plague is most commonly mistaken for the lymphadenitis accompanying staphylococcal or streptococcal infections of an extremity, sexually transmitted diseases such as lymphogranuloma venereum or syphilis, and tularemia. The systemic manifestations resemble those of enteric or rickettsial fevers, malaria, or influenza. The pneumonia resembles other bacterial pneumonias, and the meningitis is similar to those caused by other bacteria.

Prevention

Drug prophylaxis may provide temporary protection for persons exposed to the risk of plague infection, particularly by the respiratory route. Tetracycline hydrochloride, 500 mg orally once or twice daily for 5 days, is effective.

Plague vaccines—both live and killed—have been used for many years, but their efficacy is not clearly established.

Treatment

Therapy should be started immediately once plague is suspected. Either streptomycin (the agent with which there is greatest experience), 1 g every 12 hours intravenously, or gentamicin, administered as a 2-mg/kg loading dose, then 1.7 mg/kg every 8 hours intravenously, is effective. Alternatively, doxycycline, 100 mg orally or intravenously, may be used. The duration of therapy is 10 days. Patients with plague pneumonia are placed in strict respiratory isolation.

Boulanger LL et al: Gentamicin and tetracyclines for the treatment of human plague: review of 75 cases in New Mexico, 1985–1999. Clin Infect Dis 2004;38:663.

Gonococcal Infections

Essentials of Diagnosis

  • Purulent and profuse urethral discharge, especially in men, with dysuria, yielding positive smear.

  • Epididymitis, prostatitis, periurethral inflammation, proctitis in men.

  • Cervicitis in women with purulent discharge, or asymptomatic, yielding positive culture; vaginitis, salpingitis, proctitis also occur.

  • Fever, rash, tenosynovitis, and arthritis with disseminated disease.

  • Gram-negative intracellular diplococci seen in a smear or cultured from any site, particularly the urethra, cervix, pharynx, and rectum.

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General Considerations

Gonorrhea is caused by Neisseria gonorrhoeae, a gram-negative diplococcus typically found inside polymorphonuclear cells. It is transmitted during sexual activity and has its greatest incidence in the 15- to 29-year-old age group. The incubation period is usually 2–8 days.

Classification

A. Urethritis and Cervicitis

In men, there is initially burning on urination and a serous or milky discharge. One to 3 days later, the urethral pain is more pronounced and the discharge becomes yellow, creamy, and profuse, sometimes blood-tinged. The disorder may regress and become chronic or progress to involve the prostate, epididymis, and periurethral glands with painful inflammation. Chronic infection leads to prostatitis and urethral strictures. Rectal infection is common in homosexual men. Atypical sites of primary infection (eg, the pharynx) must always be considered. Asymptomatic infection is common and occurs in both sexes.

Gonococcal infection in women often becomes symptomatic during menses. Women may have dysuria, urinary frequency, and urgency, with a purulent urethral discharge. Vaginitis and cervicitis with inflammation of Bartholin's glands are common. Infection may be asymptomatic, with only slightly increased vaginal discharge and moderate cervicitis on examination. Infection may remain as a chronic cervicitis—an important reservoir of gonococci. It can progress to involve the uterus and tubes with acute and chronic salpingitis, with scarring of tubes and sterility. In pelvic inflammatory disease, anaerobes and chlamydiae often accompany gonococci. Rectal infection may result from spread of the organism from the genital tract or from anal coitus.

Gram stain of urethral discharge in men, especially during the first week after onset, shows gram-negative diplococci in polymorphonuclear leukocytes. Gram stain is less often positive in women. Culture has been the gold standard for diagnosis, particularly when the Gram stain is negative. Nucleic acid amplification tests that detect both N gonorrhoeae and Chlamydia trachomatis in cervical and urethral swab specimens and urine permit rapid diagnosis, have excellent sensitivity and specificity, and have largely replaced culture. Identification of N gonorrhoeae from rectal or pharyngeal sites, blood, and in joint fluid still requires culture.

B. Disseminated Disease

Systemic complications follow the dissemination of gonococci from the primary site via the bloodstream. Gonococcal bacteremia is associated with intermittent fever, arthralgia, and skin lesions ranging from maculopapular to pustular or hemorrhagic, which tend to be few in number and peripherally located. Rarely, gonococcal endocarditis or meningitis develops. Arthritis and tenosynovitis are common complications, particularly involving the knees, ankles, and wrists. One or occasionally a few joints usually are involved. Gonococci are isolated by culture from less than half of patients with gonococcal arthritis.

C. Conjunctivitis

The most common form of eye involvement is direct inoculation of gonococci into the conjunctival sac. In adults, this occurs by autoinoculation of a person with genital infection. The purulent conjunctivitis may rapidly progress to panophthalmitis and loss of the eye unless treated promptly. A single 1-g dose of ceftriaxone is effective.

Differential Diagnosis

Gonococcal urethritis or cervicitis must be differentiated from nongonococcal urethritis; cervicitis or vaginitis due to C trachomatis, Gardnerella vaginalis, Trichomonas, Candida, and many other pathogens associated with sexually transmitted diseases; and pelvic inflammatory disease, arthritis, proctitis, and skin lesions. Often, several such pathogens coexist in a patient. Reactive arthritis (urethritis, conjunctivitis, arthritis) may mimic gonorrhea or coexist with it.

Prevention

Prevention is based on education and mechanical or chemical prophylaxis. The condom, if properly used, can reduce the risk of infection. Effective drugs taken in therapeutic doses within 24 hours of exposure can abort an infection. Partner notification and referral of contacts for treatment has been the standard method used to control sexually transmitted diseases. Expedited treatment of sex partners by patient-delivered partner therapy is more effective than partner notification in reducing persistence and recurrence rates of gonorrhea and chlamydia. This strategy is being increasingly adopted as a means of disease control.

Treatment

Therapy typically is administered before antimicrobial susceptibilities are known. The choice of which regimen to use should be based on the prevalence of penicillin-resistant organisms. Nationwide, penicillin- and tetracycline-resistant gonococci have been increasingly observed. Consequently, penicillin should no longer be considered first-line therapy. All sexual partners should be treated and tested for HIV infection and syphilis, as should the patient as well.

A. Uncomplicated Gonorrhea

For urethritis or cervicitis, either ceftriaxone, 125 mg intramuscularly, or cefpodoxime, 400 mg orally as a single dose, is the treatment of choice. Fluoroquinolones are no longer recommended as first-line agents, especially for treatment of gonorrhea in men who have sex with men, because of emerging resistance. Spectinomycin, 1 g intramuscularly once, may be used for

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the penicillin-allergic patient. Anal gonorrhea in women responds to the same drugs, but in males ceftriaxone is most effective. Pharyngeal gonorrhea is treated by ceftriaxone in the same dosage and by trimethoprim-sulfamethoxazole, nine regular-strength tablets orally daily for 5 days. Since coexistent chlamydial infection is common, doxycycline, 100 mg orally twice daily orally for 7 days, or a single 1 g oral dose of azithromycin, concurrently, should be given; women should be tested for pregnancy before any tetracycline is prescribed (see also below).

B. Treatment of Other Infections

Salpingitis, prostatitis, bacteremia, arthritis, and other complications due to susceptible strains in adults should be treated with penicillin G, 10 million units intravenously daily, for 5 days. Ceftriaxone, 1 g intravenously daily for 5 days, or an oral fluoroquinolone (ciprofloxacin, 500 mg twice daily, or levofloxacin, 500 mg once daily) for 5 days also is effective, provided the isolate is susceptible. Endocarditis should be treated with ceftriaxone, 2 g every 24 hours intravenously, for at least 3 weeks. Postgonococcal urethritis and cervicitis, which are usually caused by chlamydia, are treated with a regimen of erythromycin, doxycycline, or azithromycin as described above.

Pelvic inflammatory disease requires cefoxitin, 2 g parenterally every 6 hours, or cefotetan, 2 g intravenously every 12 hours. Clindamycin, 900 mg intravenously every 8 hours, plus gentamicin, administered intravenously as a 2-mg/kg loading dose followed by 1.5 mg/kg every 8 hours, is also effective. Cefoxitin, 2 g intramuscularly, plus probenecid, 1 g orally as a single dose, followed by a 14-day oral regimen of doxycycline, 100 mg twice a day, is an effective outpatient regimen. Concurrent treatment for chlamydial infection also is indicated.

Centers for Disease Control and Prevention (CDC): Increases in fluoroquinolone-resistant Neisseria gonorrhoeae among men who have sex with men—United States, 2003, and revised recommendations for gonorrhea treatment, 2004. MMWR Morb Mortal Wkly Rep 2004;53:335.

Cook RL et al: Systematic review: noninvasive testing for Chlamydia trachomatis and Neisseria gonorrhoeae. Ann Intern Med 2005;142:914.

Golden MR et al: Effect of expedited treatment of sex partners on recurrent or persistent gonorrhea or chlamydial infection. N Engl J Med 2005;352:676.

Miller WC et al: Prevalence of chlamydial and gonococcal infections among young adults in the United States. JAMA 2004;291:2229.

Chancroid

Chancroid is a sexually transmitted disease caused by the short gram-negative bacillus Haemophilus ducreyi. The incubation period is 3–5 days. At the site of inoculation, a vesicopustule develops that breaks down to form a painful, soft ulcer with a necrotic base, surrounding erythema, and undermined edges. There may be multiple lesions due to autoinoculation. The adenitis is usually unilateral and consists of tender, matted nodes of moderate size with overlying erythema. These may become fluctuant and rupture spontaneously. With lymph node involvement, fever, chills, and malaise may develop. Balanitis and phimosis are frequent complications in men. Women may have no external signs of infection. The diagnosis is established by culturing a swab of the lesion onto a special medium.

Chancroid must be differentiated from other genital ulcers. The chancre of syphilis is clean and painless, with a hard base. Mixed sexually transmitted disease is very common (including syphilis, herpes simplex, and HIV infection), as is infection of the ulcer with fusiforms, spirochetes, and other organisms.

A single dose of either azithromycin, 1 g orally, or ceftriaxone, 250 mg intramuscularly, is effective treatment. Effective multiple-dose regimens are amoxicillin-potassium clavulanate (500/125 mg) three times a day orally for 7 days, erythromycin, 500 mg orally four times a day for 7 days, or ciprofloxacin, 500 mg orally twice a day for 3 days.

Granuloma Inguinale

Granuloma inguinale is a chronic, relapsing granulomatous anogenital infection due to Calymmatobacterium (Donovania) granulomatis. The pathognomonic cell, found in tissue scrapings or secretions, is large (25–90 mcm) and contains intracytoplasmic cysts filled with bodies (Donovan bodies) that stain deeply with Wright's stain.

The incubation period is 8 days to 12 weeks. The onset is insidious. The lesions occur on the skin or mucous membranes of the genitalia or perineal area. They are relatively painless infiltrated nodules that soon slough. A shallow, sharply demarcated ulcer forms, with a beefy-red friable base of granulation tissue. The lesion spreads by contiguity. The advancing border has a characteristic rolled edge of granulation tissue. Large ulcerations may advance onto the lower abdomen and thighs. Scar formation and healing occur along one border while the opposite border advances.

Superinfection with spirochete-fusiform organisms is common. The ulcer then becomes purulent, painful, foul-smelling, and extremely difficult to treat.

Several therapies are available. Because of the indolent nature of the disease, duration of therapy is relatively long. Erythromycin or tetracycline, 500 mg orally four times a day for 21 days, is effective. Ampicillin, 500 mg orally four times a day, is an alternative, but up to 12 weeks of therapy may be necessary.

Bartonella Species

A revised classification of the α2 subdivision of proteobacteria has grouped the species previously known as Rochalimaea as members of the Bartonellae based on ribosomal RNA. These organisms are responsible for a

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wide variety of clinical syndromes. Bacillary angiomatosis, an important manifestation of bartonellosis, is discussed in Chapter 31. A variety of atypical infections, including retinitis, encephalitis, osteomyelitis, and persistent bacteremia and endocarditis have been described.

Trench fever is a self-limited, louse-borne relapsing febrile disease caused by B quintana. The disease has occurred epidemically in louse-infested troops and civilians during wars and endemically in residents of scattered geographic areas (eg, Central America). An urban equivalent of trench fever has been described among the homeless. Humans acquire infection when infected lice feces enter sites of skin breakdown. Onset of symptoms is abrupt and fever lasts 3–5 days, with relapses. The patient complains of weakness and severe pain behind the eyes and typically in the back and legs. Lymphadenopathy, splenomegaly, and a transient maculopapular rash may appear. Subclinical infection is frequent, and a carrier state is recognized. The differential diagnosis includes other febrile, self-limited states such as dengue, leptospirosis, malaria, relapsing fever, and typhus. Recovery occurs regularly even in the absence of treatment.

Cat-scratch disease is an acute infection of children and young adults caused by Bartonella henselae. It is transmitted from cats to humans as the result of a scratch or bite. Within a few days, a papule or ulcer will develop at the inoculation site in one-third of patients. One to 3 weeks later, fever, headache, and malaise occur. Regional lymph nodes become enlarged, often tender, and may suppurate. Lymphadenopathy from cat scratches resembles that due to neoplasm, tuberculosis, lymphogranuloma venereum, and bacterial lymphadenitis. The diagnosis is usually made clinically. Special cultures for bartonellae, serology, or excisional biopsy, though rarely necessary, confirm the diagnosis. The biopsy reveals necrotizing lymphadenitis and is itself not specific for cat-scratch disease. Cat-scratch disease is usually self-limited, requiring no specific therapy. Encephalitis occurs rarely.

Disseminated forms of the disease—bacillary angiomatosis and peliosis hepatis—occur in HIV-infected persons. The lesions are vasculoproliferative and histopathologically distinct from those of cat-scratch disease. Unexplained fever in patients with late stages of HIV infection is not uncommonly due to bartonellosis. B quintana, the agent of trench fever, can also cause bacillary angiomatosis and persistent bacteremia or endocarditis (which will be “culture-negative” unless specifically sought), the latter two entities being associated with homelessness. Bacillary angiomatosis responds to treatment with a macrolide or doxycycline administered in standard doses for 4–8 weeks. Bacteremia and endocarditis can be effectively treated with a 4-week course of doxycycline (200 mg orally per day) for 4 weeks plus gentamicin 3 mg/kg/d intravenously for the first 2 weeks. Survival may be improved by the addition of gentamicin to the regimen. Relapse may occur.

Foucault C et al: Randomized open trial of gentamicin and doxycycline for eradication of Bartonella quintana from blood in patients with chronic bacteremia. Antimicrob Agents Chemother 2003;47:2204.

Koehler JE et al: Prevalence of Bartonella infection among human immunodeficiency virus-infected patients with fever. Clin Infect Dis 2003;37:559.

Anaerobic Infections

Anaerobic bacteria comprise the majority of normal human flora. Normal microbial flora of the mouth (anaerobic spirochetes, prevotella, fusobacteria), the skin (anaerobic diphtheroids), the large bowel (bacteroides, anaerobic streptococci, clostridia), and the female tract (bacteroides, anaerobic streptococci, fusobacteria) produce disease when displaced from their normal sites into tissues or closed body spaces.

Anaerobic infections tend to be polymicrobial and abscesses are common. Pus and infected tissue often are malodorous. Septic thrombophlebitis and metastatic infection are frequent and may require incision and drainage. Diminished blood supply that favors proliferation of anaerobes because of reduced tissue oxygenation may interfere with the delivery of antimicrobials to the site of anaerobic infection. Cultures unless carefully collected under anaerobic conditions may yield negative results.

Important types of infections that are most commonly caused by anaerobic organisms are listed below. Treatment of all these infections consists of surgical exploration and judicious excision in conjunction with administration of antimicrobial drugs.

Upper Respiratory Tract

Prevotella melaninogenica (formerly Bacteroides melaninogenicus) and anaerobic spirochetes are commonly involved in periodontal infections. These organisms, fusobacteria, and peptostreptococci may cause chronic sinusitis, peritonsillar abscess, chronic otitis media, and mastoiditis. Hygiene, drainage, and surgical debridement are as important in treatment as antimicrobials. Oral anaerobic organisms have been uniformly susceptible to penicillin, but there has been a recent trend of increasing penicillin resistance, usually due to β-lactamase production. Penicillin, 1–2 million units intravenously every 4 hours (if parenteral therapy is required) or 0.5 g orally four times daily for less severe infections, or clindamycin can be used (600 mg intravenously every 8 hours or 300 mg orally every 6 hours). Antimicrobial treatment is continued for a few days after signs and symptoms of infection have resolved. Indolent, established infections (eg, mastoiditis or osteomyelitis) may require prolonged courses of therapy, eg, 4–6 weeks or longer.

Chest Infections

Usually in the setting of poor oral hygiene and periodontal disease, aspiration of saliva (which contains

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108 anaerobic organisms per milliliter in addition to aerobes) may lead to necrotizing pneumonia, lung abscess, and empyema. While polymicrobial infection is the rule, anaerobes—particularly P melaninogenica, fusobacteria, and peptostreptococci—are common etiologic agents. Most pulmonary infections respond to antimicrobial therapy alone. Percutaneous chest tube or surgical drainage is indicated for empyema.

Penicillin-resistant Bacteroides fragilis and P melaninogenica are commonly isolated and have been associated with clinical failures. Clindamycin, 600 mg intravenously once, followed by 300 mg orally every 6–8 hours, is the treatment of choice for these infections. Penicillin, 2 million units intravenously every 4 hours, followed by amoxicillin, 500 mg every 8 hours orally, is a reasonable alternative. Metronidazole does not cover facultative streptococci, which often are present. These infections respond slowly. A duration of 3–4 weeks or more of antimicrobial therapy is typical. The second-generation cephalosporins cefoxitin, cefotetan, and cefmetazole are active in vitro against anaerobes, including those that are penicillin-resistant.

Central Nervous System

Anaerobes are a common cause of brain abscess, subdural empyema, or septic central nervous system thrombophlebitis. The organisms reach the central nervous system by direct extension from sinusitis, otitis, or mastoiditis or by hematogenous spread from chronic lung infections. Antimicrobial therapy—eg, penicillin, 20 million units intravenously, in combination with metronidazole, 750 mg intravenously, every 8 hours—is an important adjunct to surgical drainage. Duration of therapy is 6–8 weeks. Some small multiple brain abscesses can be treated with antibiotics alone without surgical drainage. Alternatively, septic internal jugular thrombophlebitis (Lemierre's syndrome) originates from mouth anaerobes and may cause septic pulmonary embolization. Severe sore throat is a concomitant.

Intra-abdominal Infections

In the colon there are up to 1011 anaerobes per gram of content—predominantly B fragilis, clostridia, and peptostreptococci. These organisms play a central role in most intra-abdominal abscesses following trauma to the colon, diverticulitis, appendicitis, or perirectal abscess and may also participate in hepatic abscess and cholecystitis, often in association with aerobic coliform bacteria. The gallbladder wall can be infected with clostridia as well. The bacteriology includes anaerobes as well as enteric gram-negative rods and on occasion enterococci. Therapy should be directed both against anaerobes and gram-negative aerobes. Agents that are reliably active against B fragilis include metronidazole, chloramphenicol, imipenem, ampicillin-sulbactam, ticarcillin-clavulanic acid, and piperacillin-tazobactam. Resistance to cefoxitin, cefotetan, and clindamycin is increasingly encountered. Most third-generation cephalosporins have poor efficacy. Non-fragilis species of bacteroides may be less susceptible to the cephalosporins.

Table 33-6. Treatment of anaerobic intra-abdominal infections.

Oral therapy
   Moxifloxacin 400 mg every 24 hours
Intravenous therapy
   Moderate to moderately severe infections:
      Ertapenem 1 g every 24 hours
         or—
      Cefotetan, 2 g every 12 hours
         or—
      Moxifloxacin 400 mg every 24 hours
   Severe infections:
      Imipenem, 0.5 g every 6-8 hours; or ceftriaxone, 1 g every 24 hours, plus metronidazole, 500 mg every 8 hours; or piperacillin/tazobactam 4.5 g every 8 hours.

Table 33-6 summarizes the antibiotic regimens for management of moderate to moderately severe infections (eg, patient hemodynamically stable, good surgical drainage possible or established, low APACHE score, no multiple organ failure) and severe infections (eg, major peritoneal soilage, large or multiple abscesses, patient hemodynamically unstable), particularly if drug-resistant organisms are suspected. An effective oral regimen for patients able to take it is presented also.

Female Genital Tract & Pelvic Infections

The normal flora of the vagina and cervix includes several species of bacteroides, peptostreptococci, group B streptococci, lactobacilli, coliform bacteria, and, occasionally, spirochetes and clostridia. These organisms commonly cause genital tract infections and may disseminate from there.

While salpingitis is often caused by gonococci and chlamydiae, tubo-ovarian and pelvic abscesses are associated with anaerobes in most cases. Postpartum infections may be caused by aerobic streptococci or staphylococci, but anaerobes are often found, and the worst cases of postpartum or postabortion sepsis are associated with clostridia and bacteroides. These have a high mortality rate, and treatment requires both antimicrobials directed against anaerobes and coliforms (see above) and abscess drainage or early hysterectomy.

Bacteremia & Endocarditis

Anaerobic bacteremia usually originates from the gastrointestinal tract, the oropharynx, decubitus ulcers, or the female genital tract. Endocarditis due to anaerobic and microaerophilic streptococci and bacteroides originates from the same sites. Most cases of anaerobic or microaerophilic streptococcal endocarditis can be effectively

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treated with 12–20 million units of penicillin G daily for 4–6 weeks, but optimal therapy of other types of anaerobic bacterial endocarditis must rely on laboratory guidance. Anaerobic corynebacteria (propionibacteria), clostridia, and bacteroides occasionally cause endocarditis.

Skin & Soft Tissue Infections

Anaerobic infections in the skin and soft tissue usually follow trauma, inadequate blood supply, or surgery and are most common in areas that are contaminated by oral or fecal flora. These infections also occur in injection drug users and persons sustaining animal to human bites. There may be progressive tissue necrosis and a putrid odor.

Several terms, such as bacterial synergistic gangrene, synergistic necrotizing cellulitis, necrotizing fasciitis, and nonclostridial crepitant cellulitis, have been used to classify these infections. Although there are some differences in microbiology among them, their differentiation on clinical grounds alone is difficult. All are mixed infections caused by aerobic and anaerobic organisms and require aggressive surgical debridement of necrotic tissue for cure. Surgical consultation is obligatory to assist in diagnosis and treatment.

Broad-spectrum antibiotics active against both anaerobes and gram-positive and gram-negative aerobes (eg, vancomycin plus piperacillin-tazobactam or ceftriaxone plus metronidazole) should be instituted empirically and modified by culture results (see Table 37-2). They are given for about a week after progressive tissue destruction has been controlled and the margins of the wound remain free of inflammation.

Talan DA et al: Clinical presentation and bacteriologic analysis of infected human bites in patients presenting to emergency departments. Clin Infect Dis 2003;37:1481.

Actinomycosis

Essentials of Diagnosis

  • History of recent dental infection or abdominal trauma.

  • Chronic pneumonia or indolent intra-abdominal or cervicofacial abscess.

  • Sinus tract formation.

General Considerations

Actinomyces israelii and other species of Actinomyces occur in the normal flora of the mouth and tonsillar crypts. They are anaerobic, gram-positive, branching filamentous bacteria (1 mcm in diameter) that may fragment into bacillary forms. When introduced into traumatized tissue and associated with other anaerobic bacteria, these actinomycetes become pathogens.

The most common site of infection is the cervicofacial area (about 60% of cases). Infection typically follows extraction of a tooth or other trauma. Lesions may develop in the gastrointestinal tract or lungs following ingestion or aspiration of the organism from its endogenous source in the mouth. Interestingly, T whippelii, the causative agent of Whipple's disease, is an actinomycete and therefore is related to the species that cause actinomycosis.

Clinical Findings

A. Symptoms and Signs

1. Cervicofacial actinomycosis

Cervicofacial actinomycosis develops slowly. The area becomes markedly indurated, and the overlying skin becomes reddish or cyanotic. Abscesses eventually draining to the surface persist for long periods. Sulfur granules—masses of filamentous organisms—may be found in the pus. There is usually little pain unless there is secondary infection. Trismus indicates that the muscles of mastication are involved. Radiography may reveal bony involvement.

2. Thoracic actinomycosis

Thoracic involvement begins with fever, cough, and sputum production with night sweats and weight loss. Pleuritic pain may be present. Multiple sinuses may extend through the chest wall, to the heart, or into the abdominal cavity. Ribs may be involved. Radiography shows areas of consolidation and in many cases pleural effusion. Cervicofacial or thoracic disease may occasionally involve the central nervous system, most commonly brain abscess or meningitis.

3. Abdominal actinomycosis

Abdominal actinomycosis usually causes pain in the ileocecal region, spiking fever and chills, vomiting, and weight loss; it may be confused with Crohn's disease. Irregular abdominal masses may be palpated. Pelvic inflammatory disease caused by actinomycetes has been associated with prolonged use of an intrauterine contraceptive device. Sinuses draining to the exterior may develop. CT scanning reveals an inflammatory mass extended to involve bone.

B. Laboratory Findings

The anaerobic, gram-positive organism may be demonstrated as a granule or as scattered branching gram-positive filaments in the pus. Anaerobic culture is necessary to distinguish actinomycetes from nocardiae because specific therapy differs for the two infections.

Treatment

Penicillin G is the drug of choice. Ten to 20 million units are given via a parenteral route for 4–6 weeks, followed by oral penicillin V, 500 mg four times daily. Alternatives include ampicillin, 12 g/d intravenously

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for 4–6 weeks followed by oral amoxicillin 500 mg three times daily. Response to therapy is slow. Therapy should be continued for weeks to months after clinical manifestations have disappeared in order to ensure cure. Surgical procedures such as drainage and resection may be beneficial.

With penicillin and surgery, the prognosis is good. The difficulties of diagnosis, however, may permit extensive destruction of tissue before the diagnosis is identified and therapy is started.

Sudhakar SS et al: Short-term treatment of actinomycosis: two cases and a review. Clin Infect Dis 2004;38:444.

Wagenlehner FM et al: Abdominal actinomycosis. Clin Microbiol Infect 2003;9:881.

Nocardiosis

Nocardia asteroides, an aerobic filamentous soil bacterium, causes pulmonary and systemic nocardiosis. Bronchopulmonary abnormalities (eg, alveolar proteinosis) predispose to colonization, but infection is unusual unless the patient is also receiving systemic corticosteroids or is otherwise immunosuppressed.

Pulmonary involvement usually begins with malaise, loss of weight, fever, and night sweats. Cough and production of purulent sputum are the chief complaints. Radiography may show infiltrates accompanied by pleural effusion. The lesions may penetrate to the exterior through the chest wall, invading the ribs.

Dissemination involves any organ. Brain abscesses and subcutaneous nodules are most frequent. This is seen exclusively in immunocompromised patients.

N asteroides is usually found as delicate, branching, gram-positive filaments. It may be weakly acid-fast, occasionally causing diagnostic confusion with tuberculosis. Identification is made by culture.

Therapy is initiated with intravenous trimethoprim-sulfamethoxazole administered at a dosage of 5–10 mg/kg/d (trimethoprim) and continued with oral trimethoprim-sulfamethoxazole, one double-strength tablet twice a day. Surgical procedures such as drainage and resection may be needed as adjunctive therapy.

Response may be slow, and therapy must be continued for at least 6 months. The prognosis in systemic nocardiosis is poor when diagnosis and therapy are delayed.

Nocardia brasiliensis typically causes a digital lesion—resembling herpetic whitlow—and ascending lymphangitis in normal hosts. Antimicrobial treatment is as for N asteroides infection, and the prognosis is excellent.

Lederman ER et al: A case series and focused review of nocardiosis: clinical and microbiologic aspects. Medicine (Baltimore) 2004;83:300.

Infections Caused by Mycobacteria

Nontuberculous Atypical Mycobacterial Diseases

About 10% of mycobacterial infections are caused by atypical mycobacteria. Atypical mycobacterial infections are among the most common opportunistic infections in advanced HIV disease. These organisms have distinctive laboratory characteristics, occur ubiquitously in the environment, are not communicable from person to person, and are often resistant to standard antituberculous drugs.

Disseminated Mycobacterium avium Infection

Mycobacterium avium complex (MAC) produces asymptomatic colonization or a wide spectrum of diseases, including coin lesions, bronchitis in patients with chronic lung disease, and invasive pulmonary disease that is often cavitary and occurs in patients with underlying lung disease. MAC causes disseminated disease in the late stages of HIV infection, when the CD4 cell count is less than 50/mcL. Persistent fever and weight loss are the most common symptoms. The organism can usually be cultured from multiple sites, including blood, liver, lymph node, or bone marrow. Blood culture is the preferred means of establishing the diagnosis and has a sensitivity of 98%.

Agents with proved activity against MAC are rifabutin, azithromycin, clarithromycin, and ethambutol. Amikacin and ciprofloxacin work in vitro, but clinical results are inconsistent. A combination of two or more active agents should be used to prevent rapid emergence of secondary resistance. Clarithromycin, 500 mg orally twice daily, plus ethambutol, 15 mg/kg/d orally as a single dose, with or without rifabutin, 300 mg/d orally, is the treatment of choice. Azithromycin, 500 mg orally once daily, may be used instead of clarithromycin. Insufficient data are available to permit specific recommendations about second-line regimens for patients intolerant of macrolides or those with macrolide-resistant organisms. MAC therapy may be discontinued in patients who have been treated with 12 months of therapy for disseminated MAC, who have no evidence of active disease, and whose CD4 counts exceed 100 cells/mcL while receiving highly active antiretroviral therapy (HAART). Antimicrobial prophylaxis of MAC prevents disseminated disease and prolongs survival. It is the standard of care to offer it to all HIV-infected patients with CD4 counts ≤ 50/mcL. In contrast to active infection, single-drug oral regimens of clarithromycin, 500 mg twice daily, azithromycin, 1200 mg once weekly, or rifabutin, 300 mg once daily, are appropriate. Clarithromycin or azithromycin is more effective and better tolerated than rifabutin, and therefore preferred. Primary prophylaxis for MAC infection can be

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stopped in patients who have responded to antiretroviral combination therapy with elevation of CD4 counts above 100 cells/mcL for 3 months.

Pulmonary Infections

MAC causes a chronic, slowly progressive pulmonary infection resembling tuberculosis in immunocompetent patients, who typically have underlying pulmonary disease.

Treatment of immunocompetent patients with pulmonary infection is empiric and based entirely on anecdotal data. A combination of agents is probably best. Rifampin, 600 mg orally once daily, plus ethambutol, 15–25 mg/kg/d orally, plus streptomycin, 1 g intramuscularly three to five times a week for the first 4–6 months, have been used. The role of rifabutin, fluoroquinolones, and the macrolides is not known, but based on their excellent efficacy in immunocompromised AIDS patients, they may actually be more effective than the relatively weak agents traditionally used in immunocompetent patients. Clarithromycin is a very potent drug in the treatment of MAC in AIDS patients. Based on this, inclusion of clarithromycin in the initial treatment regimen of immunocompetent patients is prudent. Therapy is continued for a total of 18–24 months.

Mycobacterium kansasii can produce clinical disease resembling tuberculosis, but the illness progresses more slowly. Most such infections occur in patients with preexisting lung disease, though 40% of patients have no known pulmonary disease. Microbiologically, M kansasii is similar to Mycobacterium tuberculosis and is sensitive to the same drugs except pyrazinamide, to which it is resistant. Therapy with isoniazid, ethambutol, and rifampin for 2 years (or 1 year after sputum conversion) has been successful.

Less common causes of pulmonary disease include Mycobacterium xenopi, Mycobacterium szulgai, and Mycobacterium gordonae. These organisms have variable sensitivities, and treatment is based on results of sensitivity tests. Mycobacterium fortuitum and Mycobacterium chelonei also can cause pneumonia in the occasional patient.

Lymphadenitis

Most cases of lymphadenitis (scrofula) in adults are caused by M tuberculosis and can be a manifestation of disseminated disease. In children, the majority of cases are due to nontuberculous mycobacterial species, with Mycobacterium scrofulaceum and MAC being the most common. M kansasii, Mycobacterium bovis, M chelonei, and M fortuitum are less commonly observed. Unlike disease caused by M tuberculosis, which requires systemic therapy for 6 months, infection with nontuberculous mycobacteria can be successfully treated by surgical excision without antituberculous therapy.

Skin & Soft Tissue Infections

Skin and soft tissue infections such as abscesses, septic arthritis, and osteomyelitis can result from direct inoculation or hematogenous dissemination or may occur as a complication of surgery.

M chelonei and M fortuitum are frequent causes of this type of infection. Most cases occur in the extremities and initially present as nodules. Ulceration with abscess formation often follows. The organisms are resistant to the usual antituberculous drugs but may be sensitive to a variety of antibiotics, including erythromycin, doxycycline, amikacin, cefoxitin, sulfonamides, imipenem, and ciprofloxacin. Therapy includes surgical debridement along with drug therapy. Initially, parenteral drugs are given for several weeks, and this is followed by an oral regimen to which the organism is sensitive. The duration of therapy is variable but usually continues for several months after the soft tissue lesions have healed.

Mycobacterium marinum infection (“swimming pool granuloma”) presents as a nodular skin lesion following exposure to nonchlorinated water. The lesions respond to therapy with doxycycline, minocycline, or trimethoprim-sulfamethoxazole.

Mycobacterium ulcerans infection (Buruli ulcer) is seen mainly in Africa and Australia and produces a large ulcerative lesion. Therapy consists of surgical excision and skin grafting.

Kaplan JE et al: Guidelines for preventing opportunistic infections among HIV-infected persons—2002. Recommendations of the U.S. Public Health Service and the Infectious Diseases Society of America. MMWR Recomm Rep 2002;51(RR-8):1.

Karakousis PC et al: Mycobacterium avium complex in patients with HIV infection in the era of highly active antiretroviral therapy. Lancet Infect Dis 2004;4:557.

Mycobacterium Tuberculosis Infections

Tuberculosis is discussed in Chapter 9. Further information and expert consultation can be obtained from the Francis J. Curry National Tuberculosis Center at the Web site http://www.nationaltbcenter.edu or, by phone, 415–502-4600, or fax, 415–502-4620.

Tuberculous Meningitis

Essentials of Diagnosis

  • Gradual onset of listlessness, irritability, and anorexia.

  • Headache, vomiting, and seizures common.

  • Cranial nerve abnormalities typical.

  • Tuberculosis focus may be evident elsewhere.

  • Cerebrospinal fluid shows several hundred lymphocytes, low glucose, and high protein.

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General Considerations

Tuberculous meningitis is caused by rupture of a meningeal tuberculoma resulting from earlier hematogenous seeding of tubercle bacilli from a pulmonary focus, or it may be a consequence of miliary spread.

Clinical Findings

A. Symptoms and Signs

The onset is usually gradual, with listlessness, irritability, anorexia, and fever, followed by headache, vomiting, convulsions, and coma. In older patients, headache and behavioral changes are prominent early symptoms. Nuchal rigidity and cranial nerve palsies occur as the meningitis progresses. Evidence of active tuberculosis elsewhere or a history of prior tuberculosis is present in up to 75% of patients.

B. Laboratory Findings

The spinal fluid is frequently yellowish, with increased pressure, 100–500 cells/mcL (predominantly lymphocytes, though neutrophils may be present early during infection), increased protein, and decreased glucose. Acid-fast stains of cerebrospinal fluid usually are negative, and cultures also may be negative in 15–25% of cases. Nucleic acid amplification tests for rapid diagnosis of tuberculosis have variable sensitivity and specificity and none are FDA-approved for use in meningitis. Chest x-ray often reveals abnormalities compatible with tuberculosis but may be normal.

Differential Diagnosis

Tuberculous meningitis may be confused with any other type of meningitis, but the gradual onset, the predominantly lymphocytic pleocytosis of the spinal fluid, and evidence of tuberculosis elsewhere often point to the diagnosis. The tuberculin skin test is usually (not always) positive. Fungal and other granulomatous meningitides, syphilis, and carcinomatous meningitis are in the differential diagnosis.

Complications

Complications of tuberculous meningitis include seizure disorders, cranial nerve palsies, stroke, and obstructive hydrocephalus with impaired cognitive function. These result from inflammatory exudate primarily involving the basilar meninges and arteries.

Treatment

Presumptive diagnosis followed by early, empiric antituberculous therapy is essential for survival and to minimize sequelae. Even if cultures are not positive, a full course of therapy is warranted if the clinical setting is suggestive of tuberculous meningitis.

Regimens that are effective for pulmonary tuberculosis are effective also for tuberculous meningitis (see Table 9-14). Rifampin, isoniazid, and pyrazinamide all penetrate into cerebrospinal fluid well. The penetration of ethambutol is more variable, but therapeutic concentrations can be achieved, and the drug has been successfully used for meningitis. Aminoglycosides penetrate less well. Regimens that do not include both isoniazid and rifampin may be effective but are less reliable and generally must be given for longer periods.

Some authorities recommend the addition of corticosteroids for patients with focal deficits or altered mental status. Dexamethasone, 0.15 mg/kg intravenously or orally four times daily for 1–2 weeks, then discontinued in a tapering regimen over 4 weeks, may be used.

Johansen IS et al: Improved sensitivity of nucleic acid amplification for rapid diagnosis of tuberculous meningitis. J Clin Microbiol 2004;42:3036.

Thwaites GE et al: Diagnosis of adult tuberculous meningitis by use of clinical and laboratory features. Lancet 2002;360:1287.

Leprosy

Essentials of Diagnosis

  • Pale, anesthetic macular—or nodular and erythematous—skin lesions.

  • Superficial nerve thickening with associated anesthesia.

  • History of residence in endemic area in childhood.

  • Acid-fast bacilli in skin lesions or nasal scrapings, or characteristic histologic nerve changes.

General Considerations

Leprosy is a chronic infectious disease caused by the acid-fast rod Mycobacterium leprae. The mode of transmission probably is respiratory and involves prolonged exposure in childhood. The disease is endemic in tropical and subtropical Asia, Africa, Central and South America, and the Pacific regions, and rarely seen sporadically in the southern United States.

Clinical Findings

A. Symptoms and Signs

The onset is insidious. The lesions involve the cooler body tissues: skin, superficial nerves, nose, pharynx, larynx, eyes, and testicles. Skin lesions may occur as pale, anesthetic macular lesions 1–10 cm in diameter; discrete erythematous, infiltrated nodules 1–5 cm in diameter; or diffuse skin infiltration. Neurologic disturbances are caused by nerve infiltration and thickening, with resultant anesthesia, and motor abnormalities. Bilateral ulnar neuropathy is highly suggestive. In

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untreated cases, disfigurement due to the skin infiltration and nerve involvement may be extreme, leading to trophic ulcers, bone resorption, and loss of digits.

The disease is divided clinically and by laboratory tests into two distinct types: lepromatous and tuberculoid. The lepromatous type occurs in persons with defective cellular immunity. The course is progressive and malignant, with nodular skin lesions; slow, symmetric nerve involvement; abundant acid-fast bacilli in the skin lesions; and a negative lepromin skin test. In the tuberculoid type, cellular immunity is intact and the course is more benign and less progressive, with macular skin lesions, severe asymmetric nerve involvement of sudden onset with few bacilli present in the lesions, and a positive lepromin skin test. Intermediate (“borderline”) cases are frequent. Eye involvement (keratitis and iridocyclitis), nasal ulcers, epistaxis, anemia, and lymphadenopathy may occur.

B. Laboratory Findings

Laboratory confirmation of leprosy requires the demonstration of acid-fast bacilli in a skin biopsy. Biopsy of skin or of a thickened involved nerve also gives a typical histologic picture. M leprae does not grow in artificial media but does grow in the foot pads of armadillos.

Differential Diagnosis

The skin lesions of leprosy often resemble those of lupus erythematosus, sarcoidosis, syphilis, erythema nodosum, erythema multiforme, cutaneous tuberculosis, and vitiligo.

Complications

Renal failure and hepatomegaly from secondary amyloidosis may occur with longstanding disease.

Treatment

Combination therapy is recommended for treatment of all types of leprosy. Single-drug treatment is accompanied by emergence of resistance, and primary resistance to dapsone also occurs. For borderline and lepromatous cases, a three-drug regimen such as dapsone, 50–100 mg/d, clofazimine, 50 mg/d, and rifampin, 10 mg/kg/d (up to 600 mg/d), all given orally, should be used. The triple-drug combination should be administered for a minimum of 2–3 years and, ideally, until all biopsies are negative for acid-fast bacilli. For indeterminate and tuberculoid leprosy, the dapsone-rifampin combination is recommended for 6–12 months, often followed by a course of dapsone alone for 2 or more years.

Two reactional states—erythema nodosum leprosum and reversal reactions—may occur as a consequence of therapy. The reversal reaction, typical of borderline lepromatous leprosy, probably results from enhanced host immunity. Skin lesions and nerves become swollen and tender, but systemic manifestations are not seen. Erythema nodosum leprosum, typical of lepromatous leprosy, is a consequence of immune injury from antigen-antibody complex deposition in skin and other tissues; in addition to skin and nerve manifestations, fever and systemic involvement may be seen. Prednisone, 60 mg/d orally, or thalidomide, 300 mg/d orally (in the nonpregnant patient only), is effective for erythema nodosum leprosum. Improvement is expected within a few days after initiating prednisone, and thereafter the dose may be tapered over several weeks to avoid recurrence. Thalidomide is also tapered over several weeks to a 100-mg bedtime dose. Erythema nodosum leprosum is usually confined to the first year of therapy, and prednisone or thalidomide can be discontinued. Thalidomide is ineffective for reversal reactions, and prednisone, 60 mg/d, is indicated. Reversal reactions tend to recur, and the dose of prednisone should be slowly tapered over weeks to months. Therapy for leprosy should not be discontinued during treatment of reactional states.

Britton WJ et al: Leprosy. Lancet 2004;363:1209.

Infections Caused by Chlamydiae

Chlamydiae are a large group of obligate intracellular parasites closely related to gram-negative bacteria. They are assigned to three species—C trachomatis, Chlamydia psittaci, and Chlamydia pneumoniae—on the basis of intracellular inclusions, sulfonamide susceptibility, antigenic composition, and disease production. C trachomatis causes many different human infections involving the eye (trachoma, inclusion conjunctivitis), the genital tract (lymphogranuloma venereum, nongonococcal urethritis, cervicitis, salpingitis), or the respiratory tract (pneumonitis). C psittaci causes psittacosis in humans and many animal diseases. C pneumoniae has recently been recognized as a cause of respiratory tract infections.

Chlamydia Trachomatis Infections

1. Lymphogranuloma Venereum

Essentials of Diagnosis

  • Evanescent primary genital lesion.

  • Lymph node enlargement, softening, and suppuration, with draining sinuses.

  • Proctitis and rectal stricture in women or homosexual men.

  • Positive complement fixation test.

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General Considerations

Lymphogranuloma venereum is an acute and chronic sexually transmitted disease caused by C trachomatis types L1-L3. The disease is acquired during intercourse or through contact with contaminated exudate from active lesions. The incubation period is 5–21 days. After the genital lesion disappears, the infection spreads to lymph channels and lymph nodes of the genital and rectal areas. Inapparent infections and latent disease are not uncommon.

Clinical Findings

A. Symptoms and Signs

In men, the initial vesicular or ulcerative lesion (on the external genitalia) is evanescent and often goes unnoticed. Inguinal buboes appear 1–4 weeks after exposure, are often bilateral, and have a tendency to fuse, soften, and break down to form multiple draining sinuses, with extensive scarring. In women, the genital lymph drainage is to the perirectal glands. Early anorectal manifestations are proctitis with tenesmus and bloody purulent discharge; late manifestations are chronic cicatrizing inflammation of the rectal and perirectal tissue. These changes lead to obstipation and rectal stricture and, occasionally, rectovaginal and perianal fistulas. They are also seen in homosexual men.

B. Laboratory Findings

The complement fixation test may be positive, but cross-reaction with other chlamydiae occurs. Although a positive reaction may reflect remote infection, high titers usually indicate active disease. Specific immunofluorescence tests for IgM are more specific for acute infection.

Differential Diagnosis

The early lesion of lymphogranuloma venereum must be differentiated from the lesions of syphilis, genital herpes, and chancroid; lymph node involvement must be distinguished from that due to tularemia, tuberculosis, plague, neoplasm, or pyogenic infection; and rectal stricture must be distinguished from that due to neoplasm and ulcerative colitis.

Treatment

The antibiotic of choice is doxycycline (contraindicated in pregnancy), 100 mg orally twice daily for 21 days. Erythromycin, 500 mg four times a day for 21 days, is also effective.

2. Chlamydial Urethritis & Cervicitis

C trachomatis immunotypes D-K are isolated in about 50% of cases of nongonococcal urethritis and cervicitis by appropriate techniques. In other cases, Ureaplasma urealyticum can be grown as a possible etiologic agent. C trachomatis is an important cause of postgonococcal urethritis. Coinfection with gonococci and chlamydiae is common, and postgonococcal (ie, chlamydial) urethritis may persist after successful treatment of the gonococcal component. Occasionally, epididymitis, prostatitis, or proctitis is caused by chlamydial infection.

Females infected with chlamydiae may be asymptomatic or may have signs and symptoms of cervicitis, salpingitis, or pelvic inflammatory disease. Chlamydiae are a leading cause of infertility in females in the United States.

The diagnosis of chlamydial infection has been clinical because C trachomatis is difficult and expensive to culture. The urethral or cervical discharge tends to be less painful, less purulent, and watery in chlamydial versus gonococcal infection. A patient with urethritis or cervicitis and absence of gram-negative diplococci on Gram stain and of N gonorrhoeae on culture is assumed to have chlamydial infection. Direct immunofluorescence assay, enzyme-linked immunoassay, and a DNA probe test, although less sensitive than culture, are sometimes used to confirm the diagnosis and for screening. The ligase chain reaction (LCR) test for C trachomatis has superior sensitivity compared with all other methods (eg, sensitivity of 60–70% for DNA probe versus 90–95% for LCR). LCR also has excellent specificity, approaching 100%, and it can be performed on urine. For these reasons, it will probably replace all other methods for diagnosis of chlamydial urethritis and cervicitis.

Therapy often must be given presumptively. Sexual partners of infected patients should also be treated. Recommended regimens are a single oral 1-g dose of azithromycin or 100 mg of doxycycline orally for 7 days (contraindicated in pregnancy). Erythromycin, 500 mg (not the estolate form, which is contraindicated) orally four times a day for 7 days, is recommended for the pregnant patient, although the 1-g dose of azithromycin is also safe and appears to be effective. As for all sexually transmitted diseases, studies for HIV and syphilis should be performed.

Sexually transmitted diseases treatment guidelines 2002. Centers for Disease Control and Prevention. MMWR Recomm Rep 2002;51(RR-6):1.

Chlamydia Psittaci & Psittacosis (Ornithosis)

Essentials of Diagnosis

  • Fever, chills, and cough; headache common.

  • Atypical pneumonia with slightly delayed appearance of signs of pneumonitis.

  • Contact with infected bird (psittacine, pigeons, many others) 7–15 days previously.

  • Isolation of chlamydiae or rising titer of complement-fixing antibodies.

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General Considerations

Psittacosis is acquired from contact with birds (parrots, parakeets, pigeons, chickens, ducks, and many others), which may or may not be ill. The history may be difficult to obtain if the patient acquired infection from an illegally imported bird.

Clinical Findings

The onset is usually rapid, with fever, chills, myalgia, dry cough, and headache. Signs include temperature-pulse dissociation, dullness to percussion, and rales. Pulmonary findings may be absent early. Dyspnea and cyanosis may occur later. Endocarditis, which is culture-negative, may occur. The radiographic findings in typical psittacosis are those of atypical pneumonia, which tends to be interstitial and diffuse in appearance, though consolidation can occur. Psittacosis is indistinguishable from other bacterial or viral pneumonias by radiography.

The organism is rarely isolated from cultures. The diagnosis is usually made serologically; antibodies appear during the second week and can be demonstrated by complement fixation or immunofluorescence. Antibody response may be suppressed by early chemotherapy.

Differential Diagnosis

The illness is indistinguishable from viral, mycoplasmal, or other atypical pneumonias except for the history of contact with birds. Psittacosis is in the differential diagnosis of culture-negative endocarditis.

Treatment

Treatment consists of giving tetracycline, 0.5 g orally every 6 hours or 0.5 g intravenously every 12 hours, for 14–21 days. Erythromycin may be effective as well.

Chlamydia Pneumoniae Infection

C pneumoniae causes pneumonia and bronchitis and has been associated seroepidemiologically with coronary artery disease. The clinical presentation of pneumonia is that of an atypical pneumonia. The organism accounts for approximately 10% of community-acquired pneumonias, ranking second to mycoplasma as an agent of atypical pneumonia. Its putative role in coronary artery disease remains to be defined.

Like C psittaci, strains of C pneumoniae are resistant to sulfonamides. Erythromycin or tetracycline, 500 mg orally four times a day for 10–14 days, appears to be effective therapy. Fluoroquinolones such as levofloxacin or trovafloxacin are active in vitro against C pneumoniae and probably are effective clinically. The oral dose of levofloxacin is 500 mg once a day for 10–14 days.

Kalayoglu MV et al: Chlamydia pneumoniae as an emerging risk factor in cardiovascular disease. JAMA 2002;288:2724.