28 - Infections - Etiology, Treatment, and Prevention

Editors: Skeel, Roland T.

Title: Handbook of Cancer Chemotherapy, 7th Edition

> Table of Contents > Section IV - Selected Aspects of Supportive Care of Patients with Cancer > Chapter 28 - Infections: Etiology, Treatment, and Prevention

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Chapter 28

Infections: Etiology, Treatment, and Prevention

Joan M. Duggan

Infections in patients with cancer that are commonly seen by the practicing oncologist can be associated with significant morbidity and mortality. For example, infection occurs in more than 50% of patients undergoing aggressive chemotherapy for acute leukemia. The keys to successful management of infection in the oncology patient are an understanding of the risk factors for infection and the commonly associated etiologic agents, institution of a thorough and prompt diagnostic work-up guided by the most likely etiology, and early institution of appropriate antibiotic therapy. In general, most bacterial and fungal infections seen in oncology patients develop from the patient's own endogenous flora, especially in the presence of neutropenia.

I. Etiology of infections in patients with cancer

A. General considerations

Patients with cancer are immunocompromised hosts for a variety of reasons. The underlying malignancy may damage the immune system directly or indirectly, or the treatments for the malignancy may result in neutropenia or other alterations in white blood cell (WBC) function (e.g., decreased cell-mediated immunity). Clinical changes accompanying cancer and its treatment, such as protein malnutrition or mucositis, may change immune system function as well. It is important to understand the major etiologic agents associated with the wide variety of immune system defects seen in patients with cancer for proper diagnosis and treatment. Common organisms that are associated with each of the etiologic categories are shown in Table 28.1.

B. Neutropenia

Neutropenia is generally defined as a neutrophil count of less than 500 neutrophils/ L or less than 1,000 L total WBCs. Patients with neutropenia develop infections most commonly from endogenous bacteria and fungi in the gastrointestinal (GI) tract or from indwelling intravascular access devices.

C. Altered cellular immunity

Prolonged steroid use, purine analogs (such as fludarabine), protein malnutrition, and hematopoietic stem cell transplant (HSCT) are some of the factors that can decrease cell-mediated immunity (CMI). In addition, certain malignancies such as Hodgkin's lymphoma have intrinsic abnormalities in CMI. Risk of infections from microbes controlled by CMI may increase when the CD4 cell count ( T-helper cell ) falls below 200 cells/ L. These organisms are usually opportunistic pathogens. However, because CD4 cell function may be abnormal at higher counts in oncology patients, opportunistic infections can also occur at higher CD4 cell counts. Intact CMI is required for fully functional humoral immunity as well.

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Table 28.1. Etiology of infection in patients with cancer

Immune System Deficit	Chemotherapeutic Agent	Gram-Positive Bacteria	Gram-Negative Bacteria	Fungi	Others
Neutropenia	Neutropenia 4 weeks Carboplatin, alemtuzumab, alkylating agents, cytarabine, Daunorubicin, Doxorubicin, Etoposide, Fluorouracil, Ifosfamide, methotrexate, Rituximab, vinblastine Neutropenia 4 weeks Busulfan, Carmustine, lomustine, mitomycin, purine analogs, Cladribine	Staphylococcus species (S. aureus, S. epidermidis) Streptococcus (including S. pneumoniae, S. pyogenes, viridans streptococcus), Enterococcus faecalis and E. faecium, Diphtheroids	Pseudomonas species, Enteric gram-negative rods (e.g., Escherichia Klebsiella)	Candida species (C. albicans and C. glabrata, C. krusei, and C. lusitaniae), Aspergillus, Fusarium species, Trichosporon
Decreased cell-mediated immunity (especially CD4 cell count <200/cells /mm³)	Alemtuzumab, corticosteroids, purine analogs	S. pneumoniae, Listeria monocytogenes	Neisseria meningitidis, Salmonella species	Candida, Aspergillus, endemic mycosis (e.g., Histoplasmosis, Coccidioidomycosis), Pneumocystis jiroveci, Cryptococcus neoformans	Mycobacterium (e.g., M. tuberculosis, M. avium complex), HSV, VZV, CMV, Toxoplasmosis
Decreased humoral immunity or functional asplenia	Alkylating agents, corticosteroids, methotrexate rituximab	S. pneumoniae, Haemophilum influenza, S. aureus	E. coli, N. meningitidis C. canimorsus		Malaria, Ehrlichiosis Babesiosis
Nosocomial infections
Indwelling line infections		S. epidermidis, S. aureus, Enterococcus	Gram-negative rods (e.g., Pseudomonas, Klebsiella, E. coli)	Candida species
Urinary tract infections		S. Epidermidis (with Foley), Enterococcus	E. coli, Klebsiella, Proteus, Pseudomonas, Providencia	Candida species (with Foley)
Diarrhea		Clostridium difficile
Surgical site infections (superficial)		S. aureus, S. epidermidis

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D. Altered humoral immunity

Decreased ability to produce opsonizing antibodies can occur through decreased cell-mediated immune system function, use of alkylating agents or from malignancies such as multiple myeloma or chronic lymphocytic leukemia. Common etiologic agents and organisms in patients with altered humoral immunity as shown in Table 28.1.

E. Asplenia

Splenectomy or functional asplenia can increase the risk for infections with encapsulated organisms, especially Streptococcus pneumoniae. Postsplenectomy sepsis can also occur from dog bites with Capnocytophaga canimorsus. Reports of severe infection in asplenic patients have also been described with malaria, babesiosis and ehrlichiosis.

F. Nosocomial infections

Infections acquired after 48 hours in the hospital are defined as nosocomial infections. Some of the more common causes of nosocomial infections and associated etiologic agents are listed below.

Indwelling lines. Long-term venous access catheters can become infected through a variety of mechanisms.
Urinary tract catheter. Any bladder instrumentation increases the risk of urinary tract infections (UTIs) (including intermittent catheterization, indwelling Foley catheters, and suprapubic catheters).
3. Clostridium difficile. Risk factors for C. difficile colitis include prior use of antibiotics, GI surgery, proton pump inhibitors, tube feedings or hyperalimentation, and exposure to C. difficile in the hospital environment (e.g., infected roommate).
Postoperative infections. Surgical site infections can occur at the incision or in the deep tissue/organs involved in surgery. The majority are acquired at the time of surgery. For cases not involving an enteric or mucosal surface, the most common pathogens are S. aureus and Staphylococcus epidermidis. Infections involving viscus or mucosal surfaces are usually polymicrobic, and similar to the microbes normally found in the surrounding area.
Obstruction/necrosis of tissues secondary to the underlying malignancy. Patients with tracheobronchial obstruction are predisposed to infections with oral bacterial flora, such as anaerobes and gram-negative rods. Malignancies with secondary GI obstruction predispose patients to infection with anaerobes, gram-negative rods and gram-positive cocci such as enterococcus. Genitourinary (GU) tract obstruction can result in infection with gram-negative rods, especially unusual or more resistant bacteria.

G. Other sources of infection

Travel. Most infections associated with travel are respiratory tract infections or GI tract infections. Themajority will present within the first month of return from travel. Infections that may be acquired from remote travel and reactivated in the immunocompromised patient with cancer include tuberculosis, endemic fungal infections such as Histoplasmosis, or parasitic infections such as strongyloidiasis.

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Exposure to community-acquired pathogens. Susceptible patients with cancer are at increased risk of infection when exposed to commonly occurring community pathogens such as influenza, pneumococcus, and varicella zoster virus (VZV).
Reactivation of previously latent or asymptomatic infections. Decreased function of the cell-mediated immune system can cause reactivation of previously controlled pathogens. Herpes Simplex virus (HSV) infection and VZV infections (shingles) are common reactivation infections in oncology patients. These viruses can disseminate as well. Other common pathogens that can reactivate with serious systemic infections after clinical latency include cytomegaloviruses infection and tuberculosis.

II. Diagnosis of infections in patients with cancer

A. General overview

Any patient who has cancer and develops fever or other signs and symptoms of infection (such as hypotension, tachypnea, tachycardia, organ system dysfunction, hypothermia, and/or clinical deterioration) requires urgent evaluation and prompt institution of empiric antibiotic therapy directed at the most likely clinical pathogens. Clinicians should have a low threshold for starting broad-spectrum antimicrobial therapy and should not withhold therapy while waiting for the results of diagnostic tests such as blood cultures. The general work-up and therapy should focus on the most likely infectious sources and pathogens for a given clinical scenario. Therefore, the work-up and initial therapy of a patient with fever, cough, and a bronchial obstruction due to lung cancer would be significantly different from that of a patient with febrile neutropenia and an indwelling venous access catheter.

B. Clinical history

The clinical history should be thorough and directed toward discovering underlying risk factors for infection, likely alterations in immune system function, and localizing complaints or changes in clinic status. It is important to note that severe infections in immunocompromised hosts may present with very subtle changes. For example, pneumonia in a neutropenic patient may present with only mild shortness of breath or cough initially. In addition, infections in any organ system can present with nonspecific symptoms such as fever or malaise. All new changes in clinical history should be thoroughly investigated.

Cancer treatment. In addition to knowing the type and extent of malignancy, it is important to know the treatment history as this will impact the presentation and etiology of infection in the patient with cancer.
- Chemotherapeutic agents. Many commonly used chemotherapeutic drugs are cytotoxic, resulting in significant lymphopenia and/or neutropenia. The duration, severity and type of myelosuppression can be related to the type of chemotherapeutic agent, the amount of drug exposure, and the underlying degree of bone marrow involvement (see Table 28.1).
  - CD4/CD8 suppression (cellular immune system suppression). The following chemotherapeutic
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    agents may result in prolonged suppression of the T-helper/suppressor arm of the immune system:
    - Alemtuzumab median duration of neutropenia is 28 days.
    - Corticosteroids significant T-cell function suppression can be seen with dose of equal to or more than 15 mg prednisone/day for equal to or more than 1 month.
    - Purine analogs (cladribine, fludarabine, and pentostatin) may result in CD4 cell count suppression of equal to or more than 200 for several years after therapy.
  - Suppressed B-cell function (altered humoral immunity). The following chemotherapeutic agents may cause suppression of antibody production by B cells:
    - Alkylating agents (cyclophosphamide, chlorambucil, melphalan)
    - Corticosteroids use of greater than 40 mg/day may decrease antibody production
    - Methotrexate
    - Rituximab
Type of malignancy
- Solid tumors. These malignancies can cause significant obstruction in affected tissues, leading to infection behind the obstruction. Postobstructive pneumonias are common in patients with bronchogenic carcinomas, for example. Tissue necrosis secondary to malignancy may also create an area of potential sequestrum, which can become infected during an episode of bacteremia or from translocation of bacteria from a normally nonsterile area to a sterile area. Finally, some solid tumors may mimic an infectious etiology without any microbial involvement, such as the presence of fever and malaise in a patient with renal cell carcinoma.
- Hematologic malignancies. Leukemias and lymphomas result in significant compromise of immune system function through a variety of mechanisms.

C. Clinical evaluation

The clinical examination should be thorough with special emphasis on areas of symptomatology. Like the clinical history, the review of systems and clinical examination can present with subtle or atypical findings in the presence of severe infection. Special attention should be directed to the following areas and potential infectious etiologies.

Review of systems/symptoms of infection
- Head, eyes, ears, nose, and throat (HEENT) changes in vision, ear or sinus tenderness, oral lesions, changes in dentition.
- Lungs cough, shortness of breath, pleuritic chest pain.
- Abdomen difficulty swallowing, abdominal pain, rectal pain, discomfort or pruritus, or bleeding, diarrhea, nausea or vomiting.
- Skin any new skin lesions or skin changes.
- GU system urinary frequency, dysuria, urinary urgency, GU discharge, flank tenderness, decreased urination.
- Central nervous system (CNS) altered mental status, new onset focal deficits.
- Catheter sites redness, tenderness at the insertion site including that along the subcutaneous tract of the catheter.

Signs of infection signs of infection in patients with malignancy and altered immune system function may be subtle or atypical. In general, a thorough clinical examination focusing on changes or alteration in function is essential. Special attention should be directed to the areas listed in Table 28.2 and the associated potential etiologic agents.

HEENT
- Retina. Hemorrhages, necrosis of the retina, yellow lesions next to scarred retina ( headlight in fog ), white, infiltrative lesions on the retina, chorioretinitis with retinal detachment, or fulminant endophthalmitis are all signs of serious infection.
- Sinuses. Sinus tenderness, orbital cellulitis, or edema can indicate bacterial or fungal infection of the sinuses. Black material in the sinuses may indicate mucormycosis.
- Oropharynx and dentition. Special attention should be paid to the oral cavity during clinical examination, as this area can give important clues to a wide variety of microbiology infections. Bacterial infections, especially anaerobic infections, may present with reddened gums, loosened teeth, pain or discomfort in the teeth or gums, or referred pain to the sinus area in addition to frank abscess formation. The presence of a draining sinus tract may be significant for Actinomycosis. Ulcerations can be caused by a variety of infectious agents, including viruses, fungi, and tuberculosis. Viral ulcerations are generally shallow and painful, and may have extensive oropharyngeal involvement in the patient with cancer. The viruses that usually cause ulcerations are the herpes viruses and coxsackie viruses (herpangina). Fungal infections such as Histoplasmosis may present with painful, deep ulcers with heaped up edges. Candida can present with characteristic white plaques on the buccal mucosa (thrush) or less commonly, erythema of the mucosal surfaces or angular cheilitis.

Cardiovascular system. The presence of new murmurs or suspected line infections should prompt an evaluation for endocarditis. The most common cause of endocarditis in this population is S. aureus. Pericarditis and pericardial tamponade are uncommon, but should be suspected in patients with chest pain, shortness of breath, fever and/or pericardial rub. A variety of infectious agents can cause pericarditis, including common agents such as S. aureus, S. pneumoniae and coxsackie

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viruses and uncommon agents such as Candida species and Aspergillus in patients with cancer with prolonged neutropenia and antibiotic therapy.

Table 28.2. Potential etiologic agents of infection and associated signs and symptoms

Clinical Change	Potential Etiologic Agent
HEENT
Changes in vision
Retinal hemorrhage	Staphylococcus aureus (endocarditis), CMV
Retinal necrosis	HSV, VZV
Retinal exudate with scarring	Toxoplasmosis
Chorioretinitis, white infiltrate retinol lesions, or endophthalmitis	Candida species
Sinus tenderness
Black discharge or orbital cellulitis /edema	Mucormycosis (zygomycosis)
Oropharynx
Painful, bleeding gums	Anaerobes
Ulcerations	Anaerobes
Shallow, painful	HSV, coxsackievirus
Deep, painful	Histoplasmosis
Erythema or white plaques	Candida
Cardiovascular
Murmur or line infection	Staphylococcus epidermidis, S. aureus
Chest pain/SOB/fever/rub/pericarditis	S. aureus, Streptococcus pneumonia, coxsackievirus, Candida, Aspergillus
Pulmonary
Consolidation	S. pneumoniae, Legionella sp., Haemophilus influenza
Diffuse interstitial pattern/patchy alveolar infiltrate	CMV, PCP, Mycoplasma, other viruses (e.g., influenza, adenovirus)
Postobstructive
Neutropenic	Anaerobes + Gram-negative rods S. aureus, Pseudomonas, Candida, Aspergillus
Abdomen
Pain, nausea/vomiting suspect typhilitis	Polymicrobic; gram-positive cocci, gram-negative rods, anaerobes
Rectal discomfort suspect rectal abscess	Polymicrobic; gram-positive cocci, gram-negative rods, anaerobes
Diarrhea	C. difficile
Skin
Petechia/purpura	Coxsackievirus, echovirus, CMV, Neisseria meningitidis, Haemophilus species, Rickettsia species, S. aureus, S. pneumoniae, C. canimorsus, Listeria monocytogenes
Macules/papules	Pseudomonas and other gram-negative rods, S. aureus, Rickettsia species, Candida, Aspergillus, other endemic, mycosis, viral infections (multiple), mycobacterium
Vesicles/bullae	VZV, HSV
Vesicles/bullae suspect ecthyma gangrenosus	Pseudomonas species, Vibrio vulnificus and other gram-negative rods, S. aureus, Mucormycosis, Aspergillus, Candida
Lines
Pain, swelling, erythema	S. epidermidis, S. aureus, Candida, gram-negative rods (e.g., Pseudomonas)
CMV, cytomegalovirus; HSV, herpes simplex virus; VZV, varicella zoster virus; PCP, Pneumocystis Jiroveci (carinii) pneumonia

Lungs. Signs of consolidation and/or pleural effusion may indicate the presence of pneumonia (including postobstructive pneumonia). In neutropenic hosts, pneumonia may present with minimal changes on examination. Also, atypical pulmonary infections such as Pneumocystis jiroveci pneumonia (formerly Pneumocystic carinii pneumonia/PCP), can present initially with minimal or no changes on pulmonary examination.
Abdomen. Peritonitis may present with minimal findings of pain, rebound, or rigidity and can be somewhat benign initially, especially in neutropenic hosts with neutropenic enterocolitis (typhilitis) or patients on medications such as narcotics or steroids. Perirectal abscesses can be present with minimal discomfort or pruritus and on physical examination, may reveal only minimal erythema, tenderness, or swelling.
Skin. All areas of skin including perineal area, soles and palms should be thoroughly examined for new lesions. The pattern of skin involvement and type of lesions are important. Some of the following skin changes can signal disseminated infection with the following microbes.
- Petechia and purpura. Both viral and bacterial infections may present with scattered petechiae or purpura. Neisseria meningitidis is the most common bacterial agent causing petechiae, especially in asplenic patients.
- Macules and papules. A wide variety of gram-negative bacteria (including Pseudomonas and Enterobacteriaceae) may present with papules ormacules, as can S. aureus and atypical bacteria such as Rickettsial species. Disseminated fungal infections (including Candida, Cryptococcus, Histoplasma, Coccidioides and Fusarium) will most commonly present with maculopapular, umbilicated, or nodular skin lesions. Common viral illnesses (and childhood viral illnesses such as adenovirus, rubella, or rubeola) may present with maculopapular eruptions as well. Mycobacterial infections such as Mycobacterium haemophilum may present with nodules.
- (3) Vesicles and bullae. Classic herpes virus infections, such as varicella or herpes simplex may have vesicles in localized areas (dermatomal or mucocutaneous) or extensive cutaneous dissemination with other organ system involvement such as lungs or CNS. Two bacterial infections that may present with rapidly evolving vesicles or bullae (ecthyma gangrenosum) in immunocompromised hosts are Vibrio vulnificus and Pseudomonas species. Lesions can initially present as macules with or without vesicles, but quickly evolve into hemorrhagic bullae. These bullae later slough, revealing a deep underlying ulceration with surrounding erythema. Other infectious causes of ecthyma gangrenosum include fungal infections (such as Mucormycosis, Aspergillus or Candida), S. aureus and a variety of gram-negative rods.
Lines/catheters. Infections in lines and catheters may present with minimal erythema, tenderness, and swelling.

D. Microbiologic evaluation

Any patient with cancer with suspected infection should have a complete microbiologic evaluation of blood, urine and sputum at a minimum. Other specimens should be obtained depending on the patient's presentation (e.g., stool, skin biopsy, cerebrospinal fluid). Diagnostic studies such as blood cultures may need to be repeated periodically to document adequate response to therapy or identify the etiology of infection.

Blood cultures. Blood cultures are the single most important microbiologic test ordered and should be obtained in all patients with fever or suspected infection. In patients without longer-term indwelling intravenous access, all cultures should be drawn through separate peripheral venopuncture sites. Initially two to three sets of blood cultures are drawn at least 10 minutes apart and may be repeated in 48 to 72 hours, or sooner if the patient is clinically unstable. Ideally, 10 mL of blood should be drawn in each bottle. Blood cultures should be drawn in aerobic and anaerobic bottles with enriched media, to encourage growth of bacteria in the presence of antibiotics. Fungal blood culture bottles may be used if fungal infections such as Coccidioides or Aspergillus are suspected. However, most commercially available blood culture systems are able to detect Candida species in the blood. Therapy should not be
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delayed pending results of blood cultures, but ideally antibiotics should be started after the blood cultures are obtained, provided the cultures are obtained in an urgent manner.
- Catheter-related infections. In patients with longer-term percutaneous indwelling central catheters (PICCs), subcutaneously implanted catheters, and other central catheters, blood cultures are often obtained from both peripheral sites and from the catheters. Unfortunately, positive blood cultures from catheters for organisms such as S. epidermidis, Bacillus species or diphtheroids may represent either true infection or contamination and are difficult to interpret without removal of the catheter and culture of the tip.
Sputum. Expectorated sputum should be obtained for Gram stain, culture, and sensitivity. If patients cannot produce a sputum sample and a pulmonary source of infection is suspected, bronchoscopy with or without transbronchial biopsy may be indicated. When bronchoscopy is performed on an immunocompromised host, the following studies are usually obtained on lavage and biopsy specimens: routine Gram stain, culture, sensitivity, fungal stains and culture, acid-fast bacillus stains and cultures, modified acid-fast stains (for Nocardia), viral culture, silver stain (for Pneumocystis), and histopathology.
Urine. Urine should be sent for Gram stain, culture and urinalysis. If the patient is unable to produce a clean-catch urine specimen, urine should be obtained by catheterization. Leukocytes may be absent in urinalysis in a neutropenic host.
Stool. If patients have loose stools, initial specimens at the time of admission should be sent for routine culture (often this includes Salmonella, Shigella, Campylobacter, Yersinia and Escherichia coli 0157.H7), C. difficile toxin, ova and parasites, Giardia antigen, and cryptosporidium antigen. Except for C. difficile toxin, these tests have a low yield in patients who have been hospitalized for more than 3 days and then develop diarrhea. The exception to this is reactivation of a parasitic cause of diarrhea (such as Strongyloides).
Cerebrospinal fluid. Lumbar punctures are not indicated in the routine evaluation of patients with fever unless a meningeal source is suspected (e.g., significant headache, focal deficits, altered mental status, or nuchal rigidity). A relative contraindication to lumbar puncture is thrombocytopenia (<50,000) or coagulopathy. When cerebrospinal fluid is obtained, it should be sent at a minimum for cell count with differential, glucose, protein, routine culture and Gram stain, and cryptococcal antigen. Other tests such as acid-fast bacillus smear and cultures and fungal smear and cultures should be ordered if clinically warranted.
Other microbiologic tests. Other microbiologic tests that can be clinically useful include the following:
- Cytomegalovirus (CMV) polymerase chain reaction (PCR) of blood.
- Legionella urine antigen (>93% sensitive in detecting Legionella pneumophila serogroup).
- Histoplasmosis urinary antigen.
- HSV PCR of cerebrospinal fluid.
- Semiquantitative cultures of catheter tips.

E. Radiology

Chest x-rays. All patients with malignancy and suspected infection should have a baseline chest radiograph (including a lateral view if possible).
Computer tomography (CT). CT scans should be ordered on an individualized basis. Patients with pulmonary complaints should undergo a CT scan of the chest if the chest x-ray (CXR) is noncontributory. Patients with abdominal complaints should have a CT of the abdomen and pelvis.
Magnetic resonance imaging (MRI). MRI scans are especially useful in evaluating the brain and spine, hepatobiliary system and pancreas, soft tissue and bone.
Ultrasound. Ultrasounds are noninvasive or minimally invasive tests without the need for IV contrast. All patients with suspected endocarditis should receive a TEE (transesophageal echocardiogram) unless contraindicated. Ultrasonography is especially useful in imaging the liver, biliary tree and gallbladder, pancreas, and kidneys.
Other radiological tests. Other imaging studies such as gallium scans or tagged WBC scans are relatively nonspecific and rarely used. Positron emission tomography (PET) scans detect differential glucose metabolism of normal and abnormal tissues, but cannot differentiate between infection or underlying malignancy.

F. Other tests

All patients with cancer with suspected infection should have a complete blood count with differential and basic chemistry profile including electrolytes, blood urea nitrogen, creatinine, and liver function tests in order to assess possible multiple organ system involvement and presence of neutropenia.

G. Invasive diagnostic procedures

Bronchoscopy should be performed, preferably with biopsy in all patients with pneumonia without etiology, pneumonia with failure to improve with empiric therapy, or suspected pulmonary site of infection with a negative CXR or CT scan (especially in neutropenic patients). Liver biopsy and bone marrow biopsies are rarely required, but may be indicated when a thorough fever work-up is negative in a patient with an inadequate response to empiric therapy. In addition to routine Gram stains and cultures, bone marrow aspirates and liver biopsies are often sent for acid fast bacillus smears and cultures, fungal smears and cultures, viral cultures, and histopathology for stains such as Warthin-Starry. Consultation with the clinical microbiology laboratory and pathology laboratory is important before obtaining these specimens.

III. Treatment

A. General overview

Fever or suspected infection in a patient with cancer requires urgent evaluation and initiation of treatment. In certain populations (neutropenia, asplenia), it constitutes a medical emergency. Antibiotic therapy should never be withheld while the work-up for a fever source is in progress, but empiric therapy against the most likely

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pathogens should be promptly instituted. If possible, however, blood cultures should be drawn before antibiotics are begun if this does not result in a treatment delay. Empiric therapy in febrile neutropenic and non-neutropenic hosts with suspected infection is reviewed as well as directed therapy against specific pathogens. Commonly used dosages of antimicrobials are listed in Table 28.3.

B. Febrile neutropenia

An excellent guideline for the management of a patient with febrile neutropenia has been published by the Infectious Diseases Society of America (IDSA, last updated in 2002).

Febrile neutropenia is usually defined as fever (two episodes of temperatures >100. 4F or one episode of temperature >101F) in a patient with a neutrophil count of less than 500 cells/ L or WBC count less than 1,000 cells/ L with neutrophils predicted to be less than 500 cells/ L. Most fevers in neutropenic patients stem from bacteria and fungi that are normal colonizers of the skin and alimentary canal. Mucosal damage with secondary bacterial and fungal translocation is thought to be an important initial step in the pathogenesis of febrile neutropenia.
Microbiology. The most common organisms causing fever in neutropenic hosts are gram-positive cocci such as Staphylococcus species (S. aureus and S. epidermidis), Streptococcus, Enterococcus, Pseudomonas and other gramnegative rods (such as Enterobacter and Proteus species), and anaerobes (such as Bacteroides and Clostridium species). Fungi such as Candida species occasionally can cause primary infections, but usually occur as secondary infections ( super infections ).

Empiric antibiotic therapy. All neutropenic patients with fever without localizing source or suspected infection in the absence of fever should receive urgent empiric antibiotic therapy to cover gram-positive organisms such as Staphylococcus species and Streptococcus species and gram-negative rods such as Pseudomonas. Antifungal antibiotics are not usually included in the initial empiric antibiotic regimen unless a fungal infection is suspected (i.e., use of hyperalimentation).

Monotherapy. Use of a single broad-spectrum antimicrobial such as a third- or fourth-generation cephalosporin or a carbapenem has been shown in multiple clinic trials to be as effective as multidrug treatment regimens for febrile neutropenia. Treatment options for empiric therapy include the following:
- Ceftazidime
- Cefepime
- Carbapenems (imipenem cilastatin or meropenem)
- Piperacillin tazobactam
- For patients with severe penicillin allergies, no monotherapy regimens are available and multidrug regimens are required.

Two-drug therapy. Multidrug therapy does not offer any specific clinical advantages over monotherapy

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in recent clinical trials using carbapenems or antipseudomonal cephalosporins. However, the addition of an aminoglycoside (gentamicin, tobramycin, amikacin) can be used for potential synergistic effects against gramnegative rods.

Table 28.3. Dosages of commonly used antibiotics in oncology patients

Antibacterials	Renal Adjustment Required for Cr Cl <50	Comments
Vancomycin 1 g IV q12 h	Yes	Monitor peak and trough Nephrotoxicity increased with aminoglycosides
Piperacillin tazobactam 3.375 g IV q6 h	Yes	Piperacillin needs aminoglycosides for synergy with Pseudomonas infections.
Ampicillin clavulanate 875 mg PO q12 h	Yes	Diarrhea common
Imipenem cilastatin 0.5 g IV q6 h	Yes	Seizures can occur if dose not reduced for renal insufficiency
Meropenem 1 g IV q8 h	Yes	Approved for meningitis in patients 3 months of age
Aztreonam 2 mg IV q8 h	Yes	Can use in patients with -lactam allergy
Ciprofloxacin 400 mg IV q12 h	Yes	Avoid in children <16 years old
Ceftriaxone 2 g IV q2 h	No	High doses can result in sludge in gallbladder no Pseudomonas or enterococcal coverage.
Cefepime 2 g IV q8 h	Yes	Covers Pseudomonas, not Enterococcus
Ceftazidime 2 g IV q8 h	Yes	Covers Pseudomonas, not Enterococcus
Trimethoprim culfamethiazole 1 DS PO q12 h	Yes	Can increase creatinine/PCP doses 5 mg / kg q8 h IV based on a trimethoprim component.
Metronidazole 500 mg PO q6 h	No	Dose adjustment with dialysis avoid alcohol.
Linezolid 600 mg PO or IV q12 h	No	Anemia, thrombocytopenia, leukopenia common monitor CBC weekly if treatment >2 weeks.
Daptomycin 4 mg/kg IV q.d.	Yes	Not effective in pneumonia
Quinupristin/dalfopristin 7.5 mg/kg IV q8 h	Yes	Infuse through central line
Gentamicin dosing varies based on clinical scenarios	Yes	Nephrotoxicity/ototoxicity common monitor peak and trough. Use ideal body weight or adjusted body weight with obesity.
Antifungals
Amphotericin B up to 1.5 mg/kg/day	No, unless due to drug itself	Nephrotoxicity (increased with radiographic contrast, cisplatinum, other nephrotoxic agents)
Fluconazole 200 400 mg IV q.d.	Yes	Drug drug interactions common
Voriconazole 400 mg PO q12 h on day 1, then 200 mg PO q12 h if >40 kg	No	Avoid IV if Cr Cl <50
Caspofungin 70 mg IV on day 1, then 50 mg IV q.d.	No	Decrease dose with liver dysfunction
Antivirals
Ganciclovir 5 mg/kg IV q12 h	Yes	Neutropenia, thrombocytopenia
Valganciclovir 900 mg PO q12 h	Yes	Prodrug of ganciclovir oral form only
Foscarnet 60 mg/kg IV q8 h	Yes	Significant renal toxicity
Acyclovir 10 12 mg/kg IV q8 h	Yes	Not active against CMV. Seizures can occur if dose is not adjusted for renal insufficiency.
Cr Cl, creatinine clearance.

Severe penicillin allergy. There are no published clinical trials evaluating the treatment of febrile neutropenia in patients with a severe penicillin or -lactam allergy. A fluoroquinolone with antipseudomonal activity such as ciprofloxin combined with aztreonam and vancomycin should provide effective coverage against the most likely pathogens.

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Vancomycin. Vancomycin should be included in the initial antibiotic regimen of febrile neutropenia if any of the following additional clinical situations are noted:
- Suspected catheter infection
- Cellulitis or mucositis
- Known colonization or previous infection with a -lactam resistant gram-positive organism or methicillin-resistant Staphylococcus aureus (MRSA)
- Blood cultures with gram-positive organisms
- Sepsis, hypotension or signs of cardiovascular or endovascular infection (e.g., new murmur, petechia)
- Significant institutional presence of -lactam resistant gram-positive organisms
- Use of quinolones as antibiotic prophylaxis before the onset of fever

Duration of antimicrobial therapy
- In patients in whom a source of infection is found, standard therapy should be continued for the standard duration (i.e., treat Group A streptococcal pharyngitis with penicillin for 10 days).
- In patients in whom no specific infection is found, antimicrobial therapy can generally be discontinued when the neutrophil count is more than 500 cells/mm³ and the patient is a febrile for more than 48 hours and without signs of infections.
- In patients who become a within 3 to 5 days but remain neutropenic, no specific treatment strategy is well defined. Options include the following:
  - Continue empiric antimicrobial therapy for 5 to 7 a days.
  - Continue empiric antimicrobial therapy during the period of neutropenia.
Continued fever in neutropenic patients on empiric therapy without a source. Patients with febrile neutropenia should undergo a thorough history and physical examination daily looking for a source of infection, including a review of all labs, microbiology data, and radiologic studies. If a source of fever is found, antimicrobial therapy should be adjusted accordingly for most likely etiologic organisms.
- a. If no source of fever is found after 5 days and a change of antibiotic therapy is not indicated on the basis of the results of the work-up, an empiric antifungal agent should be added.
- b. Options include amphotericin B compounds, voriconazole, or caspofungin. Both caspofungin and voriconazole have been shown to be as effective as liposomal amphotericin B. Fluconazole is generally not recommended for empiric antifungal therapy, as it does not cover Aspergillus or Candida species such as Candida krusei or Candida glabrata.

C. Empiric therapy in non-neutropenic patients

Patients with infection and neutrophil count greater than 1,000 cells/ L may present with fever or infection from a

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known or unknown source. As with febrile neutropenia, urgent evaluation and initiation of prompt empiric therapy is indicated.

Patients with altered cell-mediated immunity (CMI). Patients with altered cellular immunity due to treatment or underlying diseases (such as non Hodgkin's lymphoma in a patient with acquired immune deficiency syndrome [AIDS]) may present with fever without a known source.
- Microbiology. In addition to routine bacterial pathogens such as S. pneumoniae or S. aureus, patients with altered CMI are at risk for infection with atypical organisms such as PCP, Mycobacterium, Nocardia, Listeria, viral infections such as CMV and fungal infections such as Cryptococcus.
- Treatment. In patients with altered cell-mediated immunity, diagnostic work-up of fever before initiating treatment is important if the patient is clinically stable. Work-up before antimicrobial therapy should include at a minimum blood cultures, acid-fast bacillus blood cultures, viral cultures, urinalysis and culture, CXR, or CT scan of chest and abdomen. Urgent infectious diseases consultation is recommended for the clinically unstable patient with suspected infection and altered CMI.
Patients with altered humoral immunity and/or splenectomy. Patients with hypogammaglobulinemia or agammaglobulinemia may lack opsonizing antibodies to encapsulated bacteria.
- Microbiology. Encapsulated bacteria such as S. pneumoniae, Haemophilus influenza, N. meningitidis, C. canimorsus, and encapsulated strains of other bacteria such as S. aureus and E. coli are potential pathogens.
- Treatment. Antibiotic therapy in patients with asplenia and/or altered humoral immunity must be instituted immediately as a delay in treatment may lead to death. No clinical trials have been performed in this patient population, but treatment is aimed at covering the major pathogens. An appropriate empiric antibiotic regimen would be vancomycin and a third-generation cephalosporin such as ceftriaxone. In patients with severe penicillin allergy, a fluoroquinolone such as levofloxacin could be substituted for ceftriaxone. In patients with documented or suspected bacteremia, the duration of therapy is at least 14 days.

Nosocomial infections. Nosocomial infections are generally defined as infections occurring in a health care setting 48 hours after admission. These infections are often multidrug resistant, resulting in severely limited treatment options. They can be associated with high morbidity and mortality.

Lungs. Hospital-acquired pneumonia is commonly polymicrobic with resistant gram-negative rods (such as Pseudomonas, Klebsiella and Acinetobacter species) and gram-positive cocci (such as methicillin-resistant
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Staphylococcus aureus [MRSA]). In hospitalized patients, the oropharynx becomes colonized with microbes from the hospital environment within 48 hours. Microaspiration of oropharyngeal bacteria is the main cause of pneumonia. Empiric antimicrobial therapy should be directed against common multidrug resistant organisms such as Pseudomonas species or MRSA.

Examples of an initial empiric regimen for nosocomial pneumonia would be as follows:
- Antipseudomonal -lactam (cefepime or ceftazidime) or
- Carbapenem (imipenem-cilastatin, meropenem) or
- Piperacillin tazobactam + antipseudomonal fluoroquinolone (levofloxacin or ciprofloxacin) + vancomycin or linezolid.
Duration of therapy is probably 3 weeks in immunocompromised hosts.
Lines. Intravascular catheter-related infections are common nosocomial infections and can occur in central venous catheters (CVC) (tunneled and nontunneled), arterial catheters, and implantable devices. They are a major cause of morbidity and mortality, and may result in significant complications such as endocarditis or distant metastasis or infection. The most common organisms involved in line infections are Staphylococcus species (S. epidermidis, S. aureus), gram-negative rods, and Candida species. Treatment of catheter-related infections requires removal of the catheter if possible, in addition to systemic antibiotics.
- Empiric antibiotic therapy in patients with a nontunneled CVC. In patients with a suspected indwelling line infection with an easily removable venous access catheter (i.e., PICC line and severe infection), the line should be removed and inserted at a new site if possible. Semiquantitative cultures of the catheter tip should be performed. Empiric antibiotic therapy with vancomycin and an antipseudomonal penicillin or cephalosporin (such as piperacillin or cefepime) is indicated. If the patient has been receiving hyperalimentation through the line, empiric therapy against Candida species with amphotericin B or caspofungin may be also needed. Owing to the increasing incidence of resistant Candida species, fluconazole should not be used empirically for suspected fungemia. If associated septic thrombophlebitis is present, surgical excision or drainage of the vein is generally required.
  
  When the organism has been identified through blood cultures or by the presence of more than 100 colony-forming units (CFU)/mL from quantitative culture of the catheter tip, directed therapy can begin. If S. aureus is present on blood cultures, a TEE should be performed to rule out infective endocarditis. If there is no evidence of endocarditis, 2 weeks of antistaphylococcal therapy guided by sensitivity
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  data can be used. Otherwise, 4 to 6 weeks is indicated. Infection with distant colonization (such as osteomyelitis) may require more than 6 weeks. In patients with positive fungal cultures, an ophthalmologic examination to rule out endophthalmitis is indicated. Blood cultures need to be repeated until they are negative and antifungal therapy is continued for 2 weeks after documented clearance of the fungemia. Infection with gram-negative rods is generally treated for 2 weeks as well. In patients with coagulase-negative staphylococcus (S. epidermidis), treatment may be indicated for 5 to 7 days after catheter removal.
  
  If the catheter is not removed in nonvirulent infections such as S. epidermidis line infections, an attempt can be made to clear the catheter infection using intraluminal ( antibiotic lock therapy ) intravenous antibiotics. A common antibiotic regimen for antibiotic lock therapy for S. epidermidis is vancomycin at 1 to 5 mg/mL instilled into the catheter lumen (s) to fill all lumens completely for more than 12 hours/day for 2 weeks in combination with intravenous antibiotics. A wide range of study results using antibiotic lock therapy to clear S. epidermidis line infections have been published with success rates of 18% to 100%, but in general successful clearance of infection is usually less than 50%.
- Empiric antibiotic therapy in patients with a tunneled CVC. In patients in whom the CVC cannot be easily removed, it is important (if possible) to determine if the catheter is the actual source of infection. Insertion site infections, tunnel infections, clinically unstable patients with possible line infection, evidence of metastatic disease or infection with Candida species, gram-negative rods, or S. aureus require catheter removal and treatment as previously mentioned. Salvage therapy of the line with systemic antibiotic therapy and antibiotic lock therapy can be attempted in selected stable patients with nonvirulent pathogens such as S. epidermidis, but clinical deterioration, continued bacteremia, or failure to improve requires catheter removal.
Foley catheter/urinary tract infections (UTIs). Complicated UTIs in hospitalized patients with or without Foley catheters are commonly caused by E. coli and Enterococcus species. Other microbes that can cause nosocomial infection of the urinary tract include Pseudomonas species, and other enterobacteriaceae bacteria/gram-negative rods (Proteus, Klebsiella, Providencia). S. epidermidis may cause catheter-associated UTIs. The presence of S. aureus in the urine should prompt a search for bacteremia and metastatic staphylococcal infection. Treatment involves removal of the Foley catheter and correction of any associated obstructions or renal-related problems (e.g., azotemia) if possible. Empiric therapy for complicated UTIs could include quinolones with good urinary concentration
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such as ciprofloxacin or levofloxacin, extended spectrum -lactams such as ticarcillin clavulanate or piperacillin tazobactam, or carbapenems such as imipenem cilastatin or meropenem. Antibiotic resistance in commonly occurring gram-negative rods (such as E. coli) to trimethoprim sulfamethoxazole (TMP SMZ) is equal to or more than 20% in most areas, making this a poor choice for empiric therapy in immunocompromised hosts. Ampicillin plus gentamicin has been the traditional therapy for complicated UTIs but newer agents available carry less toxicity risks than gentamicin and are generally preferred.

Duration of therapy is usually 2 weeks but patients should be improving and a within 72 hours. Patients who remain febrile or who are initially clinically unstable should undergo ultrasound or CT to rule out perinephric abscess or obstruction.

Diarrhea

The major nosocomial pathogen causing diarrhea is C. difficile. Recently, an epidemic strain of binary toxin producing C. difficile associated with an aggressive form of colitis has been described. In addition, hospitalized patients with neutropenia and diarrhea may also develop neutropenic enterocolitis (typhlitis). Typhlitis is probably caused by mucosal disruption and enteric bacterial invasion of the mucosa during neutropenia. Clostridial organisms (e.g., as Clostridium septicum), Pseudomonas, anaerobes, and occasionally Candida are commonly occurring pathogens. Fungemia and/or bacteremia can be associated with typhilitis as well. Work-up of a hospitalized patient with diarrhea and/or neutropenia should include C. difficile toxin assay and CT of the abdomen. For diarrhea developing in the hospital, unless reactivation of a parasitic illness is suspected (e.g., Strongyloides), ova and parasite examination of stool has a relatively low yield.
Empiric therapy of suspected C. difficile colitis is metronidazole 500 mg orally three times a day or 250 mg orally four times a day. Metronidazole is preferred initially over vancomycin. Both are equally effective but use of vancomycin may lead to vancomycin-resistant enterococcus (VRE).

In patients with suspected typhlitis broadspectrum antibiotic therapy with good anaerobic coverage is indicated, such as imipenem cilastatin, meropenemor piperacillin tazobactam. If C. difficile colitis has not been excluded, oral metronidazole should be added as well. In patients with continued fever or clinical deterioration an antifungal agent such as caspofungin should be added. Initial surgical consultation is recommended for patients with suspected typhlitis, because perforation or clinical deterioration may require urgent laparotomy and resection of involved bowel.

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Table 28.4. Directed therapy against specific pathogens

Organism	Antibiotics
Staphylococcus aureus
Methicillin sensitive	Nafcillin, cefazolin, ceftriaxone
Methicillin resistant	Vancomycin, linezolid, daptomycin, quinupristin dalfopristin
Staphylococcus epidermidis	Vancomycin, linezolid, daptomycin, quinupristin dalfopristin
Enterococcus	Vancomycin, linezolid, daptomycin, quinupristin dalfopristin, penicillin/amoxicillin + aminoglycoside
Pseudomonas	Cefepime, piperacillin, imipenem or meropenem, ciprofloxacin, aztreonam + aminoglycoside
Candida
C. albicans	Fluconazole, amphotericin B, voriconazole, caspofungin
C. glabrata	Amphotericin B, caspofungin, voriconazole
C. krusei	Amphotericin B, caspofungin, voriconazole
Aspergillus	Voriconazole, amphotericin B, caspofungin
Pneumocystis jiroveci (formerly carinii)	Trimethoprim sulfamethoxazole, pentamidine, atovaquone
Cytomegalovirus	Ganciclovir, valganciclovir, foscarnet, cidofovir

D. Directed therapy against specific pathogens

Before the results of sensitivity testing, empiric therapy against specific or suspected pathogens needs to be chosen on the basis of the likely sensitivity results. Microbial sensitivities are influenced by a number of factors, including earlier antibiotic exposure, clinical scenario of infection and institutional and community resistance patterns (Table 28.4).

Staphylococcus aureus. As previously mentioned, risk factors for methicillin-resistant S. aureus (MRSA) infection include catheter infections, cellulitis, mucositis, previous colonization with resistant organisms, sepsis or possible endovascular infections, earlier use of quinolones, or significant institutional presence of MRSA. Good treatment options for MRSA include vancomycin, linezolid, daptomycin, and quinupristin dalfopristin. For methicillin-sensitive Staphylococcus aureus (MSSA), good treatment options include -lactam antibiotics such as nafcillin, cefazolin or ceftriaxone, -lactam/ -lactamase inhibitor combinations such as piperacillin tazobactam
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or vancomycin, if allergic to -lactams. Bacteriostatic antibiotics such as TMP SMZ, clindamycin, fluoroquinolones, or doxycycline should generally not be used as first-line therapy in patients with severe S. aureus infections.
Staphylococcus epidermidis. Coagulase-negative Staphylococci are often resistant to -lactams (>80%). When these infections are suspected (often line-associated) good initial antibiotic choices include vancomycin, linezolid, daptomycin, or quinupristin dalfopristin.
Enterococcus. Treatment of enterococcal endocarditis or other severe enterococcal infection generally requires synergy with a -lactam (penicillin or amoxicillin) or glycopeptide (such as vancomycin) in combination with an aminoglycoside at synergistic doses. Cephalosporins have no activity against Enterococcus. Linezolid is bacteriostatic against vancomycin-resistant enterococcus (VRE), but has been used successfully in cases of severe enterococcal infection as monotherapy. Other antibiotics with activity against enterococcus include daptomycin and quinupristin dalfopristin (active against Enterococcus faecium, but not Enterococcus faecalis). Nitrofurantoins, quinolones such as ciprofloxacin, and doxycycline also have some enterococcal activity, but should be used only for UTIs after data are available on sensitivity.
Pseudomonas aeruginosa. Serious Pseudomonas infections (e.g., bacteremia, ecthyma gangrenosum) often require synergistic combinations of antipseudomonal -lactams (such as piperacillin or cefepime) and an aminoglycoside. Other treatment options include monotherapy with an antipseudomonal -lactam, imipenem or meropenem, ciprofloxacin or aztreonam. Resistance can occur with treatment, resulting in treatment failure.
Candida species. Candida albicans is usually sensitive to fluconazole, amphotericin B, caspofungin, and voriconazole. C. glabrata and C. krusei have decreased sensitivities to fluconazole (85%and 5%sensitive, respectively) but are usually sensitive to amphotericin B, caspofungin, and voriconazole. Two other commonly seen Candida species (Candida parapsilosis and Candida tropicalis) are usually sensitive to fluconazole, amphotericin B, voriconazole, and caspofungin, but have decreased sensitivity to itraconazole.
Aspergillus. Aspergillus species (Aspergillus fumigatus, Aspergillus flavus, Aspergillus terreus and Aspergillus niger) are resistant to fluconazole. Voriconazole is more effective than amphotericin B in one large study of invasive aspergillosis in immunocompromised hosts. In addition to amphotericin B and voriconazole, caspofungin has activity in invasive aspergillosis. Combination therapy with caspofungin and voriconazole has been successfully used in patients with invasive aspergillosis, but large-scale randomized studies are lacking.
Pneumocystis jiroveci pneumonia (PCP). TMP SMZ at high doses (5 mg/kg IV q8 h) is the primary treatment for PCP. If the PaO2 is less than 70 mm/kg, prednisone
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40 mg orally q12 hours is added for 5 days, then 20 mg daily for 11 days. Other commonly used treatment choices for PCP include pentamidine (intravenous) or atovaquone (oral).
Cytomegalovirus (CMV). CMV can cause a variety of end-organ diseases. CMV pneumonia is generally treated with high-dose ganciclovir (2.5 mg/kg IV q8 h) with intravenous immunoglobulin (IVIG). CMV retinitis can be treated with oral valganciclovir or intravenous ganciclovir. Other antivirals with CMV activity include foscarnet and cidofovir.

IV. Infections in hematopoietic stem cell transplant recipients (HSCT)

The management of HSCT patients with infection is extremely complex and depends on a number of variables type of transplantation, latent infections in the recipient, timing of humoral and cellular reconstitution, development of graft-versus-host disease, conditioning regimen, and time after transplantation. Several excellent reviews of infection in HSCT recipients are available and are listed in the references.

A. Evaluation of infection based on temporal approach

One classic approach to the evaluation of infection in bone marrow transplant patients is to divide the transplant immunodeficiencies and pathogen susceptibilities into three separate periods pre-engraftment, early postengraftment, and late postengraftment. Engraftment is defined as the time when a patient can sustain an absolute neutrophil count (ANC) greater than 500 cells/ L and platelet count of more than 20,000 L for three or more consecutive days without transfusion.

Pre-engraftment (Phase I: generally first month after transplant). Pathogens likely to cause infection in the preengraftment period include the following:
- Viral. HSV, seasonal respiratory and enteric viruses
- Bacteria. S. epidermidis, S. aureus, vidians streptococcus, Pseudomonas species, Enterobacteriaceae and other gram-negative rods
- Fungus. Candida species, Aspergillus
Early postengraftment (Phase II: generally first 30 to 100 days after transplant)
- Other human herpes viruses such as Epstein-Barr virus(EBV), seasonal respiratory and enteric viruses
- Bacterial. Listeria monocytogenes, Legionella species, S. epidermidis, Streptococcus species, S. aureus
- Fungus. Aspergillus and other molds (e.g., Pseudallescheria boydii), P. jiroveci
- Parasites. Toxoplasma gondii, Strongyloides stercoralis
Late postengraftment (Phase III: generally more than 100 days after transplant).
- Viral. VZV, EBV, and other human herpes viruses (e.g., CMV, HHV-8), hepatitis B, hepatitis C, seasonal respiratory and enteric viruses
- Bacteria. Encapsulated bacteria such as S. pneumonia, H. influenza, N. meningitidis
- Fungi. P. jiroveci, Aspergillus, and other molds
- Parasitic. T. gondii

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V. Prophylaxis of infection in patients with cancer

Given the high rate of infection in oncology patients and the associated morbidity and mortality, multiple studies have evaluated preventive strategies for fungal, bacterial, and viral infections in different oncology populations.

A. Prophylaxis of infection in non-HSCT patients

Antibacterial prophylaxis. Multiple randomized placebo controlled studies of antibiotic prophylaxis in a neutropenic patients have been performed over the last 30 years with differing results. Many studies have shown reductions in febrile illnesses using antibiotic prophylaxis during a neutropenia, but significant side effects have been noted. These include fungal superinfection and development of resistant organisms. The most widely studied prophylactic antibiotics have been oral nonabsorbable antibiotics for selective GI decontamination (e.g., aminoglycosides, oral vancomycin) and systemically absorbed antibiotics such as trimethoprim sulfamethoxazole (TMP SMZ) and fluoroquinolones. Oral nonabsorbable antibiotics for prophylaxis in a neutropenic patients with cancer are not recommended on the basis of previous studies, but controversy exists regarding the use of TMP SMZ and quinolones.
- TMP SMZ. Studies on use of TMP SMZ for the most part have shown some decrease in infection rates in a neutropenia with little effect on overall mortality. The development of resistant organisms and potential bone marrow suppression has been important disadvantages in the routine prophylactic use of TMP SMZ. The current 2002 IDSA guidelines for use of antimicrobial agents in neutropenic patients with cancer recommend prophylactic use of TMP SMZ only for PCP in patients at risk.
- Fluoroquinolones. Oral quinolones have been studied extensively for prophylaxis in a neutropenic patients with mixed results. Use of agents such as ciprofloxacin in randomized trials has shown a decrease in gram-negative rod infections, but an increase in infections with resistant organisms and gram-positive cocci. The current 2002 IDSA guidelines for use of antimicrobial agents in neutropenic patients with cancer recommends against prophylactic use of quinolones in a neutropenia. However, a recent meta-analysis of antibiotic prophylaxis in neutropenia patients showed potential reduction in mortality with fluoroquinolone use. There are no adequate large-scale trials yet on the use of newer quinolones with improved grampositive-coverage (such as moxifloxacin). For now, use of quinolones for routine antibiotic prophylaxis in a neutropenia is not recommended.
Antifungal prophylaxis. The 2002 IDSA guidelines for antimicrobial prophylaxis in neutropenic patients recommends against routine use of itraconazole or fluconazole for antifungal prophylaxis. Several studies have shown a decrease in fungal infections and associated mortalities in
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patients receiving fluconazole or itraconazole prophylaxis, but this is outweighed by possible development of antifungal resistance. Additional studies are in progress for specific oncologic populations, such as AML.
Antiviral prophylaxis. Antiviral prophylaxis is not recommended for a neutropenic patients.

B. Prophylaxis of infection in hematopoietic stem cell transplant (HSCT)

The American Society for Blood and Marrow Transplantation and the IDSA recommend prophylaxis for encapsulated bacteria, Pneumocystis, HSV and VZV seropositive patients, (with prophylactic or preemptive therapy for CMV), and antifungal prophylaxis for patients on chronic steroids and until engraftment. In addition, they recommend antibiotic prophylaxis for patients undergoing dental procedures as per the current American Heart Association guidelines for endocarditis prophylaxis.

Bacterial prophylaxis. There are no recommendations for use of specific antibiotics for bacterial prophylaxis in HSCT patients. Physicians who use single antibiotics for prophylaxis of encapsulated organisms after transplant should choose agents on the basis of factors such as local antimicrobial resistance patterns. IVIG can be used in patients with severe hypogammaglobinemia during the early postengraftment phase.
Fungal prophylaxis. Fluconazole 400 mg orally per day until engraftment.
Pneumocystis jiroveci prophylaxis (PCP prophylaxis) and toxoplasmosis prophylaxis. One TMP SMZ double strength tablet daily or three times per week. Prophylaxis for PCP should begin before transplantation.
Viral prophylaxis. Multiple strategies (prophylaxis or preemptive) exist to decrease the incidence of CMV infection and reactivation in HSCT patients. One strategy is the use of intravenous ganciclovir 5 g/kg IV q12 h for 1 week, then 5 days/week till day 100 post-transplant in seropositive patients at risk. Prophylaxis against HSV reactivation is recommended for HSV seropositive transplant recipients. Acyclovir (200 mg orally three times per day) can be given at the start of conditioning until engraftment or resolution of mucositis.
Other prophylactic strategies
- Vaccination. The following vaccines are commonly given 12 to 24 months after HSCT transplantation in adults: tetanus diphtheria toxoid vaccine, hepatitis B series, 23-valent pneumococcal polysaccharide vaccine, influenza vaccine, and inactivated polio vaccine. Measles, mumps, and rubella (MMR) vaccine and varicella vaccine are contraindicated. No recommendation has yet been made on the use of meningococcal vaccine or the newly developed tetanus diphtheria acellular pertussis vaccine for adults due to limited data.
- Infection control measures. Strict attention to infection control measures should be practiced by HSCT patients, caregivers, and health care workers, especially
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  strict attention to hand washing. Some unique aspects of infection control include the following:
  - While in hospital, strict attention should be paid to air-flow and air filtration, possible exposure to construction in the hospital environment, and exposure to health care workers with seemingly minor infections such as adenovirus conjunctivitis.
  - HSCT patients should avoid exposure to respiratory and enteric viruses (i.e., wear surgical mask during close contact with people with respiratory illness).
  - Contact with sick pets should be minimized and excellent pet health should be maintained.
  - Patients should avoid reptiles, chicks, ducklings, and exotic pets.
  - Patients should avoid well water.
  - Strict attention to food safety practices (e.g., use of separate cutting boards for raw chicken; cleaning of surfaces and knives after each use; and washing all produce) should be practiced by everyone involved in meal preparation for HSCT patients.
  - Use of a lowmicrobial diet (e.g., avoid sushi, salad dressings made with raw eggs) is recommended.
  - Vaccination of family members and household contacts should be done as per current Advisory Committee on Immunization Practices (ACIP) guidelines. Currently, family members and household contacts should receive all age-appropriate vaccinations and influenza and hepatitis A, MMR and varicella vaccination if indicated. Oral polio vaccine should be avoided. Updated information about vaccines can be accessed at www.cdc.gov/nip.