Handbook of Cancer Chemotherapy (Lippincott Williams & Wilkins Handbook Series), 8th Ed.

27. Infections: Etiology, Treatment, and Prevention

Thomas J. Walsh and Joan M. Duggan

Infectious diseases are an important cause of morbidity and mortality in immunocompromised patients with cancer. Advances in the diagnosis, treatment, and prevention of these infections have been critical in improving outcome of oncology patients, particularly those with hematologic malignancies. The critical components of infectious disease supportive care include the following: recognition of risk factors that impair host defenses, understanding of the likely pathogens and their resistance patterns within one's own institution, meticulous diagnostic evaluation of symptomatic or febrile patients, and prompt initiation of a rationally based antimicrobial regimen that is active against the most likely microorganisms.

I. ETIOLOGY OF INFECTIONS IN PATIENTS WITH CANCER

A. General considerations

Infections develop in patients with cancer as the result of quantitative or qualitative defects in their innate or adaptive host defense systems. Among these components are circulating phagocytic cells, cell-mediated immunity (CMI), circulating immunoglobulins, the reticuloendothelial system (RES), endogenous cytokines, intact mucocutaneous barriers, and patency of hollow visci. Defects commonly occur in more than one system of innate and adaptive host defenses due to a multitude of etiologies, including the underlying malignancy and its treatment. Alterations of these host defense systems increase the risk for development of specific infections. The relationship between altered host defenses and infections caused by specific pathogens is delineated in Table 27.1.

B. Circulating phagocytic cells

Neutrophils (PMNs) and monocytes are key effector cells of the innate host defense system against most bacterial and fungal pathogens encountered in patients with cancer. Neutropenia (defined as an absolute neutrophil count [ANC] of 500 PMNs/(μL) increases the risk of infection in direct relation to its duration and depth. Patients with persistent neutropenia (defined as >10 days) or those with profound neutropenia (100 PMNs/(μL) have a markedly increased risk of developing serious bacterial and fungal infections. Neutropenia may develop as the direct result of a leukemic process infiltrating normal bone marrow with suppression of myelopoiesis or following cytotoxic chemotherapy. Development of mucositis in association with chemotherapy-induced neutropenia further increases the risk of infection. Neutropenia is associated with an increased risk of development of life-threatening infections caused by the endogenous mucocutaneous bacterial flora, as well as Candida spp. from the alimentary tract and Aspergillus spp. and other filamentous fungi from the external environment.

C. Cell-mediated immunity (CMI)

Altered CMI may result from the primary neoplastic process, such as Hodgkin lymphoma or hairy cell leukemia, or from therapeutic interventions, such as corticosteroids and fludarabine. Although fludarabine may induce a profound depletion of CD4 lymphocytes (T-helper cells), corticosteroids have less of an effect on the absolute number while still profoundly compromising their function. Altered CMI is associated with an increased risk of infections caused by intracellular bacterial pathogens (e.g., Listeria monocytogenes, Mycobacterium spp., and Salmonella spp.), many fungal organisms (e.g., Pneumocystis, Cryptococcus neoformans, Histoplasma capsulatum),and DNA viruses (e.g., varicella zoster virus [VZV], cytomegalovirus [CMV], Epstein-Barr virus [EBV]). As corticosteroids also affect PMN, monocyte, and macrophage function, invasive aspergillosis may also develop in patients receiving sustained and elevated dosages.

D. Circulating immunoglobulins

Hypogammaglobulinemia or dysimmunoglobulinemia may develop in patients with multiple myeloma or chronic lymphocytic leukemia. These defects in adaptive immunity are strongly associated with infections caused by encapsulated bacteria, particularly Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis.

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E. Reticuloendothelial system (RES)

Alterations of the RES most commonly develop as the result of splenectomy. Among its important functions, the spleen serves as a mechanical filter for removing opsonized or nonopsonized bacterial pathogens, as well as a setting for IVIG production. There is an increased risk in splenectomized patients for development of fulminant infections caused by S. pneumoniae, H. influenzae, Capnocytophaga canimorsus, Babesia microti, Ehrlichia chaffeensis, Anaplasma phagocytophilum, and Plasmodium falciparum.

F. Endogenous cytokines and chemokines

An elaborate network of immunoregulatory cytokines and chemokines regulates the effector cells of the innate host defense systems. These molecules mediate their effect through an intricate system of cell surface receptors. The expanding use of monoclonal antibodies to inhibit immunoregulatory molecules and their receptors has resulted in new forms of immunosuppression. For example, infliximab, which binds to tumor necrosis factor (TNF)-α, is associated with an increased risk of tuberculosis and histoplasmosis.

G. Intact mucocutaneous barriers

Cytotoxic chemotherapy, particularly regimens containing cytarabine, high-dose methotrexate, and etoposide, may cause severe mucosal disruption, which may result in the translocation of pathogenic endogenous bacterial and fungal pathogens, such as Escherichia coli, Klebsiella pneumoniae, and Candida spp., from the intestinal tract or Streptococcus mitis from the oral cavity. Vascular catheters disrupt the normal cutaneous barriers and provide a conduit for staphylococci to enter the bloodstream.

Normal bacterial flora further contribute to mucosal host defense by suppressing the growth of more pathogenic organisms. Use of broad-spectrum antibacterial agents may reduce the normal bacterial flora and allows more resistant organisms to fill the void on mucosal surfaces. Normal gastrointestinal flora also protect against the emergence of Clostridium difficile colitis. Prior use of broad-spectrum antibiotics is the strongest predictive variable for the development of C. difficile colitis in numerous studies.

H. Obstruction of hollow visci

Solid tumors or lymphoid malignancies that obstruct the upper and lower respiratory tract, biliary tree, intestines, and urinary tract result in accumulation of bacteria that are normally cleared by these structures. Obstructions in the upper respiratory tract may result in sinusitis and in the lower respiratory tract as postobstructive pneumonia caused by respiratory flora, including anaerobes. Obstructions of the gastrointestinal and biliary tract may result in polymicrobial bacteremia and ascending cholangitis. By comparison, obstruction of the urinary tract is more often associated with aerobic gram-negative bacteremia.

II. DIAGNOSIS OF INFECTIONS IN PATIENTS WITH CANCER

A. General overview

The initial assessment of possible infection in a patient with cancer includes a careful history assessing risks and symptoms, physical examination assessing for hemodynamic stability and localizing signs, and prompt completion of a laboratory diagnostic evaluation. As early symptoms and signs of infection are attenuated in immunocompromised patients, attention to subtle details in history and physical exam are important. Any clinical features suggesting infection in an immunocompromised patient with cancer should prompt initiation of broad-spectrum antibiotics. For example, the presence of localizing abdominal pain in a neutropenic patient in the absence of fever should prompt the initiation of empirical antibacterial therapy. The clinical assessment of immunocompromised febrile patients with cancer should attempt to localize the possible source of infection. Clinical localization helps to guide therapy for likely pathogens.

B. Clinical history

The clinical history is directed toward elucidating risk factors for infection and localizing symptoms. Immunocompromised patients may have minimal symptomatic findings. Deep-seated infection may present as simply fever and malaise. Pneumonia in a neutropenic patient may present initially with only mild dyspnea or cough. Patients should be queried for any history of localizing pain.

Suspected infection in neutropenic patients constitutes a medical emergency. Understanding the patient's current immune deficits is important and can guide therapy.

1. Cancertreatment. Understanding the current under lying neoplastic process and current therapy will help to assess a patient's immune status.

a. Chemotherapeutic and biologic 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 myelosuppression.

(1) Neutropenia. Alkylating agents, anthracyclines, cytarabine, methotrexate, carboplatin, busulfan, 5-fluorouracil, and nitrosoureas are examples of drugs that commonly cause dose-dependent neutropenia, depending on the protocol.

(2) Cluster of differentiation 4 (CD4) and 8 cell suppression (cellular immune system suppression). The following chemotherapeutic agents may result in prolonged suppression of the T-helper/suppressor arm of the immune system:

bull Alemtuzumab: median duration of lymphopenia is 28 days

bull Corticosteroids: severe T-cell function suppression can be seen with a dose equal to or more than 15 mg prednisone/day for a month or more.

bull Purine analogs (cladribine, fludarabine, and pentostatin) may result in CD4 cell count suppression to 200 or less for several years after therapy.

(3) Suppressed B-cell function (altered humoral immunity). The following chemotherapeutic and biologic agents may cause suppression of antibody production by B cells:

bull Alkylating agents (cyclophosphamide, chlorambucil, melphalan)

bull Corticosteroids: use of greater than 40 mg/day of prednisone equivalent may decrease antibody production

bull Methotrexate

bull Rituximab

(4) Cytokine suppression. Infliximab, adalimumab, and etanercept may be used in autoimmune diseases or for graftversus-host disease in recipients of hematopoietic stem cell transplantation (HSCT). Such agents result in altered TNF-α response with an increased risk of infections with conditions such as tuberculosis, histoplasmosis, and aspergillosis.

2. Type of malignancy

a. Solid tumors. These malignancies can cause significant obstruction in affected tissues, leading to infection behind the obstruction. For example, postobstructive pneumonias are common in patients with bronchogenic carcinomas. Colonic carcinomas may cause obstruction or perforation and may simulate diverticular abscesses. 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. For example, hepatic metastases may serve as a nidus for recurrent bacteremias of enteric gram-negative bacteria. 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.

b. Hematologic malignancies. Leukemias and lymphomas may cause severe immunodysregulation. Lymphoblastic leukemias and lymphomas also may cause B symptoms, including fever. In contrast, fever associated with nonlymphocytic leukemias is usually caused by an infection complicating neutropenia rather than B symptoms.

C. Clinical evaluation

The physical examination should be thorough with special emphasis on areas of symptomatology and likely mucocutaneous portals of entry. 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.

1. Review of systems/symptoms of infection

bull Head, eyes, ears, nose, and throat (HEENT): changes in vision, ear or sinus discomfort, oral lesions, changes in dentition

bull Lungs: cough, hemoptysis, shortness of breath, pleuritic chest pain

bull Abdomen: dysphagia, odynophagia, abdominal pain, perianal pain or pruritus, bleeding, diarrhea, nausea or vomiting

bull Skin: any new skin lesions or skin changes

bull Genitourinary (GU) system: urinary frequency, dysuria, urinary urgency, hematuria, GU discharge, flank tenderness, decreased urination

bull Central nervous system (CNS): altered mental status, new onset focal deficits, seizures

bull Catheter sites: redness, tenderness at the insertion site including along the subcutaneous tract of the catheter.

2. Signs of infection in immunocompromised patients with malignancy may be subtle or atypical, so a thorough physical examination focusing on changes or alteration in function is essential. Special attention should be directed to the areas listed in Table 27.2 and the associated potential etiologic agents.

a. HEENT

(1) Ophthalmic assessment. Hemorrhages; necrosis of the retina; yellow lesions adjacent 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. New anisocoria or extraocular muscle palsy suggests a space-occupying lesion, cavernous sinus infection, or orbital infiltrative process.

(2) Paranasal sinuses. Sinus tenderness, orbital cellulitis, or edema can indicate bacterial or fungal infection of the sinuses. Black material along the nasal turbinate mucosa may indicate mucormycosis.

(3) Oropharynx and dentition. Bacterial infections, especially anaerobic infections, may present with marginal gingivitis, 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. Hemipalatal erythema suggests ipsilateral maxillary sinus infection involving the palatine blood vessels. Ulcerations can be caused by a variety of infectious agents, including viruses, fungi, and Mycobacterium 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.

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b. 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 Staphylococcus 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 viruses and less common agents such as Candida spp. and Aspergillus spp., and the Mucorales in patients with cancer with prolonged neutropenia or corticosteroids.

c. 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 pneumonia (PCP) can present initially with minimal or no changes on pulmonary examination.

d. 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 (typhlitis) or patients receiving narcotics or corticosteroids. Perianal infections can present with minimal discomfort or pruritus and, on physical examination, may reveal only minimal erythema, tenderness, or swelling.

e. Skin. All areas of the 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.

(1) Petechiae and purpura. Both viral and bacterial infections may present with scattered petechiae or purpura. N. meningitidis is the most common bacterial agent causing petechiae, especially in asplenic patients.

(2) Macules and papules. A wide variety of gram-negative bacteria (including Pseudomonas and Enterobacteriaceae) may present with papules or macules, as can S. aureus and atypical bacteria such as rickettsial species. Disseminated fungal infections (including Candida, Cryptococcus, Histoplasma, Coccidioides, Fusarium, Scedosporium, and Aspergillus) may 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 virus (HSV), may have vesicles in localized areas (dermatomal or mucocutaneous) or extensive cutaneous dissemination with other organ system involvement such as lungs or CNS. Several bacterial infections may present with rapidly evolving vesicles or bullae (ecthyma gangrenosum) in immunocompromised hosts such as Vibrio vulnificus and Pseudomonasspp. Lesions with these infections 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 and aspergillosis, S. aureus, and a variety of gram-negative bacilli.

f. Vascular catheters. Infections in vascular catheters may present with minimal erythema, tenderness, and swelling along the exit and entrance sites, as well as along the tunnel (for chronic indwelling catheters)

D. Microbiologic evaluation

Any patient with cancer with suspected infection should have a complete microbiologic evaluation of blood, urine, and, when available, sputum. Immunocompromised patients with radiographically evident pneumonia should be evaluated for bronchoalveolar lavage. 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 to identify the etiology of infection.

1. Blood cultures. Blood cultures are the single most important microbiologic test to be ordered and should be obtained in all patients with fever or suspected infection. In patients with mul-tilumen catheters, each lumen should be separately sampled. Peripheral blood cultures should be drawn in patients without catheters. Initially, two to three sets of blood cultures are drawn 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 in adults up to a total of 30 mL. Most commercially available blood culture systems are able to detect Candida species in the blood. While antimicrobial therapy should not be delayed pending results of blood cultures, antibiotics should be initiated after the blood cultures are obtained, provided the cultures are obtained promptly.

bull Vascular catheter-related infections. In patients with longer-term percutaneous indwelling central catheters (PICCs), subcutaneously implanted catheters, and other central catheters, blood cultures should be drawn through all lumens. The presence of organisms in blood cultures in immunocompromised patients is usually considered significant.

2. Sputum. Expectorated sputum in non-neutropenic patients with suspected respiratory tract infection should be obtained for Gram stain, culture, and susceptibility. If patients cannot produce a sputum sample and a pulmonary source of infection is suspected, bronchoscopy is indicated, where feasible. When bronchoscopy is performed on an immunocompromised host, the following studies should be obtained on lavage specimens: routine Gram stain, culture, fungal stains and culture, acid-fast bacillus stains and cultures, culture for Legionella spp., modified acid-fast stains (for Nocardia), viral cultures, immunoassays or polymerase chain reaction (PCR), and immunoassay or silver stain for Pneumocystis.

3. Urine. Urine should be sent for Gram stain, culture, and urinalysis. Leukocytes are typically absent in urinalysis in a neutropenic host with urinary tract infections (UTIs).

4. 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 E. 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 stercoralis).

5. 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.

6. Other microbiologic tests. Other microbiologic tests that can be clinically useful in the appropriate clinical context include the following:

bull Serum and bronchoalveolar lavage galactomannan for detection of invasive aspergillosis

bull Serum (1 → 3)-β-D-glucan for detection of invasive fungal infections, particularly disseminated candidiasis and invasive pulmonary aspergillosis

bull CMV PCR of blood.

bull Legionella urine antigen (>93% sensitive in detecting Legionella pneumophilaserogroup)

bull Histoplasmosis urinary antigen

bull HSV PCR of cerebrospinal fluid.

E. Diagnostic imaging

1. Chest radiographs (CXRs). All patients with malignancy and suspected infection should have a baseline CXR, including a lateral view if possible.

2. Computed tomography (CT) scans should be ordered on an individualized basis. Patients with pulmonary complaints should undergo a CT scan of the chest if the CXR is noncontributory. Patients with abdominal complaints should have a CT of the abdomen and pelvis.

3. Magnetic resonance imaging scans are especially useful in evaluating the brain and spine, hepatobiliary system and pancreas, soft tissue, and bone.

4. Ultrasound. Ultrasounds are noninvasive or minimally invasive tests without the need for intravenous (IV) contrast. Patients with suspected endocarditis should receive a transesophageal echocardiogram (TEE) unless contraindicated. Ultrasonography is especially useful in imaging the liver, biliary tree and gallbladder, pancreas, and kidneys.

5. Other imaging tests. Positron emission tomography (PET) scans detect differential glucose metabolism of normal and abnormal tissues. While PET scans cannot definitively differentiate between infection and underlying malignancy, they have been used increasingly in detecting unsuspected infectious foci when the location of the malignancy is known to be elsewhere. Other imaging studies such as gallium scans or tagged white blood cell (WBC) scans are relatively nonspecific.

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 dysfunction and presence of neutropenia.

G. Invasive diagnostic procedures

Bronchoscopy should be performed when feasible in patients with pneumonia without etiology, pneumonia with failure to improve with empirical therapy, or suspected pulmonary site of infection with a negative CXR or CT scan (especially in neutropenic patients). 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 (patients with neutropenia, asplenia), it constitutes a medical emergency. Antibiotic therapy should not be withheld while the workup for a fever source is in progress, but empirical therapy against the most likely pathogens should be promptly instituted. If possible, however, blood cultures should be drawn before antibiotics are initiated 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 27.3.

B. Fever and neutropenia

An excellent guideline for the management of febrile neutropenic patients has been recently updated by the Infectious Diseases Society of America (IDSA, 2011).

1. Fever in neutropenic patients is usuallydefined as two episodes of temperatures greater than 100.4°F or one episode of temperature greater than 101°F in a patient with a neutrophil count of less than 500 cells/(μL or WBC count less than 1000 cells/(μL with neutrophils predicted to be less than 500 cells/(μL. 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.

2. Microbiology. The most common organisms causingfever in neutropenic hosts are gram-positive cocci, such as Staphylococcus species (S. epidermidis and, occasionally, S. aureus), Streptococcus, Enterococcus, and Pseudomonas, and other gram-negative bacilli (such as Enterobacter and Proteus spp.) and anaerobes (such as Bacteroides and Clostridium spp.). Fungi such as Candida species occasionally can cause primary infections, but usually occur as secondary infections.

3. Empirical antibiotic therapy. All neutropenic patients with fever without localizing source or suspected infection in the absence of fever should receive urgent empirical antibiotic therapy to cover aerobic gram-negative bacilli, including Pseudomonas aeruginosa. The extent of coverage of gram-positive organisms such as Staphylococcus species and Streptococcus species depends on the risk for skin and soft-tissue infections and of mucositis, respectively. Antifungal agents are not usually included in the initial empirical antibiotic regimen unless a fungal infection is suspected (i.e., use of hyperalimentation).

a. Monotherapy. Use of a single broad-spectrum antimicrobial such as a third- or fourth-generation cephalosporin or a carbapenem has been shown in randomized clinic trials to be as effective as multidrug treatment regimens for febrile neutropenia. Treatment options for empirical therapy include the following:

bull Ceftazidime

bull Cefepime

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bull Carbapenems (imipenem-cilastatiii or meropenem)

bull Piperacillin–tazobactam

bull For patients with severe penicillin allergies, aztreonam plus vancomycin is appropriate. Linezolid may be an appropriate substitute for vancomycin.

b. Two-drug therapy. Multidrug therapy does not offer any specific clinical advantages over monotherapy against aerobic gram-negative bacilli in clinical trials using carbapenems or antipseudomonal cephalosporins.

c. Severe penicillin allergy. Aztreonam and vancomycin should provide effective coverage against the most likely pathogens.

d. Vancomycin. Vancomycin should be included in the initial antibiotic regimen of febrile neutropenic patients if any of the following additional clinical situations are noted:

bull Suspected catheter infection

bull Cellulitis or mucositis

bull Known colonization or previous infection with methicillin-resistant S. aureus (MRSA)

bull Blood cultures with gram-positive organisms

bull Sepsis, hypotension, or signs of cardiovascular or endovascular infection (e.g., new murmur, petechiae)

bull Significant institutional presence of β-lactam–resistant gram-positive organisms

bull Use of quinolones as antibiotic prophylaxis before the onset of fever.

4. Duration of antimicrobial therapy

a. 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).

b. In patients in whom no specific infection is found, antimicrobial therapy can be discontinued when the neutrophil count is more than 500 cells/μL and the patient is afebrile for more than 48 hours and without signs of infection.

c. In patients who become afebrile within 3 to 5 days but remain neutropenic, no specific treatment strategy is well defined. Options include the following:

bull Continue empirical antimicrobial therapy for 5 to 7 afebrile days.

bull Continue empirical antimicrobial therapy during the period of neutropenia.

5. Continued fever in neutropenic patients on empirical therapy without a source. Patients with febrile neutropenia should undergo a thorough history and physical examination daily to evaluate for a source of infection, including a review of all laboratory tests, microbiology data, and radiologic studies. If a source of fever is found, antimicrobial therapy should be adjusted accordingly for most likely etiologic organisms.

a. Ifno 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 workup, an empirical 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 empirical an-tifungal therapy, as it does not cover Aspergillus or Candida species such as Candida krusei or Candida glabrata.

C. Empirical therapy in non-neutropenic patients

Patients with infection and neutrophil count greater than 1000 cells/μL may present with fever or infection from a known or unknown source. Urgent evaluation and initiation of prompt empirical therapy is indicated.

1. Patients with altered CMI. Patients with altered cellular immunity due to treatment or underlying diseases (such as non-Hodgkin lymphoma in a patient with acquired immune deficiency syndrome) may present with fever without a known source.

a. Microbiology. In addition to common 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.

b. Treatment. In patients with altered CMI, diagnostic evaluation of fever before initiating treatment is important if the patient is clinically stable. Workup before antimicrobial therapy should include at a minimum blood cultures, acid-fast bacillus blood cultures, viral cultures, urinalysis and culture, and CXR or CT scan of chest and abdomen. Urgent infectious disease consultation is recommended for the clinically unstable patient with suspected infection and altered CMI.

2. Patients with altered humoral immunity and/or splenectomy. Patients with hypogammaglobulinemia or agammaglobulinemia may lack opsonizing antibodies to encapsulated bacteria.

a. Microbiology. Encapsulated bacteria such as S. pneumoniae, H. influenzae, N. meningitidis, C. canimorsus, and encapsulated strains of other bacteria such as S. aureus and E. coli are potential pathogens.

b. 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. Treatment is aimed at covering the major pathogens. An appropriate empirical 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.

3. Nosocomial infections are generally defined as infections occurring in a healthcare 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.

a. Lungs. Hospital-acquiredpneumoniais commonlypolymicrobic with resistant gram-negative bacilli (such as Pseudomonas, Klebsiella, and Acinetobacter species) and gram-positive cocci (such as 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. Empirical antimicrobial therapy should be directed against common multidrug resistant organisms such as Pseudomonas species or MRSA. Examples of an initial empirical regimen for nosocomial pneumonia would be as follows:

bull Antipseudomonal β-lactam (cefepime or ceftazidime) or

bull Carbapenem (imipenem-cilastatin, meropenem) or

bull Piperacillin-tazobactam + antipseudomonal fluoroquinolone (levofloxacin or ciprofloxacin) + vancomycin or linezolid.

Duration of therapy is approximately 3 weeks in immu-nocompromised hosts.

b. Vascular catheters. Intravascular catheter-related infections are common nosocomial infections and can occur in central venous catheters (CVCs) (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 usually requires removal of the catheter if possible, in addition to systemic antibiotics. In recent retrospective studies, however, catheter retention in CVC infections with coagulase negative staphylococci, the most commonly recovered organism, did not impact infection resolution but did increase recurrence.

(1) Empirical 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. Semiquan-titative cultures of the catheter tip should be performed. Empirical antibiotic therapy with vancomycin and an antipseudomonal penicillin or cephalosporin is indicated. If the patient has been receiving hyperalimentation through the line, empirical therapy against Candida species with amphotericin B or caspofungin may be also needed. Owing to the increasing incidence of resistant Candidaspecies, 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.

If S. aureus is present on blood cultures, a TEE should be performed to rule out infective endocarditis in non-neutropenic patients. If there is no evidence of endocarditis, 2 weeks of antistaphylococcal therapy guided by susceptibility 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 blood 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 bacilli 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”) IV 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 IV 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%.

(2) Empirical 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 vascular catheter infection, evidence of metastatic disease or infection with Candida species, atypical mycobacteria, Bacillus spp., or S. aureus require catheter removal and treatment. Salvage therapy of the line with systemic antibiotic therapy and antibiotic lock therapy can be attempted in selected stable patients with non-virulent pathogens such as S. epidermidis, but clinical deterioration, continued bacteremia, or failure to improve requires catheter removal.

c. Foley catheter/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 meta-static staphylococcal infection. Treatment involves removal of the Foley catheter and correction of any associated obstructions or renal-related problems (e.g., azotemia), if possible. Empirical therapy for complicated UTIs could include quinolones with good urinary concentration such as ciprofloxacin or levofloxacin, extended spectrum β-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 empirical therapy in immunocompromised hosts.

Duration of therapy is usually 2 weeks but patients should be improving and afebrile 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.

d. Diarrhea

(1) 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 also can be associated with typhlitis. Evaluation 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.

(2) Empirical 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 vancomycinresistant enterococcus (VRE).

(3) In patients with suspected typhlitis, broad-spectrum antibiotic therapy with good anaerobic coverage is indicated, such as ceftazidime plus metronidazole or imipenem-cilastatin, meropenem, or 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 the involved bowel.

D. Directed therapy against specific pathogens

Before the results of susceptibility testing, empirical therapy against specific or suspected pathogens needs to be chosen on the basis of the most likely patterns of resistance. Microbial susceptibility profiles are influenced by a number of factors, including earlier antibiotic exposure, clinical scenario of infection, and institutional and community resistance patterns (Table 27.4).

1. S. aureus. As previously mentioned, risk factors for 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 van-comycin, linezolid, daptomycin, and quinupristin-dalfopristin. For methicillin-susceptible S. aureus, good treatment options include β-lactam antibiotics such as nafcillin, cefazolin or ceftriaxone, and β-lactam/β-lactamase inhibitor combinations such as piperacillin-tazobactam or vancomycin, if allergic to β-lac-tams. Bacteriostatic antibiotics such as TMP-SMZ, clindamycin, or doxycycline should generally not be used as first-line therapy in patients with severe S. aureus infections.

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2. S. epidermidis, Coagulase-negative staphylococci are often resistant to β-lactams (>80%). When these infections are suspected (often line-associated), good initial antibiotic choices include vancomycin, linezolid, daptomycin, or quinupristin-dalfopristin.

3. Enterococcus. Treatment of enterococcal endocarditis or other severe enterococcal infection generally requires synergy with a β-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 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 susceptibility.

4. P. aeruginosa. Serious Pseudomonas infections (e.g., bacteremia, ecthyma gangrenosum) may require synergistic combinations of antipseudomonal β-lactams (such as piperacillin or cefepime) and an aminoglycoside. Other treatment options include monotherapy with an antipseudomonal β-lactam, imi-penem or meropenem, ciprofloxacin, or aztreonam. Resistance can occur with treatment, resulting in treatment failure.

5. Candida species. Candida albicans is usually susceptible to fluconazole, amphotericin B, caspofungin, micafungin, anidulafungin, and voriconazole. C. glabrata and C. krusei have decreased susceptibility to fluconazole (85% and 5% sensitive, respectively) but are usually susceptible to amphotericin B, caspofungin, and voriconazole. Two other commonly seen Candida species (Candidaparapsilosis and Candida tropicalis) are usually susceptible to fluconazole, amphotericin B, vori-conazole, and echinocandins, but have decreased sensitivity to itraconazole. Newer agents such as posaconazole are generally not used as first-line Candida agents.

6. Aspergillus. Aspergillus species (Aspergillusfumigatus, Aspergillus flavus, Aspergillus terreus, and Aspergillus niger) are resistant to fluconazole. Voriconazole was more effective than ampho-tericin B in one large study of invasive aspergillosis in immu-nocompromised hosts. In addition to amphotericin B and voriconazole, echinocandins have activity in invasive aspergillosis. Combination therapy with echinocandins and voriconazole has been successfully used in patients with invasive aspergillosis, but large-scale randomized studies are lacking.

7. PCP. TMP-SMZ at high doses (5 mg/kg IV every 8 hours) is the primary treatment for PCP. If the PaO2 is less than 70 mm Hg, prednisone 40 mg orally every 12 hours is added for 5 days, then 20 mg daily for 11 days. Other commonly used treatment choices for PCP include pentamidine (IV) or atovaquone (oral).

8. CMV can cause a variety of end-organ diseases. CMV pneumonia is generally treated with high-dose ganciclovir (2.5 mg/kg IV every 8 hours) with IV IVIG. CMV retinitis can be treated with oral valganciclovir or IV ganciclovir. Other antivirals with CMV activity include foscarnet and cidofovir.

IV. INFECTIONS IN RECIPIENTS OF HEMATOPOIETIC STEM CELL TRANSPLANT (HSCT)

The management of recipients of HSCT 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 recipients of HSCT are available and are listed in “Selected Readings.”

A. Evaluation of infection based on temporal approach

One classic approach to the evaluation of infection in patients with bone marrow transplant 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 ANC greater than 500 cells/(μL and platelet count of more than 20,000 (μL for three or more consecutive days without transfusion.

1. Pre-engraftment (phase I: generally first month after transplant).

Pathogens likely to cause infection in the pre-engraftment period include the following:

bull Viral: HSV seasonal respiratory and enteric viruses

bull Bacteria: S. epidermidis, S. aureus, viridans streptococcus, Pseudomonas species, Enterobacteriaceae, and other gram-negative rods

bull Fungus: Candida species, Aspergillus.

2. Early postengraftment (phase II: generally first 30 to 100 days after transplant). Pathogens likely to cause infection in this phase include the following:

bull Other human herpesviruses such as EBV, seasonal respiratory viruses, and enteric viruses

bull Bacterial: L. monocytogenes, Legionella species, S. epidermidis, Streptococcus species, and S. aureus

bull Fungus: Aspergillus and other molds (e.g., Zygomycetes, Pseudallescheria boydii), and Pneumocystis

bull Parasites: Toxoplasma gondii and S. stercoralis.

3. Late postengraftment (phase III: generally more than 100 days after transplant). Pathogens likely to cause infection in this phase include the following:

bull Viral: VZV EBV, and other human herpesviruses (e.g., CMV, human herpesvirus-8), hepatitis B, hepatitis C, seasonal respiratory viruses, and enteric viruses

bull Bacteria: encapsulated bacteria such as S. pneumonia, H. influenza, and N. meningitidis

bull Fungi: Pneumocystis, Aspergillus, and other molds

bull Parasitic: T. gondii.

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 patients not treated with HSCT

1. Antibacterial prophylaxis. Multiple randomized placebo controlled studies of antibiotic prophylaxis in afebrile 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 afebrile 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 gastrointestinal decontamination (e.g., aminoglycosides, oral vancomycin) and systemically absorbed antibiotics such as TMP-SMZ and fluoroquinolones. Oral nonabsorbable antibiotics for prophylaxis in afebrile neutropenic patients with cancer are not recommended on the basis of previous studies, but controversy exists regarding the use of TMP-SMZ and quinolones.

a. TMP-SMZ. Studies onuseofTMP-SMZforthemostparthave shown some decrease in infection rates in afebrile neutropenia with little effect on overall mortality. The development of resistant organisms and potential bone marrow suppression are important disadvantages in the routine prophylactic use of TMP-SMZ. The current 2011 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.

b. Fluoroquinolones. Oral quinolones have been studied extensively for prophylaxis in afebrile neutropenic patients with mixed results. Use of agents such as ciprofloxacin in randomized trials has shown a decrease in gram-negative bacillary infections, but an increase in infections with resistant organisms and gram-positive cocci. More recent studies of levofloxacin demonstrate improved outcome. The current 2011 IDSA guidelines for use of antimicrobial agents in neutropenic patients with cancer recommend consideration of prophylactic use of quinolones in neutropenic patients. However, a recent meta-analysis of antibiotic prophylaxis in neutropenia patients showed potential reduction in mortality with fluoroquinolone use.

2. Antifungal prophylaxis. The 2011 IDSA guidelines for antimicrobial prophylaxis in neutropenic patients recommends against use of fluconazole for antifungal prophylaxis and consideration of use of posaconazole. Several studies have shown a decrease in fungal infections and associated mortalities in patients receiving fluconazole and posaconazole prophylaxis. Additional studies are in progress for specific oncologic populations, such as those with acute myeloid leukemia. Use of newer agents such as posaconazole has resulted in decreased fungal infections and improved overall survival, but with increased side effects in patients with neutropenia.

3. Antiviral prophylaxis with oral acyclovir in HSV-Ab–positive patients reduces the frequency of mucocutaneous HSV infection.

B. Prophylaxis of infection in HSCT

The American Society for Blood and Marrow Transplantation and the IDSA recommend prophylaxis for encapsulated bacteria, Pneumocystis, HSV, and VZV (with prophylactic or pre-emptive therapy for CMV) and antifungal prophylaxis for patients receiving chronic corticosteroids 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.

1. Bacterial prophylaxis. There are no recommendations for use of specific antibiotics for bacterial prophylaxis in patients with HSCT. 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 hypogamma-globinemia during the early postengraftment phase.

2. Fungal prophylaxis. Fluconazole 400 mg orallyper day until engraftment is currently recommended.

3. PCP and toxoplasmosis prophylaxis. One TMP-SMZ double-strength tablet daily or three times per week. Prophylaxis for PCP should begin before transplantation.

4. Viral prophylaxis. Multiple strategies (prophylaxis orpre-emptive) exist to decrease the incidence of CMV infection and reactivation in patients with HSCT. One strategy is the use of IV ganciclovir 5 g/kg IV every 12 hours for 1 week, then 5 days/week until day 100 posttransplant 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.

5. Other prophylactic strategies

a. 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.

b. Infection control measures. Strict attention to infection control measures should be practiced by recipients of HSCT, caregivers, and healthcare workers, especially strict attention to hand washing. Some unique aspects of infection control include the following;

bull While in the hospital, strict attention should be paid to air flow and air filtration, possible exposure to construction in the hospital environment, and exposure to healthcare workers with seemingly minor infections such as adenovirus conjunctivitis.

bull Recipients of HSCT should avoid exposure to respiratory and enteric viruses (i.e., wear surgical mask during close contact with people with respiratory illness).

bull Contact with sick pets should be minimized and excellent pet health should be maintained.

bull Patients should avoid reptiles, chicks, ducklings, and exotic pets.

bull Patients should avoid well water.

bull 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 recipients of HSCT.

bull Use of a low microbial diet is recommended (cooked foods are preferred; avoid sushi and salad dressings made with raw eggs).

bull Vaccination of family members and household contacts should be done as per current Advisory Committee on Immunization Practices guidelines. Currently, family members and household contacts should receive all age-appropriate vaccinations and influenza, hepatitis A, MMR, and varicella vaccinations, if indicated. Oral polio vaccine should be avoided. Updated information about vaccines can be accessed at www.cdc.gov/vaccines.

Selected Readings

Bucaneve G, Micozzi A, Menichetti F, et al. Levofloxacin to prevent bacterial infection in patients with cancer and neutropenia. NEngl J Med. 2005;353:977–987.

Centers for Disease Control and Prevention. Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients: recommendations of CDC, the Infectious Disease Society of America, and the American Society of Blood and Marrow Transplantation. MMWR Morb Mortal WklyRep. 2000;49(RR-10):1–128.

Centers for Disease Control and Prevention. Recommended adult immunization schedule-United States, October 2005-September 2006. MMWR. 2005; 54(48):Q1–Q4.

Cornely OA, Maertens J, Winston DJ, et al. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. NEngl J Med. 2007;356:348–359.

Cullen M, Steven N, Billingham L, et al. Antibacterial prophylaxis after chemotherapy for solid tumors and lymphomas. NEngl J Med. 2005;353:988–998.

Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2011;52:427–431.

Gafter-Gvili A, Fraser A, Paul M, Leibovici L. Meta-analysis: antibiotic prophylaxis reduces mortality in neutropenic patients. Ann Intern Med. 2005;142(12 Pt 1):979–995.

Garey KVV Rege M, Pai MP, et al. Time to initiation of fluconazole therapy impacts mortality in patients with candidemia: a multi-institutional study. Clin Infec Dis. 2006;43:25–31.

Hall K, Farr B. Diagnosis and management of long-term central venous catheter infections. J Vasc Interv Radiol. 2004;15:327–334.

Helbig JH, Uldum SA, Bernander S, et al. Clinical utility of urinary antigen detection for diagnosis of community-acquired, travel-associated and nosocomial legionnaires' disease. J Clin Microbiol.2003;41:838–840.

Jaksic B, Martinelli G, Perez-Oteyza J, Hartman CS, Leonard LB, Tack KJ. Efficacy and safety of linezolid compared with vancomycin in a randomized, double-blind study of febrile neutropenic patients with cancer. Clin Infec Dis.2006; 42:1813–1814.

McDonald LC, Killgore GE, Thompson A, et al. An epidemic, toxin gene-variant strain of Clostridium difficile. NEngl J Med. 2005;353:2442–2449.

Mermel L, Farr B, Sherertz RJ, et al. Guidelines for the management of intravascular catheter-related infections. Clin Infect Dis. 2001;32:1249–1272.

Pappas PG, Rex JH, Sobel JD, et al. Guidelines for treatment of candidiasis. Clin Infect Dis. 2004;38:161–189.

Raad I, Kassar R, Ghannam D, Chaftari AM, Hachem R, Jiang Y. Management of the catheter in documented catheter-related coagulase-negative staphyloccal bacteremia: remove or retain? Clin Infect Dis.2009:49:1187–1194.

Rizzo JD, Wingard JR, Tichelli A, et al. Recommended screen and preventive practices for long-term survivors after hematopoietic cell transplantation: joint recommendations of the European Group for Blood and Marrow Transplantation, the Center for International Blood and Marrow Transplant Research, and the American Society of Blood and Marrow Transplantation (EBMT/CIBMTRA/ASBMT). BoneMarrow Transplant. 2006;37:249–261.

Rubin RH, Young LS. Clinical Approach to Infections in the Compromised Host. New York: Kluwer Academic Klenum Publishers; 2002. Sable CA, Donowitz GR, Infections in bone marrow transplant recipients. Clin Infect Dis.1994;18:223.

Safdar N, Fine JP, Maki DG. Meta-analysis: methods for diagnosing intravascular device-related bloodstream infection. Ann Intern Med. 2005;142(6):451–466.

Sung L, Nathan P, Shabbir MH, Tomlinson GA, Beyene J. Meta-analysis: effect of prophylactic hematopoietic colony-stimulating factors on mortality and outcomes of infection. Ann Intern Med.2007;147:400–411.

Van Burik J, Weisdoft D. Infections in recipients of hematopoietic stem cell transplantation. In: Mandel GL, Bennett JE, Dolin R, eds. Principles and Practices of Infectious Diseases. Philadelphia: Elsevier Churchill Livingstone; 2005.

Vetter E, Torgerson C, Feuker A, et al. Comparison of the BACTEC MYCO/F lytic bottle to the isolator tube, BACTEC Plus Aerobic F/bottle, and BACTEC Anaerobic Lytic/10 bottle and comparison of the BACTEC Plus Aerobic F/bottle to the isolator tube for recovery of bacteria, mycobacteria and fungi from blood. J Clin Microbiol. 2001;39(12):4380–4386.

Walsh TJ, Pappas P, Winston DJ, et al. Voriconazole compared with liposomal am-photericin B for empirical antifungal therapy in patients with neutropenia and persistent fever. NEngl J Med.2002;346(4):225–234.

Walsh TJ, Teppler H, Donowitz GR, et al. Caspofungin versus liposomal amphotericin B for empirical antifungal therapy in patients with persistent fever and neutrope-nia. NEngl J Med. 2004;351:1391–1402.