Bethesda Handbook of Clinical Oncology, 2nd Edition

Supportive Care

36

Infectious Complications in Oncology

Sarah M. Wynne*

Juan C. Gea-Banacloche

*Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland

Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

FEVER IN NONNEUTROPENIC CANCER PATIENTS

Patients with cancer may have fever for many reasons other than infection, including the underlying malignancy, medications, blood products, and graft-versus-host disease. Infections, however, are a significant problem in patients, regardless of the type of malignancy and the stage of treatment. In addition to neutropenia, there are several other factors that contribute to increased susceptibility to infection.

  • Local factors include breakdown of barriers (i.e., mucositis and surgery) that provide a portal of entry for bacteria, and obstruction (i.e., biliary obstruction, ureteral obstruction, and bronchial obstruction) that facilitates local infection (e.g., cholangitis, pyelonephritis, and postobstructive pneumonia).
  • Intravascular devices, drainage tubes, or stents may become colonized by microorganisms and may lead to local infection, bacteremia, or fungemia.
  • Splenectomy increases the susceptibility to infection caused by Streptococcus pneumoniaeand other encapsulated bacteria.
  • Deficiencies of humoral immunity (e.g., multiple myeloma and chronic lymphoid leukemia) lead to increased susceptibility to encapsulated organisms such as S. pneumoniaeand Haemophilus influenzae.
  • Defects in cell-mediated immunity (e.g., lymphoma, hairy cell leukemia, treatment with steroids, fludarabine and other drugs, and T-cell–depleted hematopoietic stem cell transplantation) increase the susceptibility to opportunistic infections from Legionella pneumophila, Mycobacteriumspecies, Cryptococcus neoformans, Pneumocystis jiroveci, cytomegalovirus (CMV), varicella-zoster virus (VZV), and other pathogens.

Antibiotic Therapy in Nonneutropenic Cancer Patients

  • Antibiotics should be administered empirically in cases of fever in patients with cancer who do not exhibit neutropenia only when a bacterial infection is considered likely.
  • In the absence of localizing signs and symptoms, bacteremia should be considered, particularly in patients with intravascular devices. Many authorities recommend empiric antibiotics (e.g., levofloxacin and ceftriaxone) until bacteremia is ruled out.
  • Clinically documented infections and sepsis should be treated with antibiotics as warranted by the clinical scenario.

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  • Whenever antibiotics are started, a plan with specific endpoints should be formulated to avoid unnecessary toxicity, superinfection, and development of resistance.

FEVER IN NEUTROPENIC CANCER PATIENTS

Neutropenia is the most important risk factor for developing bacterial infection in patients with cancer. The risk of developing infection increases with the rapidity of onset and with the degree and duration of neutropenia. Patients with febrile neutropenia require immediate evaluation and prompt initiation of empiric antibiotics (see Fig. 36.1). Empiric broad-spectrum antibiotics with activity against Pseudomonas aeruginosa must be initiated as soon as the clinical evaluation is completed.

 

FIG. 36.1. Approach to patients with fever and neutropenia, without clinically or microbiologically documented infection. For specific infections, see text and Table 36.2. *Vancomycin should be discontinued after 48–72 hours if there is no bacteriological documentation of a pathogen requiring its use, except in soft-tissue or tunnel infections. This “rescue” antibacterial regimen will vary between institutions depending on the local patterns of antibiotic resistance. Carbapenem + fluoroquinolone/aminoglycoside + vancomycin is typical. For a detailed discussion of antifungal therapy options, see text. MRSA, methicillin (oxacillin)-resistant Staphylococcus aureus; PRSP, penicillin-resistant Streptococcus pneumoniae; ANC, absolute neutrophil count.

Definitions

  • Fever: an oral temperature higher than 38.3C or two oral temperatures >38°C measured 1 hour apart.
  • Neutropenia: an absolute neutrophil count (ANC) <500 per mm3, or an ANC between 500 per mm3and 1,000 per mm3, with a predicted decline to <500 per mm3 within 48 hours.

Etiology

  • There is a microbiologically documented infection (most commonly bacteremia) in 10% to 20% of patients with fever and neutropenia.
  • There is clinical evidence of infection in 20% to 30% of patients with fever and neutropenia.
  • There is no microbiologically documented infection and no clinical evidence of infection other than fever in 50% to 70% of patients with fever and neutropenia.
  • Gram-positive and gram-negative bacteria are isolated with similar rates of occurrence.
  • Gram-negative bacteremia may be associated with faster clinical decompensation and death; therefore, empiric treatment is targeted to cover gram-negative pathogens, particularly Pseudomonasspecies.
  • Candidaand Aspergillus species are the most common causes of fungal infections in patients with neutropenia and become more prevalent as the duration of neutropenia increases.

Evaluation

  • History and physical examination should be performed, with special attention to potential sites of infection: skin, mouth, perianal region, and catheter exit site.
  • Routine complete blood count, chemistries, urinalysis, blood and urine cultures, and chest x-ray should be obtained.
  • Any accessible sites of possible infection should be sampled for Gram stain and culture (i.e., catheter site, sputum, etc.).
  • Antibiotics should be administered as soon as cultures have been obtained.

Empiric Antibiotic Therapy

Several options are available for the initial empiric therapy of neutropenic fever with no localizing signs or symptoms of infection. Either a single antibiotic regimen or a combination of antibiotics may be used.

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Monotherapy

Monotherapy with select broad-spectrum β-lactams with activity against Pseudomonas species is as effective as combination antibiotic regimens (β-lactam plus aminoglycoside) for empiric therapy for uncomplicated fever and neutropenia, and it has fewer toxicities.

Antibiotics recommended by the Infectious Diseases Society of America (IDSA) include (doses for adults with normal renal function)

  • ceftazidime, 2 g i.v. every 8 hours
  • cefepime, 2 g i.v. every 8 hours
  • imipenem–cilastatin, 500 mg i.v. every 6 hours
  • meropenem, 1 g i.v. every 8 hours.

Combination Therapy

Combination therapy should be used empirically to broaden the antibacterial spectrum in certain clinical circumstances.

Combination therapy should be used in the following cases:

  • Severe sepsis or septic shock
  • High prevalence of multi-drug resistant gram-negative bacilli.

Effective antibiotic combinations include one of the aforementioned β-lactams (i.e., ceftazidime, cefepime, imipenem, or meropenem) and an aminoglycoside. Ciprofloxacin may be used instead of an aminoglycoside if the prevalence of quinolone-resistant bacteria is low.

Role of Vancomycin

Vancomycin should not be part of the initial empiric regimen unless one or more of the following circumstances applies:

  • Clinically suspected catheter-related infections (not the mere presence of an intravascular device)
  • Known colonization with penicillin-resistant S. pneumoniae(PRSP) or methicillin-resistant Staphylococcus aureus (MRSA)
  • Severe mucositis
  • Severe sepsis or septic shock.

Adding vancomycin to the initial regimen because of persistent fever alone does not improve the outcome and is not recommended.

Oral Therapy

Oral therapy may be acceptable for initial empiric therapy in certain patients with febrile neutropenia who are at low risk for developing infection. A scoring system based on patient characteristics and clinical symptoms may be useful in selecting patients who are eligible for oral therapy (see Table 36.1). The patients with a score of greater than or equal to 21 of 26 possible points, indicating low risk, can be considered for oral therapy. The following drug regimen is recommended: Ciprofloxacin, 750 mg PO every 12 hours, plus amoxicillin/clavulanate, 125 mg, 875 mg (amoxicillin component) PO every 12 hours.

TABLE 36.1. Multinational Association for Supportive Care in Cancer (MASCC) Index: A Scoring System Based on Patient Characteristics and Symptoms Used for Selecting Patients Who are Suitable Candidates for Oral Therapy (Score ≥21 of 26 Possible Points)

Characteristic

Score

From The Multinational Association for Supportive Care in Cancer risk index: a multinational scoring system for identifying low-risk febrile neutropenic cancer patients. J Clin Oncol 2000;18(16):3038–3051, with permission.

Burden of illness:

 

– no or mild symptoms

5

– moderate symptoms

3

No hypotension

5

No chronic obstructive pulmonary disease

4

Solid tumor or no previous fungal infection

4

No dehydration

3

Outpatient status

3

Age <60 yr

2

Most patients should be started on antibiotics as inpatients. Following discharge, these patients should see the physician daily and should be instructed to call or come to the clinic if new or worsening symptoms are noted or if persistent high fever is present.

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Modifications of the Initial Antibiotic Regimen

Modification of therapy is often necessary (30% to 50% of cases) during the course of treatment of fever and neutropenia. Specific clinical syndromes (see Table 36.2) or microbiologic isolates dictate specific modifications of therapy to the approach toward the management of the syndrome therapy.

TABLE 36.2. Specific Infectious Diseases Syndromes in Oncology Patients and Approach to Diagnosis and Management

Clinical syndrome

Diagnostic considerations

Management

VRE, vancomycin-resistant enterococci; VZV, varicella zoster virus; HSV, herpes simplex virus; DFA, direct fluorescent antibody; IVIG, intravenous immunoglobulin; CT, computerized tomography; CMV, cytomegalovirus.

Intravascular catheter associated infections

·         Infections can be local, involving the exit site or subcutaneous tunnel, or systemic, causing bacteremia

·         For local infections, check culture of exit-site discharge as well as blood cultures

·         For tunnel and systemic infections, empiric therapy should include vancomycin as well as gram-negative coverage (e.g., ceftazidime, cefepime, and ciprofloxacin)

·         Intravascular catheters should be removed in certain situations
– tunnel infections
– blood cultures remain positive for pathogens after 72 h of therapy
– specific pathogens: Mycobacterium spp,Bacillus spp., VRE, S. aureus, fungi
– case-by-case decision for C. jeikeium and gram-negative organisms

Skin/soft-tissue infections

·         Prompt biopsy with histologic staining and culture for bacteria, mycobacteria, viruses, and fungi

·         Pathogens: S. aureusS. pyogenes, gram-negative bacilli (e.g., Pseudomonas), VZV, HSV, Candida species

·         For vesicular lesions, scrape base for DFA for VZV and culture for HSV

·         Ecthyma gangrenosum: include coverage ofPseudomonas (e.g., ceftazidime, cefepime, ciprofloxacin)

·         Infections with S. pyogenes: treat aggressively with penicillin G, clindamycin, IVIG, and surgical debridement

·         Perianal cellulitis: broad-spectrum coverage including anaerobes (e.g., imipenem)

·         VZV, HSV: acyclovir

Sinusitis

·         Evaluate with CT scan and examine by otolaryngologist

·         Tissue should be biopsied if there is suspicion of fungal infection or if there is no response to antibiotic therapy after 72 h

·         Pathogens: S. pneumoniae,H. influenzaeM. catarrhalisS. aureus, gram-negative bacilli (e.g.,Pseudomonas), and fungi

·         Nonneutropenic patient: levofloxacin or amoxicillin/clavulanate

·         Neutropenic: broad-spectrum coverage including Pseudomonas (e.g., imipenem), and consider antifungal coverage (e.g., amphotericin B)

Pulmonary infections

·         CT scan and bronchoalveolar lavage should be performed early

·         Pneumonias in any patient with cancer are often caused by gram-negative bacilli and S. aureus as well as by community-acquired pneumonia pathogens:
S. pneumoniaeH. influenzaeLegionella spp.,Chlamydia pneumoniae

·         Neutropenic patients are at risk for invasive fungal infections, particularly aspergillosis

·         Patients with cell-mediated defects are at risk for infections with PCP, viruses (i.e., CMV, VZV, and HSV),Nocardia spp., andLegionella

·         Mycobacteria should also be considered, particularly in patients with previous exposure

·         For all patients, ensure adequate coverage of community-acquired pneumonia (e.g., newer-generation fluoroquinolone or azithromycin)

·         Neutropenic patients: include coverage of S. pneumoniae and Pseudomonas (e.g., newer-generation fluoroquinolone and ceftazidime); add antifungal coverage if pneumonia develops with treatment by antibiotics (e.g., amphotericin B and voriconazole)

·         Cell-mediated immunodeficiency: consider coverage of Pneumocystis with trimethoprim/sulfamethoxazole, CMV with ganciclovir and IVIG, and Nocardia with trimethoprim/sulfamethoxazole

Gastrointestinal tract infections

·         Lesions associated with mucositis can be superinfected with HSV orCandida species

·         Esophagitis can be caused by Candida species, HSV, and CMV

·         Diarrhea is most commonly caused by C. difficile (send toxin assay) but can also be caused by Salmonella,ShigellaAeromonasE. coli, viruses, parasites, etc.

·         Enterocolitis in neutropenic patients is most commonly caused by a mix of organisms includingClostridium spp. andPseudomonas

·         Mucositis or esophagitis: acyclovir and fluconazole

·         C. difficile: metronidazole or vancomycin if refractory

·         Neutropenic enterocolitis: broad-spectrum antibiotics with activity against a Pseudomonas(e.g., imipenem)

Urinary-tract infections

·         Pathogens: gram-negative bacilli, Candida species

·         Consider whether candiduria may represent disseminated candidiasis

·         Remove catheter to clear colonization

·         Neutropenic patient: treat bacteriuria/candiduria regardless of symptoms

·         Nonneutropenic patient: reserve treatment for symptomatic episodes

·         Antibiotic treatment should be tailored to the organism

CNS infections

·         Bacteria cause most cases of meningitis (e.g., S. pneumoniaeListeria, andN. meningitides)

·         In patients with cell-mediated immunodeficiency, also consider Listeria orCryptococcus

·         Encephalitis is most commonly caused by HSV but consider other viruses

·         Brain abscesses may be confused with tumor

·         Bacterial meningitis: ceftriaxone, vancomycin, and ampicillin

·         Cryptococcal meningitis: amphotericin B with flucytosine

·         Encephalitis: acyclovir (consider ganciclovir)

Empiric Antifungal Therapy

Candida and Aspergillus infections are the most common fungal infections, and their occurrence increases with increased duration of neutropenia. An antifungal agent should be added empirically for patients with neutropenia who have persistent or recurrent fever after 4 to 7 days of broad-spectrum antibiotic therapy. Treatment options include the following:

  • Amphotericin B deoxycholate, 0.6 to 1 mg/kg/day i.v.
  • Liposomal amphotericin B (AmBisome), 3 to 5 mg/kg/day i.v.
  • Voriconazole, 6 mg per kg i.v. every 12 hours for 24 hours, followed by 4 mg per kg i.v. every 12 hours
  • Itraconazole, 200 mg i.v. every 12 hours for 48 hours, followed by a 200-mg daily dosage
  • Fluconazole, 400 mg per day i.v. or PO
  • Caspofungin, 70 mg i.v. loading dose, followed by 50 mg i.v. daily

The authors' recommendations:

  • If the patient has not been receiving antifungal prophylaxis and if the patient has fever and neutropenia for more than 3 days, fluconazole 400 mg i.v. or PO daily should be added from day 4.
  • If the patient has been receiving antifungal prophylaxis or is at high risk for an Aspergillusinfection, he or she should be treated with voriconazole, caspofungin, liposomal amphotericin (5 mg/kg/day), or amphotericin B (1 mg/kg/day).

Duration of Antibiotic Therapy

  • Documented bacterial infection: Antibiotics should be continued for the standard period for that bacterial infection or should be continued until neutropenia is resolved, whichever is longer.
  • Uncomplicated fever and neutropenia of uncertain etiology: Antibiotics should be continued until the fever has resolved and until the ANC is >500 per mm3for 24 hours.
  • Antifungal agents can also be discontinued when there is no documented fungal infection.

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SPECIFIC INFECTIOUS DISEASE SYNDROMES

If a patient presents with clinical signs and symptoms of a specific infection, with or without neutropenia, the workup and therapy are guided by the clinical suspicion for that infection (Table 36.2). After patients are started on empiric antibiotics for fever and neutropenia, they must be monitored closely for the development of signs or symptoms of infection, and antibiotic therapy must be modified accordingly.

Bacteremia/Fungemia

  • A positive blood culture should prompt immediate initiation of therapy with appropriate antibiotics in a patient with neutropenia or in a patient who is not neutropenic and is febrile or unstable.
  • If the isolated organism is commonly pathogenic, such as S. aureusor gram-negative bacilli, antibiotics should be started even if the patient is afebrile and clinically stable.
  • If the isolate is a common contaminant, such as a coagulase-negative Staphylococcus, and if the patient is not neutropenic, is afebrile, and is clinically stable, it may be appropriate to repeat the cultures and observe before starting antibiotics.
  • Whenever bacteremia is documented, blood cultures should be repeated to confirm the effectiveness of the therapy, and the source of the infection should be sought.

Gram-positive Bacteremia

Gram-positive Cocci

  • Coagulase-negative Staphylococcusspecies is the most common cause of bacteremia. In the setting of neutropenia or clinical instability, vancomycin should be started.
  • S. aureusbacteremia is associated with a high likelihood of metastatic complications if not treated adequately. Intravascular devices should be removed, and transesophageal echocardiogram should be performed to rule out endocarditis.
  • Oxacillin and nafcillin are the drugs of choice for treating a S. aureusinfection; vancomycin should be reserved for the treatment of patients who are allergic to penicillin or for methicillin-resistant S. aureus (MRSA) infection.
  • Bacteremia with viridans group streptococci may cause overwhelming infection with sepsis and acute respiratory distress syndrome (ARDS) in a patient with neutropenia; vancomycin therapy should be used until susceptibility results are obtained.
  • The risk factors for viridans group streptococci bacteremia include severe mucositis (particularly, following treatment with cytarabine), active oral infection, and prophylaxis with trimethoprim/sulfamethoxazole or a fluoroquinolone.
  • Enterococci often cause bacteremia in debilitated patients who have been hospitalized for a long period and who have been receiving broad-spectrum antibiotics.
  • Vancomycin-resistant enterococci (VRE) are an increasingly common cause of bacteremia and should be treated promptly with linezolid (600 mg q12h) or quinupristin–dalfopristin (7.5 mg per kg q8h).

Gram-positive Bacilli

  • Clostridium septicumis associated with sepsis and metastatic myonecrosis during neutropenia. Treatment is with high-dose penicillin or a carbapenem.
  • Listeria monocytogenesmay cause bacteremia with or without encephalitis in patients with defects in cell-mediated immunity. Ampicillin plus gentamicin is the treatment of choice.
  • Other gram-positive bacilli such as Bacillus, Corynebacterium, Lactobacillus, and Propionibacteriumspecies are common contaminants of blood cultures, but, in the setting of neutropenia, these bacilli can cause true catheter-related infection.

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Gram-negative Bacteremia

  • Gram-negative bacteria in the blood should never be considered contaminants and should be treated immediately.
  • Therapy should be initiated with two antimicrobials to ensure adequate coverage until susceptibility results are available.
  • Escherichia coliand Klebsiella species are the most prevalent gram-negative pathogens in patients with neutropenia; however, the use of prophylactic antibiotics such as ciprofloxacin or trimethoprim/sulfamethoxazole may increase the prevalence of more resistant enteric organisms such as Enterobacter, Citrobacter, and Serratia species.
  • The prevalence of strains of Klebsiellaand E. coli that produce extended-spectrum β-lactamases (ESBLs) is increasing; carbepenems are the drugs of choice for these organisms.
  • P. aeruginosais among the most lethal agents of gram-negative bacteremia in the patient with neutropenia; combination therapy should be started to ensure that the patient is receiving at least one antimicrobial agent to which the isolate is susceptible.
  • Stenotrophomonas maltophiliais an increasingly common cause of infection in patients who have been on broad-spectrum antibiotics or in those who have intravascular catheters; trimethoprim/sulfamethoxazole is the treatment of choice. For the allergic patient, ticar cillin–clavulanate or levofloxacin may be effective.
  • Acinetobacter baumanniibacteremia is frequently associated with infected intravascular catheters in patients with cancer and is often resistant to multiple antibiotics, including imipenem–cilastatin. Ampicillin-sulbactam or colistin may be effective, but an infectious diseases specialist should be consulted.

Fungemia

  • Candidaspecies cause most cases of fungemia in patients with cancer. The prevalence of non-albicans candidemia is increasing.
  • Non-albicans species are likely to be resistant to fluconazole and should be treated with caspofungin, amphotericin B, or a lipid formulation of amphotericin B.
  • All patients with candidemia should undergo ophthalmologic evaluation with a funduscopic examination. In most cases, intravascular catheters should be removed.

Intravascular Catheter–Associated Infections

Definitions

  • Exit-site infections are diagnosed clinically by the presence of erythema, induration, and tenderness within 2 cm of the catheter's exit site.
  • A tunnel infection is characterized by erythema along the subcutaneous tract of a tunneled catheter that extends 2 cm beyond the exit site.
  • Catheter-associated bloodstream infection is defined by positive blood cultures or by a positive catheter tip culture.

Management

  • The following recommendations refer to management of implanted catheters of the Hickman-Broviac type and to long-term intravascular devices. The management of peripheral lines and non-permanenet lines includes a much lower threshold for removal of the catheter.
  • If a local infection is suspected, a swab of the exit-site discharge should be sent for culture, in addition to blood cultures.
  • Uncomplicated site infections (i.e., no signs of systemic infection or bacteremia) can be managed with local care and with oral antibiotics such as dicloxacillin.

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  • If the patient has fever in addition to an exit-site infection or if there is substantial cellulitis around the catheter site, vancomycin (i.v.) should be used empirically while awaiting culture results.
  • Tunnel infections require intravenous antibiotics and removal of the catheter; empiric therapy should include vancomycin, as well as agents such as ceftazidime, cefepime, or ciprofloxacin for coverage of gram-negative bacilli. Therapy can then be modified if an organism is identified.
  • Catheter-related bloodstream infections caused by coagulase-negative Staphylococcusor gram-negative bacilli should be treated with antibiotics for a total of 14 days. Initially, therapy should be delivered intravenously and continued as long as the patient remains neutropenic. Once cultures are found to be negative for the bacteria, therapy can be changed to oral antibiotics provided the patient is clinically stable and no longer neutropenic.
  • The management of exit-site infections and tunnel infections is illustrated in Fig. 36.2.
 

FIG. 36.2. Management of catheter-related infections. *Exit-site infection: erythema, induration, and tenderness within 2 cm of the catheter exit site; *tunnel infection: erythema, induration, and tenderness along the subcutaneous tract of a tunneled catheter that extends 2 cm beyond the exit site.

Indications for Removal of Intravascular Catheters

Indwelling intravascular catheters should be removed in the following situations:

  • Tunnel infections
  • Blood cultures remain positive after 48 to 72 hours of therapy (regardless of the pathogen)
  • Cultures are positive for
  • S. aureus
  • Bacillusspecies
  • Vancomycin-resistant enterococci
  • Mycobacteriumspecies
  • Candidaspecies

In case of catheter-related infections caused by Corynebacterium jeikeium, Pseudomonas, Stenotrophomonas, and other gram-negative pathogens, the decision of whether to remove the catheter should be made on a case-by-case basis.

Skin and Soft-tissue Infections

  • Soft-tissue infections may represent local or disseminated infection.
  • A biopsy for staining and culture for bacteria, mycobacteria, viruses, and fungi should be considered early in the evaluation of skin and soft-tissue infections.
  • Ecthyma gangrenosum often presents in patients with neutropenia as a dark, necrotic lesion but can be variable in appearance. It is a typical manifestation of P. aeruginosabacteremia and may also be caused by bacteremia from other gram-negative bacilli. Antibiotic therapy with coverage of Pseudomonas should be initiated and a surgeon should be consulted.
  • VZV and herpes simplex virus (HSV) generally present as vesicular lesions. Scrapings from the base of vesicles should be sent for direct fluorescent antibody (DFA) testing to diagnose VZV and for shell-vial culture to diagnose HSV. Treatment of VZV in the immunocompromised host involves acyclovir 10 mg per kg i.v. every 8 hours and that for HSV involves acyclovir 5 mg per kg i.v. every 8 hours.
  • Patients with cancer are at increased risk for streptococcal toxic shock syndrome and severe soft-tissue infections caused byStreptococcus pyogenes. The treatment is aggressive surgical debridement and antibiotic therapy with penicillin G and clindamycin, as well as intravenous immunoglobulin (IVIG).
  • Perianal cellulitis may develop in patients with neutropenia. Antibiotic therapy should include gram-negative and anaerobic coverage (e.g., imipenem–cilastatin or meropenem as single agents or ceftazidime plus metronidazole). A computerized tomography (CT) scan should be obtained to rule out a perirectal abscess. Incision and drainage may also be required in the setting of abscess or unremitting infection, but, if possible, this should be delayed until neutropenia is resolved.

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Sinusitis

  • In the absence of an immunocompromised state, the common pathogens of acute sinusitis in patients who are not immunocompromised are S. pneumoniae, H. influenzae, and Moraxella catarrhalisas well as S. aureus. Acute sinusitis is treated with levofloxacin, 500 mg daily, or amoxicillin–clavulanate, 875 mg twice daily.
  • In immunocompromised hosts, sinusitis can also be caused by aerobic gram-negative bacilli including Pseudomonas. Furthermore, patients with neutropenia are at high risk for fungal sinusitis.
  • During neutropenia, sinusitis should be treated with broad-spectrum antibiotics including coverage of Pseudomonas. A sinus CT scan should be obtained and an otolaryngologist should be consulted. Biopsy should be obtained if there is any suspicion of fungal infection (e.g., bone erosion on CT scan, necrotic eschar of nasal turbinates) or if there is no response to antibiotic therapy within 72 hours.
  • If fungal sinusitis is confirmed, it should be treated with surgical debridement, and antifungal treatment should be started at maximum dosing:
  • amphotericin B; 1 to 1.5 mg/kg/day
  • liposomal amphotericin B; 5 to 7.5 mg/kg/day
  • voriconazole may be substituted only after it is certain that the infection is not caused by Zygomycetes(i.e., Mucor or Rhizopus), which are not susceptible to voriconazole.

Pneumonia

Pulmonary infiltrates in the immunocompromised host can be from infectious or noninfectious causes. It is important to obtain an etiologic diagnosis, and the authors recommend early use of bronchoalveolar lavage (BAL) if a diagnostic sputum specimen cannot be obtained.

Pulmonary Infiltrates in the Neutropenic Patient

  • Adequate coverage for community-acquired pneumonia should be added to the antibiotic regimen (e.g., newer-generation fluoroquinolone in addition to ceftazidime).
  • CT scan and bronchoscopy for BAL should be performed early.
  • If pulmonary infiltrates appear while the patient is treated with broad-spectrum antibiotic therapy, the likelihood of fungal pneumonia is high. Empiric antifungal coverage with voriconazole, liposomal amphotericin B, or amphotericin B should be started immediately.

Fungal Pneumonia

  • Aspergillusspecies are the most common molds that cause disease in patients with cancer. Neutropenia is the most important risk factor followed by use of corticosteroids.
  • Clinical presentation:
  • Persistent or recurrent fever
  • Development of pulmonary infiltrates while being treated with antibiotics
  • Chest pain, hemoptysis, or a pleural rub
  • In the setting of allogeneic hematopoietic stem cell transplantation, most cases of Aspergilluspneumonia occur well into the engraftment period. The most important risk factors in this setting are graft-versus-host disease, use of corticosteroid, and CMV disease.
  • The demonstration of fungal elements in tissue obtained by biopsy is necessary for a definitive diagnosis of fungal pneumonia. When a biopsy is not possible, positive respiratory cultures (i.e., sputum or BAL fluid) are highly predictive of invasive disease in a high-risk patient.
  • Options for treatment of aspergillus pneumonia include:
  • voriconazole (6 mg per kg i.v. every 12 hours for 24 hours followed by 4 mg per kg i.v. every 12 hours)

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  • high-dose liposomal amphotericin B (5 to 7.5 mg/kg/day)
  • amphotericin B (1 to 1.5 mg/kg/day)
  • caspofungin (70 mg loading dose followed by 50 mg per day i.v.) has been approved for patients with invasive aspergillosis who are unresponsive to or intolerant of the above-mentioned antifungal agents.
  • Zygomycetessuch as Rhizopus, Mucor, and Cunninghamella species are less common causes of pulmonary infection in patients with neutropenia, and these species are resistant to voriconazole. Treatment should include early aggressive surgical debridement where feasible and high-dose amphotericin B.
  • Fusariumspecies rarely cause pulmonary infection in patients with neutropenia. Voriconazole or high-dose amphotericin can be used for treatment. Response is usually contingent on neutrophil recovery.
  • Dematiaceous fungi such as Scedosporium, Alternaria, Bipolaris, Cladosporium, and Wangiellaspecies also rarely cause pneumonia in patients with neutropenia. Treatment is with itraconazole or voriconazole.

Pulmonary Infiltrates in Patients with Defects in Cell-mediated Immunity

  • In addition to the common bacterial causes of pneumonia, patients with defects in cell-mediated immunity are at risk for infections withP. jiroveci, Nocardiaspecies, and viruses, as well as with Legionella, mycobacteria, and fungi.
  • Bronchoscopy for BAL should be performed.
  • Empiric antibiotics should include a newer generation fluoroquinolone for coverage of bacterial pathogens such as Legionellaand trimethoprim/sulfamethoxazole for coverage of Pneumocystis. Consideration should also be given to antifungal and antiviral agents depending on the clinical presentation.

Pneumocystis Pneumonia

  • Patients with pneumonia from P. jiroveciusually present with rapid onset of dyspnea, nonproductive cough, hypoxemia, and fever.
  • Radiologic studies generally show diffuse bilateral interstitial infiltrates but can show focal infiltrates.
  • Treatment should be started on the basis of clinical suspicion: trimethoprim/sulfamethoxazole 5 mg per kg i.v. every 8 hours (prednisone should be added if the partial pressure of oxygen (PO2) is <70 mm Hg).

Nocardia

  • Pneumonia from Nocardiaspecies can cause a dense lobar infiltrate or multiple pulmonary nodules with or without cavitation.
  • Diagnosis is made from material obtained at bronchoscopy, either by pathology or by culture.
  • Treatment is with trimethoprim/sulfamethoxazole, with or without ceftriaxone. Depending on the species, imipenem–cilastatin with amikacin may also be used.

Viral Pneumonia

  • Pneumonia caused by respiratory viruses [i.e., respiratory syncytial virus (RSV), influenza, parainfluenza, and adenovirus] is more common in patients with defects in cell-mediated immunity. Treatment with ribavirin (for RSV and parainfluenza) or with cidofovir (for adenovirus), may be considered, but these agents have not been shown to change outcome.

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  • CMV pneumonia is a considerable complication of allogeneic stem cell transplantation that typically develops between 40 and 100 days after transplantation. CMV pneumonia after day 100 is becoming more common and typically presents with fever, dyspnea, hypoxemia, and diffuse interstitial infiltrates.
  • After allogeneic stem cell transplantation, the presence of CMV in the BAL culture is considered sufficient to establish the diagnosis of CMV pneumonia. In other settings, tissue biopsy is required.
  • Treatment of CMV pneumonia is with ganciclovir (5 mg per kg i.v. every 12 hours) and with IVIG (500 mg per kg q48 h). Foscarnet (90 mg per kg q12 h) may be substituted.
  • HSV, VZV, and human herpesvirus 6 (HHV-6) have also been associated with pneumonitis in the immunocompromised patient.

Gastrointestinal Infections

Mucositis

  • The shallow painful ulcerations of the tongue and buccal mucosa caused by chemotherapy can become superinfected with HSV or withCandidaspecies.
  • If severe, HSV infection is treated with acyclovir 5 mg per kg i.v. every 8 hours for 7 days. If the infection is less severe, valacyclovir 1,000 mg PO every 12 hours or famciclovir 500 mg PO every 12 hours can be used.
  • Candidiasis can be treated locally with clotrimazole troches 10 mg dissolved in the mouth 5 times daily or systemically with fluconazole 200 mg PO or i.v. once followed by 100 mg daily.

Esophagitis

  • Odynophagia, dysphagia, and substernal chest discomfort can be a result of chemotherapy but may also be caused by herpes or candidal infections.
  • Endoscopy with biopsy should be performed when possible.
  • If endoscopy and biopsy are not possible, empiric therapy with fluconazole for Candidaspecies and acyclovir for HSV is recommended.
  • CMV can also cause esophagitis.

Diarrhea

  • Clostridium difficileis the most common pathogen that causes diarrhea in cancer patients.
  • Diagnosis is made by the presence of C. difficileantigen in the stool.
  • Treatment is with metronidazole 500 mg PO three times a day or, in refractory cases, with vancomycin 125 mg to 250 mg PO four times a day. Metronidazole can be given intravenously in patients who are unable to tolerate oral therapy. Treatment is continued for 10 to 14 days.
  • Bacteria such as E. coli and Salmonella, Shigella, Aeromonas, and Campylobacterspecies, as well as parasites and viruses are less common causes of diarrhea in patients with cancer. Stool should be sent for culture for bacterial pathogens and examined for ova and parasites. Specific therapy should be directed against the recovered pathogens.

Neutropenic Enterocolitis (Typhlitis)

  • Typhlitis typically presents as abdominal pain, rebound tenderness, bloody diarrhea, and fever in the setting of neutropenia. The diagnosis should be considered in the case of abdominal pain during neutropenia.

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  • The diagnosis is frequently made on the basis of characteristic CT scan findings: a fluid-filled, dilated, and distended cecum, often with diffuse cecal wall edema and, possibly, with air in the bowel wall (pneumatosis intestinalis).
  • Pathogens are typically mixed aerobic and anaerobic gram-negative bacilli (including Pseudomonas) and Clostridiumspecies.
  • Treatment is with broad-spectrum antibiotics including coverage of Pseudomonas(e.g., imipenem or meropenem or the combination of ceftazidime plus metronidazole plus vancomycin)
  • Patients should be monitored closely for the development of complications that may require surgical intervention, such as bowel perforation, bowel necrosis, or abscess formation.

Hepatosplenic Candidiasis

  • Hepatosplenic candidiasis presents typically as neutropenic fever without localizing signs or symptoms.
  • When neutropenia resolves, the patient will continue to have fever, may develop right upper quadrant pain and hepatosplenomegaly, and will have significant elevations in alkaline phosphatase levels.
  • CT scan, ultrasonography, or magnetic resonance imaging (MRI) will show hypoechoic and/or bulls-eye lesions in the liver and spleen.
  • Treatment consists of a prolonged course of fluconazole 400 to 800 mg daily.

Urinary-tract Infections

  • In the presence of neutropenia, bacteriuria should be treated even in the absence of symptoms.
  • In a patient who does not have neutropenia, treatment should be reserved for symptomatic episodes.
  • Candiduria may represent colonization in a patient with an indwelling urinary catheter, particularly in the setting of broad-spectrum antibiotics, and removal of the catheter is usually sufficient to clear it.
  • Persistent candiduria can occasionally cause infections such as pyelonephritis or disseminated candidiasis in immunocompromised patients. In addition, candiduria can indicate disseminated candidiasis.
  • Fluconazole 400 mg per day for 1 to 2 weeks is the treatment of choice for urinary tract infections. In the case of non–albicans Candida, another azole or amphotericin should be used. Caspofungin is minimally present in the urine, and there is no clinical experience in this setting.

Central Nervous System Infections

  • Changes in mentation or level of consciousness, headache, or photophobia should be evaluated promptly with MRI and lumbar puncture.
  • In addition to the usual bacterial causes of meningitis (i.e., S. pneumoniaeand Neisseria meningitides), Listeria and Cryptococcusspecies should also be considered, particularly when a defect in cell-mediated immunity is present.
  • For Listeriaspecies, the treatment of choice is ampicillin 2 g i.v. every 4 hours in combination with gentamicin loading dose of 2 mg/kg i.v. followed by 1.7 mg/kg i.v. every 8 hours. Once daily dosing (5 mg/kg) is also possible, but there is less experience.
  • For Cryptococcusspecies, treatment is with liposomal amphotericin B 3 mg/kg/day or with amphotericin B 0.5 to 0.7 mg/kg/day in combination with flucytosine 37.5 mg per kg q6h for 2 weeks. If the patient improves (i.e., is afebrile and cultures are negative forCryptococcus species), the regimen can be changed to fluconazole 400 mg daily.

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  • Encephalitis in patients with cancer is most commonly caused by HSV and should be treated with acyclovir 10 mg per kg i.v. every 8 hours. VZV, CMV, and HHV-6 are other less common causes of encephalitis.
  • Brain abscesses that develop during neutropenia are typically caused by fungi (most commonly Aspergillusand Candida). Bacterial abscesses may also be a local extension of infection (e.g., sinusitis and odontogenic infection) caused by mixed aerobic and anaerobic flora (e.g., streptococci, Staphylococcus, and Bacteroides). While the results from the biopsy and cultures are pending, empiric treatment with ceftazidime plus vancomycin plus metronidazole plus voriconazole is recommended.

PROPHYLAXIS

Antibacterial Prophylaxis

  • Fluoroquinolones are the most commonly used antibiotics for prophylaxis against bacterial infections in patients with neutropenia and can considerably reduce the occurrence of gram-negative infections. However, they may increasethe occurrence of gram-positive infections, and they do not appear to affect the outcome.
  • Fluoroquinolone prophylaxis can result in the emergence of resistance among enteric gram-negative bacteria.
  • The routine use of fluoroquinolone prophylaxis is not recommended for all patients with neutropenia but can be considered in high-risk patients such as those who are expected to have a long duration of neutropenia.

Antiviral Prophylaxis

Herpes Simplex Virus

  • Prophylaxis against HSV should be considered in patients who are seropositive or who have a history of herpetic stomatitis and are undergoing allogeneic stem cell transplantation or highly immunosuppressive chemotherapy.
  • Prophylaxis should be given, beginning with the conditioning chemotherapy before transplantation and continued for 100 days post-transplantation and until immunosuppressants are discontinued.
  • The medications of choice are valacyclovir 500 mg PO daily or acyclovir 250 mg per m2i.v. every 12 hours.

Cytomegalovirus

  • Ganciclovir, given prophylactically, can reduce the incidence of CMV disease, but its use is limited by myelosuppressive toxicity.
  • Patients who have undergone allogeneic stem cell transplantation should be monitored for CMV replication by following CMV pp65 antigenemia.
  • If patients are positive for CMV, they should be treated with ganciclovir 5 mg per kg i.v. every 12 hours for 7 days followed by 5 mg per kg i.v. daily until two CMV antigenemia results are negative for the virus 1 week apart.
  • Alternative treatments include (a) foscarnet 90 mg per kg i.v. every 12 hours for 7 days followed by 90 mg per kg daily, (b) valganciclovir 900 mg i.v. every 12 hours for 7 days followed by 900 mg daily, or (c) cidofovir 5 mg per kg i.v. weekly for 2 weeks followed by 5 mg per kg i.v. every alternate week.

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  1. jiroveci Pneumonia Prophylaxis
  • Prophylaxis against Pneumocystisspecies is generally administered to patients with lymphoma, to those who are within the 6-month post-stem cell transplantation period, and to those with a history of Pneumocystis pneumonia.
  • The regimen of choice is trimethoprim (160 mg)/sulfamethoxazole (800 mg) PO 3 days a week.
  • Alternative treatments include (a) inhaled pentamidine 300 mg every 4 weeks, (b) dapsone 100 mg daily [glucose-6-phosphate dehydrogenase (G6PDH) deficiency should be ruled out before using dapsone], or (c) atovaquone 1,500 mg daily.

Antifungal Prophylaxis

  • Antifungal prophylaxis is aimed at reducing invasive Candidainfections, particularly in patients undergoing allogeneic stem cell transplantation.
  • Fluconazole 400 mg PO or i.v. daily is the regimen of choice.
  • An alternative regimen is itraconazole 200 mg i.v. every 12 hours for 2 days followed by 200 mg i.v. daily for 12 days followed by 200 mg PO every 12 hours.
  • Prophylaxis should be continued until 100 days post-transplantation and until immunosuppressants have been discontinued.
  • Use of fluconazole has led to increased occurrence of fluconazole-resistant infections such as Candida tropicalis, Candida parapsilosis, and Candida krusei.
  • It is not known if any intervention provides adequate prophylaxis for invasive fungal infections caused by Aspergillusor other molds. Currently there is not sufficient evidence upon which to base a specific recommendation.

SUGGESTED READINGS

Dykewicz CA. Summary of the guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients. Clin Infect Dis 2001;33:139–144.

Hughes WT, Armstrong D, Bodey GP, et al. Guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis 2002;34:730–751.

Klastersky J, Paesmans M, Rubenstein EB, et al. The multinational association for supportive care in cancer risk index: a multinational scoring system for identifying low-risk febrile neutropenic cancer patients. J Clin Oncol 2000;18:3038–3051.

Mermel LA, Farr BM, Sherertz RJ, et al. Guidelines for the management of intravascular catheter-related infections. Clin Infect Dis2001;32:1249–1272.

NCCP. NCCP practice guidelines for fever and neutropenia. v.1.2004. Available athttp://www.nccn.org/professionals/physician_gls/f_guidelines.asp

Picazo JJ. Management of the febrile neutropenic patient: a consensus conference. Clin Infect Dis 2004;39:S1–S6.

Pizzo PA. Fever in immunocompromised patients. N Engl J Med 1999;341:893–900.

Vidal L, Paul M, Ben dor I, et al. Oral versus intravenous antibiotic treatment for febrile neutropenia in cancer patients: a systematic review and meta-analysis of randomized trials. J Antimicrob Chemother 2004;54:29–37.

Walsh TJ, Pappas P, Winston DJ, et al. National Institute of Allergy and Infectious Diseases Mycoses Study Group. Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy in patients with neutropenia and persistent fever. N Engl J Med2002;346:225–234.

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

Wingard JR. Empirical antifungal therapy in treating febrile neutropenic patients. Clin Infect Dis 2004;39:S38–S43.