Infections are among the most common, potentially serious complications of cancer and its treatment. This chapter discusses infections from a syndromic approach: that is, infections present to the clinician as a complex of signs and symptoms. The syndromes addressed include febrile neutropenia, pneumonia, catheter-associated infections, and gastrointestinal infections (Clostridium difficile–associated diarrhea and typhlitis). Special sections focus on fungal and viral infections.
Infection During Febrile Neutropenia
It has long been recognized that the incidence of infection is high in patients who develop a fever during neutropenia and that empiric antimicrobial therapy is warranted in such patients.
Fever is usually defined as a temperature ≥ 38.3°C (about 101°F).
Neutropenia is defined as an absolute neutrophil count (ANC) of < 500/μL, although patients with a neutrophil count between 500 and 1,000/μL in whom a decrease is anticipated are considered to be neutropenic. Patients with a neutrophil count < 100/μL are at greatest risk for infection, as are those with a rapid decrease in neutrophil count and those with protracted neutropenia (> 7 days).
Bacterial infections occurring during episodes of febrile neutropenia are caused predominantly by aerobic gram-negative bacilli (especially Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa) and gram-positive cocci (coagulase-negative staphylococci, β-hemolytic streptococci, viridans streptococci, enterococci, and Staphylococcus aureus). In recent years, multidrug-resistant organisms have become more prominent.
Fungal infections usually occur after a patient has received broad-spectrum antimicrobial therapy and/or steroids. The most common fungal pathogens are Candida species (predominantly C albicans and C glabrata) and Aspergillus species. Less common are Mucorales (Zygomycetes), Fusarium, and Scedosporium infections (see also section on “Fungal infections”).
Viral infections occurring during neutropenia are caused predominantly by herpesviruses and respiratory viruses. The herpesviruses include herpes simplex virus (HSV), varicella zoster virus (VZV), cytomegalovirus (CMV), human herpes virus 6 (HHV-6), and Epstein-Barr virus (EBV). The respiratory viruses include adenovirus, respiratory syncytial virus (RSV), parainfluenza virus, influenza A and B viruses, human metapneumovirus, and rhinovirus (see also section on “Viral infections”).
The most remarkable aspect of the febrile, neutropenic patient is the lack of physical findings. This is due to the neutropenia and the absence of an inflammatory response at the infection site. The patient may have only a fever, with or without chills or rigors. Even if the patient has pneumonia, there may be few respiratory symptoms. Likewise, a perirectal abscess may be relatively asymptomatic.
An initial evaluation and diagnostic workup of any fever in a neutropenic patient should begin immediately but should not delay the initiation of empiric therapy. A complete history (exposures, past infections, rashes, cough, abdominal pain, diarrhea) should be taken and a physical examination (of skin lesions, exit site and tunnel of central venous catheters, oropharynx, abdomen, perineum) should be performed.
Diagnostic workup should include:
- at least two sets of blood cultures: one from a peripheral vein and one from each port of a central venous catheter. If fever persists in the face of negative cultures, blood cultures for fungi and acid-fast bacilli should be considered.
- culture of any drainage from a catheter exit site
- stool examination for C difficile and other bacterial/protozoal agents, especially if diarrhea is present
- urine culture and urinalysis
- chest radiograph
- respiratory samples for culture
- cerebrospinal fluid exam and culture if meningitis is suspected
- aspiration or biopsy of any skin lesions.
CT of sinus, chest, abdomen, and pelvis can be performed, as per clinical judgement. If central nervous system infection is suspected, CT of the brain can be performed (followed by lumbar puncture).
Determination of serum transaminases, complete blood count, and serum creatinine levels is also recommended. Other useful serologies include Aspergillus galactomannan, beta-D-glucan, Coccidioides antibody panel, and histoplasmosis antigen, depending on the region.
Initial empiric antibiotic therapy
The choice of initial empiric antibiotic therapy for the febrile, neutropenic patient should be broad spectrum and is dictated in part by the susceptibility pattern of blood isolates seen at a particular cancer center (Figure 1).
If the prevalence of extended-spectrum beta-lactamase (ESBL) gram-negative bacteria is high, for example, one probably would not want to use a third-generation cephalosporin such as ceftazidime as initial empiric monotherapy. Some data suggest that prolonged use of ceftazidime monotherapy in this setting promotes the emergence of ESBL bacteria. City of Hope has used ceftazidime as initial monotherapy for the past 15 years, however, without a significant rise in the incidence of resistant gram-negative infections, and this experience has been shared by other centers. Finally, any special circumstance, such as the suspicion of an indwelling IV catheter–associated infection, may influence the antibiotic choice.
When choosing an antibiotic, the clinician should take into consideration the patient’s allergies and other drugs administered that may interact with the empiric antimicrobial agent. The clinician should adjust for hepatic and renal function to limit toxicity, ie, seizures with beta-lactams such as cefepime.
Either a single antibiotic or antibiotic combinations can be used for initial empiric therapy (see Table 1 for dosage regimens).
High-risk patients. High-risk patients require hospitalization for IV empirical antibiotic therapy. Monotherapy with an antipseudomonal β-lactam (cefepime, imipenem-cilastatin, meropenem, or piperacillin-tazobactam) is recommended. Other antimicrobials (aminoglycosides, fluoroquinolones, and/or vancomycin) may be added for management of complications (eg, hypotension and pneumonia) or if antimicrobial resistance is suspected or proven (Figure 1).
Vancomycin. Vancomycin or other agents active against aerobic gram-positive cocci are not recommended as a standard part of the initial regimen for fever and neutropenia. These agents should only be considered empirically for clinical situations such as the following:
- hemodynamic instability or other evidence of severe sepsis
- pneumonia documented radiographically
- positive blood culture for gram-positive bacteria, before the identification and susceptibility testing results are available
- clinically suspected serious catheter-related infection (eg, chills or rigors with infusion through a catheter and cellulitis around the catheter entry/exit site)
- skin or soft-tissue infection at any site
- colonization with methicillin-resistant S aureus, vancomycin-resistant enterococcus, or penicillin-resistant Streptococcus pneumoniae
- severe mucositis, if fluoroquinolone prophylaxis has been given and ceftazidime is employed as empirical therapy
Modifications to initial empiric therapy. Modifications to initial empiric therapy may be considered for patients at risk for infection with the following antibiotic-resistant organisms, particularly if the patient’s condition is unstable or if the patient has positive blood cultures suspicious for resistant bacteria. These include methicillin-resistant S aureus (MRSA), vancomycin-resistant enterococci (VRE), ESBL-producing gram-negative bacteria, and carbapenem-resistant enterobacteriaceae (CRE) (including K pneumoniae carbapenemase [KPC] or metallo-beta-lactamase producers [MBLs]). Risk factors include previous infection or colonization with the organism and treatment in a hospital with high rates of endemicity. Recommended management is as follows:
- MRSA: Consider early addition of vancomycin, linezolid, or daptomycin (daptomycin is not recommended for patients with respiratory infection, ie, pneumonia, due to inactivation by surfactant).
- VRE: Consider early addition of linezolid or daptomycin.
- ESBLs: Consider early use of carbapenem
- KPCs, MBLs: Consider early use of colistin or tigecycline (Tygacil). Caution: monotherapy with colistin has been associated with treatment failures.
Most penicillin-allergic patients. Most penicillin-allergic patients tolerate cephalosporins, but those with a history of immediate-type hypersensitivity reaction (eg, hives and bronchospams) should be treated with a combination that avoids penicillins or cephalosporins, such as ciprofloxacin plus clindamycin or aztreonam plus vancomycin.
Afebrile neutropenic patients. Afebrile neutropenic patients who have new signs or symptoms suggestive of infection should be evaluated and treated as high-risk patients.
Low-risk patients. Low-risk patients should receive initial oral or IV empirical antibiotic doses in a clinic or hospital setting. They may be transitioned to outpatient oral or IV treatment if they meet specific clinical criteria. Criteria for the low-risk designation include neutropenia expected to resolve within 7 days and no active medical comorbidity, as well as stable and adequate hepatic and renal function.
- Ciprofloxacin plus amoxicillin-clavulanate in combination is recommended for oral empirical treatment. Other oral regimens, including levofloxacin or ciprofloxacin monotherapy, or ciprofloxacin plus clindamycin, are less well studied but are commonly used.
- Patients receiving fluoroquinolone prophylaxis should not receive oral empirical therapy with a fluoroquinolone.
- Hospital readmission or continued stay in the hospital is required for patients with persistent fever or signs and symptoms of worsening infection.
Double β-lactam therapy. Double β-lactam therapy is discouraged because of concerns about increased expense and toxicity without added benefit, and the possibility of antagonism.
Changes in initial therapy
Modifications to the initial antibiotic regimen should be guided by clinical and microbiologic data (Figure 2).
Unexplained persistent fever. Unexplained persistent fever in a patient whose condition is otherwise stable rarely requires an empirical change to the initial antibiotic regimen. If an infection is identified, antibiotics should be adjusted accordingly.
Documented infections. Documented infections, confirmed either clinically and/or microbiologically, should be treated with antibiotics appropriate for the site and for the susceptibilities of any isolated organism.
• Vancomycin—If vancomycin or other antibiotic for gram-positive organisms was initiated, it may be stopped after 2 days if there is no evidence of a gram-positive infection.
• Patients who remain hemodynamically unstable—Patients who remain hemodynamically unstable after initial doses with standard agents for neutropenic fever should have their antimicrobial regimen broadened to include coverage for resistant gram-negative, gram-positive, and anaerobic bacteria and fungi.
• Low-risk patients—Low-risk patients who have initiated IV or oral antibiotics in the hospital may have their treatment approach simplified if they are clinically stable.
- An IV-to-oral switch in the antibiotic regimen may be made if patients are clinically stable and their gastrointestinal absorption is believed to be adequate.
- Selected hospitalized patients who meet criteria for being at low risk may be transitioned to the outpatient setting to receive either IV or oral antibiotics, as long as adequate daily follow-up is ensured. If fever persists or recurs within 48 hours in outpatients, hospitalization is recommended, with management as for high-risk patients.
• Empirical antifungal coverage—Empirical antifungal coverage should be considered in high-risk patients who have persistent fever without an identifiable source after 4 to 7 days of treatment with a broad-spectrum antibacterial regimen (Figure 3).
Duration of empirical antibiotic therapy
Patients with documented infections. In patients with documented infections, clinically or microbiologically, the duration of therapy is dictated by the isolated organism and site. Appropriate antibiotics should be selected based on culture and sensitivity, and continued for at least the duration of neutropenia (until ANC is ≥ 500/μL) or longer if clinically necessary.
Patients with unexplained fever. In patients with unexplained fever, it is recommended that the initial regimen be continued until there are clear signs of marrow recovery. The traditional endpoint is an increasing ANC that exceeds 500/μL.
If an appropriate treatment course has been completed and all signs and symptoms of a documented infection have resolved, patients who remain neutropenic may resume oral fluoroquinolone prophylaxis until marrow recovery.
Attempts to prevent infection in the neutropenic host focus on two broad areas: preventing acquisition of pathogenic organisms and suppressing or eradicating endogenous microbial flora.
Hand hygiene. The simplest, most effective, and least expensive way to prevent acquisition of potential pathogens is to institute strict hand-washing precautions.
Food. Food should be well-cooked. Prepared luncheon meat should be avoided. Well-cleaned, uncooked raw fruits and vegetables are acceptable, provided that freshness of ingredients and the means of preparation can be confirmed.
Water purification systems (to eliminate Legionella organisms) and high-efficiency particulate air (HEPA) filtration systems (to eliminate fungal spores) can decrease the rates of acquisition of these pathogens.
Hematopoietic cell transplantation (HCT) recipients should be placed in private (ie, single-patient) rooms. Allogeneic HCT recipients should be placed in rooms with > 12 air exchanges/hour and HEPA filtration.
Plants and dried or fresh flowers should not be allowed in the rooms of hospitalized neutropenic patients.
Hospital work exclusion policies should be designed to encourage healthcare workers to report their illnesses or exposures.
Fluoroquinolone prophylaxis should be considered for high-risk patients with expected durations of prolonged and profound neutropenia (ANC ≤ 100/μL for > 7 days). Levofloxacin and ciprofloxacin have been evaluated most comprehensively and are considered roughly equivalent, although levofloxacin is preferred in situations with increased risk for oral mucositis–related invasive viridans group streptococcal infection. A systemic strategy for monitoring the development of fluoroquinolone resistance among gram-negative bacilli is recommended. Levofloxacin use has also been associated with the emergence of hypervirulent C difficile enterocolitis.
Addition of a gram-positive–active agent to fluoroquinolone prophylaxis is generally not recommended.
Antibacterial prophylaxis is not routinely recommended for low-risk patients who are anticipated to remain neutropenic for < 7 days.
Pneumocystis jirovecii pneumonia. In patients at risk for P jirovecii pneumonia (patients undergoing allogeneic HCT, those with lymphoma, or those receiving steroids), trimethoprim-sulfamethoxazole, administered for only 2 or 3 days per week, can reduce the incidence of infection.
High-Risk. Prophylaxis against Candida infections is recommended in patients in whom the risk of invasive candidal infections is substantial, such as allogeneic HCT recipients or those undergoing intensive remission-induction or salvage induction chemotherapy for acute leukemia. Fluconazole, itraconazole, voriconazole (Vfend), posaconazole, micafungin (Mycamine), and caspofungin are acceptable choices.
Prophylaxis against invasive Aspergillus infections with posaconazole (Noxafil) should be considered for selected patients 13 years of age and older who are undergoing intensive chemotherapy for AML (acute myelogenous leukemia)/MDS (myelodysplastic syndrome) in whom the risk of invasive aspergillosis without prophylaxis is substantial.
Prophylaxis against Aspergillus infection in pre-engraftment allogeneic or autologous HCT recipients has not been shown to be efficacious. However, a mold-active agent is recommended in patients with prior invasive aspergillosis, anticipated prolonged neutropenic periods of at least 2 weeks, or a prolonged period of neutropenia immediately prior to HCT (see also the “Prevention” section under “Fungal infections”).
Low-Risk. Antifungal prophylaxis is not recommended for patients in whom the anticipated duration of neutropenia is < 7 days.
Acyclovir. Patients at risk for mucositis (ie, those undergoing induction therapy for leukemia or lymphoma or HCT) who have evidence of prior HSV infection (positive serology) should receive prophylaxis with twice-daily acyclovir (see Table 1 for dose).
Antiviral treatment for HSV or VZV is only indicated if there is clinical or laboratory evidence of active viral disease. Also see section on “Viral Infections.”
Ganciclovir. Ganciclovir has been shown to be effective “preemptively” in preventing CMV interstitial pneumonia in allogeneic HCT recipients who demonstrate evidence of viremia by polymerase chain reaction (PCR), antigen testing, or positive blood cultures (see section on “Viral infections”).