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 as a complex of signs and symptoms to the clinician. 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.

Definitions

Fever is usually defined as a temperature ≥ 38.3°C.

Neutropenia is defined as a neutrophil count 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.

Etiology

Bacteria 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, gram-positive infections have become more prominent with the increasing use of indwelling IV catheters.

Fungi 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 tropicalis) and Aspergillus species. Less common are Fusarium, Scedosporium, and Zygomycetes infections (see also section on “Fungal infections”).

Viruses 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), and Epstein-Barr virus (EBV). The respiratory viruses include adenovirus, respiratory syncytial virus, parainfluenza virus, influenza A and B viruses, and rhinovirus (see also section on “Viral infections”).

Signs and symptoms

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.

Diagnosis

An initial evaluation and diagnostic work-up of any fever in a neutropenic patient should begin immediately but should not delay the initiation of empiric therapy (see below). A complete history (exposures, past infections, rashes, cough, abdominal pain, diarrhea) should be taken and a physical examination (skin lesions, exit site and tunnel of right atrial catheter, oropharynx, abdomen, perineum) should be performed.

Diagnostic work-up 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

• urine culture and urinalysis

• chest radiograph

• aspiration or biopsy of any skin lesions.

CT If indicated by signs or symptoms, CT scans of the brain (followed by lumbar puncture), chest, abdomen, and pelvis can be performed.

Laboratory tests Determination of serum transaminases, CBC, and serum creatinine is also recommended.

Treatment

INITIAL EMPIRIC ANTIBIOTIC THERAPY

Initial antibacterial therapy in the febrile, neutropenic patient should be broad-spectrum and should be based on the prevalence and susceptibility of bacterial isolates seen in the individual hospital setting (Figure 1). When choosing an antibiotic, the clinician also should take into consideration the patient’s allergies, renal and hepatic function, and other drugs he or she is receiving that may interact with the empiric antimicrobial agent.

The choice of initial empiric antibiotic therapy for the febrile, neutropenic patient is dictated in part by the susceptibility pattern of blood isolates seen at a particular cancer center. 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 been using 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.

Either single antibiotics or antibiotic combinations can be used for initial empiric therapy (see Table 1 for dosage regimens).

Monotherapy

Ceftazidime, cefepime (Maxipime), imipenem-cilastatin (Primaxin), or meropenem (Merrem), when used as monotherapy, avoids the potential for nephrotoxicity. However, none of these antibiotics covers coagulase-negative staphylococci, methicillin-resistant S aureus (MRSA), vancomycin-resistant or vancomycin-susceptible enterococci, some strains of penicillin-resistant Streptococcus pneumoniae, and viridans streptococci. Also, ceftazidime does not cover anaerobes well, and imipenem-cilastatin may have CNS toxicity at high doses.