Types of febrile episodes

A specific causative pathogen is identified in about 20–25% of febrile episodes in neutropenic patients (microbiologically documented infections). An additional 20–25% of episodes have identifiable sites of infection (e.g., pneumonia, cellulitis, and enterocolitis) but have negative cultures (clinically documented infections). Approximately 40–45% have neither an obvious clinical focus of infection nor positive cultures, and are referred to as episodes of unexplained fever (Figure 1). The majority of these are presumed to be due to an occult infection and respond to antibiotic therapy. Fewer than 5% of febrile episodes are due to non-infectious causes such as transfusion reactions, tumor fever, or drug fever.^{2, 3}

Sites of infection

The most common sites of infection encountered in neutropenic patients are the respiratory tract followed by the bloodstream (including central line-associated bloodstream infection-CLABSI), the urinary tract, skin and skin structure infections (SSSIs), and infections originating from the oro-pharynx and the gastrointestinal tract (Figure 2). Less frequent but clinically important sites include the central nervous system, bones, joints, and end organs such as the liver and spleen. Most microbiologically documented infections are caused by the patient’s own microflora with a minority being acquired from exogenous sources/environmental exposure.

Infections in patients with solid tumors

Patients with solid tumors who are not significantly immunosuppressed also develop infections frequently. Risk factors include neutropenia that is generally short lived, disruption of normal anatomic barriers (skin and mucosal surfaces), obstruction caused by bulky or rapidly expanding tumors, radiation damage, surgical procedures, and the presence of various medical devices. The common sites of infection seen in patients with various solid tumors are summarized in Table 2. The site of infection depends on the location and size of the tumor or the site and nature of the medical device, radiation, or surgical procedure. Surgical site infections and catheter-related infections are caused most often by organisms colonizing the skin, although opportunistic pathogens such as Pseudomonas aeruginosa and other Gram-negative bacilli are beginning to emerge in this setting.¹² Removal of the offending device and complete or partial relief of obstruction are important aspects of the management of infections in patients with solid tumors. If this is not feasible, prolonged suppressive therapy might be necessary.

Bacterial infections

Currently, Gram-positive organisms cause ∼50% of bacterial infections in neutropenic patients (Table 3). Gram-negative bacilli account for ∼18%, and a substantial proportion, especially deep tissue infections, is polymicrobial.^13–16 Bacteria commonly isolated from neutropenic patients are depicted in Table 4. Geographic and institutional variations do exist.¹⁷ Consequently, clinicians should consider local epidemiology and resistance patterns when initiating empiric antibiotic therapy.

^a These data are derived from surveys conducted at the University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Gram-positive bacteria

Coagulase-negative staphylococci (CoNS) are isolated most often and predominantly cause CLABSI.¹⁸ Staphylococcus lugdunensis is a more virulent species and needs more aggressive management.^{19, 20} Staphylococcus aureus is often associated with deep-seated infections (deep abscesses and endocarditis), and all patients with S. aureus bacteremia should be evaluated for such foci.²¹ Other sites of infection include SSSIs, pneumonia, bone and joint infections, and septic thrombophlebitis. Of concern is the increasing rate of methicillin resistance among S. aureus isolates, which is now >50% at many centers.²² Many of these isolates have developed tolerance or reduced susceptibility to vancomycin (referred to as the MIC creep), thereby reducing the efficacy of this agent.^23–27 Alternative therapeutic agents include daptomycin, telavancin, dalbavancin, oritavancin, linezolid, tedizolid, and ceftaroline.^28–30

Viridans group streptococci (VGS) are encountered often in patients with acute leukemia undergoing intensive chemotherapy and in allogeneic HCT recipients.^{31, 32} Risk factors include chemotherapy with agents that induce severe oral mucositis, prophylaxis with fluoroquinolones that can promote the selection of these organisms, and treatment of chemotherapy-induced gastritis with antacids or histamine type 2 (H2) antagonists.^{33, 34} Streptococcus mitis is the predominant species. Bacteremia is the most common manifestation. Some patients develop a rapidly progressive disseminated infection involving the bloodstream, lungs, central nervous system, and skin (Figure 3). This is associated with 25–35% mortality despite aggressive therapy.³⁵ Of concern are reports that 20–60% of VGS are penicillin resistant at some institutions.^{31, 36} Beta-hemolytic streptococci also cause infections in neutropenic patients, but less often than VGS.³⁷

The enterococci colonize the lower intestinal tract.^{38, 39} Common sites of infection are the bloodstream, urinary tract, and intra-abdominal infections. Enterococcus faecalis is the predominant species accounting for 60–70% of isolates. Most E. faecalis strains are susceptible to penicillin, ampicillin, and vancomycin although these agents may lack bactericidal activity. Consequently, combinations of these agents with aminoglycosides are recommended for serious enterococcal infections. Enterococcus faecium isolates often express high-level resistance to the aminoglycosides, ampicillin, and vancomycin-resistant enterococcus (VRE). Risk factors for infection with VRE include intestinal colonization and the use of antimicrobial agents with significant activity against anaerobes (metronidazole, clindamycin, and imipenem).⁴⁰ The administration of vancomycin (both oral and parenteral) is also a risk factor. Established therapeutic options for VRE include linezolid, daptomycin, oritavancin, and quinupristin/dalforpristin.^41–43 Combination therapy may be necessary. Less common but important Gram-positive pathogens include Bacillus spp., Corynebacterium spp., Micrococcus spp., and Stomatococcus mucilaginosus.^{44, 45} Nocardiosis is caused by several Nocardia spp. (Nocardia asteroides complex, Nocardia brasiliensis, and Nocardia otitidiscaviarum). The most common sites of infection are the lungs (70%) and soft tissue sites (16%).⁴⁶ Establishing a specific microbiologic diagnosis is of paramount importance as the differential diagnosis is wide. Trimethoprim/sulfamethoxazole remains the backbone of therapy although it is often combined with the carbapenems, tetracyclines, or aminoglycosides. L. monocytogenes is primarily acquired by the consumption of raw milk or products (cheese) made from raw milk. Bacteremia (75%) and meningoencephalitis (20%) are the most common manifestations.⁴⁷

Immunoglobulins play an important role in the immune systems response to various infections by either opsonization or complement activation. Impaired humoral immunity leads to increased susceptibility to infections caused by S. pneumoniae and other encapsulated organisms.³⁷ The widespread use of the conjugate pneumococcal vaccine has led to a reduction in the frequency of pneumococcal disease especially in pediatric populations.

Gram-negative bacteria

The intestinal tract serves as an important source of infection in neutropenic patients with the predominant pathogens being enteric Gram-negative bacilli. Escherichia coli, Klebsiella spp., and P. aeruginosa remain the three primary pathogens.^{13, 48} Other Enterobacteriaceae (Citrobacter spp., Enterobacter spp., Proteus spp., and Serratia spp.) are less common. Despite a decline in the frequency of Gram-negative infections due to antibacterial prophylaxis, the proportion caused by non-fermentative Gram-negative bacilli (NFGNB) such as P. aeruginosa, Stenotrophomonas maltophilia, and Acinetobacter spp. has increased.⁴⁹ P. aeruginosa is the most frequently isolated and the most virulent NFGNB and causes between 15% and 20% of Gram-negative infections. It is also the most common Gram-negative organism isolated from polymicrobial infections.¹⁶ Infections caused by S. maltophilia are being documented more often in patients with hematologic malignancies and in HCT recipients.^{50, 51} The switch from trimethoprim/sulfamethoxazole (TMP/SMX), which is active against S. maltophilia, to the fluoroquinolones, which generally are not, as preferred agents for prophylaxis, may account for this increase. Other infrequent but important NFGNB include Achromobacter spp., Alcaligenes spp., and non-aeruginosa pseudomonads such as Pseudomonas putida and Pseudomonas fluorescens. Bacteremia is the most common site of infection followed by pneumonia and urinary tract infection. Fever is often the only manifestation of infection. Other manifestations such as ecthyma gangrenosum are uncommon (Figure 4). Polymicrobial infections and infections that are complicated by deep tissue involvement (pneumonia, neutropenic enterocolitis (NEC), and perirectal infections) are associated with greater morbidity and mortality.^{16, 52} The emergence of resistance to β-lactam agents and carbapenems is of great concern.^53–55 Some organisms, especially P. aeruginosa and Acinetobacter spp., have become multi-drug resistant.^{56, 57} Very few options to treat such organisms (colistin, tigecycline, and combination regimens) currently exist, and very few novel agents are in the developmental pipeline.^{58, 59} Many institutions now conduct surveillance studies in high-risk patients looking for fecal colonization with VRE, P. aeruginosa, extended spectrum beta-lactamase (ESBL) producers, and carbapenem-resistant Enterobacteriaceae (CRE), because positive surveillance cultures often predict subsequent infection.^60–63

Impaired cellular immunity is a risk factor for legionellosis. The most common Legionella species causing infection is Legionella pneumophila. Hospital water systems often harbor Legionella spp. and many cases of hospital-acquired legionellosis can be traced to such sources.⁶⁴ Pneumonia is the most common manifestation. The detection of urinary antigens or recovery of the organisms on special media is required to make a specific diagnosis. The fluoroquinolones and macrolides are used most often for treatment and there appears to be no advantage to using them in combination. Non-typhoidal Salmonella and Campylobacter spp. infections are also seen with increased frequency in patients with impaired cellular immunity.⁶⁵

Cell-mediated immunity plays an essential role in the control of mycobacterial infections. The association of tuberculosis and Hodgkin’s disease or hairy cell leukemia has been well established.⁶⁶ Tuberculosis can precede the diagnosis of these malignancies, occur concomitantly, or develop during or after their treatment. Pulmonary infection that produces fever, cough, and weight loss is common. Diffuse pulmonary infiltrates with or without mediastinal enlargement are the most common radiographic findings. Nontuberculous mycobacterial infections are less common.^{67, 68} They produce pulmonary infections, lymphadenitis, SSSIs, catheter-related infections, and disseminated disease. The species isolated most often are Mycobacterium avium-intracellulare, Mycobacterium abscessus, Mycobacterium chelonae, Mycobacterium fortuitum, Mycobacterium kansasii, and Mycobacterium marinum. Prolonged, multiple drug therapy is usually administered for progressive infection.⁶⁹

Anaerobes

Anaerobes are frequently involved in deep-seated, polymicrobial infections such as abdominal/pelvic abscesses, NEC, peri-rectal infections, complicated SSSIs, and pneumonia.^{52, 70} The organisms isolated most often include Peptococcus spp., Fusobacterium nucleatum, Bacteroides spp., and Prevotella spp.⁷¹ Clostridium difficile infection (CDI) is the leading infectious cause of diarrhea in cancer patients in whom there is increased severity of illness, higher mortality, and an increased risk of relapse and complications. Newer diagnostic tests are available including polymerase chain reaction (PCR)-based assays.⁷² Metronidazole is now considered inferior to vancomycin for the treatment of CDI.⁷³ Agents such as rifaximin and nitazoxamide have been used with limited success.^74–76 Fidaxomycin is an oral macrocyclic antibiotic that has been recently approved by the FDA for the treatment of CDI in adults, especially those individuals at greatest risk for relapse.^{77, 78} Fecal transplants have also been used successfully in this setting and appear to be promising.⁷⁹ Preventive measures include strict enforcements of infection control practices, appropriate antimicrobial usage, and improved environment cleaning methods.

Other opportunistic fungi

Mucormycosis (zygomycosis) is still relatively uncommon with the most common pathogens being Rhizopus spp., Mucor spp., Lichtheimia (formerly Absidia) corymbifera, Rhizomucor spp., and Cunninghamella bertholettiae. Invasive pulmonary infection is the most common form of infection. Some patients develop sinopulmonary, rhinocerebral, gastrointestinal, cutaneous, or disseminated infection.^{109, 110} The clinical presentation of mucormycosis is often indistinguishable from aspergillosis. Mucormycosis should be considered in patients who are immunosuppressed and who develop sinusitis or IFI after prolonged exposure to voriconazole, which is not active against these organisms.^111–113 Early diagnosis and administration of antifungal therapy is critical along with surgical debridment of infected tissue. Control of underlying diseases and reversal of risk factors when feasible is also of paramount importance.^{85, 114} Amphotericin B products and posaconazole are the only antifungal agents with reliable activity against Mucorales.¹¹⁵ Isavuconazole has also just been approved for the treatment of mucormycosis. Lipid preparations of amphotericin B are preferred for initial therapy, and there is some evidence to suggest that combining these preparations with an echinocandin might be beneficial.¹¹⁶ Therapy is often switched to posaconazole when feasible. Trichosporon beigelii can cause disseminated infection particularly in patients with severe neutropenia. A variety of skin lesions have been described and occur in approximately 30% of patients. Portals of entry include the gastrointestinal tract, respiratory tract, and intravenous catheter sites. Fusarium spp. have emerged as significant pathogens in patients with neutropenia.¹¹⁷ Localized infections of the lung, sinuses, and skin occur, but most patients have disseminated infection. Cutaneous and subcutaneous skin lesions are frequent.¹¹⁸ Similarly to Aspergillus spp., these organisms invade blood vessels, causing thrombosis and infarction. Usually Fusarium spp. can be isolated readily from blood culture or tissue specimens. It may be difficult to distinguish Fusarium from some other fungi on histopathologic examination. Recovery from this infection depends on resolution of neutropenia, and currently available antifungal agents are at best only marginally effective.^{119, 120}

Various other fungi cause significant infection in neutropenic patients. These organisms include Blastoschizomyces capitatus, Scedosporium spp., Geotrichum candidum, and Malassezia furfur.¹²¹ The majority of patients who are infected have hematologic neoplasms, especially acute leukemia.¹²²