SEVERITY OF NEUTROPENIA

Bacterial, fungal, viral, and parasitic organisms may cause infection in neutropenic patients.¹ Bacterial infections are the most frequent and usually the most serious. The risk for bacterial infection increases when the neutrophil count falls to less than 0.5 × 10⁹/L and becomes especially pronounced at neutrophil counts less than 0.1 × 10⁹/L.¹ The rate of decline and duration of neutropenia are important in determining the risk of bacterial infection. Disruption of mucosal barriers, especially in the oral cavity, esophagus, and bowel, further favors the development of infection by providing portals of entry.

BACTERIAL PATHOGENS

Historically, Gram-negative bacilli have been the most commonly isolated pathogens. These organisms include Klebsiella, Escherichia coli, Pseudomonas, and Proteus. These bacteria are responsible for a variety of infections, including pneumonia, soft-tissue infections, perirectal infections, and bacteremia. Urinary tract infections are less frequent unless a urinary catheter is present or urinary tract obstruction has developed. Meningitis is uncommon.

At present, roughly half of all documented infections in neutropenic patients are caused by Gram-positive pathogens. This likely results from the popularity of semipermanent venous catheters and from the use of prophylactic regimens that are active against Gram-negative rods. Staphylococcal species and Enterococcus are now the pathogens most frequently isolated from neutropenic patients.² Several reports document the increasing frequency of viridans group streptococci as a major pathogen in neutropenic patients, especially in those receiving a hematopoietic stem cell transplant, perhaps because these patients have a higher incidence of mucositis.³ Among infections caused by both Gram-negative and Gram-positive organisms, antibiotic resistance is a growing problem and is discussed under “Bacterial Infections” below. Anaerobic infections are less common unless periodontal or gastrointestinal pathology coexists.

Patients with Hodgkin lymphoma, other lymphomas, or chronic lymphocytic leukemia primarily suffer from impaired cell-mediated immunity and diminished antibody production.⁴ Consequently, the spectrum of infections in these patients differs from that found in neutropenic patients. Bacterial infections, when they occur, tend to result from encapsulated organisms such as Pneumococcus or Haemophilus. Listeria and Nocardia infections also are seen more frequently in this group of patients.⁵

FUNGAL PATHOGENS

Fungal infections are common during periods of prolonged neutropenia and in patients with lymphomas or chronic lymphocytic leukemia who have impaired cell-mediated immunity. Candida species are most frequently isolated. Historically, Candida albicans had been the most common isolate; however, in recent years the number of non-albicans Candida infections has increased, partly as a consequence of widespread prophylaxis against C. albicans.⁶ The gastrointestinal tract serves as a reservoir for Candida, and erosive esophagitis may develop. Candida may also enter the bloodstream via indwelling catheters.

Aspergillus and fungi that cause mucormycosis also may cause invasive disease. The use of mold-active prophylaxis may be associated with an increased incidence of mucormycosis.⁷ These organisms tend to colonize and infect the sinuses and bronchopulmonary tree.

Infections with Cryptococcus, Aspergillus, Coccidioides, Histoplasma, and Candida are more common in patients with leukemia or lymphoma who require chronic glucocorticoid treatment. Coccidioides and Histoplasma are endemic mycoses. Coccidioides is endemic in the southwestern United States, in particular in Arizona and the San Joaquin Valley in California. Histoplasma is endemic in the Ohio and Mississippi River Valleys. Emerging fungal infections with organisms such as Scedosporium have become more common with increased use of mold-active prophylaxis.⁸

Pneumocystis jiroveci is a ubiquitous, endogenous fungus that may cause pneumonia in neutropenic patients and in those with defective cell-mediated immunity.

VIRAL PATHOGENS

Viral infections are especially frequent in patients with impaired cell-mediated immunity. Among viruses that cause infections in immunocompromised hosts, herpes simplex, varicella zoster, cytomegalovirus (CMV), and adenoviruses are the most important. Cutaneous lesions and mucositis often are caused by herpes simplex. Herpes zoster infections may be especially severe and have a propensity for dissemination. Left untreated, primary varicella infections are associated with a high mortality rate. CMV may cause febrile illnesses associated with pneumonia, hepatitis, and/or gastrointestinal tract ulcerations. Respiratory syncytial virus (RSV) and influenza virus are important pathogens causing respiratory illness in stem cell transplant recipients in the winter months.⁹ Virus-associated hemorrhagic cystitis caused by BK virus and adenovirus is common among hematopoietic stem cell transplant recipients.¹⁰

MYCOBACTERIAL PATHOGENS

The association between lymphoid malignancies and tuberculosis, particularly among patients born outside the United States, has been recognized for more than a century. It threatens to become a more frequent, serious problem with the resurgence of tuberculosis and the increased prevalence of drug-resistant strains.^11,12 Nontuberculous mycobacterial infections are common in HIV-positive patients, but are less common in patients receiving chemotherapy.¹³

The development of an infection in a neutropenic patient may be accompanied by dramatic clinical manifestations or by none at all. Any fever that develops is very suggestive of infection. However, hypothermia, declining mental status, myalgia, or lethargy also may indicate infection in these patients. The usual local signs of infection, such as pus formation, may be absent or delayed because they are mediated by neutrophils.¹⁴

A careful physical examination should be performed when such a change in condition is observed. Special attention should be paid to the mouth and teeth for evidence of thrush, ulcerations, or periodontal disease. The skin should be examined in detail. Innocuous-appearing skin lesions may be septic emboli or evidence of disseminated fungal infection. Ordinarily trivial injuries inflicted by venipuncture or intravenous catheters may become infected and result in sepsis. An increased incidence of perianal and perirectal infection is observed in neutropenic patients.¹⁵ Examination of the rectum and perineum may provide a clue to the source of fever in patients without other clinical findings. Although such examinations should not be performed unnecessarily on an immunocompromised patient, rectal or pelvic examination should not be deferred when searching for a cause of fever.

Chest radiographic films should be obtained initially and may need to be repeated, although this practice has been questioned in patients without respiratory complaints.¹⁶ Chest computed tomography (CT) may reveal lesions not detected on routine radiograms.¹⁷ Additional imaging should be guided by clinical presentation.

Blood cultures should be collected prior to initiation of antibiotic therapy, and periodically thereafter if fever persists. If an indwelling venous catheter is present, a blood culture as well as cultures from each lumen of the catheter should be obtained for bacterial and fungal pathogens. Differential time to positivity of central and peripheral cultures may be helpful in diagnosing catheter-associated infections.¹⁸ Sending two or three cultures improves the likelihood of recovering fastidious organisms. If differential time to positivity cannot be performed, potentially infected intravenous lines should be cultured upon removal.

Other cultures should be obtained based on presenting symptoms and risk factors. Urine cultures should be sent in patients with an indwelling urinary catheter, those whose urinalysis is suspicious for infection, and those who have urinary symptoms. Sputum cultures may be helpful in patients with respiratory symptoms or findings on chest radiographs, but must be interpreted with caution, because the results may reflect the flora colonizing the oropharynx rather than the pathogens infecting the lung. Pulmonary fungal and viral infections, which may be difficult to document using conventional culture techniques, may be diagnosed by polymerase chain reaction and antigen detection sent from nasal washes or bronchoalveolar lavage samples.^19,20 Skin lesions of a suspicious nature should be biopsied and cultured. Stool should be cultured as well as examined for ova and parasites, and Clostridium difficile in patients with diarrhea. In some patients, testing for rotavirus, norovirus, and adenovirus also may be appropriate.

Patients with findings on chest CT that are consistent with pneumonia who do not respond to initial therapy and in whom initial microbiologic testing is negative may benefit from transbronchial biopsy or CT-guided biopsy of affected tissue.²¹

INITIAL TREATMENT

Bacterial Infections

Many different regimens have been evaluated and found to be acceptable for empiric therapy in febrile patients with neutropenia. Current recommendations support single-drug therapy with an antipseudomonal β-lactam as initial empiric therapy in febrile neutropenic patients.²² Piperacillin-tazobactam,²³ imipenem,²⁴ meropenem,²⁵ cefepime,²⁶ and ceftazidime²⁷ have each been studied as a single agent. These drugs are active against most of the virulent pathogens infecting neutropenic patients. Doripenem, another carbapenem with antipseudomonal activity has not been studied in a prospective randomized control trial in febrile neutropenia. Ertapenem, a carbapenem that is attractive for its daily dosing schedule, lacks activity against pseudomonas and should not be used as empiric therapy.²⁸ Differences in institutional sensitivity patterns should guide initial antibiotic selection, which should subsequently be tailored to culture results.

Although Gram-negative coverage with a single agent is associated with improved outcomes,²⁹ among patients who are unstable or in whom antibiotic resistance is suspected, it is reasonable to add a second antibiotic active against Gram-negative organisms. Aminoglycosides may provide synergy against Gram-negative bacilli and further broaden the spectrum of antimicrobial activity, but they increase the risk of nephrotoxicity. No good evidence supports the simultaneous use of two β-lactam drugs. Fluoroquinolones in conjunction with another antibiotic are effective in patients who have not received quinolone prophylaxis.³⁰

Patients with catheters, patients presenting with sepsis, patients with evidence of skin or soft-tissue infection, and other high-risk patients should be treated empirically for Gram-positive infections with vancomycin. Among patients without these risk factors, Gram-positive coverage should be added if fever persists for more than 3 to 5 days after Gram-negative treatment is initiated.²²

The emergence of multidrug-resistant organisms has influenced the approach to empiric therapy. Approximately 60 percent of the hospital-acquired strains of Staphylococcus aureus now are methicillin-resistant S. aureus (MRSA), as are a growing number of community-acquired strains.³¹ Vancomycin, quinupristin/dalfopristin,³² linezolid,³³ daptomycin,³⁴ ceftaroline,³⁵ and tigecycline³⁶ are active against MRSA. However, it should be noted that daptomycin should not be used in pneumonia because of inactivation by surfactant. Tigecycline should be avoided in bloodstream infections because of inadequate serum levels, and the drug now carries a black box warning because of increased mortality seen with this agent. Dalbavancin, a second-generation glycopeptide that can be administered once per week, has been approved for treatment of MRSA skin and soft-tissue infections.³⁷ Ceftobiprole is a broad-spectrum cephalosporin that is also active against MRSA, but is not yet approved in the United States.³⁸

The emergence of vancomycin-resistant S. aureus strains may limit the use of vancomycin in the treatment of S. aureus infections in the future, although, fortunately, these isolates are currently quite rare.³⁹ Toxicities of anti-MRSA agents as well as a comprehensive list of antibiotics with activity against MRSA still in development are reviewed in Ref. 40. Linezolid is a commonly used alternative to vancomycin, but causes thrombocytopenia and therefore must be used with caution in patients who are receiving chemotherapy.⁴¹ Daptomycin is a good alternative to vancomycin for bloodstream infections.

Vancomycin-resistant Enterococcus (VRE) is being isolated with increasing frequency and presents a major challenge, particularly among neutropenic patients.^42,43 Cefepime and ceftazidime lack activity against enterococcus. Linezolid,⁴⁴ daptomycin,⁴⁵ and quinupristin/dalfopristin,³² are the best agents currently available for treatment of serious VRE infections. Tigecycline also has activity against VRE,³⁶ but should not be used in bloodstream infections because of inadequate serum levels. Quinupristin/dalfopristin is not active against Enterococcus faecalis. The minimum inhibitory concentration of the organism should be checked before initiating daptomycin because VRE isolates can have daptomycin resistance, even in the absence of prior daptomycin usage.⁴⁶

Drug resistance among Gram-negative pathogens is also of great clinical concern in neutropenic patients. As a result of the rising prevalence of multidrug resistant Gram-negative organisms, older drugs, such as colistin, have been reintroduced into practice.⁴⁷ Enteric pathogens, particularly Klebsiella and E. coli which produce extended-spectrum β-lactamases are a large and growing clinical problem. In up to 25 percent of cases of Gram-negative rod bacteremia in neutropenic patients, cultures ultimately grow extended-spectrum β-lactamase (ESBL)-producing pathogens.⁴⁸ These organisms are resistant to all cephalosporins and exhibit varying and unpredictable degrees of sensitivity to aminoglycosides and quinolones. The carbapenems (imipenem, meropenem, doripenem, ertapenem) are active against these pathogens. Carbapenemase-producing organisms, currently relatively rare, may become an important clinical problem in the future. Data regarding treatment of infections caused by carbapenemase-producing organisms are limited to retrospective and noncontrolled, nonrandomized prospective studies but suggest that combination therapy with a carbapenem plus colistin, aminoglycoside, or tigecycline may be more effective than monotherapy.^49,50

Fungal Infections

Systemic fungal infections are relatively common in neutropenic patients, and empiric antifungal therapy should be considered in febrile patients if empiric antibiotic therapy is not effective within 5 to 7 days.⁵¹ Historically, amphotericin B deoxycholate had been the drug of choice for the majority of fungal infections that develop in neutropenic hosts, although its position has been largely supplanted by the introduction of liposomal formulations of amphotericin in most centers, newer azole drugs, and echinocandins.^52,53

There are three lipid-associated formulations of amphotericin currently available in the United States. AmBisome (liposomal amphotericin B); Abelcet (amphotericin B lipid complex); and Amphotec/Amphocil (amphotericin B colloidal dispersion). These three agents are not interchangeable. These formulations, particularly AmBisome, are less nephrotoxic, and appear to be at least as efficacious as nonlipid formulations. Infusion-related symptoms are not consistently less common with these preparations, but are generally manageable.⁵⁴ Serum creatinine, potassium, and magnesium levels should be monitored closely while giving these medications. Amphotericin products remain the first-line agent in treatment of mucormycosis, although they are frequently used in combination with echinocandins.⁵⁵

Although there are limited data to support its efficacy, it is common practice to give intravenous fluids prior to and sometimes after amphotericin infusion to mitigate nephrotoxicity.⁵⁶ Fever and chills associated with administration of amphotericin may be treated or prevented with diphenhydramine hydrochloride, acetaminophen, or hydrocortisone.⁵⁷

Fluconazole, an azole drug that can be administered orally or intravenously, is approved for treatment of C. albicans, Cryptococcus neoformans, and Coccidioides immitis. It is less active against non-albicans Candida species and is completely inactive against Candida krusei. It also lacks activity against Aspergillus.⁵⁸

In contrast to fluconazole, itraconazole has modest activity against Aspergillus. It is less active than voriconazole but may have a role in milder infections or when voriconazole is not tolerated.⁵⁹

Voriconazole is another azole drug, which is also available in intravenous and oral formulations. A large study concluded that voriconazole is as effective as liposomal amphotericin B as empiric therapy for neutropenic patients who are febrile, but these results are controversial.^52,60 Oral voriconazole may be a good alternative to the intravenous formulation in neutropenic patients with uncomplicated persistent fever.⁶¹ It is the first-line therapy against Aspergillus.⁶² Side effects of voriconazole, which may limit its use in some patients, include visual abnormalities, hallucinations, and liver function test (LFT) abnormalities. Recent data suggest that voriconazole use in transplant recipients is associated with an increased rate of nonmelanoma skin cancers. The mechanism by which this occurs is currently unknown.⁶³ Neurologic side effects may be related to blood levels of the drug, which vary widely depending upon a large number of factors including CYP2C19 genotype. There is mounting evidence that therapeutic drug monitoring improves safety and efficacy of voriconazole in the treatment of invasive fungal infections.^64,65

Posaconazole is the newest approved azole. It is now available in intravenous and oral formulations. Its primary use has been prophylactic; however, it has shown promise as salvage therapy for invasive aspergillosis.⁶⁶ Unlike the older triazoles, posaconazole is active against many species that cause mucormycosis, and it has been used successfully when other therapy has failed; however, there is no clinical trial data available at this time.⁶⁷

Isavuconazole is an investigational broad-spectrum azole available in oral and intravenous formulations. It is currently in phase III trials comparing it to voriconazole for treatment of Aspergillus. It also has some activity against species that cause mucormycosis.⁶⁸

The echinocandins, which include caspofungin, micafungin, and anidulafungin, are a class of intravenous drugs that has activity against a wide variety of Candida species as well as Aspergillus. They are generally well tolerated, and may become especially important as the prevalence of non-albicans Candida infections rises.⁶⁹ Currently, only caspofungin is approved for first-line empirical use in febrile neutropenia.⁷⁰ Caspofungin is also the only echinocandin approved as salvage therapy for aspergillosis; however, mounting evidences suggests that micafungin is also effective in the treatment of invasive Aspergillus infections.⁷¹ The echinocandins may have synergy with other antifungal agents against Aspergillus species and in treating mucormycosis.^55,72 A randomized controlled trial evaluating echinocandins as part of combination therapy in Aspergillus treatment has been performed and results are expected soon. Anidulafungin, the newest approved echinocandin, has shown excellent efficacy in the treatment of candidiasis.⁷³

P. jiroveci pneumonia may be treated with trimethoprim-sulfamethoxazole. Pentamidine or primaquine-clindamycin should be used for moderate to severe infections in patients who are allergic to or otherwise intolerant of trimethoprim-sulfamethoxazole, although data for alternative regimens is much more robust in the HIV-positive patient population.⁷⁴ Other alternative regimens include dapsone-trimethoprim and atovaquone, although these are best used for mild PCP. Glucocorticoids are commonly given as adjunctive treatment in severe PCP, though the data for this among non–HIV-infected patients are conflicting.⁷⁵

Empiric therapy with antifungal agents is currently the standard of care in high-risk neutropenic patients with persistent fever. However, preemptive antifungal treatment is being evaluated as a possible alternative to empiric therapy in select patients. With preemptive strategies, microbiologic, molecular, and radiologic monitoring is used to detect early evidence of invasive fungal infections and prompt initiation of therapy.⁷⁶ Data from studies comparing empiric therapy with preemptive strategies are mixed.^77,78,79 Surveillance with fungal cell wall components 1,3-β-D-glucan⁸⁰ and galactomannan⁸¹ in the blood plays a role in preemptive therapy. Real-time polymerase chain reaction of fungal gene products is another technique that appears to have high sensitivity and specificity for detecting candidemia, although it will require standardization before widespread use is possible.⁸²

Although currently not as large a problem as drug-resistant bacteria, the development of drug-resistant fungal organisms is a potential clinical threat. Prophylactic use of antifungals likely contributes to breakthrough infection with innately resistant species.⁸³ Cross-resistance within and between classes of antifungals is another potentially important problem, which is deserving of clinical study.⁸⁴

Viral Infections

A limited number of options are available for treatment of viral infections. Acyclovir is active against herpes simplex and, at higher doses, against varicella zoster. Other agents, such as famciclovir and valacyclovir, are as effective in treating herpes simplex and zoster infections, and may be administered less frequently, but are not available for intravenous administration.⁸⁵

Ganciclovir, valganciclovir, and foscarnet have efficacy in treatment of CMV disease and are also active against herpes simplex.⁸⁶ They are most effective when they are used early in the course of the infection. Hence, frequent screening for CMV and early preemptive treatment in high-risk patients, such as transplant recipients, may allow for improved outcomes.⁸⁷ Ganciclovir or valganciclovir is usually the first-line therapy against CMV, but results in marrow suppression in a significant percentage of patients who receive them. Foscarnet, a second-line agent, may be complicated by azotemia and electrolyte abnormalities.