General Principles

Cytotoxic therapy–induced neutropenia is a major predisposition to infection.⁶ Neutrophil counts below 1000 cells/µL (the total absolute number of polymorphonuclear neutrophils plus bands) increase susceptibility to infection in a linear fashion (i.e., the lower the neutrophil count, the greater the degree of susceptibility)¹⁸ (see Fig. 53.1). Although most research studies use 500 cells/µL as an arbitrary definition of neutropenia, intensivists must recognize that susceptibility increases as the neutrophil count declines below 500 to 1000 cells/µL. A patient with a neutrophil count of 100 cells/µL is much more vulnerable to infection than a patient with 500 or 1000 cells/µL, and a patient with zero neutrophils is at much higher risk for fulminant infection than a patient with 50 or 100 cells/µL. The trajectory of the neutrophil count is also important: a patient with a neutrophil count of 1500 cells/µL whose counts are dropping precipitously should best be treated like a patient with absolute neutropenia. Similarly, a patient with 500 neutrophils/µL whose counts are rising quickly is not nearly as vulnerable to a poor outcome as a patient with a count of 500 neutrophils/µL that is stable.

Patients with neutropenia are generally divided into high-risk and low-risk patients based on their likelihood of developing severe infectious complications. Markers for high risk include neutropenia for more than 7 days’ duration and neutrophil count less than 100 cells/µL, as well as obvious signs of a life-threatening process such as hypotension, obtundation, pneumonia, or severe abdominal pain. As Figures 53.2 to 53.4 outline, this risk assessment is used in designating empiric regimens.

Thus, although the absolute neutrophil count is an essential factor to follow, the duration of neutropenia, the functional capability of neutrophils, the integrity of physical barriers such as the skin and gastrointestinal mucosa, the patient’s microbiologic environment (endogenous and exogenous flora), and the status of other immune mechanisms also contribute to the infectious syndromes that will develop.

In the 1960s and 1970s, aerobic gram-negative bacilli such as Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa predominated as pathogens in neutropenic patients. In the 1990s the spectrum of causative pathogens in neutropenic patients shifted from a predominance of gram-negative bacilli to a majority of gram-positive cocci including streptococci, staphylococci (including oxacillin-resistant Staphylococcus aureus), and enterococci (including vancomycin-resistant enterococci).10,12–15,19–21 Candida species have also become more frequent as pathogens, especially as patients are on broad-spectrum antibacterials and have long-term venous access devices in place.

More recently, highly resistant gram-negative bacilli have become major threats for nosocomial transmission. Clinicians must consider the possibility that a patient may be colonized and then infected with a Stenotrophomonas, a Burkholderia, or a carbapenemase-producing gram-negative Enterobacteriaceae such as a Klebsiella, an Enterobacter, or an E. coli that has developed mechanisms that evade currently marketed drugs.22–26

The management of febrile, neutropenic fever is reviewed in a guideline that is widely used to direct care in North America.⁶ Figures 53.2 to 53.4 summarize important aspects of management. Table 53.3 also provides a summary of useful management information. Table 53.4 outlines common prevention strategies that will modify the spectrum of causative pathogens. Box 53.1 summarizes the organisms that most often cause disease in neutropenic patients.

Patients with neutropenia are generally suspected of being infected if the clinical syndrome is consistent with infection, or if the temperature is at least 38.3° C on one occasion or 38.1° C on two separate occasions. An elevated temperature alone should trigger the institution of broad-spectrum antimicrobials in almost all situations. Given this emphasis of using temperature as an indicator for starting antimicrobial therapy, using a validated technique to measure temperature is important. Although pulmonary artery or urinary catheter thermistors appear to provide the most accurate measurement, most experienced ICUs use tympanic membrane thermistors. Rectal probes are avoided in order to reduce the induction of perirectal infections in neutropenic patients, and to reduce the potential for fecal pathogen transmission. As noted earlier, although fever is almost always a reason to start antimicrobial therapy in this patient population, the absence of fever should not be the grounds for avoiding antimicrobials if a patient has other symptoms or signs suggesting infection. The threshold for starting antimicrobials should be very low, i.e., if there is a suspicion of infection, a broad-spectrum regimen should be started.

As noted earlier, the initial regimen should not be parsimonious in terms of spectrum. Because this population of patients is susceptible to a wide variety of bacterial and fungal pathogens, a very wide broad-spectrum regimen should be used. There are many potential regimens, each of which must be tailored to the local experience with the patient population and the hospital, specific patient factors such as evidence of prior colonization or recent antimicrobial therapy, and clinical manifestations suggesting infection. Popular regimens would include (1) meropenem or cefepime or piperacillin-tazobactam for broad-spectrum antibacterial activity plus (2) vancomycin or daptomycin for staphylococcal infections27,28 plus (3) ciprofloxacin or moxifloxacin or aztreonam for broader gram-negative bacillus coverage. Many experienced clinicians would add an echinocandin for anti-Candida activity given the frequency of intravascular catheter-associated infections due to Candida species.^29–33 Intensivists need to work closely with their infectious disease consultants, microbiology laboratories, and referring teams to develop regimens that are optimal for their hospital environment, for the patient population involved, and for the specific, unique patient who is being managed.

Empiric antiviral therapy is not usually initiated unless there is a specific reason to suspect a viral process. Antiviral agents would generally be added only if a specific viral process such as CMV colitis or disseminated herpes simplex were suspected.

For the duration of neutropenia (when the neutropenia is expected to be time-limited), broad-spectrum therapy must be continued. When a specific causative organism is identified, antimicrobial therapy should be optimized for that organism. However, unlike other immunologically normal patients, the broad-spectrum “background” (i.e., meropenem or piperacillin-tazobactam or cefepime or ceftazidime) must be continued until the neutropenia resolves, on the assumption that a patient who develops one infection is likely to develop or manifest another infectious process while the neutropenia persists.

Coverage for methicillin-resistant Staphylococcus aureus (MRSA) does not necessarily need to be continued if no MRSA is identified. There are environmental advantages to reducing vancomycin exposure.

As noted previously, there is no documented reason, even in this population, to use combination therapy to treat a specific pathogen in most situations, although combination therapy is needed for the empiric approach for the duration of neutropenia (Box 53.2). In rare situations, if the causative organism is not susceptible to agents with well-documented efficacy, combination therapy may be an appropriate strategy out of desperation. As an example, for treating enteric carbapenemase-producing organisms, a combination of tigecycline plus colistin plus an aminoglycoside might be desirable given the high minimum inhibitory concentrations for all antibiotics for these organisms and the dreadful clinical results with any therapeutic intervention.^34–38

For patients with fever and neutropenia, the cause of the fever is historically documented in only 50% to 60% of patients. The duration of therapy once empiric antimicrobials are started depends on the evolution of the neutrophil count, the patient’s clinical status, and the results of diagnostic tests. If the patient defervesces and looks clinically well, however, the broad-spectrum regimen should not be stopped until the neutrophil count is above 500 to 750 cells/µL, preferably on two occasions, and the patient has received at least 10 to 14 days of therapy.

If a neutropenic patient is started on antibacterial therapy without fungal therapy, and defervescence has not occurred by days 3 to 5, an antifungal agent should be added (Figs. 53.3 and 53.4). The choice of antifungal agent depends on the patient population and the patient’s specific history. In the current era many patients have been receiving short- or long-term prophylaxis with fluconazole, voriconazole, or posaconazole. Although in general clinicians could add fluconazole, an echinocandin (e.g., caspofungin or micafungin or anidulofungin) or liposomal amphotericin B can also be used. An echinocandin is often a preferred choice if the patient has been on long-term azole prophylaxis and if a mold infection is not suspected.^39–42

As patients receive chemoprophylaxis with quinolones or azoles during periods of intense neutropenia or immunosuppression, breakthrough pathogens are more and more likely to be resistant to the prophylactic agents.40,42 Thus empiric regimens must be chosen with keen attention to the drugs that patients have received in the recent past, as well as pathogens they have previously been colonized or infected with.

Diagnostic Approach

Patients with fever and neutropenia require aggressive diagnostic efforts to identify the cause of fever so that the appropriate antimicrobial agent is used and appropriate procedures (e.g., surgical drainage, removal of a foreign body such as a catheter) can be performed. All febrile neutropenic patients should at a minimum have two blood cultures drawn, with one drawn peripherally and one drawn through the lumen of the indwelling catheter that has either been in the longest or is most suspicious for being infected. Other sites should be cultured as clinically indicated.

Regular physical examination is necessary to identify sites that merit more focused investigation. With impaired inflammatory response, findings on examination may be subtle. Knowledge of the specific immunologic defect is important so that when cultures of blood, sputum, urine, or other appropriate body fluids or body sites are performed, special microbiologic approaches can be used to detect viruses, fungi, helminths, protozoa, and bacteria as indicated by the clinical situation. Imaging studies are also important because intra-abdominal, intrathoracic, intracerebral, and musculoskeletal processes can be clinically subtle and may not be associated with identifiable organisms in the bloodstream. A growing array of antigen detection systems and molecular and high-performance chromatographic tests are being investigated to facilitate diagnosis.

Some of these approaches, despite their promising initial reports, are not yet clinically practical because of their level of sensitivity, specificity, or the cost or expertise required to perform them adequately. For instance, the PCR test for Pneumocystis is so sensitive that there is no clear separation of patients who are colonized with Pneumocystis (and whose pulmonary dysfunction is due to another process), and the serum β-glucan antigen detection system is so nonspecific that some clinicians are not confidant that the test provides useful information.43–45 Similarly, the PCR test for respiratory syncytial virus (RSV) or influenza or parainfluenza is so sensitive that immunosuppressed patients may shed small quantities of virus for many weeks after acute infection, confusing the diagnosis of the new pulmonary processes that occur after the acute viral infection is over, and at a time when another process is causing fever or pulmonary manifestations. Thus, these new tests must be interpreted with caution.

Empiric and Specific Antimicrobial Therapy