Introduction

Numerous disease-related and chemotherapy-induced factors render patients with cancer at increased risk for infection.1,2 These factors include the type of cancer (e.g., a solid tumor versus a lymphoma or acute leukemia), the severity and duration of neutropenia, and impairments in cellular function caused by cytotoxic or immunosuppressive drugs; breaches in the integument from surgical procedures, the presence of indwelling plastic venous catheters, or mucositis of the gastrointestinal tract as a result of chemotherapy; and comorbid conditions such as malnutrition, deconditioning, or medical problems such as chronic obstructive lung disease or diabetes. Approaches to prevention, diagnosis, and management of infectious complications in patients with cancer are greatly influenced by the cumulative burden of these risk factors. Neutropenia remains one of the most important predisposing factors for infection, overriding many of the others. This chapter addresses current standards for the management of fever during neutropenia and also highlights contemporary guidelines for the prevention and treatment of common infectious complications in patients with cancer.

The association between neutropenia and increased infection risk was first demonstrated by Bodey and colleagues³ in 1966 in a study of leukemic patients undergoing cytotoxic therapy. The data show that the frequency of infectious complications is inversely related to the degree and duration of neutropenia (Fig. 36-1). Infection risk starts to increase when the absolute neutrophil count (ANC) decreases to less than 1000 cells/mm³ and increases dramatically when the ANC count is less than 500 cells/mm.³ Fewer than half of the neutropenic patients who become febrile will have an identified infection. In roughly 10% to 20% or more of patients with neutrophil counts less than 100 cells/mm³, a bloodstream infection will be identified. More than 50% of all episodes of fever and neutropenia represent “fever of undetermined origin,” with no clear infection source on physical and radiographic examination and cultures.^3,4 In addition to the severity of the ANC nadir, the duration of neutropenia is also an important determinant of both infection risk and infection type. Brief durations of neutropenia, particularly for less than 7 days, are usually associated with a rapid and favorable response to empirical antibiotic therapy. Fever often may be of unknown origin during this early phase of neutropenia, but if a causative pathogen is identified, bacteria and viruses predominate. A neutrophil count persistently less than 500 cells/mm³ for more than 7 days is associated with greater risk for infection-related morbidity and mortality and is the setting in which Aspergillus and other invasive fungal infections most often occur. Other pathogens that may cause infection during the course of prolonged neutropenia (i.e., after 7 days) include antibiotic-resistant bacteria, Candida species, and other molds. Deaths during the state of neutropenia usually are due to these subsequent infections. Overall mortality rates during the state of fever and neutropenia are less than 1% for low-risk patients and approximately 5% for those with more prolonged duration of neutropenia.^5–9

In addition to cytotoxic chemotherapy, circulating neutrophil deficiencies can result from bone marrow incompetence disorders such as myelodysplastic syndrome or crowding out of normal granulocytic precursors by tumor cells. “Functional neutropenia” describes impaired neutrophil microbicidal activity that may be a consequence of the leukemia itself or may be due to therapies such as steroids. In these instances, ineffective neutrophil killing leaves the patient highly vulnerable to infection despite seemingly normal peripheral white blood cell counts.

Sources of Infection

Colonization by pathogenic bacteria, fungi, or viruses generally is a prerequisite for infection. Accordingly, endogenous bacterial and fungal flora and latent herpesvirus infections account for a majority of initial infections in neutropenic patients with cancer.17–17 These infections include skin colonizers such as Staphylococcus aureus and coagulase-negative staphylococci, viridans streptococci, and herpes simplex from the oropharynx and gram-positive bacteria, as well as enteric gram-negative bacteria, from the gut. Candida albicans infections often are derived from the skin or the gastrointestinal or female genital tract. Latent infections that may reactivate during immunosuppression include those due to herpes simplex or varicella-zoster virus, Epstein-Barr virus (EBV), and cytomegalovirus (CMV), as well as hepatitis B and C viruses, M. tuberculosis, and Toxoplasma gondii.

Exogenous sources of infection often are found in the hospital and home environments. Contaminated blood products, hospital equipment, water sources, and nosocomial spread of organisms from health care workers represent less common, albeit significant, sources of infection. Common nosocomially spread infections include those due to Clostridium difficile, respiratory viruses, vancomycin-resistant enterococci, and other multiresistant bacteria. Water sources such as faucets and shower heads have been implicated in the spread of Legionella and Aspergillus.¹⁸ Outbreaks of Klebsiella and Enterobacter infection related to intravenous solutions have been well documented.^21–21

Foods can be a potential source of infection, particularly unwashed fruits and vegetables. Neutropenic patients generally are advised to follow safe food-handling guidelines, which include washing fruits and vegetables thoroughly, cooking eggs until the whites and yolks are completely hard, and cooking meat until it is well done.²² Potted plants, mulch, and excavation and building or renovation sites have been implicated as sources of Aspergillus and other molds that may cause disease.²³

Approach to Fever in the Neutropenic Patient

Fever often is the only reliable sign of significant underlying infection in the neutropenic patient. No specific clinical features, such as hypotension, chills or the magnitude of the increase in body temperature can accurately distinguish between fever due to an infection and that due to a noninfectious cause. Nor are laboratory tests such as C-reactive protein or procalcitonin levels considered specific or sensitive or enough to be relied on for making decisions about the use of antibiotics at the time of presentation.26–26 Therefore all febrile neutropenic patients should receive empirical broad-spectrum antibiotics, ideally within 1 hour of presentation. Although a clinically or microbiologically documented source of fever is not found in most febrile neutropenic patients, the rapid initiation of empirical antibiotic therapy remains an important standard of care for all patients in this setting. The choice of specific antibiotic regimens depends on an assessment of the patient’s infection risk during neutropenia, which depends on the duration of neutropenia, the underlying cancer, and comorbid medical conditions. Conditions and findings that may alter the empirical antibiotic regimen are shown in Table 36-1.

Definitions

Guidelines for evaluating antimicrobial therapy for fever and neutropenia have been developed by the Infectious Diseases Society of America and the National Comprehensive Cancer Network.2,26 Fever is defined as a single temperature measurement of 38.3°C (101°F) or greater in the absence of other obvious causes; a temperature of 38°C or greater for an hour or longer is considered to represent a “febrile state” that also requires prompt evaluation and intervention in the setting of neutropenia.^2,26 Neutropenia is defined as an ANC less than 1000 cells/mm³ in some centers but more often is designated by a neutrophil count of less than 500 cells/mm³, which is a level associated with a much higher risk for infection. For practical purposes, an ANC less than 500 cells/mm³, or a count that is anticipated to fall below that level within 48 hours, constitutes a state of neutropenia.

Rarely, a neutropenic patient who is afebrile may exhibit signs or symptoms of infection (e.g., abdominal pain, severe mucositis, and perirectal pain) and should be considered to have an active infection. The concomitant administration of corticosteroids also may initially blunt the fever response. Afebrile neutropenic patients who show signs or symptoms suggestive of an infection should receive empirical antibiotics immediately because of their increased risk for serious invasive infections.

Initial Evaluation

The initial evaluation should be directed toward determining the possible sites of infection and causative organisms and assessing the patient’s level of risk for infection-related complications. A thorough site-specific review of systems is essential. Pertinent history includes recent antibiotic therapy, recent surgery or other invasive procedures such as biopsies or catheter placement, and possible exposure to infections from close contacts and household members, foods, animals, or travel.

The physical examination should focus on common potential sites of infection. Worthy of emphasis in this regard is that the manifestations of infection are muted in the absence of inflammatory cells. Careful examination of the oropharynx may reveal ulcers, or plaquelike lesions may be due to herpes or thrush, and specimens for appropriate tests should be sent for evaluation. Catheter sites require careful assessment for erythema, tenderness, or discharge. With bacterial cellulitis of the skin or perirectum, induration and erythema may be minimal; pimples or pustules are uncommon without neutrophils to create pus. Similarly, few respiratory signs or symptoms may be noted, and auscultation of the lungs may reveal few adventitial sounds, but an infiltrate may be seen on radiographs. A urinary tract infection may not be associated with dysuria. Gastrointestinal tract mucositis due to cytotoxic chemotherapy can lead to sore throat, oral ulcers, and diarrhea that are indistinguishable from the signs and symptoms of infection. Abdominal pain in neutropenic patients may signify a wide variety of problems, including intestinal tumor necrosis and neutropenic enterocolitis, both of which can result in intraabdominal catastrophe or sepsis.

Initial laboratory evaluation should include a complete blood cell count and differential white cell count to determine the degree of neutropenia, liver and renal function tests, oxygen saturation determination, and urinalysis. Chest radiography should be reserved only for patients who have symptoms of respiratory tract infection. Note that radiographic findings may be minimal in neutropenic patients with pneumonia. At least two blood culture samples, each consisting of 20 to 40 mL of blood, should be obtained from both a peripheral vein and from each catheter lumen.2,4 An adequate volume of blood taken for culture will enhance the chances of recovering a pathogen.²⁷

Drawing blood samples from both a vascular catheter and a peripheral vein can help determine whether the catheter is a source of infection. If the differential time to culture positivity between catheter- and venipuncture-derived cultures is greater than 2 hours, the catheter is implicated as a source.²⁸ In patients with cancer, however, one study showed that catheter-drawn blood cultures without concomitant peripheral cultures do have very good negative predictive value and fairly good sensitivity (89%) and specificity (95%).²⁹ A positive culture result for coagulase-negative staphylococci—a common contaminant—requires two positive blood culture sets to be considered a “true positive.”²⁸

Cultures of any suggestive sites of infection should be performed: Diarrheal stools should be tested for the presence of C. difficile toxin, and specimens from oral or perineal lesions suspected to harbor herpes simplex virus (HSV) should be sent for viral cultures. Polymerase chain reaction (PCR) testing (preferred) or culture/rapid antigen testing should be performed for respiratory viruses on nasal wash or swab specimens in patients with suggestive signs or symptoms during the winter season.

Empiric Antibiotic Therapy

Monotherapy with a broad-spectrum antipseudomonal agent such as an extended-spectrum antipseudomonal cephalosporin (e.g., cefepime or ceftazidime), piperacillin-tazobactam, or a carbapenem (e.g., imipenem-cilastatin or meropenem), constitutes a standard approach to the management of fever and neutropenia in both high-risk and low-risk patients with cancer.2,8,26,38–44 The choice of agent should be based on a review of local institutional bacterial susceptibility patterns. Reports of high rates of multidrug-resistant gram-negative bacteremias in patients with cancer underscores the need to select agents based on a review of local institutional bacterial susceptibility patterns.^47–47 Some institutions routinely use combination therapy with either (1) an aminoglycoside plus either an extended-spectrum antipseudomonal cephalosporin or piperacillin-tazobactam or (2) ciprofloxacin plus an antipseudomonal penicillin. No clear benefit of combination therapy over monotherapy has been demonstrated, and increased renal toxicity has been observed with aminoglycoside use.^{2,8,26,38–44} In an era of increasing bacterial resistance, however, circumstances may arise in which initial empirical antibiotic combinations are advisable.⁴⁸ With the possibility of infection as a result of methicillin-resistant S. aureus, for example, the addition of vancomycin is prudent. If a pneumonia is identified at the outset, then adding an antipseudomonal fluoroquinolone (i.e., ciprofloxacin or levofloxacin) ensures a broadened spectrum against potentially resistant gram-negative or atypical pathogens, as well as “atypical” organisms such as Legionella.⁴⁹ The initial antibiotic regimen may be modified according to clinical, radiographic, or culture data available at the time of presentation, as outlined in Table 36-1.

High-risk patients should receive intravenous antibiotics in the inpatient setting. Again, the choice of specific regimen is highly dependent on institutional profiles of pathogen susceptibility and on potential infection sites in a specific patient. Notably, many of these patients are receiving fluoroquinolone prophylaxis and are therefore at increased risk for resistant gram-negative and gram-positive infections.⁴⁷ It is not clear, however, whether different antibiotic regimens are required for these patients at the onset of fever.

Low-risk patient who can tolerate oral agents may be treated with a combination of oral ciprofloxacin plus amoxicillin-clavulanate. In two randomized double-blind trials, this combination proved as effective as intravenous broad-spectrum monotherapy in selected low-risk patients.33,34 Ciprofloxacin should not be used as a solo agent because of its poor coverage of gram-positive organisms.^2,7 Levofloxacin has better activity against gram-positive organisms but less potent antipseudomonal activity than does ciprofloxacin, and it appears to be a reasonable alternative to combination oral empirical therapy in low-risk patients.⁵⁰

An outpatient treatment course with oral or intravenous (IV) antibiotics may be considered after a brief inpatient stay, during which IV therapy is initiated, fulminant infection is excluded, the patient is deemed to be clinically stable and at low risk for complications, assessment of family support is completed, and the status of initial culture specimens may be ascertained.2,26,31,35 In one large series, oral outpatient treatment for low-risk fever and neutropenia was deemed to be successful in 80% of patients, with 20% of patients requiring readmission to the hospital, primarily for persistent fever. Factors predicting readmission included age greater than 70 years, grade of mucositis greater than 2, poor performance status, and ANC less than 100 cells/mm³ at the outset of fever.⁵¹

Initial Empirical Therapy for Patients Who Are Clinically Unstable

Hypotension or septic shock in a neutropenic patient necessitates very broad empirical antibiotic coverage. Broad coverage is warranted in view of the high mortality rate in neutropenic patients with the systemic inflammatory response syndrome.2,26 Patients should receive multidrug therapy with an antipseudomonal beta-lactam (e.g., cephalosporin, carbapenem, or penicillin, depending on local susceptibilities) plus an aminoglycoside or ciprofloxacin (if the patient is not already receiving fluoroquinolone prophylaxis) and vancomycin or another gram-positive active agent with MRSA activity until culture results are available.

Subsequent Modifications of Empiric Antibiotic Regimens

No empirical antibiotic regimen initially administered for fever and neutropenia can be expected to cover all possible infections that may occur during the course of neutropenia. Therefore modifications of the initial regimen—that is, additions or changes of antimicrobial agents—sometimes are required. An important consideration in the management of cancer-related infection is that the mean time to defervescence for febrile patients with neutropenia who receive appropriate initial antibiotic therapy ranges from 2 to 7 days.2,5–7 Therefore at least 3 to 4 days of the initial antibiotic regimen should be given to otherwise stable patients, regardless of continued fever, to determine effectiveness. For patients with a documented infection, it is important to note that tissue-based infections such as pneumonia may take longer to respond to antimicrobial therapy.⁷

Patients who have a fever that persists beyond 4 days of initial antimicrobial therapy and who do not have an identifiable site or source of infection should undergo reassessment of their initial antimicrobial therapy. Any change in antimicrobial agents should be based on the patient’s clinical status, results of examination and cultures, and also the likelihood of early marrow recovery. Although resolution of fever may be slow, persistent fever may suggest a nonbacterial infection, a bacterial infection that is resistant to empirical antibiotics, the emergence of a secondary infection, a closed-space infection, inadequate antimicrobial serum levels, or drug fever. A careful search for these etiologic conditions should be conducted. Frequent and arbitrary antibiotic changes for persistent fever in an otherwise stable patient are to be discouraged. The clinically stable patient with persistent fever may be safely watched without altering the initial antibacterial therapy. If vancomycin was started earlier, it should be discontinued if the patient does not meet the criteria for its use.2,26,54 The addition of vancomycin without specific indications in a blind effort to suppress persistent fever has not been shown to be effective.⁵⁸ If the fever persists beyond 4 to 7 days, initiation of empirical antifungal therapy should be considered (see the next section on Empiric Antifungal Treatment).

Clinically unstable patients who are persistently febrile should be evaluated for changes in antibacterial antibiotics. Double gram-negative bacillary coverage, as reviewed earlier, is recommended. The addition of vancomycin should also be considered, particularly if the clinical indications outlined in Table 36-3 are present.

Empiric Antifungal Therapy

Empiric antifungal therapy traditionally is started when neutropenic patients demonstrate continued or recrudescent fever after 4 days or more of an empiric antibacterial regimen because the risk of invasive fungal disease, particularly invasive aspergillosis, increases with prolonged duration of neutropenia.63,64 The empiric use of amphotericin B in early studies during the 1970s and 1980s showed a reduction in breakthrough fungal infections.^38,65,66 Since then, numerous comparative studies have demonstrated that less toxic alternatives, including liposomal amphotericin B, itraconazole, and caspofungin, are not inferior to amphotericin B desoxycholate.^67–72 Voriconazole is also effective in reducing breakthrough fungal infections.⁷³ The other available echinocandins—anidulafungin and micafungin—are less well studied but presumably are effective in this setting. Itraconazole has been demonstrated to have efficacy in this setting as well, but concerns about liver and cardiac toxicities have discouraged use of this drug.^67,72

Whether all patients with persistent fever require empiric antifungal therapy, and when it should be started, are subjects of long-standing debate. Invasive fungal infections are now relatively infrequent during neutropenia with the advent of more effective antifungal prophylaxis and the use of colony-stimulating factors to abbreviate duration of neutropenia. Furthermore, fever is obviously a nonspecific surrogate marker for fungal infection. Currently, guidelines suggest that an antifungal agent be started at day 4 to 7 in high-risk patients who are not receiving antifungal prophylaxis.2,26 Candidemia is the greatest concern in these patients, and fluconazole, amphotericin B preparation, caspofungin, itraconazole, or voriconazole are considered acceptable choices. If the patient is already receiving fluconazole prophylaxis (which is commonly the case), certain non-albicans species of Candida, including C. glabrata and C. krusei, along with mold infections such as invasive aspergillosis, must be considered. Fluconazole has reduced activity against these Candida species and lacks activity against molds. At present, no data are available to guide the use of empirical antifungal therapy in patients already receiving antimold prophylaxis, such as with voriconazole, posaconazole, or an echinocandin. In all cases, symptoms and signs of invasive fungal pneumonia or sinusitis should be sought; the workup may include computed tomography (CT) scans of chest or sinuses (or both), with follow-up nasal endoscopy or bronchoalveolar lavage as indicated. Biopsy and culture of any suspected lesions should be pursued aggressively to make a definitive mycologic diagnosis that can guide therapy.

A CT scan of the chest is increasingly being used to evaluate the possibility of invasive aspergillosis in patients with prolonged fever and neutropenia; in one study, 90% of persons with proven active disease showed radiographic abnormalities by CT.⁷⁴ Macronodules with or without a halo sign are characteristic of invasive aspergillosis, with the halo sign being an especially important early clue.^75,76 Other manifestations include nodular, wedge-shaped, peripheral, multiple, and cavitary lesions. An air-crescent sign generally is a late finding. Initiation of antifungal agents on the basis of finding a halo sign has been associated with significantly better response to therapy and improved survival.^76,77 Maertens and colleagues⁷⁸ used intensive monitoring for clinical symptoms and signs, serial galactomannan testing (discussed later in this section), and early CT scanning to identify a group of patients with persistent fever while receiving fluconazole prophylaxis in whom antimold therapy did not appear to be required. These data, as well as increasing clinical experience, have led some experts to suggest withholding empiric antifungal therapy if the patient is clinically stable and has no clinical or chest CT scan signs of fungal infection, if no Candida or Aspergillus organisms are recovered from any site, and if neutrophil recovery is imminent. A high-resolution chest CT scan may be a useful screening tool in patients with persistent fever and neutropenia; any abnormalities should be investigated with nasal endoscopy or bronchoalveolar lavage; biopsy and culture of any suspected lesions should be pursued aggressively to make a definitive diagnosis; and treatment with an antimold agent should be initiated.

The serum galactomannan assay specifically detects Aspergillus organisms but not other common fungal pathogens.⁷⁹ Sensitivity varies widely in different patient populations. A recent metaanalysis reported sensitivities of 64% to 78% and specificities of 81% to 95% in patients with neutropenia or neutrophil dysfunction.⁸⁰ Many conditions affect the performance of the galactomannan assay, especially the use of concomitant piperacillin-tazobactam (false-positive) or antimold antifungal agents (false-negative). Although prospective serial galactomannan monitoring may be useful for patients at high risk for Aspergillus infections, routine use in low-risk patients is not advised.^79,80 Furthermore, a single negative test result is of little value in ruling out invasive aspergillosis, although a positive result in concert with abnormalities on the chest CT scan makes the diagnosis highly probable. Galactomannan testing of bronchoalveolar lavage fluid appears to be specific and more sensitive than culture for identifying invasive aspergillosis.^79,81,82

Duration of Antibiotic Therapy

It generally is recommended that empiric antibiotic therapy continue until recovery of the ANC to more than 500 neutrophilic cells/mm³ on one occasion, as long as the patient is clinically stable. In a stable patient who remains febrile despite the return of higher counts, it usually is safe to discontinue antimicrobial drugs and look for a source of fever. In patients who are afebrile and clinically stable but have continued neutropenia, some clinicians recommend a 2-week course of antibiotics at a minimum and then stopping the antibiotics, with close observation.2,26

Documented infections should be treated for a minimum duration of 7 to 14 days with an antibiotic regimen that is narrowed and directed toward any organisms that have been documented microbiologically. Activity against Pseudomonas aeruginosa should be maintained in most patients who remain neutropenic. Most experts prefer to continue antibiotics at least until the ANC returns to more than 500 cells/mm³. A longer course is given if clinically necessary (for example, if a documented infection is ongoing) regardless of neutrophil recovery. Persistent fever of unknown source is not a reason to continue empiric antibiotics beyond ANC recovery.2,26

For low-risk patients who typically have brief periods of neutropenia, some groups of investigators have examined the practice of stopping antibiotics before the ANC reaches 500 cells/mm³. With a clear and steady increase in the ANC or, alternatively, in the absolute phagocyte count (antigen presenting cells = polymorphonuclear neutrophils + bands + monocytes), it appears that the discontinuation of antibiotics before a count of 500 neutrophilic cells/mm³ is achieved can be safe as long as no complicating comorbid conditions are present.51,83–87

Prophylactic use of hemopoietic growth factors is common in the setting of intensive chemotherapy regimens such as stem cell transplantation. Treatment of fever or infection with growth factors, however, is not standard practice. No consistent benefit has been demonstrated in terms of morbidity (i.e., duration of fever and use of antimicrobial agents) or mortality among several randomized controlled trials of the addition of growth factors to an antibiotic regimen at the time of fever during neutropenia.90–90 The routine use of growth factors in treating febrile neutropenic patients is discouraged. Therapy with colony-stimulating factors, however, could be considered for severely neutropenic patients who have serious uncontrolled infections such as bacterial sepsis, pneumonia, severe cellulitis or sinusitis, systemic fungal infections, hypotensive episodes, or multiorgan dysfunction as a result of sepsis. Prophylactic use of the myeloid growth factors is recommended in patients at greater than a 20% risk of febrile neutropenia and in patients with important factors that increase the individual risk of neutropenic complications.⁹⁰

Bloodstream infections occur in about 10% to 20% of febrile patients during neutropenia, most often when neutrophil counts are less than 100 cells/mm³.2,26,45–47,92 The risk of bacteremia is related to the depth of neutropenia, the presence of gastrointestinal mucositis or of an indwelling catheter, or the concomitant presence of a specific site of infection such as pneumonia or soft tissue process. Most bacteremias are due to gram-positive organisms, with coagulase-negative staphylococci and streptococci predominating. Gram-negative pathogens, including Escherichia coli, Enterobacter, Klebsiella, and P. aeruginosa, are important albeit less frequently occurring pathogens.¹⁶

A classification system for bacteremias in febrile neutropenic patients has been developed by Elting and colleagues,⁷ based on the size and presence of associated tissue involvement. Complex bacteremias were those associated with deep-tissue infections of the lung, the liver or spleen, the kidney, the colon, bone and joints, veins and the heart, meninges, and soft tissues with necrosis, or affected skin or soft tissue, wounds, or cellulitis greater than 5 cm in diameter. Simple bacteremias were associated with less tissue involvement (e.g., bacteruria, otitis, pharyngitis, and an affected area of soft tissue less than 5 cm in diameter). The prognostic significance of a complex infection associated with bacteremia on survival was dramatic. At 21 days, 20% of patients with complex infections were dead, compared with only 5% of patients with simple bacteremias (P < .0001). Profoundly neutropenic patients with simple bacteremias had a much higher response rate to antibiotics than was noted in patients with complex bacteremias (94% vs. 70%; P < .0001). The median time to defervescence for patients with simple bacteremias was half that observed for patients with complex bacteremias (2.5 days vs. 5.3 days; P < .0001).

With increasing incidence of MRSA in hospitals and the community, it is recommended that vancomycin be added to standard empirical antibiotic coverage if gram-positive cocci in clusters are isolated from a blood culture, pending identification.16,48,52–54,57 Vancomycin-resistant enterococcus (VRE) also is common in high-risk cancer patients at some institutions. If gram-positive cocci in pairs and chains are identified in blood cultures in settings where VRE is prevalent, then empiric addition of an antimicrobial active against VRE (e.g., linezolid or daptomycin) is prudent, pending definite identification and susceptibility profile. Gram-negative bacteremias in the neutropenic patient are increasingly prevalent in some institutions and are associated with high mortality unless treated promptly and with appropriate antibiotics.^95–95 A variety of resistance mechanisms are evolving among gram-negative organisms. Therefore if gram-negative rods are isolated in blood cultures during fever and neutropenia, an aminoglycoside (which is preferred if the patient was heavily pretreated with fluoroquinolones) or a fluoroquinolone should be added to empiric therapy regimens to ensure coverage of resistant strains until a full susceptibility report is available.