on 04-Jun-2021 (Fri)

Cancer patients receiving cytotoxic antineoplastic therapy sufficient to adversely affect myelopoiesis and the integrity of the gastrointestinal mucosa are at risk for invasive infection due to colonizing bacteria or fungi that translocate across intestinal mucosal surfaces.

Infections in neutropenic patients can progress rapidly, leading to hypotension and/or other life-threatening complications. It is critical to recognize neutropenic fever early and to initiate empiric systemic antibacterial therapy promptly in order to avoid progression to a sepsis syndrome and possibly death [1,2].

The recommendations below are generally in keeping with the 2010 Infectious Diseases Society of America guidelines [1]. Links to guidelines are provided separately. (See 'Society guideline links' below.)

Fever — Fever in neutropenic patients is defined as a single oral temperature of ≥38.3°C (101°F) or a temperature of ≥38.0°C (100.4°F) sustained over a one-hour period [1].

Neutropenia — The definition of neutropenia may vary from institution to institution, but neutropenia is usually defined as an absolute neutrophil count (ANC) <1500 or 1000 cells/microL, and severe neutropenia is usually defined as an ANC <500 cells/microL or an ANC that is expected to decrease to <500 cells/microL over the next 48 hours [1,9]. Profound neutropenia is defined as an ANC <100 cells/microL.

The risk of clinically important infection rises as the neutrophil count falls below 500 cells/microL and is higher in those with a prolonged duration of neutropenia (>7 days). The risk for bacteremic infection rises as the ANC falls below 100 cells/microL. For the purposes of this discussion, we are defining severe neutropenia as an ANC <500 cells/microL.

Clinical circumstances that are likely to result in severe neutropenia for >7 days put patients at high risk for serious complications; these criteria are most likely to be met following induction chemotherapy for acute leukemia and during the pre-engraftment phase of myeloablative hematopoietic cell transplantation (particularly allogeneic).

The factors that are associated with serious complications are summarized in the table (table 1) and discussed in greater detail separately.

Knowledge that the ANC reaches its nadir of <500 cells/microL at a median of 12 to 14 days from day 1 of chemotherapy can guide the clinician to the correct index of suspicion regarding the likelihood of neutropenia.

Over 70 percent of cancer recipients who develop systemic therapy-related complications present to emergency triage facilities within four to six weeks of systemic anticancer treatment [10]. The use of a sensitive but nonspecific historical indicator, receipt of systemic anticancer therapy within the preceding six weeks, has been advocated for use in emergency triage departments to identify patients who are likely to be neutropenic [11].

Diagnostic evaluation — The diagnostic evaluation of patients presenting with neutropenic fever is summarized in the following table (table 2) and is discussed in detail separately. (See "Diagnostic approach to the adult cancer patient with neutropenic fever".)

General principles — Fever in a neutropenic patient should be considered a medical emergency. Broad-spectrum antibacterials should be given as soon as possible (within 60 minutes of triage) and at full doses, adjusted for renal and/or hepatic function.

Antibiotics are usually administered empirically but should always include appropriate coverage for suspected or known infections. Even when the pathogen is known, the antibiotic regimen should provide broad-spectrum empiric coverage for the possibility of other pathogens, unlike the treatment strategy adopted in many immunocompetent hosts.

● In high-risk patients, antibiotics should generally be administered intravenously (IV) in a hospital setting.

● Initial antibiotic selection should be guided by the patient's history, allergies, symptoms, signs, recent antibiotic use and culture data, and awareness of the susceptibility patterns of institutional nosocomial pathogens [14].

● Ideally, antibiotics should be bactericidal.

Febrile neutropenic patients should be monitored frequently with respect to vital signs (blood pressure, heart rate, respiratory rate, and temperature), performance status (the clinical burden of the neutropenic fever syndrome), and the ability to achieve adequate oral intake in the presence of oral or gastrointestinal mucositis. Temporarily holding administration of systemic chemotherapy should be considered during the management of the sepsis syndrome until the patient stabilizes

Afebrile neutropenic patients with new signs or symptoms that are consistent with infection should be evaluated and managed as if they are febrile [1].

Attention to fluid and electrolyte management is important given the dehydrating effects of fever, vomiting, and/or diarrhea. Urine output of >0.5 mL/kg per hour should be maintained.

Timing of antibiotics — In all febrile neutropenic patients, empiric broad-spectrum antibacterial therapy should be initiated immediately after blood cultures have been obtained and before any other investigations have been completed [11,16]. Antimicrobial therapy should be administered within 60 minutes of presentation [11,17,18].

Spectrum of coverage — Although gram-positive bacteria are the most frequent pathogens identified during neutropenic fever episodes, it is important to cover broadly for gram-negative pathogens because of their virulence and association with sepsis [18,20]. Furthermore, gram-negative organisms continue to cause the majority of infections in sites outside of the bloodstream (eg, respiratory tract, biliary tract, gastrointestinal tract, urinary tract, and skin) [21], and a rising number of infections are polymicrobial [18,20].

Although anaerobic bacteria are present in abundance in the gastrointestinal tract, it is usually not necessary to include specific anaerobic antibiotic coverage in the initial empiric regimen. Anaerobic bacteremia occurred in only 3.4 percent of episodes in a large series of cancer patients from France [22], and anaerobic bacteria are often part of polymicrobial infections [23,24]. Anaerobic coverage should be included in the regimens of patients with infections that are known or expected to be caused by anaerobes, as discussed below. (See 'Initial regimen' below.)

When using beta-lactams, correct dosing intervals should be used to ensure that drug concentrations are greater than the minimal inhibitory concentration for the pathogen. There has been increasing interest in giving prolonged infusions of beta-lactams (either an extended infusion over three or four hours or a continuous infusion) rather than traditional dosing over 30 minutes to optimize pharmacodynamics [25].

Indications for the use of prolonged infusion strategies with beta-lactams are not established, but it is reasonable to give prolonged infusions in patients with neutropenic fever who are severely ill and/or who have an elevated risk of drug-resistant gram-negative bacilli. (See "Prolonged infusions of beta-lactam antibiotics".)

Other antibiotics, such as aminoglycosides and fluoroquinolones, exhibit concentration-dependent killing and are important in the treatment of gram-negative sepsis.

The Infectious Diseases Society of America (IDSA) recommends the following approach for the initial therapy of high-risk neutropenic patients with fever (algorithm 1) [1]; we agree with this approach

Initiation of monotherapy with an antipseudomonal beta-lactam agent, such as cefepime, meropenem, imipenem, or piperacillin-tazobactam. Ceftazidime monotherapy has also been shown to be effective and continues to be used at some cancer centers with low rates of resistance. However, we generally avoid ceftazidime monotherapy because of rising resistance rates among gram-negative bacteria and its limited activity against gram-positive bacteria, such as streptococci, compared with newer alternatives.

Ceftazidime monotherapy should not be used when there is concern for a gram-positive infection, such as an infection caused by viridans group streptococci in patients with severe mucositis.

The dosing of these agents for patients with normal renal function using traditional dosing (ie, over 30 minutes) are:

• Cefepime – 2 g IV every eight hours

• Meropenem – 1 g IV every eight hours

• Imipenem – 500 mg IV every six hours

• Piperacillin-tazobactam – 4.5 g IV every six to eight hours; if there is significant concern for Pseudomonas infection (particularly in those who are severely ill or were not receiving fluoroquinolone prophylaxis at the time of onset of illness), 4.5 g IV every six hours should be given

• Ceftazidime – 2 g IV every eight hours

Other antibiotics (eg, aminoglycosides, fluoroquinolones, and/or vancomycin) may be added to the initial regimen in patients with complicated presentations (eg, hypotension and/or mental status changes), focal findings (eg, pneumonia or cellulitis), or if antimicrobial resistance is suspected or proven.

Vancomycin (or other agents that target gram-positive cocci) is not recommended as a standard part of the initial regimen but should be added in certain patients, such as those with suspected catheter-related infection, skin or soft tissue infection, pneumonia, or hemodynamic instability.

In addition, we suggest that anaerobic coverage be included if there is evidence of necrotizing mucositis, sinusitis, periodontal cellulitis, perirectal cellulitis, intra-abdominal infection (including neutropenic enterocolitis [typhlitis]), pelvic infection, or anaerobic bacteremia.

Monotherapy with a beta-lactam agent with activity against Pseudomonas aeruginosa (eg, cefepime, meropenem, imipenem, piperacillin-tazobactam, or ceftazidime) is frequently employed; clinical trials with ceftazidime, imipenem, or meropenem have demonstrated equivalent outcomes compared with two-drug regimens [26-29]. In addition, fewer adverse events have generally been seen with monotherapy regimens compared with combination regimens [30]. The majority of the regimens evaluated provided coverage targeted at gram-negative bacilli, especially P. aeruginosa.

One concern about monotherapy is the possibility that increasing rates of antibiotic resistance in a number of pathogens may reduce the efficacy of this strategy. Single agents, especially ceftazidime, may actually promote the outgrowth of resistant organisms in this group of patients who require frequent antibiotic administration [37]. It is therefore important to maintain vigilance for the emergence of antibiotic resistance locally that may necessitate a change in antibiotic practices.

Combination therapy — Numerous combination antibiotic regimens have been studied as initial empiric therapy in neutropenic fever, but none has been shown to be clearly superior to others or to monotherapy [38,39]

One approach is to use an extended-spectrum beta-lactam (eg, piperacillin, ceftazidime) in combination with an aminoglycoside. Other examples of combination regimens include double beta-lactams or a beta-lactam and a fluoroquinolone

A meta-analysis of eight randomized controlled trials that compared ciprofloxacin-beta-lactam combinations to aminoglycoside-beta-lactam regimens for the empiric therapy of neutropenic fever demonstrated similar overall efficacy for clinical cure and all-cause mortality [ 39].

Double beta-lactams are usually avoided because of overlapping toxicities. In settings characterized by a high prevalence of multidrug-resistant gram-negative bacilli, initial empirical antibacterial therapy with piperacillin-tazobactam plus tigecycline may have some advantages over the single agent for documented neutropenic fever syndromes [40].

However, those with a history of an immediate-type hypersensitivity reaction (eg, hives and/or bronchospasm) should not receive beta-lactams or carbapenems. Alternative empiric regimens for such patients include aztreonam plus vancomycin or ciprofloxacin plus clindamycin [1]. Of these regimens, we prefer aztreonam plus vancomycin out of concern for increasing the risk of Clostridioides (formerly Clostridium) difficile infection in those requiring clindamycin for an extended period.

In general, fluoroquinolones should not be used in patients who have received them recently (including those receiving a fluoroquinolone for neutropenic prophylaxis).

Even in febrile neutropenic patients with skin and soft tissue infections who had a higher incidence of proven gram-positive bacteremia compared with patients with other infections (31 versus 17 percent), the addition of empiric vancomycin did not improve outcomes and was associated with increased toxicity [45]. The risk of promoting resistance among enterococci and Staphylococcus aureus is an important reason to avoid empiric vancomycin use [1].

Vancomycin (or other agents that target gram-positive cocci) is not recommended as a standard part of the initial regimen, but gram-positive coverage should be added in patients with any of the following findings [1]:

● Hemodynamic instability or other signs of severe sepsis

● Pneumonia

● Positive blood cultures for gram-positive bacteria while awaiting speciation and susceptibility results

● Suspected central venous catheter (CVC)-related infection (eg, chills or rigors during infusion through a CVC and/or cellulitis around the catheter entry site)

● Skin or soft tissue infection

● Severe mucositis in patients who were receiving prophylaxis with a fluoroquinolone lacking activity against streptococci and in whom ceftazidime is being used as empiric therapy. Addition of gram-positive coverage is recommended in this situation because of the increased risk of viridans group streptococcal infections, which can result in sepsis and the acute respiratory distress syndrome [1,46-49].

Empiric gram-positive coverage is particularly important for patients who are colonized with methicillin-resistant S. aureus (MRSA), vancomycin-resistant enterococci (VRE), or penicillin- or ceftriaxone-resistant streptococci who become hemodynamically unstable or develop bacteremia with gram-positive cocci.

The combination of vancomycin and piperacillin-tazobactam has been associated with acute kidney injury. In patients who require vancomycin and an antipseudomonal beta-lactam, a beta-lactam other than piperacillin-tazobactam can be used (eg, cefepime). If vancomycin is used with piperacillin-tazobactam, renal function should be monitored carefully and the regimen should be adjusted to reduce further nephrotoxicity if acute kidney injury develops. (See "Vancomycin: Parenteral dosing, monitoring, and adverse effects in adults", section on 'Acute kidney injury'.)

A multicenter randomized trial of 611 febrile neutropenic patients compared the safety and efficacy of linezolid and vancomycin [50]. Patients with proven or suspected infection due to a gram-positive pathogen were randomly assigned to receive linezolid (600 mg IV every 12 hours) or vancomycin (1 g IV every 12 hours) for 10 to 28 days. The following findings were noted:

● Clinical success rates seven days after completion of therapy were equivalent with linezolid and vancomycin (87 versus 85 percent, respectively).

● Mortality rates at 16 days after completion of therapy were similar (17 of 304 patients who received linezolid [6 percent] and 23 of 301 [8 percent] who received vancomycin).

● Drug-related adverse events occurred more frequently in the vancomycin group (24 versus 17 percent for linezolid).

● In patients with documented gram-positive infections, those who received linezolid defervesced more quickly than those who received vancomycin (5.9 versus 9.1 days); there was no difference in time to defervescence among patients without documented infections.

Unexplained persistent fever in a patient who is otherwise stable rarely necessitates an empiric adjustment to the initial antibacterial regimen. However, if an infection is identified, the regimen should be adjusted accordingly.

If vancomycin or other gram-positive coverage was started initially, it may be stopped after two to three days if there is no evidence of a gram-positive infection. Vancomycin overuse has been associated with the development of resistance (eg, vancomycin-resistant Enterococcus spp).

Patients who are or become hemodynamically unstable after initial doses of a standard antimicrobial regimen for neutropenic fever should have their regimen broadened to include coverage for resistant gram-negative, gram-positive, and anaerobic bacteria as well as fungi.

Empiric antifungal coverage should be considered in high-risk patients who have persistent fever after four to seven days of a broad-spectrum antibacterial regimen and no identified source of fever.

Oral ulcerations may be due to herpes simplex virus or Candida spp. Thus, addition of acyclovir and/or fluconazole may be warranted if these findings are present.

The median time to defervescence following the initiation of empiric antibiotics in patients with hematologic malignancies, including hematopoietic cell transplant (HCT) recipients, is five days, in contrast with only two days for patients with solid tumors [1].

As stated above, modification of the initial antibacterial regimen is not needed for persistent fever alone. However, patients who remain febrile after the initiation of empiric antibiotics should be re-evaluated for possible infectious sources.

Management algorithms have been developed for the reassessment of neutropenic patients with persistent fever after two to four days (algorithm 2) and after four or more days (algorithm 3) [1]. Key factors in the management of patients with persistent fever include whether the patient is clinically stable, whether there is an identified site of infection, and when the patient is expected to recover from neutropenia. Consideration should be given to the addition of empiric antifungal therapy, as described below.

The increasing frequency of multidrug-resistant gram-negative bacterial infections is forcing the renewed use of older agents that have been used infrequently in febrile neutropenic cancer patients, such as colistin (colistimethate) and fosfomycin, and newer agents, such as tigecycline [53]. Similarly, beta-lactam- or glycopeptide-resistant gram-positive organisms have forced the use of lipopeptides (daptomycin), oxazolidinones (linezolid), and glycylcyclines (tigecycline).

The patient's risk for the following resistant organisms should be considered when choosing an empiric regimen:

● Among gram-positive organisms, pathogens with acquired resistance include coagulase-negative staphylococci, MRSA, VRE, and penicillin- and ceftriaxone-resistant Streptococcus pneumoniae and other streptococci.

● Gram-positive organisms that have intrinsic resistance to vancomycin (Leuconostoc, Lactobacillus, and Pediococcus spp).

● Multidrug-resistant gram-negative bacilli, such as P. aeruginosa, Escherichia coli, and Citrobacter, Acinetobacter, and Stenotrophomonas spp [15]. The use of fluoroquinolones for prophylaxis has contributed to the emergence of antibiotic resistance.

● The presence of extended-spectrum beta-lactamases (ESBL), plasmid-mediated AmpC-type beta-lactamases, and carbapenemase-producing bacteria (eg, Klebsiella pneumoniae carbapenemase [KPC]) can severely limit treatment options [18,54,55].

In an open-label trial that included 390 high-risk patients with hematologic malignancies, combination therapy for neutropenic fever with piperacillin-tazobactam plus tigecycline was associated with significantly higher success rates compared with piperacillin-tazobactam alone (68 versus 44 percent), especially in those with bacteremia due to E. coli or Staphylococcus epidermidis [40]. Mortality rates were similar in both groups, but the study was not powered to detect a difference in this outcome. Among E. coli bloodstream isolates, 33 percent were resistant to piperacillin-tazobactam and 7 percent were resistant to tigecycline. Of Klebsiella spp bloodstream isolates, 36 percent were resistant to piperacillin-tazobactam and 10 percent were resistant to tigecycline. In our opinion, tigecycline should only be used for empiric therapy of neutropenic fever in centers with a high rate of multidrug-resistant infections caused by E. coli or Klebsiella.

An empiric antifungal agent should be added after four to seven days in high-risk neutropenic patients who are expected to have a total duration of neutropenia >7 days who have persistent or recurrent fever and in whom reassessment does not yield a cause (algorithm 3) [1].

In patients who are clinically unstable or have a suspected fungal infection, antifungal therapy should be considered even earlier than what is recommended for empiric therapy

In an autopsy study of patients who died after prolonged neutropenic fever between 1966 and 1975, 69 percent of patients had evidence of systemic fungal infection [62]. It should be noted that over one-half of the patients in this early series had Candida infections, which may have been effectively prevented with antifungal prophylaxis strategies. For example, in one trial, fungal infections were documented in only 1 percent of persistent fevers in patients receiving fluconazole prophylaxis [63].

In patients who have not been receiving antifungal prophylaxis, Candida spp are the most likely cause of invasive fungal infection. In patients receiving fluconazole prophylaxis, fluconazole-resistant Candida spp (eg, C. glabrata and C. krusei) and invasive mold infections, particularly Aspergillus spp, are the most likely causes.

The 2010 IDSA guidelines for empiric antifungal therapy recommend amphotericin B deoxycholate, a lipid formulation of amphotericin B, caspofungin, voriconazole, or itraconazole as suitable options for empiric antifungal therapy in neutropenic patients [1].

For persistently febrile patients who have not been receiving antifungal prophylaxis and who have no obvious site of infection, such as pulmonary nodules, we favor caspofungin (or another echinocandin) since Candida spp is a likely cause in such patients and the echinocandins provide excellent coverage for Candida spp and are well tolerated.

For persistently febrile patients with pulmonary nodules or nodular pulmonary infiltrates, invasive mold infection should be strongly suspected and treated. Prompt assessment frequently requires bronchoscopy with bronchoalveolar lavage with cultures, stains, and Aspergillus galactomannan antigen testing to distinguish bacterial from mold pathogens, while simultaneously initiating antibacterial and anti-mold therapy until the specific etiology is established [66].

Voriconazole or a lipid formulation of amphotericin B are preferred in patients with pulmonary findings suggestive of an invasive mold infection due to higher failure rates with caspofungin in preventing and treating invasive aspergillosis, which is the most common cause of mold infections [67].

Most experts prefer voriconazole if aspergillosis is thought to be most likely, but if mucormycosis is suspected, an amphotericin B formulation should be given since voriconazole has no activity against the agents of mucormycosis. It is important to note that at most centers, aspergillosis accounts for the majority of invasive fungal infections in neutropenic patients.

It is also important to remember that caspofungin and other echinocandins are not active against Cryptococcus spp, Trichosporon spp, and filamentous molds other than Aspergillus spp, such as Fusarium spp. In addition, some yeasts can demonstrate relative resistance to these drugs (Candida parapsilosis, Candida rugosa, Candida guilliermondii, and non-candidal yeasts). Failure of caspofungin to prevent aspergillosis has also been reported, even though it has in vitro activity against Aspergillus spp [68]. Moreover, the echinocandins are not active against the endemic fungi (Histoplasma, Blastomyces, Coccidioides spp).

Dosing — The dosing of the various antifungal agents recommended above is as follows:

● Caspofungin – Loading dose of 70 mg IV on day 1, then 50 mg IV once daily

● Voriconazole – Loading dose of 6 mg/kg IV every 12 hours on day 1, followed by 4 mg/kg IV every 12 hours

● Amphotericin B lipid complex – 5 mg/kg IV once daily

● Liposomal amphotericin B – 3 to 5 mg/kg IV once daily

The lipid formulations of amphotericin B have replaced amphotericin B deoxycholate in most centers due to toxicity considerations, but they are more costly. Amphotericin B deoxycholate should be avoided in patients with antecedent renal disease and in those receiving other nephrotoxic drugs. Today, the lipid formulations of amphotericin B have largely replaced amphotericin B deoxycholate due to favorable toxicity profiles.