This is an update of prior guidelines on this topic and highlights recent advances in antimicrobial drug availability, clinical trial results, and extensive clinical experience since the prior guideline in 2002. All patients who present with fever and neutropenia should be treated swiftly and broadly with antibiotics to treat both gram-positive and gram-negative pathogens. Specific antimicrobial therapy should be based on a variety of factors that include high or low risk of infection based on presenting signs and symptoms, type of cancer, underlying conditions, and extent of neutropenia.
From the Northeastern Ohio Universities Colleges of Medicine and Pharmacy, Rootstown and Summa Health System, Akron, OH.
Correspondence to: Thomas M. File, Jr, MD, 75 Arch St, Suite 506 (main office; Suite 105 for Research), Akron, OH 44304. E-mail: firstname.lastname@example.org.
The author discloses that he has received recent research funding from Cerexa/Forest, Pfizer, Boehringer Ingelheim, Gilead, GlaxoSmithKline, and Tibotec and is a consultant for Cerexa/Forest, Merck, Nabriva, Pfizer, and Tetraphase.
Summarized later are several of the specific recommendations regarding antimicrobial therapy for fever in this update (specific recommendations are graded as to the strength of recommendation with A being the strongest and the level of evidence with I being the highest. My comments are in italics). The reader is referred to the guideline for other recommendations that include antimicrobial prophylaxis, role of hematopoietic growth factors, and environmental precautions.1
1. What is the role of risk assessment and what distinguishes high-risk and low-risk patients with fever and neutropenia?
* Most experts consider high-risk patients to be those with anticipated prolonged (>7 days in duration) and profound neutropenia (absolute neutrophil count [ANC] <100 cells per microliter after cytotoxic chemotherapy) and/or significant medical comorbid conditions, including hypotension, pneumonia, new-onset abdominal pain, or neurologic changes. Such patients should be initially admitted to the hospital for empirical therapy (A-II).
* Low-risk patients, including those with anticipated brief (<7 days in duration) neutropenic periods or no or few comorbidities, are candidates for oral empirical therapy (A-II).
Comments: Like many other infections, stratification of patients based on various risk factors is important for appropriate management. In addition to those characteristics mentioned previously, the Multinational Association of Supportive Care in Cancer (MASCC) Risk Index Score can also be helpful to identify patients with low or high risk of infectious complications.2 The MASCC scoring system is a summation of weighted risk factors as follows:
Low-risk patients are identified by a total score greater than or equal to 21. According to the guidelines, all patients at high risk by MASCC or by clinical criteria should be initially admitted to the hospital for empirical antibiotic therapy if they are not already inpatients (B-I). Low-risk patients have a MASCC score greater than 21 (B-I). Carefully selected low-risk patients may be candidates for oral and/or outpatient empirical antibiotic therapy (B-I).
2. What specific tests and cultures should be performed during the initial assessment?
* Include complete blood cell count with differential, creatinine and serum urea nitrogen levels, electrolytes, and liver panel.
* At least 2 sets of blood cultures are recommended, with a set collected simultaneously from each lumen of an existing central venous catheter, if present, and from a peripheral vein site.
* Culture specimens from other sites of potential infection.
* Chest X-ray if with respiratory signs or symptoms.
Comments: If fever persists after empirical antimicrobials, the panel recommends that a repeat of blood cultures may be obtained on each of the next 2 days but, beyond that, does not recommend continued daily blood cultures unless there is a clinical change. Studies regarding use of inflammation markers (eg, C-reactive protein, procalcitonin) are inconclusive in neutropenic patients.
3. In febrile patients with neutropenia, what empiric antibiotic therapy is appropriate and in what venue?
* High-risk patients require hospitalization for intravenous (IV) empirical antibiotic therapy; monotherapy with an antipseudomonal β-lactam agent, such as cefepime, a carbapenem (meropenem or imipenem-cilastatin), or piperacillin-tazobactam, is recommended (A-I).
* If with a history of an immediate-type hypersensitivity reaction (eg, hives and bronchospasm), patients should be treated with a combination that avoids β-lactams and carbapenems, such as ciprofloxacin plus clindamycin or aztreonam plus vancomycin (A-II).
* Low-risk patients should receive initial oral or IV empirical antibiotic doses in a clinic or hospital setting; they may be transitioned to outpatient oral or IV treatment if they meet specific clinical criteria (A-I). Ciprofloxacin plus amoxicillin-clavulanate in combination is recommended for oral empirical treatment (A-I). Other oral regimens, including levofloxacin or ciprofloxacin monotherapy or ciprofloxacin plus clindamycin, are less well studied but are commonly used (B-III). Low-risk patients who have initiated IV or oral antibiotics in the hospital may have their treatment approach simplified if they are clinically stable (A-I).
Comments: As reviewed in the guideline, for patents without risk for methicillin-resistant Staphylococcus aureus (although this is becoming more of an issue), monotherapy with an antipseudomonal β-lactam is as effective as multidrug combinations. Other antimicrobials (aminoglycosides, fluoroquinolones, and/or vancomycin) may be added to the initial regimen for management of complications (eg, hypotension and pneumonia) or if antimicrobial resistance is suspected or proven (B-III). Vancomycin (or other agents active against aerobic gram-positive cocci) should be considered for specific clinical indications, including suspected catheter-related infection, skin or soft tissue infection, pneumonia, blood culture positive for gram-positive bacteria before final identification, severe mucositis, or hemodynamic instability. Patients receiving fluoroquinolone prophylaxis should not receive oral empirical therapy with a fluoroquinolone (A-III).
The choice of antimicrobials for so-called β-lactam allergic patients is not well studied. In our hospital, aztreonam or ciprofloxacin will cover less than 70% of Pseudomonas. For this reason, we plan on adding 1 dose of high-dose aminoglycoside empirically until we have the 24-hour culture results available.
4. When and how should antimicrobials be modified during the course of fever and neutropenia?
* Unexplained persistent fever in a patient whose condition is otherwise stable rarely requires an empirical change to the initial antibiotic regimen. If an infection is identified, antibiotics should be adjusted accordingly (A-I).
* Patients who remain hemodynamically unstable after initial doses with standard agents for neutropenic fever should have their antimicrobial regimen broadened to include coverage for resistant gram-negative, gram-positive, and anaerobic bacteria and fungi (A-III).
* An IV-to-oral switch in antibiotic regimen may be made if patients are clinically stable and gastrointestinal absorption is felt to be adequate (A-I).
* Empirical antifungal coverage should be considered in high-risk patients who have persistent fever after 4 to 7 days of a broad-spectrum antibacterial regimen and no identified fever source (A-II).
Comments: After initiating empirical antimicrobial therapy, all patients should be monitored for clinical response, adverse effects, and emergence of second infections (often associated with multidrug-resistant organisms). As stated in the guideline, the median time to defervescence for patients with hematologic malignancies with empirical antimicrobials is approximately 5 days and 2 days for lower-risk patients with solid tumors. Once a documented infection is identified, antimicrobial therapy should be modified based on susceptibility data-certainly a principle consistent with antimicrobial stewardship.
Persistent fever lasting longer than 3 days should prompt a thorough search for a source of fever, which includes infectious (eg, Clostridium difficile, catheter-related blood stream infections, esophagitis) and noninfectious sources (eg, drug fever, thrombophlebitis, cancer related). A computed tomographic scan of the chest and sinuses is recommended for high-risk patients to further assess for possible fungal infection. As indicated in the guideline, several issues regarding early therapy for presumptive fungal infection require further study; these include the optimal trigger (eg, clinical or radiological vs. serum markers-β-d-glucan test or galactomannan assay), timing, and antifungal agent.
5. How long should empirical antibiotic therapy be given?
* The duration of therapy is dictated by the particular organism and site; appropriate antibiotics should continue for at least the duration of neutropenia (until ANC is >500 cells per microliter) or longer if clinically necessary (B-III).
* In patients with unexplained fever, it is recommended that the initial regimen be continued until there are clear signs of marrow recovery; the traditional end point is an increasing ANC that exceeds 500 cells per microliter (B-II).
* If an appropriate treatment course has been completed and all signs and symptoms of a documented infection have resolved, patients who remain neutropenic may resume oral fluoroquinolone prophylaxis until marrow recovery (C-III).
Comments: The traditional approach to duration has been to continue antimicrobial agents until the neutrophil count is greater than 500 and is showing an increasing trend. Documented infections such as blood stream infections will require 10 to 14 days of therapy even if early recurrence of white blood cells occurs. Some studies (mostly in pediatrics) have supported the cessation of antimicrobials before the 500-neutrophil count if cultures are negative for bacteria and the patient is afebrile for at least 24 hours.3-5