Received: December 28, 2020
Accepted: February 13, 2021
Mediterr J Hematol Infect Dis 2021, 13(1): e2021025 DOI 10.4084/MJHID.2021.025
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management of febrile neutropenia is a backbone of treating patients
with hematologic malignancies and has evolved over the past decades.
This article reviews my approach to the evaluation and treatment of
febrile neutropenic patients. Key topics discussed include
antibacterial and antifungal prophylaxis, the initial workup for fever,
the choice of the empiric antibiotic regimen and its modifications, and
criteria for discontinuation. For each of these questions, I review the
literature and present my perspective.
In this review, I present my perspective of the management of febrile neutropenia, based on my experience in a tertiary care university-affiliated hospital. The purpose of this review is to provide a practical approach to the management of neutropenic cancer patients, taking into consideration current recommendations, local epidemiologic aspects, and the experience in managing this complication for over 30 years. A summary of my approach to the management of febrile neutropenia is presented in Table 1.
1. Management of febrile neutropenia.
The "add-on" Strategy
Should I Give Antibacterial Prophylaxis?
My opinion. Unless there is an additional risk for potentially severe side effects, I give ciprofloxacin 500 mg BID (or levofloxacin 500 mg/d) to autologous and allogeneic HCT recipients, starting with the conditioning regimen until engraftment or until the patient develops fever requiring the initiation of empiric antibiotic therapy. I also give ciprofloxacin to patients with acute myeloid leukemia (AML) receiving consolidation chemotherapy with high-dose cytarabine. This is particularly attractive because most patients are discharged after chemotherapy and spend the period of neutropenia at home. In such situations, quinolone prophylaxis may reduce the chance of readmission to treat febrile neutropenia.
Most AML patients in induction remission are already febrile on admission. For these patients, I start empiric antibiotic therapy, even acknowledging that fever is most likely caused by the underlying leukemia. However, if there is no documentation of infection and fever resolves with chemotherapy, I discontinue empiric therapy and start ciprofloxacin. The other situation in which I consider giving quinolone prophylaxis is in induction remission for acute lymphoid leukemia (ALL). The more intensive induction remission I give, the more likely I prescribe quinolone prophylaxis. Like AML, fever in newly diagnosed ALL patients may be due to underlying leukemia, and the same strategy as described for AML applies. It is important to emphasize that quinolone prophylaxis should be considered according to local epidemiology and a periodic re-evaluation of its benefit in light of potential changes in the epidemiology over time.
Should I Give Antifungal Prophylaxis?
With the widespread use of fluconazole as prophylaxis, the incidence of invasive candidiasis dropped sharply, and invasive aspergillosis became the most frequent IFD in neutropenic patients.[34,35] In addition, other filamentous fungi such as Fusarium species and the agents of mucormycosis emerged as important pathogens in neutropenic patients.[36,37] As a consequence, primary prophylaxis with mold-active agents became an attractive strategy and has been tested in randomized clinical trials. The best evidence is for the use of posaconazole or caspofungin in AML. A study comparing posaconazole with fluconazole or itraconazole oral solution in adults showed that IFD and mortality incidence was significantly lower in posaconazole recipients.  In another study conducted in children and young adults, caspofungin use resulted in a reduction in IFD overall and aspergillosis compared with fluconazole. In this trial, most children received a protocol consisting of four cycles of intensive chemotherapy, and the benefit of caspofungin was only apparent after the second cycle. Considering that adults with AML are usually treated with one or two cycles of intensive chemotherapy. Considering that, adults with AML are usually treated with one or two cycles of intensive chemotherapy, it is not clear if caspofungin will also benefit adults with AML receiving induction remission.
A significant benefit of anti-mold prophylaxis in the pre-engraftment period after allogeneic HCT has not been observed since two randomized trials comparing voriconazole with fluconazole or itraconazole failed to show a dramatic advantage of voriconazole in terms of a reduction in the incidence of mold infection.[40,41] Likewise, a benefit of micafungin in reducing the incidence of invasive aspergillosis was not demonstrated in three studies.[42-44] Finally, in ALL, where azoles' use is restricted because of prohibitive drug interactions with vincristine, a study comparing intravenous liposomal amphotericin B (5 mg/kg twice weekly) with placebo showed similar rates of IFD.
The choice of which antifungal prophylaxis to give in neutropenic patients influences the strategies of diagnosis and monitoring for IFD during neutropenia. Patients receiving fluconazole prophylaxis are at increased risk for invasive aspergillosis. In these patients, active monitoring with serial (2-3x/week) serum galactomannan should be strongly considered. On the other hand, if posaconazole is given as prophylaxis, the rates of false-positive galactomannan increase because the pre-test probability of invasive aspergillosis is much lower. In these circumstances, serum galactomannan testing is best performed upon clinical suspicion of invasive aspergillosis rather serially.
Another consequence of the choice of antifungal prophylaxis is the selection of non-prophylactic antifungal agents during neutropenia. If empiric or preemptive antifungal therapy is considered in patients receiving fluconazole prophylaxis, the options include an echinocandin, voriconazole, and an amphotericin B's lipid formulation. However, if the patient receives posaconazole prophylaxis, the most likely choice is amphotericin B's lipid formulation.
Recently, new targeted therapies for the treatment of AML have emerged, including midostaurin, gilteritinib, enasidenib, ivosidenib, venetoclax, and others, with significant improvements in the outcome.[49,50] Most of these agents are metabolized by CYP3A4 enzymes, which are strongly inhibited by both posaconazole and voriconazole.[51,52] Incorporating these new compounds in the treatment of AML will represent a challenge for the use of mold-active azoles as prophylaxis, because the overexposure of target therapies may increase toxicity and underexposure may reduce their efficacy. An alternative would be isavuconazole, a moderate CYP3A4 inhibitor, although there are no solid data on its efficacy as prophylaxis.
My opinion. I give antifungal prophylaxis to patients with AML receiving induction remission chemotherapy and in the pre-engraftment period of allogeneic HCT. In AML, my choice between fluconazole and posaconazole is based on a bedside risk assessment of IFD that takes into account the probability of achieving complete remission with one cycle of chemotherapy (older age, high white blood cell count, relapsed AML, and high cytogenetic and/or molecular risk), co-morbidities and environmental exposure (Table 2). I give posaconazole to patients with high-risk AML and fluconazole to patients with intermediate or low-risk AML.
In the pre-engraftment period of allogeneic HCT, I use a risk stratification strategy that takes into account the predicted duration of neutropenia (stem cell source, conditioning regimen), T-cell depletion, co-morbidities, and environmental factors (Table 2). I give voriconazole or posaconazole to high-risk patients and fluconazole to low or intermediate-risk patients. In patients receiving any of the new drugs metabolized by CYP3A4, I prefer not to give a mold active azole (voriconazole or posaconazole) and consider giving an echinocandin as prophylaxis in patients at high risk for invasive aspergillosis. I also give echinocandins to high-risk patients who present increased liver enzymes during azole prophylaxis or who have severe gastrointestinal mucositis.
|Table 2. Risk assessment of invasive fungal disease in acute myeloid leukemia and allogeneic hematopoietic cell transplantation.
In both AML and allogeneic HCT, if the patient is receiving fluconazole prophylaxis, I monitor for invasive aspergillosis with serial (3x/week) serum galactomannan. In contrast, for patients receiving posaconazole, I only perform serum galactomannan (3 consecutive days) if there is any suspicion of aspergillosis or fusariosis (persistent or recurrent fever, respiratory symptoms, images, skin lesions).
What is the Workup in the First Fever?
My opinion. My working definition of fever is any axillary temperature ≥38oC. Occasionally, the patient presents signs of infection (e.g., abdominal pain in the context of gastrointestinal mucositis or cellulitis) without fever. In these situations, I trigger the workup and the initiation of empiric antibiotic therapy, regardless of body temperature. My workup starts with a detailed medical history that includes co-morbidities and prior infections (e.g., chronic lung disease, sinusitis, diabetes, smoking habit, herpes virus infection, varicella, tuberculosis), underlying disease and its status, past and recent treatment for the underlying disease, prior episodes of febrile neutropenia with information about the documentation of infection and colonization by resistant organisms, concomitant medications, and symptoms of infection. On the basis of the status of the underlying disease and recent treatment (type and date), I estimate the probable duration of neutropenia and anticipate potential non-infectious complications that may mimic infection (e.g., engraftment syndrome after HCT and differentiation syndrome in AML patients receiving retinoic acid, ivosidenib or enasidenib).[63,64] This approach is essential for the correct interpretation of clinical signs of infection throughout neutropenia.
I perform a physical examination with particular attention to the skin, nails, and respiratory and digestive tracts. I obtain at least two sets of blood cultures (aerobic, anaerobic, and fungal bottles), one from a peripheral vein and another from a catheter. I only order additional tests such as computed tomography (CT) scans or cultures from other sites if clinically indicated. These tests include PCR panel for respiratory viruses and PCR panel for diarrhea in patients with such symptoms.
What is the Empiric Antibiotic Regimen for the First Fever?
The main objective of empiric antibiotic therapy in febrile neutropenic patients is to prevent early death, an event that occurs mostly with Gram-negative bacteremia. We have recently analyzed 1,305 febrile neutropenia episodes looking at factors associated with early death and shock. None of the circumstances in which guidelines recommend the use of vancomycin was associated with shock or early death, including bacteremia due to Gram-positive organisms, catheter-related infection, skin or soft tissue infection, or inadequate Gram-positive coverage, suggesting that the empiric use of vancomycin in the first fever in neutropenic patients is likely unnecessary in the overwhelming majority of cases. Another study evaluated the impact of inappropriate antibiotic coverage at first fever in 1,605 episodes of bloodstream infections in neutropenic patients. While the mortality rate was significantly higher in episodes of Gram-negative bacteremia with inappropriate antibiotic coverage, there was no different in mortality in Gram-positive bacteremia. In other study, the implementation of a rapid microbial identification via MALDI-TOF (matrix-assisted laser desorption ionization time of flight) reduced mortality in bacteremia caused by Gram-negative but not Gram-positive bacteria, further indicating that Gram-positive infections do not result in early death in febrile neutropenic patients.
The empiric antibiotic regimen must cover the most frequent Gram-negative bacteria causing bloodstream infection in febrile neutropenic patients, taking into account local epidemiology. The emergence of infection caused by multi-drug resistant (MDR) Gram-negative bacteria has brought a great challenge for the management of febrile neutropenic patients because they are associated with high mortality rates. Strategies to overcome this problem include active screening with weekly (or on admission) rectal swabs and the initiation of an empiric antibiotic regimen active against the colonizing MDR Gram-negative bacteria.[75,76] In addition, a de-escalation strategy is applied if the patient is stable and blood cultures are negative. A study tested the time to positive blood cultures to guide early de-escalation and found that the median time to positivity of MDR Gram-negative bacteria was 10.5 hours, and 100% of cultures turned positive in less than 24 hours.
My opinion. All new patients admitted to my unit are put in contact precautions and have an anal swab performed. I strongly consider repeating the swab weekly if another patient in the unit is colonized by MDR Gram-negative bacteria. Suppose the patient is colonized by MDR Gram-negative bacteria, or had a documented infection caused by MDR Gram-negative bacteria in a previous febrile neutropenia episode. In that case, I choose an antibiotic regimen with activity against the colonizing (or previously infecting) organism. On day 3 of febrile neutropenia, if blood cultures are negative and the patient is stable, I change the antibiotic regimen to cefepime, even is the patient is still febrile (Figure 1).
|Figure 1. Strategy of
empiric antibiotic therapy in patients with colonization or a previous
episode of infection by multi-drug-resistant Gram-negative bacteria.
For patients without colonization by MDG Gram-negative bacteria, I give cefepime in extended infusion (3-4 hours), with the dose and schedule adjusted for the creatinine clearance. If the patient presents signs of typhlitis, I add metronidazole to cefepime. I do not give vancomycin or any other anti-Gram positive antibiotic such as teicoplanin, daptomycin, or linezolid. Instead, I wait for blood culture results and add vancomycin if the patient presents with bacteremia due to methicillin-resistant Staphylococcus aureus (MRSA).
When Should I Change the Empiric Antibiotic Regimen?
The time to defervescence of a febrile neutropenic patient may vary depending on the presence or absence of infection. For example, in our febrile neutropenia database with over 2,500 episodes, the median time to defervescence was three days in episodes without documented infection and four days in those with clinical or microbiological documentation. Among patients with bacteremia, the median time to defervescence was four days in Gram-negative bacteremia and five days in Gram-positive bacteremia (unpublished data). A randomized study comparing cefepime with ceftazidime plus amikacin has shown that the median time to defervescence of "responding" patients was three days. However, less than 30% of patients were afebrile after three days of antibiotics. In another study comparing cefepime with or without amikacin in febrile neutropenic patients, the proportion of patients who became afebrile after 3, 7 and 10 days of antibiotics was 39%, 70% and 83%, respectively. Taken these data, it is clear that the strategy of empiric change in the antibiotic regimen after 3-4 days of a patient with persistent fever and no new signs of infection is inappropriate and will likely result in the overuse of antibiotics without improving the outcome.
One of the most common actions of clinicians treating febrile neutropenia is to add an anti-Gram-positive antibiotic (usually vancomycin) in persistently febrile patients. A study randomized 165 neutropenic patients with a persistent fever after 2-3 days of piperacillin-tazobactam to receive vancomycin or placebo. No differences between the two groups were observed in time to defervescence, the proportion of afebrile patients in different time points, Gram-positive infections, or mortality.
Another situation in which clinicians add vancomycin empirically is when there are signs of a skin infection, such as cellulitis. A useful tool to help decision making is to check the results of baseline nasal swabs usually performed on admission to detect MRSA colonization. A study analyzed the correlation between the results of 484 nasal swabs in 194 patients with AML and subsequent documentation of infection. A negative MRSA nasal swab had a 99% negative predictive value for subsequent MRSA infections.
Another frequent empiric change in the antibiotic regimen in persistently febrile neutropenic patients is to expand Gram-negative coverage, usually switching from cefepime or piperacillin-tazobactam to meropenem. Even considering the emergence of MDR bacterial infections in neutropenic patients, this practice is not recommended for persistently febrile patients this practice is not recommended for persistently febrile patients who do not have signs of clinical deterioration. Instead, a diagnostic workup for infection and other causes of fever's persistence should be undertaken, including a thorough physical examination, repeated blood cultures, serum biomarkers of infection, and images.
My opinion. I do not change the empiric regimen on the basis of just persistent fever. I perform a careful review of symptoms and physical examination, obtain additional blood cultures, and check for results of biomarkers of infection, including serum C-reactive protein and galactomannan. On the other hand, if there are new signs of infection, I change the regimen as follows: add metronidazole if there is anal or abdominal pain, and switch beta-lactam if there is any sign of clinical deterioration, even if the patient is afebrile. In addition, I check the results of baseline blood cultures and make appropriate adjustments to the antibiotic regimen accordingly, including adjusting the dose of cefepime, taking into consideration the minimal inhibitory concentration of a Gram-negative bacteria grown in blood cultures. If the patient presents signs of a skin infection, I only add vancomycin if the patient is colonized by MRSA. I give linezolid or daptomycin to patients with documented infection by vancomycin-resistant Gram-positive bacteria, such as enterococci.
I do not give empiric antifungal therapy for persistently febrile patients. Instead, I combine serum galactomannan results with images (chest and sinuses CT scan), and start antifungal therapy in a preemptive strategy. If a chest CT scan shows images suspicious of invasive mold disease (macronodules, wedge-shaped images) and serum galactomannan is negative, I perform bronchoalveolar lavage unless the patient is hypoxemic. Additional tests that I perform frequently are abdominal CT scan in patients with clinical manifestations suspicious of typhlitis, stool tests for Clostridioides difficile in patients with diarrhea, and skin biopsy in any new skin nodular lesion.
When Should I Discontinue Antibiotics in Febrile Neutropenia?
My opinion. For patients who recover from neutropenia, I promptly discontinue the antibiotic regimen if there was no documentation of infection, regardless of the duration of empiric antibiotic treatment. For patients who recover from neutropenia but had documentation of infection, I adjust the antibiotic regimen to treat the documented infection for as long as it is needed (based on the type of infection that was diagnosed). For patients with are still neutropenic and have a documented infection, I adjust the regimen to cover the pathogen recovered in the documented infection but keep the beta-lactam until neutrophil recovery. If there is no infection documentation, I discontinue the empiric antibiotic regimen, provided that vital signs are normal and the patient has no oral or gastrointestinal mucositis. In some patients at high risk for infection (e.g., expected long duration of neutropenia), I discontinue the empiric antibiotic regimen and give a quinolone. In any case, once the empiric antibiotic regimen is discontinued, I monitor the temperature very closely and reintroduce empiric antibiotic therapy if fever recurs.
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