Early discontinuation of antibiotics for febrile neutropenia versus continuation until neutropenia resolution in people with cancer
People with cancer with febrile neutropenia are at risk of severe infections and mortality and are thus treated empirically with broad‐spectrum antibiotic therapy. However, the recommended duration of antibiotic therapy differs across guidelines.
To assess the safety of protocol‐guided discontinuation of antibiotics regardless of neutrophil count, compared to continuation of antibiotics until neutropenia resolution in people with cancer with fever and neutropenia, in terms of mortality and morbidity. To assess the emergence of resistant bacteria in people with cancer treated with short courses of antibiotic therapy compared with people with cancer treated until resolution of neutropenia.
We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 10) in the Cochrane Library, MEDLINE, Embase, and LILACS up to 1 October 2018. We searched the metaRegister of Controlled Trials and the US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov for ongoing and unpublished trials. We reviewed the references of all identified studies for additional trials and handsearched conference proceedings of international infectious diseases and oncology and haematology conferences.
We included randomised controlled trials (RCTs) that compared a short antibiotic therapy course in which discontinuation of antibiotics was guided by protocols regardless of the neutrophil count to a long course in which antibiotics were continued until neutropenia resolution in people with cancer with febrile neutropenia. The primary outcome was 30‐day or end of follow‐up all‐cause mortality.
Data collection and analysis
Two review authors independently reviewed all studies for eligibility, extracted data, and assessed risk of bias for all included trials. We calculated risk ratios (RRs) with 95% confidence intervals (CIs) whenever possible. For dichotomous outcomes with zero events in both arms of the trials, we conducted meta‐analysis of risk differences (RDs) as well. For continuous outcomes, we extracted means with standard deviations (SD) from the studies and computed mean difference (MD) and 95% CI. If no substantial clinical heterogeneity was found, trials were pooled using the Mantel–Haenszel fixed‐effect model.
We included eight RCTs comprising a total of 662 distinct febrile neutropenia episodes. The studies included adults and children, and had variable design and criteria for discontinuation of antibiotics in both study arms. All included studies but two were performed before the year 2000. All studies included people with cancer with fever of unknown origin and excluded people with microbiological documented infections.
We found no significant difference between the short‐antibiotic therapy arm and the long‐antibiotic therapy arm for all‐cause mortality (RR 1.38, 95% CI 0.73 to 2.62; RD 0.02, 95% CI ‐0.02 to 0.05; low‐certainty evidence). We downgraded the certainty of the evidence to low due to imprecision and high risk of selection bias. The number of fever days was significantly lower for people in the short‐antibiotic treatment arm compared to the long‐antibiotic treatment arm (mean difference ‐0.64, 95% CI ‐0.96 to ‐0.32; I² = 30%). In all studies, total antibiotic days were fewer in the intervention arm by three to seven days compared to the long antibiotic therapy. We found no significant differences in the rates of clinical failure (RR 1.23, 95% CI 0.85 to 1.77; very low‐certainty evidence). We downgraded the certainty of the evidence for clinical failure due to variable and inconsistent definitions of clinical failure across studies, possible selection bias, and wide confidence intervals. There was no significant difference in the incidence of bacteraemia occurring after randomisation (RR 1.56, 95% CI 0.91 to 2.66; very low‐certainty evidence), while the incidence of any documented infections was significantly higher in the short‐antibiotic therapy arm (RR 1.67, 95% CI 1.08 to 2.57). There was no significant difference in the incidence of invasive fungal infections (RR 0.86, 95% CI 0.32 to 2.31) and development of antibiotic resistance (RR 1.49, 95% CI 0.62 to 3.61). The data on hospital stay were too sparse to permit any meaningful conclusions.
We could make no strong conclusions on the safety of antibiotic discontinuation before neutropenia resolution among people with cancer with febrile neutropenia based on the existing evidence and its low certainty. Results of microbiological outcomes favouring long antibiotic therapy may be misleading due to lower culture positivity rates under antibiotic therapy and not true differences in infection rates. Well‐designed, adequately powered RCTs are required that address this issue in the era of rising antibiotic resistance.
Anat Stern, Elena Carrara, Roni Bitterman, Dafna Yahav, Leonard Leibovici, Mical Paul
Plain language summary
Stopping antibiotic therapy early versus continuing until normal neutrophil count in people with cancer with fever and low neutrophil counts
Review question- People with cancer who are treated with chemotherapy may have a low number of white blood cells, a condition known as neutropenia. White blood cells are crucial to defending the immune system against infection. In people with neutropenia who develop fever, it is unknown whether it is safe to stop giving antibiotics before the white blood cell count returns to normal or whether it is better to continue antibiotics until the white blood cell count recovers (usually to a number higher than 500 cells per microlitre).
Background- Neutrophils are a type of white blood cell crucial to the defence of the immune system against many infective pathogens including bacteria. People with cancer receiving chemotherapy suffer from decreased production of neutrophils, which means that they are exposed to severe, life‐threatening infections. When a cancer patient with neutropenia develops fever, it is crucial to start broad‐range antibacterial treatment as soon as possible in order to lower the risk of death and serious complications. To date, the best duration of course of antibiotics to give is unclear. The continuation of antibiotics beyond the required duration might result in the development of side effects and resistant bacteria.
Search date- The evidence is current to 1 October 2018.
Study characteristics- We included eight studies involving people with neutropenia and fever and comparing short antibiotic therapy to long antibiotic therapy until normalisation of neutrophils. A total of 662 episodes of fever in people with neutropenia were randomly assigned to a treatment group (314 to short antibiotic treatment and 348 to long antibiotic treatment). All trials excluded people who had bacteria growing in any culture before the time of randomisation. All studies except two excluded people with infection in a specific organ.
Study funding sources- Three trials did not report funding sources; three were funded by academic sponsors; one had academic sponsorship, but the antibiotics and placebos were provided by pharmaceutical companies; and one was sponsored by government funding.
Key results- There was no difference in mortality between the short‐ and long‐antibiotic therapy arm. There was no difference in the number of people with severe infections presenting as bacteria in blood. There were more cases of infections with positive cultures in people treated with short antibiotic courses compared to long antibiotic courses, but there was no difference in the rate of unfavourable outcome such as recurrence of fever, need for rehospitalization, and change or restart of antibiotics. We found no differences in the rate of fungal infections and development of antibiotic resistance, with few studies reporting the latter outcome. The number of days with fever was lower for people treated with short antibiotic courses compared to those treated with long antibiotic courses. In all trials the number of antibiotic treatment days was fewer in the short‐antibiotic therapy arm by three to seven days compared to the long‐antibiotic therapy arm. Data on hospital length of stay were insufficient to permit any meaningful conclusions.
Certainty of the evidence- The overall certainty of evidence was low or very low, permitting little confidence in the results presented. Most of the included studies were old and not adequately designed. There were also many differences between the studies in terms of design and inclusion criteria. We assessed the certainty of the evidence for the primary outcome of all‐cause mortality as low and for the outcomes of clinical failure and bacteraemia occurring after randomisation as very low.
Anat Stern, Elena Carrara, Roni Bitterman, Dafna Yahav, Leonard Leibovici, Mical Paul
Implications for practice
The relative paucity of data, variability of the included trials, and low certainty of the evidence preclude strong conclusions on the safety of antibiotic discontinuation before neutropenia resolution among patients with febrile neutropenia. By showing no difference in mortality and clinical failure, our review can be used to support the implementation of existing guidelines which allow for the discontinuation of antibiotics in stable patients disregarding their neutrophil count. In patients at high risk of bacteraemia, antibiotic discontinuation should be considered on an individual basis.
Implications for research
Our main conclusion is that well‐designed, adequately powered randomised controlled trials (RCTs) are needed addressing the safety of stopping antibiotics before neutropenia resolution among high‐risk haemato‐oncological patients, separately for adults and children.
Based on the review of existing trials, the design features we deem important for such a trial include the following. The trial should include a homogenous patient population with febrile neutropenia, with all patients fulfilling clear criteria for antibiotic initiation. We believe that recruitment and randomisation should occur at the time point of planned antibiotic discontinuation to avoid the need to exclude patients with documented or suspected bacterial microbiologically documented infections and clinically documented infections and to minimise the potential for selection bias. A prospective consent to participate in the study when febrile neutropenia develops can possibly be sought from patients at the time of admission to streamline recruitment and allow inclusion of a more representative sample of patients, since at the time of febrile neutropenia patients may not be well enough to provide informed consent. Patients should be included only once into the trial. All‐cause mortality should be assessed. Basing the sample size calculation on antibiotic treatment days, an indirect outcome measure, will lead to the lack of power for assessment of clinical patient‐relevant outcomes. The sample size can be performed on a hierarchical outcome or using the Desirability of Outcome Ranking (DOOR) strategy, addressing survival and patients' well‐being, to achieve a meaningful and feasible sample size (Evans 2015). In such an RCT, we would expect to see an evaluation of resistance selection or development through clinical assessment of infections caused by multidrug‐resistant bacteria and surveillance of colonisation by multidrug‐resistant bacteria.
In summary, existing RCTs cannot provide clear evidence that policies for early antibiotic discontinuation in febrile neutropenia are associated with fewer fungal infections, Clostridium difficile or secondary infections caused by resistant bacteria. Early antibiotic discontinuation in febrile neutropenia of unknown origin may be associated with higher rates of bacteraemia and documented infections, but this does not appear to translate to higher clinical failure rates or worse survival. In an era of pan‐resistant bacteria among neutropenic cancer patients, more efforts should be invested in research defining the optimal duration of antibiotics in specific patient groups.