Abstract

Abstract
Background

Bacterial infections are a major cause of morbidity and mortality in patients who are neutropenic following chemotherapy for malignancy. Trials have shown the efficacy of antibiotic prophylaxis in reducing the incidence of bacterial infections but not in reducing mortality rates. Our systematic review from 2006 also showed a reduction in mortality.

This updated review aimed to evaluate whether there is still a benefit of reduction in mortality when compared to placebo or no intervention.

We searched the Cochrane Cancer Network Register of Trials (2011), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 2, 2011), MEDLINE (1966 to March 2011), EMBASE (1980 to March 2011), abstracts of conference proceedings and the references of identified studies.

Randomised controlled trials (RCTs) or quasi‐RCTs comparing different types of antibiotic prophylaxis with placebo or no intervention, or another antibiotic, to prevent bacterial infections in afebrile neutropenic patients.

Two authors independently appraised the quality of each trial and extracted data from the included trials. Analyses were performed using RevMan 5.1 software.

One‐hundred and nine trials (involving 13,579 patients) that were conducted between the years 1973 to 2010 met the inclusion criteria. When compared with placebo or no intervention, antibiotic prophylaxis significantly reduced the risk of death from all causes (46 trials, 5635 participants; risk ratio (RR) 0.66, 95% CI 0.55 to 0.79) and the risk of infection‐related death (43 trials, 5777 participants; RR 0.61, 95% CI 0.48 to 0.77). The estimated number needed to treat (NNT) to prevent one death was 34 (all‐cause mortality) and 48 (infection‐related mortality).

Prophylaxis also significantly reduced the occurrence of fever (54 trials, 6658 participants; RR 0.80, 95% CI 0.74 to 0.87), clinically documented infection (48 trials, 5758 participants; RR 0.65, 95% CI 0.56 to 0.76), microbiologically documented infection (53 trials, 6383 participants; RR 0.51, 95% CI 0.42 to 0.62) and other indicators of infection.

There were no significant differences between quinolone prophylaxis and TMP‐SMZ prophylaxis with regard to death from all causes or infection, however, quinolone prophylaxis was associated with fewer side effects leading to discontinuation (seven trials, 850 participants; RR 0.37, 95% CI 0.16 to 0.87) and less resistance to the drugs thereafter (six trials, 366 participants; RR 0.45, 95% CI 0.27 to 0.74).

Antibiotic prophylaxis in afebrile neutropenic patients significantly reduced all‐cause mortality. In our review, the most significant reduction in mortality was observed in trials assessing prophylaxis with quinolones. The benefits of antibiotic prophylaxis outweighed the harm such as adverse effects and the development of resistance since all‐cause mortality was reduced. As most trials in our review were of patients with haematologic cancer, we strongly recommend antibiotic prophylaxis for these patients, preferably with a quinolone. Prophylaxis may also be considered for patients with solid tumours or lymphoma.

Author(s)

Anat Gafter‐Gvili, Abigail Fraser, Mical Paul, Liat Vidal, Theresa A Lawrie, Marianne D van de Wetering, Leontien CM Kremer, Leonard Leibovici

Abstract

Plain language summary

 Antibiotics to prevent bacterial infections due to chemotherapy in cancer patients with a low white blood cell count and no fever 

For patients receiving chemotherapy, there is an increased risk of infection due to a low white blood cell count (neutropenia) caused by a toxic effect of chemotherapy on the bone marrow. The objective of this review was to establish whether preventive antibiotic therapy (prophylaxis) before the development of fever prevents illness and death in people with a low white blood cell count after chemotherapy and to assess whether certain types of antibiotics are better than others. We included 109 randomised controlled trials conducted between the years 1973 to 2010.

Antibiotic prophylaxis significantly decreased the risk of death when compared to no intervention. We estimated that the number of patients needed to be treated with antibiotics in order to prevent one death from all causes was 34. Antibiotic prophylaxis also decreased the risk of death from infection and the risk of development of fever.  Although antibiotic prophylaxis may be associated with unfavourable effects and may encourage new and more resistant infection, this was not shown in existing trials. Recent studies used antibiotics of the quinolone class, which showed fewer adverse events and better outcomes than other classes of antibiotics.

Most studies were limited to haematological cancer patients (mostly leukaemia).

In conclusion, patients with a low white blood count following chemotherapy who received preventive antibiotic treatment in the absence of fever had a reduced risk of dying. This was shown mainly for haematological cancer patients. Antibiotic prophylaxis, preferably from the quinolone class of antibiotics, should be recommended for routine use in these patients.

Author(s)

Anat Gafter‐Gvili, Abigail Fraser, Mical Paul, Liat Vidal, Theresa A Lawrie, Marianne D van de Wetering, Leontien CM Kremer, Leonard Leibovici

Reviewer's Conclusions

Authors' conclusions

Implications for practice

These updated findings support antibiotic prophylaxis, preferably with a quinolone where resistance permits, for routine use in neutropenic patients because it reduces mortality. We recommend levofloxacin or ciprofloxacin for this purpose, however the decision to use prophylaxis and the type of drugs, whether a quinolone or a combination of a quinolone and a drug effective against Gram‐positive bacteria, should be taken based on the local profile of pathogens in neutropenic patients and their susceptibility to antibiotics.

Prophylaxis is strongly recommended in patients with haematological malignancies, who are usually at higher risk for infection. However, a reduction in mortality was shown for patients with solid tumours or lymphoma as well and therefore these patients are likely to benefit from prophylactic antibiotics. Since studies of these patients were few and they were clinically heterogenous (different diseases), further research is needed to identify which patients with solid tumours or lymphoma may benefit the most.

Centres that implement prophylaxis should institute surveillance measures to monitor quinolone‐resistant Gram‐negative bacteria, as well as rates of other resistant organisms (vancomycin resistant enterococci (VRE), methicillin resistant S.aureus (MRSA) and Clostridium difficile.

Implications for research

Current evidence points to an advantage in survival with antibiotic prophylaxis. Therefore, further RCTs comparing prophylaxis to placebo or no intervention are probably not warranted.

Although the evidence in favour of antibiotic prophylaxis is convincing, many of the studies included in the present analysis were of uncertain methodological quality and some of them were quite old. Thus an argument could be made in favour of a contemporary trial evaluating and comparing quinolones that has adequate randomisation, allocation concealment and blinding, and is powered to detect a difference in mortality. However, given that the mortality rates in recent trials of febrile neutropenic patients range between 1% to 8% (Cherif 2004; De Pauw 1994; Giamarellou 2000; Rolston 1992), a RCT powered to demonstrate a difference in mortality due to prophylaxis is probably not feasible since it would require an inordinately large sample size.

Further research should define which patients with solid tumours or lymphoma may benefit from prophylaxis. This could be assessed by conducting RCTs that include patients with a specific malignancy, or according to different chemotherapy protocols. Further studies should determine the advantage of antibiotic prophylaxis in the first chemotherapy cycle versus the next cycles. Data on all‐cause mortality should be reported, even if not as a primary outcome. Assessment of resistance development should be carefully planned and performed.

Future studies should assess whether antibiotics started at the onset of neutropenia are as effective as antibiotics started with chemotherapy, to limit unnecessary exposure to antibiotics.