The efficacy of systemic antibacterial prophylaxis was investigated in a multitude of clinical trials and several meta-analyses. The results of the two most important large double-blind, placebo-controlled studies are described briefly: Bucaneve et al. examined the use of levofloxacin in 675 patients with hematological malignancies or solid tumors and an expected length of neutropenia (neutrophil count less than 1,000/μl) of more than 7 days. A significant reduction of febrile episodes and microbiologically documented infections, especially gram-negative bacteremias, could be shown in the levofloxacin arm. Mortality was lower in the levofloxacin group, but the study was not powered to show this with statistical significance [1
]. In the study by Cullen et al. [12
], 1,565 patients with solid tumors or lymphomas receiving outpatient chemotherapy were given levofloxacin or placebo for an expected period of neutropenia of less than 7 days. The incidence of febrile episodes, probable infections and hospitalization for infection could be reduced significantly. Also, there were fewer severe infections and a lower overall mortality in the prophylaxis group, but this difference was not statistically significant [12
These observations were confirmed in a large meta-analysis comprising a total of 13,579 patients from 109 studies conducted between 1973 and 2010 [37
]. Most of the studies included high-risk patients with hematological diseases such as acute leukemias and compared different prophylactic strategies with placebo or no intervention. Due to the larger number of patients included in the meta-analysis compared to the single trials, a significant reduction of infection-related death with a risk ratio (RR) of 0.61 (95 % confidence interval [CI], 0.48–0.77) and a reduction in all-cause mortality (RR 0.66; 95 % CI, 0.55–0.79) were calculated for patients receiving antibacterial prophylaxis as compared to placebo or no intervention. A decrease in all-cause mortality could also be shown in the subgroup of 3,776 patients included from studies testing fluoroquinolone prophylaxis versus no prophylaxis (RR 0.54; 95 % CI, 0.40–0.74). Microbiologically documented gram-negative as well as gram-positive infections including bacteremias were significantly reduced in patients receiving antibacterial prophylaxis. An increase of 3.6 % in adverse events due to prophylaxis as compared to no prophylaxis is reported with 2.1 % more events (3.9 % versus 1.8 %) leading to treatment discontinuation [37
A meta-analysis including only randomized, blinded, placebo-controlled trials from 1987 to 2005 with a total of 2,721 patients could not demonstrate a significant, but only a trend towards, reduction of overall mortality [38
], while efficacy data were consistent with the study from Bucaneve et al. and with the 2012 meta-analysis [1
]. It has to be kept in mind that this meta-analysis was strongly influenced by the non-infectious mortality among low-risk patients in the Cullen et al. study, which might obscure a potential survival benefit with regard to the infection-related mortality (Table ).
Overview of risk reduction rates in studies on antibacterial prophylaxis in cancer patients
Antibacterial prophylaxis, particularly with fluoroquinolones, can prevent febrile episodes, clinically or microbiologically documented bacterial infections including bacteremias and hospitalization of outpatients. A reduction in infection-related as well as all-cause mortality could be shown in a large meta-analysis [37
]. In order to derive recommendations from the data described above, the risk reduction has to be weighed against adverse effects, especially the development of resistance to widely used antibacterial agents among clinically relevant pathogens. A reduction of overall mortality can be assumed in high-risk populations with a number needed to treat (NNT) below 50 (43 according to the study of Bucaneve et al., 34 according to the meta-analysis of Gafter-Gvili et al.) and avoidance of neutropenic fever with a NNT of around 5 [1
]. As with other interventions, NNT decreases with increasing underlying risk. Therefore, prophylaxis is recommended in high-risk patients. Concerning avoidance of fever and infections, this is a strong recommendation; concerning mortality reduction, the recommendation is weaker (Table ). In low-risk patients, a reduction of neutropenic fever and avoidance of hospitalization can be achieved. This effect is most pronounced during the first cycle of chemotherapy. On the other hand, a reduction of mortality was not unequivocally shown for low-risk patients. One meta-analysis showed a mortality reduction with a NNT of 72 [39
], but it included older studies with an unacceptably high baseline event rate to be attributed to low-risk patients. Assuming that in low-risk patients a similar relative risk reduction as in high-risk patients can be achieved, the NNT to prevent one infection-related death would be around 250 at a baseline risk of 1 % and a relative risk of 0.6 (i.e., otherwise healthy individuals with low-intensity chemotherapy). In addition, the prophylactic administration of a fluoroquinolone in low-risk patients would prohibit the use of a fluoroquinolone for treatment of infection in the outpatient setting. Therefore, antibacterial prophylaxis can generally not be recommended in low-risk patients. In specific situations such as the first chemotherapy cycle [15
], aggressive cytostatic regimens with high baseline infection rate or in elderly patients; however, it may be considered because it reduces the incidence of infections and febrile episodes.
Recommendations for antibacterial prophylaxis