Imran, H., Tleyjeh, I.M., Arndt, C.A., Baddour, L.M., Erwin, P.J., Tsigrelis, C., . . . Montori, V.M. (2008). Fluoroquinolone prophylaxis in patients with neutropenia: A meta-analysis of randomized placebo-controlled trials. European Journal of Clinical Microbiology and Infectious Diseases, 27, 53–63.

To determine the effectiveness of fluoroquinolone prophylaxis in neutropenic patients with cancer.

Databases accessed included MEDLINE, EMBASE, the Cochrane Library (including its database of trials, CENTRAL, and its two databases of systematic reviews, CSDR and DARE), Web of Science, International Pharmaceutical Abstracts Online, and BIOSIS through October 2005. In addition, the reference sections of eligible trials and reviews.

Key words included quinolones, neutropenia, and infection prophylaxis.

To be included, eligible trials met the following criteria: (a) randomized, controlled trial; (b) compared the use of prophylactic fluoroquinolone as a single agent with a placebo; (c) included adults (defined as those at least 16 years of age) who experienced episodes of neutropenia due to cancer chemotherapy and/or hematopoietic stem cell transplantation; and (d) measured the incidence of all-cause mortality and febrile episodes. Randomized, controlled trials published only as abstracts were excluded.

Eight clinical trials with 2,721 patients were evaluated.

One reviewer abstracted the data and two reviewers independently assessed the methodologic quality using established validity criteria. Disagreements were resolved by consensus. A random effects model, the DerSimonian and Laird method, was used for pooling dichotomous data to estimate relative risk and the associated 95% confidence interval. Heterogeneity was analyzed and subgroup analyses were performed. All analyses were performed using RevMan Analyses [v4.2.7].

Three trials included only patients with acute leukemia, two trials included patients with solid tumors, including lymphomas, and three trials included patients with both hematologic and solid malignancies. All studies including patients with hematologic malignancies or hematopoietic cell transplantation were conducted in the inpatient setting and all studies of patients with solid tumors, including lymphoma, were conducted in the outpatient setting. Fluoroquinolone prophylaxis was started at the time of initiation of chemotherapy in five studies, within 4,896 hours of the initiation of chemotherapy or stem cell infusion in two studies, and in one study it varied depending on the expected neutropenia due to a specific regimen (day 5, day 8, or day 15 post-chemotherapy). Prophylaxis duration varied among studies. The fluoroquinolones used in these studies included levofloxacin in two studies, norfloxacin in one study, ciprofloxacin in two studies, ofloxacin in one study, enoxacin in one study, and pefloxacin in one study. The duration of neutropenia was described in four studies and ranged from 2–55 days. It was defined as an absolute neutrophil count (ANC) of less than 500/mm³ in all but one study, in which less than 1,000/mm³ was considered as neutropenia. Compliance was reported to be good or excellent in five out of eight trials. All trials were double-blind. Allocation concealment and the method of randomization were adequate in five trials and unclear in three trials. Intention-to-treat analysis was performed in seven of eight trials.

Fluoroquinolone prophylaxis statistically nonsignificantly decreased all-cause mortality when compared with placebo (3.9% versus 4.5%, RR = 0.76, 95% CI [0.54, 1.08=, p = 0.13). There was no inconsistency in the results between studies (I² = 0%). Subgroup analyses of studies conducted as inpatient and outpatient also suggested a statistically nonsignificant decrease in mortality with prophylaxis. Compared to placebo, fluoroquinolone prophylaxis resulted in a nonsignificant reduction in the rate of febrile episodes (39% versus 31%, RR = 0.76, 95% CI [0.55, 1.03], p = 0.08). However, there was a large inconsistency in the results between studies (I² = 95.8%), so additional subgroup analyses were performed. The pooled RR was 0.34 (95% CI [0.14, 0.8]) for the two trials in outpatients and 0.9 (95% CI [0.7, 1.16]) for the six trials conducted in the inpatient setting (p for interaction, < 0.001). The pooled RR was 0.6 (95% CI [0.33, 1.1]) for the two trials that used levofloxacin and 0.89 (95% CI [0.65, 1.22]) for the six trials that used fluoroquinolones other than levofloxacin (p for interaction, 0.01). The RR estimate of 0.76 (95% CI [0.7, 0.83]) from the single inpatient trial that used levofloxacin was possibly different to the estimate from the other inpatient trials (p for interaction, 0.08).

Meta-analysis from eight randomized, placebo-controlled trials demonstrated a statistically nonsignificant decrease in all-cause mortality in neutropenic patients who received fluoroquinolone prophylaxis. The data indicated that fluoroquinolone prophylaxis reduced the risk of febrile episodes in neutropenic outpatients with solid tumors, including lymphomas, but not in hematology inpatients and autologous hematopoietic cell recipients. Patients with solid tumors have a lower risk of febrile neutropenia and are more responsive to prophylaxis. In contrast, hematology inpatients and autologous hematopoietic cell recipients have a high rate of febrile neutropenia and are less responsive to prophylaxis.

There was significant inconsistency between the studies that suggests that additional research is needed.

The data suggested that levofloxacin may be more effective than other fluoroquinolones. Based on the available evidence, there was no significant decrease in all-cause mortality in neutropenic patients who received fluoroquinolone prophylaxis.