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Insufficient evidence of synergistic effect of levofloxacin and rifampin against Legionella pneumophila

I read with interest the article by Baltch et al. (1) in which they described the in vitro efficacies of levofloxacin, ofloxacin, erythromycin, and rifampin against Legionella pneumophila. On the basis of time-kill experiments, they concluded that levofloxacin demonstrated superior inhibitory and bactericidal effects when it was studied alone or in combination with rifampin. Although indeed the combination of levofloxacin and rifampin appeared superior in that no regrowth of L. pneumophila was shown, the authors did not mention that the other combinations act synergistically at 0.53MIC at 72 h as well. In their Fig. 2B it can be seen that ofloxacin resulted in counts of approximately 13 10 CFU/ml and rifampin resulted in counts of approximately 5 3 10 CFU/ml, whereas the combination resulted in counts of approximately 10 CFU/ml. Similarly, in their Fig. 2C erythromycin and rifampin alone resulted in counts of approximately 10 CFU/ml, and the combination resulted in counts of approximately 10 CFU/ml. The results would have been more convincing if the authors had analyzed their time-kill curves systematically, for example, by the methods described by McFarland et al. (2) or my own group (3). Furthermore, information about the reproducibility of the time-kill experiments was lacking. However, some deduction about the reproducibility of their time-kill curves can be made from a comparison of Fig. 1 and 2.. Because the MICs of levofloxacin, ofloxacin, erythromycin, and rifampin for the isolates were identical in all three figures, I presume that the figures show the results for a single strain. The experiment with rifampin at 0.53 MIC is depicted four times (Fig. 1A, 2A, 2B, and 2C). At 24 h the log10 differences in CFU with the control without antibiotic are 4.8, 5.3, 3.9, and 4.5, respectively, whereas at 72 h these differences are 0, 6.2, 1.4, and 1.7, respectively. From these numbers it can be inferred that at 72 h the reproducibility of the time-kill curves is less than that at 24 h. Nevertheless, the authors chose to base their conclusion that ‘‘only levofloxacin plus rifampin demonstrated a synergistic effect, with no regrowth of L. pneumophila’’ on the observations made at 72 h. The absence of regrowth can be seen in Fig. 2A, where both rifampin and levofloxacin at 0.53 MIC resulted in counts of 10 CFU/ml and the combination at the same concentration resulted in 10 CFU/ml. These results are based on plating of 100-ml samples and therefore represent a difference in count between 10 colonies per plate and zero. Leaving aside the issue of the reliability of the estimate of low counts, it can be concluded that the true count in the tube containing the combination of levofloxacin and rifampin could be any number below 10 CFU/ml. According to the authors’ own definition of synergy (a 2-log difference in activity), they have not even decisively proven that levofloxacin and rifampin act synergistically at 0.53 MIC. In sum, it can be concluded the article of Baltch et al. (1), although rightfully drawing attention to the potential role of quinolones in the treatment of legionellosis, would have had additional value if extra information had been added to the results. REFERENCES