Efficacy of trovafloxacin in treatment of experimental staphylococcal or streptococcal endocarditis

Abstract

The efficacy of trovafloxacin against Staphylococcus aureus and viridans group streptococci was investigated in vitro and in an experimental model of endocarditis. The MICs at which trovafloxacin and ciprofloxacin inhibited 90% of clinical isolates of such bacteria (MIC90s) were (i) 0.03 and 2 mg/liter, respectively, for 30 ciprofloxacin-susceptible S. aureus isolates, (ii) 32 and 128 mg/liter, respectively, for 20 ciprofloxacin-resistant S. aureus isolates, and (iii) 0.25 and 8 mg/liter, respectively, for 28 viridans group streptococci. Rats with aortic vegetations were infected with either of two ciprofloxacin-susceptible but methicillin-resistant S. aureus strains (strains COL and P8), one penicillin-susceptible Streptococcus sanguis strain, or one penicillin-resistant Streptococcus mitis strain. Rats were treated for 3 or 5 days with doses that resulted in kinetics that simulated those achieved in humans with trovafloxacin (200 mg orally once a day), ciprofloxacin (750 mg orally twice a day), vancomycin (1 g intravenously twice a day), or ceftriaxone (2 g intravenously once a day). Against the staphylococci, the activities of both trovafloxacin and ciprofloxacin were equivalent to that of vancomycin, and treatment of endocarditis with these drugs was successful (P < 0.05). However, ciprofloxacin selected for resistant derivatives in vitro and in vivo, whereas trovafloxacin was 10 to 100 times less prone than ciprofloxacin to select for resistance in vitro and did not select for resistance in vivo. Against the two streptococcal isolates, trovafloxacin significantly (P < 0.05) decreased bacterial counts in the vegetations but was less effective than the control drug, ceftriaxone. Thus, a simulated oral dose of trovafloxacin (200 mg per day) was effective against ciprofloxacin-susceptible staphylococci and was less likely than ciprofloxacin to select for resistance. The simulated oral dose of trovafloxacin also had some activity against streptococcal endocarditis, but optimal treatment of infections caused by such organisms might require higher doses of the drug.

FIG. 1

Time-kill experiments in broth cultures supplemented or not supplemented with rat serum. The two ciprofloxacin-susceptible MRSA isolates (MRSA COL and MRSA P8) (A) and the two viridans group streptococci (S. sanguis “Du” and S. mitis 531) (B) were treated with the peak (2.5 mg/liter; squares) and the trough (0.5 mg/liter; diamonds) concentrations of trovafloxacin produced in humans and rats after the administration of therapeutic doses of the drug. The bacteria were grown either in plain Mueller-Hinton broth (open symbols) or in Mueller-Hinton broth supplemented with 50% decomplemented rat serum (closed symbols). Triangles, untreated control cultures. The results are the means of three independent experiments, with a relative variation between experiments of ≤15%.

FIG. 2

Concentrations of trovafloxacin in the serum of humans following the administration of an oral dose of 200 mg of trovafloxacin (open symbols) (33) and simulation of these pharmacokinetics in rats (closed symbols). The prodrug alatrofloxacin was administered i.v. to the animals with the infusion pump described in the text. The effective drug concentration was determined by a bioassay in which trovafloxacin was used as a control. Each datum point on the graph represents the mean ± standard deviation of four to six determinations with individual rats.

FIG. 3

Outcome of 3 days of therapy of experimental endocarditis caused by the ciprofloxacin-susceptible and MRSA strains COL and P8. Each dot in the figure represents the bacterial density in the vegetation of a single animal. The open dot in the MRSA COL group treated with ciprofloxacin represents the data for one animal in which the ciprofloxacin MIC for the bacteria from the valve was increased. P was <0.05 when the results were compared by the Kruskal-Wallis test. Contr, control; Cipro, ciprofloxacin; Trova, trovafloxacin; Vanco, vancomycin.

FIG. 4

Selection of ciprofloxacin (CIPRO)-resistant and trovafloxacin (TROVA)-resistant derivatives of staphylococci (A) and streptococci (B) exposed to stepwise increasing concentrations of ciprofloxacin or trovafloxacin. Series of tubes containing twofold serial dilutions of either of the test drugs were inoculated with a final concentration of 10⁶ CFU of the organisms per ml and were further incubated for 24 h at 35°C, as described in the text for the MIC tests. On the next day, the tube with the highest antibiotic concentration still showing turbidity was used to inoculate a new series of antibiotic-containing tubes. The procedure was repeated, and the increase in the MIC was followed over time. (A) Results of this kind of passage for six clinical isolates of MSSA and seven clinical isolates of MRSA. The graph indicates the median results for the test organisms. Variations between the isolates did not exceed 1 tube dilution. (B) Results of similar experiments performed with the two streptococcal isolates tested in rats.

FIG. 5

Outcomes of 3 and 5 days of therapy of experimental endocarditis due to the penicillin-susceptible streptococcus S. sanguis “Du” and the penicillin-resistant streptococcus S. mitis 531. Each dot represents the bacterial density in the vegetation of a single animal. P was <0.05 when the results were compared by the Kruskal-Wallis test.

FIG. 6

Time-kill experiments with low concentrations of trovafloxacin. The test isolates MRSA P8 and the penicillin-resistant streptococcus S. mitis 531 were treated with two times (open triangles), four times (open squares) and eight times (open diamonds) the MIC of trovafloxacin for each isolate. Closed circles represent the results for untreated control cultures.