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Antimicrobial Agents and Chemotherapy, September 2007, p. 3401-3403, Vol. 51, No. 9
0066-4804/07/$08.00+0     doi:10.1128/AAC.01520-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

In Vivo Efficacy of Moxifloxacin Compared with Cloxacillin and Vancomycin in a Staphylococcus aureus Rabbit Arthritis Experimental Model{triangledown}

Olivier Grossi, Jocelyne Caillon,* Cedric Arvieux, Cedric Jacqueline, Denis Bugnon, Gilles Potel, and Antoine Hamel

Université de Nantes, Nantes Atlantique Universités, Thérapeutiques Cliniques et Expérimentales des Maladies Infectieuses, EA 3826, Faculté de Médecine, Nantes F-44000, France

Received 4 December 2006/ Returned for modification 26 March 2007/ Accepted 7 June 2007


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ABSTRACT
 
We investigated the efficacies of moxifloxacin, cloxacillin, and vancomycin in a rabbit model of Staphylococcus aureus arthritis. No significant difference between therapeutic regimens was observed after a 7-day treatment. Oral moxifloxacin could be a suitable alternative to standard parenteral therapy for S. aureus arthritis.


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TEXT
 
Nongonococcal acute septic arthritis remains a leading cause of destructive joint disease (14, 26). Treatment includes both drainage of the infected joint and antibiotic therapy. Staphylococcus aureus is the pathogen most often involved in bacterial arthritis (9, 14, 26). Therapy consists of intravenous penicillinase-resistant penicillin or vancomycin for 1 or 2 weeks. A switch to oral therapy is typical following clinical improvement (4). The successful use of ciprofloxacin or ofloxacin alone (13, 21, 25) or in combination (8) for treatment of S. aureus skeletal infections has been described. Moxifloxacin exhibits enhanced activity against S. aureus (16, 19), has a low propensity to select in vitro and in vivo resistant mutants (1, 11, 18, 21, 25), and diffuses well in synovial fluid (SF) (6). One paper has reported the successful use of moxifloxacin in bone and joint infections in the clinical setting (12). The aim of this study was to evaluate the in vivo efficacy of moxifloxacin in comparison with cloxacillin and vancomycin in a rabbit arthritis model induced with methicillin-susceptible and -resistant S. aureus (MSSA and MRSA, respectively) strains.

Two quinolone-susceptible S. aureus strains were studied. One clinical isolate from a case of acute arthritis was an MSSA strain, and the other, isolated from blood culture, was methicillin resistant (MRSA).

The MICs of moxifloxacin and vancomycin were determined by microdilution in Mueller-Hinton broth (2, 24). The MICs of cloxacillin were determined by the same method, but with Mueller-Hinton broth containing 2% NaCl (22).

Rabbit arthritis was induced by injection of 1 ml of a 108-CFU inoculum of MSSA or MRSA into the joint space of the right knee (17). Animals infected with MSSA were randomly assigned to the moxifloxacin or cloxacillin group, and those infected with MRSA were randomly assigned to the moxifloxacin or vancomycin group. A control group without treatment was also constituted to ensure that the lowering of the bacterial concentration was not because of an immunologic response. The treatments were started 24 h after bacterial challenge, and all animals were treated for 7 days. A computer controlled the flow rate of moxifloxacin in order to simulate a human oral dose of 400 mg daily (5). Vancomycin was administered by a constant intravenous infusion and allowed to reach a 20-mg/liter serum steady-state concentration (dose of 100 mg/kg of body weight daily). Cloxacillin was injected via the intramuscular route at a dose leading to supra-MIC levels in serum (50 mg/kg three times a day) (7). Before treatment, an SF sample (SF 1) was taken from each infected rabbit knee. At the end of the treatment, all of the SF (SF 2) was removed from each infected rabbit knee by a surgical procedure. SF 1 and SF 2 samples were weighed (range, 20 to 150 mg), homogenized in 0.5 ml of saline buffer, and spread on Mueller-Hinton agar plates and on charcoal agar plates to prevent a carryover effect (30). Undiluted homogenates were also spread on agar plates containing moxifloxacin at concentrations corresponding to two and four times the MIC in order to determine resistant variants. Bacterial counts were determined after 48 h of incubation.

The moxifloxacin simulation was intended to provide pharmacokinetic parameters close to those observed in healthy volunteers after administration of a single 400-mg oral dose, including a half-life of about 8 to 12 h, a peak concentration (Cmax) of about 2.5 to 3 mg/liter, a time to Cmax of about 1 h, and an area under the concentration-time curve from 0 to 24 h (AUC0-24) of about 35 to 40 mg·h·liter–1 (26, 27, 29). A total dose of 45 mg/kg (in a volume of 50 ml) was administered to the rabbits over a 24-h period in order to simulate human serum kinetics after a 400-mg oral dose.

Free moxifloxacin and cloxacillin concentrations in serum and SF were determined by microbiologic assay methods (limits of detection, 0.125 mg/liter and 0.5 mg/liter for moxifloxacin and cloxacillin, respectively). Vancomycin dosage in serum was performed by bioassay (limit of detection, 2 mg/liter). The linearity of the standard curve used for the bioassays was 0.98 (r2). Inter- and intraplaque variations were <10%.

Statistical and pharmacokinetic analyses were performed with GraphPad Prism v4.0 (Graph Pad Software, San Diego, CA). Analyses were performed separately for each strain by comparing therapeutic regimens two by two. Student's t test was used to compare the mean difference in bacterial concentrations in SF before and after treatment ({Delta}log10 CFU per gram of SF). A P value of ≤0.05 was considered statistically significant.

MICs of moxifloxacin and vancomycin were 0.032 mg/liter and 1 mg/liter for MSSA and MRSA, respectively. MICs of cloxacillin were 0.5 mg/liter for MSSA and 4 mg/liter for MRSA. The serum pharmacokinetic profile obtained in rabbits after the first "human" oral dose of 400 mg of moxifloxacin (Cmax = 2.85 mg/liter; AUC0-24 = 37.5 mg·h·liter–1; half-life = 8.2 h) and the corresponding human data are shown in Fig. 1. Pharmacokinetic/pharmacodynamic parameters were calculated from these data as follows: AUC/MIC ratio, >1,000; and Cmax/MIC ratio = 90.


Figure 1
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  		FIG. 1. Simulated pharmacokinetics of moxifloxacin in sera of rabbits following the first "human" oral dose of 400 mg ({triangleup}) and corresponding human pharmacokinetics (x).

The mean (± standard deviation [SD]) trough concentration (Cmin) of moxifloxacin in SF (3.90 ± 1.70 mg/liter) was close to the Cmax in serum (Cmin/MIC ratio in SF = 121). The mean (± SD) concentration achieved in rabbit serum with cloxacillin was 0.80 ± 0.2 mg/liter at 6 h, which slightly exceeded the MIC, at least for the duration of 6 h (approximately 70% of the dosing interval). The Cmin of cloxacillin in SF remained about 2.90 ± 0.5 mg/liter (about 5x MIC), allowing a concentration time over the MIC of about 100% of the dosing interval. Steady-state concentrations of vancomycin in serum were 26.3 ± 2.9 mg/liter. Vancomycin dosages in SF were not performed.

The in vivo outcomes are shown in Table 1. For the control group, the mean {Delta}log10 value (± SD) was –1.1 ± 0.8 CFU/g with the MSSA strain and 0.6 ± 1.91 CFU/g with the MRSA strain. Differences in log reductions between moxifloxacin and comparators were not significant (P > 0.05; Student's t test). None of the regimens studied yielded S. aureus colonies on agar plates containing moxifloxacin at two and four times the MIC.


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  		TABLE 1. Differences in bacterial concentrations in SF between the first and seventh days of treatment

No well-conducted controlled clinical trials evaluating the efficacies of antibiotic regimens for bacterial arthritis have been published. Ten percent of S. aureus strains are methicillin resistant in this pathology only (9, 15). The recent emergence of community-acquired MRSA strains (28) susceptible to quinolones is likely to change the epidemiology of this pathology. Treatment failures of S. aureus skeletal infections observed with older fluoroquinolones were mostly related to the emergence of quinolone-resistant strains. Moxifloxacin could be preferred in this clinical setting. Indeed, studies have shown the lower propensity of moxifloxacin to select resistant mutants in vitro and in vivo among staphylococci (1, 18, 21, 25) and its activity against first-level ciprofloxacin-resistant MRSA strains, with a MIC of 0.25 µg/ml (10). Frippiat et al. recently reported favorable outcomes with moxifloxacin in association with rifampin in seven clinical cases of staphylococcal bone and joint infections (12). To date, no study has shown the efficacy of moxifloxacin against acute septic arthritis.

The present study revealed that in the arthritis model, moxifloxacin exhibited a similar in vivo efficacy to that of reference antibiotic therapy against both S. aureus strains susceptible to quinolones. The AUC/MIC ratio of >1,000 and Cmax/MIC ratio of >90 greatly overcome pharmacokinetic/pharmacodynamic ratio breakpoints (AUC/MIC ratio of >100 and Cmax/MIC ratio of >8) correlated with therapeutic success of fluoroquinolones (3). Moxifloxacin diffuses well in SF and inflammatory fluids, with a similar pharmacokinetic profile to that in serum from humans after a single oral dose (6, 29). We found that Cmin values of moxifloxacin in SF at 7 days (3.90 ± 1.70 mg/liter) were close to the Cmax in serum, probably because of accumulation.

Regarding its excellent pharmacokinetic profile and bioavailability (19, 26), oral moxifloxacin could be considered an alternative treatment for quinolone-susceptible S. aureus arthritis. However, its use in association with another antibiotic, such as rifampin, is likely warranted in the clinical setting, especially when prolonged therapy is required.


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FOOTNOTES
 
* Corresponding author. Mailing address: Laboratoire EA 3826, Faculté de Médecine, 1 rue Gaston Veil, 44035 Nantes Cedex 01, France. Phone and fax: (33) 240 41 2854. E-mail: jocelyne.caillon{at}univ-nantes.fr Back

{triangledown} Published ahead of print on 18 June 2007. Back


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Antimicrobial Agents and Chemotherapy, September 2007, p. 3401-3403, Vol. 51, No. 9
0066-4804/07/$08.00+0     doi:10.1128/AAC.01520-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.




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