Comparison of Tigecycline and Vancomycin for. Treatment of Experimental Foreign Body Infection

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1 AAC Accepts, published online ahead of print on 1 April 00 Antimicrob. Agents Chemother. doi:./aac.0-0 Copyright 00, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved Comparison of Tigecycline and Vancomycin for Treatment of Experimental Foreign Body Infection due to Methicillin-Resistant Staphylococcus aureus Pierre Vaudaux*, Bénédicte Fleury, Asllan Gjinovci, Elzbieta Huggler, Manuela Tangomo-Bento, and Daniel P. Lew Service of Infectious Diseases, University Hospitals of Geneva, CH-1 GENEVA 1, Switzerland Running title: tigecycline in staphylococcal foreign body infection *Corresponding author. Mailing address: Service of Infectious Diseases, University Hospitals of Geneva, rue Gabrielle-Perret-Gentil, CH-1 Geneva 1, Switzerland Phone: 1-. Fax: Pierre.Vaudaux@hcuge.ch Downloaded from on November, 01 by guest /1/00 :

2 ABSTRACT Twice-daily -day regimens of tigecycline ( mg/kg) and vancomycin (0 mg/kg) were compared in a rat tissue cage model of chronic foreign body infection due to methicillinresistant Staphylococcus aureus strain MRGR. Subcutaneously administered tigecycline reached tissue cage fluid levels that were nearly equivalent or slightly superior to the antibiotic MIC (0. µg/ml) for strain MRGR. After days, equivalent, significant reductions in bacterial counts were recorded in tigecycline-treated and vancomycin-treated rats, compared to untreated animals. Downloaded from on November, 01 by guest /1/00 :

3 Antimicrobial therapy of foreign body infections due to Staphylococcus aureus is challenging (), in particular for multidrug-resistant hospital-associated and communityacquired isolates of methicillin-resistant S. aureus (MRSA) (, 1, 1, 1). Tigecycline is a novel injectable glycylcycline broad spectrum antibiotic that demonstrates excellent in vitro and in vivo activity against MRSA and other multi-resistant organisms (,,,, ), and can overcome both major tetracycline resistance mechanisms, namely ribosomal protection (, ) and efflux (, ). Tigecycline has shown good activity in various animal models of serious MRSA infections (1,, 0), as well as against biofilm-embedded bacteria (1, ). We previously used a rat tissue cage model of S. aureus chronic foreign body infections for evaluating a number of antimicrobial agents, namely vancomycin (1), teicoplanin (1), imipenem (0), ceftobiprole (), daptomycin (, ), and several fluoroquinolones (, 1, ). This study reports the activity of tigecycline compared to the reference anti-mrsa agent vancomycin, in the tissue cage model of MRSA chronic foreign body infection. (This study was presented in part at the 1 th European Congress of Clinical Microbiology and Infectious Diseases, Barcelona., April 00). MRSA strain MRGR, whose properties were previously described (,, 1, -1,, ) was used for in vitro and in vivo studies. Strain MRGR is resistant to methicillin, gentamicin, erythromycin, tetracycline, and chloramphenicol (1). MICs of freshly prepared (1, 1, ) tigecycline (Wyeth Research, Collegeville, PA) or vancomycin (Vancocin, Teva Pharma AG, Switzerland) for MRSA strain MRGR or quality control S. aureus ATCC 1 were determined by broth macrodilution in cationadjusted Mueller Hinton broth (CAMHB), according to Clinical Laboratory Standards institute (CLSI) guidelines (). The animal protocol used for evaluating in vivo activity of tigecycline and vancomycin was previously described in detail (1, ) and approved by the Ethics Committee of the Downloaded from on November, 01 by guest /1/00 :

4 Faculty of Medicine, University of Geneva, and the Veterinary Office of the State of Geneva. Three weeks after subcutaneous implantation of four tissue cages per animal in anesthetized Wistar rats (), tissue cage fluids were checked for sterility (1). Pilot pharmacokinetic studies were performed on groups of non-infected rats for finding an adequate dosing regimen of tigecycline for therapy of tissue cage infections as described (). Tigecycline levels in cage fluids (and blood) were estimated by a microbiological assay (1), with a detection limit of 0. µg/ml. To account for protein binding, all plasma or tissue cage fluid samples were diluted with 1 volume of PBS and assayed in duplicate, with reference to duplicate standard concentrations (0.- µg/ml) of tigecycline, in PBS supplemented with 0% plasma or pooled tissue cage fluids, respectively. Each tissue cage was chronically infected by inoculating CFU of log-phase MRGR (). Two weeks later, all rats whose cage fluids contained CFU/ml received twice-daily doses (by the s.c. route for days) of tigecycline ( mg/kg), vancomycin (0 mg/kg), or no antibiotic (control group). Differences in CFU counts of cage fluids quantitative cultures, performed at day 1 (before treatment) and day (1 h after the last injection of either tigecycline or vancomycin), were expressed as delta log CFU/ml (), and evaluated by oneway analysis of variance (ANOVA) and post- ANOVA pair-wise comparisons between individual groups via Tukey HSD test ( using P values of <0.0 with two-tailed significance levels. Tigecycline resistance was screened by plating -fold diluted cage fluids (0-µl) onto MHA supplemented with µg/ml tigecycline. No single colony grew on tigecyclinesupplemented plates inoculated with CFU of in vitro grown cultures of strain MRGR. The MIC of tigecycline in CAMHB for MRSA strain MRGR was 0. µg/ml, namely at the upper limit of susceptibility breakpoints (), and was unaffected by supplementation of CAMHB with 0% tissue cage fluid (data not shown). Since tigecycline did not produce a Downloaded from on November, 01 by guest /1/00 :

5 log reduction in MRGR CFU/ml, it was not considered as bactericidal. Nevertheless, supra-mic levels (1,, and µg/ml) of tigecycline produced a - log decrease in MRGR CFU/ml at h. Vancomycin MIC and MBC for strain MRGR were 1 and µg/ml, respectively (1). Average tigecycline levels, scored in tissue cage fluids (n = ) from 0 to 1 h after s.c. administration, remained quite constant over time, showing -fold variations between the different time points and moderate, animal-to-animal differences (Fig. 1). A -mg/kg twicedaily regimen yielded cage fluid levels of µg/ml tigecycline at day, and µg/ml at day, thus being nearly equivalent or slightly superior to the antibiotic MIC for MRGR. Tigecycline plasma levels at h on day were 1. ± 0. µg/ml, in agreement with other reports (, 1). A 1-mg/kg twice-daily regimen led to plasma and tissue cage fluid tigecycline levels ca. -fold higher than the -mg/kg regimen (Fig. 1). Average peak and trough cage fluid levels of vancomycin were previously determined (1) as 1 and µg/ml at and 1 h, respectively. At day 1, mean bacterial counts for MRGR-infected cages were not significantly different (P = 0.) in controls (. ± 0.1 log CFU/ml; n = ), tigecycline-treated (. ± 0.1 log CFU/ml; n = ), or vancomycin-treated rats (.0 ± 0.1 log CFU/ml; n = ). At day, significant (P < 0.01 vs controls) reductions were recorded in cage fluids bacterial counts of both tigecycline-treated (-0. ± 0.1 CFU/ml; n = ) and vancomycin-treated (- 0. ± 0.1 log CFU/ml; n = ) rats, compared to controls whose counts slightly increased (+0.1 ± 0.1 log CFU/ml; n = ) (Fig. ). The slightly different CFU reductions of vancomycin-treated versus tigecycline-treated rats were not significantly different. Finally, no MRGR isolate showing increased tigecycline MIC was observed in any post-therapy cage fluid sample (n = ). The lack of emergence of MRGR derivates with diminished susceptibility to tigecycline is consistent with the difficulty to select laboratory-derived, Downloaded from on November, 01 by guest /1/00 :

6 tigecycline-resistant mutants of S. aureus (1), and contrasts with the emergence of resistant subpopulations during low-dose daptomycin therapy of S. aureus-infected tissue cages (). Several studies performed in the rat tissue cage model demonstrated the low, initial in vivo response of chronic MRSA foreign body-associated infections (,,, 1, 0, -1, -). A much greater reduction of MRSA viable counts in cage fluids requires longer periods of antibiotic therapy (), as found in clinical situations of foreign body infections (). Major pharmacokinetic properties of tigecycline, observed in human and animal studies, are very low plasma levels, long half-lifes, and high volumes of distribution indicating extensive tigecycline distribution into the tissues (,, 1,,, 0). In line with previous observations that showed a requirement for active, preferentially bactericidal, antibiotic levels in cage fluids for obtaining significant CFU reductions in MRSA-infected cage fluids (, ), we selected for therapy a twice-daily mg/kg regimen yielding cage fluid tigecycline levels above the MIC of strain MRGR for >0% of the dosing interval (, ), while minimizing the occurrence of side effects previously observed with higher dose regimens (). Our regimen is similar to those required for activity in other animal models of S. aureus hard-totreat infections, such as endocarditis or osteomyelitis (1, ), although its relevance to human therapy is not fully defined (). In addition, the incomplete in vitro killing activity of tigecycline, namely a < log reduction in MRGR CFU at h, prevents a more detailed pharmacodynamic analysis of tigecycline in vivo activity compared to those of previously evaluated, bactericidal antibiotics in MRSA-infected cages (, ). We can also speculate that other properties of tigecycline, namely its in vivo activity against intracellular, slowly growing, or biofilm-forming bacteria, might significantly contribute to tigecycline activity in MRSA-infected cages (). Indeed, high intracellular levels of tigecycline were shown to accumulate in human polymorphonuclear neutrophils and prevent growth of phagocytized Downloaded from on November, 01 by guest /1/00 :

7 bacteria (). Further studies are needed to elucidate the mechanisms of tigecycline activity against hard-to-treat MRSA infections. This study was supported in part by research grants from Wyeth Pharmaceuticals (Collegeville, PA) and grants (to P.V.) and 00-1 (to D.P.L.) from the Swiss National Science Foundation Downloaded from on November, 01 by guest /1/00 :

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14 1 Figure legends FIG. 1. Pharmacokinetic levels of tigecycline in tissue cage fluids of rats on day (open symbols) or day (closed symbols) of therapy every 1 hours with mg/kg (О) or 1 mg/kg ( ) of tigecycline. Each value is the mean of six determinations. FIG.. Decrease in viable counts of MRSA MRGR in tissue cage fluids of rats treated for days with tigecycline or vancomycin. Downloaded from on November, 01 by guest /1/00 :

15 Tigecycline levels (µg/ml) Downloaded from FIG Time of incubation (h) on November, 01 by guest

16 Delta log CFU / ml Control (n = ) Tigecycline (n = ) Mean ± SEM Vancomycin (n = ) Downloaded from FIG. on November, 01 by guest