In vivo verification of in vitro model of antibiotic treatment of device-related infection

Abstract

Device-related infections are difficult to treat with antibiotics alone. Standard susceptibility tests do not correlate with treatment success. Therefore, the utility of a pharmacokinetic in vitro model has been evaluated in comparison with the tissue-cage infection model in guinea pigs. The bactericidal activity of 28 treatment regimens has been studied by using three different test strains. In vitro efficacy was defined as reduction in the number of suspended or adherent bacteria, and in vivo efficacy was defined as reduction in the number of bacteria in tissue-cage fluid. Test results between the two models (in vivo and in vitro) correlated well, with correlation coefficients of 0.85 for in vivo efficacy versus in vitro efficacy against suspended bacteria and 0.72 for in vivo efficacy versus in vitro efficacy against adherent bacteria (P < 0.05) for Staphylococcus aureus, 0.96 and 0.82 (P < 0.05) for Staphylococcus epidermidis, and 0.89 and 0.97 for Escherichia coli, respectively. In contrast, standard susceptibility tests, ratios of MICs to trough or peak levels, ratios of the area under the curve to the MIC, or time above the MIC were not predictive for therapeutic outcome in either the in vitro or in vivo model. In both models, the bactericidal activity levels with combination regimens were significantly higher than those with single-drug regimens (P < 0.001). Furthermore, rifampin combinations with either vancomycin, teicoplanin, fleroxacin, or ciprofloxacin were significantly more bactericidal against adherent bacteria than netilmicin combinations with vancomycin or daptomycin (P < 0.01). Thus, in vivo verification of the pharmacokinetic in vitro model correlated well with the animal model. The in vitro model offers an alternative to the animal model in experiments that screen and assess antibiotic regimens against devicerelated infections.

Rapid Direct Method for Monitoring Antibiotics in a Mouse Model of Bacterial Biofilm Infection

“…This relative resistance of the biofilm to tobramycin and ciprofloxacin is in accordance with previous observations in the literature (15,27,44). Our results are consistent with those of previous studies demonstrating the significant bactericidal effect of rifampin against staphylococcal biofilm infections (1,2,12,13,27,31,37,42,(44)(45)(46)(47). In addition, our in vivo results confirm the high risk of the rapid emergence of a rifampin-resistant population, as reported previously, which can result in clinical failures when rifampin is used alone (12,23,31,44,47).…”

“…It is accepted that eradication of a foreign body-related infection generally requires long courses of combination antibiotic therapy (1,2,12,13,21,23,27,31,32,37,39,47). However, in this study the main intent of the evaluation was the application of an in vivo imaging technology to monitor the effects of different antibiotics on bacterial growth and the recurrence of infection rather than the clinical response per se.…”

Issues in Pharmacokinetics and Pharmacodynamics of Anti-Infective Agents: Kill Curves versus MIC

“…Several in vitro models were developed that simulate in vivo conditions in specific infection sites or conditions, such as an bladder (54,103), bacterial cystitis (55), otitis medium (113,35), endocarditis (79), chronic pneumonia (68), tuberculosis (9), infected fibrin clots (94), and implant-related infections (27,15). However, such attempts to more closely mimic an in vivo situation and to predict clinical response were hampered by the inability to measure pharmacokinetics (pharmacokinetic) at the site of infection.…”

N-acetylcysteine and vancomycin alone and in combination against staphylococci biofilm

“…Additionally, the emergence of antibiotic-resistant bacteria and the slow progress in identifying new classes of antimicrobial agents have encouraged research into novel therapeutic strategies (Costerton et al, 2009). One of the approaches to solve this problem is the use of antimicrobial agent combinations because the development of resistance is reduced when drugs are combined (Blaser et al, 1995;Chuard et al, 1991;Gagnon et al, 1992;Lucet et al, 1990).…”