Drug Resistance

The increasing problem of resistance to anti-infective drugs has required critical analysis of the significance of novel resistance mechanisms. The study of drug pharmacodynamics in animal models of infection either using isogenic strains with or without a resistance factor or using relevant clinical isolates can assess the importance of resistance under in vivo conditions. This information can be important in establishing resistance breakpoints for in vitro MIC testing (see below) as well as for formulating optimal dosage regimens to prevent or overcome established resistance. Generally, if resistance in vivo is less than that observed in vitro, this will be reflected by the disruption of expected relationships between drug exposure (e.g., AUC) and MIC.

The clinical relevance of resistance to extended spectrum cephalosporins by novel plasmid-mediated P-lactamases was studied by Craig and colleagues in the neutropenic mouse thigh model against several isogenic strains producing extended-spectrum P-lactamases. Mice were pretreated with uranyl nitrate to simulate human exposures to the drug. The results showed that although MICs were elevated at a high inoculum, in vivo results were best correlated with MICs obtained at the lower inoculum (W. Craig, personal communication).

Reduced susceptibility to vancomycin in enterococci, and more recently Staphylococcus aureus, is of increasing clinical concern because of the absence of alternative therapies. In experiments in the neutropenic mouse thigh model with S. aureus strains that were vancomycin-susceptible or intermediate (VISA), the efficacy was best described by the Cmax/MIC or AUC/MIC ratio. When results for the vancomycin susceptible strains were compared with those for VISA, only slightly higher vancomycin exposures (Cmax or AUC) were required for the same level of efficacy despite the higher MICs. Although further studies are required, this suggests that these strains have a reduced level of susceptibility in vivo to vancomycin that is less than that predicted by the in vitro MIC [57]. Optimization of vancomycin dosage regimens could be a successful strategy for the clinical management of strains with reduced susceptibility to vancomycin.

Drug efflux is increasingly recognized as an important mechanism of resistance in bacteria and fungi. However, little is known concerning the efficiency of these pumps to produce resistance under in vivo conditions. Using isogenic strains of Pseudomonas aeruginosa with varying levels of expression of the multicomponent mexAB-oprM efflux pump, a reduced response to levofloxacin and ciprofloxacin in the neutropenic mouse thigh model and mouse sepsis model was observed; the reduction in efficacy due to efflux was proportional to the change in AUC/MIC [58]. In contrast, Andes and Craig [59] reported that AUC/ MIC ratios associated with response in the neutropenic mouse thigh model for NOR-A efflux-related resistance to fluoroquinolones in Streptococcus pneumon-iae were lower than that in susceptible strains or strains with reduced susceptibility due to non-efflux (e.g., gyrA) mechanisms. These data suggest that efflux mechanisms of resistance may be significant in some bacteria but not in others.

Resistance to fluconazole due to target modifications and/or efflux has also been shown to be significant in vivo using pharmacodynamic modeling. Sorensen et al. studied several strains of C. albicans with over a 2000-fold range in MIC in a mouse model of disseminated candidiasis. The reduction in counts in kidneys at 24 h following fluconazole was found to be described by the AUC/MIC ratio for all doses and strains tested [44], suggesting that elevated fluconzole MICs due to target or efflux-based mechanisms correspond to similar levels of reduced activity in vivo.

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