Impact of High-InoculumStaphylococcus aureuson the Activities of Nafcillin, Vancomycin, Linezolid, and Daptomycin, Alone and in Combination with Gentamicin, in an In Vitro Pharmacodynamic Model

Abstract

We evaluated the impact of high (9.5 log 10 CFU/g) and moderate (5.5 log 10 CFU/g) inocula of methicillinsusceptible and -resistant Staphylococcus aureus (MSSA and MRSA, respectively) on the activities of nafcillin, linezolid, vancomycin, and daptomycin, alone and in combination with gentamicin in an in vitro pharmacodynamic model with simulated endocardial vegetations over 72 h. Human therapeutic dosing regimens for nafcillin, daptomycin, vancomycin, linezolid, and gentamicin were simulated. At a moderate inoculum, nafcillin (MSSA only), vancomycin, and daptomycin demonstrated equivalent and significant (P < 0.01) bactericidal (99.9% kill) activities (decreases of 3.34 ؎ 1.1, 3.28 ؎ 0.4, and 3.34 ؎ 0.8 log 10 CFU/g, respectively). Bactericidal activity was demonstrated at 4 h for nafcillin and daptomycin and at 32 h for vancomycin. Linezolid demonstrated bacteriostatic activity over the course of the study period. At a high inoculum, daptomycin exhibited bactericidal activity against both MSSA and MRSA by 24 h (decrease of 5.51 to 6.31 ؎ 0.10 log 10 CFU/g). Nafcillin (versus MSSA), vancomycin, and linezolid (MSSA and MRSA) did not achieve bactericidal activity throughout the 72-h experiment. The addition of gentamicin increased the rate of 99.9% kill to 8 h for daptomycin (P < 0.01) and 48 h for nafcillin (MSSA only) (P ‫؍‬ 0.01). The addition of gentamicin did not improve the activity of vancomycin or linezolid for either isolate for the 72-h period. Overall, high-inoculum Staphylococcus aureus had a significant impact on the activities of nafcillin and vancomycin. In contrast, daptomycin was affected minimally and linezolid was not affected by inoculum.

Reduced Vancomycin Susceptibility inStaphylococcus aureus, Including Vancomycin-Intermediate and Heterogeneous Vancomycin-Intermediate Strains: Resistance Mechanisms, Laboratory Detection, and Clinical Implications

“…Other in vitro models have demonstrated a reduced efficacy of vancomycin against hVISA and VISA (175,282), in particular in situations where a high inoculum was used (171,282).…”

Novel pharmaceutical molecules against emerging resistant gram-positive cocci

“…89,[92][93][94][95][98][99][100][101][102][103][104][105][106][107] For instance, a synergistic interaction was found for quinupristin/dalfopristin and vancomycin in two independent studies. 92,93 On the other hand, antagonistic interactions were demonstrated for the combination of linezolid plus vancomycin, 94 and linezolid plus gentamicin.…”

“…Linezolid was comparable to vancomycin in the therapy of MRSA-associated VAP, although a trend was seen for linezolid superiority. 53,54 Daptomycin is not indicated for pneumonia due to its interaction with surfactant, 70 while tigecycline is undergoing clinical evaluation. Quinupristin/dalfopristin has been compared to vancomycin for hospital-acquired pneumonia.…”

“…Otherwise, daptomycin is not approved for the treatment of bacterial pneumonia; its efficacy is significantly compromised by its interaction with pulmonary surfactant. 70 Significant drug-drug interaction occurs with the statins, and patients receiving HMG-CoA reductase inhibitors; these drugs should be suspended and avoided while the patient is undergoing a daptomycin course.…”

Vancomycin: The Tale of the Vanquisher and the Pyrrhic Victory

“…Vancomycin is considered a bactericidal antibiotic, but the slow nature of its cidal activity is an important limitation in clinical practice (4). In addition, the activity of vancomycin is inoculum-dependent (5). A large burden of bacteria and bacteria in the stationary growth phase or in an anaerobic environment impair the speed and extent of vancomycin's bactericidal activity (4,6).…”