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Activity of oritavancin and comparators invitro against standard and high inocula of Staphylococcus aureus

Abstract number: P931

Objective: Inoculum size-dependent increases in minimum inhibitory concentrations (MICs) of some antibiotics have been linked with therapeutic failures. We studied the impact of inoculum size on the growth-inhibitory and killing activities of oritavancin (ORI) and comparators in vitro against S. aureus by broth microdilution and time-kill assays at clinically-relevant concentrations of drugs.

Methods: MIC determinations and time-kill assays followed CLSI guidelines. Tests were performed at standard inocula (105 CFU/mL) and high inocula (107 CFU/mL). Drugs tested were ORI, vancomycin (VAN), daptomycin (DAP) and linezolid. In time-kill assays, drugs were tested at static concentrations approximating their free peak (fCmax) and free trough (fCmin) in plasma when administered at approved doses for complicated skin and skin structure infections. ORI fCmax and fCmin were based on a single 1200 mg dose. The S. aureus (SA) strains used were ATCC 29213 (VAN susceptible), ATCC 43300 (methicillin-resistant SA [MRSA]), ATCC 700699 (VAN-intermediate SA [VISA]) and NRS 402 (VISA).

Results: ORI MICs were 16-fold higher for all strains at the higher inoculum relative to standard inoculum. MICs of comparators were 2- to 8-fold higher when tested at the higher inoculum. In time-kill assays, when tested at its fCmin and fCmax, ORI was bactericidal against ATCC 29213 and ATCC 43300 at standard and high inocula. At its fCmax, ORI was bactericidal at standard inoculum but had no effect at the higher inoculum against both VISA strains. At fCmin, ORI had no effect on the VISA strains at either inoculum size. VAN was bactericidal against ATCC 29213 and ATCC 43300 at both inoculum sizes at both fCmax and fCmin. VAN had no effect on the VISA strains at both inoculum sizes at its fCmin but was bactericidal and bacteriostatic at fCmax against both strains at standard and high inocula, respectively. DAP had no effect on all strains at its fCmin at both inoculum sizes. At its fCmax, DAP was bactericidal against ATCC 29213 and ATCC 43300 at both inoculum sizes. Against the VISA strains, DAP at both fCmax and fCmin had no effect at both inoculum sizes.

Conclusions: ORI activity was diminished against all S. aureus strains at high inoculum size. The activity of comparator antibiotics was also diminished butto a lesser extent. In infections with a high anticipated bacterial burden, alternative dosing of oritavancin or synergistic combinations with additional agents may be warranted.

AgentFold increase in MIC at higher inoculum relative to lower inoculum
 ATCC 29213ATCC 43300ATCC 700699NRS 402
Oritavancin16161616
Vancomycin2222
Daptomycin8822
Linezolid2224

Session Details

Date: 10/04/2010
Time: 00:00-00:00
Session name: Abstracts 20th European Congress of Clinical Microbiology and Infectious Diseases
Subject:
Location: Vienna, Austria, 10 - 13 April 2010
Presentation type:
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