Use of In Vitro Vancomycin Testing Results To Predict Susceptibility to Oritavancin, a New Long-Acting Lipoglycopeptide

Abstract

Oritavancin is a recently approved lipoglycopeptide antimicrobial agent with activity against Gram-positive pathogens. Its extended serum elimination half-life and concentration-dependent killing enable single-dose treatment of acute bacterial skin and skin structure infections. At the time of regulatory approval, new agents, including oritavancin, are not offered in the most widely used susceptibility testing devices and therefore may require application of surrogate testing using a related antimicrobial to infer susceptibility. To evaluate vancomycin as a predictive susceptibility marker for oritavancin, 26,993 recent Gram-positive organisms from U.S. and European hospitals were tested using reference MIC methods. Organisms included Staphylococcus aureus, coagulase-negative staphylococci (CoNS), beta-hemolytic streptococci (BHS), viridans group streptococci (VGS), and enterococci (ENT). These five major pathogen groups were analyzed by comparing results with FDA-approved susceptible breakpoints for both drugs, as well as those suggested by epidemiological cutoff values and supported by pharmacokinetic/ pharmacodynamic analyses. Vancomycin susceptibility was highly accurate (98.1 to 100.0%) as a surrogate for oritavancin susceptibility among the indicated pathogen species. Furthermore, direct MIC comparisons showed high oritavancin potencies, with vancomycin/oritavancin MIC 90 results of 1/0.06, 2/0.06, 0.5/0.12,1/0.06, and >16/0.06 g/ml for S. aureus, CoNS, BHS, VGS, and ENT, respectively. In conclusion, vancomycin demonstrated acceptable accuracy as a surrogate marker for predicting oritavancin susceptibility when tested against the indicated pathogens. In contrast, 93.3% of vancomycin-nonsusceptible enterococci had oritavancin MIC values of <0.12 g/ml, indicating a poor predictive value of vancomycin for oritavancin resistance against these organisms. Until commercial oritavancin susceptibility testing devices are readily available, isolates that when tested show vancomycin susceptibility can be inferred to be susceptible to oritavancin by using FDA-approved breakpoints. N ewly approved (by the U.S. Food and Drug Administration [FDA] or European Medicines Agency [EMA]) antimicrobial agents rarely have validated commercial susceptibility testing products/systems available at the time of commercialization. In fact, the recent histories of such products demonstrate delays of years, even for those drugs possessing qualities that would favorably impact patient care. To support susceptibility assessments of these approved antimicrobial agents for treatment of indicated infections, clinical microbiology laboratories have resorted to "surrogate" susceptibility testing of a similar (class representative) currently tested agent to predict susceptibility of organisms to the new antimicrobial agent (1-6). This option has been successfully applied to several antimicrobial classes since the first standardization of susceptibility testing methods (7,8).Oritavancin, formerly LY333328 (9, 10), is a recently approved lipogly...

Lipoglycopeptide Antibacterial Agents in Gram-Positive Infections: A Comparative Review

“…Against vancomycin-susceptible staphylococci, streptococci, or enterococci, the three drugs show quite similar MIC distributions and are more potent than vancomycin. Yet a clear-cut correlation between the MICs of vancomycin and of the lipoglycopeptides has been demonstrated, and thus vancomycin MIC can be used as a surrogate for susceptibility to lipoglycopeptides [44][45][46]. Oritavancin is slightly more potent than the other compounds on enterococci.…”

Antibiotic Combinations and Synergistic Interactions

“…Böylece, hücre duvarı sentezinin inhibisyonu, depolarizasyonu, geçirgenliğin ve buna bağlı olarak hücre içinde antibiyotik konsantrasyonunun artışı ile hızlı hücre ölümü gerçekleşir (13,19) . Oritavansin hücre duvarı sentezi sırasında iki farklı hedefe etkili olduğu için MRSA ve vankomisine duyarlı olmayan gram pozitif bakteri enfeksiyonlarının tedavisinde etkili olur (13,19,20) .…”

New Gram-Positive Agents: the Next Generation of Oxazolidinones and Lipoglycopeptides

“…While oritavancin is active against hVISA and VISA isolates, elevated MICs of up to 4 g/ml have been reported for some strains (30). Similar to dalbavancin, there is a lack of a commercially available antimicrobial susceptibility testing method for oritavancin; however, vancomycin has been suggested as a surrogate for predicting oritavancin susceptibility in vancomycin-susceptible isolates (31).…”