Combination of cephalosporins with vancomycin or teicoplanin enhances antibacterial effect of glycopeptides against heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) and VISA

Abstract

Eight heterogeneous vancomycin-intermediate S. aureus (h-VISA) and seven VISA clinical isolates confirmed by the population analysis profile/area under the curve ratio (PAP/AUC) were collected. We further performed the PAP/AUC, time-killing methods and MIC tests using vancomycin/teicoplanin alone or combination with susceptible breakpoint concentrations of cefazolin, cefmetazole, cefotaxime, and cefepime for these isolates. The PAP/AUC MIC curve shifted left after addition of cephalosporins with vancomycin or teicoplanin for both h-VISA and VISA isolates. With the combination of different cephalosporins with vancomycin or teicoplanin, the AUC/Mu3 AUC ratio decreased to <0.9 for the standard Mu3 isolate which are compatible with the definition of vancomycin susceptible S. aureus. These decreases ranged between 1.81–2.02 and 2.37–2.85-fold for h-VISA treated with cephalosporins and vancomycin or teicoplanin, and 2.05–4.59, and 2.93–4,89-fold for VISA treated with cephalosporins with vancomycin or teicoplanin. As measured by time-killing assays, the combinations of different cephalosporins with vancomycin concentrations at 1/2 and 1/4 MIC, exhibited a bactericidal and bacteriostatic effect in VISA. The mean fold of MIC decline for vancomycin base combinations ranged from 1.81–3.83 and 2.71–9.33 for h-VISA and VISA, respectively. Overall, this study demonstrated the enhanced antibacterial activity of vancomycin/teicoplanin after adding cephalosporins against clinical h-VISA/VISA isolates.

The Potential Role of Sulbactam and Cephalosporins Plus Daptomycin Against Daptomycin-Nonsusceptible VISA and H-VISA Isolates: An In Vitro Study

“…Third, the MICs of cephalosporins for VISA/h-VISA remain very high, as seen in our previous study [8]. In this study, we used susceptible breakpoint concentrations of cephalosporins that were far lower than the MIC, and still found an enhanced synergistic effect of cephalosporins/sulbactam and daptomycin, as evidenced by a significant reduction in the daptomycin MIC.…”

“…Moreover, the antibacterial activity of cefazolin could be boosted by sulbactam for some S. aureus strains containing the ability to hyperhydrolyze it; furthermore, sulbactam also has some penicillin-binding protein (PBP)-binding activity that would complement that of cephalosporin [12]. Based on the above results and the findings of our previous study [8], we hypothesize that this additional effect of cephalosporins or sulbactam in combination with daptomycin against VISA/h-VISA may occur. In this study, we assessed the synergistic effect of a combination of cephalosporins of all generations and sulbactam with daptomycin against daptomycin-nonsusceptible VISA/h-VISA isolates.…”

“…The isolates were stored at −70 • C in Protect Bacterial Preservers (Technical Service Consultants Limited, Heywood, UK) until use. Further identification of VISA and h-VISA isolates was confirmed by population analysis profile/area under the curve ratio (PAP/AUC), as in previous reports [8,13]. Briefly, the PAP/AUC was measured for all isolates by inoculating serial 10-fold dilutions of the test organism onto increasing concentrations of vancomycin-containing brain-heart infusion (BHI) agar (Becton Dickinson, Sparks, MD, USA).…”

“…The microdilution checkerboard method was used to calculate the fractional inhibitory concentrations (FICs) for daptomycin combined with a cephalosporin, which was modified according to the CLSI [8,14,15]. In the three-drug combination checkerboard, daptomycin combined with a cephalosporin was also combined with 8 mg/L sulbactam in each well.…”

“…Studies regarding combination therapy for VISA/h-VISA are limited. Recently, one study [8] showed that adding vancomycin to cephalosporins can enhance the antibacterial activity against VISA/h-VISA. Several studies [9,10] have also shown that β-lactam antibiotics, such as oxacillin, ceftaroline, and piperacillin-tazobactam plus vancomycin, can improve the activity of vancomycin against VISA/h-VISA.…”