remains a common cause of a variety of infections causing high morbidity and mortality. 
Throughout much of the world, including such places as the United States, several European countries, much of South America, Australia, and Japan, the prevalence of methicillin resistance in S. aureus
is quite high. 
Due to the high prevalence in these areas, beta lactams cannot be used empirically and therefore vancomycin is generally considered the standard of care for suspected staphylococcal infections. This level of vancomycin selective pressure has led to an increasing problem with decreased susceptibility to vancomycin in S. aureus
, including hVISA.
Consistent with previous investigations, we found vancomycin to be mostly ineffective against hVISA strains, failing to produce bactericidal activity and resulting in MIC elevations in several strains. 
However, when vancomycin was combined with nafcillin, strong enhancement of bacterial killing was observed for all 5 strains examined. This is in spite of nafcillin concentrations being below the MIC of the organism for most (strain with nafcillin MIC 4 µg/mL) to all (all remaining strains) of the dosing interval. This is a peculiar because the time drug concentrations are above the MIC of the organism is what drives antibacterial activity for beta lactams. 
One potential reason for this observation is that the hindrance of peptidoglycan synthesis, in this case by vancomycin, can reduce beta lactam resistance. 
Though this is the case, the exact mechanism of synergy between beta lactams and glycopeptides has not been precisely elucidated to date.
Likewise, against MRSA and MSSA we observed this same enhancement in killing with the combination of vancomycin and nafcillin. Against all of these strains, similar to hVISA, vancomycin alone failed to produce bactericidal activity while nafcillin was not effective at all against MRSA and was quite effective alone against MSSA, as expected. This strong activity of nafcillin against MSSA accounts for the fact that, while the combination of vancomycin and nafcillin was better than either drug alone, the magnitude of the difference was much less for MSSA than it was for both MRSA and hVISA strains that were not susceptible to beta lactams.
The observation of synergy between beta lactams and vancomycin is not new, though the combinations have only been described once previously using simulated human pharmacokinetics. 
In that study vancomycin was combined with cefazolin against 2 MRSA strains, one hVISA strain, and one vancomycin intermediate S. aureus
strain and the combination of the 2 drugs was found to improve overall activity, but not bacterial density at the end of the experiments (48 and 72 hours). One potential reason for this disparity is that the two studies used different vancomycin dosing regimens. In their investigation, they used every 8 hour dosing as opposed to every 12 hours, however, given that the trough values in both studies were similar and that massive increases in AUC/MIC ratio have been shown not to result in improvements in vancomycin activity, 
this seems unlikely to be the reason. Another difference was that they used a different beta lactam agent (cefazolin vs. nafcillin) which may have been less active than nafcillin against S. aureus
. A final possibility is that the starting inoculums differed between the two studies, with a higher starting inoculum in the present investigation. Given that both glycopeptides and beta lactams are subject to an inoculum effect, 
where the killing effect of an antibiotic is lessened as the inoculum of organism increases, this could have led to the diminished activity of vancomycin in this study compared to their investigation where vancomycin displayed much more kill alone.
In conclusion, the combination of vancomycin and nafcillin significantly improved overall antibacterial activity, rate of bacterial killing, and remaining organism burden at 72 hours against MSSA, MRSA, and hVISA isolates over either drug alone. This improvement was seen even when the isolate was very resistant to nafcillin (susceptible breakpoint for S. aureus is MIC ≤2 µg/mL) and the nafcillin time above MIC was zero. These data support the continued evaluation of this combination, and its potential role in the treatment of S. aureus infections.