By Richard R. Watkins, MD, MS, FACP, FIDSA

Associate Professor of Internal Medicine, Northeast Ohio Medical University, Rootstown, OH; Division of Infectious Diseases, Cleveland Clinic Akron General, Akron, OH

Dr. Watkins reports that he has received research support from Allergan.

SYNOPSIS: A retrospective study that included patients from 119 Veterans Affairs hospitals found lower mortality and a similar recurrence rate for methicillin-susceptible Staphylococcus aureus bacteremia treated with cefazolin compared to nafcillin and oxacillin.

SOURCE: McDanel JS, Roghmann MC, Perencevich EN, et al. Comparative effectiveness of cefazolin versus nafcillin or oxacillin for treatment of methicillin-susceptible Staphylococcus aureus infections complicated by bacteremia: A nationwide cohort study. Clin Infect Dis 2017;65:100-106.

Beta-lactam antibiotics, most often nafcillin or cefazolin, are widely viewed as optimal therapy for methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia.1 However, nafcillin is associated with more adverse events, including acute liver and kidney injury, rashes, cytopenias, and drug fever. Cefazolin often is used for MSSA infections in hemodialysis patients because of its convenient dosing regimen (i.e., at the end of dialysis). Therefore, McDanel et al compared outcomes for patients with MSSA bacteremia treated with nafcillin or oxacillin vs. cefazolin.

The study was a retrospective cohort that included medical and surgical patients admitted to one of 119 Veterans Affairs hospitals between 2003 and 2010 with at least one blood culture for MSSA and treated with cefazolin, nafcillin, or oxacillin. The primary outcome was all-cause mortality at 30 and 90 days. Recurrent MSSA infections were classified as MSSA-positive blood cultures between 45 and 365 days after the first positive blood culture. Definitive therapy was defined as starting a definitive antibiotic between days 4 and 14 after the first positive blood culture was collected.

Of the 11,154 patients with MSSA bacteremia identified, 3,167 (28%) met inclusion criteria for the study. Of these, 1,163 received cefazolin (37%) and 2,004 (63%) received nafcillin or oxacillin. At 90 days, 25% of those who received nafcillin or oxacillin had died vs. 20% who received cefazolin (P = 0.001). In a multivariate analysis, patients treated with cefazolin had a 37% reduction in 30-day mortality risk vs. patients treated with nafcillin or oxacillin (hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.51-0.78). Furthermore, 90-day mortality risk was 23% lower in those who received cefazolin compared to nafcillin or oxacillin (HR, 0.77; 95% CI, 0.66-0.90). The odds for developing recurrent MSSA bacteremia did not differ significantly between the two groups. The risk estimates for dialysis patients were not significantly different with cefazolin vs. nafcillin or oxacillin with respect to 30-day mortality, 90-day mortality, or recurrence of MSSA bacteremia.


This is an important study because it addresses a very frequent conundrum in clinical practice: whether cefazolin is as good as nafcillin for MSSA bacteremia. Indeed, cefazolin has a number of advantages compared to nafcillin, including a more convenient dosing schedule (especially for dialysis patients), fewer side effects, and lower cost. McDanel et al have provided solid evidence from their large observational study that many patients with MSSA bacteremia treated with cefazolin have outcomes just as good as or better than patients who receive nafcillin or oxacillin. However, as supported by a well-written editorial,2 enthusiasm for treating all cases of MSSA bacteremia with cefazolin must be tempered by a more nuanced approach. One important concern is the recognition that a sizable minority of MSSA strains produce an inoculum effect, which is an increase in minimum inhibitory concentrations (MICs) due to high inoculum of MSSA (e.g., an MIC with an inoculum of 5 × 105 CFU/mL of 0.5 µg/mL increases to 128 µg/mL with an inoculum of 5 × 107 CFU/mL). This may become more pronounced when there is inadequate source control, such as an undrained abscess, resulting in high-grade bacteremia. The antistaphylococcal penicillins (e.g., nafcillin and oxacillin) seem to be less inhibited by the inoculum effect compared to cefazolin, making the latter drug a less attractive choice in infections where there is limited source control and high MSSA burden.

Despite the fact that the study by McDanel et al is the largest to date comparing cefazolin to nafcillin and oxacillin for MSSA bacteremia, several limitations must be mentioned. First, the observational design may have been influenced by confounding variables. Second, of all the patients with MSSA bacteremia who were screened, only 28% were included in the study. Thus, it is unknown how the remaining 72% of cases would have affected the results. In many of these cases, either an alternative agent (e.g., vancomycin) was used, the patient died, or the patient was discharged before receiving therapy. Third, important data were not reported, including source control; length and dose of therapy; cause of death; other sites of infection besides endocarditis, osteomyelitis, and skin and soft tissue infections; and adverse events from cefazolin vs. nafcillin or oxacillin.

So, what is the take-home message? Cefazolin is a reasonable and appropriate choice for most cases of uncomplicated MSSA bacteremia. However, the antistaphylococcal penicillins still have an important role, such as when source control is inadequate, bacterial burden is high, or the patient is critically ill. Once these conditions are mitigated, the antistaphylococcal penicillin can be switched to cefazolin to complete the course of treatment. Ideally, the issue of cefazolin vs. nafcillin or oxacillin for MSSA bacteremia needs to be addressed by a randomized clinical trial. Until then, clinicians must manage MSSA bacteremia based on careful consideration of the available data.


  1. Schweizer ML, Furuno JP, Harris AD, et al. Comparative effectiveness of nafcillin or cefazolin versus vancomycin in methicillin-susceptible Staphylococcus aureus bacteremia. BMC Infect Dis 2011;11:279.
  2. Karchmer AW. Definitive treatment for methicillin-sensitive Staphylococcus aureus bacteremia: Data versus a definitive answer? Clin Infect Dis 2017;65:107-109.