On 4/24/17, first year Infectious Disease fellow Rameez Phulphoto presented a review on a recently published article in Clinical Infectious Diseases in March of 2017. The paper, from McDanel and colleagues, focuses on the comparative effectiveness of the antibiotic cefazolin, when compared to nafcillin or oxacillin in the treatment for methicillin-susceptible Staphylococcus aureus (MSSA) infections associated with bacteremia.

This was a multicenter retrospective cohort study involving patients from 119 VA hospitals who had MSSA infection associated with bacteremia between 2003 to 2010. All patients included in the study were treated either with cefazolin, or oxacillin vs nafcillin monotherapy for their infections. Patients were excluded if they were admitted to a VA institution in which fewer than 25 cases of MSSA infections associated with bacteremia were seen during the study period, or if the patient was placed on more than one of the above antibiotic agents during their definitive treatment period (defined as initiation of antibiotics with one of the above 3 drugs between days 4-14 after the first positive blood culture was collected). Primary outcomes analyzed included 30-day and 90-day all-cause mortality and incidence of recurrent MSSA infections complicated by bacteremia between 4-5-365 days after the initially confirmed positive MSSA blood culture.

Four key points with regards to the above study were noted:

–          Of the 3,167 patients involved in this study, 1,163 (37%) of patients received cefazolin for their definitive therapy; the remainder received either oxacillin or nafcillin therapy

–          Those patients on cefazolin were noted to have higher APACHE III scores, were more likely to be on hemodialysis or have end-stage renal disease, and were more likely to have diabetes when compared to those patients that received either nafcillin or oxacillin. They however were less likely to have endocarditis.

–          Patients who received cefazolin therapy had a 37% reduction in 30- day mortality and 23% reduction in 90-day mortality when compared to patients receiving nafcillin or oxacillin, after controlling for other factors (skin/soft tissue infection, endocarditis, osteomyelitis, ICU admission, diabetes, APACHE III scores and Charlson Comorbidity index scores)

–          The odds of recurrence of infection with MSSA were similar amongst patients receiving cefazolin and nafcillin vs oxacillin, after controlling for other factors

Based on these findings, the authors surmise that patients who received cefazolin had a lower risk of mortality and similar odds of recurrent infections when compared to nafcillin or oxacillin therapy for MSSA infections complicated by bacteremia. Based on this information, they recommend consideration of cefazolin therapy over nafcillin vs oxacillin for these infections.

However, there were a number limitations in this study that should be considered. The study was a retrospective analysis, with no fixed control group and limited information gleaned from charts. Given the study design, pre-existing biases regarding treatment could not be corrected for appropriately. There was also limited information on other factors that may have attributed to infection cure and mortality (source control, dosing of medications, duration of therapy, adverse events during care), which could in turn have affected the author’s findings. In addition, a significant percentage of patients were excluded from the study based on the above exclusion criteria, and information on other anti-staphylococcal regimens (daptomycin, ceftaroline, linezolid, etc) were not incorporated into this study. The relative side effects of nafcillin and oxacillin, compared on cefazolin, were also not focused upon heavily in this study.

The Infectious Disease Society of America (IDSA) guidelines recommend that beta-lactam antibiotics are the drugs of choice for MSSA infections associated with bacteremia. Nafcillin and oxacillin are considered first line drugs, with cefazolin considered as an alternative regimen, partly due to cefazolin’s lack of CNS penetration as well as it’s slightly inferior pharmacodynamic profile when compared to continuous infusion nafcillin or oxacillin therapy. Literature in the past has also suggested possible inferiority of cefazolin when compared to nafcillin or oxacillin in high inoculum MSSA infections, based on the possible inactivation of cefazolin by type A beta-lactamases that are produced in this setting. This current study however questions whether the use of cefazolin in the treatment of MSSA infections associated with bacteremia should be expanded. This study, although not definitive, does point out the need for future prospective studies and randomized controlled trials to be performed, which would be better able to address the questions the authors proposed. In the interim, cefazolin could be considered amongst patients with MSSA bacteremia who do not have CNS involvement, and may be more convenient for patients who are undergoing hemodialysis when compared to nafcillin and oxacillin therapy, as well as associated with less side effects.

McDanel JS 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. Clinical Infectious Diseases  2017 Mar 31.