Would You Try Ceftriaxone for Methicillin-Susceptible Staphylococcus aureus Bacteremia?

Staphylococcus aureus bloodstream infections are relatively common and associated with significant morbidity and mortality. Treatment often requires weeks of antibiotics, with many patients completing their antibiotic course out of the hospital.

Intravenous (IV) cefazolin is one of the traditional first-line agents to treat methicillin-susceptible S aureus (MSSA). The disadvantage of using IV cefazolin is that it is dosed every 8 hours, which can be challenging for patients to do at home.

IV ceftriaxone, on the other hand, is dosed every 24 hours, making it a more convenient option to treat infections out of the hospital. However, the data on the use of ceftriaxone as an outpatient parenteral antibiotic therapy (OPAT) agent for S aureus bacteremia have been limited.

A retrospective study looking at multiple β-lactam antibiotics found that using a third-generation cephalosporin as initial therapy for MSSA bacteremia was associated with a higher 30-day mortality but did not specifically indicate outcomes of using it as definitive or outpatient therapy.1 A different study that did focus on the outpatient setting compared ceftriaxone with cefazolin as OPAT agents and found a higher rate of treatment failure with ceftriaxone.²

The study was limited in sample size (N = 71) and noted that place of discharge may be a possible confounding factor.² Subsequently, a larger study (N = 243) comparing ceftriaxone with cefazolin/ oxacillin as OPAT agents in patients with MSSA bacteremia showed no difference in rates of treatment failure. Although the study was larger, it was not powered to prove noninferiority.³

To better assess the role of ceftriaxone in treating MSSA bloodstream infections, Ganguly et al⁴ conducted a noninferiority retrospective study comparing ceftriaxone to IV cefazolin. They included patients with blood cultures growing MSSA who were a part of the OPAT registry in a safety-net hospital in Texas over an 8-year period. The primary outcome was treatment failure, which was a composite of repeat positive blood culture or retreatment within 6 months of completing a prescribed treatment course.

A total of 368 patients were included in the study and were selected in a 3:1 ratio of cefazolin to ceftriaxone. They had 286 patients (77.7%) in the IV cefazolin group and 82 patients (22%) in the IV ceftriaxone group. Patients were classified under each group based on what antibiotics they received at discharge because none of the patients received IV ceftriaxone initially during their admission. The dose of IV cefazolin was 2 g every 8 hours, and the dose of IV ceftriaxone was at 2 g every 24 hours.

The ceftriaxone and cefazolin groups were similar in basic demographics, comorbidities, length of stay (~15 days), and duration of outpatient treatment (~35 days). All patients had an infectious disease consult. Most patients in the study (87.5%) had an identifiable source of infection. However, the 2 groups differed in the distribution of source of infection.

More than half (54%) of the IV ceftriaxone group had a bone and joint infection vs less than a third (29%) in the IV cefazolin group. In addition, the IV cefazolin group had a higher proportion of endocarditis and central line–associated bloodstream infection (CLABSI) than the IV ceftriaxone group (32% vs 11%, respectively).⁴

Looking at the primary outcome, no significant difference in treatment failure was seen between the cefazolin and ceftriaxone groups (4% vs 2%; P = 1.00), and the noninferiority margin was met. In addition, no significant difference in 30-day readmission rates was seen between the 2 groups (22% vs 21%; P = .85).

There was a higher CLABSI rate in the IV cefazolin group vs the IV ceftriaxone group (11% vs 2%, respectively; P = .02); however, the study did not distinguish between primary versus secondary CLABSI. Patients receiving cefazolin had higher background rates of preexisting CLABSI, so it is unclear whether those patients truly developed additional central line infections while on OPAT due to frequent IV cefazolin infusion.⁴

Limitations of this study include its retrospective design because unaccounted-for factors may have led to certain patients being selected for IV ceftriaxone OPAT. Another limitation is that the study did not include variables that reflect illness severity and impact treatment success, such as source control or days of positive blood cultures. However, the comparable hospital length of stay could potentially suggest that illness severity was also similar between the 2 groups.

Despite the limitations, this study was one of the largest to address the use of IV ceftriaxone in the context of MSSA bacteremia compared with cefazolin. The authors were able to demonstrate that ceftriaxone at a convenient dose of 2 g every 24 hours is noninferior to cefazolin as a step-down OPAT agent for MSSA bacteremia, particularly in patients with bone or joint source of infection.⁴

References

1. Paul M, Zemer-Wassercug N, Talker O, et al. Are all beta-lactams similarly effective in the treatment of methicillin-sensitive Staphylococcus aureus bacteraemia? Clin Microbiol Infect. 2011;17(10):1581-1586. doi:10.1111/j.1469-0691.2010.03425.x
2. Carr DR, Stiefel U, Bonomo RA, Burant CJ, Sims SV. A comparison of cefazolin versus ceftriaxone for the treatment of methicillin-susceptible Staphylococcus aureus bacteremia in a tertiary care VA medical center. Open Forum Infect Dis. 2018;5(5):ofy089. doi:10.1093/ofid/ofy089
3. Hamad Y, Connor L, Bailey TC, George IA. Outcomes of outpatient parenteral antimicrobial therapy with ceftriaxone for methicillin-susceptible Staphylococcus aureus bloodstream infections-a single-center observational study. Open Forum Infect Dis.2020;7(9):ofaa34. doi:10.1093/ofid/ofaa341
4. Ganguly A, de la Flor C, Alvarez K, et al. Safety and efficacy of ceftriaxone in the treatment of methicillin-susceptible Staphylococcus aureus bloodstream infections: a noninferiority retrospective cohort study. Ann Pharmacother. Published online August 9, 2022. doi:10.1177/10600280221115460