S. Aureus: Ceftriaxone VS Cloxacillin

Claims on Cloxacillin being more effective

• In in-vitro studies, Ceftriaxone alone was less effective than cloxacillin for the treatment of experimental MSSA endocarditis.
• A study claimed susceptibilities to oxacillin and ceftriaxone in S. aureus; 60% of MSSA bloodstream isolates were reported to be resistant to ceftriaxone.
• The publication was subsequently retracted because the testing method used. In addition, the authors' findings were not consistent with an independent study using a standard broth microdilution method
• Furthermore several studies have showed that lower effectiveness of ceftriaxone is due to use of lower doses

Comparison in terms of MIC

• routine susceptibility testing for S. aureus is performed only for oxacillin, and the results are extrapolated to other beta-lactams, including ceftriaxone
• study have shown ceftriaxone susceptibility may be reasonably inferred based on the testing using oxacillin, as recommended by the 2014 CLSI guidelines
• Using the oxacillin test result, the very major false susceptible error was <0.1% (oxacillin-susceptible/ceftriaxoneresistant) and minor errors were only 4.3% (oxacillin-susceptible/ceftriaxoneintermediate), both of which are well within CLSI’s acceptable limits.
• based on osteoarticular infections, 2 g/day is appropriate but 1 g/day may give inadequate drug levels; thus, a higher risk for failure given ceftriaxone minimum inhibitory concentration (MIC) values against MSSA is 4 µg/mL
• A recent retrospective controlled study with a large number of MSSA PJIs, not cited by the guidelines, suggests that ceftriaxone 2 g/day and oxacillin 2 g every 6 hours have similar cure rates
• we propose using ceftriaxone for serious MSSA infections only when the oxacillin MIC is ≤0.5 µg/mL and with a minimum dosing of 2 g/day.
• Although an oxacillin MIC of 1 or 2 µg/mL does not necessarily exclude ceftriaxone use, a dosage of 2 g every 12 hours would be preferred to ensure adequate drug levels and corresponding PK/PD target attainment

Prosthetic joint infection and osteoarticular infections

• The antimicrobial agents of choice for MSSA are typically oxacillin, nafcillin, and cefazolin
• Ceftriaxone is comparable to cloxacillin in terms of skin and tissue penetrations
• Current US Food and Drug Administration (FDA)–recommended ceftriaxone dosage for MSSA is 2–4 g/day
• In this comparison of ceftriaxone versus oxacillin for MSSA osteoarticular infections, there was no difference in treatment success at 3–6 and >6 months following the completion of intravenous antibiotics. Patients receiving oxacillin were more likely to have it discontinued due to toxicity

Recommendations:

• As Ceftriaxone 2g/day is shown to be comparable to oxacillin 2g/QID for MSSA, there is no justification in using combination of both agent.
• For areas with higher oxacillin MIC, a dose of 2 g every 12 hours would be preferred to ensure adequate drug level
• However, as empirical/initial therapy without any other complications, cloxacillin is still the preferred first line choice.

Reference:

1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC127055/
2. Elevated Staphylococcus Ceftriaxone MICs are an Etest Artifact. Clin Infect Dis 2015; 60 (1): 162-163
3. http://aac.asm.org/content/59/2/1370.full
4. Outcomes of Ceftriaxone Use in Methicillin SusceptibleStaphylococcus aureus (MSSA) Bloodstream Infections. https://idsa.confex.com/idsa/2010/webprogram/Paper2970.html
5. A retrospective comparison of ceftriaxone versus oxacillin for osteoarticular infections due to methicillin-susceptible Staphylococcus aureus. http://www.ncbi.nlm.nih.gov/pubmed/22144536
6. Treatment of MethicillinSusceptible Staphylococcus aureus Osteoarticular and Prosthetic Joint Infections: Using the Oxacillin Minimum Inhibitory Concentration to Guide Appropriate Ceftriaxone Use. http://cid.oxfordjournals.org/content/57/1/161.2.full.pdf+html
7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3275755/
8. http://emedicine.medscape.com/article/2018345-overview
9. https://www.hopkinsguides.com/hopkins/view/Johns_Hopkins_ABX_Guide/540518/all/Staphylococcus_aureus
10. NAG 2014
11. HUSM Antibiotic Guideline 2014