A #PharmToExamTable question about Infective Endocarditis treatment, answered by Amanda Vanderwerf, PharmD, a 2021 Graduate of UNMC College of Pharmacy who is now an Emergency Medicine Pharmacy Resident at UNMC.
(Reviewed by Andrew Watkins, PharmD)
MSSA Infective Endocarditis
Infective endocarditis (IE) carries significant rates of morbidity and mortality and is now the third or fourth most common life-threatening infection syndrome.2 Historically, viridans streptococci were the most common cause of IE, but today Staphylococcus aureus has become the leading cause of IE in many regions of the world, accounting for 15-40% of all IE cases.1 Due to the particularly virulent nature of S. aureus, IE with this bacteria is generally associated with in-hospital mortality of 20-30%. The need for aggressive IV anti-staphylococcal antibiotics is imperative and methicillin susceptible S. aureus (MSSA) make up the majority of cases.1,5 In the 2015 Guidelines for Infective Endocarditis in Adults, anti-staphylococcal penicillins (ASP), such as Oxacillin or Nafcillin, are recommended for MSSA IE, with cefazolin listed as an appropriate alternative for patients with a history of non-anaphylactoid reactions to penicillins.2 However, many experts regularly use cefazolin for MSSA IE instead of ASP due to drug tolerability. Several studies have shown significantly higher rates of adverse drug events (ADE) with ASP such as nephrotoxicity and hepatotoxicity, and premature antibiotic discontinuation in both hospitalized patients and in the outpatient setting when compared to cefazolin.3,4,9 The lower rates of ADEs, reduced cost, and longer half-life make cefazolin an ideal agent for outpatient parenteral antibiotic therapy (OPAT) specifically. But is cefazolin really just as effective as ASP for the treatment of MSSA IE? This question has been debated due to the theoretical “inoculum effect” of cefazolin and documented treatment failures while using this agent. In an effort to find answers, there is a large amount of literature being published to clarify the risk, if any, of using cefazolin as a first line MSSA IE treatment.
What is the inoculum effect?
The cephalosporin inoculum effect is defined as a prominent rise in the antibiotic minimum inhibitory concentration (MIC) ≥16 ug/mL when in the presence of an inoculum higher than the standard bacterial inoculum recommended for in vitro testing (~107 CFU/mL vs ~105 CFU/mL). For reference, the MIC susceptibility breakpoint for cefazolin against MSSA is 2 mcg/ml.9 Therefore, when treating infections with a high bacteria burden, such as endocarditis, this inoculum effect may become more of a concern. Since the beginning of its use, it has been noted that several penicillinase-producing MSSA strains have been able to readily hydrolyze cefazolin. Subsequently, in the 1970s, cases of S. aureusendocarditis failing cefazolin therapy were described, with one of these cases showing the MSSA strain exhibiting high MICs of cefazolin when a large inoculum was used (cefazolin inoculum effect [CzIE]). The primary enzymes responsible have been further identified as Type A and Type C BlaZ.6
Review of literature
The most recent systematic literature review published in 2019 aimed to evaluate 90-day mortality for patients with MSSA bacteremia who were treated with ASP compared to cefazolin. For the primary endpoint of 90-day all-cause mortality, data from 7 studies comprising of 4391 patients showed 25.1% in the ASP group and 18.2% in the cefazolin group, resulting in a RR of 0.71, 95% CI (0.50, 1.02). Therefore, cefazolin may not be associated with increased 90-day mortality for MSSA bacteremia of any source. The relevant subgroup analysis of patients with high-inoculum infection identified 3 studies reporting on 90-day all-cause mortality (42 patients with endocarditis, 46 patients with abscesses) and 6 studies reporting on 30-day all-cause mortality (652 patients with endocarditis, 273 patients with abscesses). The authors found no association of treatments with 90-day all-cause mortality (endocarditis: RR 0.71 (0.12, 4.05); abscesses: RR of 1.17 (0.30, 4.63)) or for 30-day all-cause mortality (endocarditis: RR of 0.71 (0.37, 1.34); abscesses: RR 0.76 (0.35, 2.28)).8
However, when looking at the most recent prospective studies, there are more concerning results. Lee et al. performed the first prospective observational cohort study in 2018 comparing outcomes of cefazolin versus nafcillin for MSSA bacteremia amongst 10 Korean hospitals, aimed to specifically evaluate the clinical impact of CzIE on treatment outcomes. Overall, results of this study showed patients who received cefazolin were less likely to experience treatment failure than those receiving nafcillin (p 0.017) as well as decreased risk of 90-day mortality compared to nafcillin (p 0.008). However, when comparing the outcomes in the CzIE(+) group with those of the CzIE(-) group that received cefazolin, results showed that the treatment failure rate (p 0.049), rate of switching antibiotics because of clinical failure (p 0.036), and rate of 1-month mortality (p 0.047) were significantly higher in the CzIE(+) group than in the CzIE(-) group. Overall, 22% of isolates demonstrated CzIE.5 Although the prevalence is low, high treatment failure rates for these isolates suggests the need for rapid testing for CzIE isolates to effectively guide treatment, which is not currently performed outside of research studies. Overall, with this study only including 12 IE patients (with only 1 receiving cefazolin) it is hard to interpret these findings for this specific patient population.
Furthermore, another study by Miller et al. prospectively looked at 77 patients from 3 Argentinian hospitals with MSSA bacteremia, all treated with cefazolin. Whole-genome sequencing was performed on all isolates showing the prevalence of CzIE at 54.5%. Patients with MSSA exhibiting CzIE had increased 30-day mortality (39.5% vs 15.2%, P=0.034) compared to those without CzIE. This study included only 15 patients with complicated bacteremia, with 8 being IE.6 It is important to note that ASP are not available in Argentina, making cefazolin the primary agent of use for MSSA bacteremia, which could explain the high prevalence CzIE+ MSSA.
Conclusions
Although the retrospective studies cited above overall show no difference in outcomes between patients treated with cefazolin versus anti-staphylococcal penicillins (ASP), such as Oxacillin or Nafcillin, for MSSA bacteremia, it is suggested from the subsequent findings of the prospective trials that CzIE isolates pose a significant risk for cefazolin treatment failure. With the expanding use of cefazolin as first-line treatment for serious MSSA infections there may be a need for rapid testing for CzIE isolates to mitigate the risk of treatment failure.
Based on recent studies, the prevalence of MSSA isolates containing CzIE is still not fully understood. However, with the severe consequences at stake for IE patients, the risk of treatment failure with cefazolin may just outweigh the benefits of its favorable side effect profile and ease of use. Still, consideration must be made when using cefazolin as a first line agent for MSSA IE.
References:
- Asgeirsson H, Thalme A, Weiland O. Staphylococcus aureus bacteraemia and endocarditis – epidemiology and outcome: a review. Infect Dis (Lond). 2018;50(3):175-192. doi:10.1080/23744235.2017.1392039
- Baddour LM, Wilson WR, Bayer AS, et al. Infective Endocarditis in Adults: Diagnosis, Antimicrobial Therapy, and Management of Complications: A Scientific Statement for Healthcare Professionals From the American Heart Association [published correction appears in Circulation. 2015 Oct 27;132(17):e215] [published correction appears in Circulation. 2016 Aug 23;134(8):e113] [published correction appears in Circulation. 2018 Jul 31;138(5):e78-e79]. Circulation. 2015;132(15):1435-1486. doi:10.1161/CIR.0000000000000296
- Eljaaly K, Alshehri S, Erstad BL. Systematic Review and Meta-analysis of the Safety of Antistaphylococcal Penicillins Compared to Cefazolin. Antimicrob Agents Chemother. 2018 Mar 27;62(4):e01816-17. doi: 10.1128/AAC.01816-17. PMID: 29437617; PMCID: PMC5913998.
- Lee B, Tam I, Weigel B 4th, Breeze JL, Paulus JK, Nelson J, Allison GM. Comparative outcomes of β-lactam antibiotics in outpatient parenteral antibiotic therapy: treatment success, readmissions and antibiotic switches. J Antimicrob Chemother. 2015 Aug;70(8):2389-96. doi: 10.1093/jac/dkv130. Epub 2015 May 29. PMID: 26024869; PMCID: PMC4580536.
- Lee S, Song KH, Jung SI, et al. Comparative outcomes of cefazolin versus nafcillin for methicillin-susceptible Staphylococcus aureus bacteraemia: a prospective multicentre cohort study in Korea. Clin Microbiol Infect. 2018;24(2):152-158. doi:10.1016/j.cmi.2017.07.001
- Miller WR, Seas C, Carvajal LP, et al. The Cefazolin Inoculum Effect Is Associated With Increased Mortality in Methicillin-Susceptible Staphylococcus aureus Bacteremia. Open Forum Infect Dis. 2018;5(6):ofy123. Published 2018 May 23. doi:10.1093/ofid/ofy123
- Wang SK, Gilchrist A, Loukitcheva A, et al. Prevalence of a Cefazolin Inoculum Effect Associated with blaZ Gene Types among Methicillin-Susceptible Staphylococcus aureus Isolates from Four Major Medical Centers in Chicago. Antimicrob Agents Chemother. 2018;62(8):e00382-18. Published 2018 Jul 27. doi:10.1128/AAC.00382-18
- Weis S, Kesselmeier M, Davis JS, et al. Cefazolin versus anti-staphylococcal penicillins for the treatment of patients with Staphylococcus aureus bacteraemia. Clin Microbiol Infect. 2019;25(7):818-827. doi:10.1016/j.cmi.2019.03.010
- Youngster I, Shenoy ES, Hooper DC, Nelson SB. Comparative evaluation of the tolerability of cefazolin and nafcillin for treatment of methicillin-susceptible Staphylococcus aureus infections in the outpatient setting. Clin Infect Dis. 2014 Aug 1;59(3):369-75. doi: 10.1093/cid/ciu301. Epub 2014 Apr 29. PMID: 24785233; PMCID: PMC4110443