Staphylococcus aureus bacteremia represents significant burden on the healthcare system with early mortality rates as high as 60% and more recent studies suggesting mortality rates of 10–30% (1,2). While methicillin-resistant Staphylococcus aureus (MRSA) has garnered much of the attention due to higher mortality rates and treatment difficulties, the optimal treatment of methicillin-susceptible Staphylococcus aureus (MSSA) is still in question (1). Historically, antistaphylococcal penicillins (ASPs) such as nafcillin, oxacillin, cloxacillin, and flucloxacillin and first-generation cephalosporins, such as cefazolin, have been considered the treatment of choice for infections caused by MSSA (3-7). We read with interest the meta-analysis from Bidell and colleagues comparing ASPs to cefazolin for the treatment of MSSA bacteremia in adults (8). Over 4,300 patients were included in this analysis. The study concluded that cefazolin was associated with a lower 90-day all-cause mortality [odds ratio (OR) 0.63, 95% confidence interval (CI): 0.41–0.99] and a lower rate of treatment associated adverse events (OR 0.25, 95% CI: 0.11–0.56), though no difference in clinical failure was detected (OR 0.85, 95% CI: 0.41–1.76) (8). The authors rightfully urge caution due to the uncontrolled and retrospective nature of the included studies. While this study has re-sparked interest in the optimal antimicrobial for MSSA bacteremia, the debate between ASPs and cefazolin dates back decades to the 1970’s.
In 1975, Sabath and colleagues published a report evaluating the inoculum effect on the antimicrobial activity of ASPs and cephalosporins of beta-lactamase (Bla) producing strains of MSSA. It was shown that ASPs were more resilient to beta-lactam degradation by hydrolytic enzymes than cephalosporins (9). Simply put, the inoculum effect demonstrates that higher concentrations of colony forming units (CFU)/mL (107 CFU) result in higher minimum inhibitory concentrations (MIC). Further animal models conducted in the 1970’s and 1980’s were conflicting with some studies supporting the inoculum effect and others failing to replicate previous findings (10-14). As such, guidelines directed at infections with higher bacterial burden have historically recommended ASPs (6,7). Recently, a prospective observational study evaluated cefazolin for the presence of the inoculum effect (defined as an increase of MIC to ≥16 µg/mL when tested at 107 CFU/mL) (15). In 77 patients, 42 patients (54.5%) were positive for the inoculum effect, leading to an increased risk of 30-day mortality (risk ratio, 2.65; 95% CI: 1.1–6.42; P=0.03) (15).
Over 90% of Staphylococcus aureus strains produce a Bla, which hydrolyze penicillin (16). There have been four different types identified, A, B, C, and D (16). Type A Blas have demonstrated the most enhanced hydrolysis of cefazolin over ASPs with type C also maintaining some activity (16). Despite the limitations from the inoculum effect, cefazolin has many advantageous qualities compared to ASPs, as shown in Table 1. Regarding drug dosing, the half-life of cefazolin in patients with normal renal function is approximately 2 hours, which supports every 8 hours dosing with adjustments for patients with reduced kidney function (16). Dosing in hemodialysis has been simplified to include only a 2–3 grams dose after each hemodialysis session (16). The recommended dose of nafcillin or oxacillin directed at severe or invasive infections is 2 grams every 4 hours with no dosing reductions necessary for renal impairment (16). Continuous infusion models have been developed to circumvent the multiple daily dosing but have been associated with thrombophlebitis and extravasation (16). In addition to its favorable dosing regimen, cefazolin is also associated with considerably fewer side-effects than ASPs. Individual rates of reactions vary between studies. One study reported significantly more adverse reactions with oxacillin than nafcillin (59% vs. 28%, respectively, P<0.001) with the most common adverse effects being neutropenia, hepatotoxicity, rash, phlebitis, and fever (17). Another study reported higher discontinuation rates with nafcillin than oxacillin (18% vs. 2%, respectively, P=0.0004) and higher rates of hypokalemia (51% vs. 17%, respectively, P<0.0001) (18). In contrast, the most common adverse effect for cefazolin includes a mild rash (16).
|Advantages||Well-tolerated||Resistant to inoculum effect|
|Can be used in patients experiencing immune-mediated hypersensitivity to nafcillin||Preferential for endocarditis and meningitis|
|No drug interactions||No unnecessary Gram-negative exposure|
|Disadvantages||Subject to the inoculum effect||High rates of adverse events|
|Hydrolyzed by type A and C beta-lactamases||High rates of discontinuation due to adverse events|
|Minimal CNS penetration||Thrombophlebitis with continuous infusion|
|Higher doses needed for obese patients||Frequent daily dosing (6×/day)|
|Cytochrome p450 enzyme induction|
|Dosing||CrCl >35 mL/min: 2 grams every 8 hours||2 grams every 4 hours, no adjustment for renal dysfunction|
|CrCl 10–34 mL/min: 1 gram every 12 hours||Dose reduction for combined renal and hepatic impairment|
|CrCl <10 mL/min: 1 gram daily|
|HD: 2 grams after HD on Monday, Wednesday, and 3 grams after HD on Friday|
CNS, central nervous system; CrCl, creatinine clearance; HD, hemodialysis.
Consistent with previous reports, the study by Bidell and colleagues further demonstrated a reduction in treatment discontinuation due to adverse events with cefazolin as compared to ASPs (8). Cefazolin has consistently demonstrated that it is better tolerated than ASP, and the meta-analysis confirms this with an OR of 0.25 (95% CI: 0.11–0.56] (8). The continued debate and still unanswered question is whether cefazolin has equal efficacy compared to ASPs. This study found no difference in clinical failure (OR 0.85, 95% CI: 0.41–1.76) but noted a significant difference in 90-day mortality (OR 0.63, 95% CI: 0.41–0.99), favoring cefazolin (8). This finding is worthy of further exploration.
Taking a closer look at the included studies, 6 of the 7 are retrospective in design and 1 was a prospective observational cohort, see Table 2 (2,19-24). These design limitations are subject to a selection bias in which sicker patients or patients with deeper seated infections may be preferentially started on the presumed superior agent. Looking specifically at the five studies that included a breakdown of patients with infective endocarditis, significant differences in the baseline characteristics emerge. Using a Fisher’s exact test, patients treated with an ASP were statistically more likely to have endocarditis (8% vs. 5.7%, P=0.007). The included study by McDanel and colleagues, which accounted for over 70% of the patients and 71% of the ASP-related 90-day mortality events in the studies included in the meta-analysis, also noted the treatment differences in endocarditis patients (23). Available data to this point is only suggestive and ultimately calls for a prospective, randomized controlled trial focusing specifically on deeper seated infections with well-balanced intervention groups.
|Author/year||Design/patients||Number of patients with deep-seated infections||Clinical outcomes|
|Lee, 2011 (19)||Retrospective, case-control/cefazolin (n=49) vs. nafcillin (n=84)||Cefazolin: 1 (2%) with IE, 10 (20%) with OM; nafcillin: 13 (16%) with IE, 11 (13%) with OM||No significant difference in incidence of treatment failure|
|Paul, 2011 (20)||Retrospective cohort/cefazolin (n=72) vs. cloxacillin (n=281)||Not subgrouped by antibiotic, however 6.5% with IE and 15.3% with OM||No significant treatment differences between groups|
|Li, 2014 (21)||Retrospective cohort/cefazolin (n=59) vs. Oxacillin (n=34)||Cefazolin: 27 (18%) with IE, 18 (31%) with OM; oxacillin: 3 (9%) with IE, 20 (59%) with OM||No significant treatment differences between groups|
|Bai, 2015 (2)||Retrospective cohort/cefazolin (n=105) vs. cloxacillin (n=249)||Cefazolin: 2 (2%) with IE, 15 (14%) with OM; nafcillin: 30 (12%) with IE, 28 (11%) with OM||No difference in mortality between groups|
|Pollett, 2016 (22)||Retrospective cohort/cefazolin (n=70) vs. Nafcillin (n=30)||IE not identified as a source; for OM, 5 (7%) received cefazolin and 3 (10%) received nafcillin||Cefazolin associated with a nonsignificant reduction in mortality|
|McDanel, 2017 (23)||Retrospective cohort/cefazolin (n =1,163) vs. nafcillin/oxacillin (n=2,004)||Cefazolin: 52 (4%) with IE, 138 (12%) with OM; ASP: 145 (7%) with IE, 267 (13%) with OM||Cefazolin associated with a lower risk of 90-day mortality than ASPs|
|Lee, 2018 (24)||Prospective, observational cohort/cefazolin (n=79) vs. nafcillin (n=163)||Cefazolin: 1 (1%) with IE, 28 (35%) with OM; nafcillin: 11 (7%) with IE, 61 (37%) with OM||Cefazolin was better-tolerated than nafcillin|
IE, infectious endocarditis; OM, osteomyelitis; ASP, antistaphylococcal penicillin.
For patients initiated on nafcillin who develop a non-IgE-mediated hypersensitivity reaction, switching to cefazolin appears to be a safe and effective solution (24). Blumenthal and colleagues identified 60 patients from an outpatient parenteral antimicrobial therapy program who were switched to cefazolin during their course, with 17 patients experiencing a non-IgE-mediated reaction. All but 1 had resolution of the reaction and completed the full treatment course, and no patient developed any further complication (25). Another important consideration is the lack of central nervous system (CNS) penetration of cefazolin. As such, cefazolin should not be used for meningitis or other infections of the CNS; nafcillin or oxacillin are preferred (16).
Ultimately, for most non-CNS infections, cefazolin can be used preferentially to ASPs. In patients with slow-to-resolve or nonresolving infections a therapy change to an ASP should be considered. ASPs are preferred for meningitis given superior CNS penetration, and patients who are unable to tolerate an ASP can be treated with vancomycin and meropenem. For endocarditis, ASPs should still be considered preferentially until a large, randomized controlled trial focusing on high bacterial-burden infections is conducted with cefazolin being reserved for patients who are intolerant to ASPs (7). Finally, patients who cannot tolerate ASPs (excluding IgE-mediated reactions) can safely be switched to cefazolin. The utility of cefazolin for infections with lower bacterial burden is well-established; however, further studies are needed to define the optimal antimicrobial to treat MSSA infections with higher bacterial burden, such as infective endocarditis.
Provenance and Peer Review: This article was commissioned and reviewed by the Executive Editor-in-Chief Dr. Mi Zhou (Department of Pharmacy, Children’s Hospital of Soochow University, Soochow, China).
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/aoi.2018.10.01). The authors have no conflicts of interest to declare.
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Cite this article as: Lewis PO, Covert KL, Cluck DB. Cefazolin or nafcillin? —a commentary on the optimal treatment of methicillin-susceptible Staphylococcus aureus bacteraemias: a meta-analysis of cefazolin versus antistaphylococcal penicillins. Ann Infect 2018;2:5.