The antistaphylococcal penicillins (ASPs), such as nafcillin or oxacillin, have long been regarded as first-line treatments for methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia. These agents are effective but do not have favorable pharmacologic and toxicity profiles. Cefazoline, on the other hand, is better tolerated and easier to use but has been relegated, at least until recently, as an alternative due to concern about clinical failures linked to the cefazolin inoculum effect (CIE). The CIE is an in vitro phenomenon in which isolates are susceptible at standard inocula (10⁵ CFU/mL) but become less susceptible (≥4-fold increase in MIC) or resistant (MIC ≥16 μg/mL) at high inocula (10⁷ CFU/mL). This phenomenon is usually mediated by a type A beta lactamase that hydrolyses cefazolin but not the ASPs. Despite being described in experimental animal models and case reports of treatment failures since the 1970s, the clinical relevance of the CIE has been a matter of contention. Recently, however, the potential in vivo consequence of the CIE has been suggested more strongly. A prospective cohort study from Argentina (where ASPs are not available) that evaluated 77 patients with MSSA bacteremia treated with cefazolin or cephalotin showed a high prevalence of the CIE (54%).
1This effect was associated with an increase in 30-day mortality (relative risk [RR] 2.65, P = 0.03) in patients with CIE-positive MSSA as compared to patients with CIE-negative MSSA. In another prospective cohort study from South Korea, 22% of MSSA isolates (24/110) exhibited the CIE.
- 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: ofy123https://doi.org/10.1093/ofid/ofy123
2Among patients who received cefazolin, treatment failure (61% vs. 29%, P = 0.049) and 1-month mortality (15% vs. 0%, P = 0.047) were significantly higher in the CIE-positive than in the CIE-negative group. No difference in either outcome was noted with the nafcillin treatment group, regardless of the presence of the inoculum effect. These findings suggest that the CIE is clinically relevant and not just an in vitro or remote phenomenon. It is also prevalent among clinical isolates.
- 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: 152-158
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- The cefazolin inoculum effect is associated with increased mortality in methicillin-susceptible Staphylococcus aureus bacteremia.Open Forum Infect Dis. 2018; 5: ofy123https://doi.org/10.1093/ofid/ofy123
- Comparative outcomes of cefazolin versus nafcillin for methicillin-susceptible Staphylococcus aureus bacteraemia: a prospective multicentre cohort study in Korea.Clin Microbiol Infect. 2018; 24: 152-158
- Comparative effectiveness of cefazolin versus nafcillin or oxacillin for treatment of methicillin-susceptible Staphylococcus aureus infections complicated by bacteremia: a nationwide cohort study.Clin Infect Dis. 2017; 65: 100-106
- Cefazolin versus anti-staphylococcal penicillins for the treatment of patients with Staphylococcus aureus bacteraemia.Clin Microbiol Infect. 2019; 25: 818-827
- Meta-analysis of trials comparing cefazolin to antistaphylococcal penicillins in the treatment of methicillin-sensitive Staphylococcus aureus bacteraemia.Br J Clin Pharmacol. 2018; 84: 1258-1266
- Systematic review and meta-analysis of the safety of antistaphylococcal penicillins compared to cefazolin.Antimicrob Agents Chemother. 2018; 62: e01816-17https://doi.org/10.1128/AAC.01816-17
- Comparison of nafcillin and cefazolin for the treatment of methicillin-susceptible Staphylococcus aureus bacteremia.Am J Med Sci. 2020; 360: 35-41https://doi.org/10.1016/j.amjms.2020.04.006
- Treatment outcomes with cefazolin versus oxacillin for deep-seated methicillin-susceptible Staphylococcus aureus bloodstream infections.Antimicrob Agents Chemother. 2015; 59: 5232-5238
Published online: April 15, 2020
Accepted: April 8, 2020
Received: March 19, 2020
Conflicts of Interest: None.
© 2020 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.