β-Lactam Inoculum Effect in Methicillin-Susceptible Staphylococcus aureus Infective Endocarditis

Abstract

Importance: Infective endocarditis (IE) caused by Staphylococcus aureus is associated with high mortality, approximately 20% to 30%, mostly in the first month, with no improvement in recent decades. Current opinion is that antistaphylococcal penicillin and cefazolin are equally effective in treating methicillin-susceptible S aureus (MSSA) IE, and both are recommended as possible first-line treatments. Most MSSA strains carry the β-lactamase blaZ gene, and some blaZ-positive strains exhibit an inoculum effect, meaning increased minimum inhibitory concentrations at high inoculum. This reduced susceptibility to an antibiotic at high bacterial inoculum may be particularly relevant in IE, where vegetations have very high bacterial densities.

Objective: To evaluate the association between phenotypic characteristics of S aureus isolates, β-lactam used, and outcome in patients with MSSA IE.

Design, settings, and participants: This retrospective case series included MSSA cases treated at 3 French university hospitals between February 2016 and February 2022. The study included patients who had clinical isolates available and had definite or possible S aureus IE that involved native or prosthetic valves. Data were analyzed from July 2023 to June 2024.

Main outcomes and measures: MSSA isolates were tested for the presence of blaZ and for inoculum effects to cefazolin and oxacillin. The association between first-month mortality and the β-lactam used, the presence of blaZ, and the presence of an inoculum effect to the treatment received was evaluated.

Results: This study included 216 patients with MSSA IE (median [IQR] age, 65 [49-73] years; 152 [70.4%] male) who were treated with antistaphylococcal penicillin (139 [64.4%]) or cefazolin (77 [35.6%]). One-month mortality of left-sided IE was 44 of 180 patients (24.4%), with no overall difference between patients treated with antistaphylococcal penicillin or cefazolin. However, 1-month mortality was higher in patients infected with blaZ-positive strains than with blaZ-negative strains (38 of 129 [29.5%] vs 6 of 51 [11.8%]; P = .01), and with strains with an inoculum effect to the β-lactam received than with strains without an inoculum effect (25 of 62 [40.3%] vs 13 of 67 [19.4%]; P = .005). On multivariable analysis, the presence of an inoculum effect was independently associated with first-month mortality (HR, 2.84; 95% CI, 1.28-6.30; P = .01).

Conclusions and relevance: In this case series of MSSA IE, the presence of an inoculum effect to the β-lactam received was a risk factor for death in the first month. Phenotyping MSSA isolates for inoculum effect may guide β-lactam choice and improve outcomes.

Figure 1.. Study Flowchart

CIED indicates cardiac implantable electronic devices; CHU, Centre Hospitalier Universitaire; IE, infective endocarditis.

Figure 2.. Phylogenetic Tree of the 159 blaZ-Positive Staphylococcus aureus Strains

Maximum likelihood phylogenetic tree based on alignment of 355 bp polymerase chain reaction products from blaZ amplification. Strains with a cefazolin inoculum effect and strains with an oxacillin inoculum effect are marked with a red and blue dot, respectively. Bootstrap values are only shown above 70. The name of each strain corresponds to the first 3 letters of the hospital where it was isolated, followed by an increasing number for each hospital and finally the letter corresponding to the blaZ type. BIC indicates Bichat Hospital; REN, Rennes Hospital; TOU, Toulouse Hospital.

Figure 3.. One-Month Survival Curves in Methicillin-Susceptible Staphylococcus aureus Left-Sided Infective Endocarditis

Kaplan-Meier survival curves according to (A) the treatment with cefazolin (CFZ) or antistaphylococcal penicillin (ASP), (B) the presence or absence of blaZ, and (C) the presence or absence of an inoculum effect in the blaZ-positive group.