The Cefazolin Inoculum Effect Is Associated With Increased Mortality in Methicillin-Susceptible Staphylococcus aureus Bacteremia

Abstract

BackgroundRecent studies have favored the use of cefazolin over nafcillin for the treatment of methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia. The clinical influence of the cefazolin inoculum effect (CzIE) in the effectiveness of cephalosporins for severe MSSA infections has not been evaluated.MethodsWe prospectively included patients from 3 Argentinian hospitals with S. aureus bacteremia. Cefazolin minimum inhibitory concentrations (MICs) were determined at standard (105 colony-forming units [CFU]/mL) and high (107 CFU/mL) inoculum. The CzIE was defined as an increase of MIC to ≥16 µg/mL when tested at high inoculum. Whole-genome sequencing was performed in all isolates.ResultsA total of 77 patients, contributing 89 MSSA isolates, were included in the study; 42 patients (54.5%) had isolates with the CzIE. In univariate analysis, patients with MSSA exhibiting the CzIE had increased 30-day mortality (P = .034) and were more likely to have catheter-associated or unknown source of bacteremia (P = .033) compared with patients infected with MSSA isolates without the CzIE. No statistically significant difference between the groups was observed in age, clinical illness severity, place of acquisition (community vs hospital), or presence of endocarditis. The CzIE remained associated with increased 30-day mortality in multivariate analysis (risk ratio, 2.65; 95% confidence interval, 1.10–6.42; P = .03). MSSA genomes displayed a high degree of heterogeneity, and the CzIE was not associated with a specific lineage.ConclusionsIn patients with MSSA bacteremia where cephalosporins are used as firstline therapy, the CzIE was associated with increased 30-day mortality. Clinicians should be cautious when using cefazolin as firstline therapy for these infections.

Ability of Bicarbonate Supplementation to Sensitize Selected Methicillin-ResistantStaphylococcus aureus(MRSA) Strains to β-Lactam Antibiotics in anEx VivoSimulated Endocardial Vegetation Model

“…There remains a current debate over the most appropriate β-lactam to treat serious MSSA infections, with CFZ or OXA as the primary candidates (25, 39); most recent MSSA bacteremia studies appear to favor CFZ (16, 26, 27). Further, on balancing adverse events vs efficacy metrics, CFZ is generally regarded as a safer option, due to its decreased renal toxicity risk as compared to the antistaphylococcal penicillins (16, 27).…”

“…Further, on balancing adverse events vs efficacy metrics, CFZ is generally regarded as a safer option, due to its decreased renal toxicity risk as compared to the antistaphylococcal penicillins (16, 27). However, there remains concern about CFZ efficacy in “high-inoculum” S. aureus infections (e.g., endocarditis) due to the potential for the undetected presence and induction of genes for Types A or C cephalosporinases that hydrolyze CFZ (39, 40). In our current study, CFZ appeared to be unaffected by the high inoculum within SEVs, at least for the NaHCO 3 -responsive strains, 11-11 and MW2, with excellent CFZ bactericidal activity obtained despite starting inocula ≥ 1×10 8 CFU/g.…”

Does the Beta-Lactam Matter? Nafcillin versus Cefazolin for Methicillin-Susceptible <b><i>Staphylococcus aureus</i></b> Bloodstream Infections

“…Cefazolin is considered to be an acceptable alternative in patients who are unable to tolerate antistaphylococcal penicillins [2, 4]. However, use of cefazolin has previously been associated with treatment failure, including infections caused by isolates exhibiting a cefazolin inoculum effect in vitro [20, 21]. Impact of this inoculum effect on clinical outcomes may also depend on the local prevalence of isolates displaying the cefazolin inoculum effect [22, 23].…”

Intravenous Ceftriaxone Versus Multiple Dosing Regimes of Intravenous Anti-Staphylococcal Antibiotics for Methicillin-Susceptible Staphylococcus aureus (MSSA): A Systematic Review

“…The use of ceftriaxone in the initial management of MSSA bacteraemia is controversial given the potential severity of the condition and the limited available clinical evidence to support its use [9]. A multi-centre prospective clinical study of 77 patients treated with the narrow-spectrum anti-staphylococcal cephalosporin, cefazolin, for MSSA bacteraemia, reported an association between the cefazolin-induced inoculum effect and increased 30-day mortality [10]. Whether these concerns are clinically significant or generalisable to ceftriaxone is unclear.…”