A clinical guideline recommendation that either cefazolin or an antistaphylococcal penicillin (ASP) can serve as first-line treatment for methicllin-susceptible Staphylococcus aureus (MSSA) infective endocarditis (IE) is called into question by an investigation which suggests that a ß-lactam inoculum effect could lead to higher 30-day mortality with cefazolin.1-2
Baptiste Jean, MD, Service des Maladies Infectieuses et Tropicales, Centre Hospitalier Universitaire (CHU) de Toulouse, Université Paul Sabatier Toulouse III, Toulouse, France, and colleagues describe the inoculum effect—when in-vitro bacteria culture of high count and density demonstrates an increased antimicrobial minimum inhibitory concentration (MIC)—occurring in-vivo with the high bacterial density in vegetation lesions of IE.
The effect was exhibited with S aureus with blaZ gene producing beta-lactamase; which the investigators associated with higher 30-day all-cause mortality in left-sided IE (studied for the inherently higher mortality than right-sided IE) with cefazolin treatment than with oxacillin. An inoculum effect was also found with oxacillin, which the investigators suggest could be consistent with the phenomenon of borderline oxacillin-resistant S aureus (BORSA).
"The influence of phenotypic characteristics of blaZ on therapeutic outcomes suggests new therapeutic perspectives," Jean and colleagues indicate. "The use of phenotypic characteristics of MSSA isolates, such as inoculum effect determination, may help in the future to select the optimal ß-lactam agent.It may also prompt consideration of adding ß-lactamase inhibitors, such as clavulanic acid, to conventional therapy against ß-lactamase producing strains."
The retrospective multicenter case series included 216 patients treated for left-sided MSSA IE with either an ASP (139 [64.4%]) or cefazolin (77 [35.6%]) between February 2016 and February 2022. MICs were determined using standard (2.105 CFU/ml) and high (2.107 CFU/ml) inocula. The S aureus ATCC29213 reference strain was used as a control.
Although 30-day all-cause morality (24.4%) was similar between groups overall, the investigators detected higher mortality in patients infected with blaZ-positive strains than blaZ –negative (29.5% vs 11.8%). In addition, higher 30-day mortality was found in patients infected with strains exhibiting an inoculum to the ß-lactam than with strains without an inoculum effect (40.3% vs 19.4%).They determined through multivariable analysis that the inoculum effect was an independent factor in the higher mortality.
What You Need to Know
The study challenges current guidelines recommending either cefazolin or antistaphylococcal penicillins (ASP) for treating methicillin-susceptible Staphylococcus aureus (MSSA) infective endocarditis (IE). It suggests that a β-lactam inoculum effect, particularly in strains with the blaZ gene, could lead to higher 30-day mortality when treated with cefazolin compared to oxacillin.
The inoculum effect, where higher bacterial density leads to increased minimum inhibitory concentration (MIC), was observed in patients with MSSA IE.
Experts recommend initially treating left-sided MSSA IE with high-dose ASPs, only considering cefazolin after blood cultures clear and source control is achieved.
An accompanying editorial,3 however, suggests there may have been other factors contributing to the difference in mortality, and points to additional evidence that could have been collected to support the inoculum effect as a driver of clinical failure and mortality.
"The authors do not report data on antibiotic dosing or time to appropriate antibiotic initiation," observe Sara Cosgrove, MD, MS, Department of Medicine, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD, and Loren Miller, MD, MPH, Department of Medicine, Division of Infectious Diseases, David Geffen School of Medicine at the University of California Los Angeles.
"Given that inadequate empirical antibiotic therapy occurs in more than one-fourth of patients with S aureus bactermia, inadequate or delayed doses could be associated with failure risk in high inoculum infections," they point out.
Despite this and other limitations, as well as the obstacles in testing for the inoculum effect in clinical settings, Cosgrove and Miller find that the study provides "modest additional support" of the inoculum effect as a risk factor for poor outcomes in these patients.
"We believe it is prudent to treat left-sided MSSA IE with high doses of antistaphylococcal penicillins initially, with transition to cefazolin considered after blood cultures clear and source control is obtained given cefazolin's more favorable adverse effect profile in patients requiring prolonged treatment," Cosgrove and Miller recommend.
References
1. Delgado V, Ajmone MN, de Waha S, et al; ESC Scientific Document Group. 2023 ESC Guidelines for the management of endocarditis. Eur Heart J. 2023;44(39):3948-4042.
2. Baptiste J, Crollee M, Pollani C, et al. ß-lactam inoculum effect in methicillin-susceptible Staphylococcus aureus infective endocarditis. JAMA Netw Open 2024;7(12):e2451353. doi:10.1001/jamanetworkopen.2024.51353. Accessed February 8, 2025.
3. Cosgrove SE, Miller LG. The inoculum effect and Stapylococcus aureus infective endocarditis—Time to reconsider treatment? JAMA Netw Open 2024;7(12):e2451300. doi:10.1001/jamanetworkopen.2024.51300. Accessed February 8, 2025.
