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August 11, 2021

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Defining the Role for Ceftriaxone in the Management of Enterococcal Endocarditis

By A. Krishna Rao, MD, MS

Enterococcal infective endocarditis (EIE) is a life-threatening disease—enterococci infections constitute the third leading cause of IE, accounting for ~10% of cases without intravenous drug use, and are associated with high mortality of ~20%. While treatment with aminoglycoside-containing regimens, such as ampicillin-gentamicin (AG), has been the cornerstone of antimicrobial therapy for EIE and has been recommended by American Heart Association (AHA) guidelines since 1995, regimens can be difficult to tolerate due to toxicity, especially in older adults with comorbid disease, who are most prone to developing EIE. Ampicillin-ceftriaxone (AC) has emerged as an alternative antibiotic regimen for treatment of EIE. However, despite a favorable 2013 multicenter observational study in Europe and adoption as an alternate regimen to AG in the latest AHA guidelines, which IDSA has endorsed, clinical evidence for efficacy remains limited regarding its use in all EIE patients and in the United States.

To address this evidence gap, Shah and colleagues conducted a multicenter, retrospective, propensity-score matched cohort study comparing 90-day all-cause mortality between AG- and AC-treated patients with EIE. Their results appear in Open Forum Infectious Diseases. Manual chart review was used to confirm EIE case status and inclusion and exclusion criteria, most notably ≥48 hours of treatment and polymicrobial IE, respectively. Secondary outcomes included treatment failure (i.e., physician documentation of changing antibiotics due to failure), relapse (positive blood cultures with same species within 3 months of completion of initial regimen), and estimated duration of bacteremia (time from first positive blood culture collection to last positive culture or first negative culture). Overall mortality in the full cohort of 190 patients was high at 21%. In the propensity-score matched cohort (56 patients in each group), between the AC and AG groups no statistically significant difference was observed for 90-day mortality (11% vs. 7%; P = .55), treatment failure (0% vs. 2%; P = .5), or relapse (0% for both), but more patients in the AG cohort switched therapy (10% vs. 49%; P < .0001) due to ototoxicity, renal injury, or other adverse events, and duration of bacteremia was higher in the AC cohort (102.3 vs. 51.5 hours; P = .007).

This study provides more evidence that treatment of β-lactam susceptible EIE in all patients with AC is a safe and effective option even in a U.S.-based cohort. However, the study was observational and retrospective, and propensity-score matching is not a perfect substitute for randomization—aortic abscess presence and pacemaker removal were higher in the AC group, and there may be unmeasured confounders affecting the results. In addition, a numerically higher percentage of patients in the AC group developed Clostridioides difficile infection and bacteremia duration was longer, though kidney injury and ototoxicity was higher in AG recipients. Properly accounting for these differences, along with questions about efficacy of other cephalosporins or switching to oral regimens, as per the POET trial, underscores the necessity of multicenter randomized trials comparing different antibiotic regimens to optimize management and improve survival in this dangerous disease.

(Shah et al. Open Forum Infect Dis. 2021;8(4):ofab102.)

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