The 2015 American Heart Association (AHA) scientific statement provided an updated evidence-based framework for the diagnosis, antimicrobial management, and surgical indications in adult patients with infective endocarditis (IE), incorporating data from studies published between 2005 and 2013. It was stated that gentamicin enhances the bactericidal activity of penicillin or ceftriaxone against viridans group streptococci (VGS) and Streptococcus gallolyticus (bovis), with evidence of synergy in both in vitro studies and animal models of IE. In patients with uncomplicated IE, preserved renal function, and a rapid clinical response, a 2-week regimen that includes gentamicin is reasonable. For IE caused by group B, C, or G streptococci, gentamicin may be added during the initial 2 weeks of a 4- to 6-week course with penicillin or ceftriaxone. However, its use is not advised for right-sided staphylococcal native valve endocarditis (NVE). In staphylococcal IE involving prosthetic valves or other prosthetic material, vancomycin and rifampin are recommended for at least 6 weeks, with gentamicin limited to the first 2 weeks. [1]
The 2023 European Society of Cardiology (ESC) guidelines for the management of endocarditis recommend the use of gentamicin as adjunct synergistic antibiotic treatment in combination with beta-lactams (Strong Recommendation, Moderate Level of Evidence) or vancomycin (Strong Recommendation, Low Level of Evidence) for the treatment of penicillin-susceptible, increased exposure, or resistant to penicillin oral streptococci and Streptococcus gallolyticus group infections; patients with NVE should be treated for 4 weeks while patients with prosthetic valve endocarditis (PVE) should be treated for 6 weeks, with gentamicin added-on for the initial two weeks of treatment only.. Aminoglycosides, including gentamicin, are not recommended for the treatment of staphylococcal NVE due to its risk of renal toxicity. Short-term (2-week) and oral treatments may be used for uncomplicated right-sided native value methicillin-susceptible Staphylococcus aureus (MSSA) infective endocarditis only. Both methicillin-resistant S. aureus (MRSA) and MSSA PVE are recommended to be treated with adjunct gentamicin (both Strong Recommendations, Moderate Level of Evidence). ESC authors note the nephrotoxicity risk associated with gentamicin use and recommend continual monitoring of renal function during treatment, with a maximal treatment duration of 2 weeks. [2]
A 2022 systematic review and meta-analysis synthesized available clinical evidence regarding the efficacy and safety of adjunctive gentamicin and rifampin in the treatment of staphylococcal PVE. The review incorporated four observational studies spanning from 1975 to 2018, comprising 343 patients, of whom 44.9% had Staphylococcus aureus infections and 55.1% had coagulase-negative staphylococcal (CoNS) infections. Methicillin resistance was reported in approximately half of the isolates. Study designs included retrospective and prospective cohorts, with all trials having a moderate risk of bias based on the Newcastle-Ottawa Scale (scores ranging from 5 to 6). Antibiotic backbone therapy included glycopeptides or β-lactams, and adjunctive rifampin and gentamicin were administered in 70.3% and 83.4% of cases, respectively. Surgical intervention was performed in approximately 40% of patients, although the timing of surgery varied, and definitions of PVE and clinical outcomes lacked consistency across studies. Across three meta-analyses assessing 1-year all-cause mortality, no statistically significant differences were identified between patients receiving combination therapy (gentamicin plus rifampin) versus monotherapy or single-agent adjunctive regimens. Specifically, the addition of gentamicin to rifampin-containing regimens yielded an odds ratio (OR) of 0.98 (95% confidence interval [CI] 0.39 to 2.46; n= 2), while the addition of rifampin to gentamicin regimens resulted in an OR of 1.29 (95% CI 0.71 to 2.33; n= 2); both findings demonstrated no mortality benefit. Furthermore, rifampin use was associated with significantly longer hospitalizations (mean 42.3 vs 31.3 days; p<0.001; n= 1), and up to 31% of patients discontinued the drug due to adverse events, including hepatotoxicity, nephrotoxicity, and significant drug–drug interactions, particularly impacting anticoagulant management. One comparison found no difference in nephrotoxicity between regimens with or without gentamicin, though notable nephrotoxicity rates exceeded 50% in both arms. While not specific to gentamicin use alone, the clinical data compiled in this review failed to demonstrate improved outcomes with adjunctive rifampin or gentamicin in staphylococcal PVE and revealed a substantial burden of associated toxicity, raising concerns about the appropriateness of existing guideline recommendations favoring these combination regimens. [3]
A 2020 Cochrane systematic review examined the comparative effectiveness and safety of various antibiotic regimens for the treatment of IE based on evidence from randomized controlled trials (RCTs). The review included six RCTs enrolling a total of 1,143 participants, with only 632 analyzed due to heterogeneity in trial populations and outcome reporting. Eligible trials focused on patients with a definitive diagnosis of IE according to modified Duke’s criteria. Methodological rigor was variable, with most studies judged to be at high risk of bias due to inadequate blinding, selective reporting, and small sample sizes, and three trials had pharmaceutical sponsorship, potentially introducing further bias. Due to substantial clinical and methodological heterogeneity, a meta-analysis was not performed. Instead, findings were presented narratively across several antibiotic comparisons, including levofloxacin plus standard therapy versus standard therapy alone, daptomycin versus vancomycin or beta-lactam plus gentamicin, and partial oral versus conventional intravenous therapy. Across all comparisons, the certainty of evidence was low or very low, and no regimen demonstrated statistically significant superiority in terms of all-cause mortality, cure rates, or reduction in adverse events. For instance, one trial evaluating levofloxacin combined with standard antibiotics reported similar mortality outcomes at 28 days compared to standard therapy alone (relative risk [RR] 1.12, 95% CI 0.49 to 2.56), while a separate trial assessing oral step-down therapy for stable patients with left-sided endocarditis noted no clear difference in mortality compared to full-course intravenous antibiotics (RR 0.53, 95% CI 0.22 tp1.31). One trial assessed daptomycin against a combination of low-dose gentamicin with an antistaphylococcal penicillin (nafcillin, oxacillin, or flucloxacillin) or vancomycin, reporting cure rates of 32.1% for daptomycin (9 out of 28 patients) and 36% for the gentamicin plus penicillin or vancomycin group (9 out of 25 patients), resulting in a RR of 0.89 (95% CI 0.42 to 1.89). Another trial compared glycopeptides (vancomycin or teicoplanin) plus gentamicin with cloxacillin plus gentamicin, showing a significant difference in cure rates: 56% (13 out of 23) vs. 100% (11 out of 11) with an RR of 0.59 (95% CI 0.40 to 0.85). A different trial compared ceftriaxone plus gentamicin to ceftriaxone alone, showing cure rates of 44% (15 out of 34) vs. 64% (21 out of 33) with an RR of 0.69 (95% CI 0.44 to 1.10). Lastly, fosfomycin plus imipenem was compared with vancomycin, yielding cure rates of 25% (1 out of 4) versus 50% (2 out of 4), with an RR of 0.50 (95% CI 0.07 to 3.55). These inconclusive findings underscore the current limitations of the evidence base and highlight the need for well-designed, adequately powered RCTs to inform antibiotic selection in this high-risk population. [4]
A 2020 narrative review synthesized microbiologic, pharmacologic, and clinical data to assess the evolving role of aminoglycosides in the treatment of IE, particularly in light of rising concerns over nephrotoxicity and changing patient demographics. Literature indexed in PubMed through July 2019 was evaluated, alongside referenced observational studies and randomized trials, to determine circumstances under which aminoglycosides could be reduced or avoided. Earlier recommendations were based largely on in vitro and animal model data demonstrating synergism between aminoglycosides and β-lactams or glycopeptides, particularly against Enterococcus faecalis, streptococci, and staphylococci. However, more recent European and American guidelines have revised these recommendations, notably removing gentamicin from native-valve Staphylococcus aureus IE regimens and shortening the duration of aminoglycoside use in E. faecalis and viridans group streptococcal IE with elevated penicillin minimum inhibitory concentrations (MICs). Observational data reviewed from a Swedish cohort of 93 patients with E. faecalis IE and a Danish before-and-after study of 84 patients highlighted that a 2-week course of gentamicin yielded comparable mortality and relapse rates with significantly less acute kidney injury compared to extended 4–6 week regimens. A 2013 Spanish multicenter cohort study involving 159 episodes of E. faecalis IE treated with ampicillin-ceftriaxone and 87 treated with ampicillin-gentamicin found similar efficacy in terms of mortality and relapse across both regimens, including among those with high-level aminoglycoside resistance (HLAR), but reported a 25-fold higher rate of adverse events leading to treatment interruption in the gentamicin-containing arms. For streptococcal IE, a 2019 retrospective cohort of 414 patients showed that amoxicillin MICs between 0.25–2 mg/L were not associated with improved survival when gentamicin was added, thereby questioning the necessity of aminoglycosides in streptococcal infections with intermediate β-lactam susceptibility. In prosthetic valve IE due to Staphylococcus aureus, a retrospective Spanish cohort of 94 patients demonstrated that adjunctive gentamicin conferred no mortality benefit when rifampicin was used. These findings collectively support the assertion that aminoglycosides can be omitted or significantly minimized in nearly 90% of IE cases, especially in elderly and renally vulnerable populations. [5]
A 2020 review provided a detailed synthesis of contemporary treatment strategies for IE, emphasizing anti-infective options tailored to microbial etiology, valve involvement, and clinical severity. Utilizing a comprehensive MEDLINE search extending to May 2020, the authors critically analyzed existing literature, including in vitro experiments, animal models, observational cohorts, and limited randomized controlled trials, focusing on principal pathogens including staphylococci, streptococci, enterococci, and Gram-negative bacilli such as the HACEK (Haemophilus, Aggregatibacter, Cardiobacterium, Eikenella, and Kingella) group. Notably, aminoglycoside use has been significantly de-escalated across most IE settings due to well-documented nephrotoxicity; current recommendations limit gentamicin to a maximum of 2 weeks for select enterococcal cases or prosthetic valve staphylococcal infections, with once-daily dosing preferred. For MSSA, the preferred agents include anti-staphylococcal penicillins such as cloxacillin or oxacillin, with cefazolin as a viable alternative despite concerns about potential inoculum effect in high-burden infections. Vancomycin remains the standard for MRSA, though emerging data support high-dose daptomycin (≥8–10 mg/kg/day) as an effective alternative, especially in cases with elevated vancomycin MICs or renal impairment. In prosthetic valve endocarditis due to staphylococci, rifampin is recommended throughout the 6-week course due to its biofilm activity, although robust clinical evidence remains limited and contradictory. Overall, treatment duration remains pathogen- and setting-specific, with 4 weeks advised for most native valve infections and 6 weeks for prosthetic valve involvement, consistent with enduring experimental evidence on bacterial persistence within vegetations. [6]