Table 1.

Clinical data evaluating dual beta-lactam combination therapy in EFIE treatment (A = ampicillin; C = ceftriaxone; G = gentamicin; * = completed therapy).

Reference	Study Design	Subjects	Dose Regimen	Follow-Up	Mortality %	Renal Impairment %	Relapses%	Main Finding
Gavaldà et al. (2007) [28]	Observational, open label, non-randomized, multicenter clinical trial observing outcomes in patients receiving ampicillin plus ceftriaxone treatment.	43 patients with EFIE	A 2g q4h + C 2g q12h for 42 days (5–48)	3 months	Overall 28%	No cases occured	4.6%	The combination of ampicillin and ceftriaxone is effective and safe for treating HLAR EFIE and could be a reasonable alternative for patients with non-HLAR EFIE who are at increased risk for nephrotoxicity.
Fernández-Hidalgo et al. (2013) [29]	Non-randomized, non-blinded, comparative, multicenter cohort study comparing ampicillin plus ceftriaxone and ampicillin plus gentamicin in patients with endocarditis.	246 patients with EFIE	A 2g q4h + C 2g q12h [(A+C) n = 159] vs. A 2g q4h + G 3 mg/kg/d for 4–6 weeks [(A+G) n = 87]	11 months (4.4–22.5 months)	Overall 26 % (A+C) Overall 25% (A+G)	33% (A+C) 46% (A+G)	3% (A+C) 4% (A+G)	Ampicillin plus ceftriaxone appears as effective as ampicillin plus gentamicin for treating EFIE patients and can be used with virtually no risk of renal failure and regardless of the HLAR status.
Pericas et al. (2014) [30]	Retrospective analysis of prospectively collected data assessing antibiotic resistance, epidemiology and comparing safety and efficacy of ampicillin plus ceftriaxone and ampicillin plus gentamicin in patients with endocarditis.	69 patients with EFIE	A 2g q4h + C 2g q12h [(A+C) n = 39] vs. A 2g q4h + G 3 mg/kg/d for 4–6 weeks [(A+G) n = 30]	13 months (118–792 days)	1 year 26% (A+C) 1-year 30% (A+G)	34% (A+C) 65% (A+G)	8% (A+C) 3% (A+G)	The prevalence of HLAR EFIE has increased significantly in recent years and that alternative treatment with ampicillin and ceftriaxone is safer than ampicillin plus gentamicin, with similar clinical outcomes.
El Rafei et al. (2018) [31]	Retrospective cohort study comparing safety and efficacy of dual β-lactam therapy to penicillin-aminoglycoside combination in patients with endocarditis	85 patients with EFIE	A 2g q4h + C 2g q12h [(A+C) n = 18] vs. A 2g q4h + G 3 mg/kg/d for 4–6 weeks [(A+G) n = 67]	12 months	1-year 11% (A+C n = 13) * 1-year 9% (A+G n = 37) *	11% (A+C) 25% (A+G)	7.7 % (A+C) * 2.7 % (A+G) *	Ampicillin plus ceftriaxone appears to be a safe and efficacious regimen in the treatment of EFIE. Patients treated with this regimen had lower rates of nephrotoxicity and no differences in relapse rate and 1-year mortality as compared to that of the ampicillin plus gentamicin group.
Ramos-Martinez et al. (2020) [32]	Prospective non-randomized cohort study comparing the efficacy of shorter courses of AC (4 weeks) with respect to the recommended duration of 6 weeks for the treatment of EFIE.	109 patients with EFIE	A 2g q4h + C 2g q12h for 28 ± 4 days [(4 weeks) n = 39] vs. A 2g q4h + C 2g q12h for 42 ± 6 days [(6 weeks) n = 70]	12 months	1-year 17% (4 weeks)1-year 21.4 % (6 weeks)	25.6% (4 weeks) 28.6% (6 weeks)	5.1 % (4 weeks) 4.3 % (6 weeks)	Similar rates of relapse and mortality were recorded in patients with native valve EFIE treated with A+C for 4 and 6 weeks, suggesting that a short course of A+C might be sufficient to treat native valve EFIE.