To our knowledge, this is the second study examining the clinical outcomes of using lower-than-recommended synergistic ceftriaxone dosing (1 g 12 hourly) in dual beta lactam therapy to treat EFIE (11). It is the first study to administer and evaluate lower dose ceftriaxone regimens in EFIE treatment in inpatient settings and evaluate treatment outcomes.
Our findings are in keeping with previous studies, in demonstrating similar efficacy in terms of mortality, in hospital death and rates of relapse between patients treated with ceftriaxone and aminoglycoside-based regimens, and a higher incidence of adverse events in those treated with an aminoglycoside-based regimen (4-7, 11-19). Though a difference was noted in terms of in hospital death and all-cause mortality between the AG and AC group overall, it was not of statistical significance.
A recent study evaluating outpatient EFIE treatment with continuous benzylpenicillin infusion in combination with once daily aminoglycoside or ceftriaxone, found no difference in treatment success between the groups, and included patients who had been treated with low and high dose ceftriaxone (2 g once daily or 1 g 12 hourly) (11). Additionally, our study demonstrated that a statistically significant number of adverse events in the aminoglycoside treated patients required a change in antimicrobial therapy.
There was no significant difference between the 3 groups in the demographic measures of age, comorbidities, baseline renal function, complications of IE or presence of prosthetic device. However, a significantly greater number of cardiac and extracardiac surgeries were required during the treatment course of EFIE for patients treated with AG; this may
The adverse event most associated with aminoglycoside therapy within our study, was nephrotoxicity, reflecting the findings of previous studies. Only 1 case of nephrotoxicity was noted in our study, in the ACL group (7%), with none in the ACN (0 %) group; 8 cases were noted in the AG group (53%). In keeping with the recommendations in previous studies, we would advocate for consideration of ceftriaxone based dual beta lactam therapy to be initiated in cases of patients with or at risk of renal impairment with EFIE (6,7,11-14).
The alternative option suggested, to reduce toxicity and treatment related adverse events, is a shorter course of therapy in both AG and AC regimens. Two studies have examined shorter course (4 weeks as opposed to 6 weeks) AC regimens in treating E. faecalis endocarditis, one of which found the shorter course regimen was associated with a higher rate of relapse (14,15). Multiple Danish studies demonstrated efficacy in clinical cure, mortality and incidence of relapse with a 6-week ampicillin and 2-week aminoglycoside regimen for EFIE, the first of which resulted in a change to the Danish Society of Cardiology recommendations for aminoglycoside therapy duration in EFIE (16,17).
Many centres utilise outpatient parenteral therapy programs to facilitate ongoing administration of either AG or AC regimens in EFIE. Herrera Hidalgo et al recently demonstrated the administration of a single daily dose of 4 g ceftriaxone with ampicillin-based outpatient regimens had a higher rate of relapse in comparison to a 12 hourly 2 g dose of ceftriaxone (18). Two other small retrospective case series have demonstrated the efficacy of EFIE treatment with outpatient penicillin infusions in combination with ceftriaxone at 2 g 12 hourly dosing at achieving clinical cure (19,20).
Our study did not find a significant difference in mortality, relapse of bacteraemia or in hospital death between the low dose and high dose ceftriaxone regimen groups. However, it also did not note a significant difference in adverse events between these two groups. Beta lactam toxicity, particularly in the elderly, has been linked to altered pharmacokinetics due to multifactorial mechanisms including reduced renal clearance, and the pathophysiological changes associated with critical illness (20,21). Theoretically, modified, or reduced dosing could lower the risk of development of beta lactam related toxicity (20). However, most pharmacokinetic studies propose altered dosing be guided by therapeutic drug monitoring (i.e., with ceftriaxone levels) in at risk or elderly patients (20,21).
LIMITATIONS AND FUTURE DIRECTIONS:
There were several limitations to our study, mainly the small sample size, the implications on the statistical power of our findings, and retrospective cohort design. This was not a randomised or prospective study, and no intention to treat analysis was performed. Excluding patients who were lost to follow up, or who had different antibiotic regimens for more than 14 days, could also have contributed to selection bias. The significant differences in the demographic measures of surgeries performed and duration of treatment should also be interpreted in the context of small numbers of patients evaluated in each of the 3 antimicrobial regimen cohorts.
Additionally, we did not explore differences in clinical outcomes between patients treated with varying penicillin-based regimens (i.e., benzylpenicillin or ampicillin); this study did not explore the stability of benzylpenicillin continuous infusions in combination with outpatient ceftriaxone therapy. More recent studies have suggested lower rates of synergism with benzylpenicillin/ceftriaxone combination therapy as opposed to ampicillin/ceftriaxone therapy, as well as higher rates of unplanned readmissions (18,23). However, given differing doses and frequency of dosing in ceftriaxone doses used concurrently in these studies, such results are difficult to attribute to one component of therapy alone; this should be an avenue of further study.
TDM (therapeutic drug monitoring) was not assessed in our study for ceftriaxone. Trough gentamicin concentrations, though collected, were not always correlated with clinical evidence of gentamicin toxicity such as ototoxicity or nephrotoxicity. Though a standard 1mg/kg, three times daily gentamicin dose was used, there was some variability, at the discretion of the treating physician, in dosing for obese patients
There is preliminary data supporting the use of dalbavancin or teicoplanin in clinically stable EFIE patients (18,24,25). Exploration of alternative therapies is required, particularly regarding logistics, toxicity, and clinical cure in outpatient settings as well as evaluation of early transition to oral agents (18,24,25).
Further randomised controlled data, with evaluation of therapeutic drug monitoring of beta lactam antimicrobials, is needed to guide recommendations around lower dose ceftriaxone in EFIE.