Infective endocarditis is defined as an infection of the endocardial surface of the heart, which may include one or more heart valves, the mural endocardium, or a septal defect. Brusch, JL (2011) has written a comprehensive Medscape reference covering all aspects of infective endocarditis. Infective endocarditis is caused by a variety of pathogens. Of particular interest here is endocarditis caused by the organisms Enterococcus faecalis and Enterococcus faecium, because it represents one of the few instances where the use of gentamicin is currently justified.
For over 30 years, the use of a penicillin like antibiotic (beta-lactam) plus a low dose of an aminoglycoside such as gentamicin has been the mainstay for treatment of enterococcal endocarditis (an infection of the heart caused by Enterococcal species). It is still considered within the standard of care to use a combination of ampicillin and gentamicin for 6 weeks, or vancomycin and gentamicin for 6 weeks (AHA 2005 Guidelines); however, there are several qualifiers:
- For native valve Enterococcal endocarditis, ampicillin without gentamicin is considered an alternative.
- For prosthetic valve Enterococcal endocarditis, ampicillin plus gentamicin 3mg/kg/24hr in divided doses is recommended.
- This dosing of gentamicin is lower level synergistic dosing.
- The aminoglycoside concentration necessary for synergistic killing of pathogens responsible for infective endocarditis is 1-5 mcg/ml whereas the concentration needed to kill gram negative pathogens is 5-10mcg/ml. (reported by Le and Bayer 2003)
- The use of Once a Day (ODA) or extended interval dosing is absolutely contraindicated.
- These dosages are for persons with normal renal function.
- Renal impairment requires smaller dosing.
- Doses should be adjusted to achieve gentamicin peak serum concentrations of 3-4 mcg/ml, and a trough concentration of less than 1 mcg/ml. These limits are lower than published “laboratory normal ranges” for gentamicin peak and trough concentrations.
- Serum creatinine levels must be monitored at least twice weekly throughout therapy.
- If serum creatinine levels rise significantly, the continued use of gentamicin must be questioned, and alternative therapies instituted.
- If vancomycin is being used with gentamicin, there is an increased risk of nephrotoxicity and subsequent vestibulotoxicity.
Studies in 2007 and 2008 in Europe demonstrated the efficacy of using a combination of ampicillin and ceftriaxone rather than ampicillin and gentamicin for treatment of Enterococcal endocarditis.Gavalda et al reported on 49 patients treated in Spain for endocarditis caused by E. faecalis.
Abad et al (2011) reviewed antimicrobial therapy of sepsis and septic shock, which is often associated with enterococcal endocarditis. They note (citations omitted):
“Similarly, bacteremia from Enterococcus sp continues to be very difficult to treat, given the inherent resistance of enterococci to b-lactam antibiotics. Remarkably, there are few clinical trials that focus on the use of combination therapy for gram-positive bacteremia and sepsis. In fact, the use of initial low-dose gentamicin in the management of suspected S aureus endocarditis is based on in vitro data demonstrating that synergistic doses of aminoglycosides, in combination with antistaphylococcal penicillins or vancomycin, result in more rapid bactericidal activity against S aureus, and on in vivo data from a rabbit model of endocarditis showing more rapid eradication of S aureus from cardiac vegetations. In the same manner, the use of combination therapy for Enterococcus sp is based on a study that showed bactericidal synergism between penicillin G and streptomycin, demonstrated by in vitro time-kill techniques. In the review by Paul and colleagues a small subset of randomized trials that assessed the value of addition of an aminoglycoside in gram-positive infections was included. Three studies assessed staphylococcal endocarditis, 1 study assessed any staphylococcal infection, and 1 study assessed streptococcal endocarditis. Although the use of β-lactam-aminoglycoside treatment is standard practice with these infections, the results in the meta-analysis did not point to a clinical benefit with combination therapy. To our knowledge, there are no randomized controlled trials comparing monotherapy with combination therapy for enterococcal bacteremia. In fact, the data for combination therapy is mostly from retrospective analyses and reviews.” [emphasis supplied]
In our practice, we have encountered several clients who have had enterococcal endocarditis diagnosed and gentamicin used. Unfortunately, the prescribing physician or pharmacy did not understand the concept of synergistic dosing, and administered gentamicin at a higher dose level for many weeks. Not surprisingly, these clients suffered from gentamicin poisoning.