Enterococci account for 5-15% of cases of bacterial endocarditis.1 They are the most resistant bacteria commonly encountered in this type of infection, which is still associated with a mortality of 20-30%.2 The treatment regimen for enterococcal endocarditis recommended by the British Society for Antimicrobial Chemotherapy and the American Heart Association is a synergistic bactericidal combination of a penicillin or glycopeptide with an aminoglycoside, usually gentamicin or streptomycin.3,4 However, enterococci can acquire high level resistance to aminoglycosides, which abolishes this synergy.1 Enterococci can also exhibit high level resistance to penicillin or to glycopeptides.1 Our laboratory undertakes testing of bacteria from cases of endocarditis as a routine service; we analysed resistance among isolates from 120 cases of enterococcal endocarditis, received over 27 months.
Methods and results
Results of tests for antibiotic susceptibility were analysed for enterococci referred from patients with a clinical diagnosis of endocarditis between January 1995 and March 1998. Isolates exhibiting high level resistance to gentamicin or streptomycin were defined as those where the concentration of antibiotic required to inhibit growth on laboratory media (minimum inhibitory concentration) exceeded 2000 mg/l.1 Resistance to other antibiotics was defined according to criteria specified by the British Society for Antimicrobial Chemotherapy.5
The isolates, which were from 60 UK hospitals, comprised 106 Enterococcus faecalis, 13 E faecium, and one E avium. The table shows the major resistance characteristics of these isolates. Overall, 26% of isolates had high level resistance to both gentamicin and streptomycin (22% of E faecalis isolates; 62% of E faecium isolates). A further 28 E faecalis isolates showed high level resistance to either gentamicin (7 isolates) or streptomycin (21 isolates); four E faecium isolates and the sole E avium isolate showed high level resistance to streptomycin but not to gentamicin.
All the E faecalis isolates remained susceptible to ampicillin (minimum inhibitory concentration 0.5-4 mg/l for 105 isolates and 8 mg/l for 1 isolate), but 6 were resistant to vancomycin, with 2 exhibiting cross resistance to teicoplanin. One isolate resistant to glycopeptides also had high level resistance to both gentamicin and streptomycin. The 13 E faecium isolates were all resistant to ampicillin (>8 mg/l), with 3 also resistant to vancomycin but not teicoplanin. Two of these vancomycin resistant isolates showed high level resistance to gentamicin and streptomycin.
Comment
Treatment for enterococcal endocarditis comprises a bactericidal synergistic combination of a penicillin (usually ampicillin or benzylpenicillin) or glycopeptide with an aminoglycoside, usually gentamicin or streptomycin for at least 4 weeks.2,3 It is therefore disturbing that 26% of the enterococci in this study were highly resistant to both gentamicin and streptomycin. Aminoglycosides have no therapeutic benefit in infections involving such strains, and unnecessarily expose patients to possible ototoxic or nephrotoxic side effects. A further 28% of the isolates were highly resistant to either gentamicin or streptomycin, emphasising the value of testing both of these compounds in determining appropriate treatment.
Current guidelines recommend that endocarditis caused by enterococci with high level resistance to aminoglycosides should be treated with high dose amoxycillin or ampicillin for 6-12 weeks.2,3 However, 11% of the enterococci were E faecium, which typically is resistant to ampicillin. Moreover, amoxycillin or ampicillin would be unsuitable for patients allergic to penicillin. This latter constraint applies to other proposed regimens that combine ampicillin with imipenem or ciprofloxacin. Although glycopeptides may be considered in place of penicillin, the finding of glycopeptide resistance in several isolates, including three of the E faecium isolates, means that their efficacy cannot be guaranteed.
The picture revealed is disturbing, with frequent resistance to the recommended synergistic combinations. Evaluation in endocarditis of unconventional regimens—for example, ampicillin plus carbapenems, ampicillin plus ciprofloxacin, or ciprofloxacin plus co-trimoxazole—is desirable, although the use of such broad spectrum agents may risk selecting resistance in the body microflora. Also desirable is early evaluation, in endocarditis, of novel narrow spectrum anti-Gram positive agents, such as streptogramins, oxazolidinones, and everninomycins.
Table.
Resistance of enterococci from 120 cases of endocarditis to aminoglycosides and to cell wall active antibiotics
| Antibiotic | No (%) of isolates showing resistance
|
|||
|---|---|---|---|---|
| All species (n=120) | E faecalis (n=106) | E faecium (n=13) | E avium (n=1) | |
| Aminoglycosides: | ||||
| Gentamicin and streptomycin | 31 (26) | 23 (22) | 8 (62) | 0 |
| Gentamicin only | 7 (6) | 7 (7) | 0 | 0 |
| Streptomycin only | 26 (22) | 21 (20) | 4 (31) | 1 |
| Neither aminoglycoside | 56 (47) | 55 (52) | 1 (8) | 0 |
| Cell wall active agents: | ||||
| Ampicillin | 13 (11) | 0 | 13 (100) | 0 |
| Vancomycin and teicoplanin | 2 (2) | 2 (2) | 0 | 0 |
| Vancomycin, but not teicoplanin | 8 (7) | 4 (4) | 3 (23) | 1 |
Acknowledgments
We thank Dr Ty Pitt and his colleagues in the Epidemiological Typing Unit at the Laboratory of Hospital Infection in the Central Public Health Laboratory for confirming the species of the isolates studied.
Footnotes
Funding: Public Health Laboratory Service.
Competing financial interest: APJ and DML have received financial support from Rhône-Poulenc Rorer for work on novel streptogramins and for attending conferences.
References
- 1.Murray BE. The life and times of the enterococcus. Clin Microbiol Rev. 1990;3:46–65. doi: 10.1128/cmr.3.1.46. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Prasad A, Fraser AG. Prevention of infective endocarditis: enthusiasm tempered by realism. Br J Hosp Med. 1995;54:341–347. [PubMed] [Google Scholar]
- 3.Working Party of the British Society for Antimicrobial Chemotherapy. Antibiotic treatment of streptococcal, enterococcal, and staphylococcal endocarditis. Heart. 1998;79:207–210. [PMC free article] [PubMed] [Google Scholar]
- 4.Wilson WR, Karchmer AW, Dajani AS, Taubert KA, Bayer A, Kaye D, et al. Antibiotic treatment of adults with infective endocarditis due to streptococci, enterococci, staphylococci, and HACEK microorganisms. JAMA. 1995;274:1706–1713. [PubMed] [Google Scholar]
- 5.Working Party of the British Society for Antimicrobial Chemotherapy. A guide to sensitivity testing. J Antimicrob Chemother. 1991;27(suppl D):1–50. [PubMed] [Google Scholar]