Enterococci are resistant to low concentrations of penicillin (MIC = 2 mg/l) and vancomycin (MIC = 4 mg/l). They appear to be more susceptible to teicoplanin (MIC = 0.5 mg/l), but neither glycopeptide is bactericidal when used alone at 16 times the MIC. Cephalosporins are ineffective. A combination of penicillin, ampicillin, or a glycopeptide with an aminoglycoside is synergistic and bactericidal for strains with low-level gentamicin resistance. Combinations are more effective in sterilizing vegetations in animal models, and improved efficacy has been found in limited clinical studies.

Penicillin is less active in vitro against enterococci than ampicillin, but there have been no studies to suggest a difference in efficacy. Gentamicin will need to be administered for 4 weeks with penicillin G or ampicillin. The risk of ototoxicity can be reduced by ensuring peak levels of 3 mg/l and trough levels below 1 mg/l. A 6-week course may be necessary if symptoms have been present for more than 3 months before treatment. If toxicity prevents completion of aminoglycoside treatment, penicillin should be given for at least 6 weeks. Patients allergic to penicillin or infected by resistant organisms should be treated with a glycopeptide, but vancomycin tends to increase the risk of nephrotoxicity with aminoglycosides. Combinations of teicoplanin and gentamicin are superior to teicoplanin alone in animal models and are recommended clinically. An adequate sustained concentration of teicoplanin may be more effective than intermittent high peaks.

Enterococci showing a high-level resistance to aminoglycosides are not subject to any synergism between penicillin and gentamicin. Up to a quarter of Enterococcus fecalis and half of Enterococcus fecium are in this category. If the organism is resistant to gentamicin and streptomycin, high doses of penicillin or ampicillin given over 8 weeks can be curative in some patients but others will require surgery. Intrinsic penicillin resistance and b-lactamase production are present in increasing numbers of isolates of enterococci, but vancomycin or teicoplanin plus an aminoglycoside can be used to provide synergistic killing. Vancomycin-resistant enterococci are now causing outbreaks of infection in the United States and Europe, often centered in intensive care units. Those of the vanA genotype are resistant to both vancomycin and teicoplanin, and treatment can only be decided in consultation with the microbiology laboratory. If the resistance to aminoglycoside is low level, a combination of vancomycin, penicillin, and aminoglycoside can be tried. Enterococci of the less common vanB genotype have lower-level resistance to vancomycin and remain susceptible to teicoplanin.

Staphylococcus aureus

Endocarditis on a native valve caused by Staph. aureus is usually a rapidly progressive disease with a high mortality (up to 40 per cent). Intravenous drug abusers develop infection on the tricuspid valve which is more amenable to treatment (mortality up to 15 per cent). Almost all isolates are resistant to penicillin, but penicillin G should be used if the organism is susceptible. Flucloxacillin, nafcillin, or oxacillin are effective in disease caused by methicillin-sensitive staphylococci.

Combinations of b-lactam antibiotics and aminoglycosides exert a more rapid bactericidal activity than either drug alone both in vitro and in vegetations in animal models. However, clinical trials using aminoglycosides for the first 2 weeks of treatment failed to show any marked improvement in duration of fever, mortality, or occurrence of complications (BayerJ993). The American Heart Association recommends that gentamicin be used for 3 to 5 days to ensure rapid clearance of the organism and to minimize abscess formation, but then stopped (Wilson et..al 1.99.5). A 2-week course of gentamicin is suggested for prosthetic valve endocarditis.

United Kingdom recommendations are that gentamicin be given for no more than 2 weeks (,S..i.m.,m..o.Qs..et...a.l 1985).

Patients allergic to penicillin should be treated with vancomycin or teicoplanin for 4 to 6 weeks, preferably with aminoglycosides initially. Vancomycin serum concentrations should be 25 to 30 mg/l at peak and 10 mg/l at trough, and teicoplanin should be kept over 20 mg/l if used alone. Gentamicin may not improve outcome of treatment with vancomycin and risks increased nephrotoxicity. However, if the organism is susceptible, a course of at least 3 to 5 days is recommended, particularly if the patient experiences persistent bacteremia, neurological sequelae, or bone metastases (,B.a.y§.L1.9.9.3). The bactericidal activity of glycopeptides is slower than that of penicillins, and they should not otherwise be preferred.

Infection with methicillin-resistant staphylococci must be treated with glycopeptides. Vancomycin (30 mg/kg/day) or teicoplanin (6-12 mg/kg/day) are given for 4 to 6 weeks. Vancomycin alone results in a slow response with up to 50 per cent of blood cultures remaining positive at 1 week. Rifampin (600 mg/day orally) has high activity in vitro and can be given concomitantly. Resistance can develop, but gentamicin can be added as a third drug for 2 weeks.

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