from use in 1% of patients to 7% of patients by 1992). The quantity of vancomycin used per 1000 patient days increased 161-fold between 1978 and 1992. This experience is typical of that at other general hospitals. Such extensive use has had the potential, and now the reality, of selecting strains of vancomycin-resistant nosocomial pathogens (Enterococcus spp. and Staphylococcus hemolyticus) for which alternative therapies are extremely limited.
Enterococci are intrinsically more resistant in vitro to penicillin (MIC, 2.5–5 µg/ml) than are other streptococci (MIC, 0.02–0.08 µg/ml). Since the reports of Hunter (38) in 1947 and of Jawetz et al. (39) in 1950, the capacity of penicillin and an aminoglycoside to act synergistically against enterococci has been known. The bactericidal action of this combination is due to limited penicillin inhibition of bacterial cell wall synthesis that permits enhanced uptake of aminoglycoside, the latter then acting lethally on its ribosomal target (40). Treatment of serious enterococcal infections has involved the use of combined penicillin–aminoglycoside therapy since the 1950s. Originally, the aminoglycoside was streptomycin. By the early 1970s, 25–50% of clinical isolates showed high-level (>2000 µg/ml) resistance to streptomycin and kanamycin. Accordingly, gentamicin was substituted for streptomycin. The penicillin and gentamicin combination proved to be synergistic in vitro against all enterococci tested during the 1970s and provided effective therapy. However, in 1979 the first enterococcus isolate with high-level (>2000 µg/ml) resistance to gentamicin was identified in Paris (41). Subsequently, enterococci with high-level gentamicin resistance and resistance to penicillin–gentamicin synergy have been observed worldwide (42). By the early 1990s, in some centers, >50% of enterococcal isolates showed resistance to penicillin–gentamicin synergy. Among Enterococcus faecium isolates, which prior to 1987 had been uniformly susceptible to gentamicin at 200 µg/ml, in some hospitals as many as 70% of isolates showed high-level resistance to gentamicin.
High-level resistance to streptomycin is due either to plasmid-mediated (adenylyltransferase) modification of the drug or, occasionally, can be due to a chromosomal mutation that alters ribosomal affinity for streptomycin (42). High-level gentamicin resistance is based on enzymatic modification of the aminoglycoside by a plasmid-encoded bifunctional enzyme with both 2"-phosphotransferase and 6'-acetyltransferase activities (43). Aminoglycoside modification by this bifunctional enzyme prevents penicillin (or vancomycin) synergy with all available aminoglycosides