Emerging antimicrobial resistance and the immunocompromised host.

Infections caused by gram-positive bacteria have become the most important cause of infectious morbidity among some groups of immunocompromised patients over the last decade. Among the gram-positive bacteria, the emerging problems of resistance to antimicrobial agents include the development of resistance to beta-lactam and aminoglycoside drugs among the enterococci, making synergistic bactericidal therapy impossible; the continued spread of methicillin-resistant staphylococci; resistance to both vancomycin and teicoplanin among enterococci and staphylococci; the emergence of intrinsically vancomycin-resistant species as important pathogens; and resistance to the fluoroquinolones. It is unlikely that new therapeutic classes of antibacterial drugs will be released this decade. Therapeutic alternatives now include unusual combinations of antibiotics to which the strains may appear resistant but that exhibit synergistic activity, although this area has not yet been thoroughly explored. Therefore, control of emergence and spread of resistance through the more judicious use of existing agents, good infection control practices, and the use of imaginative combination therapy for those infected with resistant strains seem to be our best alternatives.

Constitutively vancomycin-resistant Enterococcus faecium resistant to synergistic beta-lactam combinations.

Vancomycin resistance among enterococci has recently been recognized. Synergy between vancomycin and penicillin has been shown in vitro for isolates of Enterococcus faecium resistant to both of these antibiotics. We describe three isolates of vancomycin-resistant E. faecium which demonstrate unique phenotypic characteristics. The isolates exhibited high-level resistance to both vancomycin and teicoplanin, consistent with the VanA phenotype. However, resistance in these isolates could not be induced or cured, and mating experiments failed to detect a transfer of resistance. The combination of vancomycin and penicillin did not significantly change the MIC of penicillin for any of the three isolates. Immunoblotting with polyclonal anti-VanB antibody showed no reaction with the cellular proteins of these strains. Probing with a vanA oligonucleotide revealed hybridization with chromosomal but not plasmid DNA. The mechanism of constitutive resistance of those strains remains unclear. A second mutational change, perhaps involving PBP 5, may explain the presence of resistance to synergistic combination penicillin-vancomycin therapy. In vitro evaluation of penicillin-vancomycin should be carried out in all clinical cases where this therapeutic regimen is being considered.

Enterococcal resistance to vancomycin and related cyclic glycopeptide antibiotics.

Enterococci belonging to various species resistant to vancomycin and related cyclic glycopeptide antibiotics have been isolated from hospitalized patients in France, the UK and the USA. All such strains examined display inducible synthesis of a membrane protein associated with resistance. The mechanism by which the membrane protein acts has not been definitively established, but it may block the access of the antibiotic to its peptidoglycan target. That the protein could be a bypass enzyme has not been ruled out. Transfer of glycopeptide resistance by conjugation to either Enterococcus faecium or Enterococcus faecalis and by transformation of Streptococcus sanguis Challis has been reported. The structural and regulatory genes encoding this resistance can be localized on plasmid and, apparently, chromosomal DNA. The plasmids encoding this resistance appear to differ from each other and have variable host ranges, but share at least some DNA sequence homology.