Methicillin-resistant Staphylococus aureus and vancomycin-resistant enterococci: therapeutic realities and possibilities

doi:10.1016/S0140-6736(96)11192-2

The Lancet

Volume 349, Issue 9069, 28 June 1997, Pages 1901-1906

https://doi.org/10.1016/S0140-6736(96)11192-2 Get rights and content

Summary

During the past decade much effort has been devoted worldwide to limiting the spread of methicillin-resistant Staphylococcus aureus. However, the recent emergence of almost untreatable vancomycin-resistant enterococci has led to a new and unexpected public health problem in hospitals and the community. Moreover, the threat of transfer of glycopeptide resistance to S aureus means that development of alternative antimicrobial strategies has become urgent. Whereas major advances have been made in our understanding of methicillin and vancomycin resistance mechanisms, we still need to identify the sources and reservoirs of the genetic determinants of resistance and to discover how they disseminate in the environment. The outcome of the battle between antimicrobials and bacteria is still uncertain, but the challenge is worth meeting.

Section snippets

Emergence of MRSA

By the end of the 1950s, at least 85% of S aureus strains were resistant to penicillin in the USA and France.⁷ The introduction in 1959 of the new semisynthetic penicillins methicillin and oxacillin, which are not inactivated by penicillinase, was expected to give physicians a break from the problem of resistance. However, MRSA was detected sporadically in Europe in 1961,⁸ and during the last 20 years the proportion of MRSA in hospitals has fluctuated in European countries from 1–2% or less in

Molecular mechanisms of methicillin resistance in S aureus

The main bacterial targets of the β-lactam antibiotics in S aureus are the so-called penicillin-binding proteins (PBPs), which have a functional role in the biosynthesis of the bacterial cell wall through transpeptidase and carboxypeptidase activities. The antibacterial effect of β-lactams is mediated primarily by inactivation (after covalent bond formation) of the high-molecular weight PBPs (PBP1, 2, and 3), which have the highest affinity for β-lactams antibiotics.¹¹ All the strains of S

Present and future treatments of MRSA infections

Treatment of MRSA infections is sometimes limited to either vancomycin or teicoplanin since isolates of MRSA are often resistant to other antistaphylococcal agents such as aminoglycosides, macrolides, and fluroquinolones.10, 17 However, although vancomycin is still considered the best antimicrobial agent for infections due to MRSA, its moderate extravascular diffusion and its relatively slow bactericidal effect¹⁸ may partly lower its effectiveness in vivo. Attempts have been made to combine

Epidemiology of VRE, a recently identified nosocomial pathogen

In 1991, the report by the Nosocomial Infections Surveillance System in the USA ranked enterococcus as the second most common agent of nosocomial infections for 1986 to 1989.³³ During the past 15 to 20 years, an increasing number of strains of E faecium, which is much less common than E faecalis in clinical material, became resistant to ampicillin and other penicillins, and acquired high-level resistance to aminoglycosides.³⁴ It is worth noting that high-level resistance to β-lactam antibiotics

Molecular mechanisms of vancomycin resistance in enterococci

Vancomycin and teicoplanin are high-molecular-weight molecules that inhibit cell-wall synthesis of gram-positive bacteria by interacting with the C-terminal D-alanyl-D-alanine (D-Ala-D-Ala) of the pentapeptide of the peptidoglycan precursors.⁴⁰ The interaction between the D-Ala-D-Ala terminus and glycopeptide prevents transglycosylation and transpeptidation reactions needed for the normal polymerisation of peptidoglycan. In VRE, early data provided evidence for a set of genes, harboured on a

Therapeutic options for VRE infections

It is generally admitted that treatment of systemic enterococcal infections is based on the synergistic bactericidal combination of a cell-wall-active antibiotic (such as amoxicillin or a glycopeptide) plus an aminoglycoside, usually gentamicin or streptomycin.⁴² The knowledge of the level of resistance to gentamicin expressed by the clinical strain of enterococcus is thus essential for the achievement of a therapeutic effect. Indeed, a high-level gentamicin resistance abrogates the synergism

Conclusion

The emergence of multiple drug resistance among S aureus and enterococci is a serious public health issue. If recent years have seen major advances in our understanding of the mechanisms of both methicillin resistance in S aureus and glycopeptide resistance in enterococci, the origin of the mecA and vanA/B resistance genes has yet to be established. Moreover, transfer of enterococcal glycopeptide resistance to S aureus is a main concern since it has been demonstrated under laboratory conditions

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