Glycopeptide resistance in Staphylococcus aureus

Stephanie J. Dancer*

Scottish Centre for Infection & Environmental Health, Clifton House, Clifton Place, Glasgow G3 7LN, UK

Keywords: glycopeptide-resistant Staphylococcus aureus, GRSA

Sir,

The recent leading article regarding glycopeptide-resistant Staphylococcus aureus (GRSA) missed an opportunity to strengthen concern over the increasing resistance among staphylococci.1 Transfer of vanA coding for glycopeptide resistance in S. aureus will not remain a rare occurrence—it has already happened again in the USA.1,2 It is possible that there are now staphylococcal populations that are becoming increasingly primed for such a molecular event, just as suggested for glycopeptide-intermediate S. aureus (GISA).3 Antimicrobial consumption is presumed to be the driving force behind antimicrobial resistance, so future GRSA are probably inevitable, given that glycopeptides are still first choice for invasive methicillin-resistant S. aureus (MRSA) infections. Such pressure will encourage the selection of resistant mutants in true Darwinian fashion. Few countries have demonstrated a reduction in antibiotic consumption, and there is no guarantee that these decreases can be sustained. In any case, once the molecular basis for a specific resistance mechanism has been established, it is not easily lost.

There is, however, no evidence for future prospects regarding GRSA other than consideration of the past. Following the first report 5 years ago, the global spread of GISA is now apparent, with documented outbreaks, treatment failures and deaths.4 This mirrors the situation with MRSA over the last two decades, and similarly, penicillin-resistant S. aureus during the 1950s and 1960s. It is not unreasonable to suspect that GRSA will ultimately follow the same trend. Resistance mechanisms do not appear to affect epidemiological characteristics in staphylococci. For the UK, we cannot assume that simply because GISA has not yet flourished, GRSA will not either. It has taken 30 years for MRSA to establish itself in every UK hospital, so it is premature to regard GISA as only a sporadic problem.1 There has recently been another GISA (vancomycin MIC 8 mg/L) reported in Scotland, which was responsible for the death of a previously fit woman in her fifties.5 There have almost certainly been others, but UK laboratories could be missing GISA at the present time due to technical difficulties.3,4

There may be some truth in the statement that GRSA represents untreatable infection.1 Patients with GISA infections do not usually demonstrate a favourable outcome, despite the fact that their strains are only ‘intermediately’ resistant to glycopeptides.4,5 Patients with GRSA infections are hardly likely to fare any better. It is known that patients with MRSA infections do less well than those with methicillin-susceptible S. aureus (MSSA) infections; similarly, patients with S. aureus demonstrating reduced susceptibility to vancomycin (MIC 4 mg/L) have a higher mortality compared with controls infected with vancomycin-susceptible MRSA (attributable death 63% versus 12%).4 Losing glycopeptide antibiotics as a treatment option for resistant staphylococci appears to have a significant clinical impact.1,4,5

There are problems with the other antibiotics available for treating resistant staphylococci. Chloramphenicol, rifampicin and fusidic acid are not always well tolerated and will select for resistant strains if used alone. Linezolid and quinupristin–dalfopristin are expensive, with serious adverse effects and resistance already documented. Tetracyclines and trimethoprim are impotent for serious infections and also cannot be used alone. Trimethoprim–sulfamethoxazole, itself potentially toxic, has been tried against GRSA but can hardly be considered to be our main defence against a potential global onslaught of GRSA.2 On paper, it seems as though there are still drugs available for resistant staphylococci; in reality, there are not.1 As for new agents under development, the inescapable conclusion regarding their outcome will be the same as for almost all other antibiotics, namely resistance.

In the absence of effective chemotherapy, confirmed GRSA should indeed focus our attention upon better infection control, quicker laboratory identification and research.1 Unfortunately, given our lack of success in controlling MRSA in the UK, there cannot be much optimism regarding the control of GRSA. It is already known that GISA strains can spread between patients. Healthcare staff do not necessarily need a stronger incentive to comply more vigorously with infection control procedures—NHS hospitals are dirty, cluttered and overcrowded, with deteriorating fabric, understaffing and inadequate isolation facilities. Patients are moved all over the hospital to accommodate a constant flow of new admissions. These conditions are not conducive to effective infection control. Furthermore, society itself has witnessed an erosion of hygiene standards due, perhaps, to the complacency emanating from the provision of antimicrobials. It does not help the proponents of infection control when managers and policy-makers do not really understand hygiene.

As for research initiatives, these require money and commitment, neither of which is universally apparent with the dearth in funding clinical microbiology. The current situation with resistant staphylococci will worsen before alternative strategies are found. UK laboratories are under increasing pressure with staffing shortages and budgetary restraints, and lack the infrastructure for more rapid molecular tests. Even the microbiologists cannot agree on control policies.

GISA have a whole array of reorganized genes in order to express their resistance phenotypes.4 This constitutes a heavy metabolic load, which is aptly demonstrated by their reluctance to grow in vitro. They have little difficulty, however, in colonizing and infecting patients, and the clinical failures reported are not necessarily due to simple failure of antibiotic therapy.4 There appears to be a clear genetic link between the differential regulation of resistance factors and virulence determinants, including adhesion, in these ‘intermediately resistant’ strains.4 GRSA, with one extra plasmid, has an as yet unknown potential for pathogenicity. Confirmation of the Panton–Valentine leucocidin (PVL) gene in MRSA provides further evidence that antimicrobial resistance cannot be divorced from pathogenicity, so there is no reason why GRSA could not emerge with this, or other, virulence determinants.6 Such strains do not have to be hospital acquired; indeed PVL isolates arise predominantly in the community.6 The two GRSA strains in the USA came from ambulatory patients.2

It is time to stop debating whether increasing resistance in staphylococci is a problem or not. We should consider the half a century of data that we have on staphylococcal epidemiology and antimicrobial resistance, and take action while we can. It is becoming even more important to convince healthcare managers of the need to take infection control seriously. Every patient spared MRSA is a GISA or GRSA risk alleviated, with less risk of spread to others and/or into the environment. It has already been said that the development of glycopeptide resistance in S. aureus is a potential public health disaster.

Footnotes

* Corresponding author. Tel: +44-141-300-1100; Fax: +44-141-300-1172; E-mail: stephanie.dancer{at}scieh.csa.scot.nhs.uk Back

References

1 . Johnson, A. P. & Woodford, N. (2002). Glycopeptide-resistant Staphylococcus aureus. Journal of Antimicrobial Chemotherapy 50, 621–3.[Free Full Text]

2 . Centers for Disease Control and Prevention. (2002). Public health dispatch: vancomycin-resistant Staphylococcus aureus-Pennsylvania, 2002. Morbidity and Mortality Weekly Report 51, 902–3.[Medline]

3 . Hussain, F. M., Boyle-Vavra, S., Shete, P. B. & Daum, R. S. (2002). Evidence for a continuum of decreased vancomycin susceptibility in unselected Staphylococcus aureus clinical isolates. Journal of Infectious Diseases 186, 661–7.[CrossRef][ISI][Medline]

4 . Walsh, T. R. & Howe, R. A. (2002). The prevalence and mechanisms of vancomycin resistance in Staphylococcus aureus. Annual Reviews of Microbiology 56, 657–75.[CrossRef]

5 . Dancer, S. J. (2002). Glycopeptide-intermediate Staphylococcus aureus (GISA). SCIEH Weekly Report 36, 321.

6 . Baba, T., Takeuchi, F., Kuroda, M., Yuzawa, H., Aoki, K., Oguchi, A. et al. (2002). Genome and virulence determinants of high virulence community-acquired MRSA. Lancet 359, 1819–27.[CrossRef][ISI][Medline]





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