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Published on 1 January 2005

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MRSA: the French perspective

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Xavier Bertrand
PhD
Microbiologist and Infection Control Practitionner
Service d’Hygiène Hospitalière et d’Epidémiologie Moléculaire (Infection control Department)
CHU Besançon
France
E:xbertrand@chu-besancon.fr

Staphylococcus aureus is a ubiquitous bacterium, often found in the human microflora, that causes infection when the immune system becomes compromised. Although S aureus can be found in different parts of the body, anterior nares are the main ecological reservoir in humans.(1) S aureus can cause a variety of infections, such as superficial lesions, systemic and life-threatening infections and toxinoses.(2) This microorganism has a great capacity to adapt to antibiotics, and with time it has become resistant to multiple antimicrobial agents. Methicillin- resistant S aureus (MRSA), first described in 1961 in the UK,(3) results from the acquisition of an exogenous gene (mecA), which most probably originated from Staphylococcus sciuri.(4,5) The mecA gene encodes an additional penicillin-binding protein with low affinity for beta-lactam antibiotics.(6)

Over the last four decades, MRSA has spread throughout the world and become highly endemic in many geographical areas.(7,8) This pathogen causes severe morbidity and mortality in hospitals worldwide.(9,10) Initially, MRSA nosocomial infections were mainly detected in large tertiary hospitals and in intensive care units (ICUs), where colonised and infected patients as well as colonised healthcare workers were a significant source of cross-contamination. MRSA is currently one of the most common pathogens in hospitals of different sizes and types (acute, chronic and long-term care facilities) worldwide.(11,12)

MRSA today
It is now well established that colonised and infected inpatients are the major reservoir of MRSA and that the transient carriage of this pathogen on the hands of hospital staff is the most common mechanism of patient-to-patient transmission.(13) After acquisition, MRSA strains multiply on the contaminated tissue and may then colonise and possibly infect the patient. This progression to symptomatic infection is promoted by the existence of a site of entry, such as a wound or an indwelling venous or urinary catheter.

Many studies have identified individual risk factors for MRSA infection. These factors can be divided into three categories:

  • Factors reflecting the number of potential reservoirs and the number of opportunities for cross-transmission.
  • Factors associated with the immunological status of the patient.
  • Factors related to the antibiotic treatment used to treat the patient.(12,14)

The prevalence of MRSA in hospitals continues to increase worldwide.

The European Antimicrobial Resistance Surveillance System (EARSS) reported significant differences in the frequency of MRSA in blood isolates among European countries (see Figure 1). The prevalence was lower (<2%) in Scandinavia, the Netherlands and Iceland, intermediate in central Europe (5–20%) and higher (>30%) in Southern Europe, the UK and Ireland.

[[HPE18_fig1_17]]

In the USA, the National Nosocomial Infections Surveillance (NNIS) system reported a dramatic increase in the frequency of methicillin resistance among S aureus isolated from intensive care patients between January 1998 and January 2004.

MRSA in France

Prevalence of MRSA
The prevalence of MRSA in France is among the highest in the European Union,(15) and a recent publication by a regional surveillance network showed that occurrence continued to increase between 1996 and 2000.(8) In blood cultures (the most clinically significant specimen) the proportion of MRSA in S aureus ranges from 30% to 40%. The situation in France is worrying, with the incidence of patients colonised and/or infected with MRSA (with a clinical specimen testing positive) ranging from 0.6 to 0.8 per 100 patients admitted,(16) and from 0.5 to 0.8 per 1,000 days of hospitalisation. MRSA is responsible for 6–10% of nosocomial infections and the frequency of resistance to methicillin among S aureus is higher than 50% for nosocomial infections only. MRSA is mainly implicated in surgery site infections, urinary tract infections and bacteraemias. Among multidrug-resistant bacteria, MRSA is the most frequently responsible for infections (25,000–40,000 infections per year), which calls for the implementation of a control programme in all hospital facilities.

MRSA control measures
Since the early 1990s, most ICUs (in which the risks associated with MRSA are very high) have implemented prevention measures, which have proven to be effective.(17,18) The recommendations published by the CTIN (Technical Committee for Nosocomial Infections) established MRSA as a matter of priority, suggesting that patients colonised/infected with MRSA should be identified and placed in isolation, and that complementary measures should be implemented, including screening for carriers upon admission and during hospitalisation and treating human reservoirs (see Table 1). Hand hygiene is recognised as being the best way of preventing the cross-transmission of microorganisms. Hand hygiene procedures recommended in France are washing or rubbing with alcohol-based solutions or gels. Rub-in hand disinfection, however, appears to be the best technique. It has several benefits, including better compliance and tolerance. Furthermore, it has been proven to decrease infection rates significantly as a result of improved compliance.(19) The implementation of a stringent programme for MRSA control in French hospitals has led to a decrease in the proportion of MRSA among clinical isolates of S aureus.(7,18) The report of an increase in MRSA prevalence in a regional network,(8) however, contradicts these results. The reason for this discrepancy is that national guidelines were not widely distributed to hospitals until 1999. Thus, one can assume that control measures have not been implemented until recently and that the impact on the reduction of MRSA has been delayed, as was recently shown in other countries.(20) Numerous studies suggest that the use of antimicrobials participates in MRSA spread.(21–24) This has been demonstrated in countries with very low MRSA incidence (particularly Scandinavian countries), where antimicrobial use is lower.(25) Thus, evidence supports the implementation of programmes to control and improve antibiotic use when infection control fails.

[[HPE18_table1_19]]

Resurgence of multidrug-susceptible MRSA
All MRSA strains isolated in French hospitals before 1990 were homogeneously resistant to methicillin and resistant to an increasing number of major classes of antibiotics, including aminoglycosides, fluoroquinolones and macrolides. In 1991, gentamicin-susceptible MRSA clones first emerged in a number of Parisian hospitals,(26–28) and subsequently spread to other regions. MRSA isolates are now frequently susceptible to all non-b-lactam antibiotics tested (except fluoroquinolones).(29) In other countries, such as Germany,(30) Finland(31) and Greece,(32) a similar trend of emergence and spread of MRSA with susceptibility to aminoglycosides, macrolides and other antibiotics has been observed. The switch from gentamicin-resistant MRSA to gentamicin- susceptible MRSA clones has been attributed to changes in antibiotic use.(27,33) However, this hypothesis has not been confirmed, and aminoglycoside use does not appear to play a major role in the dissemination of more susceptible strains.(29,34) Instead, fitness benefit (ie, growth advantage) may be related to the spread of these new clones.(35,36) At a practical clinical level, the continuing evolution of MRSA provides an opportunity for the controlled reintroduction of antibiotics, particularly aminoglycosides (instead of glycopetides), in anti-MRSA therapies.

Vancomycin resistance
In the past 20 years, vancomycin has become the drug of choice in the treatment of MRSA infections. In 1996, the first clinical vancomycin-nonsusceptible MRSA (GISA: glycopeptide intermediate-resistant S aureus) was isolated in Japan.(37) Although this type of strain has now been isolated in French hospitals, it remains rare, and its emergence has not significantly modified the problem of MRSA.(38–40) Most GISA described in France were thought to belong to “old” clones (gentamicin- resistant) that have been almost completely replaced with gentamicin- susceptible clones.(7,26,35) However, the recent discovery of vanA-mediated glycopeptide resistance in MRSA(41–43) may change the epidemiological picture of the glycopeptide resistance of this pathogen. It is highly likely that these newly identified strains, so-called VRSA (vancomycin- resistant S aureus), will represent a larger threat than GISA in terms of dissemination.

In France, vancomycin-resistant enterococci (VRE) are rarely isolated. The likelihood of an in-vivo transfer of the vanA operon from Enterococcus to S aureus (which occurred in the three reported cases of VRSA) is low compared with countries where VRE are endemic, such as the USA, where this pathogen was recovered. However, given the major threat presented by this pathogen, the emergence of this new type of resistance must be carefully monitored.

Community-acquired MRSA
Until recently, the problem of MRSA in France was limited to hospitals, and the great majority of MRSA acquisition occurred within hospitalisation units. The recent emergence of community-acquired MRSA (CA-MRSA), in France and worldwide, in patients with no recognised risk factors for MRSA infection is particularly worrying.(44–46) Indeed, the French Reference Centre for Staphylococcal Toxaemia found that CA-MRSA infections in France were caused by a single clone producing the Panton–Valentine leukocidin.(44,46) A specific surveillance of CA-MRSA infections is required to quantify the impact of this new kind of pathogen.

The impact of MRSA
Infection with MRSA increases the cost of hospital stay and the risk of mortality. The higher cost of treating MRSA infections is mainly due to the longer hospital stay of patients infected with MRSA, compared with patients with standard S aureus infections. In a meta-analysis study, the death rate for patients with MRSA bacteraemia was estimated to be about double that due to MSSA.(47) Moreover, MRSA surgical infections lead to an increase in mortality, hospital charges and length of stay, compared with MSSA.(48) Reducing the incidence of MRSA would reduce the mortality and public costs of S aureus infections.(49)

Many different infection control strategies have been implemented, but no single strategy has been accepted as adequate for all hospitals. However, although some healthcare professionals suggest that efforts to control MRSA are counterproductive,(50) it is now clearly established that MRSA control is cost-effective, in particular in high-risk units.(20,51,52) It seems that there is no level of MRSA prevalence for which active control measures are not warranted. Safety measures to prevent the transmission of multidrug-resistant microorganisms such as MRSA should find their way into all hospitals, with the ultimate goal of improving patient safety.

Conclusion
To combat the MRSA epidemic, healthcare workers and public health authorities must understand the importance of hospital hygiene protocols and antibiotic policies, as well as the mechanisms of regional spread of MRSA throughout hospitals.(53)

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