Intended for healthcare professionals

Clinical Review

Meticillin resistant Staphylococcus aureus in the hospital

BMJ 2009; 338 doi: https://doi.org/10.1136/bmj.b364 (Published 12 February 2009) Cite this as: BMJ 2009;338:b364
  1. Jan Kluytmans, consultant microbiologist and head of infection control1, professor of medical microbiology2,
  2. Marc Struelens, head of the department of microbiology3, director of Laboratoire de Référence des Staphylocoques4, professor of medical microbiology5
  1. 1Laboratory for Microbiology and Infection Control, Amphia Hospital Breda, 4800 RK Breda, Netherlands
  2. 2Department of Medical Microbiology and Infection Control, VU University Medical Center Amsterdam, 1081 HV Amsterdam, Netherlands
  3. 3Department of Microbiology Hopital Erasme, 1070 Brussels, Belgium
  4. 4Laboratoire de Référence des Staphylocoques, Hopital Erasme, 1070 Brussels, Belgium
  5. 5Department of Microbiology and Immunology, Faculté de Médecine, Université Libre de Bruxelles, 1070 Brussels, Belgium
  1. Correspondence to: J Kluytmans jankluytmans{at}gmail.com

    Summary points

    • Meticillin resistant Staphylococcus aureus (MRSA) is now a major cause of disease—in the US in 2005 more deaths were caused by MRSA than by HIV

    • In addition to the well established hospital associated MRSA strains, new virulent strains have recently appeared in the general population

    • Molecular technologies can rapidly detect MRSA but their cost effectiveness is unclear

    • MRSA can be controlled by strict adherence to multifaceted strategies, including screening and transmission based precautions

    • Clinicians must be aware of MRSA in community infections of skin and soft tissues and use a low threshold for microbiological testing

    • Vancomycin is the standard treatment for serious MRSA infections. Alternative new drugs include linezolid, daptomycin, and tigecycline, which should be used with specialist advice

    The burden of disease from meticillin resistant Staphylococcus aureus (MRSA) infections is high. Around 100 000 invasive MRSA infections occurred in 2005 in the United States, and the number of associated deaths was about 19 000—more than that for HIV.1 The epidemiology of MRSA has changed recently—infections are no longer confined to the hospital setting, but also appear in healthy people in the community with no established risk factors for acquiring MRSA. These community associated MRSA strains differ from hospital associated strains.2 Mathematical models show that MRSA has a high potential to become endemic in the community.3 The recent emergence of community acquired MRSA in skin and soft tissue infections calls for increased awareness among general and emergency room practitioners and a lower threshold for microbiological testing. Strategies to control hospital associated MRSA work in lower prevalence settings and may work in settings with medium to high endemic levels of hospital associated MRSA.4

    Sources and selection criteria

    We used our personal archives and also searched PubMed and the Cochrane Library (1 January 2002 to 1 July 2008) using the terms “MRSA” or “methicillin resistant Staphylococcus aureus”, with the limits “meta-analysis and randomised controlled trial”. We also reviewed the current guidelines from the US Centers for Disease Control; the Joint Working Party of the British Society for Antimicrobial Chemotherapy, Hospital Infection Society, and Infection Control Nurses Association; the Dutch Working Party on Infection Control; the Dutch Working Party on Antimicrobial Use; and the Belgian Superior Health Council. We used evidence based recommendations when available and recommendations from experts when not.

    What is MRSA and why has it become a problem?

    MRSA produces penicillin binding protein 2a, which confers resistance to all β lactam antibiotics. The gene encoding this protein is carried on a mobile genetic element, the staphylococcal cassette chromosome mec (SCCmec), of which five different types have been identified.

    MRSA was first reported in 1961, shortly after meticillin became available. However, it took several decades before it became a problem. For example, in the US and the United Kingdom the proportion of S aureus strains causing bacteraemia that were meticillin resistant started to increase around 1990, and by the start of the 21st century about half of the strains causing bacteraemia were resistant.5 At present, hospital acquired MRSA is globally endemic except in Scandinavian countries and the Netherlands, where it is controlled by extensive measures. The worldwide emergence of MRSA is mainly the result of the extensive spread of a limited number of strains in hospitals, which are high risk settings for MRSA infection. Staphylococci spread easily between humans, either directly or indirectly by contact with healthcare workers or a contaminated environment. Because they are highly resistant to drying, staphylococci can survive for months on fomites. Staphyloccocus aureus is an opportunistic pathogen that mainly infects patients who have had surgery or who have invasive devices (such as intravascular catheters). Outbreaks of staphylococci are common in these patients and can be difficult to contain.

    New strains

    Recently, new strains of S aureus with diverse genetic backgrounds have acquired the meticillin resistance cassette because of the emergence of smaller and more easily acquired cassettes (types IV and V).2 5 These community acquired strains of MRSA successfully compete with susceptible strains outside of the hospital and can cause epidemics in closed communities and healthcare institutions.

    Mortality, morbidity, and healthcare costs

    A recent population based survey in Canada found a higher mortality associated with bacteraemia caused by MRSA rather than meticillin sensitive S aureus (MSSA) (39% v 24%) in hospital settings,6 although others could not confirm this.7 Observational cohort studies have consistently found that MRSA infection is associated with excess healthcare costs and prolonged hospital stay in surgical and critically ill patients, after adjusting for comorbidities and hospital events before infection.8 In addition, in two cohort studies from Canada and the UK, MRSA did not replace MSSA but accounted for increasing rates of S aureus bacteraemia.6 7 Two surveys of all US hospitals estimated the occurrence and effects of S aureus infections over time.9 10 Infections increased from 258 000 in 1998 to 480 000 in 2005 (fig 1). In 2003, the associated incremental costs of staphylococcal disease were around $14.5bn (£10.3bn; €11bn), and nearly 60% of the infections were caused by MRSA. Therapeutic options for MRSA are limited, have more side effects, and are more costly than standard treatment with β lactam antibiotics.11

    Figure1

    Fig 1 Trends in S aureus infections in all US hospitals from two independent surveys and associated incremental costs9 10

    Who gets MRSA infection (table 1)?

    Most carriers of S aureus, both hospital inpatients and others, are healthy asymptomatic people without evident infection.12 In hospitals where MRSA is endemic, patients risk being colonised by spread from other patients or healthcare workers. Colonisation with S aureus in hospital is a risk factor for subsequent infection.12 A recent study followed patients who carried MRSA, and during one year 23% developed at least one infection with MRSA.13 In a population survey, groups at increased risk for invasive S aureus infections were those with dialysis dependence, organ transplantation, HIV infection, cancer, or diabetes.6 In hospital, invasive infections are most common in patients undergoing surgery or those with indwelling medical devices.9 10

    Table 1

     Characteristics of hospital associated MRSA compared with community associated MRSA*

    View this table:

    A new type of community acquired MRSA has recently emerged from a reservoir in animal husbandry (pigs and veal calves), and a high proportion (∼30%) of people in contact with these animals become carriers.14 The strains belong to one clonal complex (sequence type 398) and have been found in meat for sale.15 The consequences of this reservoir in food are currently unclear.

    How can we detect MRSA?

    MRSA can cause the whole spectrum of staphylococcal disease (box), and no clinical feature is characteristic of MRSA infection, so its detection depends on microbiological laboratory tests. Only a minority of people in hospital who carry MRSA will be detected by testing clinical samples.5 Asymptomatic carriers can serve as reservoirs for transmission to other patients. In countries that are still in control of MRSA, like the Netherlands and Scandinavia, screening of patients and exposed healthcare workers is part of the “search and destroy” strategy.5 The most important carriage site for MRSA is the nose,12 although a recent survey found that 25% of all carriers were identified only from throat swabs.16 Adding other non-clinical sites (perineum, groin, or axilla) is probably not useful.

    Clinical spectrum of staphylococcal disease

    Skin and soft tissue
    • Impetigo, boils, carbuncles, abscesses, cellulitis, fasciitis, pyomyositis, surgical and traumatic wound infections

    Foreign body associated
    • Intravascular catheter, urinary catheter, surgical implant, endotracheal tubes

    Intravascular
    • Bacteraemia, sepsis, septic thrombophlebitis, infective endocarditis

    Bone and joints
    • Septic osteomyelitis, septic arthritis

    Respiratory
    • Pneumonia, empyema, sinusitis, otitis media

    Other invasive infections
    • Meningitis, surgical space infection

    Toxin mediated diseases
    • Staphylococcal toxic shock, food poisoning, staphylococcal scalded skin syndrome, bullous impetigo, necrotising pneumonia, necrotising osteomyelitis

    New rapid (around two hours of laboratory time) molecular techniques are sensitive but have a limited positive predictive value. They are therefore good screening tests, but positive results require confirmation by culture, which takes two to five days.17

    How can we control MRSA?

    Search and destroy

    How to control MRSA in hospitals is a matter of continuing debate. At present, few countries can fully control MRSA, and they all apply the search and destroy strategy (fig 2). This strategy consists of active screening of high risk patients and exposed healthcare workers for carriage, strict implementation of transmission based precautions, and treatment of carriage using topical application of mupirocin nasal cream and washing with disinfecting agents, such as chlorhexidine. The full strategy is described in the Dutch national guidelines (www.wip.nl). Although this strategy is effective in countries with a low prevalence, it is unclear how best to adapt it for effective control of MRSA in countries where it is endemic.

    Figure2

    Fig 2 Trends in the proportion of meticillin resistant S aureus bacteraemia in Europe. Only countries reporting 500 cases or more a year were included. Reproduced from the European Antimicrobial Resistance Surveillance System database (www.rivm.nl/earss)

    Transmission based precautions

    Hand hygiene remains the cornerstone for effective control of infection in hospitals. However, control of MRSA requires additional measures, like isolation. A systematic review found evidence that concerted efforts that included isolation could reduce the prevalence of MRSA, but the effect of isolation measures could not be assessed because of a lack of well designed studies.4 Empirical evidence from observational cohort studies in hospitals and currently decreasing trends in several European countries after implementation of intensive national control programmes indicate that such programmes can be successful even in settings with medium to high endemic levels (fig 2). The effect of MRSA decolonisation on patients’ outcomes has not been studied systematically.

    Mathematical models have been developed to predict the effect of different control measures in high prevalence settings. One study using a compartmentalised model concluded that a proactive screening strategy (of high risk patients on admission and contacts of index patients) combined with isolation could reduce the prevalence of MRSA to less than 1% within six years. To limit the need for isolation a stepwise approach combined with the use of rapid diagnostic tests was recommended.18 Some historically controlled studies using universal screening by polymerase chain reaction showed a marked reduction in MRSA infection rates. For example, a large quasi-experimental study reported a 69.6% reduction in MRSA disease after introducing universal rapid MRSA testing and contact isolation of patients testing positive.19 However, a well designed prospective crossover study performed in surgical patients found no significant reduction in MRSA infections.20 Standard infection control measures, adjusted perioperative prophylaxis, and nasal decolonisation were applied in MRSA carriers. The authors commented that baseline MRSA infection rates were relatively low, limiting the power of the study, and that transmission of MRSA was ongoing in the intervention wards. Another cluster randomised crossover trial comparing polymerase chain reaction with conventional screening showed a positive effect on bed usage but no significant reduction of MRSA acquisition.21 In this study pre-emptive isolation was used in both groups, which may not be representative for other settings. The conclusions are that the cost effectiveness of rapid screening tests remains to be established.

    Restrictive use of antibiotics

    Observational studies have noted the role of antibiotic use as a risk factor for nosocomial transmission of MRSA. A multicentre quasi-experimental study found an 18% reduction in the prevalence of MRSA after restricting the use of fluoroquinolones hospital wide.22 Additional well designed studies are needed to determine the effect of reducing antibiotic use in hospital on the prevalence of MRSA.

    How should we treat MRSA infections (table 2)?

    Table 2

     Treatment options for meticillin resistant Staphylococcus aureus (MRSA) colonisation and infection

    View this table:

    In the community

    The worldwide rise in the prevalence of MRSA challenges the conventional approach to managing skin and soft tissue infections. Incision and drainage remain the primary treatment for boils and abscesses. Data from recent observational studies and clinical trials on the benefit of antibiotics in addition to drainage of uncomplicated infections are conflicting. Patients likely to benefit include those with large or incompletely drained abscesses, cellulitis, fever, or other signs of systemic illness. These form a minority of the patients presenting with skin and soft tissue infections, however, and antibiotics are overprescribed for this indication.

    The prevalence of MRSA in community acquired infection varies widely according to region, reaching 20-50% in skin and soft tissue infections in US cities. In those areas, experts recommend changing empirical treatment of these infections from β lactams to agents with activity against MRSA (table 2). Clinical trials are ongoing to determine the most effective oral treatments. Selection of drugs for empirical regimens should be based on local susceptibility patterns. In areas with low prevalence of MRSA in the community, clinicians should still consider MRSA in the differential diagnosis of skin and soft tissue infections. They should collect specimens from purulent lesions for culture and susceptibility testing, especially in severe or recurrent infections or in the presence of risk factors for MRSA (table 1).

    In the hospital

    Vancomycin, a glycopeptide, is the cornerstone for treating invasive MRSA infections. An alternative agent from the same antibiotic class, teicoplanin, is available in some countries. However, these agents have limited efficacy for deep seated infections, partly because of poor diffusion into tissues—such as the lung and bone—and because of a gradual decrease in susceptibility of MRSA over recent years.24 These glycopeptide intermediate strains have mutations that affect the synthesis of the bacterial cell wall and are not easy to detect in microbiology laboratories. In addition, genetic recombinant, high level glycopeptide resistant S aureus strains have been described sporadically in the US.25 To optimise treatment with glycopeptides in these strains—although not supported by controlled studies—dose adjustment on the basis of monitoring blood concentrations and administration by continuous infusion have been advocated.

    Alternative therapeutic options for parenteral treatment of invasive MRSA infection include recently licensed drugs from new antibiotic classes—linezolid, the first oxazolidinone; daptomycin, the first lipopeptide; and tigecycline, the first glycylcycline (table 2). Randomised controlled trials showed these drugs to be equivalent to vancomycin for treating skin and soft tissue infections involving MRSA.26 27 28 Linezolid is also efficacious for treating staphylococcal pneumonia, and a trial is ongoing to test whether it is more efficacious than vancomycin in ventilator associated MRSA pneumonia, as was suggested by secondary analyses of phase III trials. A large open label randomised controlled trial showed daptomycin to be equivalent to vancomycin for treating MRSA bacteraemia.29 However, daptomycin resistance develops not infrequently, and daptomycin has decreased activity against glycopeptide intermediate strains, so its use should be guided by careful microbiological monitoring of activity. Other antibacterial agents active against MRSA that are in advanced clinical development include the broad spectrum cephalosporin, ceftobiprole; the lipoglycopeptides, oritavancin, dalbavancin, and telavancin; and the trimethoprim analogue, iclaprim. In severe pneumonia with signs of necrosis, respiratory failure, and haemoptysis, infection with Panton-Valentine leucocidin producing staphylococci should be suspected and a Gram stain of respiratory secretions obtained immediately to confirm this possibility. Clindamycin and linezolid repress production of the leucocidin,30 and experts advocate treatment with high doses of these agents for necrotising staphylococcal pneumonia on the basis of experimental data and anecdotal clinical experience.23

    Ongoing research

    • Investigations into the biological and ecological determinants of the virulence and ability to colonise and transmit of Staphylococcus aureus including meticillin resistant S aureus (MRSA)

    • Development of an effective S aureus vaccine for high risk groups or the general population

    • Evaluation of the cost effectiveness of rapid MRSA detection technology, including point of care tests, for screening and treating MRSA

    • Development of new antibacterial agents and reassess the effectiveness of off-patent agents for treating MRSA, especially agents for treating deep seated infections and difficult to treat infections, such as osteoarthritis

    • Development of more effective S aureus decolonisation treatments and to investigate their effect on morbidity and mortality in carriers

    • Evaluation of the cost effectiveness of current and new MRSA control strategies, adapted to different prevalences of MRSA and different healthcare systems

    Tips for clinicians

    • Because meticillin resistant S aureus (MRSA) threatens the effectiveness of current empirical treatments for skin and soft tissue infection and pneumonia, adapt your practice according to the latest data on the local prevalence of S aureus resistance

    • Collect clinical samples for culture and susceptibility testing in patients with severe infection, infection not responding to standard treatment, and those at risk of exposure to MRSA

    • Always adhere to standard infection control precautions such as hand hygiene and prudent use of antibacterial agents

    • Understand and adhere to your local MRSA control policy and educate your patients about basic hygiene

    Additional educational resources

    Resources for healthcare professionals
    Resources for patients

    Notes

    Cite this as: BMJ 2009;338:b364

    Footnotes

    • Contributors: Both authors contributed to the literature search, planning, and writing of this review. JK is guarantor.

    • Competing interests: JK has received consulting fees from 3M, Destiny Pharma, Novabay, and Wyeth; research funds from BD, bioMérieux, and Wyeth; and speaking fees from 3M and BD. MS has received reimbursement for attending meetings from BD, bioMérieux, Pfizer; speaking fees from BD, 3M, and Pfizer; research funds from Cepheid, BD, bioMérieux, Novartis, Pfizer, Johnson & Johnson, and Wyeth; and consulting fees from 3M, Wyeth, Novartis, Eppendorf Array Technologies, and Philips Molecular Diagnostics.

    • Provenance and peer review: Commissioned; externally peer reviewed.

    References

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