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Methicillin resistant Staphylococcus aureus in the critically ill

2003; Elsevier BV; Volume: 92; Issue: 1 Linguagem: Inglês

10.1093/bja/aeh008

1471-6771

Katherine Hardy, Peter M. Hawkey, Fang Gao, B. Oppenheim,

Nosocomial Infections in ICU

Methicillin resistant Staphylococcus aureus (MRSA) is endemic within many hospitals worldwide. Critically ill patients on intensive care units have increased risk factors making them especially prone to nosocomially acquired infections. This review addresses the current situation regarding the evolution of MRSA and the techniques for identifying and epidemiologically typing it. It discusses specific risk factors, the morbidity and mortality associated with critically ill patients, and possibilities for future antibiotic treatments. Methicillin resistant Staphylococcus aureus (MRSA) is endemic within many hospitals worldwide. Critically ill patients on intensive care units have increased risk factors making them especially prone to nosocomially acquired infections. This review addresses the current situation regarding the evolution of MRSA and the techniques for identifying and epidemiologically typing it. It discusses specific risk factors, the morbidity and mortality associated with critically ill patients, and possibilities for future antibiotic treatments. Staphylococcus aureus has long been recognized as a major human pathogen responsible for a wide range of infections, from mild skin infections to wound infections and bacteraemia. Although the introduction of antibiotics over the last 50 yr has lowered the mortality rate from S. aureus infections, the bacteria have developed resistance mechanisms to all antimicrobial agents that have been produced. The introduction of penicillin offered an opportunity to successfully treat serious staphylococcal infections. However, in the same year as the first clinical success with penicillin, an enzyme produced by S. aureus, penicillinase (later known as β-lactamase) was described. This enzyme was responsible for the clinical failures that appeared soon after the introduction of penicillin.1Abraham EP Chain E An enzyme from bacteria able to destroy penicillin.Nature. 1940; 146: 837Crossref Scopus (549) Google Scholar 13Chain E Florey HW Gardner AD et al.Penicillin as a chemotherapeutic agent.Lancet. 1940; 2: 226-228Crossref Scopus (293) Google Scholar During the early 1950s, a series of semi-synthetic penicillins were developed that were stable to destruction by bacterial β-lactamases. Methicillin was one of these compounds and was introduced into clinical practice in 1959. One year after its introduction, the first methicillin resistant S. aureus (MRSA) was detected and the first clinical failure of methicillin for the treatment of S. aureus described (Fig. 1).50Jevons MP 'Celbenin'—resistant Staphylococci.BMJ. 1961; 1: 124-125Crossref Scopus (1355) Google Scholar 76Rolinson GN Letter.BMJ. 1961; 1: 125-126Crossref Scopus (44) Google Scholar The site of action for β-lactam antibiotics is the penicillin binding proteins (PBPs), which catalyse the transpeptidase reaction that cross links the peptidoglycan of the bacterial cell wall. The antibacterial effect of the β-lactam antibiotics is a result of the inactivation of the high molecular weight PBPs (PBP1, 2, and 3); the high affinity of PBP1, 2, and 3 for β-lactam antibiotics results in a stable complex being formed, which is lethal for cell growth (Fig. 2). Staphylococcus aureus strains that express high-level resistance to methicillin produce an additional low affinity penicillin binding protein (PBP2a) encoded by the mecA gene.89Utsui Y Yokota T Role of an altered penicillin-binding protein in methicillin and cephem-resistant Staphylococcus aureus.Antimicrob Agents Chemother. 1985; 28: 397-403Crossref PubMed Scopus (302) Google Scholar This is in contrast to the production of β-lactamase that destroys non-stable β-lactams such as penicillin and ampicillin. At normally inhibitory concentrations of methicillin, PBP2a retains its transpeptidase activity and takes over the role of the normal PBPs in cell wall synthesis. It is believed that MRSA has evolved from methicillin sensitive S. aureus (MSSA) by the acquisition of a large genetic element known as the staphylococcal cassette chromosome mec (SCCmec). SCCmec carries the mec gene complex and various resistance genes against non β-lactam antibiotics.55Katayama Y Ito T Hiramatsu K A new class of genetic element, Staphylococcus cassette chromosome mec, encodes methicillin resistance in Staphylococcus aureus.Antimicrob Agents Chemother. 2000; 44: 1549-1555Crossref PubMed Scopus (749) Google Scholar Despite the SCCmec complex carrying resistance genes against non β-lactam antibiotics, MRSA has until recently remained susceptible to vancomycin. Intermediate resistant strains were first reported in Japan in 1996 and have since been isolated in several countries around the world.44Hiramatsu K The emergence of Staphylococcus aureus with reduced susceptibility to vancomycin in Japan.Am J Med. 1998; 104: 7S-10SAbstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar Resistance to vancomycin in enterococci was identified in 1988 and since that time it has been anticipated that it would appear in S. aureus. Concerns were heightened when it was demonstrated in vivo that transfer of the vancomycin resistance gene, vanA could occur.69Noble WC Virani Z Cree RGA Co-transfer of vancomycin and other resistance genes from Enterococcus faecalis NCTC 12201 to Staphylococcus aureus.FEMS Microbiol Lett. 1992; 93: 195-198Crossref Google Scholar However, it was not until 2002 that the first clinical vancomycin resistant S. aureus (VRSA) was isolated from a patient. The VRSA was isolated from the catheter tip of a renal dialysis patient in Michigan and contained both the mecA and vanA gene.12CDC Staphylococcus aureus resistant to vancomycin—United States.Mor Mortal Wkly Rp. 2002; 51: 565-567PubMed Google Scholar Since this first report there has been one further report again in the USA, but unrelated to the first isolate identified (Fig. 1).11CDC Public Health Dispatch: vancomycin resistant Staphylococcus aureus—Pennsylvania, 2002.Mor Mortal Wkly Rp. 2002; 51: 902-903PubMed Google Scholar MRSA was first recognized in Europe in the early 1960s, and the number of resistant isolates and outbreaks reported increased throughout the decade. Then during the early 1970s there was a decline in the frequency of MRSA in Europe, the reasons for which are not entirely known. It may have been a result of improvements in infection control and antibiotic use.6Ayliffe GAJ The progressive intercontinental spread of methicillin-resistant Staphylococcus aureus.Clin Infect Dis. 1997; 24: S74-S79Crossref PubMed Google Scholar The second wave of MRSA occurred in the late 1970s, first in Australia, the Irish Republic, and the USA, since then the rates of MRSA have increased in virtually all countries, with a few exceptions, such as the Netherlands and Denmark.24Diekema DJ Pfaller MA Schmitz FJ et al.Survey of infections due to Staphylococcus species: frequency of occurrence and antimicrobial susceptibility of isolates collected in the United States, Canada, Latin America, Europe, and the Western Pacific Region for the SENTRY Antimicrobial Surveillance Program, 1997–1999.Clin Infect Dis. 2001; 32: S114-S132Crossref PubMed Scopus (1111) Google Scholar 30Fluit AC Wielders CLC Verhoef J Schmitz FJ Epidemiology and susceptibility of 3,051 Staphylococcus aureus isolates from 25 university hospitals participating in the European SENTRY study.J Clin Microbiol. 2001; 39: 3727-3832Crossref PubMed Scopus (248) Google Scholar Epidemic MRSA (EMRSA) strains have been described, the first of which, EMRSA-1, was isolated in a London hospital in 1981, then spreading to other hospitals in London and the South East.27Duckworth GJ Lothian JL Williams JD Methicillin-resistant Staphylococcus aureus: report of an outbreak in a London teaching hospital.J Hosp Infect. 1988; 11: 1-15Abstract Full Text PDF PubMed Scopus (80) Google Scholar Seventeen EMRSA strains have been described,5Aucken HM Ganner M Murchan S Cookson B Johnson AP A new UK strain of epidemic methicillin-resistant Staphylococcus aureus (EMRSA-17) resistant to multiple antibiotics.J Antimicrob Chemother. 2002; 50: 171-175Crossref PubMed Scopus (65) Google Scholar but the two most predominant EMRSA strains in the UK are EMRSA-15 and -16. The number of reports of EMRSA-15 and -16 have continued to rise over the last decade and are responsible for greater than 95% of all MRSA bacteraemias in the UK (Fig. 3).51Johnson AP Aucken HM Cavendish S et al.Dominance of EMRSA-15 and -16 among MRSA causing nosocomial bacteraemia in the UK: analysis of isolates from the European Antimicrobial Resistance Surveillance System (EARSS).J Antimicrob Chemother. 2001; 48: 143-144Crossref PubMed Google Scholar 65Moore PCL Lindsay JA Molecular characterisation of the dominant UK methicillin-resistant Staphylococcus aureus strains, EMRSA-15 and EMRSA-16.J Med Microbiol. 2002; 51: 516-521Crossref PubMed Scopus (81) Google Scholar EMRSA-16 is concentrated in the South East whilst EMRSA-15 is widespread throughout the country. Once endemic in a hospital EMRSA-15 and -16 are very hard to control, with previously successful preventative measures in controlling outbreaks being unsuccessful.6Ayliffe GAJ The progressive intercontinental spread of methicillin-resistant Staphylococcus aureus.Clin Infect Dis. 1997; 24: S74-S79Crossref PubMed Google Scholar Rates of MRSA on different ICUs are difficult to compare because of differing surveillance methods, lack of uniformity in diagnostic criteria, and lack of adequate systems to compare the severity of illness. In many studies, ICUs have the highest incidence of MRSA followed by surgical wards and medical wards, with the community having the lowest rates.7Barakate MS Yang Y-X Foo S-H et al.An epidemiological survey of methicillin-resistant Staphylococcus aureus in a tertiary referral hospital.J Hosp Infect. 2000; 44: 19-26Abstract Full Text PDF PubMed Scopus (42) Google Scholar 16Coello R Jimenez J Garcia M et al.Prospective study of infection, colonisation and carriage of methicillin resistant Staphylococcus aureus in an outbreak affecting 900 patients.Eur J Clin Infect Dis. 1994; 13: 74-81Crossref PubMed Scopus (220) Google Scholar The ICUs have been proposed as having a central role in the intra- and inter-hospital spread of MRSA.45Hoefnagels-Schuermans A Borremans A Peetermans W et al.Origin and transmission of methicillin resistant Staphylococcus aureus in an endemic situation: differences between geriatric and intensive care patients.J Hosp Infect. 1997; 36: 209-222Abstract Full Text PDF PubMed Scopus (34) Google Scholar It has also been noted however, that when rates of MRSA increase in an ICU there is a parallel increase in the rates on general medical wards. Patients in hospital are frequently transferred both within the hospital and between different hospitals allowing for spread both within and between hospitals, with some of the large hospitals being termed 'super spreaders' (Fig. 4). The strains carried by these patients are normally EMRSA. In contrast, patients from nursing homes may be the commonest source of MRSA imported to hospitals but their strains often differ from the epidemic strains. The laboratory plays an important role in the detection of MRSA, which necessitates the availability of rapid and reliable tests. However, timely detection of MRSA is still problematic with the majority of techniques taking longer than 48 h to produce a result. Isolation of MRSA using solid media is the most commonly used technique, with many different selective media now being available, most containing oxacillin and sodium chloride.22Davies S Zadik PM Mason CM Whittaker SJ Methicillin-resistant Staphylococcus aureus: evaluation of five selective media.Br J Biomed Sci. 2000; 57: 269-272PubMed Google Scholar The sensitivity of detecting carriers is significantly enhanced when using broth enrichment, but with the disadvantage that it takes longer to obtain a result and therefore delays implementation of infection control procedures.21Davies S Zadik PM Comparison of methods for the isolation of methicillin-resistant Staphylococcus aureus..J Clin Pathol. 1997; 50: 257-258Crossref PubMed Scopus (32) Google Scholar Development of rapid and accurate tests is crucial for the control of MRSA in hospitals and to initiate the appropriate antimicrobial treatment in critically ill patients. Advancement of molecular techniques in recent years has led to many assays being developed to detect the mecA gene, which now represents the 'gold standard' for detecting methicillin resistance. Despite many of these techniques outperforming conventional culture, they still require an overnight enrichment culture of clinical samples.52Jonas D Speck M Daschner FD Grundmann H Rapid PCR-based identification of methicillin-resistant Staphylococcus aureus from screening swabs.J Clin Microbiol. 2002; 40: 1821-1823Crossref PubMed Scopus (135) Google Scholar 87Towner KJ Talbot DC Curran R Webster CA Humphreys H Development and evaluation of a PCR-based immunoassay for the rapid detection of methicillin-resistant Staphylococcus aureus.J Med Microbiol. 1998; 47: 607-613Crossref PubMed Scopus (59) Google Scholar Techniques have recently been developed that have increased the possibilities of same day testing, combining a high degree of sensitivity and accurate identification. These methods have been described for both swabs and blood cultures, but have so far not been extensively used in routine laboratories.31Francois P Pittet D Bento M et al.Rapid detection of methicillin-resistant Staphylococcus aureus directly from sterile or nonsterile clinical samples by a new molecular assay.J Clin Microbiol. 2003; 41: 254-260Crossref PubMed Scopus (235) Google Scholar 61Louie L Goodfellow J Mathieu P et al.Rapid detection of methicillin-resistant Staphylococci from blood culture bottles by using a multiplex PCR assay.J Clin Microbiol. 2002; 40: 2786-2790Crossref PubMed Scopus (154) Google Scholar Despite their high costs, they may prove to be cost effective by reducing transmission rates. Bedside testing, which would be the most useful option is still not available. To facilitate the control of outbreaks and enable us to have an understanding of the changing epidemiology of MRSA, it is necessary for us to be able to distinguish between the different types of MRSA. There are several typing schemes available but no consensus regarding which method is the best.94Weller T Methicillin-resistant Staphylococcus aureus typing methods: which should be the International standard?.J Hosp Infect. 2000; 46: 160-172Abstract Full Text PDF PubMed Scopus (70) Google Scholar DNA-based typing methods are more discriminatory than the previously used phenotypic methods, with pulse field gel electrophoresis (PFGE) being the most widely used.17Cookson B Aparicio P Deplano A et al.Inter-centre comparison of pulsed-field gel electrophoresis for the typing of methicillin-resistant Staphylococcus aureus.J Med Microbiol. 1996; 44: 179-184Crossref PubMed Scopus (72) Google Scholar 90vanBelkum A Van Leeuwen WJ Kaufmann ME et al.Assessment of resolution and intercenter reproducibility of results of genotyping Staphylococcus aureus by pulsed field gel electrophoresis of SmaI macrorestriction fragments: a multicenter study.J Clin Microbiol. 1998; 36: 1653-1659PubMed Google Scholar Many strategies have been applied to identify both the risk factors that lead to colonization and those that lead to subsequent infection.23de Irala-Estevez J Matinez-Concha D Diaz-Molina C et al.Comparison of different methological approaches to identify risk factors of nosocomial infection in intensive care units.Intensive Care Med. 2001; 27: 1254-1262Crossref PubMed Scopus (33) Google Scholar In many cases, identification of a single risk factor is not possible because of patients being simultaneously exposed to several. Intensive care patients have risk factors making them especially prone to nosocomially acquired infection. The risk of MRSA infection in patients is much higher if they are previously colonized with MRSA.4Asensio A Guerrero A Quereda C Lizan M Martinez-Ferrer M Colonization and Infection with methicillin-resistant Staphylococcus aureus: associated factors and eradication.Infect Control Hosp Epidemiol. 1996; 17: 20-28Crossref PubMed Scopus (155) Google Scholar Between 30 and 60% of critically ill patients colonized with MRSA will develop infection.16Coello R Jimenez J Garcia M et al.Prospective study of infection, colonisation and carriage of methicillin resistant Staphylococcus aureus in an outbreak affecting 900 patients.Eur J Clin Infect Dis. 1994; 13: 74-81Crossref PubMed Scopus (220) Google Scholar 85Theaker C Ormond-Walshe S Azadian B Soni N MRSA in the critically ill.J Hosp Infect. 2001; 48: 98-102Abstract Full Text PDF PubMed Scopus (34) Google Scholar In a study of patients developing MRSA bacteraemia, 83% of patients had been colonized previously.9Blot SI Vandewoude KH Hoste EA Colardyn FA Outcome and attributable mortality in critically ill patients with bacteremia involving methicillin-susceptible and methicillin-resistant Staphylococcus aureus.Arch Intern Med. 2002; 162: 2229-2235Crossref PubMed Scopus (358) Google Scholar Case control studies examining S. aureus colonization have shown nasal colonization to be a significant risk factor for the development of wound infection.56Klutymans JA Mouton JW Ijzerman EP et al.Nasal carriage of Staphylococcus aureus as a major risk factor for wound infections after cardiac surgery.J Infect Dis. 1995; 171: 216-219Crossref PubMed Scopus (336) Google Scholar However, despite colonization rates being perceived to be higher on ICU, there are no comparative studies and along with colonization many risk factors predispose critically ill patients to infection. An example of this is the high rates of colonization in nursing homes but the low rates of infection. In several studies, the amount of time spent on ICU has been considered the most significant risk factor in acquisition of MRSA infection.60Law MR Gill ON Hospital acquired infection with methicillin-resistant and methicillin-sensitive staphylococci.Epidemiol Infect. 1988; 101: 623-629Crossref PubMed Scopus (50) Google Scholar The odds ratio for acquiring infection increased more than 2.5 times with a stay of longer than 2 weeks, and more than four times after 3 weeks in a study by Ibelings and Bruining.48Ibelings MMS Bruining HA Methicillin-resistant Staphylococcus aureus: acquisition and risk of death in patients in the Intensive Care Unit.Eur J Surg. 1998; 164: 411-418Crossref PubMed Scopus (100) Google Scholar When compared with MSSA infection, patients infected with MRSA had a significantly longer length of stay on ICU both before and after infection.15Coello R Glynn JR Gaspar C Picazo JJ Fereres J Risk factors for developing clinical infection with methicillin resistant Staphylococcus aureus (MRSA) amongst hospital patients initially only colonized with MRSA.J Hosp Infect. 1997; 37: 39-46Abstract Full Text PDF PubMed Scopus (170) Google Scholar An increasing APACHE II score has been associated with the risk of acquiring MRSA, but once the APACHE II score is greater than 21–25 a reduction is seen in the incidences of infection. Patients with the higher APACHE II scores are more likely to die of their underlying disease before acquiring MRSA, whereas less severely ill patients are exposed to a greater number of risk factors.48Ibelings MMS Bruining HA Methicillin-resistant Staphylococcus aureus: acquisition and risk of death in patients in the Intensive Care Unit.Eur J Surg. 1998; 164: 411-418Crossref PubMed Scopus (100) Google Scholar The intensity of care and staff deficits have been associated with MRSA colonization and infection; an increasing intensity of work was associated with a greater risk of MRSA acquisition in ICUs.29Dziekan G Hahn A Thune K et al.Methicillin-resistant Staphylococcus aureus in a teaching hospital: investigation of nosocomial transmission using a matched case-control study.J Hosp Infect. 2000; 46: 263-270Abstract Full Text PDF PubMed Scopus (104) Google Scholar 92Vicca AF Nursing staff workload as a determinant of methicillin-resistant Staphylococcus aureus spread in an adult intensive therapy unit.J Hosp Infect. 1999; 43: 109-113Abstract Full Text PDF PubMed Scopus (133) Google Scholar The effect of staff deficit has been significantly associated with MRSA clusters, whilst in sporadic cases staff deficit did not influence the occurrence of MRSA.37Grundmann H Hori S Winter B Tami A Austin DJ Risk factors for the transmission of methicillin-resistant Staphylococcus aureus in an Adult Intensive Care Unit: fitting a model to the data.J Infect Dis. 2002; 185: 481-488Crossref PubMed Scopus (184) Google Scholar The insertion of intravascular devices has been identified as an independent risk factor associated for MRSA bacteraemia.73Pujol M Pena C Pallares R et al.Risk factors for nosocomial bacteraemia due to methicillin-resistant Staphylococcus aureus.Eur J Clin Microbiol Infect Dis. 1994; 13: 96-102Crossref PubMed Scopus (121) Google Scholar Asensio and colleagues4Asensio A Guerrero A Quereda C Lizan M Martinez-Ferrer M Colonization and Infection with methicillin-resistant Staphylococcus aureus: associated factors and eradication.Infect Control Hosp Epidemiol. 1996; 17: 20-28Crossref PubMed Scopus (155) Google Scholar found invasive procedures including the insertion of intravascular devices to be independently associated with MRSA colonization and infection, similar to Law and Gill60Law MR Gill ON Hospital acquired infection with methicillin-resistant and methicillin-sensitive staphylococci.Epidemiol Infect. 1988; 101: 623-629Crossref PubMed Scopus (50) Google Scholar who found a 9-fold increase in MRSA acquisition if a patient had an indwelling catheter. The administration of antibiotics has the effect of altering the normal human microbial flora, decreasing the number of susceptible organisms and consequently increasing the numbers of resistant organisms. Hospitalized patients have been shown to have skin flora differing from that of healthy adults with significantly higher levels of resistant bacteria.59Larson EL McGinley KJ Foglia AR Talbot GH Leyden JJ Composition and antimicrobic resistance of skin flora in hospitalized and healthy adults.J Clin Microbiol. 1986; 23: 604-608Crossref PubMed Google Scholar Consumption of antibiotics is greatest on ICU, with reports linking the high usage to increasingly high numbers of resistant bacteria. Several studies have identified that an increased risk of MRSA infection is associated with the administration of antibiotics.29Dziekan G Hahn A Thune K et al.Methicillin-resistant Staphylococcus aureus in a teaching hospital: investigation of nosocomial transmission using a matched case-control study.J Hosp Infect. 2000; 46: 263-270Abstract Full Text PDF PubMed Scopus (104) Google Scholar 36Graffunder EM Venezia RA Risk factors associated with nosocomial methicillin-resistant Staphylococcus aureus (MRSA) infection including previous use of antimicrobials.J Antimicrob Chemother. 2002; 49: 999-1005Crossref PubMed Scopus (347) Google Scholar 73Pujol M Pena C Pallares R et al.Risk factors for nosocomial bacteraemia due to methicillin-resistant Staphylococcus aureus.Eur J Clin Microbiol Infect Dis. 1994; 13: 96-102Crossref PubMed Scopus (121) Google Scholar Comparison of patients colonized with MSSA and MRSA reveals that the number of antibiotics received and the duration of the therapy are statistically associated with an increased risk of MRSA acquisition. Association of antibiotic prescribing and MRSA rates is also supported by comparisons of prescribing regimes in different countries. Germany, which has much lower resistance rates than the USA, has a higher relative use of narrow spectrum antibiotics and a lower relative use of broad-spectrum antibiotics. Cephalosporins are the most frequently prescribed antimicrobials on ICUs in the USA but are used to a lesser extent in Germany.29Dziekan G Hahn A Thune K et al.Methicillin-resistant Staphylococcus aureus in a teaching hospital: investigation of nosocomial transmission using a matched case-control study.J Hosp Infect. 2000; 46: 263-270Abstract Full Text PDF PubMed Scopus (104) Google Scholar 38Harbarth S Albrich W Goldmann D Huebner J Control of multiply resistant cocci: do international comparisons help?.Lancet Infect Dis. 2001; 1: 251-261Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar Further evidence is also provided by the Dutch who have strict prescribing policies and very low rates of MRSA. Despite this evidence, several studies have failed to find a significant association when using logistic regression between antibiotic exposure and MRSA acquisition.41Hershow RC Khayr MD Smith NL A comparison of clinical virulence of nosocomially acquired emthicillin-resistant and methicillin-sensitive Staphylococcus aureus infections in a university hospital.Infect Control Hosp Epidemiol. 1992; 13: 587-593Crossref PubMed Google Scholar When individual antibiotic classes are examined, both cephalosporins and quinolones have been significantly associated with predisposing patients to MRSA colonization. Both increasing incidences of MRSA colonization and outbreaks of MRSA have been correlated with increasing quinolone and cephalosporin usage.42Hill DA Herford T Parratt D Antibiotic usage and methicillin-resistant Staphylococcus aureus: an analysis.J Antimicrob Chemother. 1998; 42: 676-677Crossref PubMed Scopus (34) Google Scholar 62Manhold C von Rolbicki U Brase R et al.Outbreaks of Staphylococcus aureus infections during treatment of late onset pneumonia with ciprofloxacin in prospective, randomized study.Intensive Care Med. 1998; 24: 1327-1330Crossref PubMed Scopus (37) Google Scholar A multicentre study of 50 Belgian hospitals identified an increasing incidence of MRSA with increasing use of ceftazidime, cefsulodin, co-amoxiclav, and fluoroquinolones.20Crowcroft NS Ronveaux O Monnet DL Mertens R Methicillin-resistant Staphylococcus aureus and antimicrobial use in Belgian hospitals.Infect Control Hosp Epidemiol. 1999; 20: 31-36Crossref PubMed Scopus (108) Google Scholar In a study of risk factors on ICU, Graffunder and Venezia36Graffunder EM Venezia RA Risk factors associated with nosocomial methicillin-resistant Staphylococcus aureus (MRSA) infection including previous use of antimicrobials.J Antimicrob Chemother. 2002; 49: 999-1005Crossref PubMed Scopus (347) Google Scholar found both levofloxacin and macrolides to be independently associated with MRSA infection, along with longer length of stay before infection, previous surgery, and enteral feeding tubes. Fluoroquinolones are readily excreted in sweat and achieve minimum inhibitory concentrations on the skin, therefore suppressing normal flora and allowing a higher density of skin colonization with multiple resistant bacteria.40Hawkey PM Quinolones in sweat and quinolone resistance.Lancet. 1997; 349: 148-149Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar 46Hoiby N Jarlov JO Kemp M et al.Excretion of ciprofloxacin in sweat and multiresistant Staphylococcus epidermidis.Lancet. 1997; 349: 167-169Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar There is also evidence to suggest that the excretion of β-lactam antibiotics in sweat may in part explain the resistance of staphylococcus to β-lactam antibiotics.47Hoiby N Pers C Johansen HK Hansen H Excretion of beta lactam antibiotics in sweat—a neglected mechanism for development of antibiotic resistance?.Antimicrob Agents Chemother. 2000; 44: 2855-2857Crossref PubMed Scopus (34) Google Scholar MRSA can cause a wide range of infections from superficial skin infections to severe SSI and bacteraemias. Many of the studies compare the clinical consequences of MRSA with MSSA. Mandatory reporting of all MRSA bacteraemias to the Department of Health was implemented in England in April 2001; rates during the first year of surveillance ranged from 0 to 0.66/1000 occupied bed days, with an overall rate of 0.17/1000 occupied bed days. Single speciality trusts had lower rates than general or specialist trusts, with London having the highest regional rates.2Anon The first year of the Department of Health's mandatory MRSA bacteraemia surveillance scheme in acute NHS Trusts in England: April 2001–March 2002.CDR Weekly. 2002; 12: 6-17Google Scholar Although data have only been collected for 1 yr, 14 trusts have had significant increases in their MRSA rates over this time. Previous surveillance of hospital acquired bacteraemias (HAB) demonstrated that the rates on ICU are much higher when compared with overall trends: 9.1 HAB/1000 patient days as opposed to 0.6 HAB/1000 patient days. Over 40% of the HAB were caused by staphylococci, 26% of which were S. aureus and 54% of these were methicillin resistant.79Scheme NINS Surveillance of hospital-acquired bacteraemia in English hospitals 1997–2002.in: Report, Public Health Laboratory Service. 2002: 8-9Google Scholar The percentage of S. aureus bacteraemias caused by MRSA isolates has increased from 2% in 1992 to greater than 40% in 2001, in addition to those attributable to MSSA isolates, the numbers of which have remained relatively constant (Fig. 3). Similar results were also seen in surveillance of surgical site infections (SSI) in England and Wales with staphylococci being responsible for 47% of SSI, of which 82% were S. aureus and 62% were methicillin resistant.80Scheme NINS Surveillance of surgical site infection in English hospitals 1997–2001.in: Report, Public Health Laboratory Service. 2002: 8-9Google Scholar This is similar to the results from the European Prevalence of Infection in Intensive Care study (EPIC) where MRSA accounted for 57% of all ICU acquired S. aureus.93Vincent J-L Bihari DJ Suter PM et al.The Prevalence of nosocomial infection