1 Health Protection Agency, West Midlands Public Health Laboratory, and 2 Intensive Care Unit, Heartlands Hospital, Bordesley Green East, Birmingham, B9 5SS, UK. 3 The Department of Infection and Immunity, The Medical School, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
*Corresponding author. E-mail: peter.hawkey@heartsol.wmids.nhs.uk
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Abstract |
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Br J Anaesth 2004; 92: 12130
Keywords: complications, infections, methicillin resistant Staphylococcus aureus (MRSA); epidemiology; intensive care
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Introduction |
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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 ß-lactamase) was described. This enzyme was responsible for the clinical failures that appeared soon after the introduction of penicillin.1 13 During the early 1950s, a series of semi-synthetic penicillins were developed that were stable to destruction by bacterial ß-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).50 76
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Resistance and evolution |
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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 ß-lactam antibiotics.55
Despite the SCCmec complex carrying resistance genes against non ß-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.44 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.69 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.12 Since this first report there has been one further report again in the USA, but unrelated to the first isolate identified (Fig. 1).11
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Epidemiology |
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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.27 Seventeen EMRSA strains have been described,5 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).51 65 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.6
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Identification of MRSA |
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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.52 87
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.31 61 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.94 DNA-based typing methods are more discriminatory than the previously used phenotypic methods, with pulse field gel electrophoresis (PFGE) being the most widely used.17 90
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Risk factors for colonization and infection |
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Previous MRSA colonization
The risk of MRSA infection in patients is much higher if they are previously colonized with MRSA.4 Between 30 and 60% of critically ill patients colonized with MRSA will develop infection.16 85 In a study of patients developing MRSA bacteraemia, 83% of patients had been colonized previously.9 Case control studies examining S. aureus colonization have shown nasal colonization to be a significant risk factor for the development of wound infection.56 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.
Length of ICU and hospital stay
In several studies, the amount of time spent on ICU has been considered the most significant risk factor in acquisition of MRSA infection.60 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.48 When compared with MSSA infection, patients infected with MRSA had a significantly longer length of stay on ICU both before and after infection.15
Severity of illness and intensity of care
An increasing APACHE II score has been associated with the risk of acquiring MRSA, but once the APACHE II score is greater than 2125 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.48
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.29 92 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.37
Intravascular devices
The insertion of intravascular devices has been identified as an independent risk factor associated for MRSA bacteraemia.73 Asensio and colleagues4 found invasive procedures including the insertion of intravascular devices to be independently associated with MRSA colonization and infection, similar to Law and Gill60 who found a 9-fold increase in MRSA acquisition if a patient had an indwelling catheter.
Antibiotic consumption
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.59 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.29 36 73 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.29 38 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.41 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.42 62 A multicentre study of 50 Belgian hospitals identified an increasing incidence of MRSA with increasing use of ceftazidime, cefsulodin, co-amoxiclav, and fluoroquinolones.20 In a study of risk factors on ICU, Graffunder and Venezia36 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.40 46 There is also evidence to suggest that the excretion of ß-lactam antibiotics in sweat may in part explain the resistance of staphylococcus to ß-lactam antibiotics.47
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Clinical consequences of MRSA |
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Bacteraemia, SSI, and pneumonia
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.2 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.79 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.80 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.93
MRSA pneumonia causes a significant degree of mortality amongst ICU patients, with rates of greater than 50% reported by several studies.35 75 Patients with MRSA develop bacteraemia and septic shock more frequently than patients with MSSA pneumonia.
Mortality and morbidity
The degree of morbidity and mortality attributable to MRSA is difficult to assess. Many studies have compared the mortality of MRSA and MSSA bacteraemia with conflicting results. A meta-analysis of 31 studies by Cosgrove and colleagues18 concluded that bacteraemia as a result of MRSA is associated with an increased mortality compared with MSSA bacteraemia with an odds ratio of 1.93 (95% CI, 1.542.42; P<0.01). When looked at independently, only seven of the studies had found a significant difference between the mortality rates of MSSA and MRSA bacteraemia; this may be because many of the studies were small and lacked the power to find an association. Adjustment for confounding variables is problematic; one such adjustment is needed for the severity of illness. There is a belief that patients with MRSA bacteraemia are sicker and will consequently have a higher mortality because of their underlying illness. Several studies including one by Blot and colleagues9 that have adjusted for underlying disease still found MRSA bacteraemia to have a higher attributable mortality than MSSA bacteraemia.
EPIC data found that mortality was greatest in countries with a higher ICU acquired infection rate, and was higher again in those countries with high MRSA ICU acquired infection rates.93 Univariate analysis of the data confirmed that ICU acquired infections are among the most important independent risk factors associated with mortality. Lower respiratory tract infection with MRSA has the greatest risk for increased mortality.
An examination of death certificates from 1993 to 1998 in the UK where staphylococcal infection was mentioned showed that there was an increase over the 5-yr period, with the increasing proportion being attributable to MRSA.19 On the certificates where staphylococcal infection was the underlying cause of death, the percentage where MRSA was mentioned increased from 8% in 1993 to 44% in 1998.
The 2001 report of the National Confidential Enquiry into Perioperative Deaths (NCEPOD) has found that there were four out of 222 (1.8%) deaths after general surgery with documented MRSA infection.3 Clearly, MRSA infection is a hazard for surgical patients.
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Control Of MRSA |
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Eradication from patients
Eradication of MRSA from patients has proved problematic, with many believing that there is no evidence for systemic or topical antimicrobial therapy specifically to eradicate MRSA colonization. Topical treatment with mupirocin has been shown to only marginally reduce the levels of MRSA colonization. A high success rate in initial decolonization was seen by Dupeyron and colleagues,28 but 25.9% of these patients became recolonized. However, Harbarth and colleagues39 found an eradication rate of only 44% in a test group treated with mupirocin compared with the control group that had an eradication rate of 23%. There have also been reports of mupirocin resistance in situations where it has been used for prolonged periods.64 Mupirocin has been shown to be useful in outbreak situations disrupting transmission in conjunction with other infection control procedures.43
The environment and cleaning
Although it is well recognized that the hands of health care workers are the main source of transmission for MRSA and colonized or infected patients the main reservoirs, the question of whether the environment plays a significant role remains unresolved.84 Some studies have shown the environment to play a role during outbreaks and endemic situations, whilst others have reported limited environmental contamination.10 Levels of environmental contamination have been reported to be higher in rooms of colonized or infected patients when compared with levels in unoccupied rooms.78 Variations in frequencies of environmental contamination have also been identified, depending on the site infected or colonized.10 Boyce and colleagues10 also demonstrated that environmental contamination of a patients room was sufficient to contaminate the gloves of health care workers who had contact with the environment but no direct patient contact.
The survival of S. aureus in the environment may be a critical factor in its transmission, with Jawad and colleagues49 demonstrating that S. aureus are resistant to desiccation particularly when dried in protein rich menstrum. Many studies have investigated the survival time of S. aureus, and although not directly comparable all show that S. aureus has the potential to survive for long periods under conditions found in the hospital environment.25 Staphylococci has been shown to survive for at least 1 day on five common hospital materials, with some still viable after 56 and 90 days on polyester and polyethylene plastic respectively.26 57 68
Contamination of the environment with MRSA and its ability to survive for long periods of time emphasizes the necessity for cleaning. Cleaning is often a forgotten infection control measure despite evidence that outbreaks have only been brought under control once MRSA has been eliminated from the environment. Rampling and colleagues74 showed that elimination of MRSA from the environment was only possible when emphasis was placed on dust control; previous cleaning of the ward had only provided temporary measures.
Airborne transmission
The role of airborne transmission in staphylococcal infections has been recognized since the 1960s, but there are conflicting reports over its significance.66 A study by Bauer and colleagues8 did not find any evidence of a role for airborne transmission, but Shiomori and colleagues82 suggested that airborne spread might have a role to play in the colonization of the nasal cavity or respiratory tract infections. They showed that MRSA particles in the respirable range were liberated into the air during bed making, and therefore have the potential to reach the lung and cause infection.83
Is control worth it?
Controversy exists over whether measures to control MRSA are effective, particularly in endemic situations. Guidelines have been established in several countries, some of which, like the Netherlands, have an aggressive approach to management of MRSA, to others, which opt for containment.
The cost of infection control measures is high, but studies comparing the costs involved in treating patients infected with MRSA all demonstrate that implementing infection control measures is cost effective. Selective screening and isolation of carriers on admission to ICU in a study by Chaix and colleagues14 was shown to be beneficial compared with no isolation.
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Treatment |
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Several other antibacterial agents are currently in development. Tigecycline (GAR-936) is a derivative of minocycline, a member of a new group of antibiotics, the glycylcyclines. It is in the late stages of clinical trials and has shown good activity against a broad spectrum of resistant organisms, including MRSA and VISA strains.70 Two new novel carbapenems are in trial: CP5609, which has shown potent activity and good efficacy compared with vancomycin in vitro against MRSA;67 and CS-023, which has better activity against MRSA than other carbapenems and has shown to be safe and well tolerated.33 BAL9141 and S-3578 are novel cephalosporin derivatives that have a broader spectrum of activity than vancomycin and linezolid and have been proposed as candidates for treating both systemic and local MRSA infections.53 88
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Conclusions |
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Controversy exists over whether MRSA can be brought under control and if the effort to try and control MRSA is a waste of resources. However, on ICU where MRSA contributes to the high degree of morbidity and mortality, control measures have been shown to be cost effective. The control of MRSA must be a team effort involving all health care professionals with the implementation of strict infection control programmes and rational antibiotic prescribing.
At present, the mainstay of treatment for MRSA is vancomycin, but the recent discovery of vancomycin resistant MRSA demonstrates how MRSA is constantly evolving and suggests that the future may not be bright.
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Acknowledgement |
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References |
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2 Anon. The first year of the Department of Healths mandatory MRSA bacteraemia surveillance scheme in acute NHS Trusts in England: April 2001March 2002. CDR Weekly 2002; 12: 617
3 Anon. Surgery in General: Changing the way we operate. The 2001 Report of the National Enquiry into Perioperative Deaths. 2001: 848
4 Asensio 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: 208[ISI][Medline]
5 Aucken 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: 1715
6 Ayliffe GAJ. The progressive intercontinental spread of methicillin-resistant Staphylococcus aureus. Clin Infect Dis 1997; 24: S74S9[ISI][Medline]
7 Barakate 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: 1926[CrossRef][ISI][Medline]
8 Bauer TM, Ofner E, Just HM, Daschner FD. An epidemiological study assessing the relative importance of airborne and direct contact transmission of microorganims in a medical intensive care unit. J Hosp Infect 1990; 15: 3019[ISI][Medline]
9 Blot 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: 222935
10 Boyce JM, Potter-Boyne G, Chenevert C, King T. Environmental contamination due to methicillin resistant Staphylococcus aureus: possible infection control implications. Infect Control Hosp Epidemiol 1997; 18: 6227[ISI][Medline]
11 CDC. Public Health Dispatch: vancomycin resistant Staphylococcus aureusPennsylvania, 2002. Mor Mortal Wkly Rp 2002; 51: 9023
12 CDC. Staphylococcus aureus resistant to vancomycinUnited States. Mor Mortal Wkly Rp 2002; 51: 5657
13 Chain E, Florey HW, Gardner AD, et al. Penicillin as a chemotherapeutic agent. Lancet 1940; 2: 2268[CrossRef]
14 Chaix C, Durand-Zaleski I, Alberti C, Brun-Buisson C. Control of endemic methicillin-resistant Staphylococcus aureus. A cost-benefit analysis in an intensive care unit. JAMA 1999; 282: 174551
15 Coello 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: 3946[ISI][Medline]
16 Coello 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: 7481[ISI]
17 Cookson 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: 17984[Abstract]
18 Cosgrove SE, Sakoulas G, Perencevich EN, et al. Comparison of mortality associated with methicillin-resistant and methicillin-susceptible Staphylococcus aureus bacteremia: a meta-analysis. Clin Infect Dis 2003; 36: 5339[CrossRef][ISI][Medline]
19 Crowcroft NS, Catchpole M. Mortality from methicillin resistant Staphylococcus aureus in England and Wales: analysis of death certificates. BMJ 2002; 325: 13901
20 Crowcroft NS, Ronveaux O, Monnet DL, Mertens R. Methicillin-resistant Staphylococcus aureus and antimicrobial use in Belgian hospitals. Infect Control Hosp Epidemiol 1999; 20: 316[ISI][Medline]
21 Davies S, Zadik PM. Comparison of methods for the isolation of methicillin-resistant Staphylococcus aureus. J Clin Pathol 1997; 50: 2578[Abstract]
22 Davies S, Zadik PM, Mason CM, Whittaker SJ. Methicillin-resistant Staphylococcus aureus: evaluation of five selective media. Br J Biomed Sci 2000; 57: 26972[ISI][Medline]
23 de 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: 125462[CrossRef][ISI][Medline]
24 Diekema 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, 19971999. Clin Infect Dis 2001; 32: S114-S32[CrossRef][ISI][Medline]
25 Dietze B, Rath A, Wendt C, Martiny H. Survival of MRSA on sterile goods packaging. J Hosp Infect 2001; 49: 25561[CrossRef][ISI][Medline]
26 Duckworth GJ, Jordens JZ. Adherence and survival properties of an epidemic methicillin resistant strain of Staphylococcus aureus compared with those of methicillin sensitive strains. J Med Microbiol 1990; 32: 195200[Abstract]
27 Duckworth GJ, Lothian JL, Williams JD. Methicillin-resistant Staphylococcus aureus: report of an outbreak in a London teaching hospital. J Hosp Infect 1988; 11: 115
28 Dupeyron C, Campillo B, Bordes M, et al. A clinical trial of mupirocin in the eradication of methicillin-resistant Staphylococcus aureus nasal carriage in a digestive disease unit. J Hosp Infect 2002; 52: 2817[CrossRef][ISI][Medline]
29 Dziekan 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: 26370[CrossRef][ISI][Medline]
30 Fluit 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: 3727832
31 Francois 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: 25460
32 Fridkin SK, Edwards JR, Pichette SC, et al. Determinants of vancomycin use in adult intensive care units in 41 United States hospitals. Clin Infect Dis 1999; 28: 111925[ISI][Medline]
33 Fukuoka T, Puechler K, Rennecke J, Kuwahara S. In vitro activity of CS-023 against European Clinical Relevant Bacterial Isolates. Proceedings of the 42nd ICAAC Conference 2002: F326
34 Girou E, Pujade G, Legrand P, Cizeau F, Brun-Buisson C. Selective screening of carriers for control of methicillin resistant Staphylococcus aureus (MRSA) in high risk hospital areas with a high level of endemic MRSA. Clin Infect Dis 1998; 27: 54350[ISI][Medline]
35 Gonzalez C, Rubio M, Romero-Vivas J, Gonzalez M, Picazo JJ. Bacteremic pneumonia due to Staphylococcus aureus: a comparison of disease caused by methicillin-resistant and methicillin-susceptible organisms. Clin Infect Dis 1999; 29: 11717[CrossRef][ISI][Medline]
36 Graffunder EM, Venezia RA. Risk factors associated with nosocomial methicillin-resistant Staphylococcus aureus (MRSA) infection including previous use of antimicrobials. J Antimicrob Chemother 2002; 49: 9991005
37 Grundmann 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: 4818[CrossRef][ISI][Medline]
38 Harbarth S, Albrich W, Goldmann D, Huebner J. Control of multiply resistant cocci: do international comparisons help? Lancet Infect Dis 2001; 1: 25161[CrossRef][Medline]
39 Harbarth S, Dharan S, Liassine N, et al. Randomized, placebo-controlled, double-blind trial to evaluate the efficacy of mupirocin for eradicating carriage of methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 1999; 43: 14126
40 Hawkey PM. Quinolones in sweat and quinolone resistance. Lancet 1997; 349: 1489[ISI][Medline]
41 Hershow 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: 58793[ISI][Medline]
42 Hill DA, Herford T, Parratt D. Antibiotic usage and methicillin-resistant Staphylococcus aureus: an analysis. J Antimicrob Chemother 1998; 42: 6767
43 Hill RA, Duckworth GJ, Casewell M. Elimination of nasal carriage of methicillin-resistant Staphylococcus aureus with mupirocin during a hospital outbreak. J Antimicrob Chemother 1988; 22: 37784[Abstract]
44 Hiramatsu K. The emergence of Staphylococcus aureus with reduced susceptibility to vancomycin in Japan. Am J Med 1998; 104: 7S-10S[CrossRef][Medline]
45 Hoefnagels-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: 20922[ISI][Medline]
46 Hoiby N, Jarlov JO, Kemp M, et al. Excretion of ciprofloxacin in sweat and multiresistant Staphylococcus epidermidis. Lancet 1997; 349: 1679[CrossRef][ISI][Medline]
47 Hoiby N, Pers C, Johansen HK, Hansen H. Excretion of beta lactam antibiotics in sweata neglected mechanism for development of antibiotic resistance? Antimicrob Agents Chemother 2000; 44: 28557
48 Ibelings MMS, Bruining HA. Methicillin-resistant Staphylococcus aureus: acquisition and risk of death in patients in the Intensive Care Unit. Eur J Surg 1998; 164: 4118[CrossRef][ISI][Medline]
49 Jawad A, Heritage J, Snelling AM, Gascoyne-Binzi DM, Hawkey PM. Influence of relative humidity and suspending menstrua on survival of acinetobacter spp. on dry surfaces. J Clin Microbiol 1996; 34: 28817[Abstract]
50 Jevons MP. Celbeninresistant Staphylococci. BMJ 1961; 1: 1245[ISI]
51 Johnson 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: 1434
52 Jonas D, Speck M, Daschner FD, Grundmann H. Rapid PCR-based identification of methicillin-resistant Staphylococcus aureus from screening swabs. J Clin Microbiol 2002; 40: 18213
53 Jones RN, Deshpande LM, Mutnick AH, Biedenbach DJ. In vitro evaluation of BAL9141, a novel parenteral cephalosporin active against oxacillin-resistant staphylococci. J Antimicrob Chemother 2002; 50: 91532
54 Karabey S, Ay P, Derbentli S, Nakipoglu Y, Esen F. Hand washing frequencies in an intensive care unit. J Hosp Infect 2002; 50: 3641[CrossRef][ISI][Medline]
55 Katayama 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: 154955
56 Klutymans 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: 2169[ISI][Medline]
57 Lacey RW, Barr KW, Barr VE, Inglis TJ. Properties of methicillin-resistant Staphylococcus aureus colonising patients in a burns unit. J Hosp Infect 1986; 7: 13748[ISI][Medline]
58 Lamb HM, Figgilt DP, Faulds D. Quinopristin/dalfopristin: a review of its use in the management of serious Gram positive infections. Drugs 1999; 58: 106197[ISI][Medline]
59 Larson 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: 6048[ISI][Medline]
60 Law MR, Gill ON. Hospital acquired infection with methicillin-resistant and methicillin-sensitive staphylococci. Epidemiol Infect 1988; 101: 6239[ISI][Medline]
61 Louie 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: 278690
62 Manhold 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: 132730[CrossRef][ISI][Medline]
63 Merrer J, Santoli F, Vecchi C, et al. Colonization pressure and risk of acquisition of methicillin resistant Staphylococcus aureus in a medical intensive care unit. Infect Control Hosp Epidemiol 2000; 21: 71823[ISI][Medline]
64 Miller MA, Dascal A, Portnoy J, Mendelson J. Development of mupirocin resistance among methicillin-resistant Staphylococcus aureus after widespread use of nasal mupirocin ointment. Infect Control Hosp Epidemiol 1996; 17: 8113[ISI][Medline]
65 Moore PCL, Lindsay JA. Molecular characterisation of the dominant UK methicillin-resistant Staphylococcus aureus strains, EMRSA-15 and EMRSA-16. J Med Microbiol 2002; 51: 51621
66 Mortimer EA, Wolinsky E, Gonzaga AJ, Rammelkamp CH. Role of airborne transmission in Staphylococcal infections. BMJ 1966; 1: 31822
67 Nagura J, Sugano T, Yamamoto A, et al. CP5609, a novel parenteral carbapenem: efficacy on experimental endocarditis due to methicillin-resistant Staphylococcus aureus. Proceedings of the 42nd ICAAC Conference 2002: F321
68 Neely AN, Maley MP. Survival of Enterococci and Staphylococci on hospital fabrics and plastics. J Clin Microbiol 2000; 38: 7246
69 Noble 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: 1958[CrossRef][ISI]
70 Petersen PJ, Bradford PA, Weiss WJ, et al. In vitro and in vivo activities of tigecycline (GAR-936), daptomycin, and comparative antimicrobial agents against glycopeptide-intermediate Staphylococcus aureus and other resistant Gram-positive pathogens. Antimicrob Agents Chemother 2002; 46: 2595601
71 Pittet D, Hugonnet S, Harbarth S, et al. Effectiveness of a hospital-wide programme to improve compliance with hand hygiene. Lancet 2000; 356: 130712[CrossRef][ISI][Medline]
72 Pittet D, Mourouga P, Perneger TV. Compliance with handwashing in a teaching hospital. Ann Intern Med 1999; 130: 12630
73 Pujol 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: 96102[ISI][Medline]
74 Rampling A, Wiseman S, Davis L, et al. Evidence that hospital hygiene is important in the control of methicillin-resistant Staphylococcus aureus. J Hosp Infect 2001; 49: 10916[CrossRef][ISI][Medline]
75 Rello J, Torres A, Ricart M, et al. Ventilator-associated pneumonia by Staphylococcus aureus. Comparison of methicillin-resistant and methicillin-sensitive episodes. Am J Respir Crit Care Med 1994; 150: 15459[Abstract]
76 Rolinson GN. Letter. BMJ 1961; 1: 1256
77 Rubinstein E, Cammarata SE, Oliphant TH, Wunderink RG, Group LNPS. Linezolid (PNU-100766) versus vancomycin in the treatment of hospitalized patients with nosocomial pneumonia: a randomized, double-blind, multicenter study. Clin Infect Dis 2001; 32: 40212[CrossRef][ISI][Medline]
78 Rutala WA, Blythe Setzer Katz E, Sherertz RJ, Sarubbi FA. Environmental study of a methicillin-resistant Staphylococcus aureus epidemic in a burn unit. J Clin Microbiol 1983; 18: 6838[ISI][Medline]
79 Scheme NINS. Surveillance of hospital-acquired bacteraemia in English hospitals 19972002. In: Report, Public Health Laboratory Service. London, 2002: 89
80 Scheme NINS. Surveillance of surgical site infection in English hospitals 19972001. In: Report, Public Health Laboratory Service. London, 2002: 89
81 Sebille V, Cheveret S, Valleron AJ. Modeling the spread of resistant nosocomial pathogens in an intensive-care unit. Infect Control Hosp Epidemiol 1997; 18: 8492[ISI][Medline]
82 Shiomori T, Miyamoto H, Makishima K. Significance of airborne transmission of methicillin-resistant Staphylococcus aureus in an otolaryngology head and neck surgery unit. Arch Otolaryngol Head Neck Surg 2001; 127: 6448
83 Shiomori T, Miyamoto H, Makishima K, et al. Evaluation of bedmaking-related airborne and surface methicillin-resistant Staphylococcus aureus contamination. J Hosp Infect 2002; 50: 305[CrossRef][ISI][Medline]
84 Talon D. The role of the hospital environment in the epidemiology of multi-resistant bacteria. J Hosp Infect 1999; 43: 137[CrossRef][ISI][Medline]
85 Theaker C, Ormond-Walshe S, Azadian B, Soni N. MRSA in the critically ill. J Hosp Infect 2001; 48: 98102[CrossRef][ISI][Medline]
86 Thompson BL, Dwyer DM, Ussery XT, et al. Handwashing and glove use in a long term care facility. Infect Control Hosp Epidemiol 1997; 18: 97103[ISI][Medline]
87 Towner 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: 60713[Abstract]
88 Tsuji M, Matsuda H, Miwa H, Shimada J, Kuwahara S. S-3578, a new broad spectrum cephalosporin with anti-MRSA activity: II. In vitro activity against experimental animal infection models. Proceedings of the 42nd ICAAC Conference 2002: F339
89 Utsui Y, Yokota T. Role of an altered penicillin-binding protein in methicillin and cephem-resistant Staphylococcus aureus. Antimicrob Agents Chemother 1985; 28: 397403[ISI][Medline]
90 vanBelkum 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: 16539
91 Vandenbroucke-Grauls CMJE. Methicillin-resistant Staphylococcus aureus control in hospitals: the Dutch experience. Infect Control Hosp Epidemiol 1996; 17: 5123[ISI][Medline]
92 Vicca AF. Nursing staff workload as a determinant of methicillin-resistant Staphylococcus aureus spread in an adult intensive therapy unit. J Hosp Infect 1999; 43: 10913[CrossRef][ISI][Medline]
93 Vincent J-L, Bihari DJ, Suter PM, et al. The Prevalence of nosocomial infection in intensive care (EPIC) study. JAMA 1995; 274: 63944[Abstract]
94 Weller T. Methicillin-resistant Staphylococcus aureus typing methods: which should be the International standard? J Hosp Infect 2000; 46: 16072[CrossRef][ISI][Medline]
95 Wilson P, Andrews JA, Charlesworth R, et al. Linezolid resistance in clinical isolates of Staphylococcus aureus. J Antimicrob Chemother 2003; 51: 1868