Isolation measures in the hospital management of methicillin resistant Staphylococcus aureus (MRSA): systematic review of the literature
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《英国医生杂志》
1 University Department Medical Microbiology, Royal Free Campus, Royal Free and University College Medical School, University London, London NW3 2PF], 2 Academic Department Geriatric Medicine, Royal Free Campus, Royal Free and University College Medical School, 3 Laboratory of Healthcare Associated Infection, Central Public Health, Laboratory, Health Protection Agency, London NW9 5HT, 4 Collaborative Centre for Economics of Infectious Disease, Department Public Health and Policy, London School of Hygiene and Tropical Medicine, University London WC1E 7HT, 5 Department of Biological Sciences, University of Warwick, Coventry CV4 7AL UK, 6 Division of Healthcare Associated Infection and Antimicrobial Resistance, Health Protection Agency, Communicable Disease Surveillance Centre, London NW9 5EQ, 7 University Library, Royal Free Campus, Royal Free and University College Medical School, 8 Department of Social Medicine, Bristol University Medical School, University of Bristol BS8 2PR
Correspondence to: S P Stone s.stone@rfc.ucl.ac.uk
Abstract
The incidence of hospital acquired methicillin resistant Staphylococcus aureus (MRSA) continues to rise globally.1-4 Attempts to control this spread have relied principally on three measures: hand hygiene among healthcare workers, restriction of antibiotics, and the detection and isolation of infected or colonised patients. We consider the detection and isolation of infected or colonised patients, which is central to most national guidelines.5-8
Most transmission of MRSA from patient to patient is thought to be mediated by transiently colonised healthcare workers, although airborne dispersal and transmission through contacts with contaminated surfaces may also be important. Isolation measures for patients are intended to interrupt such transmission. The most intensive forms of isolating patients are isolation wards (designated for the treatment of known or suspected carriers of MRSA) and nurse cohorting (the physical segregation of MRSA patients in one part of a ward, with nursing by designated staff who care exclusively for these patients). Other isolation measures include the use of single bedded rooms, cohorts of patients on general wards (without designated nursing staff), and barrier precautions (use of aprons or gowns, gloves, and, in some cases, masks by healthcare workers as the only physical barrier to transmission).
Such control measures may place substantial burdens on hospital resources, and the value of their continued use has been questioned.9 Earlier narrative reviews have been undertaken,10 11 but the effectiveness of isolation measures in reducing transmission and controlling MRSA has not been assessed systematically. Moreover, as much of the research in this area is known to be of a quasi-experimental nature.8 11 The associated threats to valid inferences need to be considered.12-14 We therefore undertook a systematic review of the evidence for the effectiveness of isolation measures in the management of MRSA in hospitals.
Method
The electronic search selected 4382 abstracts. Hand searching produced no additional papers. Appraisal of abstracts selected 254 papers, including 20 in languages other than English. The final review included 46 studies (table 1).17-63
Table 1 Characteristics of the 46 accepted studies
Study design
We found no randomised controlled trials and only four prospective planned comparison studies with predefined study phases.22 40 52 63 Most designs were interrupted time series—that is, time series of outcome measures recorded before and after one or more interventions. However, eight of 38 interrupted time series studies presented only collapsed data, summarising time series from each phase in a single data point. One retrospective cohort study used survey data from all Dutch hospitals.30
Ten studies did not compare isolation or screening measures with respect to isolation or screening.17 33 37 41 44 49 56 59 60 62 Review of the 36 studies allowing comparisons between isolation policies indicated that in 27 the comparisons being made were dependent on knowledge of the outcome data. Short retrospective studies with successful outcomes were particularly vulnerable to this problem; in at least seven the decision to intervene was influenced by part of the outcome data reported. This, and the predominance of unplanned retrospective reports, shows that reporting bias is likely to be important.
Threats to internal validity of evidence
In the absence of cluster randomised trials, all comparative studies were vulnerable to selection bias, yet recording and adjustment of potential confounders was minimal (table 2). In two cases we considered reported changes in case mix to represent a plausible explanation for changes in the incidence of MRSA.43 46
We identified changes in antibiotic prescribing, staff workload and ratios of staff to patients, and lengths of stay as the main potential sources of performance bias. Again, few studies reported data allowing an assessment of these, and none provided adjustment in the analysis (table 2). In a few cases some information was available that implied that performance bias could plausibly explain changes in MRSA outcomes.54 18 22 33
Similarly, studies took few measures (such as blinding of outcome assessors) to prevent detection bias, although we considered studies reporting infections with specified diagnostic criteria and bacteraemias as primary outcomes to be less vulnerable to this bias.
Trends, regression to the mean, and seasonal effects
Of 30 studies with two or more phases and pre-intervention time series, clear trends were apparent in 13. In all cases the trend was for increasing MRSA levels before major interventions.
Trends in the number of patients colonised on admission may also complicate interpretation of outcomes. Of 35 studies presenting time series data, only five of the 18 studies that assessed whether patients were colonised on admission presented sufficient data to assess trends. In two cases there was an increasing trend,32 50 in one a decreasing trend,46 and in two no clear trend.33 40 In two cases these trends provided a plausible explanation for changes in outcome measures.32 46
Regression to the mean effects were considered likely when unusually high MRSA incidence data prompted the intervention and when these data were included in the study. We considered this threat to provide a plausible explanation of outcomes in seven studies.18 22 23 24 47 48 58
Inspection showed that seasonal effects may have been important in two23 58 of 14 studies with time series of 18 months or more. In the 21 studies with shorter time series it was not possible to disentangle seasonal from intervention effects.
Changes in MRSA strain types may explain changes in outcomes. Fourteen studies reported no typing details. In one study we considered the documented introduction of a new strain believed to have greater epidemic potential to plausibly explain increased MRSA incidence and control failure.32
Statistical validity
Of the 38 interrupted time series, 24 reported results of statistical analysis. In all but one study38 where the analysis could be assessed patient outcomes were assumed by authors to be independent. Such assumptions are inappropriate when transmission from patient to patient occurs and would cause inflated rates of type I errors. In one study we considered the independence assumption to be justified as outcomes at hospital level from distinct hospitals were used.30
Evidence for control of MRSA
In 45 of the 46 studies multiple simultaneous control measures were apparent. It was not possible to assess the relative contribution of individual measures.
In 14 studies it was impossible to draw any conclusions about the effect of interventions. Most of the remaining 32 reported evidence consistent with reduction in MRSA transmission. The evidence in 18 of these we considered weak, because of poor study design or clear alternative explanations. This often applied to small and successfully controlled outbreaks managed by isolation wards or nurse cohorting.17 19 39 50 51 53 55 56 61 None the less, it remains possible that immediate deployment of nurse cohorting or an isolation ward may be successful. Fourteen studies provided "stronger" evidence or evidence of intermediate strength (tables 3 and 4).
Table 3 Studies providing stronger evidence
Table 4 Studies providing intermediate levels of evidence
Outcome of studies considered to present the strongest evidence Interrupted time series for A: Coello et al25 B: Cosseron Zerbib et al26 C: Duckworth et al28 D: Faoagli et al31 E: Farrington et al32 F: Harbath et al.35 36 Table 3 gives explanatory text. Asterisks indicate phases with most intensive isolation policies. In D and E isolation policies in both phases were similar (isolation wards), but in the second phase the capacities of the isolation wards were exceeded in both cases, and the overflow was cohorted or isolated in single rooms
The strongest evidence came from six longer time series, with detailed information on interventions and fewer plausible alternative explanations (table 3, figure). In four cases major outbreaks were controlled or MRSA numbers substantially reduced over prolonged periods25 26 28 35 36; the main isolation measures were single room in two studies,26 35 36 nurse cohorting in one,25 and isolation ward in one.28 Another isolation ward study reported failure to control the spread of MRSA,31 and another reported control by an isolation ward for many years followed by eventual failure.32
We considered eight studies (table 4) to present evidence of reduction of MRSA by measures that included an isolation ward,46 54 nurse cohorting,16 20 or other interventions. 30 38 40 One presented data indicating the failure of an isolation ward to control MRSA.27 However, these studies either had plausible alternative explanations or reported smaller changes in MRSA and did not record some important potential confounders. The evidence was therefore considered weaker than that from the first six. We found evidence from only one study that supported the hypothesis that MRSA replaces methicillin-sensitive Staphylococcus aureus (MSSA).43 MRSA and MSSA bacteraemia data from the longer time series31 32 36 contradicted this and showed that MRSA added to the total burden of infection.
Discussion
Public Health Laboratory Service. The first year of the Department of Health's mandatory MRSA bacteraemia surveillance scheme in acute NHS trusts in England: April 2001-March 2002. Commun Dis Rep CDR Wkly 2002;12: www.hpa.org.uk/cdr/PDFfiles/2002/cdr2502.pdf (accessed 22 Jul 2004).
Hiramatsu K, Hanaki H, Ino T. Methicillin resistant Staphylococcus aureus clinical strain with reduced vancomycin susceptibility. J Antimicrob Chemother 1997;40: 135-6.
Turnidge JD, Bell JM Methicillin-resistant Staphylococcus aureus evolution in Australia over 35 years. Microb Drug Resist 2000;6: 223-9.
Centers for Disease Control and Prevention. National nosocomial infection surveillance systems report, data summary from January 1992-June 2001, issued August 2001. Am J Infect Control 2002;30: 458-75.
Garner JS. Hospital infection control practices advisory commitee. Guideline for isolation precautions in hospitals. Infect Control Hosp Epidemiol 1996;17: 53-80.
Wierkgroup Infectie Preventie. Management policy for methicillin-resistant Staphylococcus aureus. Guideline No. 35A. Leiden: WIP, 1994.
Ministry of Health. Guidelines for the control of methicillin-resistant Staphylococcus aureus in New Zealand. Wellington: MoH, 2002. www.moh.govt.nz/moh.nsf/49ba80c00757b8804c256673001d47d0/ e5231b74a5dc8b22cc256c220017b248/$FILE/mrsa.pdf (accessed 12 Jul 2004).
British Society for Antimicrobial Chemotherapy, Hospital Infection Society and the Infection Control Nurses Association. Revised guidelines for the control of methicillin-resistant Staphylococcus aureus infection in hospitals. J Hosp Infect 1998;39: 253-90.
Rahman M, Sanderson PJ, Bentley AH, Barrett SP, Karim QN, Teare EL, et al. Control of MRSA. J Hosp Infect 2000;44: 151-3.
Boyce JM. Nosocomial staphylococcal infections. Ann Intern Med 1981;95: 241-2.
Stone SP. Managing methicillin-resistant Staphylococcus aureus in hospital: the balance of risk. Age Ageing 1997;26: 165-8.
Cook TD, Campbell DT. Quasi-experimentation: design and analysis issues for field settings. Chicago: Rand McNally College Publications, 1979.
Grimes DA, Schulz KF. Cohort studies: marching towards outcomes. Lancet 2002;359: 341-5.
Cochrane Effective Practice and Organisation of Care (EPOC) Review Group. Cochrane Library Database. Oxford: 2001. Issue 1. Update software.
Morton V, Torgerson DJ. Effect of regression to the mean on decision making in health care. BMJ 2003 May 17;326: 1083-4.
Cooper BS, Stone SP, Kibbler CC, Cookson BD, Roberts JA, Medley GF, Duckworth GJ, Lai R, Ebrahim S. Systematic review of isolation policies in the hospital management of methicillin-resistant Staphylococcus aureus: a review of the literature with epidemiological and economic modelling. Health Technol Assess 2003;7: 1-194.
Alvarez S, Shell C, Gage K, Guarderas J, Kasprzyk D, Besing J, et al. An outbreak of methicillin-resistant Staphylococcus aureus eradicated from a large teaching hospital. Am J Infect Control 1985;13: 115-21.
Arnow P, Allyn PA, Nichols EM, Hill DL, Pezzlo M, Bartlett RH. Control of methicillin-resistant Staphylococcus aureus in a burn unit: role of nurse staffing. J Trauma 1982;22: 954-9.
Back NA, Linnemann CC, Jr., Staneck JL, Kotagal UR. Control of methicillin-resistant Staphylococcus aureus in a neonatal intensive-care unit: use of intensive microbiologic surveillance and mupirocin. Infect Control Hospital Epidemiol 1996;17: 227-31.
Barakate MS, Harris JP, West RH, Vickery AM, Sharp CA, Macleod C, et al. A prospective survey of current methicillin-resistant Staphylococcus aureus control measures. Austr N Z J Surg 1999;69: 712-6.
Barakate MS, Yang YX, Foo SH, Vickery AM, Sharp CA, Fowler LD, et al. An epidemiological survey of methicillin-resistant Staphylococcus aureus in a tertiary referral hospital. J Hosp Infect 2000;44: 19-26.
Blumberg LH, Klugman KP. Control of methicillin-resistant Staphylococcus aureus bacteraemia in high-risk areas. Eur J Clin Microbiol Infect Dis 1994;13: 82-5.
Brady LM, Thomson M, Palmer MA, Harkness JL. Successful control of endemic MRSA in a cardiothoracic surgical unit. Med J Austr 1990;152: 240-5.
Campbell JR, Zaccaria E, Mason EO Jr, Baker CJ. Epidemiological analysis defining concurrent outbreaks of Serratia marcescens and methicillin-resistant Staphylococcus aureus in a neonatal intensive-care unit. Infect Control Hosp Epidemiol 1998;19: 924-928.
Coello R, Jimenez J, Garcia M, Arroyo P, Minguez D, Fernandez C, et al. Prospective study of infection, colonization and carriage of methicillin-resistant Staphylococcus aureus in an outbreak affecting 990 patients. Eur J Clin Microbiol Infect Dis 1994;13: 74-81.
Cosseron-Zerbib M, Roque Afonso AM, Naas T, Durand P, Meyer L, Costa et al. A control programme for MRSA (methicillin-resistant Staphylococcus aureus) containment in a paediatric intensive care unit: evaluation and impact on infections caused by other micro-organisms. J Hosp Infect 1998;40: 225-35.
Cox RA, Conquest C, Mallaghan C, Marples RR. A major outbreak of methicillin-resistant Staphylococcus aureus caused by a new phage-type (EMRSA-16). J Hosp Infect 1995;29: 87-106.
Duckworth GJ, Lothian JL, Williams JD. Methicillin-resistant Staphylococcus aureus: report of an outbreak in a London teaching hospital. J Hosp Infect 1988;11: 1-15.
El Hagrasy M. An outbreak of methicillin-resistant Staphylococcus aureus (MRSA) in a hospital in the UAE: Problems and solutions. Emirates Med J 1997;15: 17-21.
Esveld MI, de Boer AS, Notenboom AJ, van Pelt W, van Leeuwen WJ. . Nederlands Tijdschrift voor Geneeskunde 1999;143: 205-8.
Faoagali JL, Thong ML, Grant D. Ten years' experience with methicillin-resistant Staphylococcus aureus in a large Australian hospital. J Hosp Infect 1992;20: 113-9.
Farrington M, Redpath C, Trundle C, Coomber S, Brown NM. Winning the battle but losing the war: methicillin-resistant Staphylococcus aureus (MRSA) at a teaching hospital. QJM 1998:91: 539-48.
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: 543-50.
Girou E, Azar J, Wolkenstein P, Cizeau F, Brun-Buisson C, Roujeau JC. Comparison of systematic versus selective screening for methicillin-resistant Staphylococcus aureus carriage in a high-risk dermatology ward. Infect Control Hosp Epidemiol 2000;21: 583-7.
Harbarth S, Martin Y, Rohner P, Henry N, Auckenthaler R, Pittet D. Effect of delayed infection control measures on a hospital outbreak of methicillin-resistant Staphylococcus aureus. J Hosp Infect 2000;46: 43-9.
Pittet D, Hugonnet S, Harbarth S, Mourouga P, Sauvan V, Touveneau S, et al. Effectiveness of a hospital-wide programme to improve compliance with hand hygiene. Infection Control Programme. Lancet 2000;356: 1307-12.
Hartstein AI, LeMonte AM, Iwamoto PK. DNA typing and control of methicillin-resistant Staphylococcus aureus at two affiliated hospitals. Infect Control Hosp Epidemiol 1997;18: 42-8.
Jernigan JA, Titus MG, Groschel DH, Getchell-White S, Farr BM. Effectiveness of contact isolation during a hospital outbreak of methicillin-resistant Staphylococcus aureus. Am J Epidemiol 1996;143: 496-504.
Jones MR, Martin DR. Outbreak of methicillin-resistant Staphylococcus aureus infection in a New Zealand hospital. N Z Med J 1987;100: 369-73.
Kac G, Buu-Hoi A, Herisson E, Biancardini P, Debure C. Methicillin-resistant Staphylococcus aureus. Nosocomial acquisition and carrier state in a wound care center. Arch Dermatol 2000;136: 735-9.
Landman D, Chockalingam M, Quale JM. Reduction in the incidence of methicillin-resistant Staphylococcus aureus and ceftazidime-resistant Klebsiella pneumoniae following changes in a hospital antibiotic formulary. Clin Infect Dis 1999;28: 1062-6.
Law MR, Gill ON, Turner A. Methicillin-resistant Staphylococcus aureus: associated morbidity and effectiveness of control measures. Epidemiol Infect 1988;101: 301-9.
Linnemann CC, Jr., Mason M, Moore P, Korfhagen TR, Staneck JL. Methicillin-resistant Staphylococcus aureus: experience in a general hospital over four years. Am J Epidemiol 1982;115: 941-50.
Lugeon C, Blanc DS, Wenger A, Francioli P. Molecular epidemiology of methicillin-resistant Staphylococcus aureus at a low-incidence hospital over a 4-year period. Infect Control Hospital Epidemiol 1995;16: 260-7.
Mayall B, Martin R, Keenan AM, Irving L, Leeson P, Lamb K. Blanket use of intranasal mupirocin for outbreak control and long-term prophylaxis of endemic methicillin-resistant Staphylococcus aureus in an open ward. J Hosp Infect 1996;32: 257-26.
Murray-Leisure KA, Geib S, Graceley D, Rubin-Slutsky AB, Saxena N, Muller HA, et al. Control of epidemic methicillin-resistant Staphylococcus aureus. Infect Control Hosp Epidemiol 1990;11: 343-50.
Onesko KM, Wienke EC. The analysis of the impact of a mild, low-iodine, lotion soap on the reduction of nosocomial methicillin-resistant Staphylococcus aureus: a new opportunity for surveillance by objectives. Infect Control 1987;8: 284-8.
Oto MA, Pinto CME, Martinez CV, Fabio BC, Soza MA, Jerez RA, et al. Control of methicillin resistant Staphylococcus aureus at a neonatal ward. Rev Chil Pediatr 1992;63: 134-8.
Papia G, Louie M, Tralla A, Johnson C, Collins V, Simor AE. Screening high-risk patients for methicillin-resistant Staphylococcus aureus on admission to the hospital: is it cost effective? Infect Control Hosp Epidemiol 1999;20: 473-7.
Pearman JW, Christiansen KJ, Annear DI, Goodwin CS, Metcalf C, Donovan FP, et al. Control of methicillin-resistant Staphylococcus aureus (MRSA) in an Australian metropolitan teaching hospital complex. Med J Austr 1985;142: 103-8.
Pfaller MA, Wakefield DS, Hollis R, Frederickson M, Evans E, Massanari RM. The clinical microbiology laboratory as an aid in infection control. The application of molecular techniques in epidemiologic studies of methicillin-resistant Staphylococcus aureus. Diagn Microbiol Infect Dis 1991;14: 209-17.
Ribner BS, Landry MN, Gholson GL. Strict versus modified isolation for prevention of nosocomial transmission of methicillin-resistant Staphylococcus aureus. Infect Control 1986;7: 317-20.
Schlunzen L, Lund B, Schouenborg P, Skov RL. . Ugeskrift for Laeger 1997;159: 431-5.
Selkon JB, Stokes ER, Ingham HR. The role of an isolation unit in the control of hospital infection with methicillin-resistant staphylococci. J Hosp Infect 1980;1: 41-6.
Shanson DC, Kensit JC, Duke R. Outbreak of hospital infection with a strain of Staphylococcus aureus resistant to gentamicin and methicillin. Lancet 1976;2: 1347-8.
Shanson DC, Johnstone D, Midgley J. Control of a hospital outbreak of methicillin-resistant Staphylococcus aureus infections: value of an isolation unit. J Hosp Infect 1985;6: 285-292.
Souweine B, Traore O, Aublet-Cuvelier B, Bret L, Sirot J, Laveran H, et al. Role of infection control measures in limiting morbidity associated with multi-resistant organisms in critically ill patients. J Hosp Infect 2000;45: 107-16.
Stone SP, Beric V, Quick A, Balestrini AA, Kibbler CC. The effect of an enhanced infection-control policy on the incidence of Clostridium difficile infection and methicillin-resistant Staphylococcus aureus colonization in acute elderly medical patients. Age Ageing 1998;27: 561-8.
Talon D, Rouget C, Cailleaux V, Bailly P, Thouverez M, Barale F, et al. Nasal carriage of Staphylococcus aureus and cross-contamination in a surgical intensive care unit: Efficacy of mupirocin ointment. J Hosp Infect 1995;30: 39-49.
Tambic A, Power EG, Tambic T, Snur I, French GL. Epidemiological analysis of methicillin-resistant Staphylococcus aureus in a Zagreb Trauma Hospital using a randomly amplified polymorphic DNA-typing method. Eur J Clin Microbiol Infect Dis 1999;18: 335-40.
Ward TT, Winn RE, Hartstein AI, Sewell DL. Observations relating to an inter-hospital outbreak of methicillin-resistant Staphylococcus aureus: role of antimicrobial therapy in infection control. Infect Control 1981;2: 453-9.
Yano M, Doki Y, Inoue M, Tsujinaka T, Shiozaki H, Monden M. Preoperative intranasal mupirocin ointment significantly reduces postoperative infection with Staphylococcus aureus in patients undergoing upper gastrointestinal surgery. Surg Today 2000;30: 16-21.
Yoshida J, Kuroki S, Akazawa K, Chijiiwa K, Takemori K, Torisu M, et al. The order of ward rounds influences nosocomial infection. A 2-year study in gastroenterologic surgery patients. J Gastroenterol 1995;30: 718-24.
Mulligan ME, Murray-Leisure KA, Ribner BS, Standiford HC, John JF, Korvick JA, et al. Methicillin-resistant Staphylococcus aureus: a consensus review of the microbiology, pathogenesis, and epidemiology with implications for prevention and management. Am J Med 1993;94: 313-28.
Spicer WJ. Three strategies in the control of staphylococci including methicillin-resistant Staphylococcus aureus. J Hosp Infect 1984;5(suppl A): 45-9.
Bell SM. Recommendations for control of the spread of methicillin resistant Staphylococcus aureus infection. Med J Austr 1982;2: 472-4.
Farr BM, Salgado CD, Karchmer TB, Sheretz RJ. Can antibiotic resistant nosocomail infections be controlled? Lancet Infect Dis 2001;1: 38-45.
Crowcroft NS, Catchpole M. Mortality from methicillin resistant Staphylococcus aureus in England and Wales: analysis of death certificates. BMJ 2002;325: 1390-1.
Centers for Disease Control and Prevention. Staphylococcus areus resistant to vancomycin—United States, 2002. Morb Mortal Wkly Rep MMWR 2002;51: 565-7.
Perry CN, Jarvis B Linezolid: a review of its use in the management of serious gram positive infections. Drugs 2001;61: 525-51.(B S Cooper, postdoctoral )
Correspondence to: S P Stone s.stone@rfc.ucl.ac.uk
Abstract
The incidence of hospital acquired methicillin resistant Staphylococcus aureus (MRSA) continues to rise globally.1-4 Attempts to control this spread have relied principally on three measures: hand hygiene among healthcare workers, restriction of antibiotics, and the detection and isolation of infected or colonised patients. We consider the detection and isolation of infected or colonised patients, which is central to most national guidelines.5-8
Most transmission of MRSA from patient to patient is thought to be mediated by transiently colonised healthcare workers, although airborne dispersal and transmission through contacts with contaminated surfaces may also be important. Isolation measures for patients are intended to interrupt such transmission. The most intensive forms of isolating patients are isolation wards (designated for the treatment of known or suspected carriers of MRSA) and nurse cohorting (the physical segregation of MRSA patients in one part of a ward, with nursing by designated staff who care exclusively for these patients). Other isolation measures include the use of single bedded rooms, cohorts of patients on general wards (without designated nursing staff), and barrier precautions (use of aprons or gowns, gloves, and, in some cases, masks by healthcare workers as the only physical barrier to transmission).
Such control measures may place substantial burdens on hospital resources, and the value of their continued use has been questioned.9 Earlier narrative reviews have been undertaken,10 11 but the effectiveness of isolation measures in reducing transmission and controlling MRSA has not been assessed systematically. Moreover, as much of the research in this area is known to be of a quasi-experimental nature.8 11 The associated threats to valid inferences need to be considered.12-14 We therefore undertook a systematic review of the evidence for the effectiveness of isolation measures in the management of MRSA in hospitals.
Method
The electronic search selected 4382 abstracts. Hand searching produced no additional papers. Appraisal of abstracts selected 254 papers, including 20 in languages other than English. The final review included 46 studies (table 1).17-63
Table 1 Characteristics of the 46 accepted studies
Study design
We found no randomised controlled trials and only four prospective planned comparison studies with predefined study phases.22 40 52 63 Most designs were interrupted time series—that is, time series of outcome measures recorded before and after one or more interventions. However, eight of 38 interrupted time series studies presented only collapsed data, summarising time series from each phase in a single data point. One retrospective cohort study used survey data from all Dutch hospitals.30
Ten studies did not compare isolation or screening measures with respect to isolation or screening.17 33 37 41 44 49 56 59 60 62 Review of the 36 studies allowing comparisons between isolation policies indicated that in 27 the comparisons being made were dependent on knowledge of the outcome data. Short retrospective studies with successful outcomes were particularly vulnerable to this problem; in at least seven the decision to intervene was influenced by part of the outcome data reported. This, and the predominance of unplanned retrospective reports, shows that reporting bias is likely to be important.
Threats to internal validity of evidence
In the absence of cluster randomised trials, all comparative studies were vulnerable to selection bias, yet recording and adjustment of potential confounders was minimal (table 2). In two cases we considered reported changes in case mix to represent a plausible explanation for changes in the incidence of MRSA.43 46
We identified changes in antibiotic prescribing, staff workload and ratios of staff to patients, and lengths of stay as the main potential sources of performance bias. Again, few studies reported data allowing an assessment of these, and none provided adjustment in the analysis (table 2). In a few cases some information was available that implied that performance bias could plausibly explain changes in MRSA outcomes.54 18 22 33
Similarly, studies took few measures (such as blinding of outcome assessors) to prevent detection bias, although we considered studies reporting infections with specified diagnostic criteria and bacteraemias as primary outcomes to be less vulnerable to this bias.
Trends, regression to the mean, and seasonal effects
Of 30 studies with two or more phases and pre-intervention time series, clear trends were apparent in 13. In all cases the trend was for increasing MRSA levels before major interventions.
Trends in the number of patients colonised on admission may also complicate interpretation of outcomes. Of 35 studies presenting time series data, only five of the 18 studies that assessed whether patients were colonised on admission presented sufficient data to assess trends. In two cases there was an increasing trend,32 50 in one a decreasing trend,46 and in two no clear trend.33 40 In two cases these trends provided a plausible explanation for changes in outcome measures.32 46
Regression to the mean effects were considered likely when unusually high MRSA incidence data prompted the intervention and when these data were included in the study. We considered this threat to provide a plausible explanation of outcomes in seven studies.18 22 23 24 47 48 58
Inspection showed that seasonal effects may have been important in two23 58 of 14 studies with time series of 18 months or more. In the 21 studies with shorter time series it was not possible to disentangle seasonal from intervention effects.
Changes in MRSA strain types may explain changes in outcomes. Fourteen studies reported no typing details. In one study we considered the documented introduction of a new strain believed to have greater epidemic potential to plausibly explain increased MRSA incidence and control failure.32
Statistical validity
Of the 38 interrupted time series, 24 reported results of statistical analysis. In all but one study38 where the analysis could be assessed patient outcomes were assumed by authors to be independent. Such assumptions are inappropriate when transmission from patient to patient occurs and would cause inflated rates of type I errors. In one study we considered the independence assumption to be justified as outcomes at hospital level from distinct hospitals were used.30
Evidence for control of MRSA
In 45 of the 46 studies multiple simultaneous control measures were apparent. It was not possible to assess the relative contribution of individual measures.
In 14 studies it was impossible to draw any conclusions about the effect of interventions. Most of the remaining 32 reported evidence consistent with reduction in MRSA transmission. The evidence in 18 of these we considered weak, because of poor study design or clear alternative explanations. This often applied to small and successfully controlled outbreaks managed by isolation wards or nurse cohorting.17 19 39 50 51 53 55 56 61 None the less, it remains possible that immediate deployment of nurse cohorting or an isolation ward may be successful. Fourteen studies provided "stronger" evidence or evidence of intermediate strength (tables 3 and 4).
Table 3 Studies providing stronger evidence
Table 4 Studies providing intermediate levels of evidence
Outcome of studies considered to present the strongest evidence Interrupted time series for A: Coello et al25 B: Cosseron Zerbib et al26 C: Duckworth et al28 D: Faoagli et al31 E: Farrington et al32 F: Harbath et al.35 36 Table 3 gives explanatory text. Asterisks indicate phases with most intensive isolation policies. In D and E isolation policies in both phases were similar (isolation wards), but in the second phase the capacities of the isolation wards were exceeded in both cases, and the overflow was cohorted or isolated in single rooms
The strongest evidence came from six longer time series, with detailed information on interventions and fewer plausible alternative explanations (table 3, figure). In four cases major outbreaks were controlled or MRSA numbers substantially reduced over prolonged periods25 26 28 35 36; the main isolation measures were single room in two studies,26 35 36 nurse cohorting in one,25 and isolation ward in one.28 Another isolation ward study reported failure to control the spread of MRSA,31 and another reported control by an isolation ward for many years followed by eventual failure.32
We considered eight studies (table 4) to present evidence of reduction of MRSA by measures that included an isolation ward,46 54 nurse cohorting,16 20 or other interventions. 30 38 40 One presented data indicating the failure of an isolation ward to control MRSA.27 However, these studies either had plausible alternative explanations or reported smaller changes in MRSA and did not record some important potential confounders. The evidence was therefore considered weaker than that from the first six. We found evidence from only one study that supported the hypothesis that MRSA replaces methicillin-sensitive Staphylococcus aureus (MSSA).43 MRSA and MSSA bacteraemia data from the longer time series31 32 36 contradicted this and showed that MRSA added to the total burden of infection.
Discussion
Public Health Laboratory Service. The first year of the Department of Health's mandatory MRSA bacteraemia surveillance scheme in acute NHS trusts in England: April 2001-March 2002. Commun Dis Rep CDR Wkly 2002;12: www.hpa.org.uk/cdr/PDFfiles/2002/cdr2502.pdf (accessed 22 Jul 2004).
Hiramatsu K, Hanaki H, Ino T. Methicillin resistant Staphylococcus aureus clinical strain with reduced vancomycin susceptibility. J Antimicrob Chemother 1997;40: 135-6.
Turnidge JD, Bell JM Methicillin-resistant Staphylococcus aureus evolution in Australia over 35 years. Microb Drug Resist 2000;6: 223-9.
Centers for Disease Control and Prevention. National nosocomial infection surveillance systems report, data summary from January 1992-June 2001, issued August 2001. Am J Infect Control 2002;30: 458-75.
Garner JS. Hospital infection control practices advisory commitee. Guideline for isolation precautions in hospitals. Infect Control Hosp Epidemiol 1996;17: 53-80.
Wierkgroup Infectie Preventie. Management policy for methicillin-resistant Staphylococcus aureus. Guideline No. 35A. Leiden: WIP, 1994.
Ministry of Health. Guidelines for the control of methicillin-resistant Staphylococcus aureus in New Zealand. Wellington: MoH, 2002. www.moh.govt.nz/moh.nsf/49ba80c00757b8804c256673001d47d0/ e5231b74a5dc8b22cc256c220017b248/$FILE/mrsa.pdf (accessed 12 Jul 2004).
British Society for Antimicrobial Chemotherapy, Hospital Infection Society and the Infection Control Nurses Association. Revised guidelines for the control of methicillin-resistant Staphylococcus aureus infection in hospitals. J Hosp Infect 1998;39: 253-90.
Rahman M, Sanderson PJ, Bentley AH, Barrett SP, Karim QN, Teare EL, et al. Control of MRSA. J Hosp Infect 2000;44: 151-3.
Boyce JM. Nosocomial staphylococcal infections. Ann Intern Med 1981;95: 241-2.
Stone SP. Managing methicillin-resistant Staphylococcus aureus in hospital: the balance of risk. Age Ageing 1997;26: 165-8.
Cook TD, Campbell DT. Quasi-experimentation: design and analysis issues for field settings. Chicago: Rand McNally College Publications, 1979.
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