Effect of delayed infection control measures on a hospital outbreak of methicillin-resistant Staphylococcus aureus

Journal of Hospital Infection (2000) 46: 43–49 doi:10.1053/jhin.2000.0798, available online at http://www.idealibrary.com on

Effect of delayed infection control measures on a hospital outbreak of methicillin-resistant Staphylococcus aureus S. Harbarth*,Y. Martin*, P. Rohner†, N. Henry*, R. Auckenthaler† and D. Pittet* *Infection Control Programme, †Clinical Microbiology Laboratory, Department of Internal Medicine, University of Geneva Hospitals, 1211 Geneva 14, Switzerland

Summary: All patients positive for methicillin-resistant Staphylococcus aureus (MRSA) at the University Hospitals of Geneva, Switzerland, between 1989 and 1997 (N\1771) were included in a cohort study to evaluate the consequences of delayed containment of a hospital-wide outbreak occurring during a 4-year absence of MRSA control measures. The effects of efforts to control both the MRSA reservoir and the number of bacteraemic patients were assessed. Intensive infection control measures were initiated in 1993 and included patient screening, on-site surveillance, contact isolation, a computerized alert system, and hospital-wide promotion of hand hygiene. An increase in the rate of new MRSA-infected or -colonized patients was observed between 1989 and 1994 (from 0.05 to 0.60 cases per 100 admissions), which subsequently decreased to 0.24 cases in 1997 (P\0.001). However, the proportion of laboratory-documented methicillin-resistant isolates among all S. aureus showed little variation in the years from 1993 onwards (range, 19–24%), reflecting the result of an increase in the number of screening cultures. The annual number of patients with MRSA bacteraemia strongly correlated with the hospital-wide prevalence of MRSA patients (R2\0.60; P\0.01) and the rate of new MRSA patients (R2\0.97; P\0.001). Consequently, the attack rate of nosocomial MRSA bacteraemia served as an excellent marker for the MRSA patient reservoir. In conclusion, despite delayed implementation, infection control measures had a substantial impact on both the reservoir of MRSA patients and the attack rate of MRSA bacteraemia. © 2000 The Hospital Infection Society

Keywords: Methicillin-resistant Staphylococcus aureus; epidemiology; bacteraemia; surveillance; nosocomial infection; outbreak.

Introduction Since its emergence almost 40 years ago, methicillin-resistant Staphylococcus aureus (MRSA) has become a global pathogen but there is ongoing Received 10 November 1999; revised manuscript accepted 10 May 2000. Corresponding author: Didier Pittet, M.D., M.S., Infection Control Programme, Department of Internal Medicine, 24, rue Micheli-du-Crest, University of Geneva Hospitals (UGH), 1211 Geneva 14, Switzerland. Tel: 41-22/372 98 28; Fax: 41-22/372 39 87; E-mail: [email protected] Current affiliation of Dr Stephan Harbarth: Division of Infectious Diseases, Children’s Hospital, Harvard Medical School, Boston. Supported by the Max-Kade-Foundation, New York, NY.

0195-6701/00/010043]07 $35.00

debate as to the most effective control strategy.1 Despite the abundant literature on the topic, the impact of intensive control measures on the proportion of patients with severe infections (e.g., bacteraemia), as well as the most effective surveillance strategy remains controversial. Some investigators have found that active surveillance, extensive patient screening and intensive control measures decreased the MRSA reservoir with a subsequent reduction in the rate of infection, whereas others have not observed this.2–5 MRSA infections were first observed in the late 1980s at the University of Geneva Hospitals (UGH), Switzerland, with a hospital-wide outbreak occurring between 1990 and 1993. Only in

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1993 were intensive control measures introduced to curb the spread of MRSA. We have investigated prospectively all MRSA patients since 1993 in order to evaluate the result of delayed containment of the outbreak during a 4-year absence of control measures. This study provides an insight into the control of MRSA in a large Swiss university hospital, describes important surveillance indicators and explores the effect of the infection control measures on the reservoir of MRSA patients and the rate of MRSA bacteraemia.

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(2)

(3)

Methods Setting UGH is a 1400 bed healthcare centre providing primary and tertiary medical care for Geneva, Switzerland, and the surrounding area serving a population of around 800 000 inhabitants. Approximately 40 000 patients are admitted annually for a mean stay of 10 days. The infection control programme, established in October 1992, consists of a senior head physician, three research associates, eight infection control nurses (ICNs), a medical microbiologist, and support staff.6

(4)

(5)

Surveillance and infection control measures Until January 1993, no MRSA control was undertaken. Thereafter intensive control measures were implemented. All new MRSA cases were monitored prospectively from the day of the first MRSA identification until hospital discharge by regular visits of ICNs. Information for each patient was obtained by reviewing medical records, laboratory data and when necessary, telephone interviews with private physicians or outside hospitals. Data were stored on a specially-designed database (Microsoft Access v. 2.0, Microsoft Co, Ireland). In more detail, the following infection control measures were implemented:6,7 (1) All new MRSA-infected or -colonized patients were placed in contact isolation, as recommended by the guidelines of the Centres for Disease Control and Prevention (CDC), until the time of discharge or until eradication of colonization was documented by two consecutive sets of negative surveillance cultures (separated by at least 24 h). MRSA surveillance cultures included swabs of several body sites (nose,

(6)

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groin, and skin lesions). For infected patients, samples were taken from the site of infection. All patients known to have been previously colonized or infected with MRSA were isolated upon readmission to UGH and surveillance swabs were obtained.6 Two consecutive sets of negative surveillance cultures were mandatory to end contact isolation. Clinical microbiology laboratory results were monitored daily for MRSA isolates. Initially, laboratory staff contacted the ICN in charge of MRSA surveillance about every newly identified patient. In March 1994, an automatic laboratory alert system was implemented and replaced the phone calls. This computerized system facilitated early isolation of new patients and recognition of previous carriers on readmission.6 Only patients with documented MRSA infection were treated with intravenous antibiotics (usually glycopeptides). Colonized patients were treated with nasal mupirocin ointment for five days, and daily chlorhexidine body washes for 10 days.8 Following eradication, patients remaining in the hospital underwent surveillance cultures weekly for 4 weeks and then monthly to detect relapse of colonization. To detect MRSA colonization and crossinfection, surveillance cultures were obtained from roommates as soon as a new MRSA patient was identified. When feasible, the area of surveillance was widened and an outbreak investigation was attempted. Molecular typing of MRSA isolates was performed only in case of special cluster investigations.9 Systematic surveillance cultures at the time of admission were implemented in July 1994 in the hospital ward with the highest rate of MRSA colonization/infection (‘septic’ orthopaedic ward, 45 beds). This ward was the only area of the hospital where systematic screening on admission was performed until 1998. A hospital-wide education programme was initiated to improve compliance with hand hygiene. Alcohol-based bedside hand rubs were promoted in all hospital wards. As described elsewhere,10 hand hygiene compliance increased significantly between 1994 and 1997.

Definitions Colonization was defined as the isolation of MRSA from patients without symptoms, or laboratory

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results meeting the criteria for infection. Infections were defined using CDC criteria.11 Whenever asymptomatic, patients with MRSA-positive urine cultures were not considered infected, except when the physician prescribed specific antimicrobial therapy. The attack rate (cumulative incidence) was defined as the number of newly identified MRSA patients divided by the number of admitted patients (e100).12 The prevalence of MRSA-infected or -colonized patients was taken as the annual number of MRSA patients divided by the total number of patients admitted at UGH (e100).12 Data on antimicrobial agents prescribed were collected by the central hospital pharmacy and expressed as daily defined doses (DDD), one DDD being the normal adult daily dose of antibiotic treatment.

time were analysed by Poisson regression. Statistical analysis was performed using SPSS 8.0 (SPSS, Chicago, IL, USA) and STATA 6.0 (STATA; College Station, USA). All tests were two-tailed. P-values less than 0.05 were considered significant.

Microbiology

Results

S. aureus was identified using standard laboratory procedures.13 Antimicrobial susceptibility testing was performed by the disk diffusion technique in conjunction with a Mueller-Hinton oxacillin (6 mg/L) plate.14 Only one isolate per patient per year was included in the laboratory-based surveillance results.

Of the 506 012 patients admitted to UGH between 1989 and 1997, 1771 were identified as new MRSA-infected or -colonized cases. The overall attack rate during this period was 0.35 new MRSA cases per 100 admissions (mean age: 68 yrs, SD 23). A total of 1204 MRSA patients (68%) were identified while housed in acute care and 567 (32%) while in intermediate care wards. The outbreak started in early 1989 and spread rapidly through the medical, orthopaedic, and intermediate care wards. The rate of new MRSA-infected or -colonized cases increased from 0.05 to 0.57 per 100 admissions from 1989 to 1992, respectively (P\0.001, Table I). During the following 2 years it remained stable and then decreased from 0.60 to

Statistical analysis Continuous variables were expressed as the mean and standard deviation (SD) or as the median if their distribution was skewed. Correlation coefficients were generated with simple linear regression. Changes in the incidence of MRSA occurrence over

Literature review A MEDLINE review of the literature between 1978 to 1998 was conducted to study further the association between the reservoir of MRSA patients and the rate of MRSA using specific terms alone or in combination (‘S. aureus’, ‘resistance’, ‘prevalence’, ‘incidence’, ‘epidemiology’, ‘bacteraemia’). Frequently cited articles were also identified. Published work with clearly defined and retrievable epidemiologic data on nosocomial MRSA detection and bacteraemia rates was included.

Table I Evolution of important epidemiological MRSA indicators; University of Geneva Hospitals, 1989–1997 Year

Number of screening cultures

MRSA laboratory isolates*

Prevalence of MRSA patients

New cases/100 admissions

New cases/1,000 patient-days

Relative risk of MRSA acquisition [95% CI]

No. of patients with MRSA bacteraemia

No. of patients with MSSA bacteraemia

1989 1990 1991 1992 1993 1994 1995 1996 1997

0 0 0 0 1,863 7,600 9,186 9,918 10,566

03% 06% 11% 17% 19% 20% 24% 21% 19%

0.07% 0.23% 0.38% 0.84% 0.93% 1.42% 1.35% 1.02% 0.59%

0.05 0.16 0.28 0.57 0.49 0.60 0.47 0.32 0.24

0.04 0.12 0.23 0.49 0.44 0.54 0.43 0.30 0.21

Reference 3.1 [1.9–5.3] 5.7 [3.5–9.3] 11.5 [7.2–18.4] 9.8 [6.1–15.8] 11.9 [7.4–18.9] 9.4 [5.9–15.2] 6.5 [4.0–10.6] 4.4 [2.6–7.2]

1 8 13 34 26 31 23 12 10

94 78 83 96 95 102 97 98 98

* Methicillin resistance among all isolated S. aureus isolates; one isolate per patient per year (including screening cultures). MRSA, methicillin-resistant S. aureus; MSSA, methicillin-sensitive S. aureus.

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0.24 cases per 100 admissions from 1994 to 1997, respectively (P\0.001). Conversely, the prevalence of methicillin-resistance among all S. aureus patient isolates identified by the clinical microbiology laboratory showed little variation from 1993 on (range: 19–24%), reflecting the effect of the active surveillance strategy increasing the number of screening cultures. An overview of the observed trends and a comparison of important MRSA surveillance indicators are shown in Table I. Between January 1993 and December 1997, the overall incidence of MRSA infection was 0.24 episodes per 100 admissions (2.01 episodes per 10 000 patient-days). Between these times it decreased from 2.25 to 0.87 episodes per 10 000 patient-days (P\0.001). Surgical site and soft tissue infections were the most frequent (43%), followed by urinary tract (21%), bloodstream (19%), and lower respiratory tract (8%) infections. The annual number of patients with MRSA bacteraemia reached its peak in 1992 with 34 infected patients and decreased to 10 in 1997; the corresponding incidence decreased from 0.75 in 1992 to 0.27 episodes per 10 000 patient-days in 1997 (P\0.001). No correlation was observed between the annual rates of MRSA and methicillin-sensitive S. aureus (MSSA) bacteraemia (R2\0.2; P\0.22). In contrast, the annual number of patients with MRSA bacteraemia strongly correlated with the prevalence of MRSA patients (R2\0.60; P\0.01) and the number of new MRSA patients (R2\0.97; P\0.001; Figure 1A). There were no restrictions on antimicrobial therapy during the study and the use of beta-lactams and macrolides did not change substantially. A decrease in the use of aminoglycosides occurred (21.98 to 14.57 DDD per 1000 patient-days), whilst imipenem and ciprofloxacin consumption increased steadily from 11.07 and 22.34 DDD per 1000 patient-days to 18.15 and 27.86 DDD per 1000 patient-days, respectively. No prospectively collected data are available to measure accurately the costs attributable to the control of this hospital-wide outbreak. We have estimated, however, the crude costs of the total microbiology work-up (including all material and workload for 39 133 screening swabs) to be SF 1 897 950 based on Swiss hospital reimbursement regulations. Between 1993 and 1997, MRSA patient surveillance was solely the responsibility of two ICNs who spent an average of 280 h per month on this. Based on the average salary of a Swiss ICN (SF 42 per hour), this represents SF 700 000. Total

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extra costs attributable to contact isolation were almost SF 1320 per patient, representing SF 792 000 for a total of 600 patients with a mean duration of 22 isolation days (based on previously published and adapted estimates).15,16 Overall, the MRSA infection control programme, established in 1993, represented an approximate cost of almost SF 3–4 million to the institution. Discussion This study describes the epidemic occurrence of MRSA in a large cohort of hospitalized patients

Figure 1 (A) Plot of the annual number of newly identified MRSA patients (horizontal axis) versus the annual number of patients with MRSA bacteraemia (vertical axis) with the fitting of a regression line (solid line). The width of the 95% confidence bands (dotted lines) around the regression line indicates the appropriateness of the presented model. There is a linear association between the two variables (R2\0.97; P\0.001). (B) Summary of 17 hospital studies:4, 21–36 plot of the number of identified MRSA patients versus the number of MRSA bacteraemia patients with the fitting of a regression line (solid line).The width of the 95% confidence bands (dotted lines) around the regression line indicates the appropriateness of the presented model.There is a strong correlation between the two variables (R2\0.77; P\0.001).

Delayed infection control of a MRSA outbreak

and shows that transmission was eventually contained despite the delayed implementation of control efforts. Most reports of successful MRSA control have been performed in much smaller settings.17,18 Hitherto, no published study has shown that it is possible to contain a hospital-wide MRSA outbreak after several years without attempts at control with a consequent high transmission situation of more than 0.5 new cases per 100 admissions.19 In contrast to other reports,20 we successfully reduced cross-transmission using already established strategies as well as more sophisticated approaches (computerized early-warning system). However, perhaps because there was a substantial delay in implementing control measures, total eradication of MRSA was not possible. Our results extend previous findings, suggesting that the incidence of MRSA bacteraemia is associated with both the overall prevalence and the number of new MRSA-infected patients. Australian investigators examined a hospital-wide MRSA outbreak and found that the number of patients with MRSA bacteraemia increased from 0 to 39 per year between 1979 and 1989, associated with an increased number of newly-identified MRSA patients (from 11 to 720 cases; R2\0.66; P\0.002).20 The results of 17 additional cohort studies4,21–36 performed over a 20-year period in different settings (summarized in Figure 1B) confirm this hypothesis and document a similar correlation (R2\0.77; P\0.001). This suggests the existence of a strong association between the MRSA reservoir, representing the submerged part of an iceberg, and the number of MRSA bacteraemia, reflecting merely the tip. This concept has important public health implications given that methicillin resistance in S. aureus bloodstream isolates may serve as an excellent marker for the overall MRSA reservoir as recently suggested by a large report from the UK, where it increased from 1.5% during 1989–91, to 13.2% in 1995 (P\0.001).37 This study provides an opportunity to compare the application of different epidemiologic indicators for MRSA. It is still common practice to assess the evolution of MRSA within a hospital by calculating the proportion of methicillin-resistant among all S. aureus isolates reported from the clinical microbiology laboratory.34,38–39 As shown in Table I, this approach does not accurately reflect the true epidemiology of MRSA in the hospital setting nor the impact of infection control efforts. Active surveillance, together with the systematic screening of cultures to monitor known MRSA carriers,

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enhances the recovery of MRSA isolates as demonstrated in our study by the increased prevalence of MRSA patients in 1994. This would suggest that laboratory-based surveillance data for MRSA, based on the yearly calculated proportion of MRSA among all S. aureus isolates, may be flawed and should not be used as a quality marker for MRSA control efforts. We propose that validated on-site surveillance data of MRSA-infected or -colonized patients, expressed as the MRSA attack rate or MRSA incidence-density, are more meaningful indicators for this purpose. The following aspects of our control strategy should be interpreted within the context of the study design. Firstly, we do not yet have sufficient data to demonstrate the cost-effectiveness of our programme. It is possible that MRSA control may also be achieved with less resources. Using conservative estimates of attributable costs associated with severe MRSA infection (US$9500;15,40 i.e., SF 15 200) transferred to the Swiss health care setting, our programme was probably not cost-effective for the hospital, but this is offset by patient benefit. Furthermore, based on cost-effectiveness evaluation of MRSA control programmes from different countries,15,16,35,40,41 the prevention of a minimum of 220 infections during the 1993–97 study period would have offset programme costs. A refined cost-saving analysis would, however, be necessary to validate these crude estimates. Secondly, in some situations MRSA carriage may not be clearly distinguishable from MRSA infection, for example in tracheobronchitis or catheter-associated bacteriuria. In these doubtful situations, we generally followed the judgement of the treating physicians. Thirdly, we did not monitor environmental MRSA contamination. Further studies are necessary to clarify the significance of this as part of the MRSA reservoir. Fourthly, on the basis of our study, it is impossible to identify the effect of each individual intervention on MRSA transmission since we did not assess them independently. Fifthly, our review of important MRSA studies does not provide the quantitative estimates for a formal meta-analysis given the heterogeneity of the patient populations and study designs. A critical summary of these articles, however, without providing exhaustive details on each study, suggests an excellent correlation between the MRSA reservoir and related cases of bacteraemia. Finally, since screening cultures were often performed after identification of a MRSA patient by clinical cultures, there were possibly more MRSA patients than identified.

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This study in a large teaching hospital demonstrates the impact of a delayed infection strategy on the epidemic occurrence of MRSA. The control of widespread MRSA transmission by the implementation of multifocal interventions appeared to have a substantial effect on both the MRSA reservoir and the attack rate of MRSA, thus permitting the reduction of an important number of cases of avoidable MRSA bacteraemia. Acknowledgements We would like to thank all the participants in this study: A. Alexiou, J. Boissard-Sztajzel, N. Colaizzi, P. Herrault, V. Sauvan, S. Touvenau (Infection Control Programme); B. Pepey and N. Liassine (Clinical Microbiology Laboratory). We thank R. Sudan for providing editorial assistance. References 1. Harbarth S, Pittet D. MRSA – a European currency of infection control. Quart J Med 1998; 91: 519–521. 2. Kauffman CA, Terpenning MS, He X et al. Attempts to eradicate methicillin-resistant Staphylococcus aureus from a long-term-care facility with the use of mupirocin ointment. Am J Med 1993; 94: 371–378. 3. Valls V, Gomez Herruz P, Gonzalez Palacios R, Cuadros JA, Romanyk JP, Ena J. Long-term efficacy of a program to control methicillin-resistant Staphylococcus aureus. Eur J Clin Microbiol Infect Dis 1994; 13: 90–95. 4. Coello R, Jimenez J, Garcia M 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. 5. Farrington M, Redpath C, Trundle C, Coomber S, Brown NM. Winning the battle but losing the war: methicillin-resistant Staphylococcus aureus infection at a teaching hospital. Quart J Med 1998; 91: 539–548. 6. Pittet D, Safran E, Harbarth S et al. Automatic alerts for methicillin-resistant Staphylococcus aureus surveillance—Role of a hospital information system. Infect Control Hosp Epidemiol 1996; 17: 496–502. 7. Harbarth S, Pittet D. Controlling a long-term, hospital-wide epidemic of methicillin-resistant Staphylococcus aureus strains: experience from the Geneva university hospital. Hyg Med 1997; 22: 306–313. 8. Report of a combined working party of the British Society for Antimicrobial Chemotherapy, the 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: 253–290. 9. Harbarth S, Romand J, Frei R, Auckenthaler R, Pittet D. Inter- and intrahospital transmission of methicillin-resistant Staphylococcus aureus. Schweiz Med Wochenschr 1997; 127: 471–478.

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