CONCISE COMMUNICATION

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1 CONCISE COMMUNICATION Decolonization of methicillin-resistant Staphylococcus aureus using oral vancomycin and topical mupirocin B. Maraha 1, J. van Halteren 2, J. M. Verzijl 3, R. G. F. Wintermans 4 and A. G. M. Buiting 1 1 Department of Medical Microbiology, 2 Department of Hospital Hygiene and Infection Control, St. Elisabeth Hospital, PO Box 747, 5000 AS Tilburg, 3 Hospital Pharmacy Midden-Brabant, St. Elisabeth Hospital and TweeSteden Hospital, Tilburg, and 4 Department of Medical Microbiology, Franciscus Hospital, Roosendaal, the Netherlands The objective of this study was to assess the efficacy and safety of a short course of oral vancomycin and intranasal mupirocin ointment in the eradication of methicillin-resistant Staphylococcus aureus (MRSA) colonization. During an outbreak of MRSA, the colonized subjects received oral vancomycin and topical mupirocin. They were screened for MRSA 1, 3, 6 and 12 months after decolonization. A questionnaire was developed to evaluate the side-effects of oral vancomycin. Thirty-five subjects were treated. Clearance was achieved in all cases, in 24 (69%) subjects after one course of therapy. Twenty-eight (80%) subjects experienced some side-effects, including six (17%) who did not tolerate oral vancomycin. Although oral vancomycin, in combination with topical mupirocin, is effective in the elimination of MRSA colonization, there is a need for further studies to confirm our results and to evaluate the safety of oral vancomycin. Keywords MRSA, vancomycin, decolonization Accepted 29 November 2001 Clin Microbiol Infect 2002; 8: INTRODUCTION Control measures are essential to limit and prevent the spread of methicillin-resistant Staphylococcus aureus (MRSA) in outbreaks. These measures may include isolation of patients with MRSA, screening of contact patients and staff, and temporary removal of colonized staff from the medical setting [1]. It has been emphasized that eradication of MRSA carriage is justified in outbreak situations in health-care settings [1,2]. Several eradication regimens have been used. Topical agents alone or in combination with oral antibiotics have been used for the elimination of both nasal and extranasal MRSA carriage [3 10]. Intranasal application of mupirocin seems to be the most effective topical Corresponding author and reprint requests: B. Maraha, Reg. Laboratory Medical Microbiology, Albert Schweitzer Hospital, PO Box 899, Dordrecht 3300 AW, the Netherlands Tel: þ Fax: þ B.Maraha@dszh.nl agent for the eradication of MRSA nasal carriage [11 13]. Relapse and recolonization, however, are frequently reported, and clearance rates have often been unsatisfactory [1]. Several hospitals in the Netherlands use oral vancomycin in combination with topical agents for the eradication of MRSA colonization. There are, however, no data available on the effectiveness and safety of eradication regimens with oral vancomycin. Oral vancomycin has been successfully used in the treatment of postoperative MRSA enteritis [14]. Few data are available, however, on the use and the efficacy of vancomycin for eradicating the carriage of MRSA. In one study, topical application of 5% vancomycin for 2 weeks was successfully used to eradicate MRSA nasal carriage in two nurses [4]. In another study, vancomycin ointment failed to eradicate nasal carriage of methicillinsensitive staphylococci [15]. In two case reports, decolonization of nasopharyngeal MRSA colonization was achieved using a vancomycin aerosol [16,17]. ß 2002 Copyright by the European Society of Clinical Microbiology and Infectious Diseases

2 672 Clinical Microbiology and Infection, Volume 8 Number 10, October 2002 Oral vancomycin is used for treating Clostridium difficile-associated infection [18]. It has been reported that oral vancomycin is safe and well-tolerated in the context of C. difficile infection [19 23]. During an outbreak of MRSA at our hospital and in a nursing home in our region, we evaluated the efficacy and tolerance of a short course of oral vancomycin and topical intranasal mupirocin in the eradication of MRSA colonization. MATERIALS AND METHODS The index patient in this outbreak was a patient admitted, in January 1999, to the Urological Unit in our hospital from a nursing home in our region. This patient had a wound infected with MRSA which was resistant to ciprofloxacin in addition to b-lactam antibiotics. It was susceptible to mupirocin, cotrimoxazole, rifampin, gentamicin, tobramycin, and vancomycin. Surveillance cultures were obtained from all patients and staff of the Urological Unit and from staff from other units who had been in contact with the index patient. Also, all residents and staff of the nursing home where the index patient was living were screened. Culture specimens were obtained by sterile swabs twice from anterior nares, throat, perineum, and wounds if any. The swabs were cultured on sheep blood agar plates and mannitol salt agar plates containing 7.5% NaCl and 4 mg/l oxacillin [24]. To increase the sensitivity of MRSA detection, we used a staphylococcal broth containing Muller Hinton II broth (Becton Dickinson, Cockeysville, MD, USA) and ciprofloxacin 8 mg/ L (Bayer, Leverkusen, Germany). In the first screening, all three swabs were put into the same staphylococcal broth [25]. Subsequently, in subjects with a positive culture, each swab was put into a separate staphylococcal broth. Plates and broth were incubated at 35 8C in air. At 24 h, plates were examined and broth was subcultured on a sheep blood agar plate and on an agar screen plate containing 6 mg/l oxacillin; plates were again incubated at 35 8C. Plates were examined again at 24 h and 48 h. Colonies suspected of being S. aureus were identified by standard procedures, including colony morphology, Gram stain, catalase reaction, tube coagulase test, and API STAPH (biomérieux sa, Lyon, France) [26]. Susceptibility testing of S. aureus isolates was carried out by a broth microdilution method according to the guidelines of the National Committee for Clinical Laboratory Standards [27]. Methicillin resistance was determined by oxacillin disk diffusion test and by oxacillin E test [24,28]. Isolates were confirmed to be methicillin resistant by polymerase chain reaction (PCR) for the meca gene [29]. Phage typing was performed at the National Institute of Public Health and the Environment. The index patient and the colonized residents were strictly isolated in private rooms, at hospital and in the nursing home, respectively. Administration of medication, if any, and diagnostic procedures were carried out in the private room, when possible. Barriers including gloves, masks, head caps and aprons were used for any contact with the index patient and colonized residents. The importance of washing hands with 70% alcohol after each contact was emphasized. Colonized staff were not allowed to work until they were decolonized. Subjects who were colonized with MRSA received a 5-day course of oral vancomycin 250 mg every 6 h (Vancomycin CP 1, 83.3 mg/ ml; 120 ml, Eli Lilly, Indianapolis, IN,), intranasal application of mupirocin every 8 h (Bactroban 1 nasal ointment 20 mg/ml; 3 g tubes. SmithKline Beecham Farma, Brentford, UK), and a daily bath with povidone iodine shampoo (Betadine 1 shampoo, 75 mg/ml, Asta Medica, Frankfurt/Main, Germany). This course was repeated when necessary. The index patient did not undergo the decolonization regimen, because she had many wounds infected with MRSA. The four colonized residents were decolonized. Decolonization of MRSA was defined by two consecutive negative swabs 5 and 14 days following treatment. Follow-up cultures were obtained 1, 3, 6 and 12 months after decolonization. When oral vancomycin was not tolerated and the side-effects were very serious, treatment with oral vancomycin was discontinued and an alternative regimen was undertaken. A questionnaire was developed to evaluate the side-effects of oral vancomycin in all subjects. Following treatment completion and when MRSA eradication was achieved, the 35 colonized subjects received a questionnaire to assess on a scale of 1 10 (1: no effect; and 10: severe) the side-effects they experienced from oral vancomycin. Evidence of skin and soft tissue infections was monitored in all colonized subjects.

3 Concise Communication 673 RESULTS In all, 360 staff and 274 patients and residents of the nursing home were screened for MRSA colonization. Thirty-five subjects were colonized with MRSA; 31 staff and four residents of the nursing home. The PCR assay showed that all isolated strains possessed the meca gene. The strains from the 35 subjects belonged to phage type Z-151. Six subjects were colonized in the nares, the throat and the perineum; three subjects in the nares and the throat; four subjects in the nares and two subjects in the throat. In 20 subjects, it was not possible to discriminate between the colonized body sites, because in these subjects MRSA was detected only in the first screening, in which the three swabs were put into the same staphylococcal broth. None of the colonized residents of the nursing home or of the staff had infection with MRSA. The index patient was not included in the analysis because she was infected with MRSA. The mean follow-up period of the study population was 241 days (range days). The 35 colonized subjects received 55 therapy courses, with a mean of 1.6 (SD 0.9) courses per subject. MRSA clearance was achieved in all subjects; in 24 (69%) subjects after one course of therapy. In 11 subjects, more than one course was needed for decolonization (Table 1). The response rate of the questionnaire was 100%. Twenty-eight (80%) subjects experienced side-effects from oral vancomycin (Table 2). The seriousness of the side-effects in these 28 subjects ranged from 1 to 10 (mean 4.6, SD 3.0). Of the 28 Table 1 Courses of treatment Eradication course A a 24 2 A 3 3 A 2 2 A þ B b 4 A þ B þ C c 1 A þ 2 B þ C 1 No. of subjects a A, oral vancomycin 250 mg every 6 h, nasal application of mupirocin ointment every 8 h, and a daily bath with povidone iodine shampoo, for 5 days. b B, as in A, but oral vancomycin was replaced by oral cotrimoxazole 960 mg every 12 h plus rifampin 600 mg every 12 h. c C, as for A but oral vancomycin was replaced with oral tobramycin 80 mg every 6 h. Table 2 Side-effects experienced by the study subjects a Side-effect No. of subjects (%) None 7 (20) Dry mouth 10 (29) Unpleasant taste 16 (46) Stomatitis 6 (17) Nausea 6 (17) Abdominal pain 6 (17) Diarrhoea 21 (60) Flatus 4 (11) a Twenty-eight subjects experienced more than one sideeffect. subjects with side-effects, six reported the sideeffects as severe, whereas the remaining 22 subjects found that the side-effects could be tolerated. Oral vancomycin was not tolerated by 17% (6/35) of the subjects. In these subjects, oral vancomycin was discontinued and oral cotrimoxazole, 960 mg every 12 h, and oral rifampin, 600 mg every 12 h, were given for 5 days. However, two of these six subjects did not tolerate cotrimoxazole and rifampin either; so oral tobramycin, 80 mg every 6 h, for 5 days was substituted. DISCUSSION This study shows the efficacy of the combination of oral vancomycin, topical intranasal mupirocin, and a bath with povidone iodine shampoo in eliminating MRSA colonization. Oral vancomycin was not tolerated by 17% of the subjects. Eradicating regimens containing oral vancomycin are used in several hospitals in the Netherlands to eliminate extranasal colonization with MRSA. This is the first study, that assesses the efficacy of oral vancomycin in the elimination of MRSA colonization. Our approach included screening of patients, residents and staff, strict isolation of the colonized patient and the nursing home residents, and treatment of all colonized subjects. This approach was very effective in the elimination of MRSA colonization during an outbreak at our hospital and in a nursing home. We succeeded in eradicating MRSA colonization in 100% of the colonized subjects, and all subjects were still MRSA-free after a follow-up period ranging from 180 to 365 days (mean 241 days). Various topical and oral agents have been used to eradicate MRSA colonization, and variable clearance rates have been achieved. In general,

4 674 Clinical Microbiology and Infection, Volume 8 Number 10, October 2002 the results have been unsatisfactory, and relapse and recolonization have been reported [1]. Because the care staff colonized with MRSA are an important source of MRSA spread, it has been advocated that attempts should be made to decolonize them [13]. The prevalence of MRSA in the Netherlands is still very low (<0.5%) and this reflects the Dutch policy of search and destroy which includes strict control measures and the treatment of MRSA carriage [30]. In this context, we treated the study subjects regardless of the colonized body site. In the present outbreak, discrimination between the colonized body sites was possible in 15 subjects. In the remaining 20 subjects, this was not possible because the swabs from different sites were pooled in the first screening. The study subjects reported no local irritation as a side-effect; therefore, the reported side-effects could not be attributed to topical mupirocin. In addition, other studies have shown that topical mupirocin is safe and well-tolerated [5,7,12]. Previous studies reported that eradication regimens with systemic rifampin, cotrimoxazole and ciprofloxacin are associated with side-effects [7,8]. In the context of the treatment of C. difficile infection, no side-effects of oral vancomycin have been reported [19 23]. However, subjects in the present study were healthy, and patients with C. difficile infection have gastrointestinal complaints. Gastrointestinal side-effects were predominant in the present study. Therefore, side-effects of oral vancomycin in patients treated for C. difficile infection might be confused with those attributable to the C. difficile infection. Administration of vancomycin has been associated with the emergence of resistant bacteria [31]. However, a meta-analysis of 18 studies has shown that, in contrast to intravenous vancomycin, oral vancomycin contributes in a limited way to the overall risk of vancomycin-resistant enterococcus colonization [31]. This reflects the limited use of oral vancomycin. A limitation of the present study, however, is that we did not evaluate the impact of vancomycin use on emergence of vancomycin-resistant enterococcus in the study subjects. Because of the consequences of excessive use of vancomycin, it is probably undesirable to use this antibiotic in all colonized patients. One might use oral vancomycin only in patients with digestive tract colonization. In conclusion, the combination of oral vancomycin and topical agents is effective in the elimination of MRSA colonization. There is a need for further assessment of efficacy and safety of oral vancomycin in randomized controlled trials. REFERENCES 1. Mulligan ME, Murray-Leisure KA, Ribner BS et al. Methicillin-resistant Staphylococcus aureus: a consensus review of microbiology, pathogenesis, and epidemiology with implications for prevention and management. Am J Med 1993; 94: Fraise AP. Guidelines for the control of methicillinresistant Staphylococcus aureus. J Antimicrob Chemother 1998; 42: Arathoon EG, Hamilton JR, Hench CE, Stevens DA. Efficacy of short courses of oral novobiocin-rifampin in eradicating carrier state of methicillinresistant Staphylococcus aureus and in vitro killing studies of clinical isolates. Antimicrob Agents Chemother 1990; 34: Bitar CM, Mayhall CG, Lamb VA, Bradshaw TJ, Spadora AC, Dalton HP. Outbreak due to methicillin-resistant Staphylococcus aureus: epidemiology and eradication of the resistant strain from the hospital. Infect Control 1987; 8: Darouiche R, Wright C, Hamill R, Koza M, Lewis D, Markowski J. Eradication of colonization by methicillin-resistant Staphylococcus aureus by using oral minocycline rifampin and topical mupirocin. Antimicrob Agents Chemother 1991; 35: Harbarth S, Dharan S, Liassine N, Herrault P, Auckenthaler R, Pittet D. Randomized, placebocontrolled, double-blind trial to evaluate the efficacy of mupirocin for eradicating carriage of methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 1999; 43: Parras F, Del Carmen Guerrero M, Bouza E et al. Comparative study of mupirocin and oral cotrimoxazole plus topical fusidic acid in eradication of nasal carriage of methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 1995; 39: Peterson LR, Quick JN, Jansen B et al. Emergence of ciprofloxacin resistance in nosocomial methicillinresistant Staphylococcus aureus isolates. Arch Intern Med 1990; 150: 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: Walsh TJ, Standiford HC, Reboli AC et al. Randomized double-blinded trial of rifampin with either novobiocin or trimethoprim sulfamethoxazole against methicillin-resistant Staphylococcus aureus colonization: prevention of antimicrobial resistance

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Tel: Fax: CONCISE COMMUNICATION Bactericidal activity and synergy studies of BAL,a novel pyrrolidinone--ylidenemethyl cephem,tested against streptococci, enterococci and methicillin-resistant staphylococci L. M.