1 Department of Infectious Diseases, Auckland Hospital, Private Bag 92024, Auckland; 2 Department of Microbiology, Middlemore Hospital, Auckland; 3 Antibiotic Reference Laboratory, Institute of Environmental Science and Research, Wellington, New Zealand
Received 21 October 2002, returned 21 November 2002, revised 16 December 2002; accepted 17 December 2002
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Abstract |
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Patients and methods: Data from a variety of sources were used for this study: susceptibility data collected annually from diagnostic laboratories throughout NZ; a local survey of mupirocin-resistant S. aureus in the Auckland area in 1997; a national survey of S. aureus antimicrobial susceptibility in 1999; and the national methicillin-resistant S. aureus (MRSA) surveillance programme.
Results: All data sources show that there was a steady increase in mupirocin resistance among S. aureus throughout the 1990s, and rates in NZ are now markedly higher than those reported in most other comparable countries. By 1999, resistance averaged 28%, with higher rates among community-acquired compared with hospital-acquired isolates, and with a wide geographical variation in resistance. Resistance was more common among S. aureus generally than MRSA.
Conclusion: We postulate that the steady rise in mupirocin resistance among S. aureus in NZ throughout the 1990s may be due, at least in part, to the over the counter availability of mupirocin from 1991 to 2000. The current patterns of mupirocin consumption need to be reviewed and its use rationalized to maximize the chances of this antibiotic retaining beneficial antistaphylococcal activity.
Keywords: mupirocin, Staphylococcus aureus, resistance
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Introduction |
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Two mupirocin-resistant phenotypes, low-level (LMR) and high-level resistance (HMR), have been identified. LMR is thought to be the result of mutational change in the chromosomally encoded ileS-2 (mupA) gene,7 and has been shown to develop in S. aureus isolates exposed in vitro to progressively higher concentrations of mupirocin.8 The proposed genetic basis for HMR is the acquisition of a transferable plasmid containing the ileS-2 gene encoding an additional IRS enzyme.9
While the NCCLS does not provide interpretive criteria for susceptibility testing of topical agents, suggested breakpoints (MIC < 8 mg/L = susceptible, MIC 8256 mg/L = LMR, MIC 512 mg/L = HMR) have been published and are widely used.10 However, there is uncertainty over their clinical relevance. Most reports of resistance have not been accompanied by details of clinical follow-up, and there are few data correlating resistance with clinical outcomes. It has been suggested that LMR can be overcome by a high concentration of mupirocin, which is provided by the 2% (20 000 mg/L) topical preparation, especially when applied to the nasal mucosa where skin penetration is irrelevant. In one study, five of seven patients, from whom MRSA with LMR was isolated, were successfully cleared by topical mupirocin alone.3 However, Harbath et al.11 observed an increased risk of persistent MRSA carriage after mupirocin treatment in those patients colonized with LMR strains of MRSA.
Mupirocin was introduced into clinical practice in the UK in 1985, and the first report of staphylococcal resistance came 2 years later.12 Since then, varying rates of resistance have been reported. In 1993, an Irish survey of 1152 hospital and community isolates of S. aureus found 2% mupirocin resistance.13 In 1997, 3.9% of S. aureus isolates collected from 19 European hospitals were mupirocin resistant. Resistance was more common among MRSA than MSSA.14 In North America in 19901995, mupirocin resistance in MRSA was noted to be high (24%) in a veterans hospital where MRSA colonization was endemic and mupirocin commonly used.15 Similarly, in a Brazilian hospital, where mupirocin use was common, the prevalence of mupirocin resistance among MRSA was over 50% in 19941995, compared with 6% in a nearby hospital where mupirocin use was infrequent.16
Mupirocin has been marketed in New Zealand (NZ) since 1986, and from October 1991 to March 2000 could be bought over the counter (OTC) without a prescription. In this paper, we track the emergence of resistance, compare it with the situation elsewhere in the world and discuss strategies for future management of this antibiotic.
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Materials and methods |
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Data on mupirocin resistance among S. aureus were extracted from four sources that are described in Table 1.
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DNA macrorestriction analysis of the mupirocin-resistant isolates, identified during the 1999 national survey (Table 1, data source 3), was performed using a modified published method.17
Mupirocin sales
Data on mupirocin sales were obtained from GlaxoSmithKline NZ. The sales are quantified in units, where 1 unit is 15 g of a 2% preparation.
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Results |
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Mupirocin resistance among MRSA (Table 1, data source 4) was first detected in 1988, and was unexpectedly high (8.9%) due to an outbreak of infections with a resistant strain in one hospital. Subsequently, in the early 1990s, <2% of MRSA were resistant. Resistance started to increase in 1993 and during the 6 years between 1993 and 1998, 36% of MRSA were mupirocin resistant. No data are available for 1999. In 2000, resistance increased to 12.4%, and most (90%) of this resistance was HMR.
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Discussion |
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The predominance of two DNA macrorestriction types among S. aureus with HMR, and one type among the LMR isolates included in the national survey in 1999, suggests that there has been horizontal spread of a limited number of mupirocin-resistant strains. This is not so surprising for chromosomally mediated LMR, but is less expected for plasmid-mediated HMR, where horizontal spread of the plasmid among genetically diverse strains of S. aureus is likely. This lack of diversity among the isolates with HMR may, in part, be due to the fact that although the isolates for the survey were collected within a period of a few weeks, they were collected from widely separated geographical areas.
Drug company sales figures show increasing consumption of mupirocin in NZ from 1992, which coincides with the change of licensing from prescription only to OTC in October 1991. Unfortunately, there are no data on the relative proportions of OTC versus prescription sales of mupirocin, but we speculate that the OTC availability resulted in increased consumption of mupirocin, particularly in the community setting. It remains to be seen whether reintroduction of prescription-only availability in 2000 will reverse this trend.
Such a reversal was observed in Western Australia after the introduction of restrictions on mupirocin use. In 1993, 15% of 178 clinical MRSA isolates in Western Australia had HMR. In response to this, the Health Department issued guidelines that recommended that mupirocin should not be used without laboratory control, that its use should not exceed 10 days and that a patient should not have a repeat prescription within 1 month of completing the first course.19 Four years later only 0.3% of MRSA isolates referred to the reference laboratory were mupirocin resistant.20
In addition to the measures recommended in the Western Australian guidelines, we make further recommendations. Application of mupirocin to superficially infected skin lesions is effective, but the treatment course should be directed by a doctor and be neither interrupted nor prolonged. As the likelihood of successful eradication of MRSA is low when colonization is endemic, or two or more body sites are colonized,21 careful consideration of mupirocins use in this setting is advised. There is no role for its application to uninfected skin lacerations or surgical wounds in previously well individuals. There may be a role for intranasal application of mupirocin prophylactically in selected pre-operative patients.22
In cautioning against the use of mupirocin, we do not advocate using fusidic acid topically as an alternative. Resistance to this topical agent is reported, and unlike mupirocin, it is available in oral and intravenous formulations that are used for treatment of multiresistant S. aureus infections. As an alternative to topical antibiotic preparations, a hydrogen peroxide cream has been developed that has been found in one study to be as efficacious as topical fusidic acid in the treatment of impetigo.23
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Footnotes |
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References |
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