Mupirocin and Staphylococcus aureus: a recent paradigm of emerging antibiotic resistance

A. Upton1,*, S. Lang2 and H. Heffernan3

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


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Objectives: To describe trends in mupirocin resistance among Staphylococcus aureus in New Zealand (NZ), following the availability of mupirocin in 1986.

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


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Mupirocin (pseudomonic acid A) is a topical antibiotic with a unique action, binding competitively to bacterial isoleucyl-tRNA synthetase (IRS) and inhibiting bacterial protein synthesis. It has a high level of activity against staphylococci and streptococci,1 and is used in the treatment of superficial skin infections and in controlling the spread of methicillin-resistant Staphylococcus aureus (MRSA). Intranasal application for 5 days has been shown to be effective in eliminating MRSA and methicillin-susceptible S. aureus (MSSA) in healthy people, although re-colonization is seen in up to 67% of subjects 6 months later.2,3 Short-term intranasal mupirocin application may reduce post-operative infection rates and vascular and continuous ambulatory peritoneal dialysis (CAPD) catheter-related infections in dialysis patients.46

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 8–256 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 1990–1995, 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 1994–1995, 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.


    Materials and methods
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Data sources

Data on mupirocin resistance among S. aureus were extracted from four sources that are described in Table 1.


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Table 1.  Sources of data on mupirocin resistance among S. aureus in New Zealand
 
DNA macrorestriction analysis

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.


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
There are no data on mupirocin susceptibility before its introduction into NZ in 1986. Figure 1 shows the increase in mupirocin resistance among community and hospital isolates of S. aureus in the Auckland area, and among hospital isolates in the Christchurch area between 1992 and 2000 (Table 1, data source 1), and the amount of mupirocin sold in NZ between 1990 and 2000. Resistance was more prevalent in the Auckland area, and more prevalent in community-acquired, than hospital-acquired, S. aureus.



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Figure 1. Mupirocin resistance among S. aureus isolates in hospital and community laboratories (Table 1, data source 1), and units of mupirocin sold per year, 1990–2000. No data were available for Christchurch and Auckland hospital laboratories, 1990–1994, or the Auckland community laboratory, 1990–1991.

 
In a 1999 national survey (Table 1, data source 3), which included both hospital- and community-acquired S. aureus isolated throughout NZ, the prevalence of mupirocin resistance averaged 28.0%, and again mupirocin resistance was more common among community-acquired isolates (Table 2). In this survey, regional differences were also noted. Forty per cent of S. aureus isolates from the northernmost part of the country (Northland Health District) were resistant, compared with 10.3% in the southernmost part (Southland and Otago Health Districts). In general, resistance increased from south to north along the length of NZ.


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Table 2.  High- and low-level mupirocin resistance among hospital- and community-acquired S. aureus collected from laboratories throughout New Zealand in 1999a
 
Most data on mupirocin resistance in S. aureus do not distinguish between LMR and HMR. However, this distinction is available for isolates included in the 1999 national survey and a 1997 local survey (Table 1, data sources 3 and 2, respectively). In the 1997 survey of community-acquired mupirocin-resistant S. aureus in the Auckland area, 85% had HMR and 15% LMR.18 In contrast, in the 1999 national survey, the prevalence of HMR and LMR was similar among community-acquired S. aureus, whereas HMR was more prevalent than LMR among hospital-acquired isolates (Table 2). DNA macrorestriction typing of 134 mupirocin-resistant S. aureus included in the 1999 survey was performed to determine clonality. The majority (96%) belonged to one of three distinct macrorestriction profiles or types. Almost all HMR isolates belonged to two of these three types, whereas the LMR isolates were predominately the third type.

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, 3–6% 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.


    Discussion
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
We believe that mupirocin resistance in NZ has arisen largely in the community, where mupirocin has been readily available without prescription. In contrast to most reports from other countries, mupirocin resistance in NZ is more common in community-acquired, than hospital-acquired, S. aureus, and is more prevalent among S. aureus generally than MRSA. The observation that mupirocin resistance is more common among all S. aureus than MRSA is because the two MRSA strains that together account for 80% of MRSA isolations in NZ, WSPP MRSA and EMRSA-15, are both susceptible to mupirocin. The relatively restricted use of mupirocin in the NZ hospital setting may have limited MRSA exposure to mupirocin and any subsequent development of resistance. However, the WSPP MRSA strain is a community-acquired MRSA and is most common in the northern parts of NZ, which have the highest prevalence of mupirocin resistance among S. aureus.

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 mupirocin’s 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


    Footnotes
 
* Corresponding author. Tel: +64-9-378-7440; Fax: +64-9-307-4940; E-mail: ArloU{at}adhb.govt.nz Back


    References
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
1 . Sutherland, R., Boon, R. J., Griffin, K. E., Masters, P. J., Slocombe, B. & White, A. R. (1985). Antibacterial activity of mupirocin (pseudomonic acid), a new antibiotic for topical use. Antimicrobial Agents and Chemotherapy 27, 495–8.[ISI][Medline]

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5 . Sesso, R., Barbosa, D., Leme, I. L., Sader, H., Canziani, M. E., Manfredi, S. et al. (1998). Staphylococcus aureus prophylaxis in haemodialysis patients using central venous catheter: effect of mupirocin ointment. Journal of the American Society of Nephrology 9, 1085–92.[Abstract]

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