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Targeted mupirocin-based decolonization for Staphylococcus aureus carriers and the subsequent risk of mupirocin resistance in haemodialysis patients – a longitudinal study over 20 years
Corresponding author. Address: Infection Control Program, Geneva University Hospitals and Faculty of Medicine, Rue Gabrielle-Perret-Gentil 4, CH-1205, Geneva, Switzerland. Tel.: +41 223723369.
Infection Control Program, Geneva University Hospitals and Faculty of Medicine, WHO Collaborating Center, Geneva, SwitzerlandINSERM, IAME, Université Paris-Cité, Paris, France
Bacteriology Laboratory, Division of Laboratory Medicine, Department of Diagnostics, Geneva University Hospitals, Geneva, SwitzerlandGenomic Research Laboratory, Division of Infectious Diseases, Department of Medicine, University Hospitals and University of Geneva, Geneva, Switzerland
Mupirocin-based decolonization of Staphylococcus aureus carriers undergoing haemodialysis is not widely implemented due to concerns of mupirocin resistance. In our haemodialysis unit, a strategy combining universal S. aureus screening with targeted mupirocin-based decolonization was introduced two decades ago. In this study of haemodialysis patients, mupirocin resistance was assessed in blood and colonizing S. aureus isolates during two periods.
Mupirocin resistance in S. aureus was infrequent in both blood and colonizing isolates. Furthermore, in the years 2003–2021, a decreasing trend in the annual rate of S. aureus bloodstream infections was observed. Targeted mupirocin-based decolonization of S. aureus carriers undergoing haemodialysis is a sustainable measure for preventing healthcare-associated infections.
]. Significant risk reduction of up to 80% of S. aureus bloodstream infection (BSI) was observed with the use of mupirocin-containing decolonization regimens in haemodialysis (HD) patients [
]. Nonetheless, the practice of decolonizing S. aureus carriers is still not widely implemented in HD units, mainly due to concerns of emerging mupirocin resistance and logistical challenges [
A strategy of periodic universal screening of HD patients and decolonizing those detected positive for S. aureus using mupirocin-based regimens (‘screen-and-treat’) has been implemented in our HD unit for more than two decades. In this study, we aimed to assess mupirocin resistance in S. aureus blood and colonizing strains obtained from HD patients. We also describe the temporal trends of S. aureus BSI rates in this population.
Methods
Study setting
This retrospective cohort study was conducted at the University of Geneva Hospitals (HUG), the largest tertiary healthcare centre in Switzerland. Screening of S. aureus carriage of all HD patients is performed once every two months, starting in 2001. Screening samples are collected via swabbing of patients' nares and groins. If any of the body sites yields a positive culture, that patient is considered as an S. aureus carrier. Patients identified as carriers of either methicillin-susceptible or meticillin-resistant S. aureus (MSSA or MRSA) receive a topical decolonization treatment, as previously described [
Randomized, placebo-controlled, double-blind trial to evaluate the efficacy of mupirocin for eradicating carriage of methicillin-resistant Staphylococcus aureus.
]. Briefly, the treatment consists of intranasal application of mupirocin 2% twice daily and chlorhexidine 4% bathing for seven days. Additional screening is completed three days after the end of decolonization, and in case of persistent carriage, a second treatment is prescribed. If needed, a third cycle of decolonization treatment is considered on an individual basis.
Study design and data collection
We performed a retrospective analysis of prospectively collected data during the years 2003–2021, including (1) prospective surveillance of healthcare-related BSIs [
], collected by the HUG infection control team, and (2) a registry of dialysis patients collected by the haemodialysis unit. Patients on intermittent HD treatment contributed to the outcome analysis during their HD-corresponding periods only; those receiving solely peritoneal dialysis were excluded. The data in both databases is collected as part of institutional quality improvement programs; thus, institutional review board approval was not required. Data on mupirocin susceptibility of S. aureus blood isolates was available during the years 2013–2021, and of colonizing isolates from April to July 2022.
Definitions and outcomes
HD-related BSI includes all positive blood cultures in inpatients undergoing HD at HUG, as well as BSI episodes from samples drawn in the outpatient haemodialysis unit. Only the first episode during the same hospitalization was included. Our main outcomes were proportions of mupirocin resistance among S. aureus and rates of S. aureus BSI among HD patients. Attributability of BSI to intravascular catheters was also investigated.
Microbiological methods
S. aureus screening for colonization includes swabbing of nares and groin areas; each swab is evaluated for MSSA and MRSA in two separate sub-cultures using two selective chromogenic media (SAid and MRSAid, bioMérieux, Marcy l'Etoile, France). Suspected S. aureus colonies were confirmed by a previously published polymerase chain reaction (PCR) assay to assess the identification as S. aureus (femA) and the presence or absence of the mecA gene [
]. Antimicrobial susceptibilities of mupirocin have been evaluated in S. aureus blood isolates since 2013, and in colonizing isolates during April to July 2022 [
]. The disk diffusion method was used to evaluate mupirocin susceptibility, resistance was reported when the inhibition zone was <14 mm. Minimum inhibitor concentration values were not available.
Statistical analysis
Frequency of mupirocin resistance in S. aureus BSI and screening isolates was evaluated and described in proportions. We calculated annual incidence rates of S. aureus BSI episodes per 100-patient-HD-months. For numerator data, we included all S. aureus BSI episodes occurring among registered HD patients while receiving HD. For the denominator, we defined the population-at-risk as patients on regular HD, and included patients with their corresponding periods of HD (dialysis-months). For trend analysis, we used Poisson regression models. Analysis was carried out using RStudio (ver 1.3.1093).
Results and discussion
During the years 2013–2021, mupirocin resistance in blood isolates was rare (Figure 1). Twenty-eight MSSA blood isolates were retrieved from HD patients, of them 24 were tested for mupirocin resistance: 23 were susceptible and one isolate (4.2%) had intermediate susceptibility to mupirocin. During the same period, three MRSA blood isolates were retrieved and tested: two of them were susceptible and one isolate was resistant to mupirocin.
Figure 1Mupirocin susceptibility testing results of Staphylococcus aureus blood and colonizing isolates of haemodialysis patients. MRSA, meticillin-resistant S. aureus; MSSA, meticillin-susceptible S. aureus.
During the period April–July 2022, three screening surveys of S. aureus carriage were completed in the HD unit. Forty-six patients were screened, each patient was screened at least twice (interquartile range 1–3). In total, 13 S. aureus carriers (28.3%) were detected and 17 different S. aureus isolates were tested: 11 MSSA carriers with a corresponding 15 isolates, and two MRSA carriers with two isolates. Fourteen MSSA isolates (93.3%) were mupirocin susceptible and one isolate was mupirocin resistant (6.7%). Of note, the only patient carrying a mupirocin-resistant MSSA, was carrying a mupirocin-susceptible MSSA isolate in the subsequent round of screening two months later. The two MRSA isolates were mupirocin susceptible.
Between 2003 and 2021, we identified 92 S. aureus BSI episodes in HD patients, 62 caused by MSSA and 30 caused by MRSA. The patients' mean age was 64.7 (standard deviation ± 15.4) years and 63 (68.5%) were male. The annual incidence rate of S. aureus BSIs ranged between 0.037 and 0.881 per 100 patient-HD-months (Supplementary Table S1). We observed a decreasing trend of S. aureus BSI incidence by 9.8% per year (95% confidence interval 5.8–13.8%, P<0.001, Figure 2). A similar trend was observed for catheter-related BSI caused by S. aureus with 11.9% decrease per year (95% confidence interval 7.2–16.2%, P<0.001). The incidence rates of MSSA and MRSA BSIs ranged between 0.037 and 0.784 episodes and 0–0.349 per 100-patient-HD-months, respectively.
Figure 2Incidence density of Staphylococcus aureus bloodstream infection episodes in haemodialysis patients.
Continuous efforts in our hospital to screen-and-treat S. aureus HD carriers using a topical decolonization regimen including mupirocin were successful with little collateral damage in terms of mupirocin resistance. Implementing this practice over two decades, we did not observe a clinically relevant increase in mupirocin resistance in blood isolates, coupled with a constant decrease in S. aureus BSI episodes in HD patients. We assessed mupirocin resistance also in colonizing S. aureus isolates for a limited time period, and observed similar low rates of resistance.
Our findings stand in contrast to the high prevalence of mupirocin resistance observed in hospital-wide MRSA blood isolates in our centre during the years 1999–2008; however, the majority of isolates in the current study were MSSA (62/92, 67%). Thus, the mupirocin-resistance pattern previously described might have reflected a specific MRSA strain circulating at that time [
]. A recent study of US surgical patients assessed mupirocin resistance in S. aureus clinical and colonizing isolates, and showed a high resistance rate of 22% in MRSA compared with 3% in MSSA [
]. Low rates of mupirocin-resistance in S. aureus colonizing isolates of HD-patients were shown in a cohort of dialysis patients from the UK applying a screen-and-treat protocol similar to ours, mostly related to MSSA (90% of carriers) [
Meticillin-resistant Staphylococcus aureus and meticillin-susceptible Staphylococcus aureus screening in a cohort of haemodialysis patients: carriage, demographics and outcomes.
In addition to the circulating strains (MSSA or MRSA), the strategy of mupirocin use is of importance. Low mupirocin resistance rates in MRSA clinical samples were observed in a French study with a restrictive mupirocin-based screen-and-treat strategy [
]. In a recent modelling study, ‘universal decolonization’ led to significantly higher prevalence of mupirocin-resistant MRSA rates compared with a ‘screen-and-treat’ intervention (21% vs 9% in five years) [
]. Prudent implementation of a targeted rather than universal decolonization seems to help preserve mupirocin susceptibility at high levels.
Our study is not without limitations. First, MRSA isolates were infrequent, and thus the possibility of higher mupirocin resistance rates among MRSA continues to exist. As such, our findings might not be generalizable to settings with higher MRSA rates and clonal spread of mupirocin-resistant MRSA strains. Second, the effect of other preventive measures and change of care practices in HD patients during the study period were not evaluated. For example, use of arteriovenous fistula for dialysis access was more frequent in the later study years, also decreasing the risk of catheter-related S. aureus BSI. Lastly, screening isolates for susceptibility testing was only available for a short time-period in 2022 and genotyping of isolates was not performed.
In summary, we were able to show that long-term application of a ‘screen-and-treat’ mupirocin-based decolonization regimen in HD patients is a safe practice. It was not associated with an increase in mupirocin resistance and may have contributed to a substantial risk reduction of S. aureus BSI. This approach should be considered as a sustainable strategy for preventing S. aureus infections in this high-risk patient population.
Acknowledgements
The authors would like to thank Marie-Noelle Chraiti for data collection and useful advice, Carolina Fankhauser-Rodriguez and Marlieke de Kraker for their helpful comments while preparing this manuscript, Loïc Fortchantre for technical support in data curation and Bina Rabinowitz for launching this quality improvement project.
Author contributions
Conceptualization: S.H.; data curation: N.H.-K., V.O., P.S.; formal analysis: N.H.-K., J.F.; methodology: N.H.-K., N.B.; writing – original draft: N.H.-K., S.H.; writing – review and editing: all authors.
Conflict of interest statement
The authors have no conflicts of interest to declare.
Funding sources
N.H.K. received funding from Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No. 101034420, ‘Predicting the Impact of Monoclonal Antibodies & Vaccines on Antimicrobial Resistance (PrIMAVeRa)’. The JU receives support from the European Union's Horizon 2020 research and innovation and EFPIA. This communication reflects the author's view and neither IMI nor the European Union, EFPIA, or any associated partners are responsible for any use that may be made of the information contained herein. All other authors declare no competing interests.
Appendix A. Supplementary data
The following is the Supplementary data to this article.
Randomized, placebo-controlled, double-blind trial to evaluate the efficacy of mupirocin for eradicating carriage of methicillin-resistant Staphylococcus aureus.
Meticillin-resistant Staphylococcus aureus and meticillin-susceptible Staphylococcus aureus screening in a cohort of haemodialysis patients: carriage, demographics and outcomes.
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