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An outbreak of livestock-associated meticillin-resistant Staphylococcus aureus (LA-MRSA) clonal complex 398 in a regional burns centre

Published:December 10, 2021DOI:https://doi.org/10.1016/j.jhin.2021.12.005

      Summary

      Background

      Meticillin-resistant Staphylococcus aureus (MRSA) outbreaks have been reported previously in burns centres with resulting mortality and morbidity. This article describes the first human-associated outbreak in the UK caused by a strain of mupirocin-resistant (MuR) livestock-associated MRSA clonal complex 398 (LA-MRSA CC398) in an adult burns centre. The centre historically had a very low prevalence of MRSA infections.

      Aim

      To describe the clinical and epidemiological context of how the outbreak was identified and contained using a range of infection prevention and control (IPC) measures guided by both traditional and genetic methods.

      Methods

      A cluster of MuR-MRSA led to an outbreak investigation. Cases were detected via retrospective search and real-time laboratory surveillance. Isolates were sent continuously for whole-genome sequencing (WGS). A live timeline of cases and interventions was produced throughout the period.

      Findings

      The outbreak consisted of 12 cases (seven males and five females) aged between 22 and 70 years. Patients were identified between May and October 2020. All patients were colonized rather than infected. The strain acquired the plasmid bearing MupA while colonizing the index case before dissemination. The index case was found to be a chicken farmer. This outbreak was eventually controlled using IPC measures, audits, and blind staff decolonization guided by insight from WGS.

      Conclusion

      It was not possible to determine how the strain entered the centre, or if a staff carrier was involved. The outbreak demonstrated the potential for continued transmissions for months despite active surveillance and stringent control measures.

      Keywords

      Introduction

      Meticillin-resistant Staphylococcus aureus (MRSA) commonly colonizes or infects burns patients, with up to 20% of burns patients acquiring MRSA while admitted [
      • Kalligeros M.
      • Shehadeh F.
      • Karageorgos S.A.
      • Zacharioudakis I.M.
      • Mylonakis E.
      MRSA colonization and acquisition in the burn unit: a systematic review and meta-analysis.
      ]. MRSA colonization in burns patients can increase the risk of systemic infection, length of hospital stay and treatment costs [
      • Cook N.
      Methicillin-resistant Staphylococcus aureus versus the burn patient.
      ]. MRSA outbreaks within burns centres are rare but have been reported previously [
      • Garvey M.I.
      • Pichon B.
      • Bradley C.W.
      • Moiemen N.S.
      • Oppenheim B.
      • Kearns A.M.
      Improved understanding of an outbreak of meticillin-resistant Staphylococcus aureus in a regional burns centre via whole-genome sequencing.
      ,
      • Baier C.
      • Ipaktchi R.
      • Ebadi E.
      • Limbourg A.
      • Mett T.R.
      • Vogt P.M.
      • et al.
      A multimodal infection control concept in a burn intensive care unit – lessons learnt from a meticillin-resistant Staphylococcus aureus outbreak.
      ,
      • Kim J.J.
      • Blevins M.W.
      • Brooks D.J.
      • Stehle J.R.
      • McLouth C.J.
      • Viviano J.P.
      • et al.
      Successful control of a methicillin-resistant Staphylococcus aureus outbreak in a burn intensive care unit by addition of universal decolonization with intranasal mupirocin to basic infection prevention measures.
      ].
      Livestock-associated (LA) MRSA clonal complex (CC) 398 evolved from human-adapted meticillin-sensitive Staphylococcus aureus (MSSA), and jumped to livestock after acquiring genetic adaptations including the SCCmec element conferring meticillin resistance [
      • Cuny C.
      • Wieler L.H.
      • Witte W.
      Livestock-associated MRSA: the impact on humans.
      ]. LA-MRSA is known to colonize livestock asymptomatically. The clone is widespread in pig farms across Europe; up to 50% of pigs in European farms are colonized. Although LA-MRSA has been reported in the UK, it has never, to the authors' knowledge, been implicated in an outbreak. The clinical significance of LA-MRSA in human colonization and infection remains unclear. This article describes an outbreak caused by a mupirocin-resistant (MuR) strain of LA-MRSA CC398.
      In recent years, there has been an increase in mupirocin resistance in S. aureus, especially in MRSA [
      • Dadashi M.
      • Hajikhani B.
      • Darban-Sarokhalil D.
      • van Belkum A.
      • Goudarzi M.
      Mupirocin resistance in Staphylococcus aureus: a systematic review and meta-analysis.
      ]. Mupirocin is the mainstay of MRSA decolonization, and universal decolonization with mupirocin has been recommended in patients in burns intensive care units (ICU) and wards [
      • Kim J.J.
      • Blevins M.W.
      • Brooks D.J.
      • Stehle J.R.
      • McLouth C.J.
      • Viviano J.P.
      • et al.
      Successful control of a methicillin-resistant Staphylococcus aureus outbreak in a burn intensive care unit by addition of universal decolonization with intranasal mupirocin to basic infection prevention measures.
      ,
      • Johnson A.T.
      • Nygaard R.M.
      • Cohen E.M.
      • Fey R.M.
      • Wagner A.L.
      The impact of a universal decolonization protocol on hospital-acquired methicillin-resistant Staphylococcus aureus in a burn population.
      ]. An increase in the prevalence of MuR-MRSA has been recognized for several years [
      • Poovelikunnel T.
      • Gethin G.
      • Humphreys H.
      Mupirocin resistance: clinical implications and potential alternatives for the eradication of MRSA.
      ], which is concerning given the lower efficacy of alternative decolonization agents [
      • Hamson C.
      • Bignardi G.E.
      MRSA decolonisation with Prontoderm compared with chlorhexidine and mupirocin.
      ,
      • Leigh D.A.
      • Joy G.
      Treatment of familial staphylococcal infection – comparison of mupirocin nasal ointment and chlorhexidine/neomycin (Naseptin) cream in eradication of nasal carriage.
      ]. This article reports mupirocin resistance in LA-MRSA CC398 for the first time. Clinical and epidemiological contexts of this outbreak are described, together with information about how it was contained using infection prevention and control (IPC) measures guided by traditional and genetic methods.

      Methods

      Setting

      This outbreak occurred in the adult burns centre at a National Health Service hospital serving five million people across Yorkshire and Lincolnshire, UK. The centre has five adult beds and two ICU beds co-located with outpatient facilities, treating 900 patients per year, including 180 inpatients. There is a paediatric burns unit in the same building with some crossover of medical and therapy staff.
      This outbreak coincided with the coronavirus disease 2019 (COVID-19) pandemic, a period of staff shortages, redeployment of burns staff (and replacement with non-specialist staff), and busy inpatient activity. The unit experienced a multi-drug-resistant Acinetobacter baumannii outbreak in November 2018, which resulted in ongoing enhanced IPC measures.

      Identification of the outbreak

      In late June 2020, while discussing three MRSA-colonized patients at the burns multi-disciplinary team (MDT) meeting, the number of MRSA patients appeared greater than expected. The MDT decided to monitor the situation. By 13th July 2020, seven cases had been identified; of these, four were MuR-MRSA, which was unusual and prompted further investigation. Previous analysis of all burns patients between June and December 2017 had identified no cases of MRSA.

      Case definition and data collection

      A case was defined as a patient who had MuR-MRSA on screening nose and groin or burn wound swabs, whether infected or colonized. Infection was defined as clinical diagnosis by a senior burns surgeon based on signs such as cellulitis, purulence and systemic signs of infection. Colonization was defined as the presence of bacteria on wound swabs without evidence of infection. A search performed on 5th August 2020 in the ICNet database using the terms ‘MRSA screen’, ‘S. aureus (MRSA)' with the associated feature ‘mupirocin’ identified six patients. Laboratory surveillance identified subsequent cases in real-time.

      Investigations

      The hospital laboratory tested MRSA isolates for MuR using EUCAST disc diffusion methodology; high-level resistance (zone size <18 mm with 200-μg disk) isolates were reported as MuR. The first five case isolates were sent for whole-genome sequencing (WGS) on 17th August 2020, and then when isolated. The IPC team collected 22 environmental samples from macroscopically clean touchpoints using a standard wound swab. Swabs were plated on Colorex MRSA chromogenic medium (E & O Laboratories Ltd, Bonnybridge, UK) for selective MRSA isolation.

      Analyses

      The investigation team produced a timeline of cases and interventions updated throughout the period (Figure 1).
      Figure 1
      Figure 1Timeline (red dot marks the first detection of the outbreak strain). Outpatient department (OPD) care period is shown separately for those who received it. The care periods for several cases extended beyond the outbreak period and are not shown in full: Case B (18/01/2021), Case C (18/12/2021), Case G (02/11/2020) and Case L (01/12/2020). MDT, multi-disciplinary team; WGS, whole-genome sequencing; PHE, Public Health England; HPV, hydrogen peroxide vaporization.

      Interventions

      On 5th August 2020, the IPC team escalated the matter within the burns centre. The outpatient and inpatient sections are contiguous, and staff movement between these was stopped whenever possible. Movement of postoperative burns patients was restricted. The HCAI & AMR Division of the National Infection Service, Public Health England (PHE) was contacted on 17th July 2020 to arrange WGS on MuR-MRSA isolates.
      An Incident Control Group (ICG) was formed comprising representatives from a range of backgrounds within the Burns Centre, the IPC team and PHE (Appendix 1, see online supplementary material). The group met via Microsoft Teams eight times, first on 17th August 2020. Actions arising from the ICG's meetings are summarized in Table I and Figure 1.
      Table IAction log of steps taken to control outbreak
      ActionDateComment
      Staff to be identified who cared for Case E and Case G17/8/20Complete 28/8/20
      Hand hygiene audits and ‘bare below the elbows’ audits17/8/20Complete 21/8/20
      Review SOP to provide assurance of compliance17/8/20Complete 25/9/20 (nothing of concern)
      Twice-daily ‘red clean’ and after any attendance from known case17/8/20Ongoing
      Daily IPC nurse visit17/8/20Complete 25/9/20
      Send isolates for whole-genome sequencing17/8/20Complete 17/8/20
      Staff change uniform between burns and main ICU17/8/20Current practice
      HPV cleans throughout the unit (including theatres)21/8/20Complete 21/8/20
      Lead burn consultant to inform regional burn network21/8/20Complete 21/8/20
      Identification of staff names for decolonization21/8/20Complete 29/8/20 (48/49 took decolonization, first round)
      IPC nurse to attend ward meeting to support practice11/9/20Commenced 11/9/20
      Identification of staff who had contact with affected patients on or around 14/9/20 for decolonization22/9/20Complete 22/9/20 (9/9 took decolonization, second round)
      Additional HPV clean arranged22/9/20Complete 23/9/20
      Investigate recent case pathways2/10/20Complete 16/10/20 (no theme of note)
      Share audit results with MDT2/10/20Complete 9/10/20
      IPC team to assess practice2/10/20Complete 9/10/20
      Environmental swabbing2/10/20Complete 12/10/2 (isolated from OPD Room 2)
      Identify staff contacts with Case K and Case L for decolonization2/10/20Complete 16/10/20 (2/2 took decolonization, third round)
      Utilize inpatient dressing bathroom for affected patients16/10/20Complete 16/10/20
      Review dressing SOP16/10/20Complete 16/10/20
      Additional clean at the end of the morning and afternoon clinics16/10/20Complete 16/10/20
      ICU, intensive care unit; HPV, hydrogen peroxide vaporization; MDT, multi-disciplinary team; IPC, Infection prevention and control; SOP, standard operating procedure; OPD, outpatient department.
      The group reviewed all cases and revisited the standard operating procedures developed during the A. baumannii outbreak to ensure appropriateness to prevent patient-to-patient transmission.
      The ICG agreed that the centre was safe to remain open. Patients were made aware that they had MRSA colonization, but not that they formed part of a probable cluster under investigation. It was agreed that patients and the regional network would be informed if an outbreak was confirmed; this was done as further cases were identified.
      Additional ‘deep cleans’ and hydrogen peroxide vaporization of all clinical rooms, outpatients and the operating theatre were performed. All outpatient rooms were cleaned with Clinell Universal Wipes (GAMA Healthcare Ltd, Watford, UK), and additional ‘red cleans’ (environmental clean using a combined detergent and 1000 ppm chlorine-releasing agent) were performed between any known infected patients.
      Forty-nine staff were offered blind decolonization therapy using octenidine body wash (Octenisan, Schülke & Mayr UK Ltd, Sheffield, UK) and chlorhexidine 0.1%/neomycin 0.5% nasal ointment (Naseptin, Alliance Pharmaceuticals Ltd, Chippenham, UK), and 98% chose to avail of the offer. As further cases were identified and the WGS results revealed chlorhexidine resistance, staff were offered two further rounds of blind decolonization using Octenisan body wash and nasal gel or polihexanide nasal gel (Prontoderm, B. Braun Melsungen AG, Hessen, Germany), with nine (100%) taking this up in the second round, and two (100%) in the third round. Patients were given decolonization as cases were identified, initially with Octenisan body wash and Naseptin ointment, and subsequently with Prontoderm nasal gel, in line with staff treatment.

      Results

      Retrospective analysis

      Between January and December 2020, the laboratory reported 1641 S. aureus isolates from clinical samples (swabs, fluid, pus, tissue); 83% were from the plastic and burns surgery (PBS) patients. The proportion of MRSA was 13% overall and 15% for PBS patients. Of the 22 (6%) MRSA-positive patients, 12 had the outbreak strain.

      Overview of the cases

      Twelve cases (seven male and five female) aged 22–70 years were identified (Table II). The outbreak strain only colonized wounds; no patient was clinically infected. No cases were identified in the paediatric unit. Most patients had flame burns (9/12) and large burn injuries, with a mean total body surface area of 18%.
      Table IIDemographics and details of positive swabs. The genetic relatedness of the clonal complex (CC) 398 isolates shows that they are closely related genetically, and belong to the five single-nucleotide polymorphism cluster CC398–608.650.681.X suggesting a transmission event
      IDSexDetectionWhere detectedSampleCluster IDDuration of positive culture
      AM28/05/20

      03/06/20

      21/06/20
      Outpatient

      Outpatient

      Outpatient
      Arm (left)

      Arm (left)

      Forearm (left)
      CC398–608.650.681.747

      CC398–608.650.681.747

      CC398–608.650.681.802
      23
      BF19/06/20

      18/08/20
      Outpatient

      Outpatient
      Shoulder (left)

      Thigh (left)
      CC398–608.650.681.749

      CC398–608.650.681.755
      157
      CM19/06/20

      19/07/20

      20/07/20

      10/08/20

      27/08/20

      16/09/20

      16/10/20
      Inpatient

      Inpatient

      Inpatient

      Outpatient

      Outpatient

      Outpatient

      Outpatient
      Hand (left)

      MRSA screen

      Chest

      Hand (left)

      Unspecified

      MRSA screen

      MRSA screen
      CC398–608.650.681.748

      CC398–608.650.681.747

      CC398–608.650.681.799

      CC398–608.650.681.800

      CC398–608.650.681.768

      CC398–608.650.681.747

      CC398–608.650.681.801
      137
      DM20/07/20OutpatientHand (left)CC398–608.650.681.74710
      EF23/07/20

      03/08/20
      InpatientLeg (right)

      Foot (left)
      CC398–608.650.681.750 CC398–608.650.681.75021
      FF25/07/20OutpatientHand (left)CC398–608.650.681.7585
      GM14/08/20InpatientHand (left)CC398–608.650.681.75166
      HM17/08/20InpatientHand (right)CC398–608.650.681.7508
      IM01/09/20OutpatientMRSA screenCC398–608.650.681.758Single culture
      JF18/09/20OutpatientArm (right)CC398–608.650.681.7477
      KF23/09/20OutpatientArm (right)CC398–608.650.681.7687
      LM05/10/20InpatientForearm (right)CC398–608.650.681.74736
      MN/A12/10/20N/AEnvironmentCC398–608.716.747.830N/A
      MRSA, meticillin-resistant Staphylococcus aureus.
      The first case (Case A) had a negative MRSA nose and groin screen on admission, and the burn wounds showed ‘no growth’. On Day 8 of his admission, he commenced a 5-day course of piperacillin-tazobactam for ventilator-associated pneumonia. His wounds subsequently tested positive with a mupirocin-sensitive (MuS) MRSA, first on Day 8 (and 9) from burn wound screen; he was treated with Octenisan body wash and 2% mupirocin ointment nasally for 5 days. He had not previously received MRSA decolonization although his wounds were cleaned regularly with Octenisan. The patient was discharged, and the MuR-MRSA was first detected 9 days later from the same wound during an outpatient attendance. Both MuS- and MuR-MRSA isolates shared identical antibiogram except for mupirocin. The WGS analysis proved both the MuS- and MuR-MRSA isolates were otherwise indistinguishable, confirming acquisition of the MupR gene.
      The outbreak strain seemed to have acquired the resistance plasmid after the patient was discharged while attending the outpatient dressing clinic. The second case (Case B) grew MSSA in an admission wound swab, but acquired the MuR-MRSA strain after discharge in a swab taken during outpatient attendance, and continued to have the strain throughout her care. Both Cases A and B were inpatients with overlapping outpatient care.
      Of the five subsequent cases, the third (Case C), fifth (Case E) and seventh (Case G) acquired the strain during inpatient care, and the fourth (Case D) and sixth (Case F) acquired the strain during outpatient wound care post discharge. All seven patients had been to the operating theatre; Cases E and F had also been in the burns ICU.
      Case C acquired MuR-MRSA and carried it for 4 months. He also acquired MSSA during this episode, and remained colonized until hospital discharge, but lost the MuR-MRSA. Case D was admitted colonized with MSSA, and acquired MuR-MRSA 2 months later in his burn wound while an outpatient. MuR-MRSA persisted for 10 days, but MSSA remained present until discharge in October 2020. Case E acquired MuR-MRSA 1 month into her admission. She remained colonized with MuR-MRSA until repatriation to a neighbouring unit, where she screened positive for MuR-MRSA 10 days later. Further swabs over the next 7 months did not culture MuR-MRSA, but did grow other MRSA strains. Case F acquired MuR-MRSA a few days into admission, and carried it until healed 1 week later.
      Case G had a negative MRSA screen on admission, before the outbreak strain was detected 8 days later, with MSSA in his wounds throughout treatment. Case H first grew the outbreak strain 2 weeks into admission. He was repatriated to a local unit while completing decolonization, and although he did not culture the outbreak strain again, he continued to grow MuS-MRSA for a further month. Case I was positive for MuR-MRSA as an outpatient on screening; his burn wound had MSSA. He had an earlier overnight stay in the unit.
      Case J was identified from an outpatient swab. The patient attended a dressing clinic days earlier, but was first on the list. The patient grew MSSA on two previous wound swabs. Case K was detected on an outpatient swab; she previously had an inpatient stay overlapping with three cases, and grew MSSA before acquiring MuR-MRSA. Case L grew MuR-MRSA in a wound swab, having had a previous admission which overlapped with other cases. The outbreak was declared over in November 2020, 28 days after the last case was detected on 5th October 2020.

      MSSA/MRSA numbers

      The numbers of instances of MSSA infection/colonization were 99, 102 and 95 before the outbreak (April–June 2020), during the intervention (July–September 2020) and after the intervention (October–December 2020), respectively. The corresponding numbers for MRSA were 5, 11 and 6 (2, 4 and 4 excluding the outbreak strain).

      Whole-genome sequencing

      The interim WGS report confirmed that the first five isolates represented a single strain of LA-MRSA CC398 within a single cluster, with isolates varying by zero to three single-nucleotide polymorphisms (SNPs). WGS analysis of the MuS-MRSA isolate from the index case confirmed that it was indistinguishable. WGS confirmed that the MuS-MRSA isolate was mupA negative, matching susceptibility testing. The final report incorporated 23 MuR-MRSA isolates from 12 patients and one environmental sample. The 22 clinical isolates were closely genetically related within five SNPs, suggesting a transmission event (Table II). The environmental isolate was closely related to the clinical isolates with up to 25 SNPs. Two genetically unrelated MuR-MRSA isolates were sequenced as part of the investigation.

      Antimicrobial resistance

      Mupirocin resistance has not been reported previously in LA-MRSA CC398 isolates, and was encoded by mupA (a plasmid-acquired element) in this case. The outbreak strain was multi-drug resistant (aminoglycosides, macrolides, inducible clindamycin, tetracyclines, quinolones and trimethoprim). Another interesting feature was the presence of the qacA gene, encoding an efflux pump associated with resistance to quaternary ammonium compounds including chlorhexidine.

      Staff MRSA decolonization

      Forty-eight staff received blind decolonization using Octenisan wash and Naseptin nasal ointment from 21st August 2020. When WGS suggested resistance to chlorhexidine (an active ingredient of Naseptin), a second round of decolonization was offered to nine staff who had contact with affected patients; this consisted of Prontoderm nasal gel and Octenisan wash, and was provided on 22nd September 2020. Staff in contact with the final cases were offered a further round of decolonization on 16th October 2020.

      Farm link

      LA-MRSA CC398 has strong links with animal farms. As such, the authors investigated if the patients or any member of staff had any connection with farm activity, or lived in or near a farm. Notably, the index case was a chicken farmer, although he is believed to have acquired the outbreak strain as an inpatient so the significance of this is unclear. No other links to farming activity were identified.

      Discussion

      One of the first human-associated LA-MRSA CC398 isolates in Europe was detected in 2000 in a German hospital in an area of high livestock production. The incidence rose to 9.6% by 2005, and comprised 35% of all MRSA in that hospital by 2013 [
      • van Alen S.
      • Ballhausen B.
      • Peters G.
      • Friedrich A.W.
      • Mellmann A.
      • Köck R.
      • et al.
      In the centre of an epidemic: fifteen years of LA-MRSA CC398 at University Hospital Münster.
      ]. The strain has established itself as a cause of human infections in European countries, including the Netherlands and Denmark, which historically had low prevalence of MRSA. Pig movements between farms, and resistance to specific antibiotics and heavy metals, are recognized drivers of LA-MRSA CC398 spread in the Danish pig production system [
      • Sieber R.N.
      • Skov R.L.
      • Nielsen J.
      • Schulz J.
      • Price L.B.
      • Larsen A.R.
      • et al.
      Drivers and dynamics of methicillin-resistant livestock-associated Staphylococcus aureus CC398 in pigs and humans in Denmark.
      ]. Contact with, and the density of, livestock production in the area served by the hospital largely determine its prevalence [
      • Feingold B.J.
      • Silbergeld E.K.
      • Curriero F.C.
      • van Cleef B.A.G.L.
      • Heck M.E.O.C.
      • Kluytmans J.A.J.W.
      Livestock density as risk factor for livestock-associated methicillin-resistant Staphylococcus aureus, the Netherlands.
      ,
      • Ceballos S.
      • Aspiroz C.
      • Ruiz-Ripa L.
      • Reynaga E.
      • Azcona-Gutiérrez J.M.
      • Rezusta A.
      • et al.
      Epidemiology of MRSA CC398 in hospitals located in Spanish regions with different pig-farming densities: a multicentre study.
      ]. However a Danish study found colonization among hospital staff even in regions where dense livestock production was extremely low, with no detection in air or dust at the hospital, or from staff resident on farms [
      • Würtz E.T.
      • Bønløkke J.H.
      • Urth T.R.
      • Larsen J.
      • Islam M.Z.
      • Sigsgaard T.
      • et al.
      No apparent transmission of livestock-associated methicillin-resistant Staphylococcus aureus CC398 in a survey of staff at a regional Danish hospital.
      ]. LA-MRSA can survive in farm dust with a half-life of 5 days, remaining detectable for several weeks [
      • Feld L.
      • Bay H.
      • Angen Ø.
      • Larsen A.R.
      • Madsen A.M.
      Survival of LA-MRSA in dust from swine farms.
      ]. Several studies have estimated its human-to-human transmission potential as less than non-animal-associated MRSA [
      • Bootsma M.C.J.
      • Wassenberg M.W.M.
      • Trapman P.
      • Bonten M.J.M.
      The nosocomial transmission rate of resistant Staphylococcus aureus.
      ,
      • Wassenberg M.W.M.
      • Bootsma M.C.J.
      • Troelstra A.
      • Kluytmans J.A.J.W.
      • Bonten M.J.M.
      Transmissibility of livestock-associated methicillin-resistant Staphylococcus aureus (ST398) in Dutch hospitals.
      ]. Some studies have indicated that its carriage duration following exposure is short [
      • Van Cleef B.A.G.L.
      • Graveland H.
      • Haenen A.P.J.
      • Van De Giessen A.W.
      • Heederik D.
      • Wagenaar J.A.
      • et al.
      Persistence of livestock-associated methicillin-resistant Staphylococcus aureus in field workers after short-term occupational exposure to pigs and veal calves.
      ,
      • Frana T.S.
      • Beahm A.R.
      • Hanson B.M.
      • Kinyon J.M.
      • Layman L.L.
      • Karriker L.A.
      • et al.
      Isolation and characterization of methicillin-resistant Staphylococcus aureus from pork farms and visiting veterinary students.
      ], while others have suggested otherwise [
      • Köck R.
      • Loth B.
      • Köksal M.
      • Schulte-Wülwer J.
      • Harlizius J.
      • Friedrich A.W.
      Persistence of nasal colonization with livestock-associated methicillin-resistant Staphylococcus aureus in pig farmers after holidays from pig exposure.
      ,
      • Verkade E.
      • Van Benthem B.
      • Van Den Bergh M.K.
      • Van Cleef B.
      • Van Rijen M.
      • Bosch T.
      • et al.
      Dynamics and determinants of Staphylococcus aureus carriage in livestock veterinarians: a prospective cohort study.
      ]. Pets can act as a reservoir [
      • Kaspar U.
      • von Lützau A.
      • Schlattmann A.
      • Roesler U.
      • Köck R.
      • Becker K.
      Zoonotic multidrug-resistant microorganisms among small companion animals in Germany.
      ].
      LA-MRSA CC398 has been introduced to the UK from European countries on multiple occasions [
      • Sharma M.
      • Nunez-Garcia J.
      • Kearns A.M.
      • Doumith M.
      • Butaye P.R.
      • Angeles Argudín M.
      • et al.
      Livestock-associated methicillin resistant Staphylococcus aureus (LA-MRSA) clonal complex (CC) 398 isolated from UK animals belong to European lineages.
      ]. However, LA-MRSA is currently considered to be of low risk to public and animal health in the UK, with no specific UK legislation for the control of LA-MRSA, nor statutory procedures for the reporting or control of LA-MRSA in livestock [
      UK-VARSS
      UK veterinary antibiotic resistance and sales surveillance report (UK-VARSS 2019).
      ]. Since 2013, 27 LA-MRSA isolations have been reported in the UK [
      UK-VARSS
      UK-VARSS (2019) supplementary material.
      ]. No LA-MRSA was recovered in 2019 from food-producing animals in England, Wales or Scotland, but it was detected in four pig samples from Northern Ireland [
      UK-VARSS
      UK veterinary antibiotic resistance and sales surveillance report (UK-VARSS 2019).
      ].
      This outbreak is the first reported human-associated outbreak caused by a strain of LA-MRSA CC398 in the UK. Previous MRSA outbreaks have been reported in burns centres, and WGS has been used to help delineate acquisition pathways [
      • Garvey M.I.
      • Pichon B.
      • Bradley C.W.
      • Moiemen N.S.
      • Oppenheim B.
      • Kearns A.M.
      Improved understanding of an outbreak of meticillin-resistant Staphylococcus aureus in a regional burns centre via whole-genome sequencing.
      ]. Within the study outbreak, the variability of up to five SNPs observed between the isolates within a short period suggests acquisition from a single source shedding multiple variants or a transmission network. Phylogenetic analysis displayed low bootstrap values; the close genetic relatedness (Table II, Table III) indicated independent acquisition of mutations rather than an evolutionary process. The outbreak could represent a transmission network. According to a transmission model, the combined SNP cut-offs for detection of MRSA transmission within 6 months were 24 whole-genome or 13 core-genome SNPs [
      • Coll F.
      • Raven K.E.
      • Knight G.M.
      • Blane B.
      • Harrison E.M.
      • Leek D.
      • et al.
      Definition of a genetic relatedness cutoff to exclude recent transmission of meticillin-resistant Staphylococcus aureus: a genomic epidemiology analysis.
      ]. A single colonized individual could shed variants differing by up to 40 SNPs [
      • Paterson G.K.
      • Harrison E.M.
      • Murray G.G.R.
      • Welch J.J.
      • Warland J.H.
      • Holden M.T.G.
      • et al.
      Capturing the cloud of diversity reveals complexity and heterogeneity of MRSA carriage, infection and transmission.
      ]. Case C had a prolonged inpatient stay and visited the outpatient department frequently throughout the outbreak; this could be a source of dissemination to subsequent patients, but does not explain how the strain was acquired. The index case's link to chicken farming is of interest; it was considered whether the negative MRSA screen on admission could represent a false negative. However, this is unlikely because the case screened negative on two consecutive screens; the index case first acquired the strain (MuS-MRSA) on the right arm on Day 8, which subsequently acquired mupirocin resistance, and was not exposed to any selective agent during this period which could select out MRSA. Decolonization was started after detection of the strain more than 1 week after admission, which was clearly hospital-acquired. Interestingly, cross-transmissions occurred only after the strain acquired mupirocin resistance, which supports cross-transmission from patient to patient (potentially with staff as transient carriers).
      Table IIIDistance matrix showing single-nucleotide polymorphisms derived from whole-genome sequencing results (dates refer to the date that isolates were received by the reference laboratory)
      D (20/7/20)L (6/10/20)I (1/9/20)E (3/8/20)G (14/8/20)H (17/8/20)A (3/6/20)J (18/9/20)B (10/8/20)F (25/7/20)B (18/8/20)K (23/9/20)C (22/6/20)E (20/7/20)
      L (6/10/20)0
      I (1/9/20)11
      E (3/8/20)212
      G (14/8/20)1122
      H (17/8/20)11202
      A (3/6/20)001111
      J (18/9/20)0011110
      B (10/8/20)22333322
      F (25/7/20)112222113
      B (18/8/20)2233332223
      K (23/9/20)22042322434
      C (22/6/20)112322113233
      E (20/7/20)2120201132343
      A (17/8/20)10111100212321
      No difference in overall numbers of cases of S. aureus (including MRSA) were found between the pre-intervention, intervention and post-intervention periods, suggesting that additional IPC measures may not have contributed to control of the outbreak strain. It is possible that blind decolonization of frontline staff may have contributed to control of the outbreak strain. Three rounds of decolonization were offered, and the last case (Case L) was detected approximately 2 weeks after the second round. A staff member carrying the strain with a cloud of diversity as the common source remains possible but unconfirmed, as staff were not screened. Staff MRSA screening is a hotly debated issue and is not generally recommended, although it has identified carriers in previous outbreaks [
      • Baier C.
      • Ipaktchi R.
      • Ebadi E.
      • Limbourg A.
      • Mett T.R.
      • Vogt P.M.
      • et al.
      A multimodal infection control concept in a burn intensive care unit – lessons learnt from a meticillin-resistant Staphylococcus aureus outbreak.
      ], and does not preclude strain-specific screening [
      • Perry C.
      Exploring the evidence for screening staff for MRSA.
      ]. Staff may be reluctant to engage in screening for multiple reasons [
      • Wolfensberger A.
      • Schmid M.
      • Sax H.
      • Clack L.
      • Wyler C.
      • Bassler Di
      • et al.
      Determinants for voluntary participation in staff screening during an methicillin-resistant Staphylococcus aureus (MRSA) outbreak on a neonatal ward.
      ], and negative screening could be falsely reassuring due to transient carriage [
      • Perry C.
      Exploring the evidence for screening staff for MRSA.
      ]. The ramifications of positive staff being unable to work if they could not clear the organism are significant. A conscious decision was taken not to screen staff, and instead universal decolonization was offered to front-line staff. However the disadvantage of this approach is that the role of transmission between patients and staff is not known, and staff who were not colonized underwent exposure to decolonization agents unnecessarily, with the associated risk of side-effects and financial cost. Monitoring for the outbreak strain continues, and should it resurface, screening of relevant staff will be reconsidered. It is highly likely that staff redeployments due to COVID-19 and ongoing high workload were also contributing factors.
      The outbreak strain is of interest and concern, retaining the ability to transmit between humans and colonize wounds. LA-MRSA clones are generally less virulent than community-acquired MRSA clones. However, specific subgroups of LA-MRSA, including those exhibiting spa-type t571, t108 or harbouring human virulence factors such as the Panton-Valentine-Leukocidin gene, could quickly re-adapt to humans [
      • Nakaminami H.
      • Hirai Y.
      • Nishimura H.
      • Takadama S.
      • Noguchi N.
      Arthritis caused by MRSA CC398 in patient without animal contact, Japan.
      ]. This remains a cause of concern given the large reservoir in livestock [
      • Ballhausen B.
      • Jung P.
      • Kriegeskorte A.
      • Makgotlho P.E.
      • Ruffing U.
      • von Müller L.
      • et al.
      LA-MRSA CC398 differ from classical community acquired-MRSA and hospital acquired-MRSA lineages: functional analysis of infection and colonization processes.
      ,
      • Sieber R.N.
      • Larsen A.R.
      • Urth T.R.
      • Iversen S.
      • Møller C.H.
      • Skov R.L.
      • et al.
      Genome investigations show host adaptation and transmission of LA-MRSA CC398 from pigs into Danish healthcare institutions.
      ]. The clinical relevance of LA-MRSA CC398 strains remains unclear a decade after its emergence. There have been reports of bacteraemia and deep-seated infections [
      • Smith T.C.
      • Wardyn S.E.
      Human infections with Staphylococcus aureus CC398.
      ,
      • Mama O.M.
      • Aspiroz C.
      • Ruiz-Ripa L.
      • Ceballos S.
      • Iñiguez-Barrio M.
      • Cercenado E.
      • et al.
      Prevalence and genetic characteristics of Staphylococcus aureus CC398 isolates from invasive infections in Spanish hospitals, focusing on the livestock-independent CC398-MSSA clade.
      ], although not in the study cohort.
      In conclusion, this article reports an outbreak caused by a MuR-MRSA strain of LA-MRSA CC398 spanning a 4-month period. A combination of heightened IPC measures and blind staff decolonization may have helped in outbreak control. It was not possible to determine conclusively how the strain entered the centre, nor if there was a staff carrier. The decolonization regimen was guided by WGS findings of chlorhexidine resistance. WGS was also instrumental in confirming the gain of the resistance plasmid bearing the mupA gene by the strain early in the outbreak, while still colonizing the index case. The MuR phenotype helped recognition of the index and subsequent cases in real-time and has not been reported previously in LA-MRSA CC398. The outbreak was contained successfully, but it demonstrated the potential for continued transmission for months within a contact network of patients and staff despite active surveillance and stringent control measures. Further genomic analysis may shed more light on the transmission dynamics and characteristics of the strain.

      Acknowledgements

      The investigation and management of this outbreak required an MDT approach and would not have been possible without the dedication and assistance of the nurses, doctors, therapists and support staff of the Adult Burns Centre, Pinderfields Hospital; the Department of Microbiology; antimicrobial pharmacists; the IPC team; and local representatives of Public Health England.
      The authors also wish to thank Dr Tamsin Dewé MRCVS, Head of AMR Surveillance and Evidence, Antimicrobial Resistance, Policy and Surveillance Team, Veterinary Medicines Directorate, Department for Food, Environment and Rural Affairs, for advice and background on LA-MRSA surveillance in the UK. Finally, the authors wish to thank Dr Bruno Pichon, HCAI and AMR Divisional Office, PHE, Colindale, for his advice and expertise on LA-MRSA and in managing this outbreak, as well as assisting in the analysis of the genomics data in this paper.

      Author contributions

      MJS: involved in managing the outbreak, analysis of data and drafting the paper.
      CS: involved in managing the outbreak and collating data for analysis.
      SB: involved in managing the outbreak and collating data for analysis.
      PM: senior author involved in managing the outbreak and drafting the paper.
      JBS: senior author involved in managing the outbreak, data analysis and drafting the paper.
      All authors reviewed and approved the final article.

      Conflict of interest statement

      None declared.

      Funding sources

      None.

      Appendix A. Supplementary data

      The following is the Supplementary data to this article:

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