A major outbreak of methicillin-resistant Staphylococcus aureus caused by a new phage-type (EMRSA-16)

Journal

of Hospital

Infection

A major Staphylococcus

(1995)

29, 87-106

outbreak aweus

of methicillin-resistant caused by a new

phage-type

(EMRSA-16) R. A. Cox,*

C. Conquest,

* C. Mallaghan”

and R. R. Marplesf

t s of Microbiology and Infection Control, Kettering General “Departmen Hospital, Kettering, Northamptonshire and fLaboratory of Hospital Infection, Central Public Health Laboratory, Cola&dale, London, UK Accepted

fey publication

6 October

1994

Summary:

An outbreak of methicillin-resistant Staphylococcus auveus (MRSA) infection caused by a novel phage-type (now designated EMRSA16) occurred in three hospitals in East Northamptonshire over a 21-month period (April 1991-December 1992). Four hundred patients were colonized or infected. Seven patients died as a direct result of infection. Chest infections were significantly associated with the outbreak strain when compared with methicillin-sensitive S. aureus. Twenty-seven staff and two relatives who cared for patients were also colonized. A ‘search and destroy’ strategy, as advocated in the current UK guidelines for control of epidemic MRSA was implemented after detection of the first case. Despite extensive screening of staff and patients and isolation of colonized and infected patients, the outbreak strain spread to all wards of the three hospitals except paediatrics and maternity. A high incidence of throat colonization (51%) was observed. Failure to recognize the importance of this until late in the outbreak contributed to the delay in containing its spread. Key parts of the strategy which eventually contained the local outbreak were the establishment of isolation wards in two hospitals, treatment of all colonized patients and staff to eradicate carriage and screening of all patients upon discharge from wards where MRSA had ever been detected. EMRSA-16 spread to neighbouring hospitals by early 1992 and to London and the South of England by 1993. It is distinguished from other epidemic strains by its characteristic phage-type, antibiogram (susceptibility to tetracycline and resistance to ciprofloxacin), and in the pattern given on pulse field electrophoresis. Keywords: carriage;

Methicillin-resistant discharge screening.

Staphylococcus

aureus;

phage

typing;

throat

Introduction In the past decade methicillin-resistant emerged as a major infection control Correspondence to: Dr R. A. Cox, Northants NN16 8UZ. 0195%6701/95/020087+20

Kettering

Staphylococcus aweus (MRSA) has problem in hospitals in many parts

and District

$08.00/O

General

Hospital,

Rothwell

Road,

0 1995 The Hospital

87

Kettering,

Infection

Society

88

R. A. Cox et al.

of the world.’ MRSA are a heterogenous group of organisms which vary in their virulance and epidemic potential. Some strains have caused severe and life-threatening infections,’ suggesting they are at least as virulent as methicillin-sensitive S. aUYeUS (MSSA).3 Experience with some strains indicates that aggressive and costly measures are necessary to prevent spread,2 while other strains may be contained by simply reinforcing good all-round infection control standards4 As little is known about those factors that determine either virulence or the ability to spread, these characteristics cannot be predicted when a strain is first identified. As a result there is often uncertainty on the appropriate response to the presence of MRSA in hospitals. When a new strain is first recognized in a hospital, a common approach is to implement, in whole or in part, the measures advocated in the UK guidelines on the control of epidemic MRSA.’ Control measures are subsequently relaxed as experience is gained of the epidemic potential and virulence of the strain.4’6 Some have argued that general anti-staphylococcal measures should only be employed if there is evidence of cross-infection and substantial morbidity7 while others have doubted whether any specific control measures are justified.’ A logical approach might be to tailor control measures to take account of the behaviour of those strains recognized as ‘epidemic’ MRSA. These are, by definition, strains which have spread to a number of hospitals. By early 1993, 15 epidemic strains had been reported in the UK.9,‘0 This paper describes the epidemiology, laboratory characterization and control methods employed to contain an outbreak of MRSA infection caused by a hithertoundescribed strain (now designated EMRSA-16),” typing variably with phages 29, 52, 75 and 83A at 100 times routine test dilution, which had spread to 32 hospitals in the UK by May 1993 and is continuing to spread.12

Materials

and methods

Microbiological methods Screening swabs from patients were cultured on mannitol salt agar (Unipath) containing methicillin 4 mg-’ and incubated at 35°C for 48 h. Yellow colonies were tested for DNase production (DNase agar, Unipath), and subcultured onto DST agar (Unipath) plus 10% lysed blood with a strip containing 25 pg methicillin. Isolates were tested for antibiotic susceptibility using the comparative method and discs containing penicillin 1.5 IU, tetracycline 10 pg, erythromycin 5 pg, fusidic acid 10 pg, chloramphenicol 10 I-18, ciprofloxacin 1 pg, gentamicin 10 yg, netilmicin 30 pg, mupirocin 5 pg, rifampicin 2 pg, teicoplanin 30 l.tg, vancomycin 5 yg and trimethoprim 1.25 pg. All methicillin-resistant, DNase-positive isolates were checked by Staphaurex (Murex Diagnostics Ltd) and the tube coagulase test. From November 1991 all swabs from patients previously or currently colonized or infected

MRS.4

outbreak

89

with MRSA were enriched in nutrient broth containing 7% salt incubated at 30°C for 48 h before subculture on mannitol salt agar as described above. All isolates were sent to the Staphylococcus Reference Unit, Central Public Health Laboratory, Colindale. Each was subcultured overnight and types by standard methods13 with the 23 international phages at routine test dilution (RTD)-that dilution of the phage suspension that gives just confluent lysis on its propagating strain-and at RTD x 100. Four experimental phages, 88A, 90, 83C and 932, were tested at RTD x 100. Isolates found to be mupirocin resistant on disc testing were referred to the Antibiotic Reference Laboratory, Central Public Health Laboratory, Colindale. Minimum inhibitory concentration values (MIC values) to mupirocin were determined using standardized controlled disc diffusion testing with a 200 pg mupirocin disc and linear regression analysis. Selected isolates were studied further by extended susceptibility studies, simple biochemical tests and DNA restriction.*’ A particular question was the distinction of the outbreak strain from the known epidemic strain, EMRSA-3 which typed strongly at RTD x 100 with two of the four phages defining EMRSA-16.9 Representative isolates of the outbreak strain from hospital A and from two other hospitals, L and N, to which it had spread, were compared with a series of EMRSA-3 isolates by pulse field electrophoresis of SmaI digests of total DNA.14,” Statistical methods The statistical significance (PcO.05) of the results was determined the x2 technique and the Fisher exact test.

using

Surveillance methods Patients. Patients on affected wards were screened weekly until no new cases were detected after three consecutive weeks. From the start of the outbreak in April 1991 swabs were taken from the nose, wounds and any area of broken skin as well as clinically indicated cultures. Urine was examined if the patient was catheterized. From September 1991 perineal swabs were included and throat swabs were added in February 1992. Newly-diagnosed patients were re-screened and additional swabs taken from the hairline, axillae and groins. Patients were swabbed after treatment was complete and inpatients were declared ‘clear’ when they had three successive sets of negative swabs. Those patients who remained in hospital after treatment for MRSA were screened weekly for the rest of their hospital stay. Patients discharged to the community were followed up until they had at least one negative screen. Those who received regular care from district nurses were screened weekly. All patients transferred between wards and between hospitals were screened for MRSA. Where possible they were isolated in a single room until the results were known. From September 1991 pre-admission screening was arranged for all patients admitted for elective surgery if they had been in

90

R. A. Cox et al.

a care of the elderly ward since January 1991. All emergency admissions in this category were also screened. However, the yield was so poor (one colonized patient identified) that this was discontinued in March 1992. A more successful strategy was to screen all patients shortly before discharge from wards where MRSA was known to be present, or had recently been eradicated. ‘Discharge screening’ continued for four weeks after ward screening had been discontinued in acute medical and surgical wards. It has continued indefinitely in six elderly care wards.

Stuff.

Initially ward screening included staff as well as patients but when it was realized that staff colonization was uncommon, staff screening in some areas was reduced. In intensive care, orthopaedic and general surgical wards, screening of staff continued. Five thousand, one hundred and twenty screening swabs from staff were examined. Staff screening was limited to nasal swabs. Perineal and throat swabs were requested for several months but all staff carriers were initially colonized in the nose. Once a staff carrier had been identified, additional swabs were taken from throat, perineum, axillae, hairline and groin. Those who were only nasal carriers were allowed to continue on duty whilst on treatment but four who were also throat carriers were excluded from work until they had completed a course of treatment. Control measures Colonized patients and staff were given nasal mupirocin (Bactroban nasal, SmithKline Beecham) three times daily for seven days. Skin colonization was treated with chlorhexidine surgical scrub (Hibiscrub, Zeneca Pharma) as liquid soap and hexachlorophane dusting powder (Ster-zac, Hough, Hoseason & Co. Ltd) was applied to creases. Initially patients were bathed daily but many experienced itchy, dry skin and later the regimen was changed to alternate day bathing after the first three days treatment. Colonized bedsores, ulcers and broken skin were treated with povidoneiodine spray (Betadine, Seton Healthcare) or topical mupirocin ointment applied once or twice daily for seven to 10 days. Urinary infections were treated with nitrofurantoin. Throat carriage was treated with oral rifampicin and sodium fusidate given with an anti-emetic (metoclopramide) for five days. Most patients with clinical infections who required systemic treatment were given rifampicin and sodium fusidate for seven days. Some with serious, lifethreatening infection received teicoplanin which was also used for perioperative prophylaxis in colonized patients undergoing surgery. After each newly-diagnosed MRSA patient had been transferred to an isolation ward, the bed space was immmediately cleaned, the curtains removed for dry-cleaning and new curtains provided. In surgical wards and in any ward where more than one patient was detected in a bay, the

MRSA

outbreak

91

entire bay was cleaned. Mattress covers were cleaned and the mattress checked. On all wards mattress covers were tested for water-permeability and mattresses inspected. One hundred and fifty mattresses and 50 pillows, together with covers, were replaced. The entire frame of each bed was cleaned and then labelled with the date of cleaning.

Description

of the outbreak

The outbreak affected three hospitals in East Northamptonshire-the District General Hospital, (A), which provides a range of acute medical services to a local population of approximately 250 000; a hospital for the elderly in the same town (B), which provides rehabilitation, long-stay and psychogeriatric care and hospital C, situated in a town 10 miles away which provides rehabilitation, acute and long-stay care for the elderly. The course of the outbreak is shown in Figure 1. The first case was identified on 12 April 1991. An elderly patient in the female rehabilitation ward of hospital B developed an amputation wound infection 15 days postoperatively. Preoperatively and immediately postoperatively she was a patient in an acute elderly care ward in hospital A. On 22 April, MRSA with the same sensitivity pattern was isolated from wound swabs from two patients in an orthopaedic ward in hospital A. On 3 May 1991 an elderly woman in a surgical ward died of postoperative pneumonia and septicaemia. The outbreak strain was isolated from a blood culture taken before death. This patient had begun her hospital stay in an acute elderly care ward in hospital A, where her stay overlapped with the index case. She had spent five days in the intensive care unit, before transferring to a surgical ward. The link between these early cases was not established until April 1992 when MRSA was isolated from a urine sample received from a 97-yearold woman in residential home care. Her most recent hospital admission had been in April 1991 when she was a patient in the elderly care and orthopaedic wards of hospital A. Her stay overlapped with that of the first four patients and she was also cared for by a nurse on the elderly care ward who was found to be colonized. The first case in hospital C (and the fifth case overall) was identified on 13 May 1991, when MRSA was isolated from a urethral swab from an elderly woman. Screening of this ward detected another woman with MRSA colonization of a varicose ulcer. She had been in the elderly care ward of hospital A and the rehabilitation ward in hospital B at the same time as the first case. She had been discharged home on 16 April and was readmitted to hospital C on 23 April. During the summer of 1991 the outbreak strain spread to almost all acute and rehabilitation wards for elderly patients in all three hospitals. Some spread was also detected in acute surgical and orthopaedic wards in hospital A but infection control measures were successful in containing this. In the

92

R. A. Cox et al. 6 4

Swabs x lOO(

< 5 0 5

Community

Hospital

C

Hospital

B

Hospital

A

0 35 30 25 20 15 10

5 0 AMJJASONDJFMAMJJASOND 1991

1992

Figure 1. Number of infected and colonized patients detected each month from hospitals A, B, C and from the community and monthly number of swabs screened for methicillinresistant Staphylococcus auwus. A, implementation of major outbreak plan; B, peak of outbreak; C, isolation ward, hospital C, closed; D, isolation ward, hospital A, closed. (@I), Colonized; ( n ), infected.

absence of an isolation ward, patients were isolated in side rooms or attempts were made to nurse patients together, in bays within a ward. In September, 1991, the outbreak strain was introduced into the urological

MRSA

outbreak

93

ward of hospital A by two elderly patients transferred from hospital C and, for the first time, a case was identified on a general medical ward. The urological ward was closed and the hospitals’ Major Outbreak Plan was implemented (point A in Figure 1). An outbreak control team was established and it was decided to open two isolation wards-one at hospital C for elderly patients and one at hospital A for patients who were acutely ill. The isolation ward at hospital C consisted of a six-bedded bay within an elderly care ward. Although this was completely separated from the ward by double doors, and had a separate team of nurses, cases continued to occur in the main ward, particularly in the adjacent bay. A vacant ward in a more isolated part of the hospital site was therefore refurbished and the patients moved there. In hospital A a small four-bedded isolation ward was opened in late September to accommodate the increasing number of MRSA patients. The outbreak reached a peak in late January 1992 when 13 new patients were detected in a single week (point B in Figure 1). Twenty patients required isolation. This exceeded the capacity of the two isolation wards and the hospitals’ side rooms. A larger ward with twelve beds became available in hospital A and this provided isolation beds for all MRSA cases after July 1992 when the isolation ward in hospital C was closed (point C in Figure 1). In the summer of 1992 as the weekly number of new cases continued to decrease, a programme of screening was instituted for residential and nursing homes known to be caring for MRSA patients. The isolation ward in hospital A was closed in December 1992 (point D in Figure 1) and side room isolation was used thereafter. Results

Four hundred patients, 27 staff and two relatives of patients are known to have been colonized or infected with MRSA during the period April 1991-December 1991. All but five isolates belonged to the epidemic strain now designated EMRSA-16. Characteristics of the epidemic strain The outbreak strain of S. aweus demonstrated uniform resistance to penicillin, methicillin, erythromycin, ciprofloxacin and uniform susceptibility to rifampicin, chloramphenicol, tetracycline, mupirocin, vancomycin and teicoplanin. Most isolates were resistant to gentamicin and trimethoprim but susceptible to netilmicin. One isolate resistant to sodium fusidate was detected in swabs from a patient who had received a short course of sodium fusidate prior to detection of MRSA colonization. Fusidic acid-resistant and fusidic acid-sensitive isolates of the same phage-type were detected in swabs taken from different sites on the patient. All but a very few isolates typed with a consistent pattern at RTD x 100,

94

R. A. Cox et al.

Figure 2. Pulsed field electrophoresis of whole cell DNA digested with SmaI. 13 and 14 are irrelevant. Lanes 3 and 12: MG1655-molecular weight markers. EMRSA-16 from hospitals K, L and N. Lanes 8-10: EMRSA-3 from hospitals T. Lanes 4 and 11 are blank.

Lanes 1,2, Lanes 5-7: D, W and

29 inhibition or+ +, 52 weak, 75 +, 83A+ and 83C weak. The strain sometimes reacted weakly with supplementary phage, 618. Strains were uniformly urease positive, usually strongly, within 24 h and produced large amounts of protein A. Relationship between EMRSA-3 and EMRSA-16 The phage-typing pattern of EMRSA-3 had been reported as 75/83A/932 at RTD x 1OO,9similar to that of EMRSA-16 but not identical. The strains differed in urease activity with EMRSA-3 negative and EMRSA-16 strongly positive. Pulse field electrophoresis of whole cell DNA digested with SmaI was convincing. In Figure 2 the three isolates of EMRSA-16 (lanes 5, 6 and 7) are indistinguishable but differ from the three isolates of EMRSA3 (lanes 8, 9 and lo), themselves indistinguishable, in at least 13 band positions.

MRSA

95

outbreak

Table I. Rates of isolation of methicillin-resistant from swabs taken from diffeerent sites in colonized

Site

of colonization

Nose Throat Skin* Perineum csu Ulcers and * Skin: CSU,

sores

hairline, catheter

Screened 382 318 316 362 110 168

Staphylococcus patients (n = 400) Number patients colonized

aureus

of (%)

316(82) 161(51) 119(37) 161(44) 33(30) 116(60)

axilla, groin. specimen of urine.

Patients The patients’ ages ranged from 17-99 years with a median age of 78 years. Colonized and infected patients were detected on 25 wards; all hospital specialties except paediatrics and maternity had patients with MRSA at some stage during the outbreak. Evidence of cross-infection was demonstrated in 19 wards. One hundred and ninety-six patients were admitted to an isolation ward, 19 remained in hospital for more than two months and 10 required long-term hospital care. Results of screening patients. Three hundred and thirty-four (83%) patients were colonized when first found to have MRSA and 66 presented with clinical infection. Common sites of colonization were the nose, throat and broken skin such as bedsores, leg ulcers and surgical wounds (Table I). After perineal swabs were incorporated into the routine screen for MRSA, 33 of 361 patients (9%) presented with perineal colonization alone and after throat swabs were added, 19 of 207 (9%) had throat carriage alone when first screened. Seventy-one cases were identified by discharge screening, 49 on transfer between hospital wards, and one on transfer to another hospital. During this period there were 22 000 discharges from wards affected by MRSA. Three local patients were found to be colonized or infected with the outbreak strain on arrival in other hospitals, after they had been screened and found to be negative before transfer. Three patients who had not been screened on transfer were subsequently found to be positive in other hospitals. A total of 63 000 swabs was examined for MRSA during the 21 months of the outbreak (Figure 1). Between 4000-5000 swabs were examined monthly from February-December 1992 in addition to the normal workload of 6000-7000 specimens. The extra workload was accommodated by increasing overtime and employing a part-time medical laboratory scientist for 9 h per week.

R. A. Cox et al.

96 Table II. Details yloccocus aureus April 1991-December

of clinical (MRSA) 1991

infections caused by methicillin-resistant and methicillin-sensitive S. aureus

No.

Site Chest Urinary

tract

Wound: Total Amputation Fracture Prosthetic Abdominal Foot/toe Other

of patients

MRSA

of infection

22

49

10

133

7.6

39

891

4.1

31

35

12.5

1: 4

joint surgery

i 3 5

(Endocarditis)

(2)

Conjunctiva skin sepsis and vulvitis

(2)

3

79

5

511

(50) 3.6

including

Bone Joint,

MRSA %SAA

MSSA

Septicaemia

Superficial urethritis

Staph(MSSA)

bursa

1

0

1

0

0.96

Other

3

418

0.71

Total*

89

2116

4.0

* Six patients

with

MRSA

had infection

at more

than one site. SAA,

all S. aweus.

Eighty-three of the 400 patients (21%) had clinical Clinical infections. infections caused by MRSA. Sixty-six patients presented with infection and 17 colonized patients developed infection, some of them months after their initial colonization. Six patients had infection at more than one site, so a total of 89 infections was recorded. Over the same 21-month period the microbiology laboratory recorded 2116 infections in adults caused by MSSA. Thus MRSA strains represented 4% of all S. aweus isolates from adults during that time. The details of the clinical infections caused by both MRSA and MSSA are given in Table II. Significantly more chest infections were associated with MRSA than MSSA. (P
MRSA Table III. Efficacy of mupirocin methicillin-resistant Staphylococcus

nasal aureus

outbreak ointment

97 in

the

eradication

Time No.

treated

No.

255(A) 27(w (A),

(%)

relapsed

46(18) 8(30) First

treatment;

(b), repeat

within

3 months 26(57) 5

4-6

of nasal

carriage

of

to relapse% months 7U5) 2

>6 months 13(26) 1

treatment.

and MRSA septicaemia was not considered to be the cause of death. Six of 35 patients (170/)o with septicaemia due to MSSA died as a result of the infection. Four patients died of pneumonia caused by MRSA (one had septicaemia as well). One patient with MRSA infection of a laparotomy wound died following abdominal dehiscence. Thirteen patients were lost to follow-up and 109 patients Treatment. either died before treatment could be completed or were not treated, usually because they were terminally ill. Treatment could be evaluated in 278 patients (70%). Two hundred and seven (74’Y)o were cleared of MRSA after their initial course of treatment (‘clearance’ was taken as three consecutive negative sets of post-treatment swabs for hospital inpatients, but only a single set for patients in the community). Seventy-one of these 207 (34%) relapsed after apparently successful treatment. In some of these patients reinfection rather than failure to eradicate carriage may have been the cause of reisolation of MRSA. As it is not possible to distinguish relapse from reinfection all cases were regarded as relapses. Sixty-five patients were given further treatment; in 41 (63%) retreatment resulted in eradication of MRSA, but in 24 (37%) further treatment was unsuccessful. EfJicacy of mupirocin nasal ointment in eradicating carriage. Mupirocin nasal ointment failed to clear nasal carriage in 46 of 255 patients (18%) treated (Table III). Th e majority of patients in whom treatment failed (57%) relapsed within three months of treatment but two did not relapse until 13 and 14 months after treatment. None showed mupirocin resistance. Twenty-seven of the patients who relapsed after nasal mupirocin received a second course of treatment (Table III). Eight (30%) relapsed again, (with mupirocin-sensitive MRSA) but the rest remained clear when screened between two weeks and 12 months later. Two hundred and eighty-five patients received one or more courses of mupirocin ointment. Mupirocin-resistant strains of MRSA were detected in only two patients; both had received two 7-day courses of mupirocin for nasal colonization and for treatment of pressure sores. One had a mupirocin

R. A. Cox et al.

98 Table fusidate Side

IV. Incidence and rifampicin

of side

effects

in

160

effects

patients

intolerance diarrhoea

27

Jaundice syndrome

failure

Treatment side effects

Table aureus

discontinued

V. Patients with (MRSA) treated

because

clinical infections with sodium f&date

of

Percentage of infections treated *

39 * Total

44 number

cent

17

of infections

Clinical cure eradication of MRSA (“/I 27(69)

7

4.3

3

1.8

1

0.6

18

11

caused by methicillin-resistant and rifampicin Results

No. of patients

sodium

17

Rash Renal

with

Per

No.

Gastrointestinal (nausea, vomiting, anorexia)

Flu

treated

Staphylococcus

of treatment

Clinical cure MRSA persists w

Clinical failure (%)

wo)

l(3)

Died before followUP WI 3(8)

= 89.

MIC of 32-128 mg-’ (intermediate sensitivity) resistance with a mupirocin MIC of 1024 mg-‘.

and one had high level

Patients treated with sodium fusidate and rifampicin and their ef$cacy. Sodium fusidate and rifampicin were used to treat clinical infections and to eradicate throat carriage in 160 patients. The side effects of treatment are detailed in Table IV. Side effects (mainly gastrointestinal intolerance and jaundice) were sufficiently severe to cause treatment to be discontinued in 18 (11%) of patients. One 93-year-old, treated for an infected wound following a fractured femur, developed jaundice and acute renal failure. She recovered when the antibiotics were stopped. The ‘flu syndrome’16 was not observed in the 15 patients who received two courses of sodium fusidate and rifampicin; all seven patients who experienced the ‘flu syndrome’ received only a single course. Thirty-nine patients were treated for clinical infection Clinical infections. using this drug combination (Table V). In one patient with an infected

MRSA

outbreak

fractured femur wound treatment was changed 24 h she deteriorated with fever and cellulitis.

99

to teicoplanin

when

after

Eradication of throat colonization. Throat colonization was detected in 161 of the 318 patients positive for MRSA who were screened by throat culture (51%). (Throat swabs were not taken as a routine until 10 months after the start of the outbreak). One hundred and twenty-one patients were treated with sodium fusidate and rifampicin to attempt to eradicate throat colonization. Sixteen patients treated for clinical infections with this drug combination also had throat colonization, so a total of 137 patients received treatment directed at eradication of throat colonization (85% of those colonized). One hundred and sixteen patients (85% of those treated) were swabbed after the course of treatment. Treatment was unsuccessful in 24 (20%). The majority of those who relapsed did so within three months’ of treatment (14 cases). A further four cases relapsed within six months and another four within 12 months, but two remained clear for over a year. In these, persistence of throat colonization was demonstrated on re-admission to hospital, 13 and 14 months after the original course of treatment. Repeat courses of sodium f&date and rifampicin for persistant throat colonization. A total of 15 patients received a second course of sodium fusidate and rifampicin. In 13 of these, treatment was given for persistent throat colonization. In addition two patients who received a second course for clinical infections also had throat colonization. Five of these patients relapsed (33%), two within two months and three between three to six months. Results of long-termfollow-up. Sixty-nine colonized and/or infected patients were followed up for one year or longer (Table VI). Forty-seven (68%) remained clear following their initial course of treatment. In eleven (16%) treatment was apparently successful but they later relapsed; eight remained clear following further treatment and three have cleared without treatment. Eleven remained colonized having failed to respond to further treatment. Patients colonized in multiple sites were significantly less likely to be cleared after a single course of treatment than colonized at only one site (BO.01). Deaths and ye-admissions to hospital. Two hundred and thirty-eight (60%) of the 400 patients died, 113 (28%) died within one month of acquiring MRSA. One hundred and seven (37% of those surviving one month after acquisition of MRSA) were re-admitted to hospital. The re-admission of a known ‘positive’ patient led to further ward outbreaks of MRSA in the three hospitals on nine occasions. The re-admission or transfer of a known ‘positive’ patient resulted in spread to three neighbouring hospitals.

VI.

site

sites

Eradication

* Treatment was contraindicated awu.0 negative. t Repeated treatment failed

Total

Multiple

Single

Colonization

Table

to clear

followed

with

throat

swabbing

them

8 (11.5)

47 (68)

(%)

to be methicillin-resistant

3 (4.5)

3

7

25 (56)

Repeat

Clear-no treatment*

(69 patients)

showed

or moYe

Repeat course of treatment successful (%)

12 months

0

colonization.

up for

1

22 (92)

Single course of treatment successful (%)

in patients

patients

carriage.

in three

69 (100)

45 (65)

24 (35)

(%)

colonization

Total

qf

Staphylococcus

11 (16.0)

10

1

Treatment failuret (%)

%

6 R Fh

?

F

MRSA

outbreak

101

staff Twenty-seven of the 5125 health care staff who were screened (0.5%) became colonized. Two relatives who gave nursing care to patients with MRSA were also colonized. The health care staff comprised 25 nurses, one physiotherapist and one doctor. The doctor was detected when his girlfriend was identified as the source of a small outbreak of EMRSA-16 in a West Midlands Hospital. All 27 staff carriers had nasal colonization and six were colonized at more than one site. Four with throat colonization were given sodium fusidate and rifampicin. Six required more than one course of treatment (five for nasal colonization alone, one for nasal, throat and skin colonization). One nurse with psoriasis was colonized intermittently for 17 months and required repeated attempts to eradicate nasal, throat and skin carriage. cost The total cost of the outbreak was at least L403 600. The isolation wards accounted for L303 600. Other significant costs were: microbiology (E43 000), drugs (ic;17 000), c 1eaning (A25 600), replacement of mattresses and pillows (L6800) and community nurses (E7500). This figure represents the additional cost to the Health Authority of containing the MRSA outbreak. It does not include various ‘hidden’ costs such as telephone calls and travel, overtime worked by the Infection Control Team, extra secretarial support for the Outbreak Control Group and the time spent by the members of the Outbreak Control Group on implementing all the measures described. Discussion

The particular strain of MRSA associated with this outbreak was of a distinctive phage-type, showing inhibition reactions with phages 29 and 52 and weak reactions with 75, 83A and 83C at RTD x 100. The typing pattern of the previously recognized strain, EMRSA-3 was of strong reactions with 75 and 83A at RTD x 1OO.9The initial possibility was that the new strain was a derivative of EMRSA-3 but this strain differed from EMRSA-3 in producing urease and in the restriction fragment pattern after DNA digestion with SmaI (Figure 2). Like most strains of MRSA it was multiply antibiotic-resistant, but unlike some epidemic strains at the time it was resistant to quinolones.2 This limited the choice of oral therapy to rifampicin, fusidic acid, tetracycline, chloramphenicol and nitrofurantoin (for urinary tract infections). Resistance to sodium fusidate was detected in a single patient in July 1991. Resistance to this antibiotic can be produced readily in vitro17 but in vivo resistance is uncommon.18 Nevertheless, we felt it would be prudent to ensure that it was always given with another antibiotic. The combination of rifampicin and sodium fusidate proved to be effective therapy for many clinical infections (Table V) but the high incidence of side effects (Table

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IV) was a problem requiring an anti-emetic for acceptance. Mupirocin resistance was uncommon, despite the extensive successful use of this antibiotic to clear carriage from superficial sites and for topical treatment of infections (Table III). Although only 22% of patients who acquired EMRSA-16 had clinical infections, this strain caused chest infections, septicaemia and endocarditis more frequently than MSSA (Table II), suggesting that the epidemic strain is at least as virulent. Four of the five patients with MRSA septicaemia had serious pre-existing disease. We do not have information on preexisting conditions for the patients with MSSA septicaemia. The relatively high number of chest infections attributed to EMRSA-16 compared to MSSA may reflect the high incidence of throat carriage (51%) observed with this strain but MRSA was cultured from post-mortem lung on five occasions. It is likely, therefore, that at least some of the isolates from sputum originated from the lower respiratory tract. The problems that we encountered in attempting to contain the outbreak were similar to those experienced by others.2”g’20 EMRSA-16 behaved in a way that is characteristic of epidemic strains,’ in that it had a predilection for the elderly and spread commonly occurred after the transfer of a colonized or infected patient to a new ward. The failure to control the outbreak using side room isolation or cohort nursing and the large numbers of patients requiring isolation led to the decision to open dedicated isolation wards. The problems associated with establishing and running such a ward are described elsewhere.21 Other workers have described the key role that an isolation ward plays in the control of outbreaks of MRSA22,23 but the very high cost of maintaining such a facility needs to be recognized. The risks of renewed spread of MRSA associated with the re-admission of patients who had become colonized with MRSA during an earlier hospital stay soon became evident. We decided to adopt a ‘seek and destroy’ strategy to attempt to eradicate MRSA carriage in all patients who were fit enough to be treated. Where this involved the use of topical mupirocin ointment this was remarkably successful: 82% of those followed up after they had received treatment to eradicate nasal carriage remained clear, and a second course of treatment was successful in 70% of those followed up (Table III). It is not possible to distinguish relapse from reinfection but the opportunity for reinfection was slight. Patients were rescreened at home, on admission to hospital or during an inpatient stay when they were isolated in single rooms. Only two patients, who were found to be MRSA positive again during inpatient care in an isolation ward, were exposed to the risk of reinfection. The fact that some patients relapsed more than a year after treatment indicates that treatment may only reduce staphylococcal carriage to a level which cannot be detected by current screening techniques. It is therefore difficult to identify those patients who will subsequently ‘relapse’ or those who may develop secondary infection.

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The results of nasal mupirocin treatment are similar to those of Casewell and Hill who studied the efficacy of mupirocin in eliminating nasal carriage of S. aUYeUS in a group of 32 volunteers.24 S. UUY~US was not detected in any volunteer two weeks after completion of a five day course of treatment. By 14 weeks, four (12.5%) showed a relapse of colonization with their pretreatment strain. Mupirocin resistance emerged on only two occasions. Resistance to mupirocin has been described with other strains of MRSA25-27 and low level resistance of this agent has been observed in clusters of EMRSA-16 elsewhere.” The high incidence of throat carriage observed in this outbreak (51%) led us to adopt a strategy to attempt to eradicate carriage at this site in as many patients as possible. We followed the regimen of Pearman and colleagues who used sodium fusidate and rifampicin to eradicate throat carriage during an outbreak of MRSA in Western Australia.29 Experience in the UK is limited and the current guidelines advocate this approach only ‘in certain exceptional circumstances, such as transfer of a colonized patient to a rehabilitation centre or in a member of staff if the strain is susceptible.‘5 For the individual patient, the alternative to active treatment was a prolonged stay in an isolation ward, delaying transfer to residential care and essential treatment such as intensive physiotherapy, specialist rehabilitation and limb-fitting. The combination of rifampicin and sodium fusidate successfully eradicated throat carriage in 80% of the 116 patients treated. Failure to eradicate throat carriage was usually evident within three months of treatment but late ‘relapses’ over a year after treatment were observed in two patients. The revised guidelines for the control of epidemic MRSA advise against repeated short courses of rifampicin because of the risk of side effects such as the ‘flu syndrome’. We did not observe this in patients retreated with rifampicin and sodium fusidate. Girling emphasized that the ‘flu syndrome’ rarely occurs during the first month of intermittent anti-tuberculous treatment and usually appears in the fourth to sixth month.16 Pearman and colleagues had similar results when they treated 20 persistent carriers with rifampicin and sodium fusidate.29 MRSA was initially eliminated in 18, but two late recurrences were observed, one after 10 weeks. However, they did not indicate how many of their patients had throat carriage. It is still too early to judge the success of this treatment strategy but the results for patients followed up for 12 months or more are encouraging (Table VI). Sixty-eight per cent remained clear after their initial course of treatment and further therapy meant that 84% were clear when last screened. The problems we encountered with patients who were persistent carriers of MRSA resulted from the large numbers of ‘previous positives’ who

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required either re-admission to hospital or prolonged hospital care. Although 107 of the original 400 patients were re-admitted to hospital, further spread was documented on only nine occasions, seven of which occurred early in the outbreak before the importance of eradicating carriage was fully appreciated. Thus there does seem to be some correlation between the level of colonization in an individual and the likelihood of spread to others. Spread to staff was uncommon, but was important in two respects. The outbreak strain spread to another hospital via social contact between two staff members. One nurse was intermittently colonized for 17 months and was excluded from work for a total of 15 weeks. The high death rate of patients colonized with MRSA reflects the predilection of EMRSA for the elderly and for those who are already seriously ill. This may be the result of the amount of ‘hands on’ care that these patients receive or it may indicate that EMRSA is a more efficient colonizer of these particular groups. This is not unique to EMRSA-16 and has been observed with other epidemic strains.’ EMRSA-16 has spread to hospitals in neighbouring districts including a regional cardiothoracic centre. It has been associated with nosocomial outbreaks in London and a number of hospitals in the south and east of England.12 The costs involved in controlling this outbreak amounted to at least A403 600. Mehtar et al. calculated that a five week outbreak of epidemic MRSA infection cost approximately 613 000 or L2600 per week.30 Applying these costs to our own 91 week outbreak gives a figure of L236 000. Running the isolation wards accounted for two-thirds of our costs. Mehtar et al. did not have this expense although they did have to establish a ‘transfer’ ward for patients who could not be discharged from wards that they closed. A 1987 study in the North East Thames Region put the recurrent annual financial cost then of containing outbreaks at around A250 000 in the worst affected hospitals.31 This is very similar to the annual cost of E232 000 incurred during our outbreak. The high cost and the enormous efforts required to contain this outbreak invite the question as to whether it was all worthwhile. We have not succeeded in eradicating EMRSA-16 from the three hospitals but the outbreak has been contained. We continue to screen all patients prior to discharge from the elderly care wards. We are able to maintain an effective level of surveillance at modest cost (k21 000 annually). ‘Discharge’ screening gives early warning of spread in a ward. Small clusters of cross-infection have been successfully contained by swift reinforcement of the infection control measures described. Since December 1992 we have not been confronted by the simultaneous appearance of cases in acute medical, surgical and orthopaedic wards as occurred during the outbreak. The work of the hospitals continues without the disruption of ward closures; patients are discharged without delay,

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morbidity and mortality from MRSA infection has been reduced. We believe that the cost and effort were justified. But, like Faoagali and colleagues we think that it is probably only in the long-term that we will be able to judge the value of our efforts.6 In conclusion, in our experience, EMRSA-16 is at least as virulent as MRSA. Once it has spread within a hospital, containment by conventional infection control measures such as hand disinfection may not be successful. We have demonstrated that eradication or reduction of colonization in individual patients, combined with adequate isolation facilities, are key factors in the control of an outbreak. References I. 2. 3.

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Shanson DC. Clinical relevance of resistance to fusidic acid in Staphylococcus uu~eus. J Antimicrob Chemother 1990; 25: Suppl. B. 15-21. 19. Bradley JM, Noone P, Townsend DE, Grubb WB. Methicillin-resistant Staphylococcus aureus in a London Hospital. Lancet 1985; 1: 1493-1495. MT. Hone R, Coleman D, et al. Methicillin-resistant Staphylococcus auveus 20. Cafferkey in Dublin. 1971-84. Lancet 1985; 2: 705-708. Times 1993; 89: II-VI. 21. Beedle D. Beating the bug.l\iurs 22. Selkon JB, Stokes ER, Ingham HR. The role of an isolation unit in the control of hospital infection with methicillin-resistant Staphylococci. J Hosp Infect 1980; 1: 41-46. 23. Vandenbroucke-Grauls CM, Frenay HME, van Klingeren B, Savelkoul TF, Verhoef J. Control of epidemic methicillin resistant Staphylococcus aureus in a Dutch university hospital. Eur J Clin Microbial Infect Dis 1991; 10: 6-11. 24. Casewell MW, Hill RLR. Elimination of nasal carriage of Staphylococcus aureus with mupirocin (‘pseudomonic acid’)-a controlled trial. J Antimicrob Chemother 1986; 17:

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