Introduction

Meticillin-resistant Staphylococcus aureus (MRSA) is a major nosocomial pathogen which is endemic within many hospitals worldwide, and increasingly within community settings.^{1, 2} There is a wide variation in MRSA rates dependant on the country examined, with prevalence rates remaining fairly constant over the last decade in many European countries. In the UK, there is a high endemic rate with a dramatic increase in the MRSA incidence since 1993^{1, 3} (http://www.hpa.org.uk/infections/topics_az/staphylo). Even in those countries with a low prevalence rate, a high frequency of outbreaks may be seen, especially in the setting of the critically ill or immunosuppressed patient.

In the setting of haematopoietic stem cell transplants (HSCT) there are very few data describing the incidence and/or impact on morbidity and mortality of infection/colonization by MRSA. Very few studies or case reports discuss individual MRSA-infected patients and their outcomes;^{4, 5, 6, 7} however, it seems likely, at least in the UK, that there is a baseline rate of infection in most centres. Many units will not have a universal screening procedure for MRSA, and although approaches to eradication are fairly standard those to treatment may not be so.

Currently, no specific guidelines exist covering prevention, diagnosis and management of MRSA infections in recipients of HSCT. However, some recommendations can be found in the guidelines from a number of organizations (guidelines for prevention of opportunistic infections in HSCT published by the Centers for Disease Control and Prevention (CDC), the Infectious Diseases Society of America and the American Society for Blood and Marrow Transplantation,⁸ guidelines from the infectious diseases working party of the German Society of Hematology and Oncology⁹).

In early 2004, a sharp increase in the frequency of MRSA was recognized within the haematology department of our hospital. This affected both transplant and non-transplant patients. Investigations identified that transmission of MRSA was centred on the haematology day case unit, but with a knock-on effect to the in-patient wards. Control measures were introduced, but a significant number of transplant patients were exposed to MRSA in the early stages of the outbreak.

This outbreak prompted us to examine the overall frequency of MRSA in our transplant centre (pre- and post outbreak), the effects of MRSA on morbidity and mortality in this high-risk population and the effectiveness of the control strategy implemented to eradicate MRSA.

Patients, materials and methods

Patients

This is a single-centre descriptive retrospective analysis describing the outcome of a group of patients, transplanted in our unit, who became infected with MRSA. Patients were identified from databases held within the microbiology department with detailed data concerning the date and site of positive MRSA results, as well as the sensitivity patterns of the organism. The transplants took place between January 1999 and December 2005. There were 41 patients in this cohort. Patient and transplant characteristics are listed in Table 1. Of the patients, 28 had an allogeneic procedure (11 using sibling donors and 17 using unrelated donors (UDs)) and 13 an autologous procedure. Full-intensity (FI) myeloablative transplants were performed in 18 patients and eight had reduced intensity conditioned (RIC) transplants. Two patients had an FI transplant followed by an RIC transplant for disease relapse. The transplants were performed for a wide range of clinical indications and using a limited number of conditioning regimens (Table 1).

Table 1 - Patient characteristics.

Full table

MRSA policy

MRSA carriers were isolated and wound and skin precautions commenced (in accordance with local MRSA policy based on UK guidelines, for most recent see Coia et al.¹⁰). Except that only two negative MRSA screens, 1 week apart, were required for isolation to be stopped. A sticker is placed both in and on the cover of the patient's notes by the infection control team and this is signed and dated.

Prior to April 2004 no routine screening or pre-emptive treatment for MRSA was undertaken, except in patients transferred from other hospitals/units. After this time, in view of the increase in new infections (outbreak), all patients admitted to the transplant unit had swabs taken from the hickman line site, nose, perineum and any wounds areas. All patients were then commenced on nasal chlorhexidine/neomycin (naseptin) and triclosan (aquasept) washes while awaiting results of the screen. If positive, mupirocin was substituted for chlorhexidine/neomycin (naseptin) and this and triclosan (aquasept) were given for a total of 5 days. If negative, they were stopped immediately.

The same approach was taken on the non-transplant ward and in the day unit.

Techniques for MRSA detection

MRSA was detected from clinical specimens using standardized laboratory methods. Blood cultures were processed using the Bactec 9240 system (Becton-Dickinson, Le Pont De Claix, France). Other clinical specimens were cultured using a variety of agar +/- liquid enrichment cultures. Staphylococcus aureus was confirmed by positive reactions for DNAse production, positive slide agglutination using Slidex Staph Plus (Biomerieux) and meticillin susceptibility was determined using either breakpoint testing or standardized disc susceptibility testing with meticillin.

MRSA screening swabs were cultured using oxacillin-resistant screening agar (Oxoid), inoculated for 18–24 h, with meticillin susceptibility tests performed as above.

The laboratory method for screening was directed towards quicker detection of the most heavily colonized patients and was therefore not the most sensitive screening method.

Outbreak control measures

The outbreak was officially declared on 27 April 2004 and concluded in September 2004 (a 4-month period) after the institution of the following measures: the day unit was completely cleaned, including replacement flooring, and a separate room (near the day unit) was identified for the treatment/review of all known MRSA positive patients. Complete cleans of all the haematology areas including fans, radiators and curtains were performed. Every patient seen in any haematology area had swabs taken from the hickman line site (if appropriate), nose, perineum and any wounds areas. All in-patients were then commenced on treatment/prophylaxis as outlined above. The screening protocol and other measures instituted were continued after the outbreak was officially concluded.

Antibiotic policy

Over the time of the study, the antibiotics used for the empiric treatment of neutropenic sepsis were piptazobactam and gentamicin (or single agent imipenem in penicillin allergic patients). Vancomycin was added early (within 48 h if fever not settling) if line sepsis was suspected. If the patient was known to be previously MRSA positive, vancomycin was started empirically with first-line antibiotics. Patients positive for MRSA were treated as above, +/- the addition/conversion to oral linezolid or clindamycin. Hickman lines were not routinely removed; this depended on the clinical condition of the patient.

Prophylactic antimicrobials included ciproflocacin up to the time of the outbreak. Thereafter colistin alone was used.

Definitions

The likelihood of death being due to MRSA was defined as definite (MRSA isolated from clinically relevant specimen, e.g. lung tissue, blood culture in death due to septicaemia), probable (known to be MRSA infected, but specimen not available at time of death), possible (previously MRSA infected but status unknown at death) or unlikely (death known to be of another cause).

The infection and/or colonization was defined as hospital acquired if the patient had been an in-patient for more than 48 h before the specimen identifying MRSA was taken. For day unit attendees, a history of their previous attendances was assessed and health-care input from other facilities or regions was taken into account before deciding on whether it was haematology acquisition related.

Consent

Local consent practices were adhered to for sample collection and processing and the appropriate ethical considerations were undertaken. Patients all signed informed consent before transplantation, including for anonymized data collection.

Results

Frequency and site of infection

The total number of transplant patients identified to have MRSA isolated from any specimen during the time period studied was 41 (28 allogeneic and 13 autologous transplant recipients). Over the same time period there were a total of 776 transplants performed: 408 autologous, 188 sibling allogeneic and 180 UD allogeneic. Thus the frequency of MRSA in these patients was 5% overall, and in the individual groups was 3, 6 and 9%, respectively. Patients receiving transplants for CLL appeared to be at the highest risk of developing MRSA (5/24, 21%), compared with 10% (14/140) of those with AML/myelodysplasia, 4% (8/178) in non-Hodgkin's lymphoma and 4% (10/233) in myeloma. As expected, patients in the latter two groups are more likely to have had an autologous procedure.

The number of new infections per year is as follows: 1999=1; 2000=1; 2001=5; 2002=5; 2003=3; 2004=22; and 2005=4 (Figure 1). The transplant activity over these years was fairly steady (1999=96; 2000=91; 2001=94; 2002=102; 2003=111; and 2004=137) and hence the dramatic increase in MRSA in 2004 is unlikely to be due to a marked increase in at-risk patients. An absolute incidence of new infections/year is difficult to calculate as it is not only patients transplanted in the particular year who were at risk, but also patients attending the transplant clinic at any time post transplant.

Figure 1.

Pattern and frequency of MRSA infection dependant on year of acquisition.

Full figure and legend (41K)

The MRSA was asymptomatic (cultured from a surveillance swab) in only three (7%) patients. In the remainder, the MRSA infection was clinically relevant: 20 (49%) had an MRSA bacteraemia and 18 (44%) had MRSA at another site, this was in the lung/sputum in eight patients, and skin/wound in 10 patients.

Patterns of infection

There were three main patterns of MRSA positivity in these patients. Group 1 (n=15): those who were known to be MRSA positive at some time before the transplant; group 2 (n=5): those who were only known to be positive before engraftment; and group 3 (n=21): those who only became positive after engraftment and discharge post transplant (Table 2).

Table 2 - MRSA details and outcome.

Full table

Group 1: MRSA positivity at any time pre transplant

Group 1 included 15 patients. The transplant was allogeneic in six and autologous in nine patients. In most cases, the infection was acquired some weeks or months before transplant and they had previously received eradication therapy/treatment. Eleven of the patients were negative for MRSA on repeat surveillance swabs performed at the time of admission for the transplant.

In four patients the repeat swabs remained positive; however, in three patients results were only obtained once the patient had commenced conditioning therapy (in one of these a recent set of swabs had been negative). Two of these patients developed MRSA bacteraemia during the neutropenic phase, one of whom subsequently succumbed (on day +33 with a multifactorial death but MRSA clearly implicated). The other was treated successfully and remains alive with no further recurrences more than 6 months post transplant. One patient had MRSA in skin wounds and a urinary catheter and died on day +1 of persistent disease and sepsis. The final patient was colonized by MRSA, including on the hickman line tip, he was successfully treated and had no further recurrences of MRSA.

In the 11 patients with negative swabs on admission, seven did not reactivate MRSA during the neutropenic phase or at any time post transplant. In the remaining four patients, the neutropenic phase was complicated by MRSA bacteraemia. Three of these patients had received an UD allograft for relapsed AML post first allograft, CLL and AML, respectively. All three were successfully treated; however, two have extensive chronic graft-versus-host disease (GvHD) with recurrent episodes of MRSA infection (in deep sites such as lung and subcutaneous abscesses). One is early post transplant with acute graft-versus-host disease (aGvHD), but no recurrence as yet. The fourth patient had an autologous transplant for myeloma and remains alive and well 4 years post procedure with no recurrence of MRSA.

In this group, six (40%) patients have died; one death was due, at least in part, to MRSA, in another MRSA was a possible contributor. In the remaining four cases, the MRSA was deemed unlikely to have contributed to the death (although three were infective deaths, a causative agent was identified or MRSA was ruled out).

Group 2: MRSA first detected early post transplant

In group 2, there were five patients (four allogeneic and one autologous). Four patients receiving allogeneic transplants were found to be MRSA positive on days +8, +2, +7 and +6, respectively. The first of these developed a skin focus for infection and was positive for MRSA on blood culture. He died due to MRSA septicaemia on day +14. The second also developed MRSA bacteraemia, however was successfully treated. The third patient was found to be colonized on admission swabs, though the results were only available on day +2. This patient did not develop bacteraemia during the transplant, but later relapsed and had treatment complicated by MRSA bacteraemia. This was successfully treated, but the patient died due to disseminated fungal infection. The final patient grew MRSA from a sputum sample, this was successfully treated and MRSA did not recur (the patient later died from progressive disease). The fifth patient died suddenly and unexpectedly on day +4 of an autologous transplant. The post mortem revealed that bronchopneumonia and MRSA were grown from the lung tissue.

Thus in this group all five patients have died, two of the deaths being directly attributable to MRSA.

Group 3: late MRSA infection

Group 3 comprised 21 patients. The time post transplant at which MRSA was acquired was broad (1 month to 6 years, with 12 patients (57%) acquiring MRSA within the first year). Only three patients in this group had received autologous transplants. Two patients were being treated for disease relapse at 4 years and 1 year, respectively, post transplant. One of these patients developed MRSA bacteraemia and was successfully treated, whereas the other was only colonized by MRSA. The third had an empyema (17 months after), which was successfully treated.

Of the 18 recipients of allogeneic transplants, only two had no evidence of GvHD. The first had a single episode of MRSA, cultured from a surgical wound, and was successfully treated. The second had relapsed AML with low counts and was colonized by MRSA, and later died due to progressive disease. One further patient was MRSA positive, before developing GvHD he had a single episode and was treated successfully.

The remainder of the patients all had GvHD at the time of becoming MRSA positive or were on immunosuppression for a transplant-related auto-immune problem (one neutropenia and one thrombocytopenia). The majority of those with limited GvHD (four patients) had a single easily treated episode, whereas those with extensive GvHD remained colonized for long periods of time. Two patients developed MRSA pneumonia as the first evidence of infection (at 14 and 6 months post transplant, respectively) and both died due to this.

In this group, overall 11 (52%) patients have died. MRSA was definitely implicated in the death in three patients, probably implicated in two and possibly implicated in one (55% overall).

Discussion

As in many other hospitals in the UK, there is a low level of endemic MRSA in most clinical areas in the centre studied. Historically, the incidence of infection in the haematology wards has been found to be low, and therefore routine screening or prophylaxis has not been undertaken. In our centre, an increasing number of MRSA positive patients signalled an outbreak in two of the major clinical areas (the day unit and the non-transplant in-patient ward), but not in the transplant unit itself. Despite this, a number of the transplant patients became infected during attendance in the day case or during previous in-patient stays on the non-transplant ward. In addition, many of the patients receiving transplants in our unit are referred from other hospitals and it is known that some of them had become infected/colonized elsewhere.

We were able to very effectively manage the outbreak by instituting a number of actions, as outlined in the methods, which resulted in a decrease in the rate of new infections from 22 in 2004 to four in 2005. Critically, the identification of the day unit as the epicentre for cross-infection emphasizes the need for such clinical areas to be included in the infection control and screening measures for the department as a whole. In addition, the use of prophylactic ciprofloxacin on the non-transplant ward was suspended as the strains seen were universally resistant and ciprofloxacin is known to select for, and prolong the carriage of, MRSA.^{11, 12, 13}

A striking feature in these patients is the very high incidence of invasive MRSA infections, which has not been previously reported. This was particularly noted in, but not confined to, the outbreak period. This did also not differ dependant on whether the infection was obtained early or late post transplant. MRSA bacteraemia was very prevalent, as were deep infections (e.g. lung, subcutaneous abscesses) and in some cases the first presentation of MRSA was with pneumonia. Thus, individual patients who developed MRSA were likely to have a clinically relevant infection, rather than simply remaining colonized, emphasizing the vulnerability of transplant patients to this pathogen. In infected patients, MRSA was found to be a significant cause of transplant-related mortality (TRM).

Unsurprisingly, early (rather than late) infections were more likely to cause problems in patients receiving autologous transplants. Two of the six patients (33%) known to be MRSA colonized before transplant developed MRSA septicaemia and one patient died due to this cause. Even more concerning was the patient who died suddenly with MRSA pneumonia, as this had not been detected before transplant. She is likely to have acquired this during a previous admission on the high-dependency unit, but it was not picked up at the time. Due to her very early death it is possible that even if screening had been performed on admission these results would have not been known before her death. Thus, the TRM in these patients receiving autologous transplants was 29% (2/7) and this was directly attributable to MRSA. The TRM in our institution for autologous transplants is <3%, suggesting that these patients should be considered to be at very high risk and a strong argument for delaying the transplant and attempting MRSA eradication should be put forward.

Five patients receiving allogeneic transplants had MRSA complicating their neutropenic phase following transplant. In two patients this resulted in a prolongation of in-patient stay and in one patient this resulted in death.

These data would suggest that the screening procedures used were not sensitive enough¹⁴ or were performed too late to provide clinically useful information. Since the laboratory method for screening was directed towards quicker detection of the most heavily colonized patients, patients with low-level asymptomatic carriage may well have been missed. It is possible that the use of a more sensitive method of detection may shorten the time to a positive result being obtained. Even after eradication, it may still be necessary to use specific prophylactic strategies in these patients. Particularly as the 'proof' of eradication will only be as good as the detection techniques employed.

A report from a Japanese group⁶ presented similar conclusions. In their cohort, four patients were MRSA positive before transplantation. Eradication was attempted in all, but succeeded only in two. One of these received prophylaxis with vancomycin and did not reactivate MRSA, the other who did not receive prophylaxis became infected with MRSA. Two patients had persistent MRSA, one received vancomycin prophylaxis and did not develop MRSA. The other did not receive prophylaxis and died in the early post-transplant period from MRSA septicaemia.

In our cohort, 4 of 11 patients previously known to have MRSA (which was successfully eradicated based on negative admission swabs) had severe MRSA infections during the neutropenic phase. The benefit of prophylaxis for these four patients needs to be weighed against the impact of additional antibiotic exposure in all 11 patients. Certainly, the addition of vancomycin empirically in septic patients may improve outcomes.

The most recent patient received extensive eradication with linezolid, washes and protective nightwear. Swabs were negative on two separate occasions before transplant. Despite this she developed MRSA sepsis on day +5, although this was only found on peripheral but not central blood cultures. This patient had received prophylactic ciprofloxacin, which may have been implicated. Clearly, despite negative screens she was still colonized.

Late infection/colonization was a problem in the allogeneic transplant recipients. Many of these patients were chronically immunosuppressed usually due to GvHD and its treatment and are thought to have acquired MRSA due to multiple exposures on the day unit. These patients required recurrent courses of both in- and outpatient treatment for MRSA, but it has often proved to be impossible to eradicate MRSA until the immunosuppression could be stopped.

Recurrent admissions have a marked impact on the overall condition and quality of life of the patient, as well as being costly and problematic for the health service.^{15, 16} These patients require barrier care in side rooms (according to current guidelines), a situation which is not always easy to manage, especially in an emergency setting. However, adherence to current guidelines, with isolation measures to reduce MRSA transmission, is supported by a recent systematic review.¹⁷ Even as outpatients, attending the clinic or day unit, problems are encountered with patients requiring special 'areas' in which to be assessed, again not practical in many settings. Guidelines from the CDC⁸ suggest that in centres where MRSA is problematic, patients should be treated as a cohort; however, a recent paper in The Lancet suggested that in the Intensive Therapy Unit setting, moving patients into single rooms or cohorted bays was not associated with a reduction in cross-infection.¹⁸ This is in contrast to a study from Australia¹⁹ determining the incidence of colonization of patients admitted to different ward areas, which found that MRSA was never acquired by patients nursed on wards which practised an exclusion policy towards patients known to be colonized with MRSA. Whereas this is clearly reassuring, and the policy of exclusion of known patients seems a sensible one, patients are often transferred from outside hospitals in a condition that make it unsafe for them to be in a non-specialized clinical area.

Finally, the agents which are currently used for the treatment of MRSA may be insufficient. Recently, studies have been reported on the use of newer agents²⁰ and monoclonal antibodies²¹ in the treatments of MRSA. The monoclonal antibody is in phase II trials currently, but a number of effective drugs for which little resistance has developed are clinically available and frequent review and involvement in clinical trials is to be encouraged.

In conclusion, we have reported successful management of an outbreak of MRSA in our unit. Despite this, it seems unlikely that this problem will disappear completely. This pathogen is endemic in our population and the fact that many patients are received directly onto the transplant ward from referring centres means that an ongoing high-intensity surveillance program with aggressive eradication strategies is appropriate.

We currently perform and recommend a robust and early screening protocol that would identify patients at high risk. The use of molecular techniques to identify MRSA might expedite the diagnosis and aid in strain identification.⁷ If MRSA is positive, the transplant is deferred while aggressive eradication is given. Although it is not our current policy, it could be argued that even if the MRSA is thought to be eradicated, prophylactic strategies should be undertaken. In addition, agents such as ciprofloxacin should be avoided. In view of the second high-risk period during long-term immunosuppression, we recommend aggressive eradication treatment in patients with long-term colonization by MRSA as many of these will finally succumb due to MRSA sepsis.

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