Miles Denton. May, 2001. MRSA in Cystic Fibrosis [online]. Leeds University Teaching Hospitals, Leeds, UK. Available from http://www.cysticfibrosismedicine.com

What is 'MRSA'?

MRSA is short for Methicillin-Resistant Staphyloccus aureus. Methicillin was an antibiotic used to treat S. aureus in the early 1960s before it was replaced by less toxic 'cousins' such as flucloxacillin. MRSA is resistant to flucloxacillin, the most commonly used antibiotic for anti-staphylococcal prophylaxis and treatment of patients with cystic fibrosis (CF). It is also resistant to the cephalosporins. This resistance is not mediated by the production of enzymes e.g. Beta-lactamase but by the production of altered penicillin binding proteins (PBPs) with reduced affinity for flucloxacillin. Hence PBP2a replaces PBP2, found in flucloxacillin-susceptible strains and this change is conferred by the MecA gene. Many strains are also resistant to other common antibiotics such as erythromycin and the quinolones e.g. ciprofloxacin. The first reported isolation of a methicillin-resistant S. aureus occurred in London in 1961 and the name 'MRSA' has stuck since then. For many years their clinical significance was questioned until a large increase in isolations and invasive infections affecting most hospitals was reported during the early 1990s. In some hospitals in the UK almost half of S. aureus bacteraemias are now due to MRSA. MRSA colonises and infects a wide range of vulnerable patients, including those with CF. The most common hospital units affected are often intensive care units, surgical units, and certain medical specialities such as elderly medicine. The reason may relate to a number of factors, including availability of sites for the organism to colonise, for example surgical wounds or intravenous lines, and the selective pressure exerted by use of antibiotics. There are a number of different strains of MRSA. Some are particularly common and are known to cause outbreaks in the hospital settings. These are referred to as Epidemic MRSA or EMRSA for short. For reasons that are not absolutely clear, two strains, called EMRSA-15 and EMRSA-16 have been particularly successful in the UK and are now reported from the majority of hospitals. EMRSA-16 has been reported from some London CF centres but it is likely that most UK CF centres will have seen patients colonised or infected with EMRSA-15 or EMRSA-16.

What is the scale of the problem in CF?

There are no accurate figures relating to the number of CF patients colonised with MRSA or how the scale of the problem differs from unit to unit. The CF unit at the Royal Brompton Hospital in London has reported that only 26 of 974 (2.7%) patients attending between 1965 and 1997 were colonised with MRSA. However, the authors did state that prevalence was increasing, with nine cases occurring in the first seven months of 1997. A North American study analysing the sputum microbiology of 595 CF patients involved in a trial of aerosolised tobramycin found 36 (6%) positive for MRSA. However, most (>80%) of the S. aureus strains isolated in this study were methicillin-sensitive. A CF centre in Dublin reported that by 1996, 31 (12%) of its adult CF patients had acquired MRSA.

What are the risk factors?

Patients of all ages can be colonised with MRSA, including children less than 18 months. However, there have been suggestions that the risk of MRSA colonisation may increase in those patients with the greatest number and length of hospital admissions. This is supported by data from Dublin that showed that the mean age of onset of MRSA colonisation in Irish CF patients was 21.2 years. The median age of MRSA acquisition at the Royal Brompton Hospital was 23.4 years (range 11.8 to 43.3 years). There is no evidence that receiving long-term flucloxacillin prophylaxis increases the risk of being colonised with MRSA.

How can it be transmitted?

MRSA can colonise a variety of different sites in the human body, particularly the nose, the throat, and moist areas, such as armpits and groins It can be acquired in a number of ways and most cases of acquisition probably occur in the hospital setting. The organism can be transiently acquired from MRSA-positive CF patients (and their immediate environment e.g. bedding, curtains) by doctors, nurses, and physios and transferred, often via their hands, to MRSA-negative CF patients. However, one outbreak reported amongst Australian CF patients suggested that transmission had occurred from other non-CF patients in the hospital rather than between CF patients themselves. Visits to other hospital units where MRSA is a common problem e.g. for minor surgery, have also been suggested as ways in which CF patients could acquire MRSA. Alternatively, MRSA-positive CF patients could directly transfer it to MRSA-negative patients through social contact e.g. shaking hands, kissing. Acquisition by these routes could also occur outside hospital during times when CF patients socialise with each other. However, the role of coughing and airborne spread from patients with MRSA-positive sputum is uncertain. The role of acquisition in the home or community setting also remains unproven.

What are the clinical implications of MRSA?

Many CF patients are labelled as colonised with MRSA (that is to say there are no signs of infection associated with its isolation) rather than infected. Although a number of body sites can harbour MRSA, most MRSA-positive CF patients are found to carry the organism in their nose, throats and sputum, rather than on the skin. Colonisation status may also vary over time without any specific therapeutic interventions. About half of positive patients will eventually lose their MRSA for good, a quarter will be colonised continuously, and another quarter will be colonised intermittently. The duration of colonisation may also be brief. About 35% of CF patients in one study became MRSA-negative again within one month. The clinical relevance of MRSA in the sputum of CF patients remains unclear. On the whole, colonisation has not been linked with deterioration in lung function. However, as many MRSA-positive CF patients are also infected with other pathogens, such as Pseudomonas aeruginosa or Burkholderia cepacia, it can be very difficult to distinguish the clinical significance of MRSA in comparison to these other organisms. There is some evidence that being MRSA-positive may have a negative impact on growth in CF children. The reasons for this are unknown. The same study also found that these MRSA-positive patients required more courses of intravenous antibiotics and had worse chest x-ray scores than controls. However, the authors did not retrospectively examine differences in clinical condition and antibiotic use prior to MRSA acquisition. In one study of outcomes of MRSA colonisation in CF, only three patients were MRSA-positive at the time of death, and in only one of these was MRSA considered a possible contributing factor. Many CF patients now have permanent intravenous access devices such as Portocaths or PAS ports for the infusion of antibiotics. In some patients these intravenous lines have become infected and, in many instances, it has resulted in their removal. Many different organisms can be responsible for these infections, including MRSA. Intravenous access devices are now the commonest source of nosocomial MRSA bacteraemia in all patient groups.

What are the transplant implications of MRSA?

Currently most transplant centres will reject CF patients who are positive for MRSA on screening. Although there is little direct evidence relating to organ transplantation, it has been shown that MRSA-positive patients are less likely to survive other major cardio-thoracic procedures, such as coronary artery bypass grafting, than MRSA-negative patients. Transplant centres have also been concerned about the potential for cross-infection with MRSA on the intensive care unit. However, some MRSA-positive patients have been transplanted successfully. Each transplant centre will have its own approach to assessing the suitability of MRSA-positive patients for transplantation and treatment may be offered in an attempt to eradicate MRSA carriage.

How can MRSA colonisation be treated?

Although there is no evidence that MRSA colonisation of sites such as the nose, throat or skin, is harmful to patients with CF, attempts are often made to eradicate the organism. This is for a number of reasons. It is thought that eradication will reduce the risk of the colonised patient subsequently developing an established MRSA lung infection. It would also reduce the risk that the colonised individual may act as a source of MRSA for other patients. Eradication also plays an important role in determining transplant status. Eradication of MRSA can be attempted by applying mupirocin (trade name - Bactroban NasalÒ) to the insides of the nares three times a day for five days to treat nasal carriage. In addition, bathing and shampooing in disinfectants such as triclosan (trade name - Aquasept®), and the application of hexachlorophene (trade name - Ster-Zac Powder®) to the axillae and groins, can be used to reduce skin carriage. Repeated screening swabs e.g. nose, throat, axillae, and groins may be taken at weekly intervals after therapy to assess the success of eradication attempts. Most units use a 'three consecutive negatives' rule before declaring someone clear of MRSA. Even when this is achieved some patients will soon become positive again, either by acquiring a new strain or through recurrence of their old one. Some CF centres will treat patients with positive sputum or cough-swab cultures for MRSA with aerosolised vancomycin, although this approach has yet to be subjected to scientific scrutiny.

How can MRSA infection be treated?

Given the uncertainty surrounding the significance of MRSA isolation from the sputum of CF patients, antibiotics specifically targeting MRSA are not often given. When antibiotic therapy for MRSA is clinically indicated there are few available options. Currently the most commonly used agents are vancomycin and teicoplanin. Unfortunately they can only be given intravenously when used to treat MRSA. Vancomycin is more active against MRSA than teicoplanin in vitro but it can be more toxic. It can cause hot flushes and rashes, sometimes referred to as 'Red Man Syndrome', but infusing the drug over at least an hour can reduce these. It can potentiate the nephrotoxicity of other drugs e.g. aminoglycosides, and it is recommended that serum levels are monitored. It also needs to be given twice a day to most patients. For these reasons, teicoplanin is sometimes used instead. It has the advantage of fewer side-effects, once-a-day dosing, and rapid infusion over a few minutes, all of which make it much more suitable for home intravenous administration. The need for serum monitoring with teicoplanin is uncertain but some authorities have recommended that trough levels greater than 20 mg/L be achieved when treating serious infections. Other antibiotics, such as rifampicin or fusidic acid can be given in addition. They are usually given orally but cannot be given alone otherwise resistant mutants of MRSA will emerge very quickly. There is no clear evidence that other antibiotics, such as tetracycline and trimethoprim, offer enough consistent activity to be used routinely for treating MRSA. However, there is a new oral antibiotic with efficacy against MRSA, called linezolid. It has been available for use in the United Kingdom since early 2001. Although it is licensed for the treatment of respiratory tract infections, there are, as yet, no published trials of its use in CF patients. It is not licensed for use in children either and it remains to be seen if it will be effective for MRSA respiratory tract infection in CF. The cost is also prohibitive: current estimated hospital prices are in excess of £500 for a week's course of the oral preparation. There are no plans at present to make it available for community use.

What Staphylococcal prophylaxis should be given if the patient is MRSA-positive?

Although trials have shown a benefit for flucloxacillin prophylaxis, these studies only followed children up from birth to age two. It is not clear how much benefit there is from continuing flucloxacillin beyond this age but some CF centres do continue its use. However, once patients are found to be positive for MRSA, the benefit of continuing flucloxacillin is uncertain. There is no evidence to support whether a different prophylactic antibiotic, if any, will protect MRSA-colonised patients from developing deeper lung infections with the organism. This may be a future role for linezolid.

How can MRSA transmission be prevented between CF patients?

When in hospital, MRSA-positive CF patients should be managed according to local infection control and CF unit policies. In many institutions, this entails admission to a single rooms and 'barrier nursing' i.e. staff coming into contact with the patient and their surroundings wear gloves and aprons and pay close attention to cleanliness and hand-washing in particular. Not surprisingly, patients can feel stigmatised and lonely when this happens. However, proven transmission of MRSA between CF patients is extremely rare in the hospital setting. There is also no evidence to suggest that social contact outside of hospital poses a risk of MRSA transmission. Being colonised with MRSA does not appear to be a reason for limiting normal social contact with other CF patients in the community setting. However, more intimate contact, e.g. kissing, should be avoided.

Key points

MRSA has become more common amongst CF patients in recent years. This mirrors the increase seen in many other patient groups. However, the overall prevalence is still less than 10% in most CF units.

Risk factors for acquisition are unclear but increasing age, worsening clinical state, and increased frequency and duration of hospital admissions are associated with MRSA positivity. The role of previous antibiotic therapy needs further investigation.

There remain doubts regarding its clinical significance and the requirement for MRSA-specific antibiotic therapy, although some CF patients have had evidence of infection with this organism. MRSA colonisation may have a negative impact on growth but its impact on respiratory function is less clear.

MRSA is still a contra-indication to transplantation in many centres, although specific evidence of poorer outcome in CF patients is lacking.

Eradication therapies may assist in the reversal of colonisation status from positive to negative.

Although isolation is usually practised when admitted to hospital, there is no evidence that MRSA-colonised CF patients should be barred from maintaining social contacts when in the community.

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