Staphylococcus aureus and Methicillin Resistant Staphylococcus aureus

The Leeds Method of Management. April, 2008. Staphylococcus aureus and Methicillin Resistant Staphylococcus aureus [online]. Leeds Regional Adult and Paediatric Cystic Fibrosis Units, St James's University Hospital, Leeds, UK. Available from http://www.cysticfibrosismedicine.com

Introduction
Methicillin sensitive S. aureus
Evidence for MSSA exacerbating lung disease in CF
Choice of antibiotic
Continuous or intermittent antibiotics
The Leeds approach to S.aureus
Methicillin resistant S. aureus
Evidence that MRSA infection exacerbates CF lung disease
Treatment of MRSA infection
Prevention of MRSA
Eradication of MRSA
Evidence
References

Introduction

Staphylococcus aureus is one of the most important human pathogens. Most strains were initially sensitive to penicillin but emerging penicillin resistance (today less than 10% of strains remain penicillin-susceptible) stimulated the development of penicillinase-resistant compounds, such as methicillin, which first appeared in the early 1960s. Resistance to these agents rapidly developed and although methicillin was superceded by better tolerated compounds, such as flucloxacillin, the mechanism of resistance affected all these agents. Thus the name “methicillin resistant S. aureus” (MRSA) has survived to this day.

Methicillin sensitive S. aureus (MSSA)

S. aureus has been a major pathogen in CF since the disease was first described. In some clinics it has achieved a prevalence of approximately 50% in children up to 10 years of age (Beringer & Appleman, 2000) and many adults are chronically infected. Nasal carriage rates of S. aureus are significantly higher in patients with CF (66%) than in patients without CF (32%), (Goerke et al, 2000). S. aureus infection can be spread from patient to patient where there is the opportunity for prolonged and close contact. At the end of a four week summer camp four patients harboured the same strain as identified in a fifth patient at the start of the camp (Schlichting et al, 1993).

Infection may be asymptomatic, and for the majority, can be effectively treated with antibiotics. S. aureus itself is no longer a common cause of significant morbidity or mortality in CF (Hoiby & Frederiksen, 2000) but can result in scarring, tissue destruction and progressive airway obstruction, predisposing to acute P. aeruginosa infection. For this reason, as well as for its own pathogenic potential, early treatment and eradication (if possible) of S. aureus infection is recommended.

Evidence for MSSA exacerbating lung disease in CF

There are reports of S. aureus infection either having no impact on, or increasing the severity of CF lung disease. In Stutman’s study of continuous prophylactic antibiotic treatment, S. aureus colonisation in the placebo group was not associated with an increase in pulmonary symptoms (Stutman et al, 2002). However, S. aureus infection with accompanying inflammatory changes has been found in infants with CF as young as three months of age, suggesting the possibility of early lung damage (Armstrong et al, 1995). Co-infection with P. aeruginosa and S. aureus may be associated with a more rapid decline in lung function (Rosenbluth et al, 2004).

Choice of antibiotic

The first choice antibiotics are the isoxazolyl penicillins, such as flucloxacillin and cloxacillin. We suggest the addition of fusidic acid or rifampicin for the treatment of serious infections (Cystic Fibrosis Trust, 2002). In the treatment of MSSA in patients with genuine penicillin allergy agents such as erythromycin and clindamycin may be less active than pencillins. Glycopeptides such as vancomycin or teicoplanin may be useful but they are only available as intravenous agents and have significant toxicity and monitoring issues. In serious infections with S. aureus consideration should therefore be given to desensitization of penicillin-allergic patients.

Continuous or intermittent antibiotics

Approaches to the treatment of MSSA infection vary from short term antibiotic courses as a routine response to a positive sputum culture, to antibiotic therapy only if the sputum culture is associated with clinical symptoms or signs of lower respiratory tract disease, to continuous prophylactic antibiotic treatment from diagnosis (Szaff & Hoiby, 1981; Taylor & Hodson, 1993; Weaver et al, 1994). The aim of the latter is to reduce the prevalence of S. aureus infection and thereby any associated inflammatory changes and lung damage. Some authorities are concerned that continuous antibiotic prophylaxis will increase the risk of bacterial resistance and P. aeruginosa infection (Ratjen et al, 2001; Stutman et al, 2002).

The Copenhagen Centre reported a successful outcome with treatment of each MSSA isolate. The chronic infection rate was less than 10% and staphylococcal infection was eradicated in approximately 74% of cases with each fourteen days of antibiotic therapy (Hoiby & Frederiksen, 2000). We recommend flucloxacillin prophylaxis from diagnosis. Only 10% of our children have had two or more respiratory cultures positive for S. aureus over the last twelve months.

The Cochrane Review of continuous versus no prophylactic antibiotic treatment of S. aureus infection in CF found only four studies meeting its inclusion criteria (Smyth & Walters, 2003). Fewer children receiving prophylaxis had one or more S. aureus isolates when treatment was begun early in infancy and continued for up to six years of age. There was not sufficient evidence available to reach conclusions on the clinical impact of this lower infection rate. Continuous prophylaxis was not associated with an increase in the number of Haemophilus influenzae or P. aeruginosa isolates, nor with any report of MRSA or Burkholderia cepacia complex (Bcc) infection.

Whichever treatment protocol is adopted, S. aureus infection for most patients is not a major clinical problem and is not related to poor prognosis.

The Leeds approach to S. aureus

If S. aureus grows repeatedly from respiratory secretions, antibody studies suggest that it is almost certainly present in the lower airways (Strandvik et al, 1990). Comparison of cultures from the throat and bronchial tubes of the same patients supports this finding. Our present policy is to recommend long term prophylactic flucloxacillin and this is continued indefinitely (50-100mg/kg/day in divided doses to a maximum of 1 gram four times a day in adults). Experience of patients referred to Leeds for CF assessments indicates that S. aureus continues to be a cause of significant lung damage in some individuals with CF who have not received, or have failed to comply with, such preventative treatment. We believe that the lungs of treated patients have some protection from S. aureus infection. When patients are receiving long term prophylactic flucloxacillin, S. aureus is cultured infrequently (Southern et al, 1993; Littlewood et al, 1995).

If S. aureus grows repeatedly from a patient who is prescribed long term flucloxacillin one should first confirm that the drug is being taken. Another anti-staphylococcal antibiotic should be added for two weeks e.g. fucidin or rifampicin. Before accepting that it is not possible to eradicate S. aureus, the patient should receive a two week course of intravenous antibiotics e.g. flucloxacillin.

Some older patients have entrenched S. aureus infection for many years. We believe that it is reasonable to treat them with long term flucloxacillin to minimise tissue damage. Some clinics do not treat chronic S. aureus infection unless it is associated with a respiratory exacerbation. We do not agree with that policy.

Methicillin resistant S. aureus (MRSA)

MRSA was first identified in the 1960s and was recognised as a major pathogen in the 1980s with the emergence of new strains of epidemic potential. It is frequently resistant to multiple different classes of antibiotics. There is no reason to think that the risks of MRSA infection will be any less in CF than in other conditions. Chronic infection may be seen as a relative contraindication to lung transplant (Maurer et al, 1998; Rao et al, 1998).

MRSA has been isolated with increasing frequency from CF Units with prevalence rates ranging from 0% to about 23% (Burns et al, 1998; Rao et al, 1998; Cystic Fibrosis Foundation, 2002). Routine testing and standardisation of microbiological procedures is likely to identify a higher prevalence rate (Burns et al, 1998; Shreve et al, 1999) although a sizeable minority of patients may have only a transient colonisation (Thomas et al, 1998).

Epidemiological studies have suggested that nosocomial transmission during hospital admissions, rather than social contact outside of hospital, is the most significant route of transmission for MRSA (Givney et al, 1997; Garske et al, 2004). MRSA positive patients spend significantly more days in hospital than MRSA negative patients (Nadesalingam et al, 2005). Admission to general medical wards may increase the risk (Givney et al, 1997). However, the importance of community as well as nosocomial acquisition of MRSA is recognised (Charlebois et al, 2004) and has been suggested as a potential source of MRSA for CF patients (Solis et al, 2003). Antibiotic use, surgery and indwelling intravenous access devices have been identified as independent risk factors (Rao et al, 1998; Nadesalingam et al, 2005). Worse pulmonary status is also a risk factor for MRSA acquisition (Thomas et al, 1998; Miall et al, 2001).

Evidence that MRSA infection exacerbates CF lung disease

Chronic MRSA infection in CF is associated with severe bronchiectasis (Burnie et al, 2000) but no definite cause-effect relationship between MRSA infection and deterioration in lung function has been identified. Patients with better lung function appear to tolerate MRSA infection well (Rao et al, 1998). Some patients may show increased dyspnoea, wheeze and sputum production concurrent with MRSA isolation whilst others show no disease progression even when no specific treatment is given. However, we suggest a cautious interpretation of this research. Although some studies suggest that MRSA infection has only a minimal effect in CF despite its undisputed pathogenic role in non-CF patients, these studies are of short duration, uncontrolled and conducted on only a small numbers of patients. Larger studies of longer duration might show deleterious effects of MRSA infection in CF. In Miall’s study ten infected children were compared to controls from one year before to one year after the onset of MRSA infection. The MRSA group showed a non-significant trend towards decreased respiratory function, an increased requirement for intravenous antibiotic treatment in the year after the first isolate and a significantly worse height standard deviation score (Miall et al, 2001). Data from the Epidemiologic Study of CF show that compared to patients with MSSA only, patients with MRSA only, had significantly more airflow obstruction, significantly greater likelihood of hospital admission, and more treatment with oral, inhaled, and intravenous antibiotics (Ren et al, 2007).

Treatment of MRSA infection

The first choice antibiotics are the glycopeptides vancomycin and teicoplanin. In non-CF patients there is some evidence that clinical outcome may be improved if rifampicin is added to vancomycin (Burnie et al, 2000). It is not known if combination therapy improves outcome in patients with CF and MRSA infection.

Prevention of MRSA

Because of the potential for MRSA to cause significant morbidity and its inherent antibiotic resistance, management protocols should aim at prevention and, if unsuccessful, at eradication of infection (Loveday et al, 2006). Therefore we aim to minimise repeated and prolonged hospital admissions by optimal use of home intravenous antibiotic administration, invasive treatment and broad spectrum antibiotic administration (Graffunder & Venezia, 2002; Garske et al, 2004). The spread of MRSA is often through person-to-person transmission via hand contact. Patients with MRSA infection should be separated from others, taking care to minimise stigma and sense of isolation (Rao et al, 1998). The importance of hand washing and of adherence to basic good hygiene, especially with invasive procedures, must be regularly and frequently emphasised (Saiman et al, 2003). A policy for the handling and cleaning of equipment should be agreed with the hospital infection control team.

Eradication of MRSA

Eradication of MRSA may be more difficult in patients with CF since infection may involve the lower respiratory and gastrointestinal tracts as well as the nose, pharynx and skin surface. There are no comparative trials of different eradication regimens of MRSA infection in CF and therefore experience must be extrapolated from other patient groups. Suggested eradication regimens for non-respiratory tract MRSA infection are summarised below.

The Leeds protocol for Methicillin Resistant Staphyloccus aureus (MRSA) eradication in patinets with CF

1. Available data suggests intravenous vancomycin may be more suitable for the treatment of MRSA respiratory tract infections in CF patients than teicoplanin (Arrieta et al, 1992; Hassan et al, 2001).

2. There is evidence to suggest that the addition of rifampicin to intravenous vancomycin improves outcome in serious MRSA infections in comparison to vancomycin alone (Burnie et al, 2000). The addition of fusidic acid is an alternative in those strains found to be rifampicin-resistant.

3. Superficial colonisation of mucosal and cutaneous sites can be eradicated using combinations of topical antibiotics (e.g. mupirocin) and topical antiseptics (e.g. chlorhexidine 4%), (Loveday et al, 2006).

4. Combinations of oral antibiotics (e.g. rifampicin plus fusidic acid) may be considered in those found to have throat carriage (Loveday et al, 2006). However, evidence of clinical efficacy is lacking and there are significant concerns regarding toxicity.

5. The role of nebulised vancomycin remains uncertain. There are anecdotal reports of efficacy in eradicating MRSA from the respiratory tract of CF patients (Maiz et al, 1998), but there are concerns regarding the possible impact of widespread and longer term use on the emergence of resistance.

6. The role of oral linezolid in the management of MRSA colonisation and infection in CF patients remains unclear. However, there are case reports of successful management of CF patients infected with MRSA (Ferrin et al, 2002). The introduction of such an agent should be integrated into a prospective audit to monitor the outcome of such therapy.

Recommended regimens for treating MRSA colonisation/infection of non-respiratory sites – Working Party Report.

Nasal carriage: 2% nasal mupirocin – each nostril three times daily for five days

If two treatment failures (or isolate is mupirocin-resistant):
- naseptin cream (0.5% neomycin plus 0.1% chlorhexidine)

Treat all nasal carriers for skin carriage

Skin carriage: Bathe for five days with an antiseptic detergent. Options include:
- 4% chlorhexidine
- 2% triclosan
- 7.5% povidone-iodine

Wash hair twice weekly with one of the above

Apply hexachlorophance powder (e.g. CX powder) to axillae/groins

Published data on eradication strategies used against MRSA in patients with CF
Reference
Regimen
Duration
Outcome
Maiz et al

Aerosolized vancomycin 250mg in 4ml sterile

H20 nebulised twice daily* for 10 minutes

*preceeded by nebulised terbutaline 500µg

17 months
Reduced sputum counts
of MRSA but no eradication
Solis et al

Aerosolized vancomycin 4mg/kg/dose diluted in
normal saline four times daily*

*preceeded by nebulised salbutamol

Tracheostomy: 2% vancomycin cream bd; change foreign body

Nasal carriage: 2% mupirocin cream four times daily OR 2% vancomycin cream four times daily

Oropharyngeal carriage: 2% vancomycin paste OR 2% vancomycin gel OR 5mg vancomycin
Lozenges four times daily

Gastrointestinal carriage: 40mg/kg/day Vancomycin oral suspension in four divided doses

Skin carriage: 4% chlorhexidine bath/shower on alternate days.

(We do not use vancomycin cream, gel, paste or lozenges in Leeds)

5 days
Successful eradication in 7 of 12 patients for mean of 12 months
Garske et al Rifampicin 600mg od orally plus sodium fusidate 6 months 250-500mg bd orally
6 months
Successful eradication in 5 of 7 patients for mean of six months
Macfarlane et al

Nasal mupirocin 2% twice daily

Sodium fusidate 50mg/kg/day

Rifampicin 20-40mg/kg/day

Chlorhexidine for washing

5 days
Repeat still positive after first cycle. Treat with iv teicoplanin 10-15mg/kg 12h for three doses then same dose once daily for 13 days

Published data on eradication strategies used against MRSA in patients with CF
 
Figure 1: Proposed MRSA eradication protocol for Regional Adult and Paediatric Cystic Fibrosis Units, Leeds
 

Key points

S. aureus is a major pathogen in CF

• It is found in infant lungs as early as three months of age and with accompanying inflammatory changes

• MRSA is now isolated with greater frequency

• Hospital admission is a major risk factor for MRSA acquisition

Recommendations

• Prophylactic flucloxacillin should be prescribed from diagnosis and continued indefinitely

• Early treatment and eradication, if possible, of MSSA and MRSA

 

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