Staphylococcus aureus and Methicillin Resistant Staphylococcus aureus
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 Resistance to these agents rapidly developed and although methicillin was superceded by better tolerated compounds, such as flucloxacillin, the mechanism of resistance affected all these agents.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 influenzaeor 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).
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 CF1. 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
• 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
• Prophylactic flucloxacillin should be prescribed from diagnosis and continued indefinitely
• Early treatment and eradication, if possible, of MSSA and MRSA
<a name=”ref”></a>Armstrong DS, Grimwood K, Carzino R, et al. Lower respiratory tract infection and inflammation in infants with newly diagnosed cystic fibrosis. BMJ 1995; 310: 1571-1572. <a href=”http://pmid.us/7787647″>[PubMed]</a>
Arrieta AC, Stutman HR, Akaniro JC, et al. In vitro activity of teicoplanin compared with vancomycin against methicillin-resistant Staphylococcus aureus derived from cystic fibrosis sputum. Diagn Microbiol Infect Dis 1992; 15: 247-251. <a href=”http://pmid.us/1533825″>[PubMed]</a>
Beringer PM, Appleman MD. Unusual bacterial respiratory flora in cystic fibrosis: microbiologic and clinical features. Curr Opin Pulm Med 2000; 6: 545-550. <a href=”http://pmid.us/11100967″>[PubMed]</a>
Burnie J, Matthews R, Jiman-Fatami A, et al. Analysis of 42 cases of septicemia caused by an epidemic strain of methicillin-resistant Staphylococcus aureus: evidence of resistance to vancomycin. Clin Infect Dis 2000; 31: 684-689. <a href=”http://pmid.us/11017816″>[PubMed]</a>
Burns JL, Emerson J, Stapp JR, et al. Microbiology of sputum from patients at cystic fibrosis centers in the United States. Clin Infect Dis 1998; 27: 158-163. <a href=”http://pmid.us/9675470″>[PubMed]</a>
Charlebois ED, Perdreau-Remington F, Kreiswirth B, et al. Origins of community strains of methicillin-resistant Staphylococcus aureus. Clin Infect Dis 2004; 39: 47-54. <a href=”http://pmid.us/15206052″>[PubMed]</a>
Cystic Fibrosis Foundation (CFF). CFF Patient Registry Annual Data Report. Bethesda, Maryland, 2002.
Cystic Fibrosis Trust Antibiotic Group. Antibiotic Treatment for Cystic Fibrosis. 2nd Edition. London. Cystic Fibrosis Trust, September 2002.
Combined Working Party of the BSAC, HIS & ICNA. Revised guidelines for the control of methicillin-resistant Staphylococcus aureus infection in hospitals. J Hosp Infect 1998; 39: 253-290. <a href=”http://pmid.us/9749399″>[PubMed]</a>
Ferrin M, Zuckerman JB, Meagher A, et al. Successful treatment of methicillin-resistant Staphylococcus aureus pulmonary infection with linezolid in a patient with cystic fibrosis. Pediatr Pulmonol 2002; 33: 221-223. <a href=”http://pmid.us/11836802″>[PubMed]</a>
Garske LA, Kidd TJ, Gan R, et al. Rifampicin and sodium fusidate reduces the frequency of methicillin-resistant Staphylococcus aureus (MRSA) isolation in adults with cystic fibrosis and chronic MRSA infection. J Hosp Infect 2004; 56: 208-214. <a href=”http://pmid.us/15003669″>[PubMed]</a>
Givney R, Vickery A, Holliday A, et al. Methicillin-resistant Staphylococcus aureus in a cystic fibrosis unit. J Hosp Infect 1997; 35: 27-36. <a href=”http://pmid.us/9032633″>[PubMed]</a>
Goerke C, Kraning K, Stern M, et al. Molecular epidemiology of community-acquired Staphylococcus aureus in families with and without cystic fibrosis patients. J Infect Dis 2000; 181: 984-989. <a href=”http://pmid.us/10720521″>[PubMed]</a>
Graffunder EM, Venezia RA. Risk factors associated with nosocomial methicillin-resistant Staphylococcus aureus (MRSA) infection including previous use of antimicrobials. J Antimicrob Chemother 2002; 49: 999-1005. <a href=”http://pmid.us/12039892″>[PubMed]</a>
Hassan IA, Chadwick PR, Johnson AP. Clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) with reduced susceptibility to Teicoplanin in Northwest England. J Antimicrob Chemother 2001; 48: 454-455. <a href=”http://pmid.us/11533021″>[PubMed]</a>
Hoiby N, Frederiksen B: Microbiology of Cystic Fibrosis. In: Hodson ME, Geddes D (Eds) Cystic Fibrosis 2nd Edition; 2000: p 83-108.
Littlewood JM, Littlewood AE, McLaughlin S, et al. 20 years continuous neonatal screening in one hospital; progress of the 37 patients and their families. Pediatr Pulmonol 1995; Suppl 12: 374
Loveday HP, Pellowe CM, Jones SR, et al. A systematic review of the evidence for interventions for the prevention and control of methicillin-resistant Staphylococcus aureus (1996-2004): report to the Joint MRSA Working Party (Subgroup A). J Hosp Infect 2006; 639 (Suppl 1): S45-S70. <a href=”http://pmid.us/16616800″>[PubMed]</a>
Maiz L, Canton R, Mir N, et al. Aerosolized vancomycin for the treatment of methicillin-resistant Staphylococcus aureus infection in cystic fibrosis. Pediatr Pulmonol 1998; 26: 287-289. <a href=”http://pmid.us/9811080″>[PubMed]</a>
Macfarlane M, Leavy A, McCaughan J, et al. Successful decolonisation of methicillin-resistant Staphylococcus aureus in paediatric patients with cystic fibrosis (CF) using a three-step protocol. J Hosp Infect 2007; 65: 231-236. <a href=”http://pmid.us/17178427″>[PubMed]</a>
Maurer JR, Frost AE, Estenne M, et al. International guidelines for the selection of lung transplant candidates. The International Society for Heart and Lung Transplantation, the American Thoracic Society, the American Society of Transplant Physicians, the European Respiratory Society. Transplantation 1998; 66: 951-956. <a href=”http://pmid.us/9798716″>[PubMed]</a>
McCaffery K, Olver RE, Franklin M, et al. Systematic review of antistaphylococcal antibiotic therapy in cystic fibrosis. Thorax 1999; 54: 380-383. <a href=”http://pmid.us/10212099″>[PubMed]</a>
Miall LS, McGinley NT, Brownlee KG, et al. Methicillin resistant Staphylococcus aureus (MRSA) infection in cystic fibrosis. Arch Dis Child 2001; 84: 160-162. <a href=”http://pmid.us/11159295″>[PubMed]</a>
Nadesalingam K, Conway SP, Denton M. Risk factors for acquisition of methicillin-resistant Staphylococcus aureus (MRSA) by patients with cystic fibrosis. J Cyst Fibros 2005; 4: 49-52. <a href=”http://pmid.us/15752681″>[PubMed]</a>
Ramsay BW, Wentz KR, Smith AL, et al. Predictive value of oropharyngeal cultures for identifying lower airway bacteria in cystic fibrosis patients. Am Rev Respir Dis 1991; 144: 331-337. <a href=”http://pmid.us/1859056″>[PubMed]</a>
Rao G, Gaya H, Hodson M. MRSA in cystic fibrosis. J Hosp Inf 1998; 40: 179-191. <a href=”http://pmid.us/9830589″>[PubMed]</a>
Ratjen F, Comes G, Paul K, et al. Effect of continuous antistaphylococcal therapy on the rate of P. aeruginosa acquisition in patients with cystic fibrosis. Pediatr Pulmonol. 2001; 31: 13-16. <a href=”http://pmid.us/11180669″>[PubMed]</a>
Ren CL, Morgan WJ, Konstan MW, et al. Presence of methicillin resistant Staphylococcus aureus in respiratory cultures from cystic fibrosis patients is associated with lower lung function. Pediatr Pulmonol 2007; 42: 513-518. <a href=”http://pmid.us/17469151″>[PubMed]</a>
Rosenbluth DB, Wilson K, Ferkol T, et al. Lung function decline in cystic fibrosis patients and timing for lung transplantation referral. Chest 2004; 126: 412-419. <a href=”http://pmid.us/15302726″>[PubMed]</a>
Saiman L, Siegel J. Cystic Fibrosis Foundation. Infection control recommendations for patients with cystic fibrosis: microbiology, important pathogens, and infection control practices to prevent patient-to-patient transmission. Infect Control Hosp Epidemiol 2003; 24: S6-S52. <a href=”http://pmid.us/12789902″>[PubMed]</a>
Schlichting C, Branger C, Fournier JM, et al. Typing of Staphylococcus aureus by pulsed-field gel electrophoresis, zymotyping, capsular typing and phage typing: resolution of clonal relationships. J Clin Microbiol 1993; 31: 227-232. <a href=”http://pmid.us/8432807″>[PubMed]</a>
Shreve MR, Butler S, Kaplowitz HJ, et al. Impact of microbiology practice on cumulative prevalence of respiratory tract bacteria in patients with cystic fibrosis. J Clin Microbiol 1999; 37: 753-757. <a href=”http://pmid.us/9986845″>[PubMed]</a>
Smyth A, Walters S. Prophylactic antibiotics for cystic fibrosis. Cochrane Database Syst Rev 2003; 3: CD001912. <a href=”http://pmid.us/12917916″>[PubMed]</a>
Solis A, Brown D, Hughes J, et al. Methicillin-resistant Staphylococcus aureus in children with cystic fibrosis: An eradication protocol. Pediatr Pulmonol 2003; 36: 189-195. <a href=”http://pmid.us/12910579″>[PubMed]</a>
Southern KW, Littlewood AE, Littlewood JM. The prevalence and significance of chronic Staphylococcus aureus infection in patients with cystic fibrosis on long term flucloxacillin. In: Escobar H, Baquero CF, Svarez L, editors. Clinical Ecology of Cystic Fibrosis. Elsevier Science Publ. 1993: 129-130.
Strandvik B, Hollsing A, Mollby R, et al. Antistaphylococcal antibodies in cystic fibrosis. Infection 1990; 18: 170-172. <a href=”http://pmid.us/2365469″>[PubMed]</a>
Stutman HR, Marks MI. Antibiotic Prophylaxis Study Group. Cephalexin prophylaxis in newly diagnosed infants with cystic fibrosis. Sixth Annual North American Cystic Fibrosis Conference; 1992 Washington DC. <a href=”http://pmid.us/11953726″>[PubMed]</a>
Stutman HR, Lieberman JM, Nussbaum E, et al. Antibiotic prophylaxis in infants and young children with cystic fibrosis: a randomized controlled trial. J Pediatr. J Pediatr. 2002; 140: 299-305. <a href=”http://pmid.us/11953726″>[PubMed]</a>
Szaff M, Hoiby N. Antibiotic treatment of S. aureus infection in cystic fibrosis. Monogr Paediatr 1981; 14: 108 -114.
Taylor RF, Hodson ME: Cystic fibrosis: antibiotic prescribing practices in the UK and Eire. Respir Med 1993; 87: 535-539. <a href=”http://pmid.us/8265842″>[PubMed]</a>
Thomas SR, Gyi KM, Gaya H, et al. Methicillin-resistant Staphylococcus aureus: impact at a national cystic fibrosis centre. J Hosp Infect 1998; 40: 203-209. <a href=”http://pmid.us/9830591″>[PubMed]</a>
Weaver LT, Green MG, Nicholson K, et al. Prognosis in cystic fibrosis treated with continuous flucloxacillin from the neonatal period. Arch Dis Child 1994; 70: 84-89 <a href=”http://pmid.us/8129449″>[PubMed]</a>