Staphylococcus aureus ( S.aureus ) on a respiratory sample from a patient with cystic fibrosis - Management of

Publication: 22/12/2016  
Last review: 01/01/1900  
Next review: 22/12/2019  
Clinical Guideline
CURRENT 
ID: 4865 
Approved By: Improving Antimicrobial Prescribing Group 
Copyright© Leeds Teaching Hospitals NHS Trust 2016  

 

This Clinical Guideline is intended for use by healthcare professionals within Leeds unless otherwise stated.
For healthcare professionals in other trusts, please ensure that you consult relevant local and national guidance.

The Management of Staphylococcus aureus (S.aureus) on a respiratory sample from a patient with cystic fibrosis

  • Treatment Algorithm
  • Summary
    Staphylococcus aureus ( S.aureus ) on a respiratory sample from a patient with cystic fibrosis

    Positive S.aureus on a cough swab or sputum sample should initially be managed with a two week course of flucloxacillin at treatment dose before therapy is escalated.

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    Background

    What is S.aureus?

    S. aureus is a ubiquitous gram positive coccus bacterium. It is a commensal of the human skin, especially anterior nares and skin creases in patients with or without cystic fibrosis (CF).

    S. aureus is normally considered an aerobic bacterium but can also behave as facultative anaerobe and is capable of biofilm formation (Goss C et al, 2011 PMID: 21719362).

    Chronic S. aureus infection in CF lung may occur as biofilms which are associated with higher in vitro antibiotic resistance. Aktas, N et al, 2013, PMID: 24240049). S. aureus shows increased mutation rates during CF lung infection compared to nasal colonisation in healthy subjects. S. aureus isolates, like P.aeruginosa, have clearly been shown to persist in CF patients over years. (Goss C et al, 2011 PMID: 21719362)
     
    Why is it important?

    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, PMID: 2365469). S.aureus is a lung pathogen. Early infection with S.aureus is associated with bronchiectasis at age six on CT scan. [B]

    How common is Staphylococcus aureus?

    Bacterial infection due to S. aureus is one of the earliest bacteria detected in infants and children with CF, and it may be found in CF infants as early as three months of age (Armstrong 1995, PMID: 7787647). In one study, 78 bronchoscopies were performed on 38 patients. The average age at the time of bronchoscopy was 2.7 years (range 0.3-7.0 year). A significant organism was detected in 58 (74.5%) bronchoalveolar lavages (BAL). Haemophilus influenzae was detected in 27 (34.6%) samples, 16 (20.5%) samples had S. aureus, and nine (11.5%) had P. aeruginosa.  (Linanne B 2015, PMID: 25408378)

    S. aureus  is the most prevalent organism among US CF children with a peak prevalence between ages 11–15 years. Cross sectional studies show that in those under 10 years, 25−30% of patients culture S. aureus from sputum. This may be an underestimate as cough swabs in children unable to expectorate are often negative. 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, PMID: 10720521).

    Is it serious?

    There continues to be debate about the significance of S. aureus in the pathogenesis of CF lung infection. There is evidence that S. aureus can result in scarring, bronchiectasis, tissue destruction and progressive airway obstruction, predisposing to acute P. aeruginosa infection. Co-infection with P. aeruginosa and S. aureus may be associated with a more rapid decline in lung function (Rosenbluth et al, 2004, PMID: 15302726)
    For this reason, as well as for its own pathogenic potential, early treatment and eradication (if possible) of S. aureus infection is recommended.

    Can it be prevented?

    A recent Cochrane review concluded that, “Fewer children receiving anti-staphylococcal antibiotic prophylaxis had one or more isolates of S. aureus. There was no significant difference between groups in infant or conventional lung function. We found no significant effect on nutrition, hospital admissions, additional courses of antibiotics or adverse effects. There was no significant difference in the number of isolates of P. aeruginosa between groups, though there was a trend towards a lower cumulative isolation rate of P. aeruginosa in the prophylaxis group at two and three years and towards a higher rate from four to six years. As the studies reviewed lasted six years or less, conclusions cannot be drawn about the long-term effects of prophylaxis.” (Smyth A et al. 2014; PMID: 25419599). [A]

    It is recognised that there are different policies regarding prophylaxis throughout the UK, and indeed the world. This reflects the lack of good evidence to guide management.

    Currently it is standard practice in Leeds for people with cystic fibrosis to have flucloxacillin prophylaxis into adulthood. This may change as new evidence becomes available.

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    Clinical Diagnosis

    What are the symptoms?

    There is no way of differentiating lower respiratory tract infection with S. aureus from any other infection. Indeed, infection may be asymptomatic, and for the majority, can be effectively treated with antibiotics.

    How is it diagnosed?

    Children often are not sputum producers; therefore, oropharyngeal (“cough”) swabs are frequently obtained. Studies have compared oropharyngeal swabs with specimens obtained by bronchoalveolar lavage; cultures obtained from the upper airway correlated with lower airway infection (Rosenfeld M, 1999, PMID: 10536062 ). [B]

    Ramsey et al (1991, PMID: 1859056) reported a 91% positive predictive value [95% confidence interval (CI) 59-100] for S. aureus identified by oropharyngeal swab compared with bronchial cultures and an 80% negative predictive value (95% CI 52-96). This suggests that oropharyngeal swabs with positive cultures are highly predictive, but negative cultures do not rule out the presence of a pathogen. [B]

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    Investigation

    Cough or oropharyngeal swabs are the first line investigation for children who are unable to expectorate. For everyone else a sputum sample is preferred. Either a cough swab or sputum sample is obtained  at every routine clinic visit. Other investigations include induced sputum or bronchoalveolar lavage at bronchoscopy.

    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, PMID: 2365469). Comparison of cultures from the throat and bronchial tubes of the same patients supports this finding.
    Ramsey et al (1991, PMID: 1859056) reported a 91% positive predictive value [95% confidence interval (CI) 59-100] for S. aureus identified by oropharyngeal swab compared with bronchial cultures and an 80% negative predictive value (95% CI 52-96). This suggests that oropharyngeal swabs with positive cultures are highly predictive, but negative cultures do not rule out the presence of a pathogen. [B]

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    Treatment

    Patients with cystic fibrosis infected with S. aureus should be treated with anti-staphylococcal antibiotics for two weeks at treatment dose. This should be flucloxacillin in most patients (exceptions would include, for example, penicillin allergic patients).  In culture positive patients, anti-staphylococcal treatment for at least two weeks results in an eradication rate of 75% and only a few patients harbour S. aureus for more than six months thereafter. [B]

    If S. aureus grows repeatedly from a patient one should first confirm that the drug is being taken appropriately, with consideration of adherence, suitable dose and taking it on an empty stomach. [C] Another anti-staphylococcal antibiotic should be added in combination to flucloxacillin for two weeks e.g. sodium fusidate 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, vancomycin or teicoplanin, after discussion with a microbiologist.[D]

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    Treatment Algorithm

    S.aureus Eradication Protocol

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    Provenance

    Record: 4865
    Objective:

    Aims
    To improve the diagnosis and management of Staphylococcal aureus and infection in patients with cystic fibrosis.

    Objectives
    To provide evidence-based recommendations for appropriate diagnosis, investigation and management of Staphylococcal aureus infection in patients with cystic fibrosis.

    Clinical condition:

    Cystic fibrosis; S.aureus;

    Target patient group: Patients with cystic fibrosis
    Target professional group(s): Secondary Care Doctors
    Pharmacists
    Adapted from:

    Evidence base

    References  and Evidence levels:
    A. Meta-analyses, randomised controlled trials/systematic reviews of RCTs
    B. Robust experimental or observational studies
    C. Expert consensus.
    D. Leeds consensus. (where no national guidance exists or there is wide disagreement with a level C recommendation or where national guidance documents contradict each other)

    Aktas N. Panton-Valentine leukocidin and biofilm production of Staphylococcus aureus isolated from respiratory tract. J Infect Dev Ctries 2013; 7(11):888-891. PMID: 24240049

    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. PMID: 7787647

    Besier S et al. Prevalence and Clinical Significance of Staphylococcus aureus
    Small-Colony Variants in Cystic Fibrosis Lung Disease. Journal of Clinical Microbiology, Jan. 2007, p. 168–172. PMID: 17108072

    Chmiel J et al 2014. Antibiotic Management of Lung Infections in Cystic Fibrosis
    I. The Microbiome, Methicillin-Resistant Staphylococcus aureus, Gram-Negative
    Bacteria, and Multiple Infections. Ann Am Thorac Soc. 2014 Sep . PMID: 25102221

    Doring G, Hoiby N; Consensus Study Group. Early intervention and prevention of lung disease in cystic fibrosis: a European consensus. J Cyst Fibros 2004; 3: 67-91. PMID: 15463891

    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. PMID: 15003669

    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. PMID: 10720521

    Goss CH, Burns JL Exacerbations in cystic fibrosis. 1: Epidemiology and pathogenesis.. Thorax. 2007 Apr;62(4):360-7. Review. PMID: 17387214

    Goss C,  Marianne S. Muhlebach. Review: Staphylococcus aureus and MRSA in cystic fibrosis. Journal of Cystic Fibrosis 10 (2011) 298–306. PMID: 21719362

    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. PMID: 12039892

    Hoiby N, Frederiksen B: Microbiology of Cystic Fibrosis. In: Hodson ME, Geddes D (Eds) Cystic Fibrosis 2nd Edition; 2000: p 83-108.

    Kopp BT, Sarzynski L, Khalfoun S, Hayes D Jr, Thompson R, Nicholson L, Long F, Castile R, Groner J.Detrimental effects of secondhand smoke exposure on infants with cystic fibrosis. Pediatr Pulmonol. 2015 Jan;50(1):25-34. Epub 2014  Mar 9.
    PMID: 24610820

    Linnane B, Vaish S, Clarke D, O'Sullivan N, McNally P. The findings of a clinical surveillance bronchoalveolar lavage programme in pre-school patients with cystic fibrosis. Pediatr Pulmonol. 2015 Apr;50(4):327-32. PMID: 25408378

    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

    Lo, David Kh,Hurley, Matthew N,Muhlebach, Marianne S,Smyth, Alan R. Interventions for the eradication of meticillin-resistant Staphylococcus aureus (MRSA) in people with cystic fibrosis. The Cochrane database of systematic reviews, vol. 2, p. CD009650. (2015). PMID: 25927091

    Macfarlane, M,Leavy, A,McCaughan, J,Fair, R,Reid, A J M. Successful decolonization of methicillin-resistant Staphylococcus aureus in paediatric patients with cystic fibrosis (CF) using a three-step protocol. The Journal of hospital infection, vol. 65, no. 3, p. 231-236, 0195-6701 (March 2007). PMID: 17178427

    Miall LS, McGinley NT, Brownlee KG, et al. Methicillin resistant Staphylcoccus aureus (MRSA) infection in cystic fibrosis. Arch Dis Child 2001; 84: 160-162. PMID: 11159295

    Muhlebach M. Treatment intensity and characteristics of MRSA infection in CF. Journal of Cystic Fibrosis 10 (2011) 201–206. PMID: 21420912

    Nadesalingam, Kavitha,Conway, Steven P,Denton, Miles. Risk factors for acquisition of methicillin-resistant Staphylococcus aureus (MRSA) by patients with cystic fibrosis. Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society, vol. 4, no. 1, p. 49-52, 1569-1993 (March 2005). PMID: 15752681

    Nolan G, Moivor P, Levison H, Fleming PC, Corey M, Gold R. Antibiotic prophylaxis in cystic fibrosis: inhaled cephaloridine as an adjunct to oral cloxacillin.
    J Pediatr. 1982 Oct;101(4):626-30. PMID: 6981695

    Ramsey 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. PMID: 1859056

    Rao G, Gaya H, Hodson M. MRSA in Cystic Fibrosis. Journal of Hospital Infection. 1998; 49; 179-191. PMID: 9830589

    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. PMID: 15302726

    Rosenfeld M, Emerson J, Accurso F, et al. Diagnostic accuracy of oropharyngeal cultures in infants and young children with cystic fibrosis. Pediatr Pulmonol 1999; 28:321-328. PMID: 10536062

    Sagel S et al, Impact Of Psuedomonas and Staphylcoccal Infections on Inflammation and Clinical Status in Young Children With Cystic Fibrosis. J Pediatr. 2009 February; 154(2): 183–188. PMID: 18822427

    Saiman L, Siegel J. Cystic Fibrosis Foundation. Infection Prevention and Control Guideline for Cystic Fibrosis: 2013 Update. Infect Control Hosp Epidemiol. August 2014, vol. 35, no. S1. PMID:25025126

    Smyth A, Walters S. Prophylactic antibiotics for cystic fibrosis. Cochrane Database Syst Rev 2014; 3:CD001912. PMID: 25419599

    Solís, A,Brown, D,Hughes, J,Van Saene, H K F,Heaf, D P. Methicillin-resistant Staphylococcus aureus in children with cystic fibrosis: An eradication protocol. Pediatric pulmonology, vol. 36, no. 3, p. 189-195, 8755-6863 (September 2003) PMID: 12910579

    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 (Eds.) Clinical Ecology of Cystic Fibrosis. Elsevier Science Publ. 1993: 129-130.

    Strandvik B, Hollsing A, Möllby R, Granström M. Antistaphylococcal antibodies in cystic fibrosis. Infection. 1990 May-Jun;18(3):170-2. PMID: 2365469

    Thomas SR, Gyi KM, Gaya H, et al. Methicillin Resistant Staphylcoccus aureus: impact at a national cystic fibrosis centre Journal of Hospital Infection 1998; 40:203-209. PMID: 9830591

    UK CF Trust Infection Control Working Group MRSA document 41 section 6.1

    Vanderhelst, Eef,De Wachter, Elke,Willekens, Julie,Piérard, Denis,Vincken, Walter,Malfroot, Anne. Eradication of chronic methicillin-resistant Staphylococcus aureus infection in cystic fibrosis patients. An observational prospective cohort study of 11 patients. Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society, vol. 12, no. 6, p. 662-666 (December 2013) PMID: 23706641

    Approved By

    Improving Antimicrobial Prescribing Group

    Document history

    LHP version 1.0

    Related information

    Appendix 1: Drug doses

    Oral anti-staphylococcal antibiotics

    Drug

    Paediatric dose

    Adult dose

    Notes

    Doxycycline 50mg, 100mg capsules.
    100mg dispersible tablets

    >12years:
    100mg twice daily

    100mg twice daily.

    • Swallow whole with plenty of fluid while sitting or standing. Ensure taken with a full glass of water. Do not take immediately before going to bed.
    • May cause photosensitivity – use sunscreen if exposed to UV light and avoid sun lamps

    Flucloxacillin
    125mg/5ml
    250mg/ 5ml
    250mg, 500mg caps 

    1month-18years:
    25mg/kg  (max. 1 Gram) four times a day.

    1 Gram four times a day

     

     Rifampicin
    100mg/5mL
    150mg capsules
    300mg capsules

     Child 1–11 months
    5–10 mg/kg twice daily.

    Child 1–17 years
    10 mg/kg (max. per dose 600 mg)
     twice daily

     Adult
    600mg twice daily.

    Renal function should be checked before treatment.
    Hepatic function should be checked before treatment. If there is no evidence of liver disease (and pre-treatment liver function is normal), further checks are only necessary if the patient develops fever, malaise, vomiting, jaundice or unexplained deterioration during treatment. However, liver function should be monitored on prolonged therapy.
    Blood counts should be monitored in patients on prolonged therapy.
    Avoid monotherapy to prevent resistance. Interacts with many drugs (including itraconazole, posaconazole, voriconazole) so always check in BNF.
    Can cause red staining of urine, tears and saliva.
    Must be taken on an empty stomach.

     Sodium fusidate/fusidic acid

    250mg/5mL fusidic acid
    250mg tablets sodium fusidate

    Suspension
    Child 1–4 years
    250mg (5mL) three times a day.
    Child 5–11 years
    500mg (10mL) three times a day.
    Child 12–17 years
    750mg (15mL) three times a day.

    Tablets
    Child 12–17 years
    500mg every eight hours, increased to 1 Gram every eight hours for severe infections.

    Adult -suspension
    750mg (15mL) three times a day 

     Adult
    500mg every eight hours, increased to 1 Gram every eight hours, increased dose can be used for severe infections

    Dose equivalence and conversion
    Fusidic acid is incompletely absorbed and doses recommended for suspension are proportionately higher than those for sodium fusidate tablets,
    Avoid in liver disease.
    Avoid monotherapy.

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