Methicillin resistant Staphylococcus aureus ( S.aureus ) on a Respiratory Sample from a Patient with Cystic Fibrosis - The Management of

Publication: 27/02/2017  --
Last review: 04/02/2020  
Next review: 04/02/2023  
Clinical Guideline
CURRENT 
ID: 4923 
Approved By: Improving Antimicrobial Prescribing Group 
Copyright© Leeds Teaching Hospitals NHS Trust 2020  

 

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 Methicillin resistant Staphylococcus aureus (S.aureus) on a Respiratory Sample from a Patient with Cystic Fibrosis

Summary
Methicillin resistant Staphylococcus aureus ( S.aureus ) on a Respiratory Sample from a Patient with Cystic Fibrosis

Methicillin Resistant Staphylococcal Aureus (MRSA) positive cough swab requires initial management with one month of rifampicin and co-trimoxazole with skin decontamination. The evidence base and alternative approaches are discussed.

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Background

What is MRSA?

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).

Since 1960 ~80% of S. aureus isolates have been resistant to penicillin. Two years after the introduction of methicillin in 1959, S. aureus strains developed resistance through the acquisition of the mecA gene  (MRSA). Although methicillin was superseded by better tolerated compounds, such as flucloxacillin, the mechanism of resistance affected all these agents.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.

Early MRSA isolates were only associated with hospital acquisition (HA). However, during the 1990s, community associated (CA) MRSA emerged. Antibiotic use, surgery and indwelling intravenous access devices have been identified as independent risk factors1,2 . Worse pulmonary status is also a risk factor for MRSA acquisition3,4 .

Why is it important?

Staphylococcus aureus is a respiratory pathogen. CF patients infected with MRSA have lower lung function than those with methicillin sensitive Staphylococcus aureus (MSSA) as the only pathogen. Additionally MRSA positive patients had an increased rate of hospitalisation and oral, inhaled and intravenous antibiotics5,6. [B]

Patients with chronic MRSA are treated more intensely than age, gender and P. aeruginosa matched MSSA-positive patients. (Muhlebach, 2011, PMID: 21420912). [B]

MRSA has other important implications for patients with CF. In the healthcare environment strict isolation measures have to be followed for patients infected with MRSA. These measures lead to patient isolation with negative psychological impact and higher costs5. [B]

Lastly, chronic MRSA infection in patients with CF may be transmitted to other CF and non-CF patients. The potential for spread to and from CF patients in- or outside the healthcare setting makes this a public health concern. Increasingly, spread from the hospital to the community and vice versa has been described. In fact, certain observations and models predict that community associated infections entering the hospital may become the predominant source of MRSA in hospitals, thus advocating eradication in such at risk patients5. [B]

How common is Methicillin resistant 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 age7. Currently less than 3% of the population of people with cystic fibrosis have appositive culture for MRSA (CF registry data from the CF registry report 2015).

Is it serious?

In patients with cystic fibrosis, MRSA is associated with lower lung function, increased rate of hospitalization, and increased use of antibiotics. In addition there is the risk of spreading to other healthcare users and healthcare professionals.

Can it be prevented?

Given the association of MRSA with antibiotics exposure and hospital admissions, we aim to minimise repeated and prolonged hospital admissions by optimal use of home intravenous antibiotic administration, minimal invasive treatment and avoidance of broad spectrum antibiotic administration8,9. [B] 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 isolation1. The importance of hand washing and of adherence to basic good hygiene, especially with invasive procedures, must be regularly and frequently emphasised10. A policy for the handling and cleaning of equipment should be agreed with the hospital infection control team. [C]

Second hand smoke (SHS) exposure has been associated with increased incidence of MRSA in infants with CF11.  . [B]

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Clinical Diagnosis

What are the symptoms?

There is no way of differentiating lower respiratory tract infection with MRSA from any other infection. Indeed, infection may be asymptomatic. MRSA is associated with more symptoms and increased use of CF therapies6  . [B]

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 infection12. [B]

Ramsey et al 13 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 performed at every routine clinic visit. Ideally sputum should be sent for culture, but many children are unable to expectorate sputum on demand. Where possible a sputum sample should be sent.

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 airways14. Comparison of cultures from the throat and bronchial tubes of the same patients supports this finding.

Ramsey et al13 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

MRSA Eradication

Currently, there are no conclusive studies demonstrating an effective and safe treatment protocol for MRSA respiratory infection in CF15. A recent Cochrane review did not identify any randomised trials which would allow us to make any evidence-based recommendations. However, the results of several non-randomised studies would suggest that, once isolated, the eradication of MRSA is possible16, and this would be our experience in Leeds. However, there are three ongoing clinical trials which may yield useful results in the future. Recently we have started using a modified version of the protocol used in the STAR-too trial.

Different MRSA eradication schedules and outcomes:

Below are descriptions of studies that have been published. They are meant to illustrate the variety of schedules to demonstrate that that there is no definitive schedule for MRSA eradication:

Solis et al 2003; PMID: 1291057917

Treatment with life-long cefradine rather than flucloxacillin, topical application of oral and nebulised vancomycin for 5 days to clear the carriage of MRSA; and  a strict anti-staphylococcal hygiene program, including hand-washing and device policy. Fifteen children with CF (11 boys, with median age 117 months) positive for MRSA were enrolled. Of 15 children identified, only 12 (18 episodes of MRSA colonisation) were treated according to protocol. Median age of MRSA acquisition was 73 months (interquartile range, 43-134 months). In 7 patients (55%), MRSA was eradicated. Of a total of 18 MRSA episodes, the protocol was successful in 10 episodes.

Garske et al 2003; PMID: 1500366918

Adult CF patients (six male, one female) with chronic MRSA infection were treated for six months with rifampicin and sodium fusidate. Outcome data were examined for six months before treatment, on treatment and after treatment. The patients had a mean age of 29.3 (standard deviation=6.3) years and FEV1 of 36.1% (standard deviation=12.7) predicted. The mean duration of MRSA isolation was 31 months. MRSA isolates identified in these patients was of the same lineage as the known endemic strain at the hospital when assessed by pulsed-field gel electrophoresis. Five of the seven had no evidence of MRSA during and for at least six months after rifampicin and sodium fusidate.

Macfarlane et al 2007; PMID: 1717842719

Of the 17 paediatric patients treated during the five years of the study, eight (47%) were successfully decolonised following one five-day course of oral rifampicin and sodium fusidate. The success rate increased to 12 (71%) patients after a second five-day oral treatment course in the 11 patients who remained culture positive at the end of the first treatment cycle. In a further four patients, clearance was achieved with a course of intravenous teicoplanin, increasing the decolonisation rate to 16 of 17 patients (94%).

Vanderhelst et al 2013; PMID: 2370664120

Eleven CF patients, (median age: 9 years (range 1-43); median FEV1: 91%pred (95%CI 74%-100%pred)) who were chronically infected with MRSA, were treated daily for six months with rifampicin and sodium fusidate orally. This study did not include a patient control group. Two patients had to switch to an alternative schedule, using rifampicin and clindamycin, due to the resistance pattern of MRSA. Topical decolonisation measures were applied to all patients and included mupirocin-containing nasal ointment in both nostrils three times daily for five days and chlorhexidine hair and body wash once daily for five days. Microbiological eradication was achieved in all patients at the end of the six-month eradication protocol, even when significant time (range 18 months to 9 years) had elapsed since initial isolation.

The Results of the American STAR-too trial (not yet published, but presented at the ECFS conference 2015) showed that oral co-trimoxazole (or minocycline) plus rifampicin and chlorhexidine mouthwash for 2 weeks, nasal mupiricin and chlorhexidine body wipes for 5 days, and environmental decontamination for 21 days increased the success of clearance of MRSA from 22% to 81% at day 2820.

Suggested treatment protocol for MRSA positive sputum:

If the patient is on flucloxacillin prophylaxis is should be stopped. The patient should commence four weeks of rifampicin and co-trimoxazole (alternatives, depending on resistance and tolerability/side-effects, include doxycycline, clindamycin, linezolid and sodium fusidate), with Trust policy on skin decontamination[Please insert link]: nasal mupirocin 2% (three times a day for 5 days or if resistant, Naseptin® four times a day for 10 days ); bathe daily for 5 days in chlorhexidine 4%. [D]

The sputum sample should then be repeated. If the patient is unable to expectorate an induced sputum should be sent as soon as possible.

If MRSA is still present, repeat above but with the addition of nebulised vancomycin (child: 5mg/kg (max. 250mg) bd;  adult: 250mg bd) for five days [D]. See the CF pharmacopia for more information on dosing.

If MRSA is still present or the patient is unwell, treat with IV antibiotics as per the patient’s normal schedule and include IV teicoplanin as additional. [D]

Eradication is defined as 3 negative samples, each taken at least 3 days apart (as per the LHP MRSA Guideline). Ideally these should be sputum samples, but if the child is not expectorating then 2 cough swabs and one induced sputum.

Once MRSA is eradicated, if the patient had been on flucloxacillin prophylaxis it should be restarted. [D]  

An MRSA screen should include; throat, nose, axilla, and groin.

Note, this will involve the following changes to current practice:

• Co-trimoxazole will be used instead of sodium fusidate because it is a more convenient formulation and better tolerated. It was used in the STAR-too trial.

• Not using nebulised vancomycin first line because there is limited evidence and it is reported to be poorly tolerated.

• We are using a stepwise approach because no eradication programme is 100% effective.

• We will be restarting flucloxacillin much sooner because it is not selective for MRSA.

• Increased frequency of induced sputum by physiotherapists.

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Provenance

Record: 4923
Objective:

Aims
To improve the diagnosis and management of Methicillin Resistant Staphylococcal Aureus (MRSA) infection in patients with cystic fibrosis.

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

Clinical condition:

Cystic fibrosis; MRSA

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

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

2. 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

3. 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

4. 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

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

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

7.  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

8. 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

9. 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

10. 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

11. 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

12. 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

13. 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

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

15. 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

16. 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

17. 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

18. 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

19. 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

20. Goss C, Thompson V, Popowitch E. Efficacy of a protocol for eradication of newly acquired MRSA: Results of the STAR-too trial. Journal of Cystic Fibrosis. June 2015. Volume 14, Supplement 1, Page S3

See also

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

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Approved By

Improving Antimicrobial Prescribing Group

Document history

LHP version 1.0

Related information

Appendix 1

Meticillin-resistant Staphylococcus aureus (MRSA) doses for Cystic Fibrosis

First line therapy 

Drug

Paediatric dose

Adult dose

Notes

 Co-trimoxazole
120mg/5mL
240mg/5mL
480mg tablets

Child 6 months–5 years
240mg twice daily, alternatively 24 mg/kg twice daily.

Child 6–11 years
480mg twice daily, alternatively 24 mg/kg twice daily.

Child 12–17 years
960mg twice daily.

 Adult
960mg twice daily

Co-trimoxazole is associated with rare but serious side effects. Discontinue immediately if blood disorders (including leucopenia, thrombocytopenia, megaloblastic anaemia, eosinophilia) or rash (including Stevens-Johnson syndrome, toxic epidermal necrolysis, photosensitivity) develop.

 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.

Mupirocin Nasal (Bactoban®)

Apply THREE times a day for FIVE days.

Check results to ensure MRSA is sensitive to mupirocin. If resistant change to Naseptin® (see below)

 Chlorhexidine 4% body wash

Use DAILY for  five days

 

 

Alternative medications, where the above are unsuitable

 Clindamycin
150mg capsules
75mg/5mL suspension (ULM)

 

Child
3–6 mg/kg 4 times a day (max. per dose 450 mg).

 

 Adult
150–300 mg every 6 hours; increased if necessary up to 450 mg every 6 hours if required, increased dose used in severe infection.

Clindamycin has been associated with antibiotic-associated colitis, which may be fatal. Although antibiotic-associated colitis can occur with most antibacterials, it occurs more frequently with clindamycin. Patients should therefore discontinue treatment immediately if diarrhoea develops.

 Doxycycline
50mg capsules
100mg capsules
100mg dispersible tablets

Not suitable/licensed for use in children under 12 years.
Child 12–17 years
100mg twice daily

 Adult
100mg twice daily.

Capsules and tablets should be swallowed whole with plenty of fluid, while sitting or standing. Capsules should be taken during meals.

May cause photosensitivity – use sunscreen if exposed to UV light and avoid sun lamps

 Linezolid

100mg/5mL suspension
600mg tablets

 Child 1 month–11 years
10 mg/kg every eight hours (max. per dose 600 mg).

Child 12–17 years
600 mg every twelve hours.

Not licensed for use in children, although is approved for use with LTHT.

 

 Adult
600mg every twelve hours (maximum duration of treatment 28 days).

 

Monitor full blood count (including platelet count) weekly.

CHM advice (optic neuropathy)
Severe optic neuropathy may occur rarely, particularly if linezolid is used for longer than 28 days. The CHM recommends that:

  • patients should be warned to report symptoms of visual impairment (including blurred vision, visual field defect, changes in visual acuity and colour vision) immediately;
  • patients experiencing new visual symptoms (regardless of treatment duration) should be evaluated promptly, and referred to an ophthalmologist if necessary;
  • visual function should be monitored regularly if treatment is required for longer than 28 days.

Blood disorders
Haematopoietic disorders (including thrombocytopenia, anaemia, leucopenia, and pancytopenia) have been reported in patients receiving linezolid. It is recommended that full blood counts are monitored weekly. Close monitoring is recommended in patients who:

  • receive treatment for more than 10–14 days;
  • have pre-existing myelosuppression;
  • are receiving drugs that may have adverse effects on haemoglobin, blood counts, or platelet function;
  • have severe renal impairment.

If significant myelosuppression occurs, treatment should be stopped unless it is considered essential, in which case intensive monitoring of blood counts and appropriate management should be implemented.

 Naseptin®

Apply to the nasal carriage FOUR times a day for TEN days.

To use in cases of mupirocin resistance or intolerance.

 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 g every eight hours for severe infections.

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

Adult
500mg every eight hours, increased to 1g 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.

Teicoplanin

1month-11years:
10mg/kg (max: 400mg), 12 hourly for first 3 doses then 10mg/kg once daily.

12years-Adult:
400mg 12 hourly for first three doses, then once daily.

400mg 12 hourly for first three doses, then once daily. 

Drug levels can be used to optimise treatment.  For MRSA, trough before 4th or 5th dose, needs to be >20 mg/L.

Doses may be increased above 400mg if levels suggest it is necessary. 

 Vancomycin
nebulised

 Child
5mg/kg (max: 250mg) twice daily

 Adult
250mg twice daily

Use water for injection for reconstitution and make up to 4mLs with water for injection. i.e. for 250mg dose reconstitute a 500mg vial with 8mLs water for infection and use 4mL.

Administer a bronchodilator beforehand, to minimise bronchospasm.

Appendix 2

LTHT MRSA Policy

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