SCOTTISH PAEDIATRIC CYSTIC FIBROSIS MCN Pseudomonas aeruginosa eradication guideline Date Created: 27 th June 2013 Date Approved by Steering Group: 30 th May 2014 Date of Review: 31 st May 2016 Lead Author: Dr RJ Brooker Co-authors: Dr D O Brien Dr A Fall Miss K Sharpe Miss K Fok Contents 1. Definitions 2. Background 3. Microbiological surveillance a. Infection prevention b. Acquisition rates 4. Antibiotic prophylaxis 5. Antibiotic Eradication Therapy (AET) a. Time to treatment b. Antibiotic strategy c. Eradication failure d. The Artimino algorithm e. Minimum AET 6. Adjunct therapy a. Physiotherapy b. Nebuliser choice c. Mucolytic therapy d. Anti-inflammatory therapy 7. Hospital v Home treatment
8. Eradication of mucoid P. aeruginosa 9. Patient literature 10. References 1. Definitions Surveillance cultures : Periodic sampling of sputum, pharyngeal/cough swabs or broncho-alveolar lavage for the purpose of identifying the presence of a CF pathogen. Surveillance cultures are usually performed when a patient is stable. Colonisation: The presence of pathogenic bacteria in the upper or lower airways in the absence of an inflammatory response Infection: The presence of pathogenic bacteria in the upper or lower airways associated with an inflammatory response Spontaneous clearance: Subsequent culture of the CF upper and lower airways that is culture negative when the previous cultures had been positive Leeds criteria : Free of infection: P.aeruginosa isolated previously but not for more than 12 months Never infected: P.aeruginosa never isolated Chronic infection: P.aeruginosa isolated in more than 50% of months when sputum, cough or throat swab taken in the previous 12 month period Intermittent infection: P.aeruginosa isolated in 50% or less months when sputum, cough or throat swab taken in the previous 12 month period Successful eradication: definitions of successful clearance of P.aeruginosa following AET vary and it is possible that culture negativity does not necessarily mean that the pathogen was eradicated. However, for pragmatic purposes a definition of at least 3 culture negative sputum, cough or throat swabs in the 6 month period from the end of the eradication period is proposed as indicating successful AET. Failure of eradication: Subsequent cultures are positive for the pathogen, within 6 months, following treatment with antibiotics Recurrence/re-infection: Cultures of the upper or lower airways are again positive following a 6 month period when the patient was free of the pathogen following successful eradication AET: Antibiotic Eradication Therapy TIS: Tobramycin Inhalation Solution
2. Background P. aeruginosa may transiently infect the airways (range ~10-50%) indicating that some CF patients can spontaneously clear the pathogen. However, the pathogen will persist or recur and eventually develop into a chronic infection. There is increasing evidence that chronic infection, and intermittent infection, is associated with worse long-term outcome and survival. The Leeds criteria classifies patients into 4 groups (chronic, intermittent, free and never infected) and appears to correlate with clinical scores but requires frequent microbiological surveillance. There is sufficient evidence that eradication of early infection, and prevention of chronic infection, is associated with clinical benefit e.g. decline in lung function is less in those that received AET compared to chronically infected patients ( FEV1/year: -1.65% vs. -4.74%). Consequently it is accepted practice that AET is offered to all patients who have a new isolate of P. aeruginosa. A survey of the Scottish Paediatric CF clinics and centres (and 1 adult centre) shows that first line AET for patients with no symptoms or mild illness is a minimum of 3 weeks oral ciprofloxacin plus 3 months nebulised colistimethate sodium. Units in the West of Scotland use 6 months colistimethate sodium and one unit in the North uses 3 months ciprofloxacin as standard. Those units, who originally start with a short course, extend the length of ciprofloxacin treatment when early microbiological surveillance indicates failure to eradicate. No unit is currently using Tobramycin Inhalation Solution (TIS) alone, although there is evidence that this is as effective as standard therapy. Trend analysis from the CF Registry suggests that there has been a reduction in the P. aeruginosa colonisation rates from 2007-2011. This guideline is based on the European CF Consensus study group (1), the recent review article by Schelstraete et al (2) and the CF Trust UK antibiotic working group report (3). 3. Microbiological surveillance P. aeruginosa infection of CF airways may not cause symptoms and therefore routine surveillance cultures should be performed at least every 3 months. Following AET a subsequent culture should be obtained 2-4 weeks after completion of the antibiotics. Routine serological testing is not recommended. Antibiotic susceptibility testing should be considered for: a. Surveillance of resistant strains b. New isolates c. When a change of therapy is proposed because of a lack of response to treatment
There is no evidence that bacterial quantification is clinically useful at this time, nor identification of mucoid status. Currently culture-independent diagnostic methods do not offer clinical utility. Following the identification of any new isolate of P. aeruginosa it is recommended that genomic fingerprinting is performed in order that more transmissible strains are identified early (11) to alert the CF team to review their infection control measures. Genomic fingerprinting could also be considered following completion of AET to see if it is a true failure or the unlucky situation of a new environmental isolate. a. Infection prevention Rigorous AET and patient segregation by microbiological status appears to be effective in improving P. aeruginosa colonisation rates. All clinics and centres should have regular infection control inspections to ensure cross-contamination is minimised. Patients should be segregated both in the out-patient clinic and during hospital admission (preferably nursed in single occupancy cubicles). b. Acquisition rates In 2 centres in the USA annual acquisition rates for P. aeruginosa varied between 0.16 and 0.533/patient/year. Only 1 paediatric centre in Scotland has acquisition data showing an overall rate of 0.193/patient/year with an improving trend from 2007-2010. It is recommended that all centres and clinics monitor their annual acquisition rates. 4. Antibiotic prophylaxis There is no evidence to support the use of prophylactic, pre-colonisation, antipseudomonal antibiotics in CF patients. 5. Antibiotic eradication therapy a. Time to treatment The window of opportunity for successful eradication is not well defined and may be up to 12 weeks. The CF Trust recommends commencing treatment within 14 days of initial P. aeruginosa detection, which is an achievable target. b. AET strategy Whereas the success rates in different AET studies range between 63-100% (mean 81.2%), the optimal strategy, e.g. 3 step regimen of colistimethate sodium and ciprofloxacin, for antibiotic therapy for eradication of P. aeruginosa is not known. The ELITE trial (5) using TIS alone showed successful eradication in over 90% of patients at 1 month, following either 1 or 2 months treatment, with between 66 and 69% still free of infection at 2 years follow-up. Comparable results have been shown with 1 month TIS to 3 months inhaled colistimethate
sodium/oral ciprofloxacin (8), and inhaled colistimethate sodium/oral ciprofloxacin to inhaled tobramycin/oral ciprofloxacin (7). The EPIC trial suggests that oral ciprofloxacin confers no advantage over TIS alone (6). Intravenous antibiotics have been used in some AET protocols and, together with audit data from one centre in Scotland, do not show superiority over oral/inhaled therapy. However, factors pertinent to the patient and/or severity of symptoms may indicate that intravenous antibiotics will have the best chance of successful eradication. c. Eradication failure The reasons why AET is not successful will include bacterial and host factors, such as characteristics of the airway that reduces aerosol distribution and patient adherence to the treatment regimen. If eradication is not successful after the first cycle of AET there is evidence that a second cycle of treatment has a low rate of treatment failure. Patients who have failed a second attempt may be considered for a trial of intravenous antibiotics. d. The Artimino algorithm The following algorithm is suggested as a care stream for patients undergoing AET: The Artimino Algorithm e. Minimum Antibiotic Eradication Therapy (See Scottish Paediatric CF antibiotic formulary for dosing) Non-intravenous therapy:
1. Oral ciprofloxacin for 14 days AND nebulised colistimethate sodium (or continuous tobramycin), for 3 months OR 2. Nebulised tobramycin for 28 days Intravenous therapy: 1. Intravenous ceftazidime (or meropenem) AND tobramycin for 10 days FOLLOWED BY 2. Nebulised colistimethate sodium and oral ciprofloxacin as per nonintravenous therapy above 6. Adjunct therapy a. Physiotherapy: Airway clearance techniques are a key component of the physiotherapy management in cystic fibrosis and should be optimized by regular review by a specialist physiotherapist. Patients with a new growth of P. aeruginosa should be reviewed by the specialist physiotherapist to discuss and optimize their airway clearance routine (refer to the ACPCF guideline: Standards of Care and Good Clinical Practice for Physiotherapy Management of Cystic Fibrosis). This may include a change to their current technique or change in frequency of routine airway clearance. The physiotherapist should review general hygiene advice during airway clearance including care of equipment in accordance with the manufacturers guidelines. b. Nebuliser choice: research studies have used jet nebulisers to deliver aerosolized antibiotics in AET. There are no studies that compare the efficacy of the nebulisers, using oscillating (e-flow) or vibrating mesh (i-neb) technology, that are in widespread use throughout Scotland. Theoretically improved delivery time and aerosol size could increase P. aeruginosa eradication by improved adherence to treatment and better airway penetration that would favour the newer nebulisers. c. Mucolytics: there are no published studies to show that the addition of mucolytics, in particular Dornase Alpha, increases the efficacy of eradication of P. aeruginosa although, theoretically, improved clearance of airway secretions could allow better airway penetration by aerosolized antibiotics. d. Anti-inflammatory therapy: there are no published studies to show improved eradication rates with adjunct corticosteroids or macrolide antibiotics. 7. Hospital verses home treatment There are no published studies on eradication rates if AET is given at home or in hospital.
8. Eradication of mucoid P. aeruginosa There is the view that once P. aeruginosa has evolved into a mucoid strain eradication from the lower airway in not possible. Recent evidence has challenged this view and two retrospective studies (9,10) have suggested that, after the initial isolation of a mucoid P.aeruginosa, eradication is possible in ~60-70% of patients treated with a variety of AETs. 9. Patient literature See appendix 10. References 1. Doring et al for the Consensus Study Group. Treatment of lung infection in patients with CF: Current and future strategies. J Cyst Fibros 2012; 11: 461-479 2. Schelstraete et al. Eradication therapy for P. aeruginosa colonization episodes in CF patients not chronically colonized by P. aeruginosa. J Cyst Fibros 2013; 12: 1-8 3. CF Trust Report of the UK CF Trust antibiotic working group. May 2009 4. Langton and Smyth. Antibiotic strategies for eradicating P. aeruginosa in people with CF. Cochrane Database Systematic Reviews 2009; 7(4): CD004197 5. Ratjen et al. Treatment of early P. aeruginosa infection in patients with CF: the ELITE trial. Thorax 2010; 65: 286-291 6. Treggiari et al for the Early Pseudomonas Infection Control investigators. Comparative efficacy and safety of randomized regimens to treat early P. aeruginosa infection in children with CF. Arch Pediatr Adolesc Med 2011; 165(9): 847-856 7. Taccetti et al. Early antibiotic treatment of P. aeruginosa eradication in patients with CF: a randomized multicentre study comparing two different protocols. Thorax 2012; 67: 853-859 8. Proesmans et al. Comparison of two treatment regimens for eradication of P. aeruginosa infection in children with CF. J Cyst Fibros 2013; 12: 29-34 9. McPherson et al. Can mucoid P. aeruginosa be eradicated in children with CF. Pediatr pulmonol 2010; 45: 566-8 10. Troxler et al. Clearance of initial mucoid P. aeruginosa in patients with CF. Pediatr pulmonol 2-12; 46: 1113-1122 11. CF Trust Consensus Document: P. aeruginosa in people with CF. Suggestions for prevention and infection control. Second edition November 2004. Existing protocols/guidelines consulted: Royal Aberdeen Children s Hospital (also supplied audit data) Tayside Children s Hospital Wishaw Hospital Forth Valley Royal Hospital RHSC (Edinburgh) RHSC (Glasgow) Gartnavel Hospital Royal Brompton Hospital St James and Seacroft University Hospitals 2008