Non-tuberculous mycobacterial pulmonary disease, Cystic Fibrosis, Paediatrics (590)

Background

Non-tuberculous mycobacteria (NTM) are environmental organisms with relatively low virulence found in soil and water which are potential pulmonary pathogens increasingly affecting patients with cystic fibrosis (CF). The UK CF Registry suggests a prevalence of ~8% (2015) ³

Not all CF patients will benefit from treatment for NTM. In 2016 the European CF Society and the US CF Foundation published consensus recommendations on the management of NTM in CF. This Guideline is based upon the recommendations made in this paper.

Floto RA, et al. Thorax 2016;71:i1–i22.¹

Screening

The CF Foundation and the ECFS recommend that ¹

cultures for NTM be performed annually in spontaneously expectorating individuals with a stable clinical course. [Recommendation 2]
in the absence of clinical features suggestive of NTM pulmonary disease, individuals who are not capable of spontaneously producing sputum do not require screening cultures for NTM [Recommendation 3]
culture and smears for AFB from sputum should be used for NTM screening.
when being investigated for potential NTM-PD, individuals should discontinue drugs liable to compromise NTM culture (such as macrolides, fluoroquinolones, aminoglycosides, co-trimoxazole, linezolid and doxycycline) prior to sputum sample collection. In the case of azithromycin, intracellular accumulation within phagocytes may require a washout period of 2 weeks or more to allow for drug clearance . For this reason prescribed azithromycin should be stopped for 2 weeks prior to AFB screening. [Recommendation 4]

Diagnosis of CF NTM-PD

Patients are defined as having NTM-Pulmonary Disease ( NTM-PD) if they meet clinical and radiological criteria : ⁴

Positive cultures from two or more separate expectorated sputum samples, or from a single BAL.
Radiological evidence of NTM specific changes on HRCT
Clinical / FEV1 decline despite optimum treatment of other CF organisms/ morbidities

There is considerable overlap between the clinical and radiological presentation of NTM and CF as well as between NTM and infection by other CF pathogens. While some patients with persistent NTM in sputum have declining clinical and radiographic parameters, this is not true of all patients.

In identifying which patients require NTM treatment, it is essential that initially all non-mycobacterial organisms are optimally treated. Starting treatment should be a senior medical consensus decision based on the risks and benefits of treatment for each individual patient, tailored according to the specific species of NTM .³

Treatment of CF NTM-PD

M. ABSCESSUS

Treatment of CF NTM-PD due to M. abscessus includes a 3 week Intensive (Induction) Phase followed by a Continuation Phase until the patient has been clear of the organism for > 12 months ^1;2;3

RHC INDUCTION PHASE

The CF Foundation and the ECFS recommend that the intensive phase should include a daily oral macrolide (preferably azithromycin) in conjunction with 3–12 weeks of intravenous amikacin and one or more of the following: intravenous tigecycline, imipenem or cefoxitin, guided but not dictated by DST. The duration of intensive phase therapy should be determined by the severity of infection, the response to treatment and the tolerability of the regimen. Recommendation 25

DURATION 3 WEEKS ^{1; 2;3}

Drug	Route	Dose	Freq/Day
AMIKACIN ^1;2;3	IV	15mg/kg/dose	X1	Max dose 1500mg; Drug levels
Aim for trough level of <5 mg/l. Peak should be between 20-30 mg/l at 1 hr Levels should be taken pre and one hour post dose after 24 hours of treatment. If within range, pre dose levels should be taken twice weekly for duration of course. Amikacin is ototoxic, consider annual hearing test. U+Es before first dose.
AZITHROMYCIN ^1;2;3	ORAL	10 mg/kg/dose	X1	Max 500mg/day
PLUS ONE OF THE FOLLOWING -SEEK MICROBIOLOGY ADVICE FOR SELECTION
IMIPENEM ^1;2	IV 1 month – 18 yrs	20 mg/kg/dose	X2	Max 1g/day Usually first choice. Best tolerated.
TIGECYCLINE ^1;2;3	IV 1month – 18 yrs	>12 yrs 1 mg/kg/dose	X2	Max 50mg . Give anti-emetics before starting and throughout course.
CEFOXITIN ^1;2;3	IV 3 months – 18 yrs	50mg/kg/dose	X3	Max dose 12g/day Give anti-emetics

RHC CONTINUATION PHASE ^{1; 2 ; 3}

The CF Foundation and the ECFS recommend that the continuation phase should include a daily oral macrolide (preferably azithromycin) and inhaled amikacin, in conjunction with 2–3 of the following additional oral antibiotics: minocycline, clofazimine, moxifloxacin and linezolid, guided but not dictated by DST. [Recommendation 26]

DURATION –Until respiratory samples are clear of M. Abscessus for < 12 months

Drug	Route	Dose	Freq/Day
AMIKACIN ^1;2;3	NEB	500MG	X2
AZITHROMYCIN ^1;2;3	ORAL	10 mg/kg/dose	X1	Max 500mg/day
PLUS 2-3 OFTHE FOLLOWING -SEEK MICROBIOLOGY ADVICE FOR SELECTION
MOXIFLOXACIN ^1;2;3	ORAL	7.5 – 10mg/kg	X1	Max 400mg
MINOCYCLINE ^1;2;3	ORAL	>12yrs 2mg/kg/dose	X1	Max 200mg
CO-TRIMOXAZOLE ³	ORAL	<12yrs 480mg >12yrs 960mg	X2	Monitor FBC 2 weekly
LINEZOLID ²	ORAL	<12yrs 10mg/kg/dose >12yrs 10mg/kg/dose	X3 X1-2	Monitor LFTs; FBC Max 600mg

PATIENTS ON CONTINUATION PHASE M. ABSCESSUS TREATMENT WHO PRESENT WITH RESPIRATORY EXACERBATIONS OR WHO REQUIRE REGULAR IV ANTIBIOTICS COURSES

Following the IV Induction Phase, patients who present with a respiratory exacerbation or who receive regular IV antibiotics courses should be prescribed IV antibiotics which are targeted to the patient’s M abscessus . Additional IV or oral antibiotics may also be required to cover other current CF pathogens.

Where IV Imipenem + Amikacin are prescribed, Nebulised Amikacin is stopped for the duration of the IV course. All other Continuation Phase drugs are continued.

Duration – 2 weeks extended if clinically indicated. ²

M. AVIUM /INTRACELLULARE ( MAC) TREATMENT

Initial therapy should be triple oral therapy as listed below ³ .

Drug	Route	Dose	Freq/Day
RIFAMPICIN	ORAL	10-20mg/kg/dose	X1	Max 600mg Monitor renal and hepatic function and FBC before starting and regularly during treatment
AZITHROMYCIN	ORAL	10mg/kg/dose	X1	Max 500mg
ETHAMBUTOL	ORAL	15mg/kg/dose	X1	Max 1.5g Visual acuity check prior to starting and during treatment . Symptoms may occur before measurable changes can be identified. Patients should be educated about the potential side effects of ethambutol and encouraged to self-report. Monitor renal function prior to starting and regularly during treatment.

Criteria for IV therapy - one or more of ⁴ :

AFB smear positive respiratory tract samples
Radiological evidence of lung cavitation or severe infection
Systemic signs of illness

Patients who are unwell should begin by having 2 weeks intravenous therapy with amikacin and a second intravenous antibiotic (discuss with Microbiologist).

As with M. abscessus, eradication would be considered successful when sputum samples are free of M. Avium for a 1 year period. ^3;4

Last reviewed: 29/08/2017

Next review date: 01/07/2022

Author(s): Dr Jane Wilkinson.

Version: 1

Approved By: Paediatric Drugs & Therapeutics Committee

References

1. US Cystic Fibrosis Foundation and European Cystic Fibrosis Society consensus recommendations for the management of non-tuberculous mycobacteria in individuals with cystic fibrosis Floto RA, et al. Thorax 2016;71:1–22.

2. Nottingham Childrens Hospital Guidelines 2016 – M abscessus

3. Brompton Clinical Guidelines: Care of Children with Cystic Fibrosis 2017

4. An Official ATS/IDSA Statement: Diagnosis,Treatment, and Prevention of Nontuberculous Mycobacterial Diseases 2007 David E. Griffith, Timothy Aksamit, Barbara A. Brown-Elliott, Antonino Catanzaro, Charles Daley, Fred Gordin, Steven M. Holland, Robert Horsburgh, Gwen Huitt, Michael F. Iademarco, Michael Iseman, Kenneth Olivier, Stephen Ruoss, C. Fordham von Reyn, Richard J. Wallace, Jr., and Kevin Winthrop, on behalf of the ATS