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Appendix II - Treatment of Non-Tuberculous Mycobacteria (NTM)

1. Background 

 

Nontuberculous mycobacteria (NTM) are environmental organisms with relatively low virulence, found in soil and water that are potential pulmonary pathogens increasingly affecting patients with cystic fibrosis (CF).  The prevalence of NTM among CF patients, based on a recent large multicentre trial undertaken in the US, where NTM was defined as at least one positive NTM culture, is 13%.   There is some evidence for an association between NTM in CF and older age, poor nutrition, increased frequency of intravenous antibiotic administration, diabetes, treatment with corticosteroids or non-steroidal anti-inflammatory drugs, allergic bronchopulmonary aspergillosis (ABPA), Pseudomonas, Staphylococcus or Aspergillus chronic infection, and deteriorating lung function, but these have not been found consistently.  The commonest NTM species affecting CF patients are Mycobacterium abscessus (M. abscessus) and Mycobacterium avium complex (MAC); the former is the more prevalent among European Centres.  The natural history of NTM disease may vary between species; several case reports suggest that M. abscessus follows a more fulminant course and is associated with a less good outcome. 

 

2. Indication for treatment of NTM

  

The presence of NTM in the sputum of patients with CF poses a significant diagnostic dilemma, as it may represent transient contamination, colonisation or infection.  Not all patients will benefit from treatment for NTM.  The most recent American Thoracic Society (ATS) consensus statement, although not specific to CF, provides useful guidance in evaluating NTM lung disease, and includes:

  1. High resolution computed tomography (HRCT) chest scan,

  2. Three or more sputum samples for acid fast bacilli (AAFB) analysis and

  3. Exclusion of an alternative diagnosis

 

Patients are defined as having NTM disease if they meet clinical and radiological criteria with positive cultures from two or more separate expectorated sputum samples, or from a single bronchial wash/lavage or from a biopsy with a positive culture.   However, there is considerable overlap between the clinical and radiological presentation of NTM and CF per se, 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 maximally treated.  Patients should be under close surveillance and the following flow chart be used to guide treatment.

 

Figure 1:  Flow diagram of a recommended protocol for diagnosing and treating NTM in patients with CF.  (Reproduced from Olivier et al 2003(4))

Figure 1:  Flow diagram of a recommended protocol for diagnosing and treating NTM in patients with CF.  (Reproduced from Olivier et al 2003(4))
 

Treatment should be tailored according to the specific species of NTM, which will be considered separately. 

 

3. Treatment of M. abscessus

 

M. abscessus is universally resistant to standard antituberculous agents and no antibiotic regimen based on in vitro susceptibilities has been shown to produce long-term sputum conversion in patients with this organism. 

 

3.1) Dosage and Administration

 

The regimen in Table 1, based on a 3 week intensive phase followed by a prolonged continuation phase, is recommended as first line therapy.  If patients do not tolerate or have side effects to any of the continuation drugs, alternative agents are suggested in Table 2.  Patients on first line maintenance therapy will be regarded as ‘failing’ treatment or relapsing if they have the following:

  • Increasing sputum and breathlessness

  • Fevers

  • Sweats

  • Rising CRP

  • No response to treatment with non-mycobacterial antibiotics

  • Persistent positivity on sputum AAFB smear

 

In this case they will be given second line intensive and maintenance treatment, as charted in Table 3.

 

Maintenance treatment should include four drugs in total (either nebulised or oral preparation). 

 

If a patient is admitted with an exacerbation during their maintenance phase, then all the maintenance drugs should be continued whilst being treated with the intensive phase drugs (except minocycline/doxycycline which should be stopped if tigecycline is used). 

 

A favourable response to treatment will be defined as when a patient is rendered sputum culture negative on serial samples collected over a period of one year.  At this point the organism will be regarded as eradicated and maintenance therapy may be stopped.

 

Table 1. First line intensive and continuation therapy for M. Abscessus

 

 

Intensive phase therapy (2 weeks)

 

Amikacin

Adults

Children

 

IV 7.5mg/kg bd

IV 30mg/kg od

Meropenem

Adults

Children

 

IV 2g tds

IV 40mg/kg (max 2grams) tds or as per CIVAS dose bands

Cefoxitin

Adults and

Children

 

IV 200mg/kg/day in 3-4 divided doses (max 12 grams/day)

Clarithromycin

Adults

Children

 

500mg bd orally

7.5mg/kg (max 500mg) bd orally

Continuation therapy (>/= 18/12 depending on response)

 

Amikacin

Adults & children >12 yrs

Children over 6 years

 

nebulised 500mg bd

nebulised 250mg bd

Ciprofloxacin

Adults

Children

 

750mg bd orally

20mg/kg(max 750mg)bd orally

Minocycline

Adults and children over 12 years

 

100mg bd orally

 

Clarithromycin

Adults

Children

 

500mg bd orally

7.5mg/kg (max 500mg)bd orally

 

 

  • If the patient has allergies to any of first line IV drugs, add tigecycline.  Tigecycline should be prescribed with regular anti-emetics such as ondansetron.

 

Patients on long term azithromycin should discontinue it if they begin clarithromycin.

 

Table 2. Alternative drugs if patient is unable to tolerate or has side effects to any of the first line oral continuation drugs.

 

 

Unable to tolerate

Drug to consider

Ciprofloxacin

Moxifloxacinø(adults only)

400mg daily orally

Minocycline

Doxycycline^

Adults and children over 12 years

Co-trimoxazole

Adults and children over 12 years

Children ≥6-12 years

100mg bd orally

 

 

960mg bd orally

480mg bd orally

Clarithromycin

Azithromycin#

Adults

Children

500mg od orally

10mg/kg (max 500mg) od orally

 

 

ø Avoid moxifloxacin in patients less than 18 years of age. Can be used in adults if compliance is likely to be poor

^Avoid minocycline, doxycycline and tigecycline in patients less than 12 years of age

#Azithromycin is recommended if compliance is likely to be poor, or if a patient is on concomitant medication which interacts with clarithromycin.


Table 3. Second line intensive and continuation therapy for M. Abscessus

 

 

Intensive phase therapy (2 weeks)

 

Amikacin

Adults

Children

 

IV 7.5mg/kg bd

IV 30mg/kg od

Meropenem

Adults

Children

 

IV 2g tds

IV 40mg/kg tds (or as per CIVAS dose bands)

Tigecycline^

Adults

Children over 12 years

 

IV 50mg bd**

IV 1mg/kg (max 50mg) bd

Clarithromycin

Adults

Children

 

500mg bd orally

7.5mg/kg (max 500mg) bd orally

Continuation therapy (>/= 18/12 depending on response)

 

Amikacin

Adults & children>12 yrs

Children over 6 years

 

nebulised 500mg bd

nebulised 250mg bd

Meropenem

Adults & children > 12 yrs

Children  6 -12 years

 

nebulised 250mg bd

nebulised 125mg bd

Minocycline

Adults and children over 12 years

 

100mg bd orally

Clarithromycin

Adults

Children

 

500mg bd orally

7.5mg/kg (max 500mg) bd orally

 

If the patient is unable to tolerate or has side effects to the oral drugs in the second line continuation therapy regimen, consider the alternative oral agents listed in Table 2.

 

^Avoid minocycline, doxycycline and tigecycline in patients less than 12 years of age

**Begin tigecycline at a dose of 50mg bd or 1mg/kg bd for children. If unable to tolerate this due to vomiting the dose can be reduced to daily or alternate day dosing or 2 days out of 3. Tigecycline should be prescribed with regular IV anti-emetics such as ondansetron.

 

3.2) Counselling - general

 

  • Patients will be counselled on the treatment regimen for M. abscessus, and its potential benefits and adverse effects.  In particular they will be advised that treatment will be a minimum of 18 months and this may not ultimately result in their becoming culture negative for this organism.

  • Patients will be advised that they will receive regular monitoring throughout the duration of treatment – see individual drug monographs for details.

  • Female patients of child bearing age will be advised to use adequate contraception during treatment.

  • Patients will be advised to report side effects of treatment as soon as possible. 

 

3.3) Monitoring - general 

 

  • Full blood count and the patient’s renal and hepatic function must be checked prior to initiating treatment.

  • Renal and liver function should be checked at 12 weekly intervals unless stated otherwise in drug monographs.

  • If LFTs rise to five times the upper limit of normal at any stage, all oral drugs should be stopped. Once LFTs return to normal, each drug should be re-introduced one at a time and LFTs measured daily, as per 1998 BTS TB guidelines.  This may be an indication to begin using two nebulised treatments.  In re-introducing the oral drugs, begin with the one least likely to cause liver abnormalities first. 

 

4. Treatment of Mycobacterium Avium Complex (MAC) 

 

It is recommended that the following treatment regimen is used, which follows the ATS guidelines.

 

4.1) Dosage and Administration

 

Initial therapy should be triple oral therapy as listed in Table 2.  Patients who are unwell should begin by having 2 weeks intravenous therapy with amikacin and a second anti-pseudomonal antibiotic.

 

Table 4. Drug treatment for MAC

 

Drug

Dose

Rifampicin

Adults

 

Children

 

 450mg od (if <50kg) orally

 600mg od (if >50kg) orally

10mg/kg (max 600mg) od orally

Clarithromycin

Adults

Children

Or Azithromycin

Adults

Children

 

500mg bd orally

7.5mg/kg (max 500mg) bd orally

 

500mg od orally

10mg/kg (max 500mg) od orally

Ethambutol

Adults and children

 

15mg/kg (max 1.5gms) od orally

 

4.2) Counselling - general

  • Patients will be counselled on the treatment regimen for MAI, and its potential benefits and adverse effects.  In particular they will be advised that treatment will be a minimum of 18 months or until they have been culture negative for a period of 12 months.

  • Patients will be advised that they will receive regular monitoring throughout the duration of treatment.

  • Female patients of child bearing age will be advised to use adequate contraception during treatment.

  • Patients will be advised to report any potential side effects of treatment as soon as possible. 

 

4.3) Monitoring - general

  • Full blood count and the patient’s renal and hepatic function must be checked prior to initiating treatment.

  • Renal and liver function should be checked at 12 weekly intervals.If LFTs rise to five times the upper limit of normal at any stage, all drugs should be stopped. Once LFTs return to normal, each drug should be re-introduced one at a time and LFTs measured daily, as per 1998 BTS TB guidelines.

 

5. Treatment of other NTM

 

Treatment of other NTM should be guided by the sensitivities of the organism, and should include a combination of 3 drugs.

 

6. References

 

  1. CF Trust.  Antibiotic treatment for cystic fibrosis: report of the UK cystic fibrosis trust antibiotic working group.  3rd Edition.  May 2009

  2. Griffith DE, Aksamit T, Brown-Elliott BA, Catanzaro A, Daley C, Gordin F, et al. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med 2007 Feb 15;175(4):367-416.

  3. Olivier KN, Weber DJ, Wallace RJ, Jr., Faiz AR, Lee JH, Zhang Y, et al. Nontuberculous mycobacteria. I: multicenter prevalence study in cystic fibrosis. Am J Respir Crit Care Med 2003 Mar 15;167(6):828-34.

  4. Olivier KN, Weber DJ, Lee JH, Handler A, Tudor G, Molina PL, et al. Nontuberculous mycobacteria. II: nested-cohort study of impact on cystic fibrosis lung disease. Am J Respir Crit Care Med 2003 Mar 15;167(6):835-40.

  5. Cullen AR, Cannon CL, Mark EJ, Colin AA. Mycobacterium abscessus infection in cystic fibrosis. Colonization or infection? Am J Respir Crit Care Med 2000 Feb;161(2 Pt 1):641-5.

  6. Jeon K, Kwon OJ, Lee NY, Kim BJ, Kook YH, Lee SH et al.  Antibiotic treatment of Mycobacterium abscessus lung disease: a retrospective analysis of 65 patients. Am J Respir Crit Care Med. 2009 Nov 1;180(9):896-902.

  7. British National Formulary.

 

7. Drug monographs

 

7.1 Cefoxitin

 

Counselling

  • No specific counselling required

 

Monitoring

  • No specific monitoring required

  

Cautions

 

  • Reduce dose if GFR < 20ml/minute

 

Contraindications

 

  • Hypersensitivity to cefoxitin. Due to lack of data, cefoxitin should not be used in patients who are allergic to cephalosporins

  • Clinical observation and laboratory data have shown a partial cross-allergy between cefoxitin, other beta-lactams and penicillins.

 

Interactions

 

  • Interference with laboratory examinations: false-positive glucose parameters in urine may occur when using the reduction method. Use specific glucose oxydase tests instead

  • Blood for creatinine levels should not be taken within 2 hours of a cefoxitin dose due to risk of falsely elevated creatinine levels.

 

Adverse effects

 

  • Thrombophlebitis

  • Hypersensitivity reactions

  • Nausea and vomiting

  • Diarrhoea

  • Increases in serum creatinine and urea

  • Transient increases in liver enzymes 

 

7.2 Ethambutol

 

Counselling

 

  • Advise patients to report any visual changes e.g. loss of acuity, colour blindness and restriction of visual fields immediately

 

Monitoring

 

  • Visual acuity should be tested using a Snellen chart before starting treatment

 

Cautions

 

  • Impaired renal function – reduce dose if GFR <20ml/minute

  • Patients unable to understand warnings about visual side-effects

 

Contraindications

 

  • Optic neuritis

  • Poor vision

 

Interactions

 

  • None known

 

Adverse Effects

 

  • Royal College of Ophthalmology document, revised in 2010 suggests that Ethambutol ocular toxicity is extremely rare in children. They recommend that screening for ocular side effects in children under 16 years not be performed. A baseline test however can be performed in children old enough to cooperate, refer to ophthalmologist at Chelsea & Westminster Hospital.

  • Optic neuritis

  • Red/green colour blindness

  • Peripheral neuritis

  • Rash, pruritis, urticaria

  • Thrombocytopenia

 

7.3 Rifampicin

 

Counselling

 

  • Take 30 to 60 minutes before food

  • May colour urine, tears and soft contact lenses red or pink

  • Female patients taking oral contraceptives should use additional  contraceptive methods

 

Monitoring

 

  • Patients with pre-existing liver disease –LFTs should be measured at baseline, weekly for 2 weeks then fortnightly for 6 weeks. If liver function is unchanged, further tests are only necessary if symptoms develop

  • Patients with normal liver function – measure LFTs at baseline then only if symptoms of liver dysfunction develop

 

Cautions

 

  • Hepatic impairment

  • Acute porphyria

 

Contraindications

 

  • Jaundice

  • Hypersensitivity to rifamycins

 

Interactions

 

  • Clarithromycin – reduced plasma concentration of clarithromycin

  • Chloramphenicol – reduced plasma concentration of chloramphenicol

  • Warfarin – reduced anticoagulant effect

  • Rosiglitazone – reduced plasma concentration of rosiglitazone

  • Phenytoin – reduced plasma concentration of phenytoin

  • Fluconazole, itraconazole, posaconazole and voriconazole– reduced plasma concentration of all, avoid using with voriconazole

  • Caspofungin – initially increased then reduced levels of caspofungin, consider using increased dose

  • Diltiazem, nifedipine, nimodipine and verapamil – reduced plasma concentrations

  • Ciclosporin, sirolimus, tacrolimus – reduced plasma concentration, monitor levels

  • Corticosteroids – reduced steroid effect, double steroid dose

  • Oral contraceptives (oestrogen and progestogen containing) – reduced contraceptive effect, use other methods

 

Adverse Effects

 

  • Anorexia, nausea, vomiting, diarrhoea

  • Headache

  • Drowsiness

  • Altered liver function, jaundice

  • Flushing

  • Urticaria and other rashes

 

7.4 Tigecycline

 

Counselling

 

  • Advise patient that tigecycline may cause nausea, which can be severe in some patients. Anti-emetics must be prescribed pre-emptively.

 

Monitoring

 

  • Prothrombin time or other suitable anticoagulation test should be used to monitor patients if tigecycline is administered with anticoagulants.

  • Biliary excretion accounts for 50% of excretion therefore patients with cholestasis should be closely monitored.

 

Cautions

 

  • Cholestasis and hepatic impairment. Reduce dose in severe hepatic impairment

  • Children under 18 years of age due to lack of safety and efficacy data

 

Contraindications

 

  • Hypersensitivity to tigecycline or tetracyclines.

  • Children under 12 years of age due to teeth discolouration

 

Interactions

 

  • Concurrent use of antibiotics with oral contraceptives may render oral contraceptives less effective.

  • Decrease in clearance of warfarin, the mechanism is unknown. This interaction is unlikely to result in significant INR changes. Monitor INR closely

 

Adverse Effects

 

  • Nausea, vomiting, diarrhoea.

  • Abdominal pain, dyspepsia, anorexia

  • Elevated liver function tests, bilirubinaemia

  • Pruritis

  • Rash

  • Headache

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