• Summary
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• Background
• Clinical Diagnosis
• Severity Assessment
• Investigation
• Treatment

Aims

• To improve the diagnosis and management of Mycobacterium abscessus respiratory tract infections in people with cystic fibrosis

Key diagnostic criteria:
Any growth of Mycobacterium abscessus from a respiratory sample from a person with cystic fibrosis. The clinical significance of such growths should be evaluated using American Thoracic Society criteria (Griffith et al, 2007; Daley et al, 2020)

Investigations required

• Microbiology: Sputum or BAL for AAFB smear and culture
• Radiology: CXR, HRCT

Antimicrobial treatment
International treatment guidance has recently been updated (Daley et al, 2020). The development of antimicrobial resistance is a major concern so monotherapy or sub therapeutic doses (e.g. three times a week azithromycin) should be avoided. Regimens should be instigated under the instruction of a CF consultant following discussion with Microbiology. Susceptibility testing should be performed on all new isolates to guide therapy, particularly with respect to amikacin and macrolides [C]

Early Eradication Treatment
All patients should receive an intensive induction course of intravenous and oral antibiotics for two to three weeks. At least three active antimicrobial agents should be used [C]:
Amikacin or tobramycin
Meropenem
Cefoxitin

The inclusion of an oral macrolide, azithromycin* (based on susceptibilities) in this initial regimen is recommended, (daily regimen, not three times per week). Clarithromycin is not recommended due to the interaction with  CFTR modulators drugs. If a patient has an allergy to one of the above IV agents, tigecycline can be substituted (avoid where possible <12 years, use anti-emetics).

Regimens may be adjusted based on susceptibilities following discussion with Microbiology, but these results will often not be available till later in the eradication course.
For Dosages please see Appendix.
Patients should then commence maintenance therapy.

Maintenance Therapy
This should be continued for 12-18 months or longer if necessary. A regimen comprising a total of at least three active drugs (oral and nebulised combination) are recommended from the following options [C]:

Nebulised amikacin or nebulised/inhaled tobramycin
Oral azithromycin daily regimen (not three times/week), Oral moxifloxacin (adults and children >5 years) or ciprofloxacin (children ≤5 years)
Oral minocycline (>12 years) or oral co-trimoxazole (contains trimethoprim and suxamethoxazole) (≤12 years)
If a patient has allergy to one of the above, consider doxycycline (>8 years) or linezolid (limited long course safety data) or clofazimine.
Regimens may be adjusted based on sensitivities following discussion with Microbiology.
In patients who do not isolate Mycobacterium abscessus again following the commencement of the early eradication therapy, and have at least 3 clear AAFB samples over a 6 month period, the maintenance therapy can be discontinued after 6 months and further samples for AAFB should be taken off treatment every two months for the next 12 months. In non-expectorating patients induced sputum or broncho-alveolar lavage for AAFB should be performed at least once, after treatment is discontinued. If Mycobacterium abscessus is regrown then maintenance therapy should be recommenced.

For Dosages please see Appendix.

For exacerbations use three intravenous antibiotics as above and continue the maintenance treatment (except minocycline/doxycycline, which should be discontinued if tigecycline is used). Consider iv tobramycin instead of iv amikacin dependent on susceptibilities.
*If the patient is receiving CFTR corrector therapy it may be preferable to use azithromycin in preference to clarithromycin.

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Mycobacterium abscessus is a fast-growing non-tuberculous mycobacterium (NTM), considered to be the most pathogenic and most resistant to treatment of the NTM affecting people with cystic fibrosis (CF), often associated with an accelerated decline in lung function (Chan 2010, Esther 2010). Like Mycobacterium tuberculosis, NTM are Acid and Alcohol-fast bacilli (AAFB).

The incidence and prevalence of Mycobacterium abscessus pulmonary infection in cystic fibrosis has been increasing over the past decade, with between 3-10% of patients affected (CFF Registry 2010, Roux 2009). Historically it was thought to be acquired from environmental sources, such as water, sewage, and vegetation. However, more recent reports from a lung transplantation clinic (Aitken 2012) and an adult CF Centre (Bryant 2013) suggest that cross-infection may occur between people who are immunosuppressed or have cystic fibrosis, despite apparent careful concordance with standard cystic fibrosis cross-infection precautions (Bryant 2013). Investigation of the outbreak did not demonstrate a common source, other than overlapping in-patient stays or outpatient visits. The authors suggested that transmission may be airborne or via fomites, and subsequently isolation precautions have been increased, with single use clinic rooms, and negative pressure in-patient rooms, though so far effectiveness of these increased precautions has not been proven (Bryant 2013). Infection Prevention recommendations are thus based on expert opinion and not upon evidence.

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Regular sampling of CF patients for Acid and Alcohol Fast Bacilli (AAFB) is recommended, at least annually, or more frequently in patients with respiratory decline, to identify infected patients. However, not all patients will have symptoms, particularly in the early stages of infection. Early identification allows prompt treatment and enhanced isolation procedures.

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If the sample is reported as “Acid and Alcohol-fast bacilli seen” this is referred to as being “Smear positive” and reflects a high bacterial load.

If the sample is reported as “Acid and Alcohol-fast bacilli not seen” this is referred to as “Smear negative”. Although positive smears have been associated with infectivity in cases of Mycobacterium tuberculosis it is not clear in the context of M. abscessus in CF as to whether a negative smear indicates non-infectivity. Indeed, the work of Bryant et al (2013) suggested that smear-negative individuals could still be ‘infectious’. At present all CF patients growing M. abscessus should be considered as potentially infectious and managed accordingly.

M. abscessus is known to cause chronic, lifelong infections in some people with CF but there is no means of identifying from the outset which will go on to develop such infections. Recent data also suggest that following initial culture lung function declines and is not recovered if specific treatment is delayed (Jones et al. 2013). Therefore an attempt may be made to eradicate the organism when the first positive sample is recorded once two repeat samples have been obtained for AAFB microscopy/culture. However, these therapies are potentially toxic so a clinical decision may be taken on a case-by-case basis to await further clinical, radiological and microbiological findings before deciding on treatment [C]

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Routine cough swabs from CF patients are unlikely to demonstrate AAFB infection, even if present. Therefore the laboratory requires sputum (spontaneously expectorated or induced with hypertonic sodium chloride) or broncho-alveolar lavage (BAL) samples. AAFB microscopy, culture, and susceptibilities need to be specifically requested by the clinician.

Try to obtain two repeat samples for confirmation of AAFB prior to eradication regimen.

CT scan changes can be non-specific but granulomas, “tree in bud” and mucous plugging are generally seen.

 In addition to routine monitoring see individual drug profiles for specific baseline monitoring.

Monitoring - general

• Baseline tests required before treatment:
• U&Es including magnesium, phosphate and calcium
• Liver function tests (LFTs)
• Vitamin D level
• Full blood count (FBC) including clotting profile
• Electrocardiogarm (ECG)
• Audiometry

In addition see individual drugs for drug specific baseline monitoring.

• Ongoing monitoring for patients on longterm oral medication:
• FBC every three months until six months. Consider reducing frequency after six months if stable and no changes to medication. If using linezolid please see drug monograph for FBC frequency recommendations.
• If deranged LFTs, clotting baseline and repeat if indicated.
• U&Es monthly
• 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.

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Early Eradication Therapy [C]
All patients should receive an intensive induction course of active intravenous and oral antibiotics for two to three weeks. At least three active antimicrobial agents from the following option should be used:

The inclusion of an oral macrolide*, azithromycin (based on susceptibilities) in this initial regimen is recommended, (daily regimen, not three times per week)

PLUS at least two from the following:
IV Amikacin or tobramycin
IV Meropenem
IV Cefoxitin

If a patient has an allergy to one of the above, tigecycline can be substituted (avoid where possible <12 years, use anti-emetics).
For Dosages please see Appendix.

Patients should then commence maintenance therapy.

*If the patient is receiving CFTR corrector therapy it may be preferable to use azithromycin in preference to clarithromycin.

Maintenance Therapy [C]
This should be continued for 12 to 18 months or longer if necessary. A regimen comprising a total of  at least three active drugs (oral and nebulised combination) are recommended from the following options:

Nebulised amikacin or nebulised/inhaled tobramycin
Oral azithromycin (daily regimen not three times per week)
Oral moxifloxacin (adults and children >5 years) or ciprofloxacin (children ≤5 years)
Oral minocycline (>12 years) or oral Co-trimoxazole (contains trimethoprim and suxamethoxazole) (≤12 years)

If a patient has allergy to one of the above, consider doxycycline (>8 years) or linezolid (limited long course safety data) or clofazimine.

In patients who do not isolate Mycobacterium abscessus again following the commencement of the early eradication therapy, and have at least three clear AAFB samples over a six month period, the maintenance therapy can be discontinued after six months and further samples for AAFB should be taken off treatment every two months for the next 12 months. In non-expectorating patients, induced sputum or broncho-alveolar lavage for AAFB should be performed at least once, once treatment is discontinued. If Mycobacterium abscessus is regrown then maintenance therapy should be recommenced.

Regimens may be adjusted based on sensitivities following discussion with Microbiology.
For Dosages please see Appendix.

*If the patient is receiving CFTR corrector therapy it may be preferable to use azithromycin in preference to clarithromycin
Infective Exacerbations [C]
For exacerbations use three intravenous antibiotics as listed under ‘Early Eradication Therapy’ above and continue the maintenance treatment (except minocycline/doxycycline, which should be discontinued if tigecycline is used).

Assessment of Response [C]
Monitor response in terms of reduction in cough/sputum production, improvement in lung function, and sputum samples for AAFB every four to eight weeks during therapy.

Drug Monitoring
Hearing (Audiology) should be checked as amikacin or tobramycin (intravenous or nebulised) is commenced, and annually thereafter and sooner if there are any concerns regarding hearing loss.
Full blood count, renal, and liver function must be checked prior to starting treatment and then at least 3 monthly whilst on treatment (unless otherwise indicated in specific drug monographs).

ECG must be checked prior to treatment.
If liver function tests become elevated to five times normal at any stage, all oral drugs should be stopped until liver function normalises, then reintroduced one at a time with regular monitoring as per 1998 British Thoracic Society TB Guidelines, starting with drugs least likely to cause liver problems first.

Counselling of parents/patients
Patients and parents should be counselled that this organism is often associated with lung function decline, and so far has been difficult to eradicate. Treatment is thus intensive and prolonged. Some of the drugs used have potential side effects, thus there will be careful monitoring, particularly of hearing and liver function. Females of child bearing age should take adequate contraceptive precautions during therapy. Patients or parents should be advised to report any suspected side effects of treatment promptly.

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