Table XVI.

Drugs used in non-tuberculous mycobacteria (NTM) disease, monitoring and adverse drug reactions

Drug	Dosing	Monitoring	Serious adverse effects
Clarithromycin (oral) or iv infusion (500 mg twice daily through a large proximal vein if not tolerated orally)	500 mg twice daily or 500 mg PO twice daily TIW	Monitor QTc prolongation if administered with drugs having potential to prolong QTc, audiograms at baseline, one month, and then every three months; inhibits hepatic metabolism of several agents including rifabutin and some protease inhibitors. Drug levels need not be monitored. Avoid concomitant use of ivabradine, ticagrelor, decrease dose of rifabutin if co-administered with clarithromycin. Increases plasma concentrations of antileptics, phenytoin, carbamazepine (monitor plasma levels), ciclosporin, linezolid (monitor drug level), sirolimus and tacrolimus; coumarins: warfarin; theophylline	GI disturbances including taste perversion, headache, QTc prolongation especially when co-administered with drugs that have the potential to prolong the QT interval, ototoxicity, dermatological: (toxic epidermal necrolysis and Stevens-Johnson syndrome) hepatic dysfunction, Clostridium difficile-induced diarrhoea.
Azithromycin (oral)	250-500 mg daily	Monitor QTc prolongation if administered with other drugs having potential to prolong QTc; audiogram at baseline, one month, and then every three months	GI disturbances, QTc prolongation when administered with drugs having potential to increase QTc, ototoxicity, hepatitis
Ethambutol (oral)	15 mg/kg per day or 25- 30 mg/kg thrice weekly. Target level 2-6 mg/l; drug levels routinely not measured; only in special situations like renal impairment and poor treatment response.	Crcl ≥30 ml/min: no dose adjustment; Crcl <30 ml/min: 15-25 mg thrice weekly; baseline eye examination and monthly visual acuity tests/colour discrimination tests (Ishihara). Baseline and every three months. Funduscopic monitoring.	Dose dependent optic (retrobulbar) neuropathy (>30 mg/kg/day or 15-25 mg/kg in CKD); generally, reverses on prompt discontinuation; red-green colour blindness; risk increases with concurrent use of isoniazid; hyperuricemia.
			Rare: interstitial nephritis, cholestatic jaundice, neutropenia and thrombocytopenia, reversible cutaneous hypersensitivity disappearing on desensitisation
Rifampicin (oral)	<50 kg: 450 mg once daily or >50 kg: 600 mg once daily (should be taken 30-60 min before food or 2 h after food)	Monitor LFTs, including ALT, AST, alkaline phosphatase, and bilirubin levels	Red/orange discoloration of secretions, GI disturbances, hepatitis, hypersensitivity (fever, rash)
Rifabutin (oral)	Routinely 300 mg daily, rarely 450 mg; may administer thrice weekly	Monitor LFTs, including ALT, AST, alkaline phosphatase, and bilirubin levels	Red/orange discolouration of secretions; GI disturbances, loss of taste, hypersensitivity, polyarthralgia, polymyalgia, anterior uveitis and leukopenia (in combination with clarithromycin)
Isoniazid (oral)	5 mg/kg per day (maximum of 300 mg)	Monitor LFTs including ALT and AST levels in patients at risk	Hypersensitivity reaction, hepatitis, peripheral neuropathy, haematological abnormalities (agranulocytosis, megaloblastic anaemia, thrombocytopenia), psychosis (rare) drug induced lupus (rare), arthralgia, rhabdomyolysis
Amikacin (intravenous)	15 mg/kg once daily for 5 days (Monday-Friday) or 15-25 mg thrice weekly. Consider starting with 8-10 mg/kg per day for the elderly and patient with mild renal impairment and titrate upward to goal Cmax.	Target Cmax 25-35 μg/ml for daily dose and >35-45 μg/ml with thrice weekly administration. Audiometry should be done at baseline and subsequently monthly. A final audiometry should be done 2 months after the final dose. Monitor renal functions weekly in first month, twice weekly in second month and fortnightly thereafter. Preferably avoid or dose adjustment required in CKD.	Nephrotoxicity: Higher chances in old age and with prolonged use. Ototoxicity: auditory>vestibular; ototoxicity includes hearing loss, loss of balance and tinnitus. Hearing loss occurs first and is detected by audiometric testing. Ototoxicity in audiogram is defined as 20 dB loss from baseline at any one test frequency or a 10 dB loss at any two adjacent test frequencies. Hearing loss is usually permanent. Vertigo, loss of balance and tinnitus.
Amikacin (inhalation) Arikayce (liposome inhalation)	250 mg/ml solution diluted with 3 ml of 0.9% sodium chloride daily, can be increased to 500 mg once daily depending on patient’s tolerance. In patient with reactive airways disease, inhaled bronchodilators can be administered prior to administration to reduce the risk of wheezing and coughing. Oral inhalation, used in a limited and specific population of patients. Use Arikayce vials only with Lamira Nebulizer system. The recommended dosage in adults is once daily oral inhalation of the contents of one 590 mg/8.4 ml of Arikayce vial. Pre-treatment with inhaled bronchodilator should be considered in patients with a history of hyperactive airway disease.	Observe amikacin trough and creatinine levels after 1-2 wk of therapy, then repeat in one month; audiogram at baseline and then in one month; if all normal, then creatinine and amikacin trough levels, and audiograms every three months. Arikayce use should be reserved for those adults who have limited or no alternative treatment options, for the treatment of MAC lung disease as part of a combination antibacterial drug regimen. This indication is approved under accelerated approval based on achieving sputum culture conversion (defined as 3 consecutive negative monthly sputum cultures) by month 6. Arikayce has only been studied in refractory MAC lung disease (patient who did not achieve negative sputum cultures after minimum of 6 consecutive mo of multidrug background regimen therapy)	Dysphonia, respiratory concerns (bronchiectasis exacerbation, dyspnoea); watch for systemic adverse effects as well.
			Arikayce related increased risk of respiratory adverse events include, common: dysphonia (50%) and coughing (30%), and uncommon: hypersensitivity pneumonitis, haemoptysis, bronchospasm, exacerbation of underlying pulmonary disease. Other adverse reactions include ototoxicity, nephrotoxicity, neuromuscular blockade and embryo-foetal toxicity when administered to a pregnant woman.
Linezolid (oral or intravenous)	600 mg daily; may decrease dose to 300 mg after 3-6 months	Careful monitoring for haematological toxicity, lactic acidosis, peripheral and optic neuropathy (often reversible); pyridoxine 100 mg can be administered to prevent haematological toxicity; to prevent serotonin syndrome, avoid tyramine rich food items and medications known to raise serotoin production; monitor CBC count with differential count weekly for 2 wk, then twice weekly.	Haematological toxicity, lactic acidosis, myelosuppression, peripheral and optic neuropathy and serotonin syndrome. Haematological toxicity (early) and lactic acidosis may occur in a few weeks to months whereas neurological toxicity occurs after 3-4 months (late)
Levofloxacin (oral)	500-1000 mg daily	Consider ECG monitoring if additional risk factors present; Dose adjustment required in CKD. Crcl ml/min=750-1000 mg daily, Crcl <30 ml/min=750-1000 mg thrice weekly	GI upset, dizziness, hypersensitivity, photosensitivity, headache, insomnia, tendinitis, tendon rupture, peripheral neuropathy, CNS effects, headache, agitation, depression, paranoia, seizures, QTc prolongation on ECG
Moxifloxacin (oral)	400 mg daily	Consider ECG monitoring if additional risk factors present; no dose adjustment is required in CKD; hepatobiliary excretion; avoid concomitant use of antacids with aluminium sucralfate, phosphate binders, calcium, iron, or aluminium containing medications to avoid malabsorption	Tendinitis, tendon rupture, peripheral neuropathy, CNS effects, QTc prolongation on ECG
Doxycycline (oral)	100 mg twice daily	Monitor clinical symptoms of the patient	GI disturbances, photosensitivity
Minocycline (oral)	100 mg twice daily	Monitor clinical symptoms of the patient	GI disturbances, photosensitivity, hyperpigmentation of the skin and CNS effects
Trimethoprim/sulphamethoxazole (oral)	One double-strength twice or thrice daily	Monitor potassium at baseline, 2 wk, 12 wk then monthly	GI disturbances, cytopenia, renal failure, hyperkalemia
Bedaquiline (oral)	400 mg daily 2 wk and subsequently 200 mg thrice weekly for next 22 wk	Administration with food increases bioavailability; baseline ECG, then 2, 12, 24 wk after initiation to monitor QTc prolongation esp. in combination with clarithromycin, clofazimine and flouroquinolones; stop drug if QTc>500 ms; monitor serum calcium, magnesium and potassium	QTc prolongation, nausea, arthralgia, headache, subjective fever, anorexia
Clofazimine (oral)	50-100 mg daily	ECG monitoring is required if used in combination with bedaquiline, flouroquinolones and macrolides (clarithromycin or azithromycin); monitor serum magnesium, potassium and calcium levels for QTc prolongation correct low levels before stopping the offending drugs ; not used in pregnancy and severe hepatic insufficiency; skin hyperpigmentation can prevented by applying sunscreen and lubricants	GI disturbances, dermatological discoloration: pink to brownish-black skin; discoloration appears within 4 wk and disappears after 6-10 months of the discontinuation, cornea, retina and urine; acne flare within 1-4 wk, ichthyosis and dry skin, QTc prolongation
Tobramycin (intravenous)	5-7 mg/kg per 24 h daily	Obtain peak level 2 and 6 h post dose until therapeutic goal back-extrapolated Cmax 10 the tobramycin MIC, along with undetectable trough. Observe weekly CBC count, creatinine level, tobramycin troughs weekly (should remain <1.2 mg/ml); baseline and monthly audiograms and vestibular function tests	Nephrotoxicity, ototoxicity
Imipenem/cilastin (intravenous)	1g every 12 h (preferred). May consider 500 mg every 12 h for small, frail, or elderly patients	Monitor serum creatinine level, CBC count with differential count, ALT/AST levels weekly; dose adjustment required in CKD	GI disturbances, seizures, rash, cytopenia
Tigecycline (intravenous)	100 mg loading dose, subsequently 25-50 mg once daily (consider lower dose of 25 mg in case of intolerance to higher dosing)	Obtain serum creatinine level, CBC count, ALT/AST levels weekly; monitor INR and reduce warfarin dose	GI disturbances, hepatitis, prolonged aPTT, prolonged PT
Tedizolid (intravenous)	200 mg every 24 h	Monitor CBC count weekly 2 wk, then twice weekly	Myelosuppression, peripheral neuropathy, serotonin syndrome
Cefoxitin (intravenous)	Preferred: 1-2 g every 6-8 h Alternative: 3 g every 12 h	Weekly CBC count monitoring with differential count, creatinine level, and ALT level	Rash, neutropenia, thrombocytopenia

ALT, alanine transaminase; AST, aspartate transaminase; CBC, complete blood cell; CKD, chronic kidney disease; CNS, central nervous system; Crcl dB, decibel on audiogram; ECG, electrocardiogram; GI, gastrointestinal; LFT, liver function test; MAC, Mycobacterium avium complex; MIC, minimum inhibitory concentration; mo, months; PO, oral; TWI, three times per week; aPTT, activated partial thromboplastin time, PT, prothrombin time; NTM-PD, non-tuberculous mycobacterial pulmonary disease. Source: Refs 1,17,144,190