Treatment intolerance is common in Mycobacterium avium complex pulmonary disease (MAC-PD) often leading to treatment discontinuation and increasing the risk of mortality.
However the World Bronchiectasis Conference heard that judicious use of multi-drug antimicrobial regimens can help sustain tolerability of the most important drug classes while awareness of and regular monitoring for the common and important adverse reactions can help identify problems early.
Baseline and ongoing lab monitoring, audiograms, vision testing, ECG and spirometry were generally recommended.
Infectious diseases physician Associate Professor Shannon Kasperbauer told the conference that a recent US study [link here] found 43% of patients in a Stanford University cohort were intolerant to prescribed antibiotic therapy.
“Unfortunately, of those, almost half discontinued treatment completely,” she said.
Other research had shown that common adverse reactions including hepatotoxicity, leukopenia and thrombocytopenia infrequently led to treatment discontinuation (1-2.8% of patients) while less common cutaneous reactions and ocular toxicity were much more likely to lead to discontinuation (11.8% and 96.2%, respectively).
Associate Professor Kasperbauer, from National Jewish Health in Denver, Colorado, said ototoxicity was a potentially devastating adverse reaction for patients.
“Our patients already struggle with a stigmatizing disease with chronic cough, and we add ototoxicity to their disease and that adds to anxiety, depression, social isolation, cognitive decline and even unemployment. So I would implore you to monitor for this side effect and take it quite seriously.”
She said both the macrolides and immunoglycosides have the potential to cause ototoxicity however it was a transient, often reversible side effect with the macrolides but irreversible with cumulative exposure to the aminoglycosides.
She recommended monthly monitoring via audiogram when patients were on IV aminoglycosides, every 3-6 months on inhaled aminoglycosides and 6-12 months on oral macrolides.
Management strategies included switching from azithromycin to clarithromycin, decreasing the frequency of administration from daily to three times weekly treatment, and in the case of IV aminoglycosides, switching from IV to inhaled amikacin.
“Fortunately, hope is on the horizon. We now have a phase two study underway…a small molecule that competitively binds to the receptors of the cochlear hair cells, and has been shown in animal studies to mitigate ototoxicity related to aminoglycosides.”
Associate Professor Kasperbauer said visual changes including trouble with color discrimination were a rare side effect with ethambutol.
“Again, my patients are told that they should be seeing ophthalmologists somewhere between every three to six months while on treatment. But even more important than that is telling your patients to read fine print every day and contact you if they’re noticing changes in their vision.”
She said treatment was a ‘marathon, not a sprint’ for patients with MAC-PD so holding treatment for a week or two while waiting for an ophthalmology opinion was not a big problem in the overall disease journey. It was also possible to reintroduce treatment at a lower dose or frequency.
Other side effects worth looking for in patients on ethambutol included peripheral neuropathy, gastrointestinal and hypersensitivity reactions.
The conference heard that rifampin was ‘the great interactor’ with innumerable drug-drug interactions including with hormonal oral contraceptives, corticosteroids, warfarin, beta blockers, statins, azoles, antidepressants and chemotherapy.
Associate Professor Kasperbauer said hepatotoxicity, hypersensitivity and haematological effects were all known effects.
She said a rifampin-induced immune-mediated thrombocytopenia can be life threatening.
“It usually occurs days to weeks after starting rifampin in someone who’s previously been on rifampin. So they’re sensitised to the drug, and it is possible to develop thrombocytopenia again if you try to introduce rifabutin so I would not advise that. Fortunately, it’s probably the least important drug in our cocktail, and there are other options to use.”
Rifabutin was also associated with adverse effects including anterior uveitis, cytopenias, hepatotoxicity, drug interactions and arthralgias and a silver skin discolouration.
Associate Professor Kasperbauer joked that darker skin pigmentation was a highly sought after reaction to treatment with clofazimine.
“I hesitate to call it an adverse reaction for our patients, but at least in my Caucasian patients, they like their clofazimine tan.”
Discontinuation was more likely to follow gastrointestinal side effects while sun sensitivity, dry skin and ichthyosis were also possible effects.
QTc prolongation was also an important side effect that should be monitored in all patients starting NTM therapy. Management included holding the drug and any other QTc prolonging agents and optimising electrolytes, or decreasing the dose or discontinuing the drug.
Linezolid adverse events were very common and included drug-drug interactions for example with antidepressants and can lead to serotonin syndrome, peripheral neuropathy, bone marrow suppression and optic neuritis
“In the NTM field we do recommend that you start at a once daily dosing of linezolid, rather than twice daily dosing which is recommended for staphylococcal infections. And then, unfortunately, if you do have a patient that’s experiencing neuropathy or bone marrow suppression, it requires stopping the drug.”
She said dysphonia was reported in 45.7% of patients starting amikacin liposome inhalation suspension (ALIS) in the CONVERT trial [link here], along with high rates of cough (37.2%), dyspnea (21.5%), haemoptysis (17.5%) and oropharyngeal pain (10.8%).
Consequently, ALIS has a black box warning associated with the increased risk of respiratory adverse events, including hypersensitivity pneumonitis (seen in about 1.8% of the patients in the CONVERT trial), bronchospasm and exacerbations of underlying pulmonary disease that have led to hospitalisation.
“The good news is that if you’re able to work with your patients and give them mitigation strategies, most of these side effects go away by week four to six,” Associate Professor Kasperbauer said.
Other strategies include gargling with glycerin, changing drug administration to evening to give patients’ vocal cords a break, or lozenges for dysphonia; pretreatment with bronchodilators for cough and dyspnea, and brief treatment interruptions or switching to three times weekly administration.
Associate Professor Kasperbauer said she encouraged the use of therapeutic drug monitoring to try and target a therapeutic window at which there was less toxicity.