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Pharmacotherapy Considerations for Agents Used in the Treatment of Non-Tuberculosis Mycobacterial Infections in Cardiothoracic Transplant Recipients


Robin Klasek, PharmD
rklasek@houstonmethodist.org

Kyle Dawson, PharmD, BCPS
Houston Methodist
Houston, TX, USA
kldawson@houstonmethodist.org



The number of identified non-tuberculosis mycobacteria (NTM) species has increased rapidly over the last decade, and, due to their impaired immunity, cardiothoracic transplant recipients are now at an even greater risk of infection from these organisms [1,2]. Recent increases in the incidence/prevalence of NTMs can be attributed to advancements in the techniques for their detection and identification [1]. The incidence of NTM infections is greater in lung and heart transplant recipients, with rates up to approximately 8% and 3%, respectively. The most common manifestations of NTM infections are pulmonary and skin, or soft tissue infections, and the frequency and manifestation of NTM diseases are partially determined by the geographic distribution of the different species [3]. Worldwide, mycobacterium avium complex (MAC) is the predominant isolate found in most countries, followed by M. xenopi, M. kansasii and other rapidly growing NTM species, especially M. abscessus [4]. Treatment strategies vary across centers globally in terms of choice of agents, timing of therapy, and treatment duration. The development of drug resistance is a recognized problem, and thus multi-agent therapy is recommended [5]. While treatment response isn't necessarily correlated to in vitro susceptibilities for all NTMs, susceptibility testing can help direct therapy and monitor for resistance [5]. This article aims to discuss pharmacotherapy considerations for agents commonly used in the management of NTM infections in cardiothoracic transplant patients.

Macrolides are recommended for multiple NTM infections, including MAC and M. abscessus. Monotherapy with macrolides is not recommended due to the high risk of resistance, and some NTMs (M. fortuitum and M. smegmatis) have been associated with in vivo macrolide resistance despite susceptible MICs [5]. Clarithromycin use for NTMs is common; however, due to inhibition of both P-glycoprotien and CYP450 enzymes, it has strong drug interactions with immunosuppressive agents (i.e., calcineurin inhibitors and mTOR inhibtors) used in transplant recipients [6,7]. Additionally, clarithromycin is often not well-tolerated due to gastrointestinal side effects [8]. Azithromycin is a favorable alternative in transplant patients due to a lesser effect on CNI/mTOR kinetics and better GI tolerability [3,9]. Drug levels should be monitored more closely upon initiation of any macrolide therapy and dose reductions of CNIs/mTORs shortly after clarithromycin initiation of at least 50% will likely be necessary [9]. Other concerns with macrolide therapies include increased risk of C. difficile infection, QTc prolongation, and abnormal liver function tests (LFTs)/hepatitis [8].

Rifamycins are recommended in the treatment of MAC and M. kansasii, among other NTMs [5]. This drug class has strong drug-drug interactions with CNIs/mTORs due to CYP450 and P-gp induction [10,11,12]. Concomitant therapy with CNIs and mTORs can result in drastically reduced exposure to the immunosuppressants. Rifabutin is often the preferred rifamycin in transplant patients due to its lesser effect on CNI pharmacokinetics [3]. The dose of CNIs/mTORs will likely need to be increased by at least twofold with rifamycin initiation, but it may take anywhere from a few days to weeks before the full effect of the interaction can be seen. Drug levels should be monitored closely during this time [9]. For those patients receiving azole antifungals for treatment or prophylaxis, co-administration with rifamycins can result in a significant reduction of systemic exposure to the azole antifungal and increased risk of toxicity form the rifamycin agent [13]. Consequently, if possible, concomitant administration of azoles and rifamycins should be avoided. If benefit outweighs risk and both agents are to be administered, therapeutic drug monitoring of the azole and clinical monitoring for rifamycin toxicity is recommended [14]. Rifamycin toxicity can also occur when used in combination with clarithromycin [15]. Long-term therapy with rifamycins is associated with increased LFTs/hepatotoxicity, anemia, neutropenia, thrombocytopenia and GI side effects [10,16,17]. Lastly, rifamycins have numerous interactions with other commonly used drugs [18]

While used in the treatment of multiple NTMs, ethambutol is most notably recommended for the treatment of MAC [5]. This antibiotic has no known drug interactions with immunosuppressive agents. However, ethambutol has a unique adverse reaction profile which includes visual changes, red/green color blindness, optic neuritis and peripheral neuropathy. Patients should be questioned regarding visual disturbances, including blurred vision, on a routine basis. Periodical testing of visual acuity and color vision should be performed for patients taking higher doses or receiving the drug for more than 2 months [19,20]. A recent study suggests lesser risk of ethambutol toxicity with thrice weekly dosing [21].

For all NTM infections, the treatment duration depends on clinical response, and in many cases, will continue for six to twelve months after resolution of symptoms and/or conversion of sputum cultures. The table below highlights some of the important pharmacotherapy considerations for both the aforementioned agents as well as other commonly used drugs for the treatment of NTMs. The reader is referred to the ATS/IDSA guidelines for a more detailed discussion of diagnosis and treatment of NTMs [5]. Also, articles in the American Journal of Transplantation by Keating and Trofe-Clarke are recommended for further information on treating NTMs in transplant recipients [3,9].

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Disclosure Statement: The authors have no conflicts of interest to disclose.


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