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Current and Emerging Therapies for Non-Cystic Fibrosis Nontuberculous Mycobacterial Lung Disease: What Pharmacists Need to Know

INTRODUCTION

Human infections due to Mycobacterium tuberculosis (known as tuberculosis or TB) are well known by medical providers, but nontuberculous mycobacterial (NTM) infections, also known as mycobacterium other than tuberculosis, are not as well known. Similar to TB, NTM infections can manifest in myriad syndromes, including skin and soft tissue infections and lymphadenitis, but they occur most often as pulmonary infections. Treatment of mycobacterial infections involves complex medication regimens taken for long periods of time, and pharmacists have ample opportunities to be involved in the care processes of patients with mycobacterial disease. This review will describe the microbiology, epidemiology, and treatment of pulmonary NTM disease caused by the 3 most common isolated species, with a focus on potential contributions of pharmacists.

MICROBIOLOGY

Mycobacteria are aerobic, acid-fast positive organisms with a thick, lipid-rich, hydrophobic cell wall.¹ The impermeability of the cell wall, along with its ability to form biofilms, renders mycobacteria resistant to antimicrobials, high temperatures, and disinfectants.² NTM are ubiquitous in the environment, but they have a preference for water and soil reservoirs. The mode of transmission is not well established, but inhalation and ingestion are the leading hypotheses of transmission: direct person- to-person transmission is not thought to play a significant role. Hospital water systems, hemodialysis centers, peat-rich potting soil, and hot tubs are commonly colonized with NTM and, in some cases, can lead to nosocomial outbreaks.^3,4

NTM comprises more than 100 species, many of which were discovered only in recent years due to advances in culturing and molecular techniques.⁵ The various species have classically been divided into rapid (< 7 days) and slow (> 7 days) growers. Of those known to cause human disease, notable rapid growers include Mycobacterium abscessus complex (MABC), M. fortuitium, and M. chelonae; slow growers are M. avium complex (MAC) and M. kansasii. MABC comprises subspecies abscessus, bolletii, and massiliense, and MAC is further divided into M. avium, M. intracellulare, and M. chimaera.⁵ Among these isolates, MAC is the most common cause of pulmonary disease, followed by M. kansasii, and M. abscessus.⁶ The vast majority of cultures positive for NTM are from pulmonary sources, and skin and soft tissue infections are the second-most common source of isolates. Identification of the mycobacterial species is key to the proper management of the associated disease.

EPIDEMIOLOGY

The true incidence of NTM infections is difficult to determine, since positive cultures do not always indicate the presence of clinical disease. Given the nearly universal presence of NTM in the environment, each culture result needs to be weighed carefully in the context of several factors, including imaging and patient symptoms, to determine its relevance. Another consideration making determination of disease incidence difficult is that reporting of NTM to public health officials is not mandated, as it is with TB.

Despite these barriers to identification and reporting of NTM infections, there is a general consensus that NTM infections are increasing throughout the world⁷: a review that evaluated the use of laboratory results along with patient characteristics reported an NTM incidence of 4.1 to 14.1 cases per 100,000 patient years.⁸ However, it has been a matter of debate whether the disease incidence is truly increasing or if improved ability to detect disease through newer culture techniques and clinician awareness is the cause of the increase.⁹ Proposed reasons for a rise in NTM infections include air pollution, an aging population, increases in comorbidities, and the increasing use of immunosuppressive therapies.^4,10

Host factors

Most people are likely exposed to NTM in their lifetimes, though only a few people will develop an active infection. The factors predisposing certain patients to NTM infection are not well understood, but certain demographic characteristics are common among those diagnosed with clinical disease. One patient group with a known predisposition to NTM infection is slender, postmenopausal women with mitral valve prolapse.^11,12 Pulmonary NTM infection is also strongly associated with pre-existing lung disease such as bronchiectasis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, and pneumonitis.¹³ However, the question of which comes first—the bronchiectasis or the NTM infection— has been difficult to delineate: bronchiectasis is considered a risk factor for NTM, though it may be a clinical manifestation of the disease itself. Interestingly, cigarette smoking in the absence of COPD is not an established predisposing factor for NTM infection. The immunosuppressed population, including patients with HIV/AIDS, those who received a solid organ transplant, and those on anti-tumor necrosis factor alpha therapy, is an established at-risk group. The factors influencing these increased risks are outside the scope of this monograph and will not be discussed in detail.

PRESENTATION AND DIAGNOSIS

The American Thoracic Society (ATS) and the Infectious Diseases Society of America (IDSA) jointly published a guideline to aid in the diagnosis and management of NTM disease.⁶ Diagnosis involves the synthesis of patient signs and symptoms, symptom severity, radiologic results, and microbiologic cultures along with the exclusion of other potential causes of disease. Clinical symptoms are variable and not present in all patients, but commonly reported symptoms are chronic cough with or without sputum production, weight loss, fatigue/malaise, and night sweats. A hallmark radiographic sign of pulmonary NTM is the "tree in bud" finding of small nodules of less than 0.5 mm in diameter. Other signs include fibrocavitary disease, parenchymal destruction, and diffuse consolidations due to hypersensitivity pneumonitis.⁵

Since mycobacteria are ubiquitous in the environment, the microbiology criteria for diagnosis mandates at least 2 or more positive sputum cultures, at least one culture from a bronchial washing or lavage, or biopsy positive with histologic features of mycobacterium.⁶ Most laboratories use at least a 6- week incubation period for mycobacterial cultures, which results in the need for ongoing culture surveillance from the provider suspecting NTM disease. Other disease states, including TB, malignancy, and invasive fungal or bacterial infections, should be ruled out prior to initiation of NTM therapy.¹⁴

TREATMENT

Treatment of NTM lung disease depends on several factors: the causative species, disease severity, and patient-specific risk factors and considerations. Dosing frequency, potential adverse effects drug interactions, and goals of care are also important issues that the care team must consider when choosing therapy for NTM infections. Two guidelines are available to guide the selection of treatment.

Mycobacterium avium complex

Pulmonary MAC disease is usually classified as 1 of 2 clinical entities: cavitary disease or nodular/bronchiectatic disease. The more severe form of progressive apical fibrocavitary lung disease tends to present in middle-aged males who have a history of cigarette smoking and alcohol consumption. The less aggressive disease presents with nodular infiltrates and tends to occur in post- menopausal white women.

Treatment for MAC pulmonary disease follows 1 of 2 treatment paradigms: daily drug therapy or thrice-weekly therapy. Outcomes are comparable between daily and thrice-weekly therapy in patients with the less severe form of pulmonary disease (nodular/bronchiectatic MAC lung disease).^15-17 Reduced overall pill burden and the potential for decreased adverse effects and toxicity with lower drug exposure makes 3-times-weekly therapy a desirable approach, especially for older patients—a group that accounts for a significant portion of the infected population. However, in patients with cavitary disease, a 3-times-weekly drug dosing regimen with a macrolide, ethambutol, and rifampin has shown a very low rate of culture conversion (only 4%) at 12 months of therapy.¹⁶ The recommend regimens for initial treatment of MAC pulmonary disease from the 2007 ATS/IDSA and 2017 British Thoracic Society (BTS) guidelines are outlined in Table 1.^6,18

Macrolides are the primary class of medications used to treat pulmonary MAC infection. Clarithromycin and azithromycin have excellent in vitro activity against MAC; minimum inhibitory concentration (MIC) values are attainable in serum with standard doses of clarithromycin and azithromycin; and clarithromycin and azithromycin provide enhanced concentrations at the site of infection in both phagocytes and tissue.^19-21

Two early, open-label, non-comparative trials demonstrated that azithromycin and clarithromycin monotherapy yielded favorable microbiologic and clinical responses. Azithromycin and clarithromycin monotherapy provided rates of microbiologic conversion of 38% and 58%, with notable reductions in sputum microbiologic growth of 76% and 79%, respectively.^15,20,22 However, macrolide resistance developed with clarithromycin monotherapy.¹⁵

Multi-drug therapy with a macrolide backbone provides more favorable outcomes than macrolide monotherapy. Ethambutol and rifamycins have synergy against MAC isolates²³ and have provided protection against the development of macrolide resistance in disseminated MAC disease,²⁴ which has led to its use in combination with macrolide therapy. Clinically, combination therapy with clarithromycin, a rifamycin, ethambutol, and an early period of 2 to 4 months of streptomycin yielded 36 of 39 (92%) patients with sputum conversion and prolonged maintenance of negative cultures after therapy completion.²¹ Enhanced clinical improvement and maintenance of culture negativity were also achieved when azithromycin was combined with rifabutin, ethambutol, and an initial 2 months of streptomycin.²⁵

Rifampin is the preferred rifamycin for the treatment of MAC pulmonary disease. Rifabutin has microbiologic activity against MAC isolates and has more potent in vitro activity against MAC than rifampin.²⁶ However, rifabutin's adverse effects (e.g., arthralgias, neutropenias, cytopenias, uveitis) are notable in older patents. As such, rifabutin is poorly tolerated compared to rifampin in a common patient population with MAC disease, which has led to the use of rifampin as the preferred initial rifamycin for MAC pulmonary disease.^{15,21,22,25,27,28}

An initial period of 2 to 3 months of an injectable agent (usually streptomycin or amikacin) is provided as an option in severe MAC disease. The lack of a strong recommendation for routine use in all cases is attributable to a lack of definitive clinical outcome enhancement when used as an adjunct to therapy. For instance, when intramuscular (IM) streptomycin was administered 3 times weekly for the first 3 months of therapy (added to rifampin, ethambutol, and clarithromycin), it yielded a statistically significant improvement in microbiologic sputum conversion (71.2% vs. 50.7%) at 2 years, though clinical relapse rate, clinical symptom improvement, and radiologic findings did not otherwise differ.²⁹ Further, the IM administration route can be a deterrent to streptomycin use. Amikacin has a similar kinetic profile and similar safety data to streptomycin,³⁰ so it is often the selected aminoglycoside agent in severe cavitary disease.

Mycobacterium kansasii

M. kansasii infections tend to have a similar presentation and clinical course to TB. Patients can have fever, chills, weight loss, and night sweats. Cavitary disease often has a predilection for the upper lobes of the lungs, though non-cavitary bronchiectatic disease is also seen. Surgery does not have a role in M. kansasii infections because drug therapy achieves excellent clinical and microbiologic responses.⁶

Treatment for M. kansasii is daily therapy with a 3-drug combination. The recommended treatment regimen described in the 2007 ATS/IDSA and 2017 BTS guidelines is outlined in Table 2.^6,18 Historically, when investigating drug therapy for M. kansasii, drugs used for TB were evaluated, leading to early clinical data supporting the use of rifampin, ethambutol, and isoniazid (INH). One consideration of M. kansasii drug sensitivity is the MIC results for INH: this drug is useful in multi-drug regimens to treat M. kansasii and clinical data support its use, but the MICs of INH tend to be quite high, though this may not always translate into lack of response. Resistance may be reported at an MIC of 1 mcg/mL, but resistant isolates have been shown to respond to multi-drug regimens containing rifampin.^31,32 Macrolides have been shown to have excellent in vitro activity against M. kansasii isolates and efficacy has been demonstrated in a small trial,³³ leading to the incorporation of macrolide therapy as a third option in place of INH in the BTS guidelines. Similar to its role in TB, rifampin is of critical importance to the success of the treatment regimen for M. kansasii.

Mycobacterium abscessus

M. abscessus pulmonary infection has been notoriously challenging to treat: isolates have large variability in antibiotic sensitivity and outcomes for drug therapy (particularly macrolides) vary in the literature. Many factors contribute to these challenges, but the variation in antibiotic responses of different subspecies plays a significant role in the difficult nature of M. abscessus treatment. The predominant difference contributing to macrolide response among the subspecies of M. abscessus (M. abscessus subspecies abscessus, M. abscessus subspecies bolletii, and M. abscessus subspecies massiliense)—collectively referred to as MABC—is the presence of a functional inducible erm gene for macrolide resistance. Further, no multi-drug regimen to treat M. abscessus pulmonary disease has been found that reliably leads to cure or culture conversion for an extended duration. This must be considered when determining goals of therapy for patients: antibiotic therapy is often aimed more at improving quality of life and achieving symptomatic improvement through suppression of microbial growth than at curing the infection. However, with limited disease and surgery, prolonged culture conversion is possible.³⁴

Drug sensitivity results, patient tolerability, and a patient's ultimate goals of care will dictate the selection of a treatment course for M. abscessus pulmonary disease. The clinical treatment paradigms highlighted by the 2007 ATS/IDSA guidelines and 2017 BTS guidelines are similar. Both recommendations advocate the use of an initial intensive phase of intravenous (IV) therapy with an oral macrolide followed by a continuation phase of oral antimicrobials that are selected on the basis of patient tolerability and the antibiotic sensitivity profile. Table 3 lists the recommendations for the initial intensive phase of therapy for M. abscessus treatment. Neither the ATS/IDSA nor the BTS guidelines' determinations are based on randomized controlled trial data. Most data were from observational studies, case series, and case reports; guideline recommendations also incorporate expert opinions.^6,18

The regimen selected for initial therapy within the ATS/IDSA and BTS guidelines constitute agents shown in the majority of large case series to result in clinical improvement, microbiological improvement, radiological improvement, and symptom improvement. The guidelines advocate the use of these initial agents for a period of at least 4 weeks up to 4 months, though they acknowledge that tolerability may challenge patients and limit treatment duration.^6,18 The BTS guidelines further advocate for consideration of extending initial IV therapy up to 3 to 6 months if tolerated by patients with inducible or constitutional macrolide resistance, as outcomes are worse in this setting.¹⁸

Clinical outcomes are improved when M. abscessus isolates are macrolide susceptible and macrolides are included in the treatment program.^35,36 However, subspecies have varying macrolide resistance profiles. Subspecies bolletii and abscessus have copies of a functional erm41 gene for inducible resistance; subspecies massiliense has a nonfunctional erm gene and lacks inducible resistance.³⁷ MABC isolates can also have acquired (rrl) resistance. Erm41 induction leads to methylation of the macrolide binding site on the 23S rRNA, and rrl mutations change the structure of the 23S rRNA, permanently preventing macrolide binding to the active site. Acquired resistance can be seen on standard resistance panels, but inducible resistance is not detectable by this ^method38 and requires culture sensitivity assessment at day 3 to 5 and again at day 14 for detection. However, DNA sequencing techniques can identify a functional erm41 gene sooner.³⁶ Despite the presence of inducible resistance, macrolides may retain in vivo efficacy in 20% of M. abscessus subsp. abscessus isolates.³⁹ Furthermore, azithromycin may be preferred over clarithromycin, since it has less potential to induce the erm41 gene.⁴⁰

After the initial, intensive phase of IV therapy, 2 to 4 oral agents with activity according to the sensitivity panel are typically chosen on the basis of patient tolerability, drug interactions, and patient- specific factors with goals of care in mind. Potential agents include nebulized amikacin, ongoing oral macrolide (clarithromycin/azithromycin), clofazimine, linezolid, minocycline, moxifloxacin, and sulfamethoxazole-trimethoprim.^6,18

NTM treatment duration and goals of therapy

For pulmonary disease caused by MAC or M. kansasii, where curative potential is a possibility, the duration of antimicrobial therapy is usually 18 to 24 months. This includes the continuation of therapy for 12 months after culture conversion.^6,18 M. abscessus pulmonary disease is more challenging and curative potential may not be possible for many patients, except for cases of minimal disease with surgical intervention. In this circumstance, goals of care should be decided between patient and provider. Often, goals are designed to minimize symptoms through bacterial burden reduction and ongoing antimicrobial suppression and balance the benefits of therapy with the tolerability of the selected antibiotic regimen. Therapeutic failure is determined in cases of MAC or M. kansasii if patients do not have clinical response after 6 months and/or lack culture conversion by 6 to 12 months.

In cases of M. abscessus, the clinical case and goals of care should be ascertained by an experienced NTM provider to determine if the symptom-guided goals are appropriately met by the antimicrobial program, assuming adjustments have been made to the regimen accordingly. For patients who undergo surgery with curative intent, antibiotic regimens are typically continued for 12 months after surgery and culture conversion.^41,42

Table 4 lists the product information, standard dosing, and adverse effects for the agents used to treat pulmonary NTM disease.

REFRACTORY NTM DISEASE

The treatment of pulmonary NTM disease is notably limited by a lack of randomized controlled trial data. Refractory disease treatment is even more limited, with small case series, observational studies, and retrospective reports providing the majority of information on treatment options. Often, MIC data yielded from antibiotic sensitivity assessments in patients with refractory disease suggest that in vitro activity may offer the possibility of clinical benefit. Typically, 1 or 2 agents are selected to add to a current regimen on the basis of patient-specific factors, end organ function, potential adverse drug reactions, drug interactions, or medication availability. Data regarding some of the agents used in refractory pulmonary NTM disease are outlined below. The use of inhaled liposomal amikacin in the clinical setting is increasing and ongoing randomized trials are investigating its applications in NTM treatment, so this agent is discussed in detail.

Inhaled amikacin

Amikacin sulfate in a concentration of 250 mg/mL is often used to compound the IV formulation of administered amikacin. Dosing is variable, but, commonly, 1 mL of this concentration of amikacin is added to 3 mL saline; this mixture is then administered via nebulizer once daily over 20 to 30 minutes. The dose is usually increased after 1 to 2 weeks to 250 mg twice daily. Then, as tolerability allows, the dose can be further increased to 500 mg twice daily, which is the typical maximum recommended dose. Inhaled amikacin has several benefits over parenteral amikacin: 1) the theoretical advantage of delivering a high concentration of drug directly to the site of action favors efficacy of the antimicrobial; 2) direct delivery via the lung reduces systemic exposure and minimizes toxicity; and 3) durations of therapy can be extended due to the lower risk of systemic toxicity that limits the chronic use of IV aminoglycosides.

Amikacin liposome inhalation suspension (ALIS) consists of small, charge-neutral liposomal particles; the amikacin sulfate salt form provides amikacin in its water-soluble, positively-charged form. Amikacin liposome inhalation suspension offers potential benefits over the sulfate form. First, with a neutral charge, the liposomal particles can theoretically penetrate macrophages more efficiently and provide higher intracellular amikacin directly to the site of mycobacteria. Second, the charge-neutral liposomes should theoretically be able to more effectively penetrate electrically charged biofilm than the amikacin salt. Finally, the liposomal delivery to intracellular lung tissue should serve to create a drug depot where drug action is sustained over time and systemic exposure may be even less than with the amikacin salt form.^43,44

Two small, retrospective case series of 20 and 25 patients with refractory MAC or MABC pulmonary infection showed benefit with the addition of inhaled amikacin sulfate to current antibiotics.^45,46 Inhaled amikacin sulfate led to sputum conversion in 25% to 44% of patients with 30% improvement in computed tomography imaging of the chest and 27% to 45% improvement in symptom scores. Adverse effects varied, and no patients discontinued treatment in one of the studies and only mild oral discomfort/hoarseness was reported.⁴⁶ However, 30% of patients in the other study discontinued treatment, with ototoxicity, hemoptysis, nephrotoxicity, dysphonia, and vertigo cited as the reasons for discontinuations.⁴⁵

A phase 2 randomized controlled trial involving 89 patients evaluated the addition of ALIS to current therapy in refractory MAC or MABC pulmonary disease against placebo. While a decrease was seen in mean semi-quantitative mycobacterial culture (the primary outcome), this change did not reach clinical significance (p = 0.072). However, there were statistically significant improvements in the secondary outcomes of sputum conversion (32% vs. 9%, p = 0.006) and the 6-minute walk test. In all, 15% of patients discontinued ALIS in this study, most commonly due to bronchiectasis exacerbation and dyspnea.⁴⁷ A larger phase 3 study with ALIS is currently underway.

Other agents for the treatment of refractory disease

Moxifloxacin 400 mg daily demonstrated successful culture conversion when added to patients' antimicrobial regimen in the setting of refractory MAC pulmonary disease. Of 41 patients evaluated in a retrospective case series, 12 (29%) ultimately had culture conversion after moxifloxacin addition.⁴⁸

Bedaquiline has shown potent in vitro activity against both MAC and MABC isolates. Currently, bedaquiline is approved in the United States (U.S.) for TB treatment, but it lacks approval for NTM. In a retrospective case evaluation of 10 patients from Texas with refractory MAC or MABC, bedaquiline demonstrated favorable clinical results. Six (60%) patients had improvement in semi-quantitative cultures, 4 (40%) had radiographic improvement, and 9 (90%) had symptom improvement.⁴⁹ The high cost of bedaquiline is a considerable barrier to its use.

Linezolid has in vitro data and limited outcome data in NTM infections, but tolerability is a concern. An evaluation of 102 patients with NTM infections (majority were pulmonary infections, 44% MABC and 33% MAC) noted that 46 patients experienced adverse effects (e.g., peripheral neuropathy, thrombocytopenia, anemia) at a median of 20 weeks, with 90% of the patients discontinuing therapy due to the adverse effects.⁵⁰ Tedizolid appears to have better in vitro activity against NTM and may offer a more favorable adverse effect profile, though this is yet to be demonstrated in clinical trials.⁵¹

Clofazimine has in vitro activity against both MAC and MABC. A 2003 study evaluated a regimen of clofazimine, ethambutol, and a macrolide (clarithromycin/azithromycin) in 30 patients with MAC pulmonary disease. Four patients discontinued treatment early due to clarithromycin intolerability, but all 26 patients who completed the regimen demonstrated sputum conversion.⁵² Data were also published that supported clofazimine use in refractory NTM pulmonary disease. A total of 41 (50%) of 82 patients converted sputum within 12 months of therapy.⁵³ Further retrospective data support clofazimine use in MABC refractory lung disease.⁵⁴

THE PHARMACIST'S ROLE IN NTM TREATMENT

Pharmacists can assist at multiple points in the care continuum of patients with NTM disease, both in traditional and progressive ways. Some of the well-established functions that pharmacists provide are easily extrapolated to NTM therapy (Table 5).

Pharmacists can be resources for patients and offer advice on what to expect from extended antibiotic therapy; they can also help ensure that patients are aware of monitoring requirements, provide insight on common drug interactions, and assist with mitigation of some adverse effects (Table 4). For example, pharmacists can inform patients that the rifamycins will stain body fluids orange. Additionally, the pharmacist should offer a recommendation to contact lens wearers who will take a rifamycin to consider daily-wear contacts or glasses to avoid the appearance of eye discoloration that may occur with staining of extended wear contact lenses. Pharmacists can ensure that patients are aware of ways to monitor for ethambutol eye toxicity by advising monthly self-assessments for visual acuity (e.g., looking at a phone book or novel at the same distance once monthly to determine any changes from baseline) and color discrimination (e.g., performing a monthly ishihara test, which is available online and for mobile devices). Further, the pharmacist can offer spacing instructions for fluoroquinolones and divalent cation supplements, such as calcium and iron, to optimize medication absorption and counsel patients to take macrolides with food to minimize some of the gastrointestinal side effects. As drug therapy experts, pharmacists can and should provide tips and advice for drug administration that will help avoid common drug interactions and adverse effects of NTM medication therapy.

Pharmacists are well equipped to support the care team with therapeutic drug monitoring (TDM). Given the high risk of adverse effects of amikacin such as ototoxicity and nephrotoxicity, TDM is a standard of care for patients receiving amikacin. A calculated maximum concentration (C_max) should be determined using 2-hour and 6-hour serum levels drawn after the end of the infusion. The goal C_max target level is 35 to 45 mcg/mL (for the 15 mg/kg daily dose) or 65 to 80 mcg/mL (for the 25 mg/kg thrice-weekly dose) for patients with normal renal function. Target troughs are undetectable (Figure 1). If multiple post-dose levels are not feasible, a 1-hour post-infusion 'peak' may be obtained, with a goal level of 25 to 35 mcg/mL for a 15-mg/kg dose for patients with normal renal function. Once the C_max goal is reached with a given dosing regimen, trough levels and serum creatinine should be monitored at least once weekly. Baseline and periodic audiograms should also be obtained.

Figure 1. Therapeutic Drug Monitoring of Amikacin

Table 6 includes the optimal timing and levels for common doses of oral agents used in NTM therapy. TDM of oral agents in the treatment of NTM is less well established, but, given the extended duration of antimicrobial treatment, consideration should be given to optimizing drug exposure and minimizing toxicity through serum level assessment. Charles Peloquin, PharmD, an expert in mycobacterial pharmacotherapy, provides a detailed review of TDM in the setting of NTM disease that can serve as a useful resource for pharmacists.⁵⁵ While TDM of oral antimicrobials is not standard of care for all patients, it should be considered in the following circumstances: concern for adequate drug absorption (e.g., surgical history of Roux-en-Y, graft-versus-host disease of the gut, severe gastrointestinal disease such as Crohn's Disease), drug interactions in which increased or decreased antimicrobial exposure is expected, renal/hepatic dysfunction, or lack of clinical/microbiologic response to therapy.

Pharmacists can also assist the care team with obtaining medications. Bedaquiline and clofazimine require additional steps for procurement for patient use. Bedaquiline is approved by the U.S. Food and Drug Administration (FDA) for TB treatment but not for NTM treatment.⁴⁹ Given the high cost of the drug, insurance prior authorization can be a barrier to acquisition for treatment of NTM disease, but pharmacists can help delineate the indications for use and assist with prior authorization for the care team when necessary. Clofazimine is FDA approved for leprosy, but it is not available through traditional U.S. pharmaceutical distribution. Clofazimine use requires institutional review board (IRB) approval and submission of a drug application through the FDA. The drug application component can be accomplished by submission of a single-patient investigational new drug application directly to the FDA or individual patients can be added to an intermediate-sized investigational new drug application through the drug manufacturer's expanded access program.⁵⁶ Pharmacists can be engaged in the IRB approval process and submission of the drug applications as key participants in the care team.

Exciting roles for pharmacists to become more involved in different aspects of care for patients with NTM disease are developing and expanding, including research and publication (particularly in the area of TDM), expansion of medication therapy management services for NTM patients, monitoring and dosing of NTM therapies and/or culture results in outpatient parenteral antimicrobial therapy clinics staffed by pharmacists, outpatient antimicrobial stewardship efforts, and the development of monographs, evidence-based reviews, and formulary recommendations. Pharmacists perform many of these roles already and their involvement will continue to improve the overall care of patients with NTM disease.

The monograph was reviewed on October 1, 2018 and January 15, 2019 and no updates are needed.

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