Bedaquiline as Treatment for Disseminated Nontuberculous Mycobacteria Infection in 2 Patients Co-Infected with HIV

Nontuberculous mycobacteria can cause disseminated infections in immunocompromised patients and are challenging to treat because of antimicrobial resistance and adverse effects of prolonged multidrug treatment. We report successful treatment with bedaquiline, a novel antimycobacterial drug, as part of combination therapy for 2 patients with disseminated nontuberculous mycobacteria co-infected with HIV.

Nontuberculous mycobacteria can cause disseminated infections in immunocompromised patients and are challenging to treat because of antimicrobial resistance and adverse effects of prolonged multidrug treatment. We report successful treatment with bedaquiline, a novel antimycobacterial drug, as part of combination therapy for 2 patients with disseminated nontuberculous mycobacteria co-infected with HIV.
this drug was withheld until his renal function recovered. On its reinitiation at the same dose, tinnitus developed, prompting permanent withdrawal of amikacin. Because of excellent progress, tigecycline was replaced with linezolid at that time. 18 Fluorodeoxyglucose-positron emission tomography/computed tomography imaging was used to monitor disease response ( Figure 2). Although pulmonary and hepatic lesions emerged intermittently, they were consistently culture negative and are believed to represent immune-mediated lesions. His most recent scan 36 months after treatment began showed ongoing, but greatly reduced, 18 fluorodeoxyglucose avidity in all areas. Therefore, he continues maintenance therapy with clofazimine and azithromycin, despite evidence of clarithromycin resistance in vitro. This combination (clofazimine and azithromycin) has been well tolerated, and the condition of the patient continues to be favorable.
Case-patient 2 was a 30-year-old man who had pyrexia, pancytopenia, and lymphadenopathy. Advanced HIV infection had been diagnosed 1 month earlier (CD4 count 10 cells/µL, viral load >1 million copies/mL). He started antiretroviral therapy 10 days before he came to the hospital. Culture of lymph node, peripheral blood, and sputum all yielded M. avium. Treatment with azithromycin, rifabutin, and ciprofloxacin was initiated. Ethambutol was excluded because of color blindness.
The patient initially transferred his care to another hospital but returned 6 months later because   (6). His treatment was intensified by addition of amikacin and, after discussion with ophthalmologists, ethambutol. Because he continued to have fevers, meropenem, which covered the possibility of bacterial sepsis, and clofazimine were initiated, leading to symptomatic improvement. Because his symptoms worsened again on brief cessation of meropenem, it was continued. Treatment for this patient required multiple modifications because of adverse drug effects (Fig-ure 1, panel B). Amikacin was stopped because of renal toxicity. Given the extensive in vitro resistance, best practice recommendation to add 2 drugs synchronously, lack of access to bedaquiline at this time, and evidence for a possible benefit of tigecycline in combination with a macrolide (7), tigecycline and linezolid were initiated in its place, causing nausea and anemia, respectively. He also had arthralgia secondary to moxifloxacin and QTc prolongation caused by azithromycin, which required their cessation.
Shortly after linezolid and azithromycin were discontinued, his fevers and neutropenia returned. Mycobacterial blood cultures again showed M. avium despite prolonged treatment and immune reconstitution. Although bedaquiline sensitivity of this isolate was not determined in vitro, compassionate access to bedaquiline was obtained from Janssen-Cilag, and treatment was initiated at month 13 (dosing as reported for case-patient 1), along with tedizolid. Rifabutin was discontinued because of concerns over its effect on bedaquiline pharmacokinetics.   After bedaquiline and tedizolid were initiated, his fevers resolved, and he made a steady recovery and had no side effects. Given his high risk for relapse, he received bedaquiline for 18 months on the advice of the British Thoracic Society panel, ensuring a year of effective therapy since his last positive blood culture. He has successfully immune reconstituted, continues to receive only antiretroviral therapy, and remains healthy.

Conclusions
Treating disseminated NTM infections is challenging and often complicated by antimicrobial resistance and adverse effects of combination drug therapy. In multidrug-resistant M. tuberculosis, bedaquiline has been shown to decrease the time to sputum culture negativity and improve outcomes (8), leading to interest in its use for NTM infections.
In vitro sensitivity of NTM to bedaquiline has been demonstrated (9,10), although several species, including M. novocastrense, M. shimodei, and M. xenopi, are intrinsically resistant (11). In addition, although bedaquiline is bactericidal against many mycobacterial species, it might only be bacteriostatic against M. avium (12). Despite this feature, bedaquiline has been used in salvage treatment for pulmonary infections with NTM (13), but little experience regarding its use for disseminated NTM infections has been published.
These 2 case-patients were given bedaquiline on compassionate grounds, given the lack of alternative options because of drug resistance and toxicity. For both patients, bedaquiline enabled construction of an antimicrobial drug regimen that included >2 drugs to which the organism was susceptible in vitro and probably contributed to their positive outcomes. Both patients tolerated the drug and made good clinical progress after its initiation. Given the need for combination therapy, it is impossible to attribute the positive outcome of these cases to a single drug. Both patients received bedaquiline and clofazimine because there is evidence that this combination is synergistic against NTMs in vitro (14). Case-patient 2 only achieved sustained mycobacterial culture negativity after treatment with bedaquiline and tedizolid.
Use of bedaquiline as salvage therapy for pulmonary NTM infection is often complicated by the emergence of drug resistance and disease relapse (15). These case-patients received bedaquiline for >1 year, and neither showed evidence of the acquisition of drug resistance or disease relapse over that time or since. These case-patients provide support for use of bedaquiline for treatment of disseminated NTM infection, particularly when standard regimens cannot be used because of drug resistance or adverse drug effects.