1400. Pretomanid in the Treatment of Patients with Tuberculosis in the United States: the Bedaquiline, Pretomanid and Linezolid (BPaL) Accelerated Monitoring (BAM) Project

Abstract Background In August 2019 the U.S. FDA approved pretomanid as part of a 6-month all-oral BPaL (bedaquiline, pretomanid, and linezolid) regimen for treating pulmonary extensively drug-resistant (XDR) or treatment-intolerant or nonresponsive multidrug-resistant (MDR) tuberculosis (TB). In the study supporting approval, 89% of patients had a favorable outcome, and all reported ≥ 1 adverse event. We describe the reported use of BPaL in the United States. Methods Using the 2020 CDC Report of a Verified Case of Tuberculosis (RVCT) MDR TB supplemental form, TB programs and providers submitted data for patients who began taking BPaL between Aug 1, 2019 and May 1, 2020, for retrospective descriptive analysis. Results Programs and providers reported 17 TB patients aged a mean of 41 years (range 23–76) who received BPaL: 11 (65%) were male; 15 (88%) were non-U.S. born; 15 (88%) had pulmonary TB disease only; two (12%) had both pulmonary and extrapulmonary disease. Of all patients, 16 had Mycobacterium tuberculosis isolated from sputum and 7 (44%) had cavitary disease. The preliminary drug susceptibilities were 8 MDR patterns, 8 pre-XDR, and 1 unreported. Three patients received BPaL as their only treatment; six first received treatment for drug-susceptible TB, and eight received other regimens for MDR TB before BPaL. Eleven (65%) patients had ≥ 1 side effect reported during any TB treatment, including peripheral neuropathy (n=5), depression (n=4), vestibular dysfunction (n=3), and vision changes (n=3). Timing related to specific TB drug use was not reported. Sixteen (94%) patients received less than the approved initial dose of 1200 mg linezolid daily, and 15 (88%) patients underwent monitoring of linezolid exposure. All 16 patients with M. tuberculosis in initial sputa converted to negative culture results within 6 months of starting treatment. At 12 months after BPaL initiation, all patients had completed treatment, without TB recurrences or deaths reported. Conclusion In the early period after FDA approval, most U.S. patients received BPaL off-label with an initial linezolid dose lower than the approved 1200mg yet still achieved good outcomes. Most reported patients underwent some monitoring of linezolid exposure. Monitoring of BPaL use is important and should continue. Disclosures All Authors: No reported disclosures


Session: P-80. Tuberculosis and other Mycobacterial Infections
Background. Non-tuberculous mycobacteria (NTM) are causes of pulmonary and extrapulmonary disease that frequently affect immunocompromised hosts (ICH). Current treatment guidelines recommend a macrolide-based, multi-drug regimen that includes rifampin. Rifampin is a potent cytochrome P450 (CYP) 3A inducer, which often results in drug-drug interactions in ICH receiving multiple CYP substrates. One way to mitigate rifampin's CYP induction is to utilize clarithromycin, a CYP inhibitor, as the accompanying macrolide. We evaluated the incidence of NTM treatment-related adverse events (AEs) in patients who received a clarithromycin-based regimen compared to patients who received an azithromycin-based regimen.
Methods. We conducted a retrospective review of NTM infection in 30 immunocompromised adults. All participants had a positive culture for a NTM and had received a rifamycin (rifampin or rifabutin) with a macrolide (azithromycin or clarithromycin) for treatment at Brigham and Women's Hospital between 01/01/2011-10/18/2020 or Dana-Farber Cancer Institute between 06/03/2015-07/01/2020. The primary outcome was the incidence of NTM treatment-related AEs in patients who received a clarithromycin-based regimen compared to those who received an azithromycin-based regimen.
Results. There were no significant differences in the reasons for discontinuation of NTM treatment or 90-day mortality between groups. The number of AEs possibly related to NTM treatment were similar in patients who received a clarithromycin-based regimen and those who received an azithromycin-based one (10/13 vs. 14/17; p=0.73). The most common AE was liver function test abnormalities (Table 1). Additionally, the proportion of patients requiring dose adjustments for interacting medications and patients with out-of-range tacrolimus levels were similar between the two groups (23.1% vs. 29.4%; p=0.76 and 8.0% vs. 6.0%; p=1.00, respectively).   Background. In August 2019 the U.S. FDA approved pretomanid as part of a 6-month all-oral BPaL (bedaquiline, pretomanid, and linezolid) regimen for treating pulmonary extensively drug-resistant (XDR) or treatment-intolerant or nonresponsive multidrug-resistant (MDR) tuberculosis (TB). In the study supporting approval, 89% of patients had a favorable outcome, and all reported ≥ 1 adverse event. We describe the reported use of BPaL in the United States.

Pretomanid in the Treatment of Patients with Tuberculosis in the United
Methods. Using the 2020 CDC Report of a Verified Case of Tuberculosis (RVCT) MDR TB supplemental form, TB programs and providers submitted data for patients who began taking BPaL between Aug 1, 2019 and May 1, 2020, for retrospective descriptive analysis.
Results. Programs and providers reported 17 TB patients aged a mean of 41 years (range 23-76) who received BPaL: 11 (65%) were male; 15 (88%) were non-U.S. born; 15 (88%) had pulmonary TB disease only; two (12%) had both pulmonary and extrapulmonary disease. Of all patients, 16 had Mycobacterium tuberculosis isolated from sputum and 7 (44%) had cavitary disease. The preliminary drug susceptibilities were 8 MDR patterns, 8 pre-XDR, and 1 unreported. Three patients received BPaL as their only treatment; six first received treatment for drug-susceptible TB, and eight received other regimens for MDR TB before BPaL. Eleven (65%) patients had ≥ 1 side effect reported during any TB treatment, including peripheral neuropathy (n=5), depression (n=4), vestibular dysfunction (n=3), and vision changes (n=3). Timing related to specific TB drug use was not reported. Sixteen (94%) patients received less than the approved initial dose of 1200 mg linezolid daily, and 15 (88%) patients underwent monitoring of linezolid exposure. All 16 patients with M. tuberculosis in initial sputa converted to negative culture results within 6 months of starting treatment. At 12 months after BPaL initiation, all patients had completed treatment, without TB recurrences or deaths reported.
Conclusion. In the early period after FDA approval, most U.S. patients received BPaL off-label with an initial linezolid dose lower than the approved 1200mg yet still achieved good outcomes. Most reported patients underwent some monitoring of linezolid exposure. Monitoring of BPaL use is important and should continue.
Disclosures. Background. Tumor necrosis factor (TNF)-α inhibitors are known for the reactivation of latent tuberculosis (TB). As a paradox, it has been reported to have a role in the treatment of immune reconstitution inflammatory syndrome (IRIS) from anti-TB therapy.
Methods. We report a case of paradoxical worsening of central nervous system TB after initiation of anti-TB medications, which was treated successfully with infliximab (TNF-α inhibitor).

Results.
A 34-year-old man from Nepal with a history of untreated latent TB presented with complaints of occipital headache, slurred speech, and witnessed seizure. His physical exam was consistent with hyperreflexia. MRI of the brain revealed multiple small contrast-enhancing lesions in cerebral hemispheres. CT Chest showed bilateral centrilobular nodules suggestive of miliary TB. Cerebrospinal fluid (CSF) analysis showed pleocytosis, high protein, and low glucose. He was started on isoniazid, rifampin, ethambutol, and pyrazinamide along with high-dose dexamethasone for TB meningitis. Later, MTB DNA probe from bronchioalveolar lavage and CSF detected Mycobacterium Tuberculosis which was pan-susceptible. Repeat MRI of the brain 6 months into therapy revealed worsening of brain lesions. Moxifloxacin and linezolid were added to the regimen given clinical progression on first-line therapy. 6-months into this enhanced regimen he started experiencing blurring of vision. Visual field mapping showed left homonymous hemianopia. Repeat MRI of the brain confirmed extensive changes of basilar meningitis completely enveloping the optic chiasm. IRIS from TB was suspected. His prednisone dose was increased, and 3-doses of infliximab infusion were, 2-weeks apart were administered which showed clinical and radiological improvement. MRI Brain MRI Brain (axial T2/flair sequence) shows hyperintensities in multiple locations including the involvement of the left optic nerve and the left occipital region.
Conclusion. Exacerbation of pre-existing clinical symptoms, formation of new lesions, or cavitation of prior pulmonary infiltrates is known as tuberculosis IRIS or paradoxical reaction. Despite the clinical and radiological exacerbation, mycobacterial cultures usually stay negative. Continuation of anti-TB medications and high-dose corticosteroids are the backbone of treatment but in refractory cases, immune modulation is needed with anti-TNF-α agents.
Disclosures. All Authors: No reported disclosures