Acquired rifamycin resistance among patients with tuberculosis and HIV in new York City, 2001-2023.

Introduction: Acquired rifamycin resistance (ARR) in tuberculosis (TB) has been associated with HIV infection and can necessitate complicated TB treatment regimens, particularly in people living with HIV (PLWH). This work examines clinical characteristics and treatment outcomes of PLWH who developed ARR from 2001 to 2023 in New York City (NYC) to inform best practices for treating these patients. Methods: PLWH who developed ARR 2001-2023 were identified from the NYC TB registry. Results: Sixteen PLWH developed ARR; 15 were diagnosed 2001-2009 and the 16th was diagnosed in 2017. Median CD4 count was 48/mm3. On initial presentation, 14 had positive sputum cultures; of these, 12 culture-converted prior to developing ARR. Ten patients completed a course of TB treatment but subsequently relapsed; in six of these cases, ARR was discovered upon relapse, triggering treatment with a non-rifamycin-containing regimen, while in the other four, ARR was discovered during a second round of rifamycin-containing treatment. Three patients were lost to follow-up during their initial course of TB treatment and later returned to care; after being restarted on a rifamycin-containing regimen, ARR was discovered. Finally, three patients culture-converted during their first course of treatment but subsequently had cultures that grew rifamycin-resistant Mycobacterium tuberculosis prior to treatment completion, leading to changes in their treatment regimens. Among the 16 patients, eight died before being cured of TB, seven successfully completed treatment, and one was lost to follow-up. Conclusions: PLWH should be monitored closely for the development of ARR during treatment for TB, and sputum culture conversion should be interpreted cautiously in this group. Collecting a final sputum sample may be especially important for PLWH, as treatment failure and relapse were common in this population. The decrease in the number of cases of ARR among PLWH during the study period may reflect the decrease in the total number of PLWH diagnosed with TB in NYC in recent years, improved immune status of PLWH due to increased uptake of antiretroviral drugs, and improvements in the way anti-TB regimens are designed for PLWH (such as recommending daily rather than intermittent rifamycin dosing).

Rifampin Mono-Resistant Tuberculosis in New York City, 2010-2021: A Retrospective Case Series.

Background: Although relatively rare, rifampin mono-resistant tuberculosis (RMR TB) poses important challenges to effective TB treatment and control. Information on the burden of RMR TB and treatment outcomes is needed to inform diagnosis and management. Methods: Standardized variables were collected from the New York City (NYC) tuberculosis surveillance system for patients treated for RMR TB in NYC during 2010-2021. Results: Of 7097 TB cases reported in 2010-2021, 31 (<1%) were treated clinically as RMR TB. Five (16%) of these patients had HIV. Seventeen patients (55%) had TB that was rifampin-resistant by both molecular and phenotypic drug susceptibility testing; 2 (6%) had rifampin resistance by phenotypic tests, and molecular tests were not done; and 12 (39%) were identified based only on molecular tests. Among these 12, 7 were rifampin-sensitive by phenotypic tests, and phenotypic testing could not be done for the other 5. Ten of the 31 (32%) were diagnosed in 2010-2015; the other 21 (including 10/12 diagnosed by molecular tests alone) were diagnosed in 2016-2021. Of the 31 patients, 21 (68%) completed treatment (median treatment duration of 18 months). Although the interval between tuberculosis treatment initiation and change to a non-rifamycin-containing regimen decreased significantly during the study period, the overall duration of treatment did not decrease significantly between 2010 and 2021. Conclusions: Molecular drug susceptibility tests identified cases of RMR TB that were not detected by phenotypic testing and helped enable timely adjustment of tuberculosis treatment regimens. Short-course regimens are needed to reduce duration of treatment for RMR TB.

Implementation of Bedaquiline, Pretomanid, and Linezolid in the United States: Experience Using a Novel All-Oral Treatment Regimen for Treatment of Rifampin-Resistant or Rifampin-Intolerant Tuberculosis Disease.

BACKGROUND: Rifampin-resistant tuberculosis is a leading cause of morbidity worldwide; only one-third of persons start treatment, and outcomes are often inadequate. Several trials demonstrate 90% efficacy using an all-oral, 6-month regimen of bedaquiline, pretomanid, and linezolid (BPaL), but significant toxicity occurred using 1200-mg linezolid. After US Food and Drug Administration approval in 2019, some US clinicians rapidly implemented BPaL using an initial 600-mg linezolid dose adjusted by serum drug concentrations and clinical monitoring. METHODS: Data from US patients treated with BPaL between 14 October 2019 and 30 April 2022 were compiled and analyzed by the BPaL Implementation Group (BIG), including baseline examination and laboratory, electrocardiographic, and clinical monitoring throughout treatment and follow-up. Linezolid dosing and clinical management was provider driven, and most patients had linezolid adjusted by therapeutic drug monitoring. RESULTS: Of 70 patients starting BPaL, 2 changed to rifampin-based therapy, 68 (97.1%) completed BPaL, and 2 of the 68 (2.9%) experienced relapse after completion. Using an initial 600-mg linezolid dose daily adjusted by therapeutic drug monitoring and careful clinical and laboratory monitoring for adverse effects, supportive care, and expert consultation throughout BPaL treatment, 3 patients (4.4%) with hematologic toxicity and 4 (5.9%) with neurotoxicity required a change in linezolid dose or frequency. The median BPaL duration was 6 months. CONCLUSIONS: BPaL has transformed treatment for rifampin-resistant or intolerant tuberculosis. In this cohort, effective treatment required less than half the duration recommended in 2019 US guidelines for drug-resistant tuberculosis. Use of individualized linezolid dosing and monitoring likely enhanced safety and treatment completion. The BIG cohort demonstrates that early implementation of new tuberculosis treatments in the United States is feasible.

Cohort study of the mortality among patients in New York City with tuberculosis and COVID-19, March 2020 to June 2022.

Both tuberculosis (TB) and COVID-19 can affect the respiratory system, and early findings suggest co-occurrence of these infectious diseases can result in elevated mortality. A retrospective cohort of patients who were diagnosed with TB and COVID-19 concurrently (within 120 days) between March 2020 and June 2022 in New York City (NYC) was identified. This cohort was compared with a cohort of patients diagnosed with TB-alone during the same period in terms of demographic information, clinical characteristics, and mortality. Cox proportional hazards regression was used to compare mortality between patient cohorts. One hundred and six patients with concurrent TB/COVID-19 were identified and compared with 902 patients with TB-alone. These two cohorts of patients were largely demographically and clinically similar. However, mortality was higher among patients with concurrent TB/COVID-19 in comparison to patients with TB-alone, even after controlling for age and sex (hazard ratio 2.62, 95% Confidence Interval 1.66-4.13). Nearly one in three (22/70, 31%) patients with concurrent TB/COVID-19 aged 45 and above died during the study period. These results suggest that TB patients with concurrent COVID-19 were at high risk for mortality. It is important that, as a high-risk group, patients with TB are prioritized for resources to quickly diagnose and treat COVID-19, and provided with tools and information to protect themselves from COVID-19.

Low-Level Rifampin Resistance and rpoB Mutations in Mycobacterium tuberculosis: an Analysis of Whole-Genome Sequencing and Drug Susceptibility Test Data in New York.

Rapid and reliable detection of rifampin (RIF) resistance is critical for the diagnosis and treatment of drug-resistant and multidrug-resistant (MDR) tuberculosis. Discordant RIF phenotype/genotype susceptibility results remain a challenge due to the presence of rpoB mutations that do not confer high levels of RIF resistance, as have been exhibited in strains with mutations such as Ser450Leu. These strains, termed low-level RIF resistant, exhibit elevated RIF MICs compared to fully susceptible strains but remain phenotypically susceptible by mycobacterial growth indicator tube (MGIT) testing and have been associated with poor patient outcomes. Here, we assess RIF resistance prediction by whole-genome sequencing (WGS) among a set of 1,779 prospectively tested strains by both prevalence of rpoB gene mutation and phenotype as part of routine clinical testing during a 2.5-year period. During this time, 139 strains were found to have nonsynonymous rpoB mutations, 53 of which were associated with RIF resistance, including both low-level and high-level resistance. Resistance to RIF (1.0 µg/ml in MGIT) was identified in 43 (81.1%) isolates. The remaining 10 (18.9%) strains were susceptible by MGIT but were confirmed to be low-level RIF resistant by MIC testing. Full rpoB gene sequencing overcame the limitations of critical concentration phenotyping, probe-based genotyping, and partial gene sequencing methods. Universal clinical WGS with concurrent phenotypic testing provided a more complete understanding of the prevalence and type of rpoB mutations and their association with RIF resistance in New York.

Bedaquiline for the Treatment of Multidrug-resistant Tuberculosis in the United States.

BACKGROUND: In 2012, the Food and Drug Administration approved use of bedaquiline fumarate as part of combination therapy for multidrug-resistant tuberculosis (MDR TB). We describe treatment outcomes, safety, and tolerability of bedaquiline in our case series. METHODS: Data on patients started on bedaquiline for MDR TB between September 2012 and August 2016 were collected retrospectively through 4 TB programs using a standardized abstraction tool. Data were analyzed using univariate methods. Adverse events were graded using the Common Terminology Criteria for Adverse Events. RESULTS: Of 14 patients, 7 (50%) had MDR, 4 (29%) had pre-extensively drug-resistant (XDR), and 3 (21%) had XDR TB. All had pulmonary TB, 5 (36%) had pulmonary and extrapulmonary TB, and 9/13 (69%) were smear positive. One patient (7%) had HIV coinfection, 5 (36%) had diabetes mellitus, and 5/14 (36%) had previous treatment TB. All patients were non-US-born and 5/14 (36%) had private insurance. All patients achieved sputum culture conversion within a mean of 71 days (26-116); 5 after starting bedaquiline. Twelve (86%) completed treatment and 1 (7%) moved out of the country. One patient (7%) had QTc prolongation >500 milliseconds and died 20 months after discontinuing bedaquiline of a cause not attributable to the drug. Common adverse events were peripheral neuropathy 7/14 (50%), not customarily associated with bedaquiline use, and QTc prolongation 6/14 (43%). CONCLUSIONS: Of 14 patients, 1 (7%) had an adverse event necessitating bedaquiline discontinuation. Safety, culture conversion, and treatment completion in this series (7%) support use of bedaquiline for the treatment of MDR/XDR TB.

Linezolid use for treatment of multidrug-resistant and extensively drug-resistant tuberculosis, New York City, 2000-06.

UNLABELLED: Rationale Linezolid may be effective for the treatment of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB); however, serious adverse events are common and there is little information on the management of these toxicities. METHODS: We retrospectively reviewed public health and medical records of 16 MDR TB patients, including 10 patients with XDR TB, who were treated with linezolid in New York City between January 2000 and December 2006, to determine treatment outcomes and describe the incidence, management and predictors of adverse events. RESULTS: Linezolid was added to MDR TB regimens for a median duration of 16 months (range: 1-29). Eleven patients (69%) completed treatment, four (25%) died and one (6%) discontinued treatment without relapse. Myelosuppression occurred in 13 (81%) patients a median of 5 weeks (range: 1-11) after starting linezolid, gastrointestinal adverse events occurred in 13 (81%) patients after a median of 8 weeks (range: 1-57) and neurotoxicity occurred in seven (44%) patients after a median of 16 weeks (range: 10-111). Adverse events were managed by combinations of temporary suspension of linezolid, linezolid dose reduction and symptom management. Five (31%) patients required eventual discontinuation of linezolid. Myelosuppression was more responsive to clinical management strategies than was neurotoxicity. Leucopenia and neuropathy occurred more often in males and older age was associated with thrombocytopenia (P < 0.05). CONCLUSIONS: The majority of MDR TB patients on linezolid had favourable treatment outcomes, although treatment was complicated by adverse events that required extensive clinical management.