Promethazine use and QT prolongation risk during treatment with a shortened all-oral regimen for MDR/RR-TB

Q: What is the clinical evidence from this study?

Study design: Cohort. Population: Multidrug- or rifampicin-resistant tuberculosis (MDR/RR-TB) (n=247). Intervention: Promethazine vs. Unexposed periods. Primary outcome: Time to first clinically relevant QTc prolongation (incident grade ≥3, >500 ms) (HR 7.0, 95% CI 1.4-35.3).

Q: What does this research mean for the field?

Promethazine use is associated with a significantly increased risk of clinically relevant grade ≥3 QTc prolongation in patients receiving a shortened all-oral MDR/RR-TB regimen. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

Edmund Q L Shen; Letizia Trevisi; Stephane Mpinda; Allison LaHood; Llang Maama; Meseret Tamirat; Sebakeng Phate; Lawrence Oyewusi; Matthew L. Romo; Elna Osso; Michael Rich; Carole Diane Mitnick; Kwonjune J. Seung; Molly F Franke; Kunda Kwabisha Mikanda

doi:10.1093/jacamr/dlag215

September 1, 2026JAC-Antimicrobial ResistanceOpen Access

Promethazine use and QT prolongation risk during treatment with a shortened all-oral regimen for MDR/RR-TB

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Key result

Promethazine exposure during MDR-TB therapy linked to ~7-fold higher incidence of severe QTc prolongation.

HR 7.0
95% CI 1.4-35.3
n=247

Why the study?

Whether adjunctive promethazine increases the risk of clinically relevant QTc prolongation during shortened all-oral MDR/RR-TB regimens containing multiple QTc-prolonging agents was unclear.

Does adjunctive promethazine increase the risk of clinically relevant QTc prolongation in patients receiving a shortened all-oral regimen for MDR/RR-TB?

Key Points

To evaluate whether adjunctive promethazine exposure increases the risk of clinically relevant QTc prolongation in patients receiving a shortened all-oral regimen for multidrug- or rifampicin-resistant tuberculosis.
Conducted a secondary analysis of a prospective observational cohort in Lesotho among 247 participants aged ≥15 years receiving a 9- to 12-month all-oral regimen (bedaquiline, linezolid, levofloxacin, clofazimine, delamanid) for pulmonary MDR/RR-TB.
Modelled time-varying promethazine exposure using the Andersen-Gill formulation of Cox regression with time-to-first grade ≥3 (>500 ms) QTc event as the primary endpoint, alongside comparator analyses for metoclopramide and ondansetron.
Grade ≥3 QTc prolongation occurred in 10 of 247 participants (4.0%), with incidence rates of 7.4 per 10 000 person-days during promethazine-exposed periods versus 1.3 per 10 000 person-days during unexposed periods (HR 7.0, 95% CI: 1.4–35.3).
No comparable risk elevation was observed with exposure to metoclopramide (1.4 versus 1.7 events per 10 000 person-days; HR 1.0, 95% CI: 0.3–3.6), ondansetron (0 events), or episodes of nausea, dizziness, or vomiting (HR 1.5, 95% CI: 0.3–6.9).

Study Design

Type

Cohort (n=247)

Multicenter

Yes

Structured PICO

Does adjunctive promethazine increase the risk of clinically relevant QTc prolongation in patients receiving a shortened all-oral regimen for MDR/RR-TB?

P

Population

247 patients aged ≥15 years with pulmonary MDR/RR-TB and no baseline QTc prolongation, treated with a 9- to 12-month all-oral regimen.

E

Exposure

Time-varying exposure to adjunctive promethazine (prescribed for anti-emesis).

C

Comparator

Unexposed person-time periods; comparator analyses were also conducted with time-varying exposure to metoclopramide, ondansetron, and episodes of nausea, dizziness, and vomiting.

O

Outcome

Time to first clinically relevant QTc prolongation (incident grade ≥3, >500 ms event) during treatment.safety

Main Result

Hazard Ratio: 7 (95% CI 1.4–35.3)

Absolute Event Rate: 7.4% vs 1.3%

Adjunctive promethazine significantly increases the risk of severe QTc prolongation in patients treated with a QTc-burdening MDR/RR-TB regimen, highlighting the need for safer antiemetic alternatives in this setting.

Limitations

Small number of incident QTc events, limiting multivariable adjustment and statistical precision.
Residual confounding by unmeasured on-treatment factors cannot be excluded.
Promethazine exposure was derived from prescription records rather than plasma drug concentrations.
Small number of incident QTc events, limiting multivariable adjustment and statistical precision
Residual confounding by unmeasured on-treatment factors cannot be excluded
Promethazine exposure was derived from prescription records rather than plasma drug concentrations

Implication

Caution advised with promethazine in MDR/RR-TB; hypothesis-generating for antiemetic selection pending trials.

Abstract

Background Shortened all-oral regimens for multidrug- or rifampicin-resistant tuberculosis (MDR/RR-TB) combine multiple QTc prolonging agents, including bedaquiline and delamanid, which act partly through hERG potassium channel binding. Promethazine, a first-generation antihistamine used for nausea during TB therapy, shares this mechanism. Whether adjunctive promethazine further raises the risk of clinically relevant QTc prolongation in this setting is unclear. Methods We conducted secondary analyses from a prospective observational cohort study of patients ≥15 years in Lesotho who received a 9- to 12-month all-oral regimen (bedaquiline, linezolid, levofloxacin, clofazimine, delamanid) for pulmonary MDR/RR-TB. We modelled time-varying promethazine exposure using the Andersen-Gill formulation of Cox regression, with time-to-first grade ≥3 (>500 ms) QTc event as the outcome of interest. We conducted comparator analyses with time-varying exposure to metoclopramide, ondansetron, and episodes of nausea, dizziness, and vomiting. Results Among 247 participants (median age 41, 63.2% living with HIV), 62 (25.1%) received promethazine. Grade ≥3 QTc prolongation occurred in 10 (4.0%). Incident clinically significant QTc prolongation was higher during promethazine-exposed than unexposed periods (7.4 versus 1.3 per 10 000 person-days; HR 7.0, 95% CI: 1.4–35.3). No comparable elevation was seen in analyses of exposure to metoclopramide (HR 1.0, 95% CI: 0.3–3.6), ondansetron, or episodes of nausea, dizziness, or vomiting (HR 1.5, 95% CI: 0.3–6.9). Conclusions Promethazine use was associated with increased risk of clinically relevant QTc prolongation within a QTc-burdened all-oral MDR/RR-TB regimen. These findings provide preliminary evidence that clinicians may consider when selecting anti-emetics as part of MDR/RR-TB therapy with a shortened all-oral regimen and highlight the importance of evaluating adjunctive medications in DR-TB care.

Discussion

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Cite This Study

Shen et al. (2026) conducted a cohort in Multidrug- or rifampicin-resistant tuberculosis (MDR/RR-TB) (n=247). Promethazine vs. Unexposed periods was evaluated on Time to first clinically relevant QTc prolongation (incident grade ≥3, >500 ms) (HR 7.0, 95% CI 1.4-35.3). Promethazine exposure during a shortened all-oral MDR/RR-TB regimen was associated with a higher incidence of grade ≥3 QTc prolongation (7.4 vs 1.3 per 10,000 person-days; HR 7.0) compared to unexposed periods.

synapsesocial.com/papers/6ac835407c3139e1cb0e7dae https://doi.org/10.1093/jacamr/dlag215

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Promethazine use and QT prolongation risk during treatment with a shortened all-oral regimen for MDR/RR-TB

Key Points

Study Design

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

Promethazine use and QT prolongation risk during treatment with a shortened all-oral regimen for MDR/RR-TB

Key Points

Study Design

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

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