Bedaquiline microbiology

Bedaquiline
SIRTURO® FDA Package Insert
Description
Clinical Pharmacology
Indications and Usage
Microbiology
Contraindications
Warnings and Precautions
Adverse Reactions
Overdosage
Dosage and Administration
How Supplied
Labels and Packages

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Chetan Lokhande, M.B.B.S [2]

Microbiology

Mechanism of Action

Bedaquiline is a diarylquinoline antimycobacterial drug that inhibits mycobacterial ATP (adenosine 5'-triphosphate) synthase, an enzyme that is essential for the generation of energy in Mycobacterium tuberculosis.

Mechanisms of Resistance

Mycobacterial resistance mechanisms that affect bedaquiline include modification of the atpE target gene. Not all isolates with increased minimum inhibitory concentrations (MICs) have atpE mutations, suggesting the existence of at least one other mechanism of resistance.

Spectrum of Activity

Bedaquiline has been shown to be active against most isolates of Mycobacterium tuberculosis.

Susceptibility Test Methods

In vitro susceptibility tests should be performed according to published methods1,2. Based on the available information, susceptibility test interpretive criteria for bedaquiline cannot be established at this time. When susceptibility testing is performed by the 7H10 or 7H11 agar method, a range of concentrations from 0.008 microgram per mL to 1.0 microgram per mL should be assessed. The minimum inhibitory concentration (MIC) should be determined as the lowest concentration of bedaquiline that results in growth of less than or equal to 1% of the residual subpopulation. When susceptibility testing is performed by the resazurin microtiter assay (REMA) method, a range of concentrations from 0.008 microgram per mL to 1.0 microgram per mL should be assessed. The MIC should be determined as the lowest concentration of bedaquiline that prevents a visible change of resazurin color from blue to pink. All assays should be performed in polystyrene plates or tubes. Löwenstein-Jensen (LJ) medium should not be used. The actual MIC should be reported. A specialist in drug-resistant TB should be consulted in evaluating therapeutic options. The bedaquiline agar (left) and REMA (right) MIC distributions against clinical isolates resistant to isoniazid and rifampin from Studies 1, 2, and 3 are provided below.

MICs for baseline M. tuberculosis isolates from subjects in Studies 1 and 3 and their sputum culture conversion rates at Week 24 are shown in Table 2 below. No correlation was seen between the culture conversion rates at Week 24 and baseline MICs.

In SIRTURO-treated patients from Studies 1, 2, and 3, with at least a four-fold increase in bedaquiline MIC from baseline and with atp operon sequencing results, no coding variation in the atp operon was seen, suggesting a mechanism of resistance other than mutations in the atpE gene. Of these subjects for the agar method, patients who experienced failure to convert their sputum or relapsed (n = 9) had post-baseline isolates with 4-fold to greater than 8-fold increases in MIC (corresponding to post-baseline MICs of 0.24 to greater than 0.48 microgram/mL). For the REMA method, patients who experienced failure or relapsed had post-baseline isolates with 4-fold to greater than 16-fold increases in MIC (corresponding to post-baseline MICs of 0.015 to 1.0 microgram/mL). All 9 subjects with increased MICs and failure or relapse were infected with MDR-TB isolates that were resistant to additional antimycobacterial drugs in their treatment regimen.

Quality Control

Susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of testing. Assays using standard bedaquiline powder should provide the following range of MIC values shown in Table 3.a

References

Adapted from the FDA Package Insert.