Pretomanid Mechanism and BPaL Use in Drug-Resistant TB

　　1.Drug Class

　　Pretomanid is a nitroimidazo-oxazine antimycobacterial prodrug.

　　It requires intrabacterial activation and is not a standalone first-line TB drug.

　　2.Activation

　　Mycobacterium tuberculosis uses:

　　Fgd1→reduced F420;

　　Ddn nitroreductase→reduces pretomanid imidazole ring;

　　des-nitro metabolites+reactive nitrogen species.

　　Human enzymes lack F420-dependent denitration,giving selectivity but also a resistance route via ddn/fgd1/fbi mutations.

　　3.Dual Activity

　　Aerobic:block ketomycolate synthesis→weaken cell wall→kill replicating bacilli.

　　Anaerobic:nitric oxide release→respiratory poisoning→kill non-replicating persisters.

　　4.Who It Is For

　　Adults with:

　　MDR/RR-TB;

　　pre-XDR/XDR context;

　　inadequate response or intolerance to standard regimen;

　　given with bedaquiline+linezolid±moxifloxacin.

　　Not for drug-susceptible TB,latent TB,extrapulmonary label use,children,or unknown allergy.

　　5.Dosing

　　oral,with food;

　　once daily;

　　fixed short-course regimen length per protocol(~26 weeks);

　　directly observed therapy;

　　no double dose on miss.

　　6.Safety Monitoring

　　Hepatotoxicity

　　ALT/AST/bilirubin at baseline,weekly month 1,every 2 weeks month 2,then monthly.

　　Myelosuppression(linezolid-driven)

　　CBC at baseline,week 2,monthly;hold/reduce linezolid if anemia,neutropenia,or platelets<50×10⁹/L.

　　QT prolongation

　　ECG before and during therapy;caution with bedaquiline,long QT,hypokalemia.

　　Neuropathy/optic

　　Numbness,visual change→linezolid toxicity review.

　　7.Resistance Note

　　Do not escalate dose on failure.

　　Resistance usually comes from lost activation(Ddn/F420),not target mutation;monotherapy selects resistant clones.Keep combination complete.