ATS GUIDELINES Bundle

9 Table 2a. Clinical Strategy to Build an Individualized Treatment Regimen for MDR-TB • Build a regimen using ≥5 drugs to which the isolate is susceptible (or has low likelihood of resistance), preferably with drugs that have not been used to treat the patient previously. • Choice of drugs is contingent upon capacity to appropriately monitor for significant adverse effects, patient comorbidities, and preferences/values (choices therefore subject to program and patient safety limitations). • In children with TB disease who are contacts of infectious MDR-TB source cases, the source case's isolate DST result should be used if an isolated is not obtained from the child. • TB expert medical consultation is recommended (ungraded good practice statement). STEP 1 Choose one later-generation fluoroquinolone • Levofloxacin • Moxifloxacin STEP 2 Choose both of these prioritized drugs • Bedaquiline • Linezolid STEP 3 Choose both of these prioritized drugs • Clofazimine • Cycloserine/terizidone STEP 4 If a regimen cannot be assembled with five effective oral drugs, and the isolate is susceptible, use one of these injectable agents a • Amikacin • Streptomycin STEP 5 If needed or if oral agents preferred over injectable agents in STEP 4, use the following drugs b • Delamanid c • Pyrazinamide • Ethambutol STEP 6 If limited options and cannot assemble a regimen of five effective drugs, consider use of the following drugs • Ethionamide or prothionamide d • Imipenem-cilastin/clavulanate or meropenam/clavulanate e • p-Aminosalicylic acid f • High-dose isoniazid g e following drugs are no longer recommended for inclusion in MDR-TB regimens: • Capreomycin and kanamycin • Amoxicillin/clavulanate (when used without a carbapenem) • Azithromycin and clarithromycin a Amikacin and streptomycin should be used only when the patient's isolate is susceptible to these drugs. Because of their toxicity, these drugs should be reserved for when more effective or less toxic therapies cannot be assembled to achieve a total of five effective drugs. b Patient preferences in terms of the harms and benefits associated with injectables (the use of which is no longer obligatory), the capacity to appropriately monitor for significant adverse effects, consideration of drug-drug interactions and patient comor-bidities should be considered in selecting Step 5 agents over injectables. Ethambutol and pyrazinamide had mixed/marginal performance on outcomes assessed in our PS-matched IPDMA. However, some experts may prefer these drugs over injectable agents to build regimen of at least 5 effective oral drugs. Use pyrazinamide and ethambutol only when the isolate is documented as susceptible. c Data on dosing and safety of delamanid are available in children ≥3 years of age. d Mutations in the inhA region of the M. tuberculosis genome can confer resistance to ethionamide/ prothionamide as well as to INH. In this situation, ethionamide/prothionamide may not be a good choice unless the isolate is shown to be susceptible with in vitro testing. e Divided daily intravenous dosing limits feasibility. Optimal duration of use not defined. f Fair/poor tolerability and low performance. Adverse effects reported to be less common in children. g Data not reviewed in our PS-matched IPDMA, but high-dose isoniazid can be considered despite low-level isoniazid resistance but not with high level INH resistance.

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