Drug-resistant tuberculosis

Background

• Mycobacterium tuberculosis infection that is resistant to both first-line drugs, isoniazid and rifampin

Classification

• Multidrug resistant tuberculosis (MDR-TB): resistance to isoniazid and rifampicin
  • Rifampin monoresistance is quite rare, so MDR is usually inferred from rifampin resistance alone
• Extensively drug-resistant tuberculosis (XDR-TB): resistance to at least isoniazid and rifampicin, and to any fluoroquinolone, and to any of the three second-line injectables
• Totally drug-resistant tuberculosis (TDR-TB): not well-defined

Resistance Mechanisms

• 90% of isoniazid resistance is from known mutations in either the katG or InhA genes
• 95% of rifampin resistance is from known mutations in the rpoB gene

Risk Factors

• The strongest predictor of MDR-TB is prior TB treatment (increases from 3% to 18% of cases)
• Residence in country with higher rate of MDR-TB: India (8%/13% new/previous treatment), Philippines (12%/15%), China (7%/8%), Viet Nam (14%/10%), Pakistan (8%/7%), Ethiopia (6%/13%), Somalia (6%/8%), Haiti (unclear), Hong Kong (5%/7%), Afghanistan (unclear)
• Exposure to person with MDR-TB
• HIV infection
• Other risk factors include younger age and more recent arrival from endemic country

Management

• Rapid PCR testing for rifampin resistance should be considered in all patients, but definitely done if at increased risk of MDR-TB
• Referral to a specialized TB program
• First-line is generally a fluoroquinolone, bedaquiline, linezolid, clofazimine, and cycloserine
• Other regimens are any five drugs to which it is susceptible, in order of preference:
  • Group A: fluoroquinolones (except ciprofloxacin), bedaquiline, linezolid
  • Group B: clofazimine, cycloserine (or terizidone)
  • Group C: ethambutol, pyrazinamide, delamanid, amikacin (or streptomycin), imipenem-cilastatin (or meropenem), ethionamide, p-aminosalicylic acid
• For low-burden disease, can consider a 4-drug regimen
• Duration
  • Intensive phase (5 drugs) of 5 and 7 months after culture conversion, followed by consolidation phase with 4 drugs
  • Total treatment duration between 15 and 21  months after culture conversion

Novel Regimens

• Bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM) for 6 months now recommended by WHO

Specific Resistance Patterns

Resistance To	Replace With	Regimen	Total Duration
INH	FQN	6 months RMP+EMB+PZA+FQN	6 months from date FQN started
INH	FQN	2 months RMP+EMB+PZA+FQN then 4 months RMP+EMB+FQN	6 months from date FQN started
RMP	FQN	2 months daily INH+EMB+PZA+FQN then 10-16 months INH+EMB+FQN	18 months from date FQN started
RMP	None	2 months INH+EMB+PZA, then 16 months INH+EMB	18 months from date FQN started
EMB	None	2 months INH+RMP+PZA, then 4 months INH+RMP	6 months from start of therapy
PZA	None	2 months INH+RMP+EMB, then 7 months INH+RMP	9 months from start of therapy
INH+EMB	FQN	6 months daily RMP+PZA+FQN	6 months from date FQN started
INH+PZA	FQN	9 months RMP+EMB+FQN	9 months from date FQN started
INH+EMB+PZA	FQN+injectable	2 months TMP+FQN+injectable, then 7 months RMP+FQN	9 months from date FQN started