Drug-resistant tuberculosis: Difference between revisions

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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

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

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+== Background ==
-* [[Mycobacterium tuberculosis]] infection that is resistant to both first-line drugs, isoniazid and rifampin
+* [[Mycobacterium tuberculosis]] infection that is resistant to both first-line drugs, isoniazid and [[rifampin]]
-== Classification ==
+=== 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
-* 8 months of an intensive four-drug regimen that includes any four drugs to which it is susceptible, in order of preference:
+* Referral to a specialized TB program
-** Any first-line agents to which it is still susceptible
+* First-line is generally a [[Fluoroquinolones|fluoroquinolone]], [[bedaquiline]], [[linezolid]], [[clofazimine]], and [[cycloserine]]
-** A fluoroquinolone (except ciprofloxacin)
+* Other regimens are any five drugs to which it is susceptible, in order of preference:
-** An injectable: kanamycin, or other parenteral agent
+** Group A: [[fluoroquinolones]] (except [[ciprofloxacin]]), [[bedaquiline]], [[linezolid]]
-** Other second-line agents, starting with ethionamide
+** Group B: [[clofazimine]], [[cycloserine]] (or [[terizidone]])
-* Followed by 12 months of a less intensive regimen (at least three effective drugs), for a total of at least 20 months
+** 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
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