Module 3: Drug-Resistant TB

Learning Objectives Describe how drug resistance emerges Explain the difference between primary and secondary resistance Explain indications for drug susceptibility testing Name 6 ways to prevent MDR TB

Types of TB Resistance Confirmed mono-resistance: Tuberculosis in patients whose infecting isolates of M. tuberculosis are confirmed to be resistant in vitro to one first line anti- tuberculosis drug Confirmed poly-resistance: Tuberculosis in patients whose infecting isolates are resistant in vitro to two or more first line anti- tuberculosis drug other than both isoniazid and rifampicin. Confirmed MDR-TB: Tuberculosis in patients whose infecting isolates are resistant in vitro to at least both isoniazid and rifampicin.

Multi-Drug Resistant TB MDR TB does not simply mean resistance to more than one drug, it specifically means resistance to at least both isoniazid (H) and rifampin (R)

Drug Resistance Patterns Predicted by (mis)use of drugs over time Influenced by –Dates drug first used in humans –Penetration into local marketplace (changes in cost, regulatory approval) –Evolution of National TB Program (NTP) regimens –Introduction of free-of-charge Rx –Availability as OTCs

(H)Isoniazid (R)Rifampin (Z)Pyrazinamide (E)Ethambutol First-Line Second-Line Anti-TB Drugs Streptomycin Cycloserine Ethionamide Amikacin Ciprofloxacin

Drug-Resistant TB Drug-resistant TB is transmitted the same way as drug-susceptible TB Drug resistance is divided into two types: - Primary resistance refers to cases initially infected with resistant organisms - Acquired resistance develops during TB therapy

Persons at Increased Risk for Drug Resistance History of treatment with TB drugs Contacts of persons with drug-resistant TB Smears or cultures remain positive despite 2 months of TB treatment Received inadequate treatment regimens for >2 weeks

“Inadequate Treatment” Multi-factorial –Lack of adherence/intermittent or interrupted therapy –Malabsorption –Inappropriate regimens; to properly treat TB one must always add at least two drugs to a failing regimen –Sub-therapeutic dosing –Expired or substandard drugs

Example of Management Errors Resulting in Acquired Drug Resistance 35 MDR TB cases referred to US TB specialty hospital Average 3.9 errors per patient –Inadequate primary regimen –Addition of single drug to failing regimen –Failure to address non-adherence Isoniazid alone used for misdiagnosed LTBI –i.e., active TB patients on monotherapy Mahmoudi A, Iseman MD. JAMA 1993;270:65-68

Biologic Basis of Drug Resistant M. tuberculosis

Selected Spontaneous Mutations Drug Frequency Isoniazid 1/1,000,000 Pyrazinamide 1/1,000,000 Streptomycin 1/1,000,000 Ethambutol 1/100,000 Rifampin 1/100,000,000 H and R resistance mutation frequency = 1:10 14

Pathogenesis Susceptible bacilli are killed Resistant bacilli grow and become dominant Further sequential selection can produce multi-drug resistance

INH RIF PZA INH Spontaneous drug- resistant mutations in bacterial population Selection of INH-resistant bacterial population

INH RIF INH Additional spontaneous mutations Selection and establishment of MDR

Indications for DST Drug susceptibility testing indicated for –all retreatment cases prior to initiation of treatment –Any patient who does not respond to therapy Conduct culture and DST for patients who – Have positive smears despite 2 months of therapy

Consequences of MDR Delay in diagnosis Treatment duration extended –18 to 24 mo. Second line drugs –Effectiveness decreases –Toxicity increases Expensive to treat Community transmission

How we can prevent MDR TB Initial treatment with standardized regimens (HRZE) Directly observed therapy (DOT) Drug susceptibility testing for all retreatment cases Infection control precautions Monitor drug resistance through surveys Effective contact management