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 = 1:1014

Pathogenesis

• Susceptible bacilli are killed

• Resistant bacilli grow and become dominant

• Further sequential selection can produce multi-drug resistance

INHRIFPZA

INH

Spontaneous drug-resistant mutations in bacterial population

Selection of INH-resistant bacterial population

INHRIF

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