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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
Anti-TB Drugs

First-Line Second-Line

• (H) Isoniazid • Streptomycin


• (R) Rifampin • Cycloserine
• (Z) Pyrazinamide • Ethionamide
• (E) Ethambutol • 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
Spontaneous drug-
resistant mutations in
bacterial population INH
RIF
PZA

INH

Selection of INH-resistant bacterial population


Additional spontaneous
mutations

INH INH
RIF

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