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