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