3.0 Drug Resistance (1)

8/11/2019 3.0 Drug Resistance (1)

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Module 3: Drug-Resistant TB


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Learning Objectives

Describe how drug resistance

emerges

Explain the difference betweenprimary and secondary resistance

Explain indications for drug

susceptibility testing Name 6 ways to prevent MDR TB


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Types of TB Resistance

Confirmed mono-resistance: Tuberculosis in patientswhose infecting isolates of M. tuberculos is areconfirmed to be resistant in vitro to one first line anti-tuberculosis drug

Confirmed poly-resistance:Tuberculosis in patientswhose infecting isolates are resistant in vitro to two ormore first line anti- tuberculosis drug other than bothisoniazid and rifampicin.

Confirmed MDR-TB:Tuberculosis in patients whose

infecting isolates are resistant in vitro to at least bothisoniazid and rifampicin.


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Multi-Drug Resistant TB

MDR TBdoes not simply mean resistance

to more than one drug, it specificallymeans resistance to at least both isoniazid

(H) and rifampin (R)


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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


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(H) Isoniazid

(R) Rifampin

(Z) Pyrazinamide (E) Ethambutol

First-Line Second-Line

Anti-TB Drugs

Streptomycin

Cycloserine

Ethionamide Amikacin

Ciprofloxacin


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Drug-Resistant TB

Drug-resistant TB is transmitted the same way as

drug-susceptible TB

Drug resistance is divided into two types:

-Primary resistancerefers to cases initially

infected with resistant organisms

-Acquired resistancedevelops during TB therapy


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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 despite2 months of TB treatment

Received inadequate treatment regimens for>2 weeks


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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


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Example of Management Errors Resulting in

Acquired Drug Resistance

35 MDR TB cases referred to US TB specialty hospit

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


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Biologic Basis of Drug

Resistant M. tubercu los is


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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


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Pathogenesis

Susceptible bacilli are killed

Resistant bacilli grow and become dominant

Further sequential selection can produce

multi-drug resistance


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INHRIF

PZA

INH

Spontaneous drug-

resistant mutations in

bacterial population

Selection of INH-resistant bacterial population


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INHRIF

INH

Additional spontaneou

mutations

Selection and establishment of MDR


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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 oftherapy


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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


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How we can prevent MDR TB

Initial treatment with standardized regimens(HRZE)

Directly observed therapy (DOT)

Drug susceptibility testing for all retreatmentcases

Infection control precautions

Monitor drug resistance through surveys Effective contact management

3.0 Drug Resistance (1)

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