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
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