2. 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
3. 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.
4. 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)
5. 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
7. 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
8. 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
9. “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
10. 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
12. 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
13. Pathogenesis
• Susceptible bacilli are killed
• Resistant bacilli grow and become dominant
• Further sequential selection can produce
multi-drug resistance
16. 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
17. 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
18. 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
Editor's Notes
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Abbreviated MDR TB
Multi-drug resistant tuberculosis is disease caused by Mycobacterium tuberculosis, resistant to at least isoniazid and rifampin, the two most potent anti-TB medications.
MDR is an imperfect name as it does not simply mean resistance to more than one drug
TB strains resistant to more than one drug other than HR referred to as “poly-resistant”
Country and regional-level drug resistance patterns are predicted by the use and mis-use of drugs over time in a given area.
Drug resistance depends upon when a drug was first introduced, how accessible it is to consumers (determined by regulatory approval and price), what the NTP regimens include, and whether prescription drugs are available free-of-charge or available over-the counter. For example, in some countries where fluoroquinalones area available over the counter, the rate of FQ resistance among MDR patients who have not even received FQs for their TB can be as high as 20%.
Any history of exposure to anti-Tb drugs indicates increased risk of resistance to TB drugs; and
Contacts of drug-resistant cases are at increased risk of drug resistance.
Patients whose smears remain positive through the intensive phase have an increased risk of resistance, another reason to be sure that the continuation phase is not initiated without bacteriological confirmation of smear-conversion.
And finally, patients who received inadequate treatment—which can be defined in many ways--are also at increased risk– and we will get more into this during the lecture.
Inadequacy can refer to many things.
Treatment is inadequate as a result of frequent interruptions, intermittent therapy and default
Malabsorption is also an issue because patients don’t actually absorb the full dose of the drug-
A regimen can be inadequate because it contains a drug to which the patient is not fully susceptible- regimens should contain only drugs to which the patient is fully susceptible
Sub-therapeutic dosing can result in inadequate treatment, failure or relapse because the patient is not receiving enough drugs- i.e., a therapeutic dose. Monthly weighing is essential b/c as the patient recovers and gains weight, you wants to be sure the dosing remains adequate to the patient’s weight.
The purchase of substandard drugs or the use of expired drugs also contributes to inadequate treatment, again, because the patient is not receiving an effective regimen. It is important to verify that all stocks are not expired, and stored in a cool, dry place, out of direct sunlight.
Tuberculosis mycobacterium are estimated to have spontaneous random mutations for resistance to specific drugs at the rates indicated in the table.
Put simply, about 1 in a million organisms will have a random mutation making it INH resistant. Ethambutol resistance, which occurs in about 1, 100,000 organisms is then 10X more common.
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So how does drug-resistant TB develop?
Drug-resistant TB emerges when drug-susceptible bacilli are killed and leave resistant organisms to grow and become dominant. Over time, as the numbers of resistant bacilli increase, further random mutations produces multidrug resistance.
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Here’s an illustration of how drug resistance develops. The empty circles represent drug-susceptible organisms. The lettered circles represent drug-specific resistant organisms.
Drug-resistant mutants are selected when therapy is inadequate, for instance, when a single drug, in this case isoniazid, is used to treat a large population of bacilli. The treatment with a single drug kills the majority of the bacilli in the population, but the small number of mutants resistant to the drug continue to multiply.
If an appropriate regimen is started, as illustrated at the top, all drug-susceptible and drug-resistant bacilli are killed.
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Now in the inadequate regimen, continued growth of the selected isoniazid-resistant organisms over time leads to an abundance of resistant organisms, and results in clinical drug resistance. Furthermore, in a large population of resistant organisms, additional doubly resistant organisms exits.
Again, if the treatment regimen is inadequate and a single drug, rifampin, is added, further selection of multidrug resistant organisms can occur.
Drug Susceptibility Testing, or DST, is indicated for ALL retreatment cases prior to the initiation of therapy
It is also indicated for any patient who is not responding to therapy
