Unit 11: Drug Resistance
and MDR-TB
Botswana National Tuberculosis Programme
Manual Training for Medical Officers
Objectives
At the end of this unit, participants will be able to:
• Describe the development of drug resistance
• Select and manage patients with mono-, multiand poly-drug resistant TB
• Identify when to perform sputum culture and
sensitivity tests and whom to refer for
subsequent categories of treatment
Unit 11: Drug Resistance and MDR TB
Slide 11-2
Drug Resistance Definitions
• Drug Resistance: isolates of M. tuberculosis
resistant to 1 or more anti-TB drugs
• Primary Resistance
• Any patient with resistance and <1 month of ATT
• Often contacts of drug resistant patients infected with
DR strain
• Acquired Resistance
• Development of in vitro resistance to anti-TB drugs
during TB therapy
Unit 11: Drug Resistance and MDR TB
Slide 11-3
Types of Resistance
• Confirmed mono-resistance: resistance to one
first line drug
• Confirmed poly-resistance: resistance to two or
more first line drugs, but not both isoniazid and
rifampicin
• Confirmed multi-drug resistant TB (MDR-TB):
resistance to at least both isoniazid and
rifampicin
Unit 11: Drug Resistance and MDR TB
Slide 11-4
Multi-Drug Resistant (MDR) TB
• Resistance to both isoniazid and rifampicin
• Loss of 2 most powerful TB drugs
• Disastrous for patient and community
• Category IV regimens
•
•
•
•
•
Less effective
Longer duration
More side-effects
Much more expensive +++
Lower chances of cure
Unit 11: Drug Resistance and MDR TB
Slide 11-5
MDR in Botswana
In 2005, MDR made up:
• 0.8% of new cases, 10.0% of retreatment
cases
In 1999, MDR made up:
• 0.5% of new cases and 9.0% of retreatment
cases
Unit 11: Drug Resistance and MDR TB
Sources: Talbot E, et al., 2003 (1999)
Decosas J, et al., 2005 (2005)
Slide 11-6
XDR-TB:
Extensively Drug Resistant TB
Tuberculosis resistant to:
INH & rifampicin
+
A fluoroquinolone
(ciprofloxacin, ofloxacin)
+
One or more of the second
line injectable ATT drugs:
kanamycin OR amikacin OR capreomycin
Unit 11: Drug Resistance and MDR TB
Slide 11-7
XDR-TB in South Africa
Study in 2006, Kwazulu-Natal:
• 544 TB patients suspected to have resistance; 221
had MDR-TB
• 53 of the 221 (24%) met criteria for XDR-TB
• 44 of the 53 were tested for HIV
• All were positive; 15 on ARVs
• 52 of 53 patients died within 25 days of suspecting
resistance– suggests high virulence
Unit 11: Drug Resistance and MDR TB
Source: The Lancet, 2006.
Slide 11-8
Risk Factors for Resistance (1)
Any patient with prior history of TB:
• Failure of first-line regimen
• Failure of re-treatment regimen and chronic TB
cases
• Patients who remain sputum smear-positive at two or
three months of short course chemotherapy
• Patients who revert from smear-negative to smearpositive at the end of the intensive phase
Unit 11: Drug Resistance and MDR TB
Slide 11-9
Risk Factors for Resistance (2)
•
•
•
•
•
Exposure to a known MDR-TB case
Poor adherence, malabsorption
Cavitary disease (high burden of organisms)
Inadequate treatment regimen
Administering fewer than the recommended
number of drugs (e.g., INH/RIF only during
intensive phase)
Unit 11: Drug Resistance and MDR TB
Slide 11-10
Suspected Drug Resistance
• When treatment is unsuccessful
• Relapse
• Treatment failure
• Return after default
• If patient is a contact of a patient with known
resistance
• Patient is a suspect while waiting for results
Unit 11: Drug Resistance and MDR TB
Slide 11-11
Confirmed Drug Resistance
• Confirmed by culture and drug sensitivity testing
(C/DST)
• Culture takes approximately 28-42 days; DST an
additional 28-42
• Culture and DST are indicated for ALL patients with
suspected drug resistance
• MDR-TB is a laboratory diagnosis
• All patients started on Category II regimen must
have culture and DST obtained
Unit 11: Drug Resistance and MDR TB
Slide 11-12
Confirmed MDR-TB
• All patients with confirmed MDR should be
referred for initiation and follow-up to:
• North: Nyangabgwe Referral Hospital,
Francistown
• South: Princess Marina Hospital, Gaborone
Unit 11: Drug Resistance and MDR TB
Slide 11-13
Development of Drug Resistance (1)
Two steps: Mutation and Selection
1. Mutation
•
•
Mutations conferring drug resistance occur in
individual organisms at a very low rate
With high numbers of organisms (lung cavity)
small populations resistant to each drug will exist
Unit 11: Drug Resistance and MDR TB
Slide 11-14
Development of Drug Resistance (2)
2. Selection
•
•
Organisms with resistant mutations to a
particular drug will have an advantage over
susceptible organisms when all are exposed to
that drug
The resistant organisms can outgrow the
susceptible organisms
Unit 11: Drug Resistance and MDR TB
Slide 11-15
Spontaneous Mutations to
Anti-Tuberculosis Medications
• Ethambutol and pyrazinamide: 1 in every 100,000 cell
divisions
• Isoniazid and streptomycin: 1 in every 1,000,000 cell
divisions
• Rifampicin: 1 in every 100,000,000 cell divisions
• Spontaneous development of MDR-TB bacilli is extremely
rare:
• 1 in every 100,000,000,000,000 (1014) cell divisions
• The product of the two probabilities of isoniazid and
rifampicin mutation
Unit 11: Drug Resistance and MDR TB
Slide 11-16
Development of Drug Resistance (3)
Spontaneous
drugresistant
mutations in
bacterial
population
INH
RIF
PZA
INH
Unit 11: Drug Resistance and MDR TB
Selection of
INH-resistant
bacterial
population
Slide 11-17
Development of Drug Resistance (4)
Additional
spontaneous
mutations
INH
INH
RIF
Selection and
establishment
of MDR
Unit 11: Drug Resistance and MDR TB
Slide 11-18
Pathogenesis of
Secondary Drug Resistance
Weeks of Rx:
0
16
24
+
+
+
INH
R
R
R
RIF
S
R
R
EMB
S
S
R
INH
RIF
EMB
Meanwhile, in the lab:
Culture
Unit 11: Drug Resistance and MDR TB
Slide 11-19
Common Forms of
Cross-Resistance
•
•
•
•
•
All rifamycins
Low-level INH resistance and ethionamide
Ethionamide and prothionamide
Amikacin and kanamycin
Fluoroquinolones (cipro and oflox– some next
generation FQL, such as Lfx and Mfx, may
retain activity)
• Do not use drugs for which resistance crosses
over
Unit 11: Drug Resistance and MDR TB
Slide 11-20
Prevention of Drug Resistance
• Provide high enough concentrations of drugs to kill
susceptible organisms
• Use drug combinations that are able to kill the small
numbers of organisms resistant to one or another of
the drugs
• Potent regimen (bactericidal, R and H)
• Multi-drug therapy for drugs to protect each other
from acquiring resistance
• Correct prescription, standardised regimens
• Adherence
Unit 11: Drug Resistance and MDR TB
Slide 11-21
Diagnosing MDR-TB
• Diagnosed through culture and DST of
specimens, usually sputum, from TB patients
• Obtain drug susceptibility testing for TB
patients that have risk factors for MDR-TB
• Chronic TB cases are especially at risk of
having MDR-TB
Unit 11: Drug Resistance and MDR TB
Slide 11-22
Pre-treatment Evaluation and
Care for MDR-TB Patients
• Initial labs include:
• HIV test, sputum smear microscopy, culture &
DST, pregnancy test
• Baseline renal, thyroid, and liver function tests
• Care can be hospital-based, clinic-based, or
community-based, but MUST have
uninterrupted quality drug supply
• Care should be given through multidisciplinary
team of providers
Unit 11: Drug Resistance and MDR TB
Slide 11-23
Treating Monoand Poly-resistant
TB
Needs to be managed by a specialist
Drug Resistance
Pattern
Suggested Regimen
Minimum Treatment
Duration (months)
H (+ S)
R, Z, E
H and Z
R, E, fluoroquinolones
9-12
H and E
R, Z, fluoroquinolones
9-12
R
H, E, fluoroquinolones + at least 2 months
of Z
6-9
12-18
R and E (+ S)
H, Z, fluoroquinolones + injectable agent for
at least first 2-3 months
18
R and Z (+ S)
H, E, fluoroquinolones + injectable agent
for at least first 2-3 months
18
H, E, Z (+ S)
R, fluoroquinolones + oral second-line
agent + injectable agent first 2-3 months
18
Unit 11: Drug Resistance and MDR TB
Slide 11-24
Category IV Drug Groups (1)
• Group I: first-line oral drugs
• H,R,E,Z
• Group II: injectable agents
• strep, amikacin, kanamycin, capreomycin
• Group III: fluoroquinolones
• Cfx, Ofx, Lfx, Mfx
Unit 11: Drug Resistance and MDR TB
Slide 11-25
Category IV Drug Groups (2)
• Group IV: oral bacteriostatic second-line drugs
• ethionamide, prothionamide, cycloserine,
terizidone, PAS, thiacetazone
• Group V: third-line agents with unclear efficacy
• clofazimine, amox/clav, linezolid
Unit 11: Drug Resistance and MDR TB
Slide 11-26
Basic Principles of
Individualised (Category IV) Regimen
Eliminate drugs that are not safe in the patient
• Ethionamide in pregnancy
• Cycloserine in someone with serious mental
health problems
• Injectable in pregnancy
• Severe allergy
Unit 11: Drug Resistance and MDR TB
Slide 11-27
Designing a Treatment Strategy
• Treatment strategy dependant on several
factors including:
•
•
•
•
National drug resistance surveys
Availability of drugs
Prevalence of drug resistance
Previous second-line drug exposure
• ALWAYS submit sputum for culture and
sensitivity testing if drug resistance suspected!
Unit 11: Drug Resistance and MDR TB
Slide 11-28
Standardised MDR
Treatment Regimens (1)
• A standardised Category IV treatment regimen
has been developed for Botswana
• Uses 5 initial drugs to cover most patterns of
resistance with at least 4 effective drugs
• First-line (H,R,E,S) results should be available
• An injectable agent and a fluoroquinolone
(FQL) are the core of the regimen
Unit 11: Drug Resistance and MDR TB
Slide 11-29
Standardised MDR
Treatment Regimens (2)
Continuation Phase
(min. 18 months)
•
•
•
•
Ethionamide
Ciprofloxacin
PZA
Ethambutol (if DST
sensitive)
• Cycloserine (if resistant
to ethambutol)
Unit 11: Drug Resistance and MDR TB
Intensive Phase
(min. 6 months)
•
•
•
•
•
Amikacin
Ethionamide
PZA
Ciprofloxacin
Ethambutol (if DST show
strain is sensitive)
• Cycloserine (if DST show
strain is resistant to
Ethambutol)
Slide 11-30
Building an MDR
Treatment Regimen
• Include drugs from Groups 1-4 in a
hierarchical order based on potency
•
•
•
•
Step 1: use any first-line drug still susceptible
Step 2: add an injectable agent
Step 3: add a fluoroquinolone
Step 4: use the remaining group IV drugs to make
a regimen with at least 4 effective drugs
• “More is better than less”
Unit 11: Drug Resistance and MDR TB
Slide 11-31
Duration of Treatment
• Injectable agent: minimum of 6 months
• Total treatment: 18 months after culture
conversion
• Some patients with extensive disease and
extensive prior treatment may be treated for 24
months
Unit 11: Drug Resistance and MDR TB
Slide 11-32
Monitoring During Treatment (1)
Monitoring Evaluation
Recommended Frequency
Evaluation by clinician
At baseline and at least monthly until culture
conversion, then every 2-3 months
Review by treatment caregiver
At every DOT encounter
Sputum smear and cultures
Monthly until the end of treatment
Weight
At baseline then monthly
Drug susceptibility testing
At baseline and every three months for patients
who remain culture positive.
Chest x-ray
At baseline and then at the end of treatment unless
indicated
Serum creatinine
At baseline and then monthly when receiving
injectable agent
Unit 11: Drug Resistance and MDR TB
Slide 11-33
Monitoring During Treatment (2)
Monitoring Evaluation
Recommended Frequency
Serum potassium
At baseline and then monthly when receiving
injectable agent
Thyroid stimulating hormone
Every six months if receiving ethionamide and /or
PAS; and monitor monthly for signs and symptoms
of hypothyroidism
Liver serum enzymes
Every 1-3 months in patients receiving
pyrazinamide for extended periods or for patients
at risk for or with symptoms of hepatitis
HIV testing
At baseline, and repeat if initially negative and
signs and symptoms of HIV infection develop
Pregnancy test
At baseline for women of childbearing age and
repeat if indicated
Unit 11: Drug Resistance and MDR TB
Slide 11-34
Interim Outcome Measures (1)
• Culture conversion: defined as two
consecutive negative cultures taken at least
30 days apart in patients with initially culturepositive TB
• Smear conversion:
• Two negative specimens at least 30 days apart
• With or without baseline culture
Unit 11: Drug Resistance and MDR TB
Slide 11-35
Interim Outcome Measures (2)
Time to sputum conversion
• Interval between start of treatment and date of
obtaining first negative specimen
• Record separately for smear and culture on
MDR patient treatment card
• Average time to culture conversion = 2 months
Unit 11: Drug Resistance and MDR TB
Slide 11-36
Special Situations (1)
• Fertile women
• Avoid pregnancy: use injectable medroxyprogesterone (Depo-Provera) and/or condoms
• Pregnancy
• Postpone second line until delivery if it is safe
• Due to potential drug toxicity
• Cycloserine may be safer than ethionamide
Unit 11: Drug Resistance and MDR TB
Slide 11-37
Special Situations (2)
• Breast-feeding
• If possible, smear + mothers should avoid contact with
their babies until they are smear negative
• Treatment of mother outweighs risks of toxicity to baby
• If safe and sustainable, artificial feeding would avoid risk of
infant toxicity
• Children
• Can use needed second-line agents
• Ciprofloxacin, ethionamide, cycloserine and amikacin successfully
used
• Monitor weight at each visit and adjust doses as needed
Unit 11: Drug Resistance and MDR TB
Slide 11-38
Common Side Effects (1)
• G.I. complaints
•
•
•
•
•
•
Ethionamide
Cycloserine
PAS
Quinolones
Clofazimine
Rifabutin
Unit 11: Drug Resistance and MDR TB
• Hepatotoxicity (early
symptoms are anorexia
and malaise, then abd
pain, vomiting, jaundice)
•
•
•
•
•
•
Isoniazid
Rifampicin
Ethionamide
Pyrazinamide
PAS
Fluoroquinolones
Slide 11-39
Common Side Effects (2)
• Behavioral changes
•
•
•
•
Cycloserine
Ethionamide
Isoniazid
Quinolones
• Hearing loss, vestibular
toxicity
• Aminoglycoside
• Capreomycin
• Hypothyroidism
• Ethionamide
• PAS
Unit 11: Drug Resistance and MDR TB
• Visual changes
•
•
•
•
Ethambutol
Rifabutin
Isoniazid
Linezolid
• Hypokalemia,
hypomagnesemia
• Aminoglycosides
• Capreomycin
• Rash
• All
Slide 11-40
Common Side Effects (3)
• Bone Marrow Suppression
• Rifampicin
• Isoniazid
• Linezolid
• Peripheral neuropathy
•
•
•
•
Isoniazid
Ethionamide
Cycloserine
Linezolid
Unit 11: Drug Resistance and MDR TB
• Seizures
• Isoniazid
• Cycloserine
• Fluorquinolones
• Headache
•
•
•
•
•
Fluroquinolones
Isoniazid
Cycloserine
Ethionamide
Ethambutol
Slide 11-41
Monitor for Efficacy
• Evidence of improvement
• Conversion of sputum smear and culture to
negative
• Culture conversion approximately 2 months
• Culture conversion is not the same as a cure
• Patients may initially convert and later revert to
culture positive status
• Chest X-ray may be unchanged or only show
slight improvement
Unit 11: Drug Resistance and MDR TB
Slide 11-42
Outcome Measures
•
•
•
•
•
•
Cure
Treatment Completed
Death
Treatment default
Treatment failure
Transfer out
Unit 11: Drug Resistance and MDR TB
Slide 11-43
Extensively Drug
Resistant (XDR) TB
• Also referred to as eXtremely Drug Resistant
TB in the past
• Term coined in early 2006 following a joint
survey by WHO and CDC
• Survey analysed data collected between
2000-2004; findings:
• XDR-TB in all regions of the world
• 4% of MDR-TB cases in US and 19% in Latvia
met criteria for XDR-TB
Unit 11: Drug Resistance and MDR TB
Source: WHO, 2008.
Slide 11-44
XDR-TB – Anti-TB Drugs
• XDR-TB virtually untreatable currently
• Global Alliance for Drug Development
• In clinical development:
• Moxifloxacin (INH sub.), Nitroimidazole PA-824
• In Discovery phase:
• Nitroimidazole Analogs
• Mycobacterial Gyrase Inhibitors
• InhA Inhibitors
• Pleuromutlinis
• Linezolid
Unit 11: Drug Resistance and MDR TB
Source: Global Alliance for TB Drug Development, 2007.
Slide 11-45
XDR-TB:
What Can We Do Meanwhile?
• Strengthen basic TB care, manage simple TB
• Prompt diagnosis and treatment of drug resistant
cases to prevent further transmission
• Send sputums for DST for 2nd line medicines
• Increase collaboration between HIV and TB control
programmes
• Retreatment cases
• Prevent transmission in the health care settings
Unit 11: Drug Resistance and MDR TB
Slide 11-46
Global Response to
MDR-TB & XDR-TB in 2007
• Strengthen basic activities to control TB and
HIV/AIDS
• Scale-up programmatic management
• Strengthen laboratory services
• Expand surveillance
• Foster infection control measures
• Strengthen ACSM
• Resource mobilization
• Promote research and development
Unit 11: Drug Resistance and MDR TB
Source: WHO, 2007.
Slide 11-47
Key Points
• It is better to prevent than to treat drug
resistance and MDR
• Standarised MDR treatment regimen should
be used whenever possible
• Side effects of MDR treatment are frequent
but manageable
• Important to monitor closely for treatment
efficacy and toxicity
Unit 11: Drug Resistance and MDR TB
Slide 11-48