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Management of
Drug-Resistant
Tuberculosis
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International Standard 12
Management of Drug-Resistant TB
Objectives: At the end of this presentation,
participants will be able to:
 Describe the principles upon which treatment of
drug-resistant TB is based
 Understand the essential features of MDR-TB
case management
 Recognize the importance of patient-centered
DOT in MDR-TB treatment
 Become familiar with common side effects of
drugs used in the treatment of MDR-TB
ISTC TB Training Modules 2009
Management of Drug-Resistant TB
Overview:
 Definitions and predictors of
drug resistance
 Treatment principles
 Case-management principles
 Patient-centered directly
observed therapy
 Common side effects of
MDR-TB treatment
International Standards 12
Standard 12: Management of Drug-Resistant TB
(1 of 2)
 Patients with or highly likely to have tuberculosis
caused by drug-resistant (especially MDR/XDR)
organisms should be treated with specialized
regimens containing second-line antituberculosis
drugs
 The regimen chosen may be standardized or based
on suspected or confirmed drug susceptibility
patterns
 At least four drugs to which the organisms are
known or presumed to be susceptible, including an
injectable agent, should be used, and treatment
should be given for at least 18–24 months beyond
culture conversion
ISTC TB Training Modules 2009
Standard 12: Management of Drug-Resistant TB
(2 of 2)
 Patient-centered
measures, including
observation of treatment,
are required to ensure
adherence
 Consultation with a
provider experienced in
treatment of patients with
MDR/XDR tuberculosis
should be obtained
ISTC TB Training Modules 2009
Drug-Resistant TB: Definitions
 Mono-resistant: Resistance to a single drug
 Poly-resistant: Resistance to more than one
drug, but not the combination of isoniazid and
rifampicin
 Multidrug-resistant (MDR): Resistance to at
least isoniazid and rifampicin
 Extensively drug-resistant (XDR): MDR plus
resistance to fluoroquinolones and at least 1 of
the 3 injectable drugs (amikacin, kanamycin,
capreomycin)
ISTC TB Training Modules 2009
Drug-Resistant TB: Definitions
 Primary drug-resistance: “New Cases”
Drug resistance in a patient who has never
been treated for tuberculosis or received less
than one month of therapy
 Secondary (acquired) drug-resistance:
“Previously Treated Cases”
Drug resistance in a patient who has
received at least one month of anti-TB
therapy
ISTC TB Training Modules 2009
Recognizing Predictors of Drug-resistant TB
Assess drug resistance in any patient being
started on treatment for tuberculosis
 Nonadherence, default
 History of prior treatment
 Exposure to possible drug-resistant source
case
 Community prevalence of drug resistance
If drug resistance is suspected based on any of
the above factors, culture and susceptibility testing
should be performed for at least INH and
rifampicin
ISTC TB Training Modules 2009
Empiric Regimens for Drug-resistant TB
Predicted
Resistance Pattern
Empiric Regimen
(minimum duration)
INH
RIF, EMB, PZA (6-9 mo)
INH, EMB
RIF, PZA, Fluoroquinolone +
Injectable (9-12 mo)
RIF
INH, EMB + PZA (18 mo minimum)
RIF, EMB
INH, Fluoroquinolone,
PZA + Injectable
(18-month minimum)
INH = Isoniazid, RIF = Rifampicin, EMB = Ethambutol, PZA = Pyrazinamide
Note: PZA does not prevent acquired resistance to companion drugs.
ISTC TB Training Modules 2009
Multidrug-Resistant TB
“I have been treated several times over the past five years
and I’m still coughing and can’t gain weight!”
ISTC TB Training Modules 2009
MDR/XDR Treatment Strategies: WHO
Three approaches to treatment:
 Standardized regimens
 Empiric regimens
 Individualized treatment regimens
(based on DST results)
The choice among these should be based on:
 Availability of second-line drugs
 Local drug-resistance patterns, and the history of use
of second-line drugs
 Drug susceptibility testing of first- and second-line
drugs
ISTC TB Training Modules 2009
Categories of Antituberculosis Drugs: WHO
 Group 1 – First-line drugs: Isoniazid, rifampicin,
ethambutol, pyrazinamide
 Group 2 - Injectable agents: Kanamycin,
amikacin, capreomycin, streptomycin
 Group 3 - Fluoroquinolones: Levofloxacin,
moxifloxacin, ofloxacin
 Group 4 - Oral bacteriostatic agents:
Ethionamide, cycloserine, para-aminosalicylic acid
(PAS), prothionamide, terizadone
 Group 5 – Unclear role: Clofazamine, linezolid,
amoxicillin/clavulanate, Imipenem/cilastatin,
thioacetazone, high-dose isoniazid, clarithromycin,
ISTC TB Training Modules 2009
Designing an MDR/XDR Treatment Regimen
General Principles, WHO
 Use of at least four drugs highly likely to be
effective
 Do not use drugs for which there is
cross-resistance
 Eliminate drugs that are unsafe for the patient.
 Include drugs from groups 1-5 in a hierarchical
order based on potency
 Be prepared to prevent, monitor and manage
adverse effects from the drugs selected
ISTC TB Training Modules 2009
Additional Important Principles: WHO
 Use direct observation of treatment (DOT)
with a patient-centered approach to care
 Use daily, not intermittent, administration
 Treatment duration of a minimum of 18-24
months after culture conversion
 When possible, continue injectable for
minimum six months (at least 4 months
post-culture conversion)
 Continue at least three oral drugs for full
treatment duration
ISTC TB Training Modules 2009
Potential Effectiveness: WHO
Effectiveness is supported by a number of factors:
 Demonstrated susceptibility




No history of treatment failure with the drug
No contacts with resistance to the drug
Resistance rare in similar patients (surveys)
Drug is not commonly used in the area
If at least four drugs are not certain to be effective,
use five to seven drugs, depending on specific
drugs and degree of certainty.
ISTC TB Training Modules 2009
Cross-Resistance: WHO
 All rifamycins: high level cross-resistance
 Fluoroquinolones: variable, but probably
should be assumed to be cross-resistant
 Amikacin and kanamycin: generally highly
cross-resistant, but both should be tested
 Capreomycin and aminoglycosides:
occasional cross-resistance,
susceptibilities should be tested
ISTC TB Training Modules 2009
Drug Contraindications: WHO
 Known severe drug allergy
 Unmanageable drug intolerance
 Risk of severe toxicity, with symptoms
such as renal failure, hepatitis, hearing
loss, depression, and psychosis
 Drugs of unknown quality (lack of quality
assurance exposes patient to risks with
unknown benefits)
ISTC TB Training Modules 2009
Determining Drugs to Use: WHO
 Use any first-line drug likely to be effective
(Group1)
 Include aminoglycoside or capreomycin
(Group 2)
 A fluoroquinolone should always be used if
deemed likely to be effective (Group 3)
 Use remaining Group 4 drugs to make a
regimen of at least four effective agents
 Use Group 5 drugs as needed to make a
regimen of at least four effective agents
ISTC TB Training Modules 2009
Empiric Regimens for MDR-TB
Predicted
Resistance Pattern
Empiric Regimen
INH, RIF
Fluoroquinolone, PZA, EMB,
Injectable
INH, RIF, EMB
Fluoroquinolone, PZA,
Injectable, CS, + PAS or ETH
INH, RIF, PZA
Fluoroquinolone, EMB,
Injectable, CS, + PAS or ETH
INH, RIF, PZA, EMB
Fluoroquinolone, Injectable, CS,
PAS or ETH, + one more drug
INH = Isoniazid, RIF = Rifampicin, EMB = Ethambutol, PZA = Pyrazinamide
CS = Cycloserine, PAS = P-aminosalicylic acid, ETH = Ethionamide
ISTC TB Training Modules 2009
Building a Regimen for MDR-TB
STEP 1
Begin with any
first-line agents
to which the
isolate is
susceptible
Add a
fluoroquinolone
and an
injectable drug
based on
susceptibilities
ISTC TB Training Modules 2009
Use any
available
One of
these
First-line
drugs
Fluoroquinolones
Injectable
agents
Pyrazinamide
Levofloxacin
Amikacin
Ethambutol
Moxifloxacin
Capreomycin
Ofloxacin
Streptomycin
One of
these
Kanamycin
Building a Regimen for MDR-TB
STEP 2
If 4 drugs are
not identified in
Step 1:
Add second-line
drugs until you
have four to six
drugs to which
the isolate is
susceptible (and
preferably which
have not been
used to treat the
patient
previously)
ISTC TB Training Modules 2009
Pick one or more of these
Oral second-line drugs
Cycloserine
Ethionamide
PAS
Building a Regimen for MDR-TB
STEP 3
If there are not
four to six
drugs available
in the above
categories,
consider
third-line drugs
in consultation
with an expert.
ISTC TB Training Modules 2009
Consider use of these
Third-line drugs
Clofazimine
Imipenem
Linezolid
Clarithromycin
Amoxicillin/
Clavulanate
Building a Regimen for XDR-TB
STEP 1
Begin with any
first-line agents
to which the
isolate is
susceptible
Add a
fluoroquinolone
and an
injectable drug
based on
susceptibilities
ISTC TB Training Modules 2009
Use any
available
One of
these
First-line
drugs
Fluoroquinolones
One of
these
Injectable
agents
Pyrazinamide Levofloxacin
Ethambutol
Moxifloxacin
Ofloxacin
Amikacin ?
Capreomycin ?
Streptomycin ?
Kanamycin ?
Commonly not
susceptible
Select agent
based on history
and susceptibility
testing
By definition
there is
fluoroquinolone
resistance
Building a Regimen for XDR-TB
STEP 2
Add secondline drugs until
you have four
to six drugs to
which the
isolate is
susceptible
(and preferably
which have not
been used to
treat the
patient
previously)
ISTC TB Training Modules 2009
Pick one or more of these
Oral second-line drugs
Cycloserine
Ethionamide
PAS
With XDR-TB, often
all three of these agents
are necessary
Building a Regimen for XDR-TB
STEP 3
If there are not
four–six drugs
available in the
above
categories,
consider thirdline drugs in
consultation
with an expert.
ISTC TB Training Modules 2009
Consider use of these
Third-line drugs
Clofazimine
Imipenem
Linezolid
Clarithromycin
Amoxicillin/
Clavulanate
Initiating Treatment: WHO
 Ensure laboratory services for hematology,
biochemistry and audiometry are available
 Establish a clinical and laboratory baseline
before starting the regimen
 Initiate treatment gradually when using drugs
that cause gastro-intestinal intolerance
 Ensure availability of ancillary drugs to manage
adverse effects
 Use DOT for all doses
ISTC TB Training Modules 2009
MDR/XDR-TB: Management Principles
 Isolate until three consecutive sputum AFB
smears (or documented culture conversion) are
negative and there has been a good clinical
response to treatment
 Initiate MDR-TB treatment under close
supervision to provide patient education and
monitoring and to treat drug toxicity
 Tailor toxicity monitoring to specific drugs
employed
 Seek consultation with an expert as soon as
drug resistance is known
ISTC TB Training Modules 2009
MDR/XDR-TB: Management Principles
 Use daily patient-centered DOT throughout
entire treatment course
 Record drugs given, bacteriological results,
chest radiographic findings, and the occurrence
of toxicities
 Optimize management of underlying medical
conditions (example: diabetes) and nutritional
status
ISTC TB Training Modules 2009
MDR/XDR-TB: Monitoring
 Collect sputum specimens for smear and culture
periodically during treatment once culture
negative
 Obtain end-of-treatment sputum specimen for
smear and culture
 Perform chest radiograph periodically during
treatment and at end of treatment
 Resources permitting, monitor minimum of two
years following treatment (quarterly during first
year, every six months during second year)
ISTC TB Training Modules 2009
MDR/XDR-TB: Laboratory Testing
 As soon as rifampicin
resistance is known,
order second-line
drug susceptibility
testing
 Repeat susceptibility
testing on cultures
that remain positive
after two–three
months of treatment
ISTC TB Training Modules 2009
Patient-centered DOT
More Than Watching Patients
Swallow Their Pills
 DOT is a support system that enables
the completion of the long, difficult
course of MDR-TB treatment
 A patient requires respect and dignity
regardless of social class, educational
level or unhealthy behaviors
 The whole patient, lifestyle and support
system are assessed and routinely
addressed in the delivery of care
 Goal: Inspire and empower patient via
a relationship of trust and support
ISTC TB Training Modules 2009
Directly Observed Treatment
Effect on Resistance and Relapse
Self-RX
DOT
N=407 (pre 1987)
N=581 (1987 +)
Primary R
13.0%
6.7%
Secondary R
10.3%
1.4%
Relapse
20.9%
5.5%
MDR relapse
6.1%
0.9%
* P < 0.001
ISTC TB Training Modules 2009
Weis SE, et al. NEJM 1994; 330(17): 1179-84
Common Adverse Effects
G.I. complaints
Ethionamide
Cycloserine
PAS
Fluoroquinolones
Clofazimine
Rifabutin
Hepatotoxicity
(early symptoms are anorexia
and malaise, then abdominal
pain, vomiting, jaundice)
INH
Rifampicin/rifabutin
Ethionamide
PZA
PAS
Fluoroquinolones
ISTC TB Training Modules 2009
Common Adverse Effects
Peripheral neuropathy
INH
Ethionamide
Cycloserine
Linezolid
Ethambutol
Rash
All
Headache
Fluoroquinolones
Isoniazid
Cycloserine
Ethionamide
Ethambutol
Seizures
Cycloserine
ISTC TB Training Modules 2009
Common Adverse Effects
Hypothyroidism
Ethionamide, PAS
Hearing loss,
Vestibular toxicity
Aminoglycosides,
Capreomycin
Behavioral changes
Cycloserine, Ethionamide,
Isoniazid, Fluoroquinolones
Visual changes
Ethambutol, Rifabutin,
Isoniazid, Linezolid
Renal failure
Hypokalemia,
Hypomagnesemia
Aminoglycosides,
Capreomycin
ISTC TB Training Modules 2009
Management of Drug-Resistant TB
Summary:
 Treatment of MDR-TB is complex and
costly. It is much easier to prevent than to
treat. XDR-TB is even more difficult!
 Expert consultation should be obtained
whenever possible when MDR- or XDRTB is suspected.
ISTC TB Training Modules 2009
Management of Drug-Resistant TB
Summary (cont.):
 Patients can be treated with a
standardized or an empiric regimen.
Ideally the regimen should be guided by
drug-susceptibility tests.
 There are sound principles that can be
used to guide the design of a treatment
regimen.
ISTC TB Training Modules 2009
Management of Drug-Resistant TB
Summary (cont.):
 Considerable attention must be paid to
treatment supervision and support.
 A patient-centered approach to DOT is an
important element of successful care.
 Adverse effects of second-line drugs are
common and may be severe. Monitoring
for these effects is essential.
ISTC TB Training Modules 2009
Summary: ISTC Standard Covered*
Standard 12:
 Patients with TB caused by drug-resistant
(especially MDR) organisms should be
treated with specialized regimens containing
second-line antituberculosis drugs.
 At least four drugs to which the organisms
are known or presumed to be susceptible
should be used (treatment for at least 18
months).
*[Abbreviated version]
ISTC TB Training Modules 2009
Summary: ISTC Standard Covered*
Standard 12 (cont.):
 Patient-centered measures are required to
ensure adherence.
 Consultation with a provider experienced in
treatment of patients with MDR-TB should be
obtained.
*[Abbreviated version]
ISTC TB Training Modules 2009
Alternate Slides
ISTC TB Training Modules 2009
Resources
 WHO: Guidelines for the Programmatic
Management of Drug-Resistant Tuberculosis,
Emergency Update 2008
www.who.int/tb
 Drug-Resistant Tuberculosis,
A Survival Guide for Clinicians, 2nd edition 2008
www.nationaltbcenter.ucsf.edu
 The PIH guide to the Medical Management of
Multidrug-Resistant Tuberculosis, International
Edition. Partners in Health 2003.
www.pih.org
ISTC TB Training Modules 2009
Purpose of ISTC
ISTC TB Training Modules 2009
ISTC: Key Points
 21 Standards (revised/renumbered in 2009)
 Differ from existing guidelines: standards
present what should be done, whereas,
guidelines describe how the action is to be
accomplished
 Evidence-based, living document
 Developed in tandem with Patients’ Charter
for Tuberculosis Care
 Handbook for using the International
Standards for Tuberculosis Care
ISTC TB Training Modules 2009
ISTC: Key Points
 Audience: all health care practitioners,
public and private
 Scope: diagnosis, treatment, and public
health responsibilities; intended to
complement local and national guidelines
 Rationale: sound tuberculosis control
requires the effective engagement of all
providers in providing high quality care and
in collaborating with TB control programs
ISTC TB Training Modules 2009
Questions
ISTC TB Training Modules 2009
Management of Drug-Resistant TB
1. The 5 year-old son of a woman you are currently
treating for known isoniazid and rifampicin resistant
tuberculosis presents with cough and malaise for
three weeks and an abnormal chest film. Of the
following available regimens, choose the one best
option:
A. Begin empiric treatment with at least four drugs that the
mother’s organism is known to be susceptible to
B. Begin empiric treatment with the standard initial regimen of
isoniazid, rifampicin, ethambutol, and pyrazinamide with the
addition of a fluoroquinolone
C. Begin empiric treatment with the standard initial regimen of
isoniazid, rifampicin, ethambutol, and pyrazinamide
D. Treat first for a potential community-acquired pneumonia with a
fluoroquinolone
ISTC TB Training Modules 2009
Management of Drug-Resistant TB
2. Reasonable steps for building a regimen for
multidrug-resistant tuberculosis after drugsensitivities results are known include all of the
following except:
A. Always start by choosing any available first-line drug that the
isolate remains susceptible to
B. Aim for a total of four to six drugs that the isolate is known to
be sensitive to (preferably not drugs used previously by the
patient)
C. Second-line agents (like cycloserine, ethionimide, and PAS)
would be preferred over injectable agents to minimize
healthcare resources used in association with injections and
improve patient comfort
D. If there are not four to six drugs available among the first- and
second-line agents, third-line agents could be considered,
preferably in consultation with an expert
ISTC TB Training Modules 2009
Management of Drug-Resistant TB
3. Clinical management and monitoring plans for
the care of MDR/XDR-TB should include (as
resources permit) all of the following except:
A. Daily patient-centered directly observed treatment
(DOT) throughout the entire treatment course
B. Diligent recording of drugs given, bacteriological
results, chest film findings and any occurrence of
medication toxicity
C. Periodic sputum specimens for smear and culture,
both to document culture conversion and monitor
for signs of treatment failure
D. Monthly sputum for drug-sensitivity testing
throughout the entire course of treatment
ISTC TB Training Modules 2009