Multidrug-Resistant TB:

A Challenge and Its Prevention

Dr. Hermawan Chrisdiono,

Sp.P
RSUD Kabupaten Kediri

Infection
Exposed
to
DR-TB

Disease

Infection
with
drug resistant
strain
Risk factors

Risk factors

Drug-resistant
tuberculosis
Risk
factors

Drug-susceptible
Tuberculosis
Expose
d to
DS-TB

Infection with
drug-susceptible
strain

DOTS acceleration
ISTC 2006/2009
TB/HIV Collaboration
DOTS-plus

DOTS

TB CASES
HIV Epidemic
& MDR-TB

Patientcentered care
approach

DEFINITION
Primary resistance
drug resistance among new cases
never received TB drugs or received them for
<1
month
new terminology adopted by WHO :
Resistance
among new cases

Secondary (Acquired) resistance

drug resistance in a patient who previous

received at
least 1 month of TB therapy
WHO/IUATLDadopted
Global Project by
Drug-Resistance
Report No. 3
new terminology
WHO :Surveillance
Resistance
among

 Mono Drug Resistance

against only one drug

Definition
s

Poly Drug Resistance

against two or more drugs, but not against both H and R,
e.g. against S and H
(These are less serious because they can be effectively treated with the
cat I and II regimen, using first-line TB drugs)

Multi Drug Resistance

against at least H and R

Extensive Drug Resistance (XDR-TB)

MDR
AND against a fluoroquinolone
AND against one or more of the injectable drugs:
kanamycin, amikacin, capreomycin

Complete (Totally) Drug Resistance

How Does Drug-Resistant TB Develop

Wild
Wild M.
M. tuberculosis
tuberculosis
strain
strain
Spontaneous mutation
Drug-resistant
Drug-resistant strain
strain
Selection by poor
regimen, drug supply or
adherence
Acquired
Acquired drug
drug resistance
resistance
Transmission due to
diagnostic delays,
overcrowding and
inadequate infection control
Primary
Primary drug
drug resistance
resistance

The March of Resistance

Drug
suscepti
ble TB*
*or limited
resistance
manageable
with 4 drug
regimen DOTS

MDRTB

XDRTB

Total
DR TB

1990

2006

Resistance to
H&R

Resistance to HR
and 2nd line drugs

Arises from
Arises from
mismanageme mismanagemen
nt of TB
t of MDR
Treatable with Treatment
2nd line drugs

Treatment
options
seriously
restricted

Resistance
to all
available
drugs
No
treatment
options

MDR-TB causes
(from program
perspective)

Regimen prescription (providers!)

Wrong drugs or combination of drugs
Wrong duration

Drug management
Quality
Loose drugs instead of FDCs
Penetration in local marketplace

Case management (providers!)

No observation (DOT)

Risk factors MDR-TB

(from patient history)
Previous treatment
Relapses
Failures
Chronics

Contacts with drug resistant TB

Residence/birth in high prevalence setting
Failure to convert at 2 months
HIV infection
Inadequate infection control measures

Causes of Inadequate antituberculosis

treatment

Magnitude of the MDR-TB

problem
WHO estimates incident cases in
2003 458.000 (95% conf limits,
321.000-689.000)
Most MDR TB cases are not
diagnosed !!
Prevalent cases estimates to be
two or three times higher than
incident cases

Estimated Global MDR

Cases
Estimated global incidence and proportion
of MDR among TB cases, 2004
2004
New Cases
Previously
treated cases
Total cases

TB cases

MDR cases

8,897,743

272,906

2.7

982,639

181,408

18.5

9,880,382

424,203

4.3

Zignol M, et al. JID 2006; 194: 479-85

Distribution of MDR: No Prior

Treatment

Distribution of MDR rates among new cases (previously untreated)

Zignol M, et al. JID 2006; 194: 479-85

Distribution of MDR: Prior

Treatment

Distribution of MDR rates among previously treated cases

Zignol M, et al. JID 2006; 194: 479-85

Problem analysis MDR in

Indonesia
Only 20% of hospitals & < 5% of private
providers are currently involved in DOTS
No data on TB drug resistance, except for
few small studies (West Java MDR: 5% !!!).
Some second line drugs are free available on
the market and currently used in first line
regimens!
Neglect to take treatment history causes
miss- classification and under-treatment..

Risk factors for increase of

MDR
in Therapeutic
Indonesia
(1)
chaos : prescription of inadequate

doses / combinations of drugs

Many TB patients are treated by private providers,
not following DOTS

unsupervised treatment, no monitoring

no registration, no reporting
high costs to the patients (fees)
Un-controlled use of second-line drugs in hospitals
and private sector (quinolones, kanamycin etc)
Poor treatment performance in most hospitals:
low conversion rate & low cure rate because many
patients drop-out from treatment.
inadequate drug supplies and distribution

Risk factors for increased

MDR
in Indonesia (2)

Currently the chronic TB cases

cannot be treated (no DOTS plus
available)
These chronic cases continue to
transmit drug resistant TB

TB- HIV is looming

The real
MDR-TB/
XDR-TB in
Indonesia

MDR-TB: A Challenge to
Health System
Case identification of MDR-TB requires culture,
species identification, and drug susceptibility
testing
How many quality assured laboratory to be
established to ensure accessibility, taking into
account the size of population, geographic
characteristics and the epidemic of tuberculosis?

Treatment success (%)

MDR is More Costly to Cure

(Peru)
100

$20-40

$50 400

$1,000 - 10,000

80
60
40
20
0

All TB

Re-treatment

MDR TB

MDR-TB is harder to cure

100

all TB

MDR-TB

Treatment success (%)

80
60
40
20
0

Russia

Dominican
Rep.

Korea

Peru

Hong Kong

Espinal MA et al. JAMA 2000; 283:2537-2545

Individual Impact of MDR

Average direct medical costs per
case in the US: $27,752 [Burgos, et al. CID
2005; 40: 968-75]

Long treatment duration (18-24

mos.), often difficult and toxic
Long periods of isolation may be
necessary
Depression is common
Disease may be incurable (chronic)
Higher rate of death

History

1994

Global drug resistance surveillance project launched

1999

Stop TB Working Group on DOTS-Plus for MDR-TB

1999

Negotiations with pharmaceutical industries

2000

Green Light Committee Initiative launched

2000

First DOTS-Plus project launched

2002

The Global Fund decides that all MDR-TB drugs

should go through the GLC mechanism

2005

MDR-TB control proven feasible and cost-effective

2006

WHO MDR-TB guidelines, Global Plan to Stop TB,

New Stop TB Strategy (DR-TB component 2)

2006

2009

New funding Initiatives UNITAID

WHA recommended tool for scaling up MDR-TB
management

DOTS-Plus scale up of through the GLC

September 2005 35 projects

GLC approved projects through June 2009

Uncertain
demand

1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.

Belize
Bolivia
Costa Rica
Dominican Republic
Ecuador
El Salvador
Guatemala
Haiti
Honduras
Mexico
Nicaragua
Paraguay
Peru
Uruguay

1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.

Burkina Faso
Cameroon
DR Congo
Ethiopia
Guinea
Kenya
Lesotho
Liberia
Mozambique
Rwanda
Senegal
Swaziland
Uganda
Tanzania

Higher
price

1.
2.
3.
4.
5.
6.

Egypt
Jordan
Lebanon
Pakistan
Syria
Tunisia

1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.

Azerbaijan
Armenia
Belarus
Bulgaria
Estonia
Georgia
Kazakhstan
Kyrgyzstan
Latvia
Lithuania
Moldova
Romania
Russia
Serbia
Tajikistan
Ukraine
Uzbekistan

1.
2.
3.
4.
5.
6.
7.
8.

Bangladesh
Bhutan
India
Indonesia
Myanmar
Nepal
Sri Lanka
Timor-Leste
1.
2.
3.
4.
5.
6.
7.

GLC-approved projects in 66 countries

~ 54'550 patients approved for

Cambodi
a
China
Micronesi
a
Mongolia
Philippin
es
Samoa
Vietnam

Parameters to consider
when designing a DOTSPlus strategy
Government and NTP commitment
Well performing basic DOTS
Program is able to implement the 5 components of
DOTS-Plus
Rational case-finding strategy using quality assured
smear, culture and DST ( concordance with a SRL)
Representative DRS data for rational country/areaspecific treatment design and planning of procurement
Reliable DOT throughout treatment
Free effective side-effect management
Regular supply of ALL drugs involved!

Assessment of sites: Issues that

need to be addressed in all sites
Lack of EQA assured lab capacity
Inadequate use of available second
line drugs (inadequate regimens,
financial barriers, no SL-DST)
No experience with 4 types of SLD
Alternative for family member DOT
Funding of hospitalization, lab tests,
human resources, incentives.

Why should Indonesia consider

to use the GLC mechanism ?

Access to a complex market of

quality assured second line
drugs
Preferential prices (pooled
procurement)
Technical assistance ; benefiting
from GLC experiences worldwide
Requirement of the GFATM
grant / International quality label

Preparation
Programmatic management of DR-TB (DOTSPlus)
Assesment / Situation Analysis
DOTS progress & capacity
capacity)

(case management, Lab

Magnitude of MDR-TB (DRS, Treatment Failure Rate etc)

Resistance pattern (DRS)
Drug distribution (Cat-1 and cat-2)

Analysis on relevancy
Feasibility
Lab preparation (improvement & EQA)
Pilotting (Area & Institution)

Scale-up step-wise

How to detect
MDR-TB

M(X)DR-TB Suspects

(1)

High probability of resistance

I am
a
suspect
MDR-TB

Failures Cat II and

Chronics (>80%),
Failure Cat I
Exposure to known MDRTB case (80%)

M(X)DR-TB Suspects

(2)

Middle probability of
Failures resistance
from private sector
I am
a
suspect
MDR-TB

Cat I remaining AFB+ at

months 2-3
Relapses
Return after default
Exposure in institutions with
high MDR-TB
Residence in high MDR-TB
prevalence area
History!! of poor (or
unknown) quality TB drugs,
poor

M(X)DR-TB Suspects

(3)

Low probability of resistance

Diarrhoea:
malabsorption of
drugs
HIV in some
areas associated
with MDR-TB

MDR-TB suspects in
Indonesia

Chronic cases

Patients failing re-treatment (category 2)

Including second line drugs such as quinolones and

kanamycin (in hospital, private sector)

Patients failing first line (category 1) treatment

Patient still smear positive at month 3 of first line
(category 1) treatment
Relapse cases
Patients who return after default

Proven with information from the TB register

Patients reporting previous TB treatment

Proven with previous patients card and from history

After category 1 and/or category 2 treatment

Symptomatic TB suspects reporting close contact

with confirmed MDR-TB patients

Including health care workers in the MDR-TB ward

How to Designing
MDR-TB Regimen

Principles of MDR treatment

At least 4 drugs with (almost) certain
effectiveness
No drugs from failing regimen.
Initial phase 6 months, at least 6 days
per week
Smears and culture monthly till culture
conversion
Continuation (after conversion) for at
least 18 months
DOT throughout
DST guiding treatment

Grouping of anti TB drugs

Grouping

Drugs

Group 1 : first-line oral

anti TB drugs

INH (H), Rif (R), Ethambutol

(E), Pyrazinamide (Z)

Group 2 : injectable anti

TB agents

Streptomycin (S), Kanamycin

(Km), Amikacin (Am),
Capreomycin (Cm), Viomycin
(Vi)

Group 3 :
fluoroquinolone

Cypro (cfx), oflo (ofx), levo

(lfx), moxifloxacin (mfx),
gatifloxacin (gfx)

Group 4 : oral
bacteriostatic secondline anti TB agents

Ethionamid (Eto),
Protheonamide (Pto),
cycloserin (Cs), Terizidone
(Trd), p-aminocaliclic acid
(PAS), Theocetazon (Th)

Group 5 : anti TB agents

with unclear efficacy
(not recommended by
WHO for routine use in

Clofazimine (Cfx),
Amoxicillin/Clavulanat
(Amx/Clv), Linezolid (Lzo)

WHO, 2006

Second-Line Drug Classes for MDR TB Treatment

Aminoglycosides
Polypeptides
First
line
drugs

Fluoroquinolones

+
Thioamides
Serine analogues

Amikacin, Kanamycin
Capreomycin
Ciprofloxacin, Ofloxacin
Ethionamide, Prothionamide
Cycloserine

PAS
WHO. Guidelines for the programmatic management of drug-resistant tuberculosis. 2006.

You Cannot Cure MDR-TB

As Fast As You Can Create
It
Lalloo UG et al
Recent Advances in the Medical & Surgical Treatment of MDR-TB
Curr Opin Pulm Med (2004)

Management Principles
Isolate until three consecutive
sputum AFB smears are negative
and there has been a good clinical
response to treatment
Initiate MDR-TB treatment in hospital
if possible to provide patient
education and monitoring and to
treat drug toxicity
Tailor toxicity monitoring to specific
drugs employed

Management Principles (2)

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 and nutritional
status

Framework Component 3:
Appropriate treatment strategies that utilize SLDs
under proper management conditions
Management of
adverse
drug reactions and
co-morbidities
Health education
and
counseling
Provision of
enablers

You just have to take the

pills and thats it!
E. Jaramillo, 2006

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)

How do we respond to the

MDR-TB/XDR-TB problem?
We need to address the known factors
contributing to drug-resistance
1.
2.
3.
4.
5.
6.
7.

No supervised treatment
Bad adherence / supervision
No standard treatments
Frequent drug stock-outs
Anti-TB drugs of poor quality
Non-programmatic management
No hospital infection control

To implement
a good DOTS
Programme,
with quality

Prior to starting an MDR-TB project, it is mandatory to address

adequately all these factors
J P Caminero

Summary

Treatment of MDR TB: not cost

effective
Technically difficult and
yields low cure rates
Expensive, drawing
resources away from the
treatment of pansusceptible disease
Treatment of drugresistant strains, when
improperly monitored,
give rise to even more
resistant organisms
Decreased virulence and
transmissibility of MDR
TB strains

Summary (2)

DOTS! and nothing else!

TB is being defeated
by model DOTS
program.
DOTS is our best
hope of preventing
the emergence of
resistance to anti-TB
drugs

TOP MANAGEMENT
PREVENTION
DOTS STRATEGY

MDR-TB

ISTC
2006/200
9

Thank You