Multidrug resistant tuberculosis, Extended - Drug resistant tuberculosis, DOTS

A Global Emergency

Kills 5,000 people per day

2.3 million people die each year

Highly prevalent in Pakistan-the estimated

incidence is around 2,50,000 per year

Ranks 6th among the 22 high burden countries of

TB in the world.

The 22 countries most affected by

tuberculosis are Afghanistan, Bangladesh,

Brazil, Cambodia, China, the Democratic

Republic of Congo, Ethiopia, India,

Indonesia, Kenya, Myanmar, Nigeria,

Pakistan, Peru, the Philippines, Russia, South

Africa, Thailand, Tanzania, Uganda, Vietnam

and Zimbabwe

Emergence of multi-drug resistant

(MDR-TB), extremely drug resistant

tuberculosis (XDR-TB) and latent TB

have been the major constraints in

the eradication of TB.

Data from the latest 12 month

period

the highest ever number of infectious

patients – 2.3 million people – were

cured with the launch of DOTS

87% of treated patients being cured

85% global target was exceeded

estimated half a million MDR-TB cases

occur per year

almost 30 000 were officially reported

6000 known to be treated

but almost 29 ,000 people are expected to

be treated in 2010.

Eradicating M. tuberculosis infection

Preventing development of drug

resistance

Preventing relapse of infection

Occur in a patient who has never

received antituberculosis therapy

The development of resistance during or

following chemotherapy in patients who

previously had drug-susceptible

tuberculosis.

Main cause of primary drug resistance due Main cause of primary drug resistance due

to transmission of resistant strains.to transmission of resistant strains.

Cases of tuberculosis caused by an

isolate of Mycobacterium

tuberculosis that is resistant to one

of the first-line antituberculosis

drugs: INH, RMP, PZA, EMB, or

streptomycin

A.Genetic mutations occur spontaneously- confer resistance to Anti-Tuberculous drugs are present in Wild type M tuberculosis isolates occur by chance alone do not depend upon prior drug exposure not linked occur in frequency specific for each drug

1 in 107 for INH 1 in 108 for STM and INH

1 in 1010 for RMP 1 in 1014 for INH & RMP

Wild TB Strain

Strains with genetic drug resistance

Acquired drug resistance

Primary Drug Resistance

Spontaneous mutation

Selection: Inadequate treatment

B. Treatment with a Single TB drug-

Due to natrural occurrence of spontaneous mutations, treatment with one drug (or one efective drug) leads to development of resistance .

- drug susceptible bacteria will be killed

- drug resistant bacteria will survive

1950s-1970s:1950s-1970s: Mycobacterium tuberculosis resistant to Mycobacterium tuberculosis resistant to

INH, streptomycin and / or PASINH, streptomycin and / or PAS 1980s-curreny:1980s-curreny: TB that is resistant at least to INH

and RMP Isolates that are multiply-resistant

to any other combination of anti-TB drugs but not to INH and RMP are not classed as MDR-TB

))

While community based information is

lacking, laboratory data suggests an

increasing frequency of MDR from 14% in

1999 to 28% in 2004[6] and 47% in 2006[8].

(referemces: 6. utt T, Ahmad RN, Kazmi SY, Rafi N. Multi-drug resistant tuberculosis in Northern Pakistan. J Pak Med Assoc. 2004;54:469–472(PUBMED)

8. rfan S, Hassan Q, Hasan R. Assessment of resistance in multi drug resistant tuberculosis patients. J Pak Med Assoc. 2006;56:397–400. [PubMed]

MDR Bacilli-resistant to at least INH and RM.

Are the consequence of human error in any of

the following:

prescription of chemotherapy

management of drug supply

case management

process of drug delivery to the

patient

MDR-TB plus - resistance to one of the fluroquinolones

Ofloxacin Levofloxacin Moxifloxacin AND-resistance to one of the second line injectables

AmikacinKanamycinCapreomycin

XDR plus cycloserine, PAS, all

injectables

15 TDR isolates identified in IRAN

Resistance to all major

anti-TB drugs

Treatable but requires

extensive chemotherapy

upto 2 yrs of treatment.

Expensive

Drugs are toxic to the

patient

Previous treatment especially if prolonged

Contact with drug resistant patient

Country of origin East Europe Former USSR

Middle East South

and SE Asia

Latin America Africa

Age (In MDR area, commoner in children)

HIV (Where MDR common)

Substance abuse and homelessness

Drug Gene

Rifampicin rpoB

Streptomycin rps

Isoniazid No:

base pairs

katG

inhA

Programmatic Drugs: InadequateSupply/Quantity

Patients: Inadequate drug intake

Absence of guidance orInappropriate guidelinesNon-compliance with guidelinesInadequate training of health staffNo monitoring of treatmentPoorly organized orfunded TB control programmes

Non-availability ofcertain drugs (stock outsor delivery disruptions)Poor qualityPoor storage conditionsWrong dosages or combination

Poor adherence (orpoor DOT) – lack of Informationnon-availability of free drugsAdverse drug reactionsSocial and economic barriersMalabsorptionSubstance abusedisorders

Treat with adequate number of drugs to prevent emergence of further resistance

- use more drugs if susceptibility tests pending (often start with 5-6 drugs)

DRUG SELECTION - at least 3 new drugs not previously not

used - those with proven or suspected

susceptibility - as many bactericidal drugs as possible -Any first line drugs with proven

susceptibility Limit toxicity a much as possible

Step 1

Strep 2

Step 3

Use any

available

plus

One of these

plus

One of these

1st line drugsPZA & EBM

Fluroquinolones

LevofloxacinMoxifloxacin

Injectable agentsAmikacin

Capreomycin Streptomycin

Kanamycin

Oral 2nd line drugs

Cycloserine Ethionamide

PAS3rd line drugs

ImepenemMacrolidesLinezolid

Amoxicillin/Clavulante

Begin with a 1st line agents to which the isolateIs susceptibleAdd a fluroquinolones and an injectable drugBased on susceptibllity

Add 2nd line drugsUntil u have 4-6 drugs to which isolate is susceptible

if there are not 4-6 drugs Available, consider 3rd line in consult with MDRTB experts

Treat at least 18-24 months after

conversion of the culture to the negative

Continue injectables to at least 6-12 months

after conversion of the culture to the

negative

Shorter therapy for limited, primary or early

disease

Primarily available for INH & rifampin

gene probe for rpoB ( for Rifampicin)is

available in some countries & this serves

as a useful marker for MDR-TB

If a gene probe (rpoB) test - positive, then it

is reasonable to omit RMP and to use

SHEZ+MXF+cycloserine

Careful history taking for previous treatment regimens.

Compliance of the drugs in the previous regime

Determine the status of sputum smears at all junctures (in

terms of positivity ,conversions and sensitivities – if available).

Confirmed/ Strongly suspect MDR TB

Counsel the Patient and family members

Send Tissue / sputum for culture and sensitivity testing (if

available)

Start MDR Regimen

Depends on a number of factors:

How many drugs the organism is resistant to

(the fewer the better),

How many drugs the patient is given (Patients

treated with five or more drugs do better),

Whether an injectable drug is given or not (it

should be given for the first three months at

least),

The expertise & experience of the physician

responsible

How co-operative the patient is with treatment

(treatment is long, requires persistence &

determination on the part of the patient),

HIV positive or not (HIV co-infection is

associated with an increased mortality

Hurdles in the success of the treatment

Lack of awareness/misconceptions about

the disease

Late / improper diagnosis

Limited accessibility to diagnostic facilities

Incorrect treatment by doctors

Patients’ non-compliance to treatment

Socio-economic factors

Dates and chemotherapy Smear results

Culture results

Susceptibilityresults

Radiologicalresults

Clinicalresults

a)Date of diagnosis: ..................

b ) Date of starting first course of chemotherapy:

Drugs taken (dose, frequency, duration) i..e.: H300, 7/7, 6 Months R450, 7/7, 6 Months S1g, 7/7, 2 Months

c) Date of completing or stopping first

course of chemotherapy

d) Date of starting second course of chemotherapy: ……………....................... Drugs taken (dose, frequency, duration) ......., .........., ........

......., .........., ........e) Date of completing second course of chemotherapy: ..........................

f) Date of starting third course of chemotherapy: ........................(to be continued ...)

Resistance-

Suggested regimen

Length Comments

Isoniazid and PZI

Amik,

RIF,E,Mox

9 months to a year

Anticipate good response

Isoniazid and E

Amik,RIF,

PZI,Mox.

9-12/12

Isoniazid and RIF

Amik,PZI,

E,Mox.

At least 18/12

Consider surgery

Resistance Suggested regimen

Length Comments

INH,RIF,

PZI

Amik,E,

Mox,Eth,Cy

18-24/12

After cul-ve

Consider surgery

INH,RIF,

PZI,E

Amik,Mox.Eth,Cy,Clar

As above As above

The top priority is not the management but the prevention of MDR Tuberculosis

In new cases

Best prevention - give each new case

of sputum positive pulmonary

tuberculosis an effective regimen of

short course chemotherapy with four

drugs at least for 4 months, given

under direct observation

In the group of TB patients previously treated with one or several courses of chemotherapy & who remain sputum positive (by smear and/or culture), 3 subpopulations can be observed:

• patients excreting bacilli still susceptible to all antituberculosis drugs

• patients excreting bacilli resistant to at least isoniazid, but still susceptible to rifampicin;

• patients excreting bacilli resistant to at least isoniazid and rifampicin

In patients who have failure after the 1st

course of chemotherapy ( WHO

recommended or any other)– WHO Tx

regimen of 8 months ( using 5 drugs for the 1st

2 months, 4 drugs in the 3rd month and 3 drugs

for the remaining 5 months ( 2

SHRZE/1HRZE/5HRE), given under direct

observation

Rank

Drugs Average daily dosage

Type of antimycobacterial activity

1

2

3

4

5

6

7

Aminoglycosides

a. Streptomycin

b. Kanamycin/Amikacin

c. Capreomycin

Thioamides

(Ethionamide / rothionamide)

Pyrazinamide

Ofloxacin

Ethambutol

Cycloserine

PAS acid

15 mg/kg

10-20 mg/kg

20-30 mg/kg

7.5-15 mg/kg

15-20 mg/kg

10-20 mg/kg

10-12 g

Bactericidal against actively

multiplying organisms

Bactericidal

Bactericidal at acid pH 7.5-10

Bactericidal

Bacteriostatic

Bacteriostatic

Bacteriostatic

Aminoglycosides Kanamycin, Amikacin, Capreomycin ( useful in cases with

tubercle bacilli resistant to streptomycin,

amikacin and kanamycin) Thiamides- Ethionamides Prothionamides

Fluroquinolones Ofloxacin Ciprofloxacin (Complete cross resistance within

the group) Sparfloxacin – should be avoided due

to severe cutaneous side effects ( photo sensitisation)

Norfloxacin should not be used as it does not give adequate serum level

Cycloserine ( or terizidone)- bactriostatic agent no cross reaction with other ATT limited use due to the high toxicity

Para-aminosalicyclic acid-valuable for preventing resistance to INH-& Streptomycin

Treat for 6 months or observe without treatmnet

* use drugs source case is sensitive to

* Choose 2: EMB, FQN, PZA Follow for 2 years regardless of

treatment * Chest X-ray and clinical

evaluation

1970’s Tanzania Dr Karel Styblo strategy

1991 WHO TB a global problem

In 1992 The WHO Global Tuberculosis Program

developed a new strategy-DOTS ( brand

name of the WHO Recommended TB

Control Strtegy)

1993 WHO promoted Styblo’s strategy (DOTS)

Implemented in 200+ countries

That the highest ever number of infectious

patients – 2.3 million people – were cured.

With 87% of treated patients being cured,

the 85% global target was exceeded for the

first time since it was established in 1991

A total of 53 countries surpassed this

treatment milestone

Directly

Observed

Treatment

Short-course

To achieve universal access to high-quality

diagnosis and patient-centered treatment

To reduce suffering and socio-economic burden

associated with TB

To protect the poor and vulnerable populations

from TB, TB/HIV and MDR-TB

To support development of new tools and

enable their timely and effective use

National TB Control Program adopted DOTS strategy first in 1995

Political commitment with increased and

sustained financing

Case detection through quality assured

bacteriology

Standardized treatment with supervision and

patient support

An effective drug supply and management system

Monitoring and evaluation system, and impact

measurement

DIRECTLY OBSERVED TB SHORT COURSE

Comprehensive TB management

strategy Consists of 5

elements Now expanded

Stop TB Strategy

DIRECTLY OBSERVED TREATMENT

A part of the DOTS strategy

Direct supervision of

individual patients to ensure treatment adherence

Health inspectors

Pharmacists

Malaria field workers

Workplace

supervisors

Railwayschool

teachers

Cured patients

Wife of medical officers

Mid-wife

Self help group

volunteers

Senior dressers

Multi purpose health

workers

Prompt sputum conversion, cessation

of transmission

Halts generation of resistant (MDR-TB)

strains

Lessening of relapse rates

Early recognition of drug toxicity

Treatment with properly implemented

DOTS has a success rate exceeding 95%

prevents the emergence of further multi-

drug resistant strains of tuberculosis

The WHO extended the DOTS programme

in 1998 to include the treatment of MDR-

TB (called "DOTS-Plus").

Country population 163,902,000

Established no. of new TB cases 297,108

Established TB incidence(all cases per one

lakh population)

181

DOTS population coverage (%) 99

Rate of new SS+c ases(per 100.000

population)

81

DOTS caes detection rate

(new SS+ cases) (%)

67

DOTS treatment success rate,2006

(new SS+ cases) (%)

88

New Multidrug resistant TB cases(%) 3.2

New MDR-TB cases rose from 2.0 percent

in 2003 to 3.2 percent in 2007.

Pakistan accounts for 57 percent of the

MDR-TB burden within WHO’s Eastern

Mediterranean Region.

Extensively drug-resistant TB has not

been reported in the country.

New developments in eradicating tuberculosis

May 2009- a new antibiotic

Moxifloxacin has completed

phase II trial and is expected to

reduce the drug regimen by several

months

Standard TB drugs are dissolved into/adsorbed to fine,

particulate carriers (simple and economical)

Can be given orally (as well as IV), in distinction to

liposomes

Taken up by RES, mononuclear cells and solid organs

Extremely long half-lives (give every 2 weeks?)

More effective sterilizing than std. drug forms

A new compound exhibiting a completely

new mode of action (inhibition of ATP

synthase) against mycobacteria

The compound is being developed in

phase IIa trials for the treatment of active

tuberculosis as TMC207

Cytokines IL-2 Gamma-interferon

Immunomodulators Mycobacterium vaccae

Development of affordable newdrugs, diagnostics and vaccines

BCG vaccine (for TB) currently administered against infection only reduces the risk of TB in infants but offers no protection against pulmonary TB and infection in adolescence or adulthood.

A new TB vaccine, developed at the Oxford University called MVA85A/AERAS-485 holds promise. It has entered Phase II b trial in April 2009 and is being carried out in South Africa.

New challenges addressed by new Stop TB

Strategy

Strengthen TB control

Prevent drug resistance

Treat 50 million TB cases

Saves 14 million lives