Multi Drug Resistance Assay: A New Dimension for Host Directed Therapy

PRESENTED BY: CYRIL JOSE KESRIN AMRA

OP 1

Introduction

Availabilility of many anti-TB drugs to treat people with tuberculosis (TB), but resistance to these drugs is a growing problem.

People with drug-resistant TB require “second-line” TB drugs that, compared with “first-line” TB drugs used to treat drug-susceptible TB, cause more side effects and must be taken for longer.

A rapid and accurate test could identify people with drug-resistant TB, likely improve patient care, and reduce the spread of drug-resistant TB.

Types of resistance

Rifampicin resistance• TB bacteria do

not respond to rifampicin therapy

• Require second line treatment

Multi drug resistance• Resistant to

atleast rifampicin and isoniazid

• Need second line of treatment

Extensively drug resistant• Resistant to

first and second line drugs

• Resistant to fluoroquinolones

Conventional therapy

1st line

Isoniazid

Rifampicin

Pyrazinamide

Ethambutol

Selection of individualized MDR-TB regimens

Based on the patient's history of past drug use and on DST of isoniazid, rifampicin, the second-line injectable agents and a fluoroquinolone. Although resistance can develop in less than 1 month, if a patient has used a drug for more than 1 month with persistently positive smears or cultures, the strain should – as a general rule – be considered as “probably resistant” to that drug, even if DST results indicate that it is susceptible.

Another important limitation is the turnaround time for DST results…so the WHO recommends much rapid and simpler Genotypic MDR assays.

Different levels of MDR observed are

Cross resistanceDifferent minimum inhibitory

concentrationResistance to one or more drug of

a particular group

MDR assays are conducted onSputum specimenCulture isolates

Assay Methods

Molecular methods

• Line Probe assay• Loop mediated isothermal

amplification• Oligonucleotide microarray• Xpert MTB/RIF

Non molecular methods

• Fluorescent light emitting diode• Colorimetric assay• MDR XDR Color test

WHO recommended MDR assaysConventional phenotypic DST to evaluate emergence of additonal drug resistance. to confirm resistance to other drugs.

Genotype MTBDR assayWHO recommends SL-LPA for patients with confirmed RR-TB or MDR TB as the initial test to detect resistance to FQs & 2nd line injectable drugs.

Among patients prescribed conventional MDR-TB, MDR assays can help to decide who would benefit from new medicines to strengthen the regimen

WHO recommended MDR-TB regimenTreated with different combination of 2nd line drugs.Short term MDR-TB regimen.In patients with rifampicin-resistant or multidrug-resistant TB who have not been previously treated with second-line drugs and in whom resistance to fluoroquinolones and second-line injectable agents has been excluded or is considered highly unlikely, a shorter MDR-TB regimen of 9-12 months may be used instead of a conventional regimen (conditional recommendation, very low certainty in the evidence)

Good quality drugs

Political and administrative commitment

Good quality

diagnosis

Directly observed treatment

Systemic monitoring

and accountability

Elements of DOTS

Problems associated with the DOTS strategy (observed in India)Resistance to DOTS therapy reportedDOTS plus strategy yet to be launched to tackle the MDR-TB issue which comprises of 2nd line drug.

DOTS strategy in India

Personalisation of medicines Why do we generalise TB like most other diseases...???

Especially since MDR cases are advancing in current scenario...why do we still follow the same treatment regimen in almost the entire population..???

Don’t you feel there is a need for MDR assays before prescribing an anti-TB drugs..???

Why do we have to wait to ascertain the ineffectiveness of the regimen till the patient is not responding to the treatment pattern...??

As a budding pharmacist...many of you all like me would be concerned to protect the molecular integrity of the newly launched anti-TB drugs..!!!Due to their haphzard prescription...!!!......Aren’t we...???

Challenges

Ahead...!!!!

India has 121 labs performing XPERT MTB/RIF.

Only 0.2% TB cases reportedly undergoes DST testing in these labs...!!!!

Will the newly launched molecules bedaquilline and Delamanid face the

same fate as streptomycin..????

Risks Strategy

prior treatment for tuberculosis as a risk factor for drug resistant tuberculosis

Simultaneous MDR Genotypic assays alongwith TB diagnosis for detecting presence of any resistance to first line drugs.

inadequate treatment in both the public health system and the hospital system because they have disease that is resistant to isoniazid or rifampin (or both) but are still given these first line TB drugs as part of standard treatment)

• selection of treatment regimens on the basis of testing for initial drug resistance

• enhance the continuity of treatment after patients leave the hospitals

Emergence of drug resistance by strains due to genetic mutations allow them to survive even in the presence of these agents.

using several anti-TB agents concurrentlyUse of a shorter MDR-TB treatment regimen