Multi-drug Resistant Tuberculosis Hail M. Al-Abdely Consultant, Infectious Diseases, KFSH&RC.

Multi-drug Resistant Multi-drug Resistant TuberculosisTuberculosisHail M. Al-AbdelyHail M. Al-Abdely

Consultant, Infectious Consultant, Infectious Diseases, KFSH&RCDiseases, KFSH&RC

Presentation OutlinePresentation Outline

Definition of MDR TBDefinition of MDR TB Epidemiology of MDR TBEpidemiology of MDR TB Genesis of MDRGenesis of MDR Mechanism of resistanceMechanism of resistance TreatmentTreatment Chemoprophylaxis for MDR TB Chemoprophylaxis for MDR TB

exposureexposure

Definition of MDR TBDefinition of MDR TB

1950s-1970s: 1950s-1970s: – M. tb resistant to INH, streptomycin M. tb resistant to INH, streptomycin

and/or PASand/or PAS 1980s-current: 1980s-current:

– M. tb resistant to at least INH and M. tb resistant to at least INH and RifampinRifampin

Why INH and RifampinWhy INH and Rifampin Most potent and bacteriocidalMost potent and bacteriocidal Tb can be treated effectively with INH+Rif Tb can be treated effectively with INH+Rif

alonealone Mono-resistance to one of them can be Mono-resistance to one of them can be

treated effectively with a regimen treated effectively with a regimen containing the other agent with very low containing the other agent with very low failure rate (2.5-5%)failure rate (2.5-5%)

Failure rate when INH+Rif resistant is 44% Failure rate when INH+Rif resistant is 44% in non-HIV and 70% in HIV patientsin non-HIV and 70% in HIV patients

Duration required for cure doubles to Duration required for cure doubles to triples.triples.

Tuberculosis notification rates, 2000Tuberculosis notification rates, 2000

25 - 49

50 - 99100 or more

0 - 9

10 - 24

No report

Rate per 100 000

The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement.

Global Tuberculosis Control. WHO Report 2002. WHO/CDS/TB/2002.295

25 - 49

50 - 99100 or more

0 - 9

10 - 24

No report

Rate per 100 000

The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement.

Global Tuberculosis Control. WHO Report 2002. WHO/CDS/TB/2002.295

25 - 49

50 - 99

100 - 300

0 - 9

10 - 24

300 or more

No estimate

Rate per 100 000

Estimated TB incidence rates, 2000Estimated TB incidence rates, 2000

The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement.

Global Tuberculosis Control. WHO Report 2002. WHO/CDS/TB/2002.295

Epidemiology of MDR TBEpidemiology of MDR TB

85,008 (4.5)Western Pacific

75,062 (2.5)Southeast Asia

45,964 (7.9)45,964 (7.9)Eastern Mediterranean

25,199 (1.8)Africa, high HIV

15,014 (1.9)Africa, low HIV

17,269 (5.5)Eastern Europe

8508 (2.2)Latin America

882 (0.7)Established market economies

272,906 (3.2)All countries (n = 136)

No. of MDR TB cases (% of all new cases)Geographic region

Dye et al. Global Burden of Multidrug-Resistant TB. JID 185(8), 2002Dye et al. Global Burden of Multidrug-Resistant TB. JID 185(8), 2002

WHO Surveillance and Incidence of WHO Surveillance and Incidence of MDR TBMDR TB

Country % MDR TB of all new cases

Estonia 14.1

Latvia 9.0

China (non-DOTS) 7.7

China (DOTS) 2.8

Russia 6.0

India 3.4

Iran 5.8

Dominican 6.6

Ivory Cost 5.3

Dye et al. Global Burden of Multidrug-Resistant TB. JID 185(8), 2002Dye et al. Global Burden of Multidrug-Resistant TB. JID 185(8), 2002

WHO Estimates of MDR TB in Some Arabian CountriesWHO Estimates of MDR TB in Some Arabian Countries

Country % MDR TB of all new cases

Morocco* 2.2

Oman* 0.8

Algeria 0.7

Egypt 5.6

Jordan 2.8

Kuwait 3.3

Lebanon 3.4

Saudi Arabia 3.0

Sudan 10.1

Syria 6.7

Yemen 12.4

Dye et al. Global Burden of Multidrug-Resistant TB. JID 185(8), 2002Dye et al. Global Burden of Multidrug-Resistant TB. JID 185(8), 2002* Surveyed* Surveyed

Genesis of MDR TBGenesis of MDR TB

Resistance is a man-made amplification of a Resistance is a man-made amplification of a natural phenomenon.natural phenomenon.

Inadequate drug delivery is main cause of Inadequate drug delivery is main cause of secondary drug resistance.secondary drug resistance.

Secondary drug resistance is the main cause of Secondary drug resistance is the main cause of primary drug resistance due to transmission of primary drug resistance due to transmission of resistant strains.resistant strains.

MDR due to spontaneous mutations is not MDR due to spontaneous mutations is not possible as the genes encoding resistance for anti possible as the genes encoding resistance for anti TB are unlinked.TB are unlinked.

Strains with genetic drug resistance

Wild M. TB strain

Acquired drug resistance

Primary drug resistance

Spontaneous mutationSpontaneous mutation

Selection: inadequate treatmentSelection: inadequate treatment

TransmissionTransmission

Development of anti-tuberculosis drug resistanceDevelopment of anti-tuberculosis drug resistance

Pablos-Mendez et al. WHO, 1997Pablos-Mendez et al. WHO, 1997

Clinical factors promoting resistanceClinical factors promoting resistance

Delayed diagnosis and isolationDelayed diagnosis and isolation Inappropriate drug regimen.Inappropriate drug regimen.

– Inadequate initial therapyInadequate initial therapy– Incomplete course of treatmentIncomplete course of treatment– Inappropriate treatment modificationsInappropriate treatment modifications– Adding single drug to a failing regimenAdding single drug to a failing regimen– Inappropriate use of chemoprophylaxisInappropriate use of chemoprophylaxis

Poor adherence and incomplete F/UPoor adherence and incomplete F/U Failure to isolate MDR TB patientsFailure to isolate MDR TB patients Failure to employ DOTFailure to employ DOT Over the counter anti TBOver the counter anti TB Faked drugsFaked drugs

Mechanism of ResistanceMechanism of Resistance

TB specific drugsTB specific drugs– INH, PZA, ETHINH, PZA, ETH

Antibiotics with activity against TBAntibiotics with activity against TB– RIFRIF– AminogycosidesAminogycosides– FlouroquinolonesFlouroquinolones

INHINH– Chromosomally mediatedChromosomally mediated– Loss of catalase/peroxidaseLoss of catalase/peroxidase– Mutation in mycolic acid synthesisMutation in mycolic acid synthesis– Regulators of peroxide responseRegulators of peroxide response

Mechanism of resistanceMechanism of resistance

RifampinRifampin– Reduced binding to RNA polymeraseReduced binding to RNA polymerase

Clusters of mutations at “Rifampin Clusters of mutations at “Rifampin Resistance Determining Region” (RRDR)Resistance Determining Region” (RRDR)

– Reduced Cell wall permeabilityReduced Cell wall permeability

Mechanism of resistanceMechanism of resistance

Treatment of MDR TBTreatment of MDR TB

Factors determining SuccessFactors determining Success– Culture of MDR TBCulture of MDR TB– Reliable susceptibilityReliable susceptibility– Reliable history of previous drug Reliable history of previous drug

regimensregimens– Program to assure delivery of prescribed Program to assure delivery of prescribed

drugs (DOT)drugs (DOT)– Correct choice of modified treatment Correct choice of modified treatment

regimenregimen– Reliable follow upReliable follow up

Iseman M. NEJM, 329:784, 1993Iseman M. NEJM, 329:784, 1993

New Chemotherapeutic AgentsNew Chemotherapeutic Agents Not many. Low interest from industryNot many. Low interest from industry Derivatives of RifamycinDerivatives of Rifamycin

– Rifabutin: Sensitive subset of Rifampin resistant strainsRifabutin: Sensitive subset of Rifampin resistant strains– Rifapentine: Extended half-life but more mono-Rifapentine: Extended half-life but more mono-

resistance to rifamycinsresistance to rifamycins– KRM-1648. benzoxazinorifamycin. In vitro and animal KRM-1648. benzoxazinorifamycin. In vitro and animal

models.models. New flouroquinolonesNew flouroquinolones

– Gatifloxacin, Moxifloxacin, levofloxacin, sparfloxacinGatifloxacin, Moxifloxacin, levofloxacin, sparfloxacin NitroimidazolesNitroimidazoles

– related to metronidazole. May work better against latent related to metronidazole. May work better against latent bacillibacilli

Avoiding pro-drug problemsAvoiding pro-drug problems

ChemoprophylaxisChemoprophylaxis

Determinants of interventionDeterminants of intervention– Likelihood of infection with MDR TBLikelihood of infection with MDR TB

LowLow IntermediateIntermediateHighHigh

– Likelihood of developing MDR TBLikelihood of developing MDR TB Immune suppressionImmune suppression

Likelihood of infection with MDR TB

Intermediate to highLow

High possibility for disease

YesNo

Consider Multidrug prophylaxis

Confirmed R to INH+RIF

Standard recommendation

For non-MDR TB contacts