Multi-drug Resistant TuberculosisHail M. Al-AbdelyConsultant, Infectious Diseases, KFSH&RC

Presentation OutlineDefinition of MDR TBEpidemiology of MDR TBGenesis of MDRMechanism of resistanceTreatmentChemoprophylaxis for MDR TB exposure

Definition of MDR TB1950s-1970s:

M. tb resistant to INH, streptomycin and/or PAS1980s-current:

M. tb resistant to at least INH and Rifampin

Why INH and RifampinMost potent and bacteriocidalTb can be treated effectively with INH+Rif aloneMono-resistance to one of them can be treated effectively with a regimen containing the other agent with very low failure rate (2.5-5%)Failure rate when INH+Rif resistant is 44% in non-HIV and 70% in HIV patientsDuration required for cure doubles to triples.

Tuberculosis notification rates, 2000

Estimated TB incidence rates, 2000The 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 TB

WHO Surveillance and Incidence of MDR TBDye et al. Global Burden of Multidrug-Resistant TB. JID 185(8), 2002

Country% MDR TB of all new casesEstonia14.1Latvia9.0China (non-DOTS)7.7China (DOTS)2.8Russia6.0India3.4Iran5.8Dominican6.6Ivory Cost5.3

WHO Estimates of MDR TB in Some Arabian CountriesDye et al. Global Burden of Multidrug-Resistant TB. JID 185(8), 2002* Surveyed

Country% MDR TB of all new casesMorocco*2.2Oman*0.8Algeria0.7Egypt5.6Jordan2.8Kuwait3.3Lebanon3.4Saudi Arabia3.0Sudan10.1Syria6.7Yemen12.4

Genesis of MDR TBResistance is a man-made amplification of a natural phenomenon.Inadequate drug delivery is main cause of secondary drug resistance.Secondary drug resistance is the main cause of primary drug resistance due to transmission of resistant strains.MDR due to spontaneous mutations is not possible as the genes encoding resistance for anti TB are unlinked.

Clinical factors promoting resistanceDelayed diagnosis and isolationInappropriate drug regimen.

Inadequate initial therapyIncomplete course of treatmentInappropriate treatment modificationsAdding single drug to a failing regimenInappropriate use of chemoprophylaxisPoor adherence and incomplete F/UFailure to isolate MDR TB patientsFailure to employ DOTOver the counter anti TBFaked drugs

Mechanism of ResistanceTB specific drugs

INH, PZA, ETH

Antibiotics with activity against TB

RIFAminogycosidesFlouroquinolones

Mechanism of resistanceINH

Chromosomally mediatedLoss of catalase/peroxidaseMutation in mycolic acid synthesisRegulators of peroxide response

Mechanism of resistanceRifampin

Reduced binding to RNA polymeraseClusters of mutations at Rifampin Resistance Determining Region (RRDR)

Reduced Cell wall permeability

Treatment of MDR TBFactors determining Success

Culture of MDR TBReliable susceptibilityReliable history of previous drug regimensProgram to assure delivery of prescribed drugs (DOT)Correct choice of modified treatment regimenReliable follow up

Iseman M. NEJM, 329:784, 1993

New Chemotherapeutic AgentsNot many. Low interest from industryDerivatives of Rifamycin

Rifabutin: Sensitive subset of Rifampin resistant strainsRifapentine: Extended half-life but more mono-resistance to rifamycinsKRM-1648. benzoxazinorifamycin. In vitro and animal models.New flouroquinolones

Gatifloxacin, Moxifloxacin, levofloxacin, sparfloxacinNitroimidazoles

related to metronidazole. May work better against latent bacilliAvoiding pro-drug problems

ChemoprophylaxisDeterminants of intervention

Likelihood of infection with MDR TBLowIntermediateHigh

Likelihood of developing MDR TBImmune suppression

Likelihood of infection with MDR TBIntermediate to highLowHigh possibility for diseaseYesNoConsider Multidrug prophylaxisConfirmed R to INH+RIFStandard recommendation For non-MDR TB contacts