Causal Agent Mycobacterium tuberculosis complex Polyvalent behaviour depending

Causal Agent - Mycobacterium tuberculosis complex - Polyvalent behaviour depending on medium.

Bacillary populations ■ In a tuberculosis patient, there are different bacillary populations formed of bacilli in different situations - Location - p. H - Replication rate, susceptibility to drugs,

Bacillary populations 1. Rapidly multiplying bacilli Failure - Optimum medium: Extracellular. PH 6. 5 -7, maximum oxygenation (cavern wall) - Large number of bacilli → High probability of spontaneous natural mutations Many Millions Natural Resistant Mutants

Bacillary populations 2. Slow multiplication Bacilli - Intramacrophagic location. Acid p. H. Population<105 No Naturally Resistant Mutants Relapses

Bacillary populations 3. Intermittently growing bacilli - Unfavourable conditions. Solid caseum. Extracellular - Relapse capacity - Population <105 No Naturally Resistant Mutants Relapses

The possibility to generate MDR in NTP conditions The Risk to Amplify Resistances with Non Adequate Strategies

Post-Antibiotic Effects with M. tuberculosis Lag Periods before Commencement of Growth after Exposure in 7 H 10 Medium streptomycin Isoniazid Ethambutol Sequential Monotherapy INH Rifampicin 0 1 2 3 4 5 6 7 8 9 10 Lag after 24 hr exposure to drug (days) Mitchison DA, et al. Postgr Med J 1971; 47: 737 -

The possibility to generate MDR in NTP conditions 2 HRZE / 4 HR Pansusceptible Initial Res. H Initial MDR

The possibility to generate MDR and XDR in NTP conditions 2 HRZE / 4 HR Strict DOT Pansusceptible Bad Maintained Adherence CURE Danger ! Intermittent Tr.

The possibility to generate MDR in NTP conditions 2 HRZE / 4 H R Sm (-) 2ºMonth % CURE Extend 1ª Phase Initial Res. H Sm (+) 2º M. Go to 2ª Phase ¡ High Risk MDR-TB !, but Susceptible ZE

The Risk to Amplify Resistance in the Failures to Cat. I receiving Category II Regime (2) FAILURE 2 HRZE/ 4 HR 2. Initial Resistance to H (+%) 2 HRZE/4 H R MDR, but suscpt. Z+E 2 HRZES/1 HRZE/5 H R E Risk to Amplify Resistance E (Avoidable if DST before 3 rd Month

The possibility to generate MDR in NTP conditions 2 HRZE / 4 H R CURE (20 -50%) Initial MDR-TB, Amplifying Resist. to Z+E

The Risk to Amplify Resistance in the Failures to Cat. I receiving Category II Regime (3) FAILURE 2 HRZE/4 HR 3. Initial M. D. R. (-%) 2 HRZE/4 H R Resistance to HR+E+Z 2 HRZES/1 HRZE/5 H R E Risk to Amplify Resistance to S

>108 organisms in TB cavity 1 100 100 Likelihood of Natural Resistance Rifampin 1/108 INH, Strep, EMB 1/106 resistant RIF INH Strep EMB

For New Cases Never Treated >108 Organisms in TB Cavity 1 resistant RIF 100 resistant INH 100 resistant Strep 100 resistant EMB 0 resistant INH+Rif+EMB

If Treated With INH Only 108 Organisms: 1 resistant RIF 100 resistant INH 100 resistant Strep 100 resistant EMB 100 organisms resistant to INH remain in cavity Organisms Multiply New 108 Organisms: 1 resistant Rif 108 resistant INH 100 resistant Strep 100 resistant EMB

108 Organisms: Organisms 1 Resistant Rif 108 Resistant INH 100 Resistant Strep 100 Resistant EMB If Treated with INH and RIF 1 organism resistant to RIF and INH MDR-TB Organisms Multiply

Bacteriological Fundaments of TB Treatment 1. Drug combinations The combination of drugs prevents the appearance of resistance, because it avoids the selection of naturally resistant mutants