1 MDR-TB is a manmade problem..it is costly, deadly, debilitating, and the biggest threat to our current TB control strategies 2 1
India has the highest TB burden in the world 3 4 2
5 M. tuberculosis Resistance Indian Perspective 6 3
M. tuberculosis Resistance Bangladesh Perspective Bangladesh First National TB Drug Resistance Survey (2010 2011): 2011) 1.4% in new cases (lower than estimation, Global:3.4%), 28.5 % in previously treated cases ( higher than estimation, Global: 20%). No XDR TB. Total estimated number of MDR TB in 2012 was about 4150 7 Basic Concepts of Resistance of M. Tuberculosis Resistance is a man mademade 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. 8 4
9 M. tuberculosis Resistance Natural Resistance When any live species reach a certain number of divisions (in order to perpetuate the species), they undergo genomic mutations at random. Spontaneous mutations develop as bacilli proliferate This always occurs in the successive divisions of each species. It is therefore a dynamic function. 10 5
M. tuberculosis Resistance Natural Resistance Therefore, when live species attain a number about 10,000 to 1 million, many of the individual organisms contain genetic mutations Fortunately, the majority of these mutations do not have an obvious phenotypic expression Sometimes, it is necessary to expose the species to selective pressure to express the selected mutation Man-made phenomenon starts 11 M. tuberculosis Resistance Natural Resistance Ever since M. tuberculosis has attacked humans, it has always presented multiple genomic mutations in its continuous divisions Some of these mutations affect the genes in which anti-tuberculous drugs work This means that these antibiotics cannot work against M. tuberculosis, and therefore phenotypically, they show resistance to them 12 6
Genetic Markers of Resistance to Anti-TB Drugs Drug Isoniazid Rifampicin Ethambutol Streptomycin Pyrazinamide Fluoroquinolones Gene katg, InhA rpob embb rpsl pnca gyra, gyrb 13 No. of bacilli required for the appearance of a mutant gene Estimated bacterial populations in the different TB lesions Isoniazid 1X10 5 10 6 bacilli Sm+ve TB 10 7 10 9 bacilli Rifampicin 1 X 10 7 10 6 bacilli Cavitary TB 10 7 10 9 bacilli Streptomycin 1 X 10 5 10 8 bacilli Caseous foci 10 2 10 4 bacilli Ethambutol 1 X 10 5 10 6 bacilli EPTB 10 4 10 6 bacilli Pyrazinamide 1 X 10 2 10 4 bacilli? Sm ve TB 10 4 10 6 bacilli Fluoroquinolone 1 X 10 5 10 6 bacilli? Lymph node 10 4 10 6 bacilli In larger bacterial populations, the probability that resistant mutants are present is higher The prevalence of wild type resistant mutants in an untreated M. 14 tuberculosis populations is very small 7
Basic Concept of Resistance Spontaneous mutations develop as bacilli proliferate to >10 8 15 M. tuberculosis Resistance Selection of resistant mutants If Smear positive TB is treated with just ONE drug (H), for each million bacilli, it will kill 9,99,999 (10 6-1), but it will select the ONE resistant mutant that exists. If this TB has a minimum of 1,000 million (10 9 ) organisms, in 2-8 weeks it will have selected the 1,000 mutant bacilli (1 per million) that are resistant in this population. These 1,000 bacilli are insufficient to cause clinical symptoms or to be smear +ve; Good Clinical Progress! The problem is that these 1,000 soon will be 10 9. 16 8
Drug resistant mutants in large bacterial population Multidrug therapy: No bacteria resistant to all 3 drugs INH RIF PZA Monotherapy: INH resistant bacteria proliferate INH 17 Appearance of resistance to INH administered as Monotherapy Resistant Mutants The fall and Rise Mechanism Sensitive Bacilli No. of viable bacilli Months after Start of Treatment Mitchison DA. En: Heaf F, et al. Churchill, London, 1968 18 9
INH resistant bacteria multiply li l to large numbers INH 2 nd spontaneous mutations develop as bacilli proliferate to >10 8 INH RIF INH mono resistant mutants killed, IR resistant mutants proliferate MDR TB IRP 19 Bacteriological Principles of TB Treatment Drug combinations The combination of drugs prevents the appearance of resistance, because it avoids the selection of naturally resistant mutants 20 10
M. Tuberculosis Resistance Mono-Resistance: Resistance to single drug Poly-Resistance: Resistance to 2 or more drugs independent of which drugs The worst situation is resistance to H+R which is more difficult to cure For this reason, these patients receive a special name MDR 21 Extensively-Drug-Resistant TB (XDR) MDR + resistance it to fluoroquinolone and 1 of the 3 secondline injectable drugs (amikacin, kanamycin, capreomycin) TDR TB: Resistant to all locally tested anti TB drugs 22 11
A controversial Issue Do we need a new definition of resistance beyond XDR TB 23 Already there are TB Cases with organisms Resistant to all these Drugs Totally-Drug Resistant (TDR-TB)? TB)? Ma Z, Lienhard C. Clin Chest Med 30 (2009) 755 768 24 12
TDR-TB Definition: Some Issues Raised The definition should be based on testing for all drugs 11 categories of drugs Does testing 1. INH of only 1 drug in a class mean resistance to all 2. Rifamycins drugs in 3. that Pyrazinamide class? 4. Ethambutol Third line 5. Quinolones drugs (Group 5 drugs) are now used and are found to be working 6. Streptomycin 7. Second line aminoglycosides Amx/Clav, 8. Polypeptides Cfz, Lzd, monobactams, clarithromycin etc. 9. Thioamides DST for 10. several Serine anti TB drugs is not reliable or reproducible 11. PAS Several new anti-tb drugs are in the pipeline Unintentionally labeling the patient incurable or untreatable 25 Totally Drug Resistant (TDR TB) W.H.O. Meeting 21 22 March, 2012 So, a new definition iti of resistance beyond XDR TB is not recommended,because: Technical difficulties with DST of many anti TB drugs The lack of standardised DST methods for several anti TB drugs (including new investigational drugs) Insufficient evidence to link such DST results to treatment outcomes of patients 26 13
MDR-TB Suspects 1. Failure of Category I 2. Fil Failure of Ct Category II re treatment t t regimens and Chronic TB cases 3. Close contact of MDR TB cases 4. Failure of anti TB Treatment in the Private sector 5. Delayed convertors of Cat I/Cat II (remains positive at months 3/4 6. Relapses (Category I and Category II) 7. Return after Defaults (Category I and Category II) 27 MDR-TB Suspects 7. Exposure in institutions that have MDR TB out breaks or ahigh MDR TB prevalence 8. Residence inareas with high h MDR TB prevalence 9. HO using anti tuberculosistuberculosis drugs of poor or unknown quality 10. Treatment in programs that operate poorly (especially HO frequent drug stock outs) outs) 11. Co morbid conditions associated itd with malabsorption 12.HIV co infection 13.Any smear negative or EPTB doing clinically poor on anti TB 28 14
4/9/2015 Multidrug-Resistant TB I have been treated several times over the past five years and I m still coughing and can t gain weight! The image cannot be display ed. Your computer may not hav e enough memory to open the image, or the image may hav e been corrupted. Restart y our computer, and then open the file again. If the red x still appears, y ou may hav e to delete the image and then insert it again. The image cannot be display ed. Your computer may not hav e enough memory to open the image, or the image may hav e been corrupted. Restart y our computer, and then open the file again. If the red x still appears, y ou may hav e to delete the image and then insert it again. 29 Diagnosis of MDR-TB Gold standard test: Culture of patient specimen (sputum) to assess inhibition of M tuberculosis growth in the presence of antibiotics (phenotypic assay) Solid media assays: Result may not be available for 3 6 wks Automated liquid culture systems: Faster and more sensitive than solid media cultures; results available in 1 2 wks Rapid molecular tests can identify genotypic resistance very early Xpert TB/RIF identifies M tuberculosis and rifampicin resistance using cartridge based real time PCR in 2 hours Line probe assays (eg, Hain Line probe assays (eg Hain GenoType) identify genotypic resistance to GenoType) identify genotypic resistance to both isoniazid and rifampicin in 1 2 days Average Turnaround Time for Diagnostic Tests Rapid Molecular Tests 2 hrs -2 days Liquid Culture Media 1-2 wks Solid Culture Media 3-6 wks Phenotypic DST 4-12 wks 30 15
Factors determining Success in Treatment of MDR TB Culture of mycobacterium tuberculosis Reliable susceptibility Reliable history of previous drug regimens Correct choice of modified treatment regimen Availability of drugs Program to assure delivery of prescribed drugs Reliable follow up 31 Initiating Treatment: WHO Ensure laboratory services for hematology, biochemistry; and audiometry Establish a clinical and laboratory baseline before starting the regimen Initiate treatment gradually when using drugs that cause gastro intestinal intolerance Ensure availability of ancillary drugs to manage adverse effects Use DOT for all doses 32 16
Treatment of DR-TB Anti-tuberculosis drug regimen for DR- TB should always include at least FOUR effective but possibly as many as SIX or SEVEN drugs The number of drugs used varies depending on the extent of disease and the potency of the available agents 33 Rational Classification of Anti-TB Drugs Caminero JA, et al. Lancet Infect Dis 2010; 10: 621 2929 Group 1: First Line Drugs, Oral: (R,H,E,Z) Z E Group 2: Quinolones: (Ofx, Lfx, Mfx,Gfx) 1 Group 3: 2 nd line Injectables: (Km, Ak, Cm) Group 4: Other Less Effective Second Line Drugs: Eto/Pto, Cs/Tz, PAS) Group 5: Reinforcement Drugs: (Cfz., Amx/Clv, Lzd, Ipm, Thz, Clr, High dose INH): 0.5 drug 1 Until 4 New Exceptional If < 4 34 17
Designing an MDR/XDR Treatment Regimen: General Principles, WHO Regimens should be based on the history of drugs taken by the patient Drugs commonly used in the country and the prevalence of resistance to first and 2nd line drugs should be considered in developing a regimen Use at least four drugs highly likely to be effective The regimen should include at least one injectable and one FQ Use daily DOT, not intermittent administration Contd.. 35 Designing an MDR/XDR Treatment Regimen: General Principles, WHO Do not use drugs for which there is cross resistance Eliminate drugs that are unsafe for the patient Include drugs from groups 1 5 in a hierarchical order based on potency The regimen chosen may be standardized or individualized based on DST Be prepared to prevent, monitor and manage adverse drug reactions Optimize management of underlying medical conditions 36 18
Standard Regimen for MDR -TB Treatment Minimum total 20 months and at least 18 months past culture conversion o Intensive Phase Minimum 8 months (or four months after culture conversion) Pyrazinamide (Z) 500 mg Levofloxacin (Lfx) 250 mg Ethionamide (Eto) 250 mg Cycloserine (Cs) 250 mg Kanamycin (Km) 1gm Continuation Phase Minimum 12 months Pyrazinamide (Z) 500 mg Levofloxacin (Lfx) 250 mg Ethionamide (Eto) 250 mg Cycloserine (Cs) 250 mg 37 MDR-TB: Monitoring Monthly collect sputum until smear and culturebecome negative Obtain end of treatment sputum specimen for smear and culture to document cure Perform chest radiograph periodically during treatment and at end of treatment Monitor ( clinical & sputum) minimum of two years following treatment: quarterly during first year, every six months during second year 38 19
39 Linezolid for Extensively Drug Resistant Tuberculosis N Engl J Med 2013; 368:290 291 Original Article Multidrug Resistant Tuberculosis and Culture Conversion with Bedaquiline N Engl J Med 2014; 371:723 732August 21, 2014 Original Article Delamanid for Multidrug Resistant Pulmonary Tuberculosis N Engl J Med 2012; 366:2151 2160June 7, 2012 20
Role of SURGERY in MDR-TB - Only indicated if : - 4 drugs are not available (rare) - The lesion is localised (very rare) - There is sufficient respiratory reserve (very rare) - Even in this situation, it must be remembered: - High morbidity-mortalitymortality - Lesions are not sterilised Only indicated in exceptional circumstances (in XDR)! 41 Caminero JA. Int J Tuberc Lung Dis 2006, 10: 829-837 Common adverse effects of 2nd-line drugs Drugs Ethionamide, prothionamide PAS Cycloserine Kanamycin, amikacin Capreomycin Fluoroquinolones Adverse effects GI upset, hepatitis, hypothyroidism GI upset, hepatitis, hypothyroidism Neurological ad psychiatric disturbances (suicidal ideation) Nephrotoxicity, ototoxicity electrolyte imbalance Well tolerated 42 21
Management of MDR-TB in Special Situations Pregnancy: aminoglycosides arenot safe Liver dysfunction: Z, eth/pro, PAS, FQs are hepatotoxic Renal dysfunction: Requires dose adjustment HIV Co infection: 43 THE BEST WAY TO AVOID MDR-TB To Give the best initial treatment when the patient presents with TB for the first time 2 HRZE / 4 HR - Advisable Daily, at least in the Intensive Phase, but preferably throughout treatment - EMB throughout treatment if Smear + at the end of the 2 nd month, or until susceptibility H+R is known 44 22
THE BEST WAY TO AVOID MDR-TB Directly Observed Treatment is fundamental to prevent emergence of Resistance 45 Professor Michael Iseman, the US Guru of MDR-TB has Ten commandments for physicians: The first is never to add a single drug to a failing regimen And the other nine are To repeat the first commandment nine times to make sure that the message is understood! 46 23
Challenges Long duration ADRs HIV Co infection Infection control 47 Treatment Issue: Shorter Regimen Damien Foundation regimen of just 9 months with SLDs achieved relapse freecure rates approaching 85%. This promising 9 month regimen includes 4 month intensive phase (or until smear conversion) with high doses of gatifloxacin, high dose H, km, prothionamide, clofazimine (Cf), E and Z, and 5 month Continuation Phase with high doses of gatifloxacin, Cf, E and Z. *Van deum A, et al. Short, highly effective, and inexpensive standardized treatment regimen of MDR TB. Am J Respir Crit Care Med 2010; 182: 684 92. *Aung KJM, et al. Successful 9 month Bangladesh regimen for MDR TB among over 500 consecutive patients. Int J Tubercl Lung Dis 2014;18: 1180 87 Resource poor countries can implement Damien Foundation experience. (Guideline for clinical and operational Management of DR TB. IUATLD 2003) 48 24
Summary Treatment of MDR TB is complex and costly. It is much easier to prevent than to treat. t XDR TB is even more difficult! Expert consultation should be obtained whenever possible when MDR or XDR TB is suspected.. 49 Summary (cont.) Patients can be treated with a standardized or an empiric ii regimen. Ideally the regimen should be guided by drug susceptibilitytests. Lab tests do not replace clinical judgment. There are sound principles that can be used to guidein designingtreatment regimens.. 50 25
Summary (cont.) Considerable attention must be paid to treatmentt tmonitoring i and support. A patient centered approach to DOT is an important element of successful care. Adverse effects of second line drugs are common and may be severe. Monitoring for these effects is essential. 51 Thank You All National Martyrs Memorial, Bangladesh 52 26