TB Intensive San Antonio, Texas April 6-8, 2011 Drug Resistant TB Barbara Seaworth, MD Thursday April 7, 2011 Barbara Seaworth, MD has the following disclosures to make: Has received research funding from Otsuka Pharmaceuticals. No relevant financial relationships with any commercial companies pertaining to this educational activity. 1
Drug Resistant TB: An Update Barbara J Seaworth Professor of Medicine University of Texas Health Science Center, Tyler Medical Director Heartland National TB Center MDR TB Definitions TB resistant to INH and Rifampin TB - No Prior Therapy aka Primary MDR TB TB Prior Therapy aka Acquired MDR TB Results from exposure to a patient with infectious MDR TB Results from inadequate treatment and/or non adherence 2
XDR TB MDR TB Plus resistance to one of the fluoroquinolones Ofloxacin Levofloxacin Moxifloxacin AND Resistance to one of the second line injectables Amikacin Capreomycin Kanamycin PRE XDR TB MDR TB AND either resistance to a fluoroquinolone OR resistance to one of the second line injectables. One step away from XDR TB! California (1993-2004): 18 % of their MDR TB cases are pre-xdr TB» Extensively Drug Resistant TB in California 1993-2006. CID 2008 47; 450-7 3
Is This XDR TB? 22 year old who acquired TB overseas Resistant to: Susceptible to: INH Kanamycin Rifampin PAS Ethambutol PZA Ethionamide Streptomycin Ofloxacin Global Epidemiology of MDR and XDR Tuberculosis Assessing the risk in your foreign born patients And in those who travel to TB endemic sites 4
Updates the 2008 report Country wide data from China Evidence of decrease in primary MDR in eastern European countries Suggestion of linkage of MDR and HIV in eastern European countries MDR and XDR: 2010 Global Report on Surveillance and Response - New Cases 5
MDR and XDR: 2010 Global Report on Surveillance and Response - Prior Treatment 6
XDR TB (%) of MDR Cases WHO 4th Global Report Drug Resistant TB, 2008 55 countries 7
Countries Reporting XDR TB January 2010 58 countries MDR and XDR: 2010 Global Report on Surveillance and Response WHO % with DST 8
MDR and XDR: 2010 Global Report on Surveillance and Response WHO <16,000 actually treated! Only ~1-3 % of MDR is diagnosed with DST Only ~ 1% MDR is treated according to WHO standards 9
Prevalence of 2 nd Line Drug Resistance in MDR TB Patients PETTS Study in 7 of 8 countries* 522 MDR isolates 109 (20%) had resistance to either an injectable second line drug (SLD) or FQN Pre XDR TB 30 XDR 285 resistant to all 1 st line drugs Preserving Effective TB Treatment Study: *Estonia, Latvia, Peru, Philippines, Russia, South Africa, South Korea, and Thailand 10
Emergence of Totally Drug Resistant (TDR) TB XDR TB plus cycloserine, PAS, all injectables 15 TDR isolates; 56% Iranian, 30% Afghan Cases + smear/culture after 18 months Rx VNTR profiles and spoligotyping different Not explained by transmission. Chest 2009; 136:420-425 XDR TB in California 1993-2006 12 of 18 pts were XDR at time of presentation 10 of 12 (83%) were foreign born Disease diagnosed median 0.9 year after arrival in U.S. (MDR 3.7 years, TB in general 9 years) 7 of 18 (46.7%) born in Mexico (27% of MDR born in Mexico) Early in study most foreign born from Asia Later in study most were from Mexico Extensively Drug Resistant TB in California 1993-2006. CID 2008 47; 450-7 11
Dye, Bull WHO 2009:87 TB/HIV: High Incidence Areas The dramatic increase in the number of people living i with HIV in the past decade d has fuelled the South African TB epidemic National estimates of HIV among TB patients now range from 60% to 80% The Asia and Pacific regions This region has more than half the global burden of TB and 12% of the global burden of HIV. Only 20% of persons with HIV know their status WHO and Stop TB HIV TB Newsletter, Oct 2009 12
Why Do We Have Drug Resistance? Inadequate Treatment Incorrect regimen (lack of drugs or knowledge) Poor adherence Treatment Failure/Relapse with drug resistant TB Transmission of drug resistant TB 13
Which Patients are at Risk of Drug Resistant TB? Birth/ residence in country with high incidence of drug resistant TB U.S. residents who travel to high risk areas Exposure to patient with relapse or failure Prior treatment for TB Treatment failure Relapse in a patient not on DOT Poor adherence Clinical deterioration during 4 drug therapy NEW FACE OF TUBERCULOSIS Hookah pipe 21 yr old Russian college student Weight loss, fever, cough Abnormal CXR Community acquired pneumonia Continues to get worse BAL + M TB on culture Remains + after several weeks of RIPE CXR and patient are worse Contact Investigation College campus Hookah bar Model Club Face Book In Egypt at least 17% of TB Is transmitted Through smoking at a Hookah Bar 14
XDR-TB Extensively Drug Resistant Tuberculosis control Isoniazid Ethambutol Rifampin control control control control control Streptomycin Rifabutin Ethionamide Kanamycin Ofloxacin Capreomycin Bad Bugs: Are There Drugs to Treat This Patient? 56 yr old male, born in US, No prior treatment TST positive, abnormal CXR, Culture - M TB Cough, fever, sweats, weight loss x 4 months Resistant to: INH, Rifampin, Rifabutin PZA Ethambutol Streptomycin, Capreomycin, Amikacin Levofloxacin Ethionamide 15
Primary MDR TB DOB:10-10-52, Date of film: 2-23-06 Inadequate Public Health Response from Past? Contact to father who died with MDR TB in 1994 Father s culture resistant to: INH, Rifampin, Rifabutin PZA Ethambutol Streptomycin, t Capreomycin, Amikacin i Ofloxacin Ethionamide Father was drug susceptible at first diagnosis! 16
Drug Resistant TB Humanitarian Volunteer Dec, 2009-22 yr old US born female Returns from 14 month visit to the former USSR 2 week history of cough. RX 2 week course azithromycin. Jan, 2010- returns to the former USSR. TST +20 mm Feb, 2010- CXR reveals RUL infiltrate with possible cavitation. CXR Overseas 2/10/10 17
Initial Presentation (2) Feb 12, 2010 Patient asymptomatic and initiated on first line TB therapy (INH/Rifampin/Ethambutol/PZA) Sputum in Ukraine + AFB smear, culture pending March, 2010 Returns back to the US for further care. Continued on TB therapy (HREZ) Started Moxifloxacin (3/30-4/13/10). Repeat sputum cultures done. Patient Reported as MDR TB April 27, 2010- Reported sputum culture (2/12/10) positive MDR TB. Patient evaluated at health department. Asymptomatic and tolerating TB meds. PMHx: ADHD Meds: Ritalin, HREZ 18
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Susceptibility Testing Ukraine 2/12/2010 US Lab 1 2/12/2010 CDC Lab 2/12/2010 INH (0.2, 1.0) R R R R Rifampin (1.0, 5.0) R R R R EMB (5.0) EMB (10.0) R --- PZA R R R R Strepromycin (2.0) Streptomycin (10.0) R --- R S R S R --- R S NJH Lab 4/29/2010 50% R (7.5 mcg) R ( 2 and 4) Kanamycin --- S R S (6) Amikacin (4.0) R --- S S (6) Ciprofloxacin (1.0) Ciprofloxacin (2.0) Ofloxacin (1.0) Ofloxacin (2.0) --- S --- S R --- --- S R --- R Ethionamide R R S (10) PAS S S S S 20
Chronic MDR TB (Pre XDR) 2005: Referred to Binational Project Resistance: INH, Rifampin, Rifabutin, Strep, PZA, EMB, Ethionamide, Levofloxacin and Imipenem Susceptible: Amikacin, Capreo, Cycloserine, PAS, Linezolid Intermediate: Moxifloxacin Treatment: Amikacin, Capreo, Moxifloxin 800mg, PAS and Linezolid 600mg Culture conversion at 3 months Extensive MDR TB, Nuevo Laredo, Date of film: 02-13-06 21
IF YOU DIAGNOSE XDR TB - THIS WOULD BE A GOOD TIME TO CONSIDER MEDICAL CONSULTATION! BUT ANYTIME YOU HAVE A QUESTION IS A GREAT TIME How do WHO and National TB Program Policies Lead to High Rates of MDR TB? Global standard - diagnosis by smear only No cultures or susceptibility tests Drug resistance is not recognized Standardized treatment regimens This allows further development of resistance AMPLIFICATION OF RESISTANCE 22
INH Resistant TB Young male with INH resistance TB no prior therapy Treatment with RIPE x 2 months No response to treatment Referred when results of cultures identified First step Collect new cultures see where you are! Also request 2 nd line susceptibility tests 1 st culture INH, EMB, strep, kanamycin, amikacin, capreomycin 2 nd culture new Rifampin resistance PRE XDR TB! Aggressive new treatment regimen needed Pathogenesis of Drug Resistance How Does Drug Resistance Develop? 23
Treatment with a Single TB Drug Leads to Drug Resistance Spontaneous mutations result in small numbers of drug resistant bacilli Treatment with one drug -- (or one effective drug) kills all but resistant bacilli Drug resistant bacteria will survive eventually replace the susceptible population. Increase In Streptomycin-Resistant Mutants During Monotherapy Weeks of SM-resistant SM-resistant treatmentt t mutants t mutants t (%) 0 (before) 1 / 88,750 0.0011 2 1 / 13,174 0.0075 3 1 / 817 0.12 4 1 / 588 0.17 5 1 / 367 0.27 Pyle M. Proc Mayo Clinic 1947;22:465 24
Isoniazid Resistance After 2 Months of Isoniazid Monotherapy Retrospective analysis from isoniazid treatment trial 1952 among patients with drug-susceptible isolates before starting #Patients Cavities %Cult + % resistant 45 0 40% 22% 57 1+ 44% 40% 89 2+ 70% 61% 43 3+ 88% 87% Fox W, Sutherland I. Thorax 1955;10:85-98 Never Treat Active TB With A Single Drug! Always Use At Least 2 Drugs To Which h The TB Is Susceptible. 25
Drug-resistant mutants in large bacterial population INH RIF PZA EMB Multidrug therapy: No bacteria are resistant to all 3 drugs Monotherapy: INH-resistant bacteria proliferate INH Spontaneous mutations develop as bacilli proliferate to >10 8 INH resistant bacteria multiply to large numbers INH INH RIF INH mono-resist. mutants killed, RIF-resist. mutants proliferate MDR TB 26
Primary MDR TB 43 year old Vietnamese female presented with cough and hemoptysis TST+, CXR large thick walled cavity, Smear + AFB Started on standard treatment for TB RIPE Improved clinically and radiographically Lab notes probable bl resistance to INH, rifampin, i & EMB CDC rapid molecular susceptibility - mutations for INH, rifampin, ethambutol but no others Why is she better? M.D. 3/25/2011 27
MDR TB after Two Months of Treatment with INH, Rifampin, Ethambutol, and PZA January, 2011 at diagnosis March 29, 2011 after 2 mo RX Fall and Rise phenomenon Toman s Tuberculosis 2nd Ed. 28
Primary MDR TB What now? Stop current therapy Repeat smears and cultures Want to determine if she is still susceptible to PZA MDR regimen, don t trust PZA, repeat susceptibility Despite improvement, new sputum culture quickly grows MTB Susceptibility pending. 29
Principles of Treatment and Management of MDR TB Treat patients with likely drug resistant disease with an adequate number of drugs to prevent emergence of further resistance (amplification of resistance). Use 5 active drugs initially Use more drugs if susceptibility tests pending 5 or > drugs associated with better outcomes Step 1 Begin with any First line agents to Which the isolate is Susceptible Add a Fluoroquinolone And an injectable Drug based on susceptibilities Use any available First-line drugs Pyrazinamide Ethambutol PLUS One of these Fluoroquinolones Levofloxacin Moxifloxacin PLUS One of these Injectable agents Amikacin Capreomycin Streptomycin t Kanamycin Step 2 Add 2 nd line drugs until you have 4-6 drugs to which isolate is susceptible (which have not been used previously) Step 3 Pick one or more of these Oral second line drugs Cycloserine Ethionamide PAS Consider use of these If there are not 4-6 drugs available consider 3 rd line in consult with MDRTB experts Third line drugs Imipenem Linezolid Macrolides Amoxicillin/Clavulanate Clofazamine BS 30
Principles of Treatment and Management of MDR TB Treat at least 18-24 months after conversion of the culture to negative Continue injectable at least 6-12 months after conversion of culture to negative After culture conversion change to 3x/week therapy Shorter therapy for limited or primary TB International Standards for TB Control 3/24/2006 WHO guidelines for MDR TB 2009 Case Study: Immigrant from Nepal History: TB treated t for one year Reported normal exit CXR and cleared Coughing during flight Weight loss, malnutrition, (76 lbs) Sputum + for AFB Treatment: INH, rifampin, EMB, PZA plus Moxifloxacin Was this a good idea? 31
Recent Immigrant from Nepal Recent Immigrant From Nepal Culture positive for M TB Initial: resistant to INH, rifampin, EMB, PZA Susceptible to ethionamide, levofloxacin, amikacin Treatment: Amikacin, Moxi, EMB, Cycloserine Should we worry about fluoroquinolone resistance? 32
Recent Immigrant from Nepal Patient improves clinically Gains 25 pounds Cough and fever resolve, night sweats gone Smears and cultures convert at 12 weeks Last positive culture now Moxifloxacin resistant Repeat sensitivity on last positive culture to look for further resistance! Case Study 26 year old Vietnamese female diagnosed with smear and culture + M TB June 2008 Weight loss, hemoptysis, fever, short of breath, rapid heart rate Extensive bilateral cavitary infiltrates Started on standard TB treatment RIPE Cough, fever, and shortness of breath worsen Admitted to ICU end of July 33
Case Study Patient deteriorating Impending respiratory failure From an area of the world with not only MDR TB but XDR TB Physician adds moxifloxacin alone 7/27/08 8/1/08 nurse calls lab and they report possible resistance to everything I asked her to clarify what that meant No Time to Wait For Lab Results We have preliminary i MTB drug susceptibility test t results for patient - -. specimen # - -, DOC=06-13- 08. We have repeated the test a second time. The test results indicate MDR TB to include resistance to INH, Streptomycin, Ethambutol and Rifampin. We are checking to determine if the culture is pure before we report out a preliminary report. The culture will be sent to - - this week for extended susceptibility testing and genotyping Sent 8/4/08 34
COMMUNICATION AND PARTNERSHIP BETWEEN THE LABORATORY AND PROVIDERS IS ESSENTIAL The healthcare providers knew the patient was getting worse The laboratory knew the specimen did not look like drug susceptible TB September 2010 35
Performance of MDDR Drug Gene Sensitivity Specificity (%) (%) Rifampin rpob 96.1 97 INH inha + katg 88.6 98.7 FQ gyra 82.2 97 Kanamycin rrs + eis 86.88 96.99 Amikacin rrs 87.9 99 Capreomycin rrs + tlya 44.6 85.9 36
Extensively Drug Resistant (XDR) TB Recent Outbreak in Kwazulu Natal, SA 1500 patients evaluated 544 (35%) with TB 995 (65%) without TB 221(41%) MDRTB 323 (59%) Susceptible * Moll A et al, 2006 53 (10%) XDRTB 52 died, All HIV+ died Time to death=16 d 37
Mortality Associated with MDR TB Outbreak in New York, 1990s Facility %HIV-infected % Mortality Median interval Hosp. A 93 72 7 weeks Hosp. B 100 89 16 weeks Hosp. C 95 77 4 weeks Hosp. D 91 83 4 weeks Hosp. E 14 43 4 weeks Hosp. F 82 82 4 weeks Hosp. I 100 85 4 weeks Infection Control Start of therapy Hypothetical Infectiousness t=0 t1 t2 t3 Disease Progression (t) 38
3% of cases were in HCWs 4/10 (40%) died Symptom onset to effective RX 8 39 weeks! 39
Tuberculosis in Community Based Health Care Researchers Retrospective analysis 180 researchers Desmond Tutu TB Center, Stellenbosch Univ. Western Cape Africa 11 cases TB All in community based researchers Incidence 4.39/100 person years Standardized TB morbidity ratio 2.47 Exceeded standard population by 147% Classens, Int J Tuberc Lung Dis Dec 2010 40
TREATMENT OUTCOMES Culture Conversion California: (1993-2006) XDR TB - 46.7% MDR TB 87.3% XDR TB - 195 days MDR TB 98.5 days Germany: (2004-2006) XDR TB 80% MDR TB 87.2% Latvia: (2000) MDR TB 77% - median time 60 days South Korea: (1995-2004) XDR TB - 66% MDR TB 67% Early Treatment Outcomes and HIV Status of Patients with Extensively Drug-Resistant Tuberculosis in South Africa: A Retrospective Cohort Study" The Lancet Vol. 375; No. 9728: P. 1798-1807 (05.22.10)::Keertan Dheda, PhD; and others 21/195 (10%) of patients over age 16 died before treatment was initiated 62/174 (36%) who began treatment (82 HIV-positive), died during F/U. Number of deaths was not significantly different between HIVpositive or -negative patients. HIV, 34 of 82 (41 percent) died versus 28 of 92 (30 percent) among HIV negative (p=0.13). Independent predictors of death included treatment with moxifloxacin; (p=0.03), previous culture-proven multidrug-resistant TB (p=0.001) number of drugs used in a regimen (p<0.0001). 41
Kim et al. Am J Resp Crit Care Med; 182:113, 2010 Factors Associated with Good Treatment Outcomes for MDR TB Younger age Absence of cavities HIV negative Primary disease Hospitalization Culture conversion by 3 months? Surgery Sensitivity to ofloxacin No prior therapy with ofloxacin Fewer # drugs MTB is resistant to More effective drugs in regimen Appropriate therapy Linezolid? 42
New Treatments for MDR TB TMC 207 Otsuka PA 128 Linezolid NIH and TBTC studies in progress Already in wide use globally Int J Resp Crit Care Med, 2010 43
Kaplan-Meier survival plot of time to adverse outcome Van Deun, Int J Resp Crit Care Med, 2010 Proportion with Successful Outcomes Clofazamine throughout No INH Van Deun, Int J Resp Crit Care Med, 2010 44
The Union to test MDR-TB regimen that shortens treatment by more than half A clinical trial testing a new MDR-TB regimen that shortens the treatment time by more than half will begin enrolling patients in four countries in early 2011. Sponsored by The Union, the trial will compare the 9-month regimen with existing standardized treatment in four countries that will be selected later this year. A clinical trial testing a new MDR-TB regimen that shortens the treatment time by more than half will begin enrolling gpatients in four countries in early 2011. Sponsored by the International Union Against Tuberculosis and Lung Disease (The Union), the trial will compare the 9-month regimen with existing standardized treatment in four countries that will be selected later this year. The shorter regimen demonstrated cure rates exceeding 80% in a pilot program. TMC 207 in Primary MDR TB Diacon, NEJM June 4, 2009 45
Management of Contacts of MDR TB Treat for 6 months or observe without treatment Use drugs source case is sensitive to Choose 2: EMB, FQN, PZA HIV positive and immunocompromised persons should be encouraged to accept treatment Treat HIV-positive persons for 12 months Follow for 2 years regardless of treatment CXR and clinical evaluation THEY ALWAYS COME BACK Unless You Do It Right The First Time! 46