MULTIDRUG- RESISTANT TUBERCULOSIS Dean Tsukayama Hennepin County Medical Center Hennepin County Public Health Clinic
I have no relevant financial relationships.
Discussion includes off label use of: amikacin clofazimine levofloxacin/moxifloxacin linezolid
Learning Objectives Define multidrug-resistant tuberculosis Discuss the factors that promote tuberculosis drug resistance Describe the necessary components for tuberculosis control and elimination
Multidrug-resistant tuberculosis (MDR-TB) Mycobacterium tuberculosis that is resistant to both isoniazid and rifampin
First line TB drugs isoniazid rifampin pyrazinamide ethambutol
Second line TB drugs Traditional injectable agents (amikacin, capreomycin) fluoroquinolone (levofloxacin, moxifloxacin) ethionamide cycloserine para-aminosalicylic acid
Definitions Drug Resistance Single Poly Multi (MDR) Extensive (XDR) ethambutol isoniazid pyrazinamide rifampin two or more first-line drugs, but not MDR isoniazid and rifampin isoniazid, rifampin, quinolone, injectable agent
Drug-resistant Tuberculosis Consequences longer and more expensive treatment less effective and more toxic medication increased treatment failure and death specter of untreatable tuberculosis Bull World Health Organ 2012, 90:111
Treatment Outcome of DRTB Initial drug resistance associated with treatment failure 1 - pansentitive- 0.9% - single drug resistance- 8% - polydrug resistance- 21% Outcome of MDR-TB best with combined 18 month therapy (minimum) and DOT (69% versus 58%) 2 1. Lew. Ann Intern Med 149:123, 2008 2. Orenstein. Lancet Infect Dis 9:153, 2009
MDR-TB 2015 estimated 480,000 cases - 3.9% of new cases - 21% of previously treated cases 580,000 cases of MDR/RR 250,000 deaths, more than half were in India, China, and the Russia may be an underestimate of true numbers Source: tbfacts.org
Multidrug-Resistant TB (MDR TB) Cases, Minnesota, 2011 2017 Data as of 10.13.2017 11 Number of confirmed cases 9 7 5 2 Hmong case-patients 0 2011 2012 2013 2014 2015 2016 2017 Year 14 (82%) of 17 case-patients were Hmong
Mycobacterium tuberculosis A successful pathogen Oldest MTB: evolved 70,000 years ago Found in human settlements: 9000 years ago Worldwide prevalence of infection: 2 billion annual cases of disease: 10.4. million annual mortality: 1.8 million a TOP TEN cause of death Source: World Health Organization website
Prevalence of naturally occurring resistance Isoniazid: 3.5/10 6 Rifampin: 1.2/10 8 Streptomycin: 3.8/10 6 Ethambutol: 3.1/10 5 From: A Clinician s Guide to Tuberculosis. Michael D. Iseman, 2000
S531L mutation Rifampin Resistance Resistance in beta subunit of the RNA polymerase (rpob) 1. single nucleotide change (SNP) causes change in the amino acid coded 2. amino acid change leads to configurational change in protein structure 3. Structure change can result in drug resistance 4. 90% of rifampin resistance is a result of SNPs in rpob 5. common mutation is at position 531 6. Not all mutations leading to mutations are known. 7. some SNPs have no consequence for protein structure SNP: single nucleotide polymorphism
Rifampin Resistance Resistance extends treatment duration to a minimum of one year Rarely see single drug resistance. Usually a surrogate for MDR. Rifampin dependent strains have been reported
Drug Resistance in M. tuberculosis Edward D. Chan and Michael D. Iseman Current Opinion in Infectious Diseases 2008, 21:587 595
KwaZulu Natal Gandhi et al. Lancet 368:1575, 2006 53 cases of extensively drug-resistant tuberculosis reported from a hospital in South Africa Represented 6% of all patients with culture-confirmed tuberculosis All 44 patients tested for HIV were positive 52 patients died The mean time to death was 16 days from the time of diagnosis 55% had no prior TB treatment 67% had a recent hospital admission
Evolution of F15/LAM4/KZN Strain of Mycobacterium tuberculosis in KwaZulu-Natal Resistance first noted in: INH RIF STR ETB THI ETH CAP KAN FQN 1994 1994 1994 1994 1997 1997 1998 1998 1999 INH- isoniazid RIF- rifampin STR- streptomycin ETB- ethambutol THI- thiacetazone ETH- ethionamide CAP- capreomycin KAN- kanamycin FQNfluoroquinolone MDR found in 1994 Progressively increasing poly-drug resistance with time XDR found in 2001 XDR outbreak in 2005
Risk factors for acquiring drug-resistant tuberculosis Previously treated tuberculosis Inadequate therapy unrecognized initial drug resistance poor adherence to therapy inadequate dosing of medication adding a single drug to a failing regimen needed medications are unavailable Exposure to drug-resistant case
Resistance- clinical settings Primary- transmission of drug-resistant strain to an uninfected person Acquired- conversion of a pan-sensitive strain to a drug-resistant strain during therapy Amplified- progressive acquisition of more drug resistance during repeated treatment episodes Sally M Blower & Tom Chou. Nature Medicine 10:1111, 2004
KZN: All 44 patients tested for HIV were positive estimated 14 million co-infected people TB is the leading cause of death in HIV-infected patients increases progression from latent to active TB 20x atypical presentation of pulmonary tuberculosis more extrapulmonary disease immune reconstitution inflammatory syndrome (IRIS) higher relapse after standard treatment more re-infection with new exposure HIV and TB TB accelerates the progression of HIV infection to AIDS
Principle of TB Management Identification and treatment of active tuberculosis cases Drug susceptibility testing Screening and treatment of latent tuberculosis Contact investigation Respiratory isolation
Diagnosis of TB microscopy AFB histology molecular culture
Diagnostic delay result in treatment delay conventional culture takes up to 6 weeks conventional susceptibility (agar-proportion) require culture growth, then add 2-4 weeks for results liquid media has decreased time to culture and antibiotic resistance results molecular diagnosis of MTB is available on the day of testing and has helped greatly, but is not as sensitive as culture molecular diagnosis of drug resistance also a significant advance, but not completely accurate
AFB Smear False-positive result from nontuberculous mycobacteria False negative in up to 50% of culture-positive cases Only test available for diagnosing TB in many parts of the world
Microscopic Observation Drug Susceptibility Sputum sample is directly inoculated into liquid medium Growth is recognized by characteristic cord formation Can inoculate into medium with antibiotic to test for drug resistance. Excellent sensitivity and specificity
Boehme et al. NEJM 363:1005, 2010 Cepheid GeneXpert
Antibiotic Treatment Must be effective against different metabolic states of MTB (rapid growing, slow growing, dormant) Must be effective in different environmental conditions (anaerobic, acidic, cavity, intracellular, granuloma) Combination treatment required overcome intrinsic resistance associated with large population of organisms single drug unlikely to be effective in all settings rapid emergence of resistance with monotherapy
Action of Drugs in Tuberculosis Treatment Int J Tuberc Lung Dis 2:10, 1998
Treatment of MDR-TB
New MDR-TB guidelines WHO treatment guidelines for drug-resistant tuberculosis. 2016 update
Successful Treatment of MDR-TB Resources Success Rate (%) Yes 75 No 50 Successful treatment of: drug-susceptible tuberculosis- 85-90% Bangladesh regimen- 88% XDR- 25% XDR- resistant to isoniazid, rifampin, injectable agent, fluoroquinolone
Short course treatment for MDR tuberculosis Bangladesh regimen MDR: resistant to isoniazid and rifampin standardized 9 month regimen of 7 drugs: gatifloxacin, clofazimine, ethambutol, pyrazinamide, prothionamide, kanamycin, isoniazid (high dose) Regimen not based on individual drug susceptibility testing success rate of 87.9% in 206 patients difficult to adopt in regions where drug susceptibility testing is available AJRCCM 182:684, 2010
New Drugs Mechanisms of drug action conversion of pro-drug to active form cell wall synthesis cell membrane disruption DNA function ribosomal transcription ATP production efflux pumps New or repurposed drugs fluoroquinolone linezolid clofazimine carbapenem + beta-lactamase inhibitor bedaquiline delamanid verapamil
Resistance- clinical settings Primary- transmission of drug-resistant strain to an uninfected person KZN: 55% had no prior TB Acquired- treatment conversion of a pan-sensitive strain to a drug-resistant strain during therapy Amplified- progressive acquisition of more drug resistance during repeated treatment episodes Sally M Blower & Tom Chou. Nature Medicine 10:1111, 2004
Latent Tuberculosis Screening and Treatment Recommended by US Preventive Services Task Force for high risk populations Essential for goal of eliminating tuberculosis Not done in resource-poor countries Inadequate treatment data in MDR-TB
Contact investigation Evaluate persons with most exposure to the index case If transmission found (infection or disease), expand the evaluation group Those at risk for progression to disease can get window prophylaxis until a follow-up screening test is negative Genotyping of MTB isolate can document TB transmission
Whole Genome Sequencing MDR TB in Hmong Minnesotans 2016 2017 Father of patient 3 Patient 3 8 Genetically related Senior Center Exposure Patient 5 MRCA = most recent common ancestor 7 Patient 9 4 2 MRCA Patient 12 6 Patient 4 Patient 8 Patient 14 Patient 1 1 2 3 Patient 11 Patient 10 2 2 1 Patient 2 6 Patient 13 Patient 6 Patient 7
KwaZulu Natal Gandhi et al. Lancet 368:1575, 2006 53 cases of extensively drug-resistant tuberculosis reported from a hospital in South Africa Represented 6% of all patients with culture-confirmed tuberculosis All 44 patients tested for HIV were positive 52 patients died The mean time to death was 16 days from the time of diagnosis 55% had no prior TB treatment 67% had a recent hospital admission
TB is a disease of poverty Most countries do not have the resources to: 1. quickly and accurately diagnose tuberculosis 2. determine drug resistance 3. treat multidrug-resistant tuberculosis 4. adequately identify contacts of tuberculosis patients 5. place infectious patients into isolation Leads to: 1. more patient at risk for exposure 2. development of drug resistance 3. need for longer treatment courses and treatment failure Most cases of pulmonary cases in the world are diagnosed by sputum smear or clinically Less than 20% of estimated MDR cases are diagnosed and treated appropriately Very little treatment of latent tuberculosis Limited ability to do contact investigation Lack of effective respiratory isolation in hospitals
TB Incidence and per capita GDP European Respiratory Journal 32:1415, 2008
State of the Art Culture-confirmed diagnosis Drug susceptibility testing If needed- 2nd line drug susceptibility, drug levels Directly observed therapy Never add a single drug to a failing regimen Infection control Contact investigation Treatment of latent tuberculosis Use of molecular testing when appropriate
TB can be eliminated Reservoir is human We know how to diagnose and treat the disease Many countries have TB annual incidence of 10 cases per 100,000 compared to the global average of 142 cases per 100,000 US goal is to decrease the rate to 0.1 cases per 100,000 by 2050 (currently 3/100K)
TB can be eliminated, BUT MTB has been a very successful pathogen TB is a disease of poverty TB anywhere is TB everywhere Drug resistance is of increasing concern Long treatment course required, contributes to: treatment failure drug resistance
Needed faster and more accurate diagnosis of tuberculosis and drug resistance more effective drugs better drug combinations innovative ways to test new drug combinations in vitro and clinically new approaches: vaccine and immunotherapy give already proven diagnostic and therapeutic resources to regions of the world where they are desperately needed
Summary Drug-resistant tuberculosis is a growing problem The epidemic is fueled by sub-optimal therapy and control measures We currently have, but may be losing, the tools we need to control tuberculosis New diagnostic and treatment options will have a positive impact Tuberculosis affects everyone but is primarily a disease of poverty