Multidrug-resistant Tuberculosis Page 1 of 42 Multidrug-resistant Tuberculosis Pennan Barry, MD, MPH California MDR TB Consult Service Surveillance and Epidemiology Section Curry International Tuberculosis Center Clinical Intensive September 2019 • Describe the national and global epidemiology of MDR TB • Recognize who is at higher risk for MDR TB • Discuss interpretation of molecular tests for drug resistance • List the general principles of MDR-TB treatment • Discuss the challenges in managing contacts of MDR TB • Identify resources for education, training, and expert consultation Objectives 1
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Multidrug-resistant Tuberculosis Page 1 of 42
Multidrug-resistant Tuberculosis
Pennan Barry, MD, MPH
California MDR TB Consult Service
Surveillance and Epidemiology Section
Curry International Tuberculosis Center
Clinical Intensive
September 2019
• Describe the national and global epidemiology of MDR TB
• Recognize who is at higher risk for MDR TB
• Discuss interpretation of molecular tests for drug resistance
• List the general principles of MDR-TB treatment
• Discuss the challenges in managing contacts of MDR TB
• Identify resources for education, training, and expert consultation
Objectives
1
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Terminology
• Mono-resistant: resistant to only one drug
• Poly-resistant: resistant to more than one drug, but not the combination of INH and RIF
• Multidrug-resistant (MDR): resistant to at least INH and RIF
• Pre-extensively drug-resistant (Pre-XDR): MDR plus resistance to fluoroquinolone (FQ) or a second-line injectable (Amikacin, Kanamycin, or Capreomycin)
• Extensively drug-resistant (XDR): MDR-TB plus resistance to a FQ and at least one second line injectable
Global MDR Burden
• 2017 Estimate: 558,000 incident cases
– 47% from China, India, and Russia
• Surveillance by country and region
– 2017: Data from 82% (160/194) of countries since 1994
– Continuous surveillance (91) vs epidemiological surveys (69)
– National vs subnational
– National drug resistance surveys ongoing in 12 countries
3WHO Global Tuberculosis Report, 2018
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Percentage of New Cases with MDR TBOverall: 3.5%
4WHO, Global Tuberculosis Report, 2018
5WHO, Global Tuberculosis Report, 2018
Percent of Previously Treated Cases with MDR-TBOverall: 18%
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XDR-TB
• 127 countries have reported XDR-TB
• 8.5% of MDR-TB cases, increase from 6.2% in 2016
Primary Anti-TB Drug Resistance, United States, 1993–2016*
* As of June 21, 2017. Note: Based on initial isolates from persons with no prior history of TB; multidrug-resistant TB (MDR-TB) is defined as resistance to at least isoniazid and rifampin.
Re
sist
an
t (%
)
Year
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8
Primary Anti-TB Drug Resistance, United States, 1993–2017*
*As of June 1, 2018 Note: Based on initial isolates from persons with no prior history of TB; multidrug-resistant TB (MDR TB) is defined as resistance to at least isoniazid and rifampin.
* As of June 1, 2018. Note: Based on initial isolates from persons with no prior history of TB; multidrug-resistant TB (MDR-TB) is defined as resistance to at least isoniazid and rifampin.
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XDR-TB* Case Count, Defined on Initial DST,†
by Year, 1993–2017§
* XDR-TB , extensively drug-resistant TB.† DST, drug susceptibility test.§ As of June 1, 2018.Note: XDR-TB is defined as resistance to isoniazid and rifampin, plus resistance to any fluoroquinolone and at least one of three injectable second-line anti-TB drugs.
Number and Proportion MDR TB by Country/Region of Origin, CA 2014–2018
Countries with >20 cases tested for MDR 29
Country/Region No. %PPV
(99% spec)PPV
(98% spec)
Former Soviet Republics 6 14.0 94% 89%
Peru 5 13.2 94% 88%
Laos 12 10.0 91% 84%
Burma 2 3.3 76% 62%
Nepal 1 2.9 74% 59%
Philippines 32 2.0 66% 50%
India 9 2.0 66% 50%
Ethiopia 1 1.9 65% 48%
Vietnam 16 1.8 64% 47%
China 9 1.4 57% 40%
Guatemala 2 1.2 54% 37%
United States 13 0.9 46% 30%
Mexico 8 0.4 28% 16%
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MDR-TB Cases by Country/Region of Origin and Years in the US, CA 2014–2018
Country/Region
TotalMDR TB
cases
≤ 4 years in US
No. (%)>4 years in US
No. (%)
All Countries (excl U.S.)
106 48 (3.6) 56 (1.1)
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How to interpret results of molecular tests for resistance
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Case 1
• 70 yo asymptomatic man from India with abnormal preimmigration CXR, no TB history
• Domestic CXR with multifocal infiltrates
• Sputum smear positive x 3
• Xpert positive: rifampin resistant
What do you do next?
• Start MDR treatment
• Order pyrosequencing or MDDR
• Start RIPE
• Repeat Xpert on another specimen
• Start treatment for monoRif resistance
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Case 1
• Treatment held; PSQ available within 2 days and clinically stable
• Pyrosequencing:– katG mutation: INH R
– rpoB 531TTG mutation: RIF R
– gyrA (FQ): no mutations
– rrs (amikacin): no mutations
What do you do next?
• Start MDR treatment
• Order MDDR
• Start RIPE
• Repeat Xpert on another specimen
• Order second line DSTs
• Cancel DSTs (already have molecular results)
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Case 2
• 70 yo man from Mexico in US x 25 years with 4 weeks of cough, no TB history
• CXR with multifocal infiltrates
• Sputum smear positive x 3
• Xpert positive, rifampin resistant
What do you do next?
• Start MDR treatment
• Order pyrosequencing or MDDR
• Start RIPE
• Repeat Xpert on another specimen
• Start treatment for monoRif resistance
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Case 2
• RIPE started
• PSQ:
– katG/inhA: no mutationINH Sens
– rpoB: 514TTT silent mutation: RIF Sens
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How to interpret molecular test for resistance
• Put into clinical and epidemiologic context!
• Confirm non-sequencing tests (e.g., Xpert) with sequencing test
• Consider Rif resistance on Xpert to be MDR (not just rifampin monoresistant)
• Can usually treat based on sequencing test results; follow the growth based DST results
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Limitations / Areas for Caution
• Molecular tests vs. DST discordance
– Undescribed mutations outside of loci in current molecular tests resistance
– Emerging resistance in mixed populations may not be detected
– “Disputed” mutations
• DSTs show susceptible but associated with clinical treatment failure
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Experts on Xpert: A Laboratorian and a Clinician Discuss Interpretation of Xpert MTB/RIF ResultsThis 90-minute webinar discussed the principles of Xpert MTB/RIF testing, highlighting it as an important tool for the rapid diagnosis of TB and how to best utilize the tool. A laboratorian and a clinician reviewed the rules set by the manufacturer, presented cases that addressed pitfalls in interpretation of test results, and offered expert opinion on how to proceed. The training was created for physicians who diagnose and treat patients with TB. The webinar may also be of interest to microbiologists. The webinar content is more advanced, and does not spend time on the basics.
Patients …[with]MDR are at high risk for treatment failure and further acquired resistance; they must be referred immediately to a specialist or consultation obtained from specialized treatment centers.
– Total duration at least 18 months AND at least 15 months after culture conversion
– Intensive phase (injectable only) 6-7 months
• Survival Guide – Expert consensus for U.S. Setting: – Use culture conversion to guide minimum duration – Intensive phase: at least 6 mo beyond culture conversion for
use of injectable agent– Total duration: at least 18 months beyond culture conversion
• No hard and fast rules; WHO: Surgery “may be used”
• Metaanalysis suggests success
• Consider if:
Very extensive resistance
Residual large cavity
Predominantly one-sided disease
Previous MDR treatment failure
Marrone MT, et al. Surgical interventions for drug-resistant tuberculosis: a systematic review and meta-analysis. Int J Tuberc Lung Dis 2013;17(1):6-16.
MDR-TB Clinical Case Management
• Seek consultation with MDR-TB expert as soon as multidrug resistance known
• Use daily DOT throughout entire treatment course
– No intermittent therapy for drug resistance!!
• Use case management tools (drug-o-gram) to follow serial changes in drugs, bacteriology, CXR, toxicities
• Optimize management of underlying medical conditions and nutritional status (i.e. diabetes)
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Therapeutic Drug Monitoring
• Cycloserine:
– absorption variable
– therapeutic and toxic levels are very close
– drug levels are highly recommended
– Draw 2 hours after dose
• AK, PAS, FQ, ETA, Linezolid (esp low dose)
– Some experts use routinely for all
Common Side EffectsG.I. symptoms Ethionamide, PAS, Quinolones, Clofazimine,
– Effective treatment, Isolation until noninfectious
• Preventing progression to active disease in infected MDR-TB contacts
– MDR LTBI treatment and monitoring
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Pulmonary MDR-TB considered infectious until: CDPH/CTCA Guidelines
• Effective MDR regimen tolerated for 2 weeks AND
• Favorable clinical response AND
• 3 consecutive sputum smears are AFB negativeAND
If high risk setting: (congregate, vulnerable contacts)
• 2 consecutive negative sputum cultures
Guidelines for the Assessment of Tuberculosis Patient Infectiousness and Placement into High and Lower Risk Settings, 2017: https://ctca.org/wp-content/uploads/2018/11/InfectiousnessOctober2017.pdf
Preventing Progression to Active TB
• Some published data on LTBI treatment for MDR-TB contacts; No randomized trials reported
• CDC guidance last in 1992
• Contact investigation and management principles same as drug susceptible:
– Drug resistant TB is not more infectious, but consequences of transmission are greater
– Consider infectiousness of index case, duration/intensity of contact, immune status of contact, LTBI test results
– Rule out active disease prior to starting LTBI treatment
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Fluoroquinolones for MDR Contacts
• Published data from 2 MDR outbreaks in Chuuk:
– 104 of 119 received LTBI treatment x 12 months
• Adults: MFX + EMB (n=24) or MFX/LFX alone (n=51)