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
6
0
1
2
3
4
5
6
7
8
9
10
1994 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 2016
Isoniazid MDR-TB
7
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.
0
1
2
3
4
5
6
7
8
9
10
1993 1995 1997 1999 2001 2003 2005 2007 2009 2011 2013 2015 2017
Isoniazid MDR TB
Re
sist
ant
(%)
Year
9
Primary Isoniazid Resistance Among U.S.-Born versus Non-U.S.–Born Persons, United States, 1993–2017*
0
2
4
6
8
10
12
14
1993 1995 1997 1999 2001 2003 2005 2007 2009 2011 2013 2015 2017
U.S.-born Non-U.S.–born
Year
Iso
nia
zid
-Re
sist
ant
(%)
* As of June 1, 2018. Note: Based on initial isolates from persons with no prior history of TB.
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10
Primary MDR-TB Among U.S.-Born versus Non-U.S.–Born Persons, United States, 1993–2017*
0
1
2
3
1993 1995 1997 1999 2001 2003 2005 2007 2009 2011 2013 2015 2017
U.S.-born Non-U.S.–born
Year
Mu
ltid
rug
-Re
sis
tan
t(%
)
* 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.
11
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.
0
2
4
6
8
10
12
1993 1995 1997 1999 2001 2003 2005 2007 2009 2011 2013 2015 2017
Cas
e c
ou
nt
Year of diagnosis
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Multidrug-resistant TB CasesCalifornia, 1995‒2017
47 46 42 36 39 34 31 41 33 37 36 34 28 31 33 23 35 14 26 18 23 29 300
0.5
1
1.5
2
0
5
10
15
20
25
30
35
40
45
501
99
5
19
96
19
97
19
98
19
99
20
00
20
01
20
02
20
03
20
04
20
05
20
06
20
07
20
08
20
09
20
10
20
11
20
12
20
13
20
14
20
15
20
16
20
17
Nu
mb
er
of
MD
R c
ase
s
MDR cases Pct MDR
Pe
rce
nt
of
cult
ure
po
sca
ses
12
Who is at higher risk for MDR-TB?
• History of previous TB treatment, particularly if recent
• Known exposure to MDR-TB case
• HIV (+)
Higher incidence of Rifampin mono resistance
• Poor response to standard 4-drug treatment
Culture remains (+) after 2 months treatment
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Proportion MDR varies by birthplaceCalifornia, 2011-2018
Credit: Julian Boyce
Proportion MDR varies by birthplaceCalifornia, 2011-2018
Credit: Julian Boyce 2%
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Credit: Julian Boyce
MDR more common <4 years after US arrivalCalifornia, 2011-2018
MDRNot MDR
4y
Who is at higher risk for MDR-TB?
• NonUS-born arrived in U.S. within last 4 years• Immigration from or recent extended travel to country with > 2%
MDR among cases from that country diagnosed in California/U.S.• These countries* are:
• Other state or locally identified risk groups, including:– Hmong refugees– Persons of Tibetan origin
*California data from 2014-2018 and U.S. data from 2013-2017
† Current U.S. data are available from the CDC, Division of TB Elimination (DTBE) (www.cdc.gov/tb) 17
India Peru Ethiopia, Eritrea Former Soviet states
Korea Ecuador Nigeria Mongolia
Burma Guatemala Nepal Dominican Republic
Laos
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Order Xpert or PSQ for Patients with MDR Risk!
Among 42 smear positive MDR cases with MDR risk, 20 did not get Xpert or PSQ on sputum (California, 2012-2016)
18Lowenthal, Clin Inf Dis 2019
Molecular Testing for Drug Resistance
19
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Chapter 3, page 48
Next Generation Sequencing
• Whole genome sequencing
– In use in UK and New York State
– Requires growth of organism (slower)
– CRyPTIC Consortium
• Targeted sequencing
– Under development
– May not require culture growth
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Molecular Testing: Drugs/LociAntimicrobial agent Gene/locus
Sensitivity(Sequencing)
Specificity(Sequencing)
Assays
Isoniazid (INH) katG86.0 99.1 Hain, PSQ, MDDR
INH and Ethionamide inhA promoter
INH ahpC promoter 4.5 100 PSQ
INH fabG1 PSQ, MDDR
Rifampin (RIF) rpoB 97.1 97.4 Xpert, Hain, PSQ, MDDR
Ethambutol (EMB) embB 78.8 94.3 Hain, MDDR
Pyrazinamide (PZA) pncA 86.0 95.9 MDDR
Fluoroquinolones gyrA 79.0 99.6 Hain, PSQ, MDDR
Amikacin (AMK) rrs 90.9 98.4 Hain, PSQ, MDDR
Capreomycin (CAP)rrs
55.2 91.0 MDDRtlyA
Lin, et al., Clin Lab Med. 2014 Jun;34(2):297-314. doi: 10.1016/j.cll.2014.02.005
http://www.cdc.gov/tb/topic/Laboratory/MDDRUsersGuide.pdf
Lin, et al., J Clin Micro. 2014;52:475 22
Types of mutations
Silent (synonymous)
• Nucleic acid change
• No amino acid change
• Not associated with drug resistance generally – 514 (TTCTTT) mutation in rpoB
is the most common silent mutation
Missense (nonsynonymous)
• Nucleic acid change
• Amino acid change
• Some are associated with resistance
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Molecular Testing for Rifampin (rpoB)
• Rifampin cornerstone of TB treatment
– Resistance requires a longer duration of therapy
– Rif resistance without INH resistance rare
Rif resistance ≈ MDR
Xpert Probes: Coverage of rpoB
427
428
429
430
431
432
433
434
435
436
437
438
439
440
441
442
443
444
445
446
447
448
449
450
451
452
Codon#
Most common silent mutation
(433 TTT)
Most common resistance mutation
(450 TTG)
Location of silent mutation Location of missense mutation
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Xpert Probe B mutation might be silent
• ~20% of all mutations detected in the rpoB core
region are Silent!(In California and other low MDR areas)
• Most common is 433TTT
• Mutations detectable by probe B:
– 70% is this silent mutation
– Disputed mutation: 435TAC, 435TTC,
– RIF-R mutations: 435GTC, 432AAA, GAA, etc.
26
Xpert interpretatiom-Curry Center-9/26/18
Xpert Performance Rifampin Resistance
• Pooled median sensitivity:
– 95% (95% CrI: 90, 97)
• Pooled median specificity:
– 98% (95% CrI: 97, 99)
Steingart 2014 Cochrane Review (http://tbevidence.org/wp-content/uploads/2014/01/Steingart-Cochrane-Library-Updated-Xpert-SR.pdf)
27
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Number and Proportion MDR TB by Country/Region of Origin, CA 2014–2018
Countries with >30 cases tested for MDR 28
Country/Region No. %Former Soviet Republics 6 14.0
Peru 5 13.2
Laos 12 10.0
Burma 2 3.3
Nepal 1 2.9
Philippines 32 2.0
India 9 2.0
Ethiopia 1 1.9
Vietnam 16 1.8
China 9 1.4
Guatemala 2 1.2
United States 13 0.9
Mexico 8 0.4
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)
30
How to interpret results of molecular tests for resistance
31
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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
32
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)
33
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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
34
Case 2
• RIPE started
• PSQ:
– katG/inhA: no mutationINH Sens
– rpoB: 514TTT silent mutation: RIF Sens
35
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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
36
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
37
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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.
38https://www.currytbcenter.ucsf.edu/trainings/experts-xpert-laboratorian-and-clinician-discuss-interpretation-xpert-mtbrif-results
MDR TB Treatment
39
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Ask for help!MDR TB Needs Expert Consultation
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.
— CDC, ATS, IDSA Treatment Guidelines, 2003
http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5211a1.htm
Evolving recommendationsChoosing a regimen
2016 CITC/CA DPH “Survival Guide” 3rd edition
2015 WHO CompanionHandbook 2016 WHO DR-TB Guidelines
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WHO announces landmark changes in MDR-TB treatment regimens — 17 AUGUST 2018, GENEVA
42https://www.who.int/tb/features_archive/new_MDR_regimens/en/
First ever U.S. DR-TB Guidelines – in progress……. expected late 2019
How many drugs for MDR?Initial phase
Goal: 4-6 likely effective drugs optimally at least 5
• WHO Guidelines 2019: at least 4
• Studies suggest better outcomes with at least 5 drugs
• Expert input: • Consider more if extensive disease and/or resistance
• Four may be sufficient with limited disease and/or limited resistance
• Also depends on which drugs (e.g., NIX-TB had 3 drugs; BDQ,LZD,Pa)
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WHO Reclassified MDR Medications
44Adapted from: WHO treatment guidelines for multidrug- and rifampicin-resistant tuberculosis, 2018 update. [Pre-final text]
Group A:Include all three
Levofloxacin ORMoxifloxacin
Lfx , Mfx
Bedaquiline Bdq
Linezolid Lzd
Group B:Add one or both
Clofazimine Cfz
Cycloserine Cs
Group C:Add to complete the regimen (ranked by relative balance of benefit to harm)
Ethambutol E
Delamanid Dlm
Pyrazinamide Z
Imipenem-cilastatin OR
Meropenem (PLUS clavulanate)
Ipm-Cln
Mpm
Amikacin (OR Streptomycin) Am (S)Ethionamide Eto
p-aminosalicylic acid PAS
WHO Reclassified MDR Medications
45Adapted from: WHO treatment guidelines for multidrug- and rifampicin-resistant tuberculosis, 2018 update. [Pre-final text]
Group A:Include all three
Levofloxacin ORMoxifloxacin
Lfx , Mfx
Bedaquiline Bdq
Linezolid Lzd
Group B:Add one or both
Clofazimine Cfz
Cycloserine Cs
Group C:Add to complete the regimen (ranked by relative balance of benefit to harm)
Ethambutol E
Delamanid Dlm
Pyrazinamide Z
Imipenem-cilastatin OR
Meropenem (PLUS clavulanate)
Ipm-Cln
Mpm
Amikacin (OR Streptomycin) Am (S)Ethionamide Eto
p-aminosalicylic acid PAS
First line drugs demoted
First line drugs demoted
BDQ and LZD for all cases(BDQ for age 6y+)
No injectable for most!!(No capreomycin for any)
Need to address access!
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Data for recommendations from meta-analysis (not RCTs)
• Individual patient data metaanalysis, n=13,104
• Propensity score matched (attempt to control for differences)
• Drugs analyzed only when susceptible
46The Collaborative Group for the Meta-Analysis of Individual Patient Data in MDR-TB treatment Lancet 2018; 392: 821–34
Use these drugs
47
https://www.who.int/tb/publications/2019/consolidated-guidelines-drug-resistant-TB-treatment/en/
< 1.0 is good
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Don’t use these drugs
48https://www.who.int/tb/publications/2019/consolidated-guidelines-drug-resistant-TB-treatment/en/
49
Medicine(ranked by
relative balance of benefit to harm)
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50
We are using Bedaquiline moreBDQ use by year, MDR Service
3 0 0 2 7 200%
20%
40%
60%
80%
100%
0
5
10
15
20
2013 2014 2015 2016 2017 2018
% o
f C
on
sult
s
Pat
ien
ts o
n B
DQ
51
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Choosing to use all-oral regimens in California
Status-quo• Very good TB
outcomes with prior regimens (88% success)
• Can routinely provide appropriate monitoring(audiogram, electrolytes, creatinine, vestibular)
52
All-oral
• We do see (and worry about) hearing loss/tinnitus
• PICC / IM injections carry risk or pain
• Injectable administration is inconvenient and expensive
• We have other options
We are using injectables lessInjectable use by year, MDR Service
53
0%
20%
40%
60%
80%
100%
2015 2016 2017 2018
% P
atie
nts
on
In
ject
able
Multidrug-resistant Tuberculosis Page 28 of 42
2019: MDR Regimen Questions
• When (if ever) to use injectable?
• Use Clofazimine in all?
– Difficult to get
– FQ, BDQ, CFZ all prolong QTc
• How long to use BDQ? >6months?
• What will ATS/CDC/IDSA/ERS MDR Guidelines say?
54
“Bangladesh Regimen”Short course treatment for MDR
• Recommended by WHO 2016
• Observational data impressive (85-90% cure)
• RCT noninferior
• Contraindications: resistance to any drug in regimen, extrapulmonary disease, pregnancy
• Should this be used in the U.S.?
WHO, 2016. http://who.int/tb/Short_MDR_regimen_factsheet.pdf 55
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Short(er) Course Regimen for MDR-TB
Isoniazid*
Moxifloxacin*
Pyrazinamide
Ethambutol
0 1 2 3 4 5 6 7 8 9+
months
Clofazimine
Prothionamide
Kanamycin
Initial Phase (7 drugs) Continuation Phase (4 drugs)
*High dose
Barriers to Implementing
• Clofazimine availability
• Contains injectable
• Few qualify by strict criteria (15% in California)
• How to substitute for adverse events or resistance?
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Pretomanid
• FDA approved August 14, 2019 (not available yet)
• Nitroimidizole (same class as delamanid)
• Approved for:
– use with LZD 1200mg and BDQ (NIX-TB study)
– XDR TB
– MDR TB in patients “intolerant or nonresponsive” to treatment
• Several other ongoing trials (ZeNIX, SimpliciTB)
58
Beyond susceptibility results, consider:
• Cross-resistance
– low level INH-R (inhA, ahpC, fabG) Ethionamide R)
– Moxifloxacin Levofloxacin
– Clofazimine ↔ Bedaquiline
• Side effect profile
• Avoid drugs used previously
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Medication Fact Sheets
• Drug class/trade name• Activity against TB• Cross-resistance• Dose (adult, peds, renal)• Route of administration• Preparation/storage• Pharmacokinetics• Oral absorbtion/metabolism• CSF penetration• Special circumstances• Adverse
reactions/contraindications• Monitoring• Costs/patient education
Treatment Duration(Longer regimens)
• WHO 2019 Guideline:
– 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
• ATS/CDC/IDSA/ERS Guideline pending
• Future: NIX, ZeNIX, others studying shorter regimens
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Surgery?
• 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,
Rifabutin, Linezolid
Hearing loss, vestibular toxicity Injectables
Renal insufficiency/Electrolyte Injectables
Hepatotoxicity PZA, PAS, Rifabutin, Ethionamide, Quinolones
Peripheral neuropathy Linezolid, INH, Quinolones, Ethionamide, Cycloserine
Neuropsychiatric: depression, agitation, psychosis, difficulty concentrating, insomnia
Cycloserine, Quinolones, Ethionamide
QTc prolongation Bedaquiline, Clofazimine, Quinolones
Rash All
Visual changes EMB, Rifabutin, Linezolid
Hypothyroidism Ethionamide, PAS
Headache Quinolones, Cycloserine, Ethionamide, EMB
Chapter 9
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QTc Prolongation
• Use Fredericia formula (most ECG machines use Bazett)
• QTc has substantial diurnal variation (up to 75ms)– Longest in AM
• Prolonged QTcF: >470 for females; >450 for men– Repeat ECG after 30 minutes to confirm
– QTcF >500ms is more concerning; requires action
• Think about/address other prolonging drugs and conditions (in addition to TB meds)
Challenge TB 2018 QTc Guide: https://www.challengetb.org/publications/tools/pmdt/Guidance_on_ECG_monitoring_in_NDR_v2.pdf 70
Monitor MDR-TB patients for treatment response
• Collect sputum monthly throughout
• End-of-treatment sputum for smear and culture
• CXR quarterly and at end of treatment
• Monitor for 2 years after treatment
– Quarterly: first year, Q6 months: second year)
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88% of MDR cases have good outcomesCalifornia 2009–2018
Off Treatment191
On Treatment50
Moved23
0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%
All MDR Casesn=267
*Includes 1 patient with relapse 8 years later with matching genotype but nonMDR DSTs
72
Cure/Complete169
0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%
Off Treatmentn=191
Death=9 (5%)Default/LTFU=7Failure(ADR)=5*Failure(micro)=1
Died before Rx=3
Prevention
• Preventing acquired drug resistance
– DOT and daily therapy as appropriate
• Preventing transmission of MDR-TB to contacts
– 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)
• Children: LFX + EMB (N=17) or LFX + Ethionamide (n=12)
– 11 stopped early; 6 received >6 mos
– 0 cases in treated vs 3 among 15 refused (36 mo f/u)
76Bamrah et al, Int J Tuberculosis Lung Dis 2014
Treatment Regimens for MDR-TB Contacts
• FQ monotherapy
• FQ + EMB
• Monitor for 2 years only – acceptable
• FQ + PZA – very poorly tolerated
• PZA + EMB
• Other combinations? Duration?
– BDQ, LZD, ETA, CS, PAS
Multidrug-resistant Tuberculosis Page 40 of 42
Resources
78
Resources: COEs• Curry International Tuberculosis Center
1-877-390-NOTB or 1-877-390-6682 www.currytbcenter.ucsf.edu
• Heartland National Tuberculosis Center1-800-TEX-LUNG or 1-800-839-5864www.heartlandntbc.org
• New Jersey Medical School Global Tuberculosis Institute1-800-4TB-DOCS or 1-800-482-3627www.umdnj.edu/globaltb
• Southeastern National Tuberculosis Center1-800-4TB-INFO or 1-800-482-4636http://sntc.medicine.ufl.edu
• Mayo Clinic Center for Tuberculosis 855-360-1466http://centerfortuberculosis.mayo.edu/
Multidrug-resistant Tuberculosis Page 41 of 42
MDR Resources
• Curry Survival Guide v3 (2016)– https://www.currytbcenter.ucsf.edu/products/cover-pages/drug-resistant-tuberculosis-
survival-guide-clinicians-3rd-edition
• Partners in Health Guide (2013) – http://www.pih.org/library/pih-guide-to-the-medical-management-of-multidrug-resistant-tuberculosis-
2nd
• WHO MDR Guides– Companion Guide (2014)
http://apps.who.int/iris/bitstream/10665/130918/1/9789241548809_eng.pdf
– Guideline (2019)https://apps.who.int/iris/bitstream/handle/10665/311389/9789241550529-eng.pdf?ua=1
• International Union Guide (2018)– http://origin.theunion.org/what-we-do/publications/technical/english/TheUnion_DR-TB-Guide.pdf
80
California Resources
• MDR-TB Service
Provides clinical consultation, case management, CI assistance – 510-620-3000
• CA Microbial Diseases Lab
pyrosequencing for drug resistance
phenotypic DST for first-line drugs and amikacin, moxifloxacin, capreomycin, and ethionamide
Multidrug-resistant Tuberculosis Page 42 of 42
Acknowledgments
• Lisa True
• Lisa Chen
• Neha Shah
• Grace Lin
• Gisela Schecter
• Janice Westenhouse
• Marya Husary
• Julian Boyce
• Adam Readhead
Pennan Barry(MD)
Kristen Wendorf
(MD)
MaryaHusary(Project
Specialist)
Lisa True(RN)
Phil Lowenthal
(epi)
Shereen Katrak
(MD)
Neha Shah
(ret.)
Leslie Henry
(RN)