mdr tb keh - curry international tuberculosis center · drug‐resistant tb: survival guide,...

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MDR TB AND CASESTUDIESChris Keh, MDDirector, TB Prevention and Control Program, SFDPHHS Assistant Clinical Professor, Infectious Diseases, UCSFSeattle, CITC Clinical IntensiveJune 15, 2018

Objectives

Explain factors which could lead to increased multidrug-resistant tuberculosis and how best to prevent and decrease the possibilitiesDescribe the rationale for the multidrug-resistant tuberculosis

treatment guidelines and apply them to achieve optimal patient outcomes

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Disclosures

I will be presenting information on investigational or off-label use of second / third line TB drugs (e.g. Amikacin, Delamanid, Linezolid, Amoxicillin-clavulanate, Kanamycin, Meropenem, Augmentin, Fluoroquinolones, Rifabutin, Clofazimine, Imipenem).

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Objectives

MDR TB epidemiology (US) / BackgroundMolecular diagnostics / DSTMDR Treatment Infection Control Summary

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Drug-Resistant TB: DefinitionsMono-resistant: Resistance to a single drug Poly-resistant: Resistance to more than one drug, but not the

combination of isoniazid and rifampicinMultidrug-resistant (MDR): Resistance to at least isoniazid and

rifampicin Extensively drug-resistant (XDR): MDR + resistance to

fluoroquinolones and 1 of the 3 injectable drugs (amikacin, kanamycin, capreomycin)

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.

Resistan

t (%

)

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

Year

INH resistance = 8.7%

MDR TB = 1.2%

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Primary MDR‐TB, United States, 1993–2016*

0

0.5

1

1.5

2

2.5

3

0

50

100

150

200

250

300

350

400

450

1994 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 2016

Year

Number of cases Percentage of total casesPercentageNo. of cases

* As of June 21, 2017

• 78 total cases reported in 2016 (1.2% of cases)• 90% of primary MDR cases attributed to non‐U.S.—born • 1 case of XDR reported in 2016

Case 1 Case: Gisela Schecter, MD

21-year-old Filipina woman with Type I DM recently emigrated from the Philippines

No TB screening at the time of immigration

History of treatment for TB with INH +/- RIF as a child and, more recently, with INH, RIF, PZA and EMB given by SAT last year

Presented with cough x 5 months, progressive SOB/DOE x 6 weeks, pleuritic chest pain and fever to 101 degrees

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Do you suspect DR? Why?21-year-old Filipina woman with Type I DM recently

emigrated from the Philippines

No TB screening at the time of immigration


Presented with cough x 5 months, progressive SOB/DOE x 6 weeks, pleuritic chest pain and fever to 101 degrees

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INH = 3.5 x 10-6

RIF = 1.2 x 10-8

EMB = 3.1 x 10-5

PZA = 1.0 x 10-5

Strep = 3.8 x 10-6

INH+RIF = 4.2 x 10-14

(Approximately 107 to 109 organisms per cavity)

Frequency of Random Naturally Occurring Resistance Mutations

Share of Global Incidence (%)WHO 2016 report

Estimated global incidence and proportion of MDR among TB cases

Estimated:• 490,000 new cases of MDR• 4.1% of all new cases and

19% of previously treated cases have MDR (or R-Resistance)

• Of notified cases – almost half are from India, China, and the Russian Federation

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Most Important Predictors for Drug Resistance Previous episode(s) of TB treatmentWorsening clinical and/or radiographic findings while on TB

therapyOrigin from, history of residence in, or frequent travel to a

region or country with a high prevalence of drug-resistant TB Exposure to an individual with known (or highly suspected)

infectious drug-resistant TB, or exposure to individuals in congregate settings where drug resistance has been documented

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Drug‐Resistant TB: Survival Guide, 3rd edition

Additional Factors for Clinical Suspicion

Presence of RIF resistance predicts MDR (Rifampin mono-resistance is rare)HIV+ (higher incidence of RIF mono-resistance)

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Objectives


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Case 2: 31 yo M with HIV and cough x 1 yr18

• Hemoptysis, 30 kg weight loss, fatigue• Has been living in Thailand for years• CD4=280, VL ND, on ART

• Presented to ER on 5/3• Sputum smear = numerous AFB on 5/4• GeneXpert = POSITIVE MTB, RIF

resistance DETECTED on 5/4• Active TB regimen (expanded) started 5/4

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Case 3: 45 yo Chinese M with dry cough x 1 yr19

• Leg weakness and weight loss• Moved to US 7 years ago with hx IVDU• New dx of DM (HbA1c 13.6%) and HCV

with liver mass/HCC

• Presented to ER on 6/3• Sputum smear = numerous AFB on 6/4• GeneXpert = POSITIVE MTB, RIF

resistance DETECTED on 6/4• Active TB regimen (expanded) started 6/4

Case 4: 43 yo M recently immigrated from Philippines

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• Severe back pain, fatigue, loss of appetite, weight loss• Dx with Pott’s Diseases C7-S1 based on FNA that was smear neg, culture

pos• Started on RIPE, but then PZA stopped due to uric acid elevation• After 2 months of treatment, worsening back pain• Repeat MRI with concern for progression of disease

• What are your questions?

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Rapid Molecular Diagnostics

NAAT/Beacon (GeneXpert)

Sequencing (Molecular Detection of Drug Resistance “MDDR”, CDC)

Xpert MTB/RIF Test Performance

Sensitivity Specificity

Smear pos. TB 95‐98%99%

Smear neg. TB 60‐72%

Rifampin “R” 98‐99% 99‐100%

NEJM 361:1005, 2010; Am J Crit Care Med 184:132, 2011

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• Provides both MTB identification and detection of RIF resistance (rpoB)• RIF mono‐resistance is rare; thus detection of RIF resistance on

geneXpert is a red flag for possible MDR.• Run‐time ~2 hours• May give false negative if low DNA copies• May yield no results if inhibitors present

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Xpert MTB/RIF Report23

MTB DETECTED or NOT DETECTED Rif Resistance DETECTED or NOT DETECTED

Not useful to follow once positive (DNA can be detected even after completion of adequate tx).

Rapid Molecular Testing to Identify Drug Resistance

Sequencing (“MDDR” at CDC)• Short turnaround time• Screen for resistance: INH, RIF, EMB, PZA, FQ, injectable• Reports specific mutation• Smear positive sputum or culture• Requested by/through state public health lab

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MDDR submission criteriaHigh-risk of RMP resistance or MDR TB Known RMP resistance (by rapid test or by culture-based DST)High public health impact (e.g., daycare workers, nurses)Adverse reactions to critical anti-TB drug (e.g.,allergy to RMP)Mixed or non-viable cultures Isolates which fail to grow in DST medium

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https://www.cdc.gov/tb/topic/laboratory/mddrusersguide.pdf

Performance characteristics of MDDR by DrugDrug Locus or Loci

examinedSensitivity (%) Specificity (%)

RMP rpoB 97.1 97.4

INH inhA + katG 86.0 99.1

FQ gyrA 79.0 99.6

KAN rrs + eis 86.7 99.6

AMK rrs 90.9 98.4

CAP rrs + tlyA 55.2 91.0

EMB embB 78.8 94.3

PCA pncA 86.0 95.9

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https://www.cdc.gov/tb/topic/laboratory/mddrusersguide.pdfAdditional resource: Helpful table DR mutations: Survival Guide v3 pages 46‐47

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Rapid Molecular Testing- Benefit

Short turnaround time (compared to phenotypic methods) Earlier initiation of effective tx Decreased period of infectiousness Improved pt outcome Earlier involvement of MDR expert Earlier request for 1st/2nd line susceptibilities

High stakes setting MDR suspect Pregnancy HIV/immunocompromised Do Not Board decisions Public health settings (shelter, congregate, schools)

Rapid Molecular Testing- points to consider

False negatives may occur Inhibitors Low DNA load NTM/mixed

Results can help to guide early changes in treatment, but must always be confirmed with phenotypic data (susceptibility testing)

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Remember! Drug Susceptibility Testing (DST)

Smear and culture (drug susceptibility testing) remain the gold standard 1st-line DST at local / commercial labsMany states perform basic 2nd-line DST CDC performs expanded 2nd-line DST

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CDC- Drug Susceptibility Testing (DST)

Isoniazid Rifampin Ethambutol CiprofloxacinOfloxacin Streptomycin Kanamycin

CapreomycinAmikacin Rifabutin Ethionamide Para-aminosalicylic acid (PAS) Pyrazinamide* Bedaquiline**

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*Tested by MGIT 960 (all others indirect proportion)**Available upon request

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Other- Drug Susceptibility Testing (DST)(i.e. may need to send to commercial lab)

Linezolid Cycloserine

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Objectives


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MDR Treatment- General Principles

Seek expert consultationNever add a single drug to a failing regimenWhen choosing drugs: Consider cross-resistance Consider side-effects Avoid drugs used previously to treat patient’s TB

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CITC Warmline Consultation

Curry International Tuberculosis Center1-877-390-NOTB OR 1-877-390-

6682 www.currytbcenter.ucsf

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Use anyavailable

One of these

One of these

First‐line drugs

Fluoroquinolone Injectable agents

Pyrazinamide

Ethambutol

Levofloxacin

Moxifloxacin

Capreomycin

Kanamycin

Amikacin

Streptomycin*

Building a Regimen for MDR-TB (1)

Begin with any first‐line agents to which the isolate is susceptible

Add a fluoroquinoloneand an injectable drug based on susceptibilities

STEP 1

* Only use if documented sensitivity


Pick one or more of these

Oral second‐line drugs

Cycloserine

Ethionamide

PAS

Linezolid


Add second‐line drugs until you have four to six drugs to which the isolate is susceptible (and preferably which have not been used to treat the patient previously)

STEP 2


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Consider use of these

Third‐line drugs

Bedaquiline

Delamanid

Clofazimine

Imipenem

Amoxicillin/Clavulanate

Meropenem / Clavulanate

Clarithromycin

High‐dose INH


If there are not 4‐6 drugs available in the above categories, consider third‐linedrugs in consultation with an expert

STEP 3


Treatment Duration 2003 ATS/CDC/IDSA guidelines: 18-24 moWHO 2016 Intensive phase at least 8 months Total duration at least 20 months (if no prior rx for MDR; if prior MDR rx at

least 24 months) Allows use of short 9-12 month regimen for specific circumstances

Survival Guide – Expert consensus: Utilize culture conversion to help guide minimum duration within U.S. high‐resource setting

• Intensive phase: at least 6 mo beyond culture conversion for use of injectable agent

• Total duration: at least 18 months beyond culture conversion

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Short course “Bangladesh” regimen (9-12 mo)

Intensive phase (4-6 mo): Kanamycin, gatifloxacin, prothionimide, high-dose INH, clofazamine, ethambutol, PZA Continuation (5 mo): gatifloxacin, clofazamine, ethambutol, PZA2005-2011: Treatment success 84.5% (n=515)

KJM Aung et al. Int J Tuberc Lung Dis 2014 ;18(10)

Ongoing multi-country observational study Separate STREAM trial [randomized 9 mo (except uses Moxi) vs

“standardized” regimen]; adds BDQ arm (6 and 9 month regimens)

Bedaquiline (Janssen) Class – diarylquinolineMechanism of action - novel ATP

synthase inhibitorActivity In vitro – bactericidal (replicating

and dormant) Animal – bactericidal and sterilizing

activity Early bactericidal activity similar to

isoniazid or rifampicin

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When an effective treatment regimen cannot be provided: BDQ may be used for 24 weeks of treatment in adults with

laboratory-confirmed pulmonary MDR-TB BDQ may by used on a case-by-case basis in children, HIV

infected persons, pregnant women, extrapulmonary MDR-TB, and patients with comorbid conditions

BDQ may be used on a case-by-case basis for durations longer than 24 weeks (5.5 mo. ½ life)

DOSE: 400 mg once daily for 2 weeks, then 200 mg three times a week for 22 weeks, taken with food

CDC MMWR 2013;62;1‐12

CDC Provisional Guidelines: Bedaquiline

CDC Provisional Guidelines: Bedaquiline

No dose adjustment with mild/mod renal impairmentDrug interactions – metabolized through CYP3AHepatotoxicity AST, ALT, bilirubin, alkaline phosphatase

monthly Cardiac toxicity Baseline ECG and then 2, 12, and 24 weeks Baseline K, Ca, Mg levels Discontinue if QTcF >500 ms or ventricular

arrthymiasCDC MMWR 2013;62;1‐12

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Common Adverse Effects

G.I. complaints

Ethionamide CycloserinePAS Fluoroquinolones ClofazimineRifabutin

Hepatotoxicity

(early symptoms are anorexia and malaise, then abdominal pain, vomiting, jaundice)

INH Rifampicin/rifabutin Ethionamide PZA PAS Fluoroquinolones


Peripheral neuropathy

INH EthionamideCycloserineLinezolidEthambutolFluoroquinolones

Rash All

Headache

Fluoroquinolones Isoniazid CycloserineEthionamide Ethambutol

Seizures Cycloserine

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Hypothyroidism Ethionamide, PAS

Hearing loss, Vestibular toxicity

Aminoglycosides, Capreomycin

Behavioral changesCycloserine, Ethionamide, Isoniazid, Fluoroquinolones

Visual changes Ethambutol, Rifabutin, Isoniazid, Linezolid

Renal failureHypokalemia, Hypomagnesemia

Aminoglycosides, Capreomycin

Just one example of the tools needed

GI complaints (very very very common)- Drug ramping (CS, PAS, ETA) Supportive care (H2 blockers, PPI, antacids) Split dosing (for some meds), QHS dosing, admin with food Anti-emetics, pre-medication, benzodiazepines Crushing, cutting, liquids, capsules surrounding tablets Alternative: ginger, sea-band, lemon heads, other Switching to IV formulation PEG, J-tube

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Additional monitoring (drug dependent)

EKG (bedaquiline, fluoroquinolones high dose or combined with other QTc prologing agents)Drug levels (e.g. aminoglycosides, PAS, cycloserine,

ethionamide)Audiology (aminoglycosides)- monthly until 1 month post-d/c

of injectable TSH, pregnancy test, PSQ-9, vestibular exam, visual

acuity/IshiharaDrug-drug interactions- anti-depressants, QTc prolonging

agentsDecision of IM vs IV

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Case 1- What would you start?21-year-old Filipina

woman with Type I DM recently emigrated from the Philippines


RIPE + Moxi

Molecular testing shows resistance to RIF/INH

MDR consultation: Start EMB, PZA, Moxi, PAS, Cycloserine, Amikacin

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Case 2- What would you start?49

• Hemoptysis, 30 kg weight loss, fatigue• Has been living in Thailand for years• CD4=280, VL ND, on ART• Sputum smear = numerous AFB on 5/4• GeneXpert = POSITIVE MTB, RIF

resistance DETECTED on 5/4

• Initial start: RIPE + FQ + amikacin + linezolid

• After PSQ, MDDR, DST adjusted to: EMB, PZA, FQ, amikacin, linezolid, bedaquiline(+/- PAS)

Case 3: What would you start?50

• Leg weakness and weight loss• Moved to US 7 years ago with hx IVDU• New dx of DM (HbA1c 13.6%) and HCV

with liver mass/HCC• Sputum smear = numerous AFB on 6/4• GeneXpert = POSITIVE MTB, RIF

resistance DETECTED on 6/4• Initial start: RIPE + FQ + amikacin +

linezolid• After PSQ, MDDR, DST adjusted to:

PZA,FQ, amikacin, linezolid, bedaquiline

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Case 4: 43 yo M recently immigrated from Philippines

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• Severe back pain, fatigue, loss of appetite, weight loss• Dx with Pott’s Diseases C7-S1 based on FNA that was smear neg, culture

pos• Started on RIPE, but then PZA stopped due to uric acid elevation• After 2 months of treatment, worsening back pain• Repeat MRI with concern for progression of disease

• Initial start: RIPE + linezolid + FQ + injectable• After PSQ, MDDR, DST adjusted to: FQ, amikacin, linezolid, PAS, cycloserine

Objectives


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Infection Control considerations Drug-resistant TB is similar in transmissibility to drug-susceptible TB (WHO 2014) Because MDR-TB transmission has more serious consequences, criteria for release from isolation is more conservative, in particular for high-risk settings. Some experts would consider MDR-TB patients potentially infectious as long as their sputum cultures remain positive. Example criteria for smear positive: Drug-susceptible TB: smear conversion x 3 AND at least 14 days of treatment AND clinical improvement MDR TB: smear conversion x 3 (no subsequent positive smear) AND at least 14 days of treatment AND clinical improvement AND at least 2 consecutive negative sputum cultures without subsequent positive

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* CTCA/CDPH Criteria for Infectiousness and Placement in High and Lower Risk Settings

Objectives


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Summary High-risk MDR: Action Steps

Obtain rapid molecular test for drug sensitivity E.g. Xpert RIF/MTB (local), MDDR (CDC)

Order both first (local) and second-line (state or CDC) DSTConsider initiation of expanded regimenNever add a single drug to a failing regimenConsult your friendly neighborhood MDR expert

Summary: MDR PearlsDOT should be performed (7 days / wk ideal, 5 days / wk

acceptable)Use a case management / tracking tool; drug-o-grams can be

your friend TB treatment requires multi-disciplinary collaboration for

optimal care! Divide and conquer: Nursing, TB case managers Physicians (pulmonary / ID, hospitalist, primary care, TB control) Infection control Social workers, contact investigators, community outreach workers Specialty care: e.g ophtho, neurology, audiology, HIV, endocrine, etc.

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Snapshot comparisonDrug‐susceptible TB MDR TB

Average treatment duration = 6 months Average treatment duration = =18‐24 months or more

Average cost = 18,000 Average cost = 134,000 (MDR) – 494,000 (XDR)

Average isolation = 5‐14 days minimum(in many cases may be longer)

Average isolation = 2 months minimum(in many cases may be longer)

Average number of drugs used initially = 4 Average number of drugs used initially = 6‐8

Common complications: hepatitis, rash, GI upset Many more complications: nephrotoxicity, peripheral neuropathy, optic neuritis, ++ GI upset, vestibular/ototoxicity, bone marrow suppression, hepatotoxicity, depression, CNS toxicity

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Helpful resources Treatment Guidelines: CDC/ATS/IDSA, Treatment of Tuberculosis, 2016

(MDR guideline in progress) Regional Training and Medical Consultation

Centers (RTMCC), http://www.cdc.gov/tb/education/rtmc/

Drug-Resistant Tuberculosis: A Survival Guide for Clinicians, Curry Center (2016)

WHO 2016 GuidelinesMed side effects: Tuberculosis Drug Information Guide, Curry

Center

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Design by Mehroz Baig v. 2017-4-14

THANK [email protected]

Special thanks to Lisa Chen, MD for slides and guidance

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mdr tb keh - curry international tuberculosis center · drug‐resistant tb: survival guide,...

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