MDR TB AND CASE STUDIES

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1 MDR TB AND CASE STUDIES Chris Keh, MD Director, TB Prevention and Control Program, SFDPH HS Assistant Clinical Professor, Infectious Diseases, UCSF Seattle, CITC Clinical Intensive June 15, 2018 Slide 2 Objectives Explain factors which could lead to increased multidrug-resistant tuberculosis and how best to prevent and decrease the possibilities Describe the rationale for the multidrug-resistant tuberculosis treatment guidelines and apply them to achieve optimal patient outcomes 1

2 Slide 3 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). Objectives 4 MDR TB epidemiology (US) / Background Molecular diagnostics / DST MDR Treatment Infection Control Summary 2

3 Drug-Resistant TB: Definitions Mono-resistant: Resistance to a single drug Poly-resistant: Resistance to more than one drug, but not the combination of isoniazid and rifampicin Multidrug-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, * Resistant (%) Isoniazid MDR TB Year INH resistance = 8.7% MDR TB = 1.2% * As of June 21, 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. 3

4 Primary MDR TB, United States, * No. of cases Number of cases Percentage of total cases 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 Year Percentage * As of June 21, 2017 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 4

5 Case 1 Case: Gisela Schecter, MD Case 1 Case: Gisela Schecter, MD 5

6 Case 1 Case: Gisela Schecter, MD 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 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 6

7 Frequency of Random Naturally Occurring Resistance Mutations 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 (Approximately 10 7 to 10 9 organisms per cavity) 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 WHO 2016 report Share of Global Incidence (%) 7

8 Most Important Predictors for Drug Resistance Previous episode(s) of TB treatment Worsening clinical and/or radiographic findings while on TB therapy Origin 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 Drug Resistant TB: Survival Guide, 3 rd edition Slide 15 Additional Factors for Clinical Suspicion Presence of RIF resistance predicts MDR (Rifampin monoresistance is rare) HIV+ (higher incidence of RIF mono-resistance) Slide 16 Drug Resistant TB: Survival Guide, 3 rd edition 8

9 Objectives 17 MDR TB epidemiology (US) / Background Molecular diagnostics / DST MDR Treatment Infection Control Summary Case 2: 31 yo M with HIV and cough x 1 yr 18 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 9

10 Case 3: 45 yo Chinese M with dry cough x 1 yr 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 19 Case 4: 43 yo M recently immigrated from Philippines 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 20 What are your questions? 10

11 Rapid Molecular Diagnostics NAAT/Beacon (GeneXpert) Sequencing (Molecular Detection of Drug Resistance MDDR, CDC) Xpert MTB/RIF Test Performance 22 Sensitivity Specificity Smear pos. TB 95 98% Smear neg. TB 60 72% 99% Rifampin R 98 99% % NEJM 361:1005, 2010; Am J Crit Care Med 184:132, 2011 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 11

12 23 Xpert MTB/RIF Report 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 12

13 Slide 25 MDDR submission criteria High-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 Performance characteristics of MDDR by Drug Slide 26 Drug Locus or Loci Sensitivity (%) Specificity (%) examined RMP rpob INH inha + katg FQ gyra KAN rrs + eis AMK rrs CAP rrs + tlya EMB embb PCA pnca Additional resource: Helpful table DR mutations: Survival Guide v3 pages

14 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 1 st /2 nd 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) 14

15 Slide 29 Remember! Drug Susceptibility Testing (DST) Smear and culture (drug susceptibility testing) remain the gold standard 1 st -line DST at local / commercial labs Many states perform basic 2 nd -line DST CDC performs expanded 2 nd -line DST Slide 30 CDC- Drug Susceptibility Testing (DST) Isoniazid Rifampin Ethambutol Ciprofloxacin Ofloxacin Streptomycin Kanamycin Capreomycin Amikacin Rifabutin Ethionamide Para-aminosalicylic acid (PAS) Pyrazinamide* Bedaquiline** *Tested by MGIT 960 (all others indirect proportion) **Available upon request 15

16 Other- Drug Susceptibility Testing (DST) (i.e. may need to send to commercial lab) Linezolid Cycloserine Slide 31 Objectives 32 MDR TB epidemiology (US) / Background Molecular diagnostics / DST MDR Treatment Infection Control Summary 16

17 MDR Treatment- General Principles Seek expert consultation Never add a single drug to a failing regimen When choosing drugs: Consider cross-resistance Consider side-effects Avoid drugs used previously to treat patient s TB Slide 33 Drug Resistant TB: Survival Guide, 3 rd edition CITC Warmline Consultation Curry International Tuberculosis Center NOTB OR

18 Building a Regimen for MDR-TB (1) STEP 1 Begin with any firstline agents to which the isolate is susceptible Use any available First line drugs One of these Fluoroquinolone One of these Injectable agents Add a fluoroquinolone and an injectable drug based on susceptibilities Pyrazinamide Ethambutol Levofloxacin Moxifloxacin Capreomycin Kanamycin Amikacin Streptomycin* * Only use if documented sensitivity Drug Resistant TB: Survival Guide, 3 rd edition Building a Regimen for MDR-TB (2) STEP 2 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) Pick one or more of these Oral second line drugs Cycloserine Ethionamide PAS Linezolid Drug Resistant TB: Survival Guide, 3 rd edition 18

19 Building a Regimen for MDR-TB (3) STEP 3 If there are not 4 6 drugs available in the above categories, consider third line drugs in consultation with an expert Bedaquiline Delamanid Clofazimine Consider use of these Third line drugs Amoxicillin/ Clavulanate Meropenem / Clavulanate Imipenem Clarithromycin High dose INH Drug Resistant TB: Survival Guide, 3 rd edition Treatment Duration 2003 ATS/CDC/IDSA guidelines: mo WHO 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 19

20 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, PZA : 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 diarylquinoline Mechanism of action - novel ATP synthase inhibitor Activity In vitro bactericidal (replicating and dormant) Animal bactericidal and sterilizing activity Early bactericidal activity similar to isoniazid or rifampicin 20

21 CDC Provisional Guidelines: Bedaquiline 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 No dose adjustment with mild/mod renal impairment Drug interactions metabolized through CYP3A Hepatotoxicity 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 arrthymias CDC MMWR 2013;62;

22 Common Adverse Effects G.I. complaints Hepatotoxicity (early symptoms are anorexia and malaise, then abdominal pain, vomiting, jaundice) Ethionamide Cycloserine PAS Fluoroquinolones Clofazimine Rifabutin INH Rifampicin/rifabutin Ethionamide PZA PAS Fluoroquinolones Common Adverse Effects Peripheral neuropathy Rash Headache Seizures INH Ethionamide Cycloserine Linezolid Ethambutol Fluoroquinolones All Fluoroquinolones Isoniazid Cycloserine Ethionamide Ethambutol Cycloserine 22

23 Common Adverse Effects Hypothyroidism Hearing loss, Vestibular toxicity Behavioral changes Visual changes Renal failure Hypokalemia, Hypomagnesemia Ethionamide, PAS Aminoglycosides, Capreomycin Cycloserine, Ethionamide, Isoniazid, Fluoroquinolones Ethambutol, Rifabutin, Isoniazid, Linezolid Aminoglycosides, Capreomycin Just one example of the tools needed Slide 46 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 23

24 Slide 47 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/ishihara Drug-drug interactions- anti-depressants, QTc prolonging agents Decision of IM vs IV Case 1- What would you start? 21-year-old Filipina woman with Type I DM recently emigrated from the Philippines 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 RIPE + Moxi Molecular testing shows resistance to RIF/INH MDR consultation: Start EMB, PZA, Moxi, PAS, Cycloserine, Amikacin 24

25 Case 2- What would you start? 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) 49 Case 3: What would you start? 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 50 25

26 Case 4: 43 yo M recently immigrated from Philippines 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 51 Initial start: RIPE + linezolid + FQ + injectable After PSQ, MDDR, DST adjusted to: FQ, amikacin, linezolid, PAS, cycloserine Objectives 52 MDR TB epidemiology (US) / Background Molecular diagnostics / DST MDR Treatment Infection Control Summary 26

27 Slide 53 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 * CTCA/CDPH Criteria for Infectiousness and Placement in High and Lower Risk Settings Objectives 54 MDR TB epidemiology (US) / Background Molecular diagnostics / DST MDR Treatment Infection Control Summary 27

28 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) DST Consider initiation of expanded regimen Never add a single drug to a failing regimen Consult your friendly neighborhood MDR expert Summary: MDR Pearls Slide 56 DOT 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. 28

29 Slide 57 Snapshot comparison Drug 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 Average isolation = 2 months minimum (in many cases may be longer) (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 58 Helpful resources Treatment Guidelines: CDC/ATS/IDSA, Treatment of Tuberculosis, 2016 (MDR guideline in progress) Regional Training and Medical Consultation Centers (RTMCC), Drug-Resistant Tuberculosis: A Survival Guide for Clinicians, Curry Center (2016) WHO 2016 Guidelines Med side effects: Tuberculosis Drug Information Guide, Curry Center 29

30 59 THANK YOU! Special thanks to Lisa Chen, MD for slides and guidance Design by Mehroz Baig v