Selected highlights: Treating Drug resistant TB: High resource, low incidence settings

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1 Selected highlights: Treating Drug resistant TB: High resource, low incidence settings Regional Training and Medical Consultation Centers (RTMCCs) Pennan Barry, Lisa Chen, Connie Haley, Alfred Lardizabal, Barbara Seaworth; NAR February 2017 MDR TB in the United States ( ) Year Total MDR US Born Foreign born CDC. Reported TB in the US, Drug Resistant TB in Canada ( ) Characteristic Susceptible Resistant MDR Total non MDR ( XDR) 1993 Canadian born Foreign born Country # Cases Philippines 32 China 29 Vietnam 18 India 16 South Korea 8 PLoS One 2013; 8 (1): e3466. doi: /journal.pone

2 MDR TB in New York City Top 10 Country of Birth Country of Birth # MDR % China Ukraine USA Burma 3.8 India 3.8 Nepal 3.8 Ecuador 3.8 Kazakhstan Uzbekistan Kryghstan Philippines Dominican Republic Ghana Data courtesy NYC Department of Health & Mental Hygiene Bureau of TB Control Number and Proportion MDR TB by Country/Region of Origin, CA Country/Region No. % Former Soviet Republics 12.2 Laos 6.1 Burma India Guatemala 3.0 Korea (N&S) Peru Ethiopia Philippines Vietnam China (incl Taiwan) United States Cambodia Mexico Countries with >20 cases tested for MDR Real case Practical Walk through select issues encountered 2

3 0 yo man with diabetes Philippines to US late 1990s Hemoptysis x several weeks Works in banking Tobacco hx Traveled to Philippines 2 yrs ago 0 yo man with diabetes Philippines to US late 1990 s Hemoptysis x several weeks Works in banking Tobacco hx Travelled to Philippines 2 yrs ago Let s talk about risk factors Case: CXR Hemoptysis, cough x weeks No weight loss, fevers, or night sweats Admitted and isolated Next tests? 3

4 What is the Added Value of NAAT? AFB smear ( ): 0 70% of smear /culture + cases will be + by NAAT start treatment (earlier) If NAAT ( ) likelihood of TB lower Still start treatment if suspicion is high AFB smear (+): NAAT (+) can confirm TB quickly If NAAT ( ), prevent falsely diagnosing TB (likely NTM if inhibitors ruled out; result repeated) Release from isolation (2 Xperts finds all smear +) NTCA /APHL Consensus Statement: Luetkemeyer Clin Infect Dis 2016 Xpert MTB/RIF Test Performance Compared with Culture, U.S. patients Sensitivity Specificity 1 Xpert 2 Xperts Smear (+) 96.7% (9/61) Smear ( ) 9.3% (16/27) 100% (62/62) 71.4% (20/28) 99.2% Luetkemeyer Clin Infect Dis 2016 Initial diagnostic tests Smear positive x3 (cultures sent) Xpert MTB/RIF: Positive for Mtb and RIF resistance 4

5 Benefits of Molecular Tests for Drug Resistance Reduced time to detection of resistance Time from empiric (first line) treatment to MDR treatment 40 days less (median) Less transmission Less acquired resistance while DSTs pending Less ineffective LTBI treatment given to contacts Banerjee et al, J Clin Micro, 2010 Xpert Performance Rifampin Resistance Pooled median sensitivity: 9% (9% CrI: 90, 97) Pooled median specificity: 98% (9% CrI: 97, 99) Steingart 2014 Cochrane Review ( Cochrane Library Updated Xpert SR.pdf) Chapter 3, page 3

6 Xpert Probes: Coverage of rpob Codon # Most common silent mutation (14 TTT) Most common resistance mutation (31 TTG) Location of silent mutation Location of missense mutation Note: codon numbering follows E coli. Subtract 81 for MTB numbering Number and Proportion MDR TB by Country/Region of Origin, CA Country/Region No. % Former Soviet Republics 12.2 Laos 6.1 Burma India Guatemala 3.0 Korea (N&S) Peru Ethiopia Philippines Vietnam China (incl Taiwan) United States Cambodia Mexico Countries with >3 cases tested for MDR Number and Proportion MDR TB by Country/Region of Origin, CA PPV (99% spec) PPV (98% spec) Country/Region No. % Former Soviet Republics % 87% Laos % 72% Burma % 63% India % 60% Guatemala % 60% Korea (N&S) % 9% Peru % 6% Ethiopia % 0% Philippines % 4% Vietnam % 40% China (incl Taiwan) % 37% United States % 28% Cambodia % 2% Mexico % 22% Countries with >3 cases tested for MDR 6

7 MDR TB Cases by Country/Region of Origin and Years in the US, CA Country/Region Total MDR TB cases 2 years in US No. (%) >2 years in US No. (%) All Countries (excl US)* (3.7) 71 (1.2) Former Soviet Republics 2 (33.3) 3 (8.6) Vietnam* 13 9 (7.9) 3 (0.4) China (incl Taiwan)* 7 (8.8) 2 (0.4) Philippines* 27 8 (4.0) 19 (1.4) Guatemala 1 (3.9) 4 (2.9) India 12 3 (3.3) 9 (3.2) All Other Countries 10 2 (1.1) 8 (0.9) Mexico 11 0 (0.0) 11 (0.7) Korea, North and South 7 0 (0.0) 7 (3.2) Laos 6 0 (0.0) (4.6) * Difference is statistically significant Increased Risk for MDR TB? (by country of origin) California Groups with high prevalence of MDR Hmong refugees, Tibetan ancestry Persons born in former USSR, Laos, Burma, Korea, Peru, Central America, India Recent arrivers to US (e.g., within 2 years) especially from China, Vietnam, Philippines Caveat: Few cases in CA from Haiti, South Africa, Dominican Republic, others Also see: ATS/IDSA/CDC Diagnosis of TB Guidelines 2016 DOI: /cid/ciw694 Increased Risk for MDR TB: Who to test (ATS/IDSA/CDC Diagnostic Guidelines) History of previous TB treatment Born in or lived for >1 year in country with: 20/100,000 TB incidence OR 2% primary MDR Contact to MDR TB case HIV infected Higher incidence of Rifampin resistance ATS/IDSA/CDC Diagnosis of TB Guidelines 2016 DOI: /cid/ciw694 7

8 Chapter 3, page 48 Initial diagnostic tests Smear positive x3 (cultures sent) Xpert MTB/RIF: Positive for M.tb and RIF resistance PSQ: rpob mutation No gyra, rrs, inha, or katg Rif resistance MDR Rif resistance without INH resistance rare ~90% (114 of 129) Rif resistant cases MDR (California, ) MDR Rif mono R 0% 20% 40% 60% 80% 100% 8

9 How to Interpret Molecular Test for Resistance Put into clinical and epidemiologic context! Confirm non sequencing tests (e.g., Xpert) with sequencing Consider Rif resistance on Xpert as MDR (not rifampin monoresistant) Can usually treat based on sequencing test results; follow the growth based DST results Discordance between molecular and phenotypic tests can be confusing with multiple causes ( disputed mutations, undescribed/unknown mutations, etc.) When in doubt: seek consultation Basic Steps: Choosing a Regimen Resources: First ever U.S. DR TB Guidelines in progress. (additional individual patient data meta analysis by Menzies group) 2016 WHO DR TB Guidelines 2016 CITC/CA DPH Survival Guide 3 rd edition 201 WHO Companion Handbook At the start: Empiric Regimen Decision: Begin empiric MDR regimen Ask for help: Expert consultation Empiric (expanded) regimen for MDR: 4 first line + FQ + injectable (+ consider additional second line drug) This case (Xpert, then PSQ results)? 9

10 How many drugs for MDR? Goal: 4 6 likely effective drugs (and optimally at least ) Survival Guide 3 rd edition Recent studies suggest better outcomes with at least 6 drugs mortality with at least likely effective drugs (2013 Mitnick, PLOS Peru), (2014 Velasquez, CID Russian Fed.) PETTs prospective observational study: 9 countries, 169 adults: at least 6 potentially effective drugs 36% greater likelihood of culture conversion (201 Yuen; PLOS) WHO likely effective = not previously used and/or proven in vitro drug susceptibility How many drugs for MDR? Goal: 4 6 likely effective drugs (and optimally at least ) Survival Guide 3 rd edition Recent studies suggest better outcomes with at least 6 drugs Expert mortality input: with at least likely effective drugs (2013 Mitnick, PLOS Peru), (2014 Velasquez, CID Russian Fed.) - Consider more if extensive disease and/or resistance PETTs prospective observational study: 9 countries, - Four may be sufficient with limited disease and/or 169 adults: at least 6 potentially effective drugs 36% limited resistance greater likelihood of culture conversion (201 Yuen; PLOS) WHO WHO likely 2016: effective at least = likely not previously effective drugs, used and/or including proven PZA in vitro drug susceptibility Building an Individualized Regimen for MDR TB STEP 1 Begin with any First line agents to which the isolate is susceptible Add a fluoroquinolone and an injectable drug based on susceptibilities Use any available First line drugs Pyrazinamide Ethambutol One of these Fluoroquinolones Levofloxacin Moxifloxacin One of these Injectable agents Amikacin Capreomycin Kanamycin 1 Streptomycin 2 1. Not available in U.S. 2. SM: use only if not previously used and if documented susceptibility 10

11 Building an Individualized Regimen for MDR TB STEP 1 This case: (INH) Use any available First line drugs Pyrazinamide Ethambutol One of these Fluoroquinolones Levofloxacin Moxifloxacin One of these Injectable agents Amikacin Capreomycin Kanamycin 1 Streptomycin 2 1. Not available in U.S. 2. SM: use only if not previously used and if documented susceptibility Building a Regimen for MDR TB (2) STEP 2 Add second line drugs until you have 4 6 drugs (optimally at least ) 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 3 3. Although considered a third line drug, many experts now use LZD as a second line drug option 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 MDR TB expert Consider use of these Third line drugs Bedaquiline Meropenem/ Delamanid 4 Clavulanate Amoxicillin/ Clofazimine Clavulanate Imipenem Clarithromycin High dose INH 4. Awaiting FDA approval 11

12 Other considerations when choosing drugs Beyond susceptibility results, consider: Cross resistance (Survival Guide table pg. 76) Avoid drugs used previously Side effect profile Treatment Duration 2003 ATS/CDC/IDSA guidelines: months WHO 2011 (& 2016) based on individual patient meta analysis: 32 studies, over 9000 pts. (Ahuja et al, PLoS Med 2012); 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) Survival Guide 3 rd Ed Expert consensus: Utilize culture conversion to help guide minimum duration within U.S. high resource setting Intensive phase: at least 6 months beyond culture conversion for use of injectable agent Total duration: at least 18 months beyond culture conversion (at least 24 months for pre XDR/XDR) Short course regimen & New Drugs WHO 2016: recommends use of Bangladesh short course regimen (9 12 mo) more next session! CDC 2013: Use Bedaquiline when INH/RIF resistant and an effective treatment regimen cannot be provided: - BDQmay be usedfor 24 weeks of treatment in adultswith laboratory confirmed pulmonary MDR TB (case by case basis in children, HIV infected persons, pregnant women, extrapulmonary MDR TB, and with comorbid conditions; & for durations longer than 24 weeks) WHO endorsed BDQ (2013) and delamanid (2014) along with push for global access to linezolid and clofazimine 12

13 Outcomes: U.S. based practice Task Order 28: random sample MDR cases from CA, TX, NYC (N=13, of total US 370) 21% Acquired resistance (any) 90% Ambulatory care (>80% doses done as outpt) 73% were hospitalized 1 6 times during course 90% assigned case managers 81% documented expert consultation 97% culture conversion if eligible (median 2 mos) 78% Treatment completion 9% died during treatment, 2% lost to follow up Marks S., Emerging Infectious Diseases, May 2014 Linezolid Oxazolidinone (Zyvox ) Inhibits protein synthesis Approved for drug resistant gram positive bacterial infections; used off label for drug resistant TB Increasing clinical experience Early in vitro and mouse studies suggested bacteriostatic/low early bactericidal affect New evidence that LZD has bactericidal and sterilizing action No cross resistance reported Step 1 Begin with any First line agents to Which the isolate is Susceptible Use any available First line drugs PLUS One of these Fluoroquinolones PLUS One of these Injectable agents Add a quinolone and an injectable drug based on susceptibilities Pyrazinamide Ethambutol Levofloxacin Moxifloxacin Amikacin Capreomycin Streptomycin Kanamycin Step 2 Add 2 nd line drugs until you have 4 6 drugs to which isolate is susceptible (which have not been used previously) Pick one or more of these Oral second line drugs Cycloserine Ethionamide PAS Linezolid A Survival Guide for Clinicians, roducts/drug resistant tuberculosissurvival guide clinicians 3rd edition Step 3 If there are not 4 6 drugs available consider 3 rd line in consult with MDRTB experts Consider use of these Third line drugs Bedaquiline Meropenemi/clavulanate Delamanid Amoxacillin/clavulanate Clofazamine Clarithromycin Imipenem High dose INH BS 13

14 WHO Drug Resistance Guidelines Use at least drugs consisting of: - 1 Drug from Group A - 1 Drug from Group B - At least 2 drugs from Group C - Use the core drugs from D1 if susceptible (with INH) - Use D3 drugs if need drugs - Use D2 drugs if not enough effective drugs Use injectable for intensive phase for 4 6 months Continue rest of meds for continuation phase of 7 mos 2016 WHO DR TB Gls: eng.pdf?ua=1 Efficacy of Linezolid Case reports and retrospective studies suggested that LZD is effective in treating MDR and XDR TB Randomized clinical trial (Lee et al 2012): 41 patients, sputum culture+ XDR TB, no response to any available treatment during previous 6 months Randomly assigned to LZD 600mg/d immediately vs. delayed after 2 mos, w/o change in background regimen After confirmed sputum culture conversion or 4 months (whichever came first), patients underwent a second randomization to continued LZD 600 mg/d or 300mg/d for at least an additional 18 months, with monitoring Lee M et al. N Engl J Med 2012; 367: Efficacy of Linezolid Culture conversion: By 4 mos: 79% (1/19 ) immediate start tgroup vs. 3% (7/20 ) delayed start (P = 0.001) By 6 mos: 87% (34/39) of all patients Lee M et al. N Engl J Med 2012; 367: Lee et al. N Engl J Med. 201 Jul 16;373(3):

15 Efficacy of Linezolid RCT (Tang 201): - 6 patients with culture (+) cavitary pulmonary XDR TB who failed 1y tx with 2 nd line drugs - Randomly assigned LZD group vs. control group - LZD 1200/d 4 6 weeks, then mg/d (based on weight, tolerability) - 2 y of individually based treatment regimens based on medication history and DST results (WHO recommended) LZD accelerated the cavity closure rate and sputum culture conversion rate Tang Set al. EurRespirJ 201;4: Efficacy of Linezolid By 24 months: Sputum-culture conversion: LZD group 78.8% vs. 37.6% control group (p<0.001) Cavity closure rate: LZD 69.7% >> control group ( p<0.0). Tang Set al. EurRespirJ 201;4: Efficacy of Linezolid Tang Set al. EurRespirJ 201;4:

16 Toxicity Profile is Major Factor Limiting Wider Use of LZD LZD inhibits intracelluar mitochondrial protein synthesis Long term administration of the drug associated with mitochondrial toxicity - Myelosuppression (anemia, leukopenia, thromocytopenia) - Optic and peripheral neuropathy may be irreversible - Hyperlactatemia - (nausea and vomiting also common) Clinically Significant Event=81% Most AE resolved after reducing or temporarily discontinuing LZD dose 2 stopped LZD permanently due to anemia Tang Set al. EurRespirJ 201;4: Time to Linezolid Related Adverse Events Tang Set al. EurRespirJ 201;4:

17 Linezolid Toxicity is Dose Related Retrospective study of prev. treated MDR/XDR pts (KOH, 2012): - 73% (33/4) taking 300mg LZD were cured - 14 (27%) d/cd LZD due to neurotoxicity; 8 (16%) had myelosuppression Systematic review and meta analysis (Cox, 2012): - No significant difference in treatment success for LZD dose 600 mg/d vs. >600 mg or duration of therapy ( 7 vs. >7 months) - Fewer AE with LZD 600mg/d (34.4% vs. 49.9% p=0.07) - Fewer d/cd tx with LZD 600 mg 929.% vs. 60.8%, P= 0.0) RCT (Lee, 2012): - Patients on 300mg/d had fewer AE (69%) vs. 600mg/d (88%) after 2nd randomization; 11 pts on 600mg required decr dose Koh et al. Antimicrob Chemother 2012; 67: ; Cox et al INT J TUBERC LUNG DIS 16(4): Lee et al. N Engl J Med 2012; 367: LZD Trough Concentration Correlates with Mitochondrial Toxicity Song 201 (substudy of Lee 2012, 201): - Evaluated 38 patients taking LZD who had AE associated with mitochondrial dysfunction (optic and peripheral neuropathy, bone marrow suppression; no lactic acidosis occurred) - Serially measured mitochondrial competence and trough levels of LZD at 300mg and 600mg doses Patients on 600mg dose had higher risk of AE than those on 300mg (HR 3.10, 9% CI ) Song et al. EBioMedicine 2 (201) Mitochondrial Function Levels Decrease with Increasing LZD Dose Song et al. EBioMedicine 2 (201)

18 Therapeutic Drug Monitoring (TDM): LZD trough predicts toxicity Increasing LZD trough concentrations associated with: Lower mitochondrial i function (Spearman s ρ=-0.48; P=0.00) Increased mitochondrial toxicity All patients with trough >2 μg/ml developed AE, whether on 300mg or 600mg. Figure: Time to AE from LZD start (A) or second randomization (B) by mean LZD trough concentration. 3=300mg dose; 6=600mg dose Song et al. EBioMedicine 2 (201) Testing for Drug Resistance Critical concentration, sensitive or resistant - Level of drug that inhibits 9% of wild type strain (never exposed to drug), but doesn t suppress resistant strain Usually the CC is sufficient in TB, but the MIC can also guide management of a difficult case Minimum inhibitory concentration (MIC) - Organism tested at a series of drug concentrations, MIC is the lowest concentration that inhibits growth - Serum levels 4 16x > MIC used in bacteria - LZD MIC range 0.06 to 1 mg/ml A Survival Guide for Clinicians, resistant tuberculosis survivalguide clinicians 3rd edition Managing Side Effects When serious side effects occur, consider decrease in dose or increase dosing interval - Use TDM to ensure trough <2 - Use MIC and 2 and 6h TDM levels to determine if lower LZD dose is 4 16x over the MIC Colony stimulating factors may be effective adjunctive therapy and may allow for continued treatment with LZD if cost not prohibitive Patient education about side effects is critical. Patients should also be cautioned to report any adverse side effects while receiving LZD, especially visual changes or sudden loss of vision 18

19 Conclusions: Walking the LZD tightrope without falling off. Early cidal effect and sterilization of persisters Careful monitoring for toxicity Insufficient evidence for optimal LZD dose, duration - TDM, MIC may enable decreased dose/frequency and AE - Higher dose initial phase, lower in continuation phase? - Thrice weekly dosing may reduce mitochondrial toxicity? Clinical factors - Ensure susceptibility to LZD - Good CNS penetration - Consider other toxicity risk factors (eg HIV, other meds) Newer oxazolidinones may have less toxicity - SIVEXTRO (tedizolid phosphate), Sutezolid? Other Precautions and Adverse Events Not recommended in pregnancy, breastfeeding (lim. data) No dose adjustment needed in renal disease Rarely associated with increased transaminases (Ok to use in mild liver disease) Contraindications: - Hypersensitivity to oxazolidinones - Neuropathy (pain, numbness, tingling or weakness in extremities). Drug Interactions: Administration of LZD with serotonergic agents (SSRIs, MAOIs) can lead to serious and potentially fatal CNS reactions, such as serotonin syndrome or neuroleptic malignant syndrome like rxns Avoid food and drinks that contain tyramine: aged cheeses, dried meats, sauerkraut, soy sauce, tap beers, red wines resistant tuberculosis survival guide clinicians 3rd edition References Observational studies Sotgiu et al. Efficacy, safety and tolerability of linezolid containing regimens in treating MDR TB and XDR TB: systematic review and meta analysis. Eur Respir J 2012; 40: Migliori, et al. A retrospective TBNET assessment of linezolid safety, tolerability and efficacy in multidrug resistant tuberculosis. Eur Respir J 2009; 34: Villar et al. Linezolid safety, tolerability and efficacy to treat multidrug and extensively drug resistantresistant tuberculosis. Eur RespirJ 2011; 38: De Lorenzo et al. On linezolid efficacy and tolerability. EurRespirJ 2012; 39: Sotgiu et al. Linezolid to treat extensively drug resistant TB: retrospective data are confirmed by experimental evidence. EurRespirJ 2013; 42: Sotgiu et al Linezolid to treat MDR /XDR tuberculosis: available evidence and future scenarios. EurRespirJ 201; 4: 2 29 Sotgiu, et al. Low minimal inhibitory concentrations of linezolid against multidrug resistant tuberculosis strains. EurRespirJ 201; 4:

20 References Meta analyses Sotgiu et al. Efficacy, safety and tolerability of linezolid containing regimens in treating MDR TB and XDR TB: systematic review and meta analysis. EurRespirJ 2012; 40: Chang et al. WHO group drugs and difficult multidrug resistant tuberculosis: a systematic ti review and cohort analysis and metaanalysis. Antimicrob Agents Chemother 2013; 7: Cox H, Ford N. Linezolid for the treatment of complicated drugresistant tuberculosis: a systematic review and meta analysis. Int J Tuberc Lung Dis 2012;16:447e4 References Randomized Clinical Trials Lee et al. Linezolid for treatment of chronic extensively drugresistant tuberculosis. N Engl J Med 2012; 367: Lee et al. Linezolid for XDR TB Final Study Outcomes. N Engl J Med. 201 Jul 16;373(3):290 1 Tang et al. Efficacy, safety and tolerability of linezolid for the treatment of XDR TB: a study in China. EurRespirJ 201; 4: Song et al. Linezolid Trough Concentrations Correlate with Mitochondrial Toxicity Related Adverse Events in the Treatment of Chronic Extensively Drug Resistant Tuberculosis.EBioMedicine 2 (201) References LZD use in meningitis: Sun et al. Linezolid manifests a rapid and dramatic therapeutic effect for patients with life threatening tuberculous meningitis. Antimicrob Agents Chemother. 2014;8(10): Li et al. Linezolid is Associated with Improved Early Outcomes of Childhood d Tuberculous Meningitis. i i Pediatr Infect Dis J Jun;3(6): Pediatrics Garcia Prats AJ, Rose PC, Hesseling AC, Schaaf HS. Linezolid for the treatment of drug resistant tuberculosis in children: a review and recommendations. Tuberculosis (Edinb) Mar;94(2):

21 Case Management & Monitoring Case Management Chapter 8, page 213 Monitoring and Case Management Isolation issue can he go home? Planning for outpatient injections/infusions Patient education and concerns (cost, anxiety) Monitoring for toxicities 21

22 Question: When to discharge from hospital? Pt is still smear positive On expanded MDR regimen Lives at home with wife and 2 adult daughters (all IGRA negative) Pt very concerned about high deductible and big hospital bill **A patient may be considered for placement in a lower risk setting without meeting these criteria if no previously unexposed persons will be present (see section: Home isolation) Chapter 8, page 230 Home Isolation Many patients with drug resistant TB do not require hospitalization and may be on home isolation at the start of treatment Some patients may be hospitalized to initiate treatment and become ready for discharge prior to becoming non infectious 22

23 Providing the Injectable Agent Chapter 8, page 21 Patient Education: Communicating Effectively Recognize and address the patient s fears and concerns Patients are less likely to comprehend treatment information if they are fearful or preoccupied with worries about their jobs or family members Case Management 23

24 Monitoring for Toxicities Chapter 8, page 23 Chapter 8, page 234 Drug Level Monitoring When to order: Injectable (especially impaired renal function or age 60+) Cycloserine to establish safe and effective dose for patient Malabsorption Lack of expected clinical response Few effective drugs in regimen to optimize Drug drug interactions, e.g. rifamycins and HIV antiretrovirals Renal impairment e.g., EMB Where to send: National Jewish or University of Florida Amikacin often done locally How/when to collect: See pages 7 and 8 24

25 Comorbidities: DR TB and diabetes Slower response to treatment Potential lower drug levels Increased risk of acquired drug resistance Poorer outcomes in treatment MDR TB Recommendations for Treating TB in the Presence of DM Follow renal function Decrease frequency of injectable if impaired Treat GI symptoms aggressively Manage neuropathy Change meds if possible Add tricyclics or gabapentin Consider TDM If initially INH resistant, DO NOT use intermittent treatment and strongly consider RIF & EMB levels DR TB Contacts Rx Options Duration 6 12 months Two drug combo or fluoroquinolone alone Avoid PZA (risk vs. benefit) Observation/clinical monitoring option 2

26 Next Set of DST Results CDC MDDR results: Confirmed PSQ results No pnca mutation embb mutations identified (silent and neutral mutation so not associated with resistance) Get these results soon after start any changes? Chapter 3, pages Update ( weeks into rx): Phenotypic DST: sensitive to INH, EMB, PZA (confirms RIF mono resistant) 26

27 Regimen Options for Mono/Poly DR Case: RIF mono resistant INH, EMB, PZA, Levo (Treatment Chap table 1, pg 70) Update ( weeks into rx): Phenotypic DST: sensitive to INH, EMB, PZA (confirms RIF mono resistant) Last update on management. Rx for contacts? Patient education? What Happens if a Patient with MDR TB becomes Pregnant? Stuff Happens! 27

28 Objectives Utilize evidence base in literature to inform recommendations for drug regimens for pregnant women with MDR TB Identify potential toxicity considerations of specific second line drugs Describe risks and benefits to inform parents to better enable them to participate in decisions regarding treatment options Results Initial search 270 All 12 articles described case reviews All were observational studies No comparison groups Treatment regimens were individualized Based on drug susceptibility testing and tolerability Contributors: Sundari Mase, Barbara Seaworth, Farah Parvez Fayez Kheir, Rishi Kowalski, Giovanni Sotgiu, After Sonya Title/Abstract Shin, Graham Bothamley Preliminary Summary of Data 12 studies included 6 case series and 6 case reports 99 pregnant women and 87 newborns Among pregnant women, 84 had MDR TB, 9 XDR TB, 3 had other DR TB, 3 were clinically diagnosed 11 women had surgical resection 28

29 Preliminary Summary of Data Maternal Outcomes Of 99 women, 12 did not complete therapy or were lost to follow up and, therefore, were excluded from maternal outcomes analysis Of the 87 women who received treatment: 71% had good outcomes Cured (n=0), completed treatment (n=12) Mortality (n=13; 14.9%) Treatment Failure (n=6; 6.9%) Pregnancy Outcomes Among 87 pregnancy women, there were 9 induced abortions Of the 78 deliveries Of the 78 deliveries: Healthy (n=68; 87.2%) Mortality (n=3; 3.8%) TB (n=3; 3.8%) TB (n=1) and LTBI (n=2) Pre term / Low Birth Weight (n=4;.1%) 29

30 Largest Series Reviewed Retrospective review of 3089 patients started on MDR TB treatment from July 1996 to December 200 in Peru: (33.4%) women of child bearing age (age, 1 4 yrs.) - 38 (3.6%) reported to be pregnant while receiving MDR TB treatment 14 women no changes in treatment regimen during pregnancy 14 women had MDR TB treatment was suspended after determination of pregnancy 13 women (34.2%) subsequently resumed treatment after discussion with a physician a median of 1.9 weeks (IQR, weeks) after suspension Palacios E, Dallman R, Muñoz M, et al. Drug resistant tuberculosis and pregnancy: treatment outcomes of 38 cases in Lima, Peru. Clin Infect Dis 2009;48(10): Children Follow up data were available for 26/38 children 2/26 children healthy, including those treated for LTBI or active TB 2 children were treated for latent TB (IPT per NTP protocol) 1 child treated successfully for active MDR TB at 19 months based on mom s DST 1 child died of pneumonia shortly after birth (no TB reported) 2 children have minor health problems: 1 child was born with testicular malformation (unlikely related to exposure to 2 nd line TB drugs in utero) 1 child has idiopathic growth retardation but has otherwise remained healthy Palacios E, Dallman R, Muñoz M, et al. Drug resistant tuberculosis and pregnancy: treatment outcomes of 38 cases in Lima, Peru. Clin Infect Dis 2009;48(10): Drobac et al CID 1 June, 200:40 30

31 Drobac et al CID 1 June, 200:40 Fetal / Newborn Adverse Outcomes Long term follow up (Drobac et al, 200, n=6) Median age (1. 6. years) Reversible skin bronzing from Clofazimine (2) Mild speech delay (1) Hyperactivity (1) Possible mild ototoxicity due to Capreomycin exposure in 1 st trimester No congenital abnormalities or TB infection at birth 1 MDR TB (household transmission from uncle) 31

32 Options for Treatment of TB During Pregnancy Need to consider risks and benefits for the mother and fetus. Option 1: Stop or delay MDR TB treatment Consider short delay if TB not immediate threat to the health of the patient 1 st trimester Rarely consider late stages of pregnancy risk to infant and public health impact Option 2: Terminate the pregnancy Option 3: Continue treatment while pregnant Treatment is challenging but not contraindicated. There is minimal data about the safety of second line antituberculous agents during pregnancy Safety Classification of Medications During Pregnancy A = safety established in human studies B = safety presumed based on animal studies Ethambutol, Bedaquiline C = safety uncertain; no human or animal studies reveal an adverse effect INH, Rifampin, PZA, FQNs, Ethionamide, Cycloserine, PAS D = safety uncertain; evidence of risk but use is justified in certain circumstances Streptomycin toxicity to the developing fetal ear (8 11%)? Amikacin and Capreomycin Ethionamide Safety class C Animal studies (high doses); 2 studies of 47 cases and 1 of 70 cases without adverse effects; In another study, 7 of 23 children had congenital malformations The use is controversial given the mixed data; if an adequate regimen cannot be constructed without it, the use of ethionamide is justified Given its gastrointestinal side effects, nausea and vomiting during pregnancy may be aggravated 32

33 Recommendations During the first 20 weeks of pregnancy, avoid the injectable if possible Exception: if the risk of morbidity or mortality is high, an injectable agent should be used (preferably CM) There is limited evidence, but clinical experience has shown that Cycloserine, fluoroquinolones, and PAS may be used in pregnant patients Family Planning Of 38 Peruvian women who received MDR TB therapy while pregnant: 3 patients (7.9%) were pregnant at the initiation of MDR TB therapy and had been pregnant for a median of 82months 8.2 (IQR, months) 3 patients (92.1%) became pregnant while receiving treatment; these patients became pregnant a median of 9.7 months (IQR, months) after treatment initiation Palacios E, Dallman R, Muñoz M, et al. Drug resistant tuberculosis and pregnancy: treatment outcomes of 38 cases in Lima, Peru. Clin Infect Dis 2009;48(10): Treatment of MDR During Pregnancy Risks vs. Benefits Risks Unknown drug teratogenicity Increased risk when therapy is delayed Maternal morbidity Prematurity Small for gestational age births Up to 6 fold increase in perinatal mortality Postnatal infection can be rapidly progressive, disseminated and fatal Congenital TB Mortality up to 38% Drobac et al CID 1 June, 200:40 (Peru study F/U) Benefits Prevent progressive disease in mom Prevent disease in infants Lessen or eliminate infection control risks ik at dli deliver Lessen or eliminate duration of time mom and baby are separated postpartum 33

34 Conclusion Evidence to support treatment of MDR TB during pregnancy Benefits to mom and baby outweigh risks Long term pediatric outcomes studies are needed No evidence in the literature to support a particular treatment - Treatment regimens were individualized and highly varied SLD have been used in pregnancy with success Treatment decisions should be made with patients References Gupta, CID 2012: TB in Pregnant and Postpartum Women; Epidemiology, Management and Research Gaps Bar Oz, Eur J Obstet & Gynecol & Reprod Biol 2009: The Safety of Quinolones A meta analysis of Pregnancy Outcomes Palacios, CID 2009: Drug Resistant Tuberculosis and Pregnancy: Treatment Outcomes of 38 Cases in Lima, Peru Drobac, CID 200 Treatment of Multidrug Resistant Tuberculosis during Pregnancy: Long Term Follow Up of 6 Children with Intrauterine Exposure to Second Line Agents Good, Am J Obstet Gynecol 1981: Tuberculosis in Association with Pregnancy The end. Mayo Clinic Center for Tuberculosis Curry International Tuberculosis Center Global Tuberculosis Institute at Rutgers Southeastern National Tuberculosis Center Heartland National Tuberculosis Center Regional Training and Medical Consultation Centers Here to help :) 34