Diagnosis of MDR TB Neha Shah, MD, MPH

TB Nurse Case Management Lisle, Illinois April 27-28, 28 2010 Diagnosis of MDR TB Neha Shah, MD, MPH April 27, 2010 Drug Resistant TB Neha Shah MD MPH Centers for Disease Control and Prevention Division of Tuberculosis Elimination Chicago Department of Health "The findings and conclusions in this presentation are those of the author(s) and do not necessarily represent the views of the Centers for Disease Control and Prevention/the Agency for Toxic Substances and Disease Registry." 1

Multi-drug Resistant TB MDR 3 MDR TB is a manmade problem.. It is costly, deadly, debilitating, and the biggest threat to our current TB control strategies. 2

Drug-Resistant TB Primary Resistance Secondary Resistance Caused by person-to-person transmission of drug-resistant organisms Develops during TB treatment: Patient was not given appropriate treatment regimen OR Patient did not follow treatment regimen as prescribed 6 3

Drug Resistant TB Multi-drug resistant TB (MDR) Resistant to INH AND Rifampin Pre-XDR TB Resistant to INH and Rifampin AND EITHER Resistance to any fluroquinolone OR Resistant to one of the 2nd line injectables 7 Extensively Drug Resistant (XDR) TB 8 4

Epidemiology Outline Pathogenesis Laboratory Resources Management and Treatment Infection control Case studies 9 Epidemiology 10 5

Distribution of proportion of MDR- TB among new TB cases, 1994-2009 11 Argentina Armenia Azerbaijan Australia Bangladesh Botswana Brazil Canada Chile Czech Rep. Ecuador Countries with XDR-TB confirmed cases as of June 2008 Italy Japan Latvia Lesotho Lithuania Mexico Moldova Mozambique Namibia China, Hong Kong SAR Netherlands Nepal Russian Fed. Slovenia The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the WHO co oncerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimita ation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. WHO 2005. All rights reserved Estonia France Georgia Germany Ireland India Norway Peru Philippines Poland Portugal Rep of Korea South Africa Spain Swaziland Sweden Thailand UK Islamic Rep. of Iran USA Ukraine Israel Romania Vietnam Based on information provided to WHO Stop TB Department - June 2008 6

Primary Anti-TB Drug Resistance United States, 1993 2008* 10 % Resistant 5 0 1993 1996 1999 2002 2005 2008 Isoniazid MDR TB *Updated as of May 20, 2009. Note: Based on initial isolates from persons with no prior history of TB. No. of Cases 500 400 300 200 100 0 Primary MDR TB United States, 1993 2008* 1993 1996 1999 2002 2005 2008 Percentage 3 2 1 0 No. of Cases Percentage *Updated as of May 20, 2009. Note: Based on initial isolates from persons with no prior history of TB. 7

Have germs, will travel Migrating populations in the 1990s Compared 4 x to increase 1960-75, in volume four-fold as increase compared in to migration 1960-75 Source: Population Action International 1994 15 Primary Isoniazid Resistance in U.S.-born vs. Foreign-born Persons, United States, 1993 2008* % Resistant 14 12 10 8 6 4 2 0 1993 1996 1999 2002 2005 2008 U.S.-born Foreign-born *Updated as of May 20, 2009. Note: Based on initial isolates from persons with no prior history of TB. 8

Primary MDR TB in U.S.-born vs. Foreignborn Persons, United States, 1993 2008* 3 % Resistant 2 1 0 1993 1996 1999 2002 2005 2008 U.S.-born Foreign-born *Updated as of May 20, 2009. Note: Based on initial isolates from persons with no prior history of TB XDR TB Case Count defined on Initial DST by Year, 1993 2008* 12 10 Case Count 8 6 4 2 0 1993 1996 1999 2002 2005 2008 Year of Diagnosis Drug susceptibility test. *Reported incident cases as of May 20, 2009. 9

XDR TB counted cases, 1993 2007* XDR TB Cases (Initial DST) by Race/Ethnicity XDR TB Cases (Initial DST) in U.S.- born vs. Foreign-born Persons Black, 21% Asian, 21% Unknown, 2% White, 21% Hispanic, 35% 1993-1999 U.S.-born 17 (65%) Foreign-born 9 (35%) + Two cases of unknown origin 2000-2007 5 (25%) 15 (75%) 19 XDR TB Cases in the United States (Initial DST), 1993 2007* 11 2 1 1 1 2 8 NYC 16 New Jersey 3 2 1 * Preliminary data- not for distribution 20 10

Number of TB drug resistant cases, Chicago 2005-2009 2004 2005 2006 2007 2008 2009 Total Cases 308 329 287 259 214 202 INH R (RIF S) RIF R (INH S) 15 (4.9%) 16 (4.9%) 18 (6.3%) 19 (7.3%) 17 (7.9%) 19 (9.4%) 0 0 0 2 1 2 (0%) (0%) (0%) (0.8%) (0.5%) (1%) MDR 2 (0.6%) 0 (0%) 0 (0%) 1 (0.4%) 1 (0.5%) 1 (0.5%) 21 Pathogenesis of drugresistant TB 22 11

Pathogenesis TB drug resistance Spontaneous mutations occur naturally Occur by chance alone Do not necessarily depend on prior drug exposure Are present in wild type TB isolates 23 Spontaneous mutations develop as bacilli proliferate to >10 8 Drug Mutation Rate Rifampin 10-8 Isoniazid 10-6 Pyrazinamide 10-6 24 12

Drug-resistant mutants in large bacterial population Multidrug therapy: No bacteria resistant to all 3 drugs INH RIF PZA Monotherapy: INH-resistant bacteria proliferate INH 25 INH resistant bacteria multiply l to large numbers INH Spontaneous mutations develop as bacilli proliferate to >10 8 INH RIF INH mono-resist. mutants killed, RIF-resist. mutants proliferate MDR TB 26 13

Low Rifabutin Drug Levels Associated with Rifampin Resistance Pharmokinetic evaluation of HIV+ patients with rifabutin (Rifabutin 300mg/INH 300mg daily Patients with treatment failure or relapse with acquired rifamycin resistance had significantly lower rifabutin levels measured by area under curve Patients also had significantly lower INH levels Acquired Rifamycin Resistance USPHS 23 INH + rifabutin twice weekly in continuation 169 patients enrolled 3 treatment failures + 6 relapses; 9/169 (5.3%) 8/9 (89%) acquired rifamycin resistance Risk factors for ARR: Twice weekly RX during first 2 months Low CD4 CD4 < 100: 9/73 (12%) CD4 > 100: 0/65 (0%)» Burman. Am J Respir Crit Care Med 2005 14

What Situations Contribute to Drug Resistant TB? Individual level Treatment errors Missed opportunities for treatment of contacts Public health policy TB in immigrants, refugees, foreign born visitors and students Poor infection control (especially developing countries) Lack of policies to deal with untreatable patients Causes of Inadequate TB Treatment WHO 2006 Drug Resistant TB 15

Who is at risk for MDR TB? Foreign-born HIV+/IVDU History of previous TB treatment History of exposure to MDR-TB case TB treatment failures or interruptions 31 Diagnosis of MDR TB 32 16

Role of the Laboratory Detect drug resistance to enable clinician to design effective multidrug regimen Initial M. tuberculosis isolate tested against primary drugs INH, RIF, PZA, EMB For Rif-R isolates, test secondary drugs as needed 33 FQ, AMI, KAN, CAP Reasons for Discordant DST Results Differential growth kinetics Different inoculation methods Different methods or media Cross-contamination Transcription, labeling li errors Problem strains and drugs 34 17

Difficult Strains Strains sent to >100 laboratories for analysis Resistant t Strains Agree Disagree Rifampin (n=19) 16 3 Isoniazid (n=40) 30 10 Strain INH-R RIF-R 1 31/88 (35%) 106/108 2 112/112 74/117 (62%) *CDC unpublished data. J. Ridderhof, P. Angra 35 Drug Susceptibility Testing Every confirmed case gets susceptibility testing Tests should be repeated if: Patient has positive culture after 3 Drug susceptibility testing on solid media months of treatment OR Patient does not get better 36 18

Treatment and Management 37 Principles of Drug Resistant Tuberculosis Standard of care always exclude active tuberculosis before treating LTBI Avoid use of a single TB drug Standard of care start with 4 drugs INH resistance common ~ 7 8% PZA does not protect rifampin Ethambutol will protect rifampin if INH resistance 19

Why is MDR so challenging? Treatment of case Less effective, toxicity and side effects <80% cure Higher relapse rates (30 40%) Unclear prophylaxis for contacts Prolonged infectiousness Costly 39 Principles INH resistant treatment Active cases Rifampin, EMB, PZA Low level INH resistant can be given INH No data on clinical significance 6 9 months Add fluroquinolone if extensive disease or immunosuppression Contacts: Rifampin 40 20

Principles of Rifampin resistant treatment Rifmapin most important drug in regimen Poor outcomes Need as much attention as MDR cases Treatment options INH, EMB, PZA, Levofloxacin x 12 months; +/- Injectable x 2 months At least 12 18 months 41 Protecting Rifampin Rifampin single most important TB drug If INH resistant, EMB will protect Rifampin PZA Not active in cavities and rapidly growing lesions Does not protect Rifampin Prevent relapse Shortens therapy duration Mostly for dormant bugs 42 21

MDR TB drug options Injectables Streptomycin Amikacin Kanamycin Capreomycin Fluoroquinolones Levofloxacin Moxifloxacin Oral meds PAS Cycloserine Ethionamide Third line Linezolid Imipenem Agumentin Macrolides 43 Principles for MDR treatment Seek consultation with MDR-TB expert Use at least 3 previously unused drugs Proven or suspected to be sensitive to Any first lines with proven susceptibility 44 22

Principles for MDR treatment Initially, one drug should be bactericidal injectable Continue injectable 6-12 months after culture conversion Duration: 18 24 months after conversion of culture Monitor closely for side effects (of which there are many) 45 Principles for MDR treatment NEVER add a single drug to a failing regimen If culture still positive, add 2 more drugs Daily DOT REQUIRED throughout entire treatment course 46 23

Building a MDR treatment regimen Step 1 Begin with first-line agents to which isolate susceptible ADD Fluoroquinolone AND Use any One of One of available PLUS these PLUS these First-line drugs Fluoroquinolones Injectable agents Amikacin Pyrazinamide Gatifloxacin Capreomycin Ethambutol Levofloxacin Streptomycin Moxifloxacin Kanamycin Injectable based on susceptibilities Principals of Treatment and Management of MDR TB Levofloxin or Moxifloxin Both highly hl bactericidal id Both well absorbed Avoid calcium and magnesium containing antacids and supplements, multivitamins, iron, enteral supplements, sucralfate Good penetration to all tissue sites No need to decrease dose of moxifloxin in renal insufficiency 24

Principals of Treatment and Management of MDR TB Which fluoroquinolone? Levofloxin: 750mg/day Extensive experience with long term use and pushing drug levels to 1000 +mg/day Peak level at 12 Moxifloxin: 400mg/day Early bactericidal activity rivals rifampin, potentially greater than levofloxin Peak level at 4 Prolonged half life Principals of Treatment and Management of MDR TB Which injectable? All are bactericidal Streptomycin: document susceptibility, more auditory toxicity, less renal Amikacin: easy to get drug levels Capreomycin: smaller volume if IM injection planned Toxicity depends on total dose 15mg/kg 5 x/week first 4-6 months 15mg/kg 3 x/week next 6 8 months Attempt to reach peak serum level of 25 Dual injectable therapy? (Capreomycin and Amikacin) When extensive drug resistance and extensive disease 25

Building a MDR Treatment Regimen Step 2 Add second-line drugs until you have 4-6 drugs the isolate is susceptible to (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 Building a MDR Treatment Regimen Step 3 If there are not 4-6 drugs available in the above categories, consider thirdline drugs in consultation with an MDR-TB expert Consider use of these Clofazimine Linezolid Amoxicillin/ clavulanate Third-line drugs Imipenem Macrolides High-dose Isoniazid 26

When to start treatment? Wait to identify enough drugs to constitute an appropriate regimen VS Empirically start enough drugs to cover for unsuspected additional resistance 53 When to start treatment? Consider how sick patient is HIV positive patients should be started on treatment immediately Are others still exposed? At all costs avoid creating a more resistant bug 54 27

Ensure Toxicity Monitoring Ethionamide and PAS TSH (baseline, Q 2-3 monthly); monthly LFTs Severe nausea and vomiting Better tolerated if slowly ramped up May require premed with anti-emetic Non-caffeinated carbonated beverage and soda crackers may help PAS check serum electrolytes and CBC must give Paser granules with acidic food/drink Ensure Toxicity Monitoring Fluoroquinolones (levofloxacin, moxifloxacin) No specific laboratory tests Monitor for signs of acute tendon rupture QT prolongation can occur; consider obtaining baseline EKG Linezolid CBC (weekly initially then monthly if stable) Monitor for c/o optic and/or peripheral neuropathy 28

Ensure Toxicity Monitoring Aminoglycosides and polypeptides Monthly assess: Hearing (Audiogram) Vestibular function (Rhomberg, past-to-point) Serum electrolytes (including Ca+ and Mg++) Serum creatinine Cycloserine Weekly depression monitoring Serum drug level to ensure within therapeutic range Monitor Clinical Response Bacteriology 3 sputa prior to treatment initiation Weekly sputum until smear negative Monthly throughout treatment; at Rx completion TB Symptoms Weekly, noting improvements/worsening of symptoms (cough, weight, fever, etc.) Radiology Every 3 6 months throughout treatment and at completion of treatment 29

Cost of MDR Treatment Capreomycin 1gm IV TIW x6 months 2500 Levofloxacin 740mg po daily x 2 years 11600 Ethionamide 500mg po daily x 2 years 5500 Cycloserine 500mg po daily x 2 years 8200 PAS 4gm BID x 2 years 6500 Ehtambutol 800mg daily x 2 years 5000 Vit B6 50mg daily x 2 years 40 $39,340 Ranges from $28,217 - $1,278,066 59 Address Other Medical Issues If patient has HIV, coordinate management Optimize nutrition consider nutritional consultation in patients with substantial weight loss, diabetes or substance abuse history Assess for potential drug-drug interactions Dose adjustments may be required in patients with compromised renal function Pregnancy discuss options based on stage of pregnancy; teratogenicity of drugs must be considered 30

Address Other Social Issues Cultural and language barriers Substance abuse Incarceration Homelessness Unemployment and migration for work Post-Treatment Monitoring Monitor for a minimum of 2 years following treatment Clinical evaluation quarterly during year 1 Then every 6 months during year 2 31

Outcomes 63 Culture conversion California (1993 2006) XDR: 46.7%, 195 days MDR: 87.3%, 98.5 days Germany (2004 2006) XDR: 80% MDR: 87.2% Lativia (2000) MDR 77%, 60 days South Korea (1995 2004) XDR 66% MDR 67% 64 32

Fighting TB and HIV We can t fight AIDS unless we do much more to fight TB. Nelson Mandela, International AIDS Conference, Thailand 14 July, 2004. Nelson Mandela at 2004 International AIDS Conference Image source: BBC News Online (http://news.bbc.co.uk/1/hi/world/asia-pacific/3895525.stm) Extensively Drug Resistant (XDR) TB Recent Outbreak in Kwazulu Natal, SA 1500 patients evaluated 544 (35%) with TB 995 (65%) without TB 221(41%) MDRTB 323 (59%) Susceptible * Moll A et al, 2006 53 (10%) XDRTB 52 died, All HIV+ died Time to death=16 d 33

Factors associated with good treatment outcomes HIV negative Younger age No cavitary lesions Sensitivity to ofloxacin No prior therapy with ofloxacin Few resistant drugs Appropriate therapy Primary disease? Surgery Culture conversion by 3 months 67 Contacts 68 34

Management of Contacts End of infectious period when CULTURE negative Few guidelines for contacts of MDR CDC contact guidelines:..estimating risk after exposure to a person with pulmonary TB without lung cavities includes a cut-off of 120 hours of exposure per month This is for non-cavitary disease No recommendations or guidelines for cavitary disease 69 Treatment of MDR Contacts Sparse data on treatment regimens Choose 2 drugs source case is sensitive to Treat for 6 months or observe without treatment HIV and immunocompromised should be strongly gyencouraged to take treatment HIV patients should be treated for 12 months Follow for 2 years with CXR and clinical evaluation 70 35

Treatment Outcomes of MDR Contacts Schaaf et al followed 119 children who were contacts to active cases of MDR TB. Sixty-one children were infected (51%) and 14 (12%) had active disease. Two (5%) of 41 children who received preventive therapy developed TB, compared to 13 (20%) who did not (OR 4.97). Schaaf et al. Pediatrics 2002 109:765-771 71 Treatment Outcomes of MDR Contacts Conover study, during two years of follow-up no further cases of MDR-TB were identified. Preventive regimens were determined by the treating physician and were typically a combination of two of the following EMB PZA Ofloxacin All medications were given by DOT. Conover et al IJTLD 5(1):59-64 72 36

Case Presentation 73 History of Present Illness On 11/09: 20 year old female presented to OSH with dry cough for 4 months ROS: 15 pound weight loss Occasional hemoptysis No fever or SOB 74 37

Additional History Family History: no one previously sick No recent travel Immigrated from Kyrgystan 6/2008 Social History quit smoking 3 months ago No IVDU or EtOH use 75 Additional History Past Medical History: h/o BCG vaccine Work History Working in small, not well ventilated Kabob house Was symptomatic while working there Taking English as Second Language (ESL) classes on weekend 76 38

Hospital Admission #1 PE: nontib contributory t HIV: negative CXR: cavitary lesion RUL 77 78 39

Hospital Course #1 Sputum: smear negative, culture pending Started on RIPE 11/27/2009 Discharged to follow-up with CDPH 79 Laboratory Results IDPH notifies CDPH of drug susceptibility results 1/8/2010 from OSH specimen INH, Rifampin and PZA resistant Specimen sent to CDC for 2 nd line testing Rapid PCR: sensitive to floroquinolone and injectables Final sensitivities: sensitive all 2 nd line EMB resistant 80 40

What would you do? 81 Treatment Management EMB monotherapy for 2 months Consulted with Heartland Stop all medications and wait for 2 nd line results Monitor pt monthly Pt minimal symptoms Feeling better Sputums continue to be positive 82 41

Laboratory Results 1/21: rapid PCR testing showed no resistance to quinolone and injectables 2/4: IDPH reports EMB resistance on different specimen using PCR 2/16: Resistance: INH (high level), RIF, EMB, STR, PZA, and rifabutin Sensitive: Kan, AMik, Cap, ethionamide, PAS, and FQ 83 Hospitalization #2 Admitted to Stroger 2/22/2010 Repeat CXR and CT 84 42

85 Hospitalization #2 2/23: PAS, Ethionamide, Moxifloxacin, Amikacin, Cycloserine 2/23: sputum positive Tolerating meds well 86 43

Contacts 3 roommates 2 TST positive All 3 QFN-gold negative 1 boyfriend: currently QFN-gold and symptom negative 2 nd screening pending culture conversion 87 Institutional Investigation ESL class Restaurant 88 44

Patient feeling better Sputums 3/15 rare 3/17 negative 3/31 rare Still not able to return to school or work yet CXR improving Current Status 89 Other concerns Incentives Apartment subsidized Medications free from Stroger No fly list Concern of flying Contagious Patient non-complaint No good way to get off list Parents: Concerned daughter getting appropriate care and support Turmoil in home country 90 45

Challenges Almost all contacts foreign born with BCG No great treatment option for contacts Small concern flight risk No treatment for 2 months Side effects of medications Multiple jurisdictions 91 Summary MDR and XDR is here Can be treated and cured BUT consult experts first Requires longer duration and more medications with higher side effect profile No great options for contacts Never add 1 medication to a failing regimen! 92 46

Acknowledgements Slides modified from following presentations: ti Dr. Barbara J Seaworth Dr. Karen Lewis Dr. Sundari Mase Multidrug-Resistant Tuberculosis (MDR TB) and Extensively-Drug Resistant (XDR) TB: A Web-Based Seminar 93 Thanks Questions. 94 47