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Sapna Bamrah, MD Sundari Mase , MD MPH Division of TB Elimination, CDC

Treatment of MDR LTBI in Contacts of Two Multidrug-resistant Tuberculosis Outbreaks — Federated States of Micronesia, 2008–2012. Sapna Bamrah, MD Sundari Mase , MD MPH Division of TB Elimination, CDC . International Union Against Tuberculosis & Lung Disease North American Region Meeting

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Sapna Bamrah, MD Sundari Mase , MD MPH Division of TB Elimination, CDC

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  1. Treatment of MDR LTBI in Contacts of TwoMultidrug-resistant Tuberculosis Outbreaks — Federated States of Micronesia, 2008–2012 Sapna Bamrah, MD SundariMase, MD MPH Division of TB Elimination, CDC International Union Against Tuberculosis & Lung Disease North American Region Meeting February 25, 2012 National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention Division of TB Elimination

  2. Treatment of MDR LTBI in Contacts of Two Multidrug-Resistant TB Outbreaks • Epidemiology of TB in Federated States of Micronesia and background on the MDR TB outbreaks • Review of outbreak responseand treatment of contacts with MDR LTBI • Findings from the observational cohort study

  3. U.S. Affiliated Pacific Islands (USAPI) http://www.pacificcancer.org/site-media/uspi-map-big.jpg

  4. Source: CDC. Reported tuberculosis in the United States, 2011. TB Case Rates per 100,000 182 160 TBcaserateper100,000 92.3 89.9 9.1 8.8 3.8 3.6 U.S. state with highest incidence

  5. The 4 States of FSM:Yap, Chuuk, Pohnpei, & Kosrae

  6. MDR TB in Chuuk, FSM • During April 2007–June 2008, four cases of laboratory-confirmed MDR TB were reported in Chuuk • Three (75%) of 4 patients had died • 2-year-old child and mother with MDR TB  evidence of recent transmission • No 2nd line medications available as of June 2008

  7. Emergence of MDR TB in Chuuk State • Strain A resistant to INH, RIF, PZA, EMB, & streptomycin • Primary resistance • Likely imported • Strain B resistant to INH, RIF, & ethionamide • Secondary resistance • Circulating strain resistant to INH & ethionamideacquired RIF resistance

  8. Summary Results of Chuuk Investigation, July 2008 Strain AVillage • Two distinct, simultaneous MDR TB outbreakson Weno Island 232 identified and evaluated contacts TB Clinic, Hospital 5 initial cases Strain B Village

  9. Should Infected Contacts of MDR TB Cases be Treated? Few evidence-based recommendations for the treatment of MDR TB contacts Balancing risk of treating vs. not treating Feasibility of providing treatment to completion Toxicity concerns — “above all, do no harm” Length of treatment

  10. Reasons to Treat Infected Contacts of MDR TB Cases Treat MDR TB while bacterial burden low Decrease likelihood of progression to TB disease Severe consequences of clinically active MDR TB for patient and community

  11. South African series 13 (20%) of 64 children who did not receive any treatment developed TB 2 (5%) of 41 children who received 2–3 drug treatment developed TB Use of Fluoroquinolones in Children for Treatment of MDR TB: Literature SchaafHS, Gie RP, Kennedy M, Beyers N, Hesseling PB, Donald PR. Evaluation of young children in contact with multidrug-resistant pulmonary tuberculosis: a 30-month follow-up. Pediatrics 2002; 109: 765–71.

  12. Challenges of Treating MDR LTBI — Tolerability Following 1992 MDR TB outbreak in hospital, decision to treat MDR LTBI in16 employees 6-month PZA + ofloxacin regimen 14 of the 16 experience adverse events and discontinue treatment CDC/ATS guidelines in 2000: 6–12 month course of PZA + FQ or EMB PZA + levofloxacin poorly tolerated in subsequent case series All 17 contacts discontinued treatment due to intolerability (median therapy 32 days) Horn DL, Hewlett D, Alfalla C, Peterson S. (1994). Limited tolerance of olfoxacin and pyrazinamide prophylaxis against tuberculosis. NEJM 330(17):1241. Papastavros, Dolovich, et al. (2002). "Adverse events associated with pyrazinamide and levofloxacin in the treatment of latent multidrug-resistant tuberculosis." CMAJ 167(2):131-6.

  13. LTBI Treatment of MDR TB Contacts in Chuuk — Objectives Determine feasibility of implementing MDR LTBI treatment and follow-up in a resource-limited setting Study tolerability of MDR LTBI regimens Potentially, study efficacy of MDR LTBI regimens

  14. MDR LTBI treatment by DOT for 1 year FQ-based regimens Children received FQ + ethambutol or ethionamide Monthly questionnaires by field workers Symptom screen and missed doses Quarterly visit by healthcare provider Biannual chest radiograph and clinical evaluation Contacts followed for 2 years after completion Chuuk MDR LTBI Management Plan

  15. MDR TB Contact Evaluation • Among the 232 identified contacts, 6% attack rate during July 2008–Jan 2009 • 5 patients diagnosed with MDR TB • 9 additional patients developed MDR TB while awaiting LTBI treatment • Two contacts who had not been identified during contact investigations also found to have MDR TB • 119 other TST (+) with no evidence of active disease

  16. Treatment of MDR TB Contacts in FSM Study Results

  17. MDR LTBI Treatment Initiated Treatmentn=105 MDR LTBI n=119 Refused Treatment n=14

  18. Contacts with LTBI, by Age MDR LTBI n=105 Age 12–17 yearsn=17 Adultsn=62 Age 5–11 yearsn=20 Including 21 healthcare workers Age <5 yearsn=6

  19. Chuuk Experience — Follow-up Visits • TB program conducted monthly visits with the 105 patients to record • Occurrence of TB symptoms and side effects • Number of missed doses • 1,038 (82%) monthly visits completed during treatment • Post-treatment follow-up • 90% at 18 months • 50% at 24 months • 85% at 36 months

  20. Chuuk Experience — Adherence

  21. Chuuk Experience — Discontinuation of Treatment • 12 patients discontinued treatment • 3contacts after becoming pregnant • 1 additional patient restarted and completed post-delivery • 5 contacts after being lost to follow-up • 4 healthcare workers • 1 adult household contact • 4 contacts due to side effects • 3 healthcare workers • 1 child with elevated liver enzymes

  22. Chuuk Experience — Discontinuation due to Side Effects

  23. Chuuk Experience — Side Effects • 52 patients reported side effects but completed treatment • Patients reported side effects at159(15%) of 1,038 monthly visits

  24. Chuuk Experience — Timing of Side Effect Onset during MDR LTBI Treatment

  25. Chuuk Experience — Efficacy • 14 contacts refused MDR LTBI treatment • 2 developed MDR TB disease • Other patients who developed TB disease • 12 contacts not offered LTBI treatment • 10 previously not identified • 2 lost to follow-up after initial evaluation • No contacts treated for MDR LTBI developed TB disease

  26. MDR TB Cases ─ Chuuk, 2007–2012* (n=33) Follow-up investigation, medications available for MDR LTBI treatment Culture-confirmedMDR TB Clinical case No. Cases 5 Initial cases * as of January 31, 2012

  27. Treatment effectiveness No randomized trials to show efficacy Efficacy difficult to demonstrate with low numbers Important outcomes High completion rate Regimens were safe and tolerable LTBI treatment by DOT is doable No patients treated for MDR LTBI developed TB disease ChuukExperience — Conclusions

  28. Pharmacokinetics Studies of Levofloxacin in Children Treated for, or Exposed to,Multidrug-Resistant Tuberculosis — United States Affiliated Pacific Islands, 2010–2011 Sundari Mase, MD, MPHJohn Jereb, MDCharles Peloquin, PharmDTerence Chorba, MD, DSc SapnaBamrah, MD Division of TB Elimination, CDC IUATLD NAR Meeting February 25, 2012 National Center for HIV/AIDS, Viral Hepatitis, STD & TB Prevention Division of TB Elimination Acknowledgments:Krista Powell, MD, MPH Richard Brostrom, MD, MPHSteve Kammerer, MBA Lakshmy Menon, MPH

  29. Burning Question • What is the optimal dosing of levofloxacin suspension in children?

  30. ** Patients / Parents consented to public use of picture Photo by Richard Brostrom, MD, MS-PH

  31. Levofloxacin • Second or third generation fluoroquinolone • Levo-enantiomer of oflaxacin • 1987: patented • 1993: approved in Japan • 1996: approved in the United States • Broad-spectrum antibiotic • Inhibits bacterial type II topoisomerases, topoisomerase IV and DNA gyrase

  32. Labeled Indications for Levofloxacin By organism* Staphylococcus aureus Staphylococcus epidermidis Streptococcus pneumoniae Streptococcus pyogenes Enterococcus faecalis Mycoplasma pneumoniae Chlamydophila pneumonia Moraxella catarrhalis Haemophilusinfluenzae Haemophilusparainfluenzae Klebsiella pneumonia Pseudomonas aeruginosa Proteus mirabilis Serratiamarcescens Escherichia coli By disease Nosocomial pneumonia Community acquired pneumonia Acute bacterial sinusitis Acute bacterial exacerbation of chronic bronchitis Skin and skin-structure infections Chronic bacterial prostatitis Complicated and uncomplicated urinary tract infections Acute pyelonephritis Inhalational anthrax, post-exposure *If susceptible. Depends on disease category. Partial list.

  33. Levofloxacin Uptake Dynamics and Elimination • ≥ 90% absorption from oral dose • Plasma peak from oral dose at 1–2 hr • Linear correlation between dose and peak (and AUC) • Plasma half-life 5–8 hours • Elimination half-life 6–8 hours • 28%–40% blood-protein bound • > 80% renal elimination (unchanged) • Therapeutic cations (Mg, Al, Ca): decreased availability • Food: unimportant delay in absorption • Citrus fruit inhibition of organic acid transporting protein 1A2 (“grapefruit juice” effect)1 1. Wallace AW, Victory JM, Amsden GW. J ClinPharmacol 2003;43:539–544

  34. Levofloxacin Physiological Distribution • Fast, fast, fast • 60%–70% in CSF with un-inflamed meninges • Tissue and cell concentration exceed plasma • Bone and cartilage • Soft tissues including lung and liver • Inflammatory exudates • Bronchial fluid • Urine • Macrophages • PMNs

  35. Rare but Serious Levofloxacin AEs • Severe hypersensitivity • Clostridium difficile-associated diarrhea • Tendon rupture • Exacerbation of myesthenia gravis • Psychosis and paranoia • Convulsions • Peripheral neuropathy, irreversible • Hepatitis • Autoimmune hemolytic anemia • Thrombocytopenia, TTP • Rhabdomyolysis • Toxic epidermal necrolysis

  36. Levofloxacin FDA-Specified Cautions • Black-box warnings • Tendonitis and tendon rupture • Exacerbation of weakness in myasthenia gravis • Pregnancy Category C • No teratogenesis in rats and rabbits • Not studied for safety in humans • Nursing mothers: levofloxacin may enter breast milk

  37. Dosing recommendations: Levofloxacin Children • Modeling for anthrax post-exposure: designed for decreasing max. levels and sparing min. levels, AUC1,2 • Age 6 months to <5 years: 10 mg/kg twice daily • Age ≥5 years: 10 mg/kg daily (max 500 mg or 750 mg) 1. Chien S, Wells TG, Blumer JL, et al. J ClinPharmacol 2005;45:153–160 2. Li F, Nandy P, Chien S, Noel GJ, Tornoe CW. Antimicrob Agents Chemother 2010;54:375–379

  38. PK Study During Treatment of MDR TB and LTBI,Chuuk • Adults: Moxifloxacin or Moxifloxacin + EMB • Children: Daily Levofloxacin or Levofloxacin + EMB • 15–20 mg/kg for children 5 years old or younger • 10 mg/kg for children ≥5 years old • Target Cmax 8–12 μg/ml • All treatment DOT daily for 1 year • PK study • 33 children, median age 8 years, range 1–14 years • Dose observed at hospital • Blood collection at 1, 2, 6 hours after dose • Drug concentrations measured by Charles Peloquin

  39. Photo courtesy of Dr. Sapna Bamrah, CDC, DTBE

  40. Photo courtesy of Dr. Sapna Bamrah,CDC, DTBE

  41. Photo courtesy of Dr. Sapna Bamrah,CDC, DTBE

  42. Cmax= -0.564522 + 0.753985*dosage

  43. PK Study During Treatment of MDR LTBI,Contacts in Majuro • Children: Daily Levofloxacin + EMB • 15–20 mg/kg for children ≤5 years old • 12 mg/kg (weight corrected) for children older than age 5 years • Target Cmax 8–12 μg/ml • All treatment DOT daily for variable periods (≥6 mo.) • PK study • 17 children, median age 11 years, range 1–15 years • Dose observed at hospital • Blood collection at 0, 1, 2, 6 hours after dose • Drug concentrations measured by Charles Peloquin

  44. Limitations and Conclusions • Limitations • Homogeneous population • Only seven children five and under • Conclusions • Even at high doses, levo is well tolerated • All children, regardless of age, will likely achieve a Cmax of 10 ug/ml on a levo dose of 15 mg/kg • Children should be weighed at regular intervals and dosage adjusted

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