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 February 25, 2012 National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention Division of TB Elimination

Treatment of MDR LTBI in Contacts of Two Multidrug-Resistant TB Outbreaks 1.

Epidemiology of TB in Federated States of Micronesia and background on the MDR TB outbreaks 2.

Review of outbreak response and treatment of contacts with MDR LTBI 3.

Findings from the observational cohort study

U.S. Affiliated Pacific Islands (USAPI)

http://www.pacificcancer.org/site-media/uspi-map-big.jpg

TB Case Rates per 100,000 200 160 2009 2010

160 182

120 80

92.3 89.9

40

9.1

8.8

3.8 3.6

0 United States Hawaii USAPI FSM U.S. state with highest incidence

Source: CDC. Reported tuberculosis in the United States, 2011.

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

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 2 nd line medications available as of June 2008

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 & ethionamide acquired RIF resistance

Summary Results of Chuuk Investigation, July 2008



Two distinct, simultaneous MDR TB outbreaks on Weno Island 5 initial cases 232 identified and evaluated contacts Strain A Village TB Clinic, Hospital Strain B Village

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

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

Use of Fluoroquinolones in Children for Treatment of MDR TB: Literature



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

Schaaf HS, 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.

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.

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

Chuuk MDR LTBI Management Plan



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

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

Treatment of MDR TB Contacts in FSM

STUDY RESULTS

MDR LTBI Treatment Initiated Treatment n=105 MDR LTBI n=119 Refused Treatment n=14

Contacts with LTBI, by Age Adults n=62 Including 21 healthcare workers MDR LTBI n=105 Age 12 –17 years n=17 Age 5 –11 years n=20 Age <5 years n=6

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

Chuuk Experience — Adherence Patients Treatment completion, all (N=105) Healthcare personnel

(n=21)

Number 93 14 Percent 89 70 Child <12 yrs

(n=26)

25 96

Chuuk Experience — Discontinuation of Treatment



12 patients discontinued treatment

   3 contacts 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

Chuuk Experience — Discontinuation due to Side Effects Patient Healthcare worker Healthcare worker Healthcare worker Symptom Foot and joint pain Nausea / GI symptoms HA / Fatigue Resolved after Discontinuation Yes Yes Yes Child <12 yrs Elevated liver enzymes Yes

Chuuk Experience — Side Effects



52 patients reported side effects but completed treatment

 Patients reported side effects at

159 (15%)

of

1,038

monthly visits

Symptom Total reported Nausea Headache or dizziness Fatigue Tendon / joint pain Number 253 112 72 22 21 Percent 44 28 4 4

Chuuk Experience — Timing of Side Effect Onset during MDR LTBI Treatment 30% 25% 20% % Reporting Side Effect Each Month Cumulative % Discontinued Due to Side Effect 15% 10% 5% 0% 1 2 3 4 5 6 7 8 Month of Treatment 9 10 11 12

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

10 8 MDR TB Cases ─ Chuuk, 2007–2012* (n=33) Culture-confirmed MDR TB Clinical case Follow-up investigation, medications available for MDR LTBI treatment 6 5 Initial cases 4 2 0 * as of January 31, 2012

Chuuk Experience — Conclusions



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

Pharmacokinetics Studies of Levofloxacin in Children Treated for, or Exposed to, Multidrug-Resistant Tuberculosis — United States Affiliated Pacific Islands, 2010–2011 Sundari Mase, MD, MPH John Jereb, MD Charles Peloquin, PharmD Terence Chorba, MD, DSc Sapna Bamrah, MD Division of TB Elimination, CDC

Acknowledgments: Krista Powell, MD, MPH Richard Brostrom, MD, MPH

IUATLD NAR Meeting

Steve Kammerer, MBA Lakshmy Menon, MPH

February 25, 2012

National Center for HIV/AIDS, Viral Hepatitis, STD & TB Prevention Division of TB Elimination

Burning Question



What is the optimal dosing of levofloxacin suspension in children?

** Patients / Parents consented to public use of picture

Photo by Richard Brostrom, MD, MS-PH

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

Labeled Indications for Levofloxacin By disease By organism*

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.

Staphylococcus aureus Staphylococcus epidermidis Streptococcus pneumoniae Streptococcus pyogenes Enterococcus faecalis Mycoplasma pneumoniae Chlamydophila pneumonia Moraxella catarrhalis Haemophilus influenzae Haemophilus parainfluenzae Klebsiella pneumonia Pseudomonas aeruginosa Proteus mirabilis Serratia marcescens Escherichia coli

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 Clin Pharmacol 2003;43:539–544

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

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

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

Dosing recommendations: Levofloxacin Children



Modeling for anthrax post-exposure: designed for decreasing max. levels and sparing min. levels, AUC 1,2

  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 Clin Pharmacol 2005;45:153–160 2. Li F, Nandy P, Chien S, Noel GJ, Tornoe CW. Antimicrob Agents Chemother 2010;54:375–379

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

Photo courtesy of Dr. Sapna Bamrah, CDC, DTBE

Photo courtesy of Dr. Sapna Bamrah, CDC, DTBE

Photo courtesy of Dr. Sapna Bamrah, CDC, DTBE

Cmax= -0.564522 + 0.753985*dosage

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

18 16 14 12 10 4 2 8 6 0 0

Cmax v Dosage - Chuuk and Majuro

y = 0,7678x - 0,7465 R² = 0,7222 5 10

Dosage (mg/kg)

15 20 25

4 2 8 6 18 16 14 12 10

Cmax v Dosage

y = 1,1615x - 5,6923 R² = 0,4604 0 0 Majuro 5 Chuuk 10 15

Dosage (mg/kg)

Линейная (Majuro) y = 0,754x - 0,5645 R² = 0,7664 20 25 Линейная (Chuuk)

Cmax v Dosage by Sex

18 16 14 12 10 8 6 4 2 0 0 y = 0,7036x - 0,3862 R² = 0,7707 y = 0,8004x - 0,7682 R² = 0,7119 5 Male Female 10

Dosage (mg/kg)

15 Линейная (Male) 20 Линейная (Female) 25

6 4 2 0 0 16 14 12 10 8 2 4

Half-life v Age - Chuuk and Majuro

6 8

Age (years)

10 12 14 16

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

Acknowledgments

• • • • • • • Dorina Fred and Lyma Setik, Chuuk State TB Program Mayleen Ekiek, FSM Dept of Health Kennar Briand, RMI TB Program Richard Brostrom, CDC, DTBE Sandy Althomsons CDC, DTBE Krista Powell, CDC, DTBE Maryam Haddad, CDC, DTBE

Acknowledgments

• • • • • • • • • • • • • Chuuk State Governor’s Office Chuuk State Dept of Health Services Chuuk State TB Program FSM National TB Program Village Chiefs, other community leaders Centers for Disease Control and Prevention U.S. Department of Interior WPRO, World Health Organization Secretariat for the Pacific Community DLS & MDL contract labs CNMI Public Health Department Pacific Islands Health Officers Association Pacific Islands TB Controllers Association

Multidrug-resistant TB (MDR TB)



TB that is resistant to at least isoniazid & rifampin (most effective medications)



Public health emergency

    Case-fatality rate is higher Longer duration of treatment More costly to treat Adverse effects of treatment more common

FSM

Economy Geography

Economy & Geography — FSM

• Economic assistance provides >50% of GDP • About 2,500 miles from Hawaii • Over 600 islands • Land area: 270 square miles • Spread over 1,000,000 square miles • Estimated population: 107,434

Principles of LTBI Treatment for Contacts of MDR TB Cases

   

Always exclude TB disease before beginning LTBI treatment Estimate likelihood of infection with and risk of progression to MDR TB Choose LTBI regimen of ≥2 drugs to which source case susceptible Efficacy largely dependent on adherence and completion of therapy



Education of patients is important

Photo courtesy of Dr. Sapna Bamrah, CDC, DTBE