Transcript Investigation of Multidrug-resistant TB — Republic of the

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 rate per 100,000
TB Case Rates per 100,000
200
182
2009
160
160
2010
120
92.3 89.9
80
40
3.8 3.6
9.1
8.8
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 2nd 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




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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
MDR
LTBI
n=105
Adults
n=62
Including 21
healthcare
workers
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
Number
Percent
Treatment
completion, all
(N=105)
93
89
Healthcare personnel
(n=21)
14
70
Child <12 yrs
(n=26)
25
96
Chuuk Experience —
Discontinuation of Treatment

12 patients discontinued treatment
 3 contacts after becoming pregnant


5 contacts after being lost to follow-up



1 additional patient restarted and completed post-delivery
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
Symptom
Resolved after
Discontinuation
Yes
Healthcare worker
Foot and joint
pain
Healthcare worker
Nausea / GI
symptoms
HA / Fatigue
Yes
Elevated liver
enzymes
Yes
Healthcare worker
Child <12 yrs
Yes
Chuuk Experience — Side Effects

52 patients reported side effects but completed
treatment
 Patients reported side effects at159 (15%) of
1,038 monthly visits
Symptom
Number
Total reported
253
Percent
Nausea
Headache or dizziness
112
72
44
28
Fatigue
Tendon / joint pain
22
21
4
4
% Patients Reporting Complaints
Chuuk Experience — Timing of Side Effect
Onset during MDR LTBI Treatment
30%
% Reporting Side Effect Each
Month
25%
Cumulative % Discontinued
Due to Side Effect
20%
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
MDR TB Cases ─ Chuuk,
2007–2012* (n=33)
No. Cases
10
8
6
Culture-confirmed
MDR TB
Clinical case
Follow-up investigation,
medications available for
MDR LTBI treatment
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:
IUATLD
Krista Powell, MD, MPH
NAR Meeting
Richard Brostrom, MD, MPH
February 25, 2012
Steve Kammerer, MBA
Lakshmy Menon, MPH
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
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
*If susceptible. Depends on
disease category. Partial list.
Levofloxacin Uptake Dynamics and Elimination



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

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
≥ 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
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Bone and cartilage
Soft tissues including lung and liver
Inflammatory exudates
Bronchial fluid
Urine
Macrophages
PMNs
Rare but Serious Levofloxacin AEs
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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, 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 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

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
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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



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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
Cmax v Dosage - Chuuk and Majuro
18
y = 0.7678x - 0.7465
R² = 0.7222
16
14
Cmax (ug/ml)
12
10
8
6
4
2
0
0
5
10
15
Dosage (mg/kg)
20
25
18
Cmax v Dosage
16
y = 0.754x - 0.5645
R² = 0.7664
14
y = 1.1615x - 5.6923
R² = 0.4604
Cmax (ug/ml)
12
10
8
6
4
2
0
0
5
10
15
20
25
Dosage (mg/kg)
Majuro
Chuuk
Linear (Majuro)
Linear (Chuuk)
Cmax v Dosage by Sex
18
16
y = 0.8004x - 0.7682
R² = 0.7119
14
Cmax (ug/ml)
12
10
y = 0.7036x - 0.3862
R² = 0.7707
8
6
4
2
0
0
5
10
15
20
Dosage (mg/kg)
Male
Female
Linear (Male)
Linear (Female)
25
Half-life v Age - Chuuk and Majuro
16
14
Half-life (hours)
12
10
8
6
4
2
0
0
2
4
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



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Case-fatality rate is higher
Longer duration of treatment
More costly to treat
Adverse effects of treatment more common
Economy & Geography — FSM
FSM
Economy
•Economic assistance provides >50% of GDP
Geography
•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


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
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