TB Treatment

12/28/2011
1
TB Intensive
San Antonio, Texas
November 29-December 2, 2011
TB Disease: ATS/CDC/IDSA
Treatment GuideIines
Barbara Seaworth, MD, FIDSA, FACP
November 30, 2011
Barbara Seaworth, MD, FIDSA,
FACP has the foIIowing discIosures
to make:
Is on the HHSC advisory committee for the
EIimination of TubercuIosis and receives
research funding from Otsuka
PharmaceuticaIs.

No other reIevant financiaI reIationships
with any commerciaI companies pertaining
to this educationaI activity

12/28/2011
2
Treatment of
Tuberculosis

Barbara J Seaworth MD
Medical Director
Heartland National TB Center
Objectives
· Identify standard regimens for treatment of
drug susceptible TB
· Discuss strategies resulting in improved
patient outcomes
÷ Intensity of dosing
÷ Prolongation of therapy
· Recognize those at risk of poor outcomes
· Manage a TB suspect

12/28/2011
3
Purpose 1 5. Recommended Treatment Regimens 36
What's New Ìn this Document 1 CONTENTS OF 6. Practical Aspects of Treatment 42
Summary 1 THE 80-Page 7. Drug Interactions 45
1. Introduction and Background 13 Document 8. Treatment in Special Situations 50
2. Organization and Supervision of Treatment 15 9. Management of Relapse, Treatment Failure, and
Drug Resistance
66
3. Drugs in Current Use 19 10. Treatment of Tuberculosis in Low-Income Countries:
Recommendations and Guidelines of the WHO and the
IUATLD
72
4. Principles of Antituberculosis Chemotherapy 32 11. Research Agenda for Tuberculosis Treatment 74
USPHS/IDSA
Evidenced-based Rating Scale
· Strength of the Recommendation
÷ A = Preferred
÷ B = Acceptable alternative
÷ C = Offer when unable to give A or B
÷ D = Should generally NOT be offered
÷ E = Should NEVER be offered

· Quality of Supporting Evidence
÷ I = Randomized clinical trial
÷ II = Clinical trial, not randomized
÷ III = Expert opinion
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Strategies Stressed in Guidelines
· Identification of patients at increased risk of relapse
÷ Obtain sputum smear and culture at end of initial phase of
treatment (2months)

· Extended therapy for patients with drug-susceptible
pulmonary TB
÷ Who have cavitation on initial CXR
and
÷ Who have a positive sputum culture at 2 months

· Counting Doses
÷ Define treatment completion by number of doses taken as
well as duration of treatment
Strategies Stressed in Guidelines

· RIFABUTIN (RBT): May be used as a primary
drug for patients (especially HIV+) receiving
medications having unacceptable interactions
with rifampin (e.g. Protease Inhibitors,
methadone)

· Fluoroquinolones (Levofloxacin or
Moxifloxacin) may be used when first line drugs
are not tolerated or the organism is resistant
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Treatment of Culture-Positive Drug
Susceptible Pulmonary TB
· General conclusions from the literature
÷ 6 mo (26 wk) is the MINIMUM duration of RX
÷ 6 mo regimens require rifampin and INH
throughout and PZA for the first 2 months
÷ 6 ÷ 9 mo regimens are effective without INH if
PZA given throughout
÷ Intermittent regimens (2-3x/wk): DOT ONLY!
· Drug susceptible isolate
Treatment of Culture-Positive Drug
Susceptible Pulmonary TB
· General conclusions from the literature:
÷ Without PZA - minimum duration is 9 months
÷ Without rifampin - minimum duration is 12
months (up to 18 months)
÷ Streptomycin and ethambutol (EMB) are
approximately equivalent in effect
· Because of high incidence of Streptomycin resistance
ethambutol is preferred for initial therapy
÷ Use streptomycin only if isolate is proven susceptible
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Treatment Regimens for TB Disease
· Initiation phase of therapy
÷ 8 weeks
÷ INH, Rifampin and PZA +/-EMB
· Continuation phase of therapy
÷ 16 weeks
÷ INH and Rifampin
Treatment of
Culture Positive Pulmonary Tuberculosis
Regimens Rated A-1 (HIV Uninfected)
INITIAL PHASE
2 mo I,R,Z,E daily (56 doses, 8wks) or
2 mo I,R,Z,E 5x/wk (40 doses, 8wks) then
CONTINUATION PHASE
-4 mo - I,R daily (126 doses, 18 wks) or
-4 mo ÷ I,R 5x/wk (90 doses, 18 wks) or
-4 mo ÷ I,R, 2x/wk (36 doses, 18 wks)
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Treatment of
Culture Positive Pulmonary Tuberculosis


÷ Regimens Rated A-II (HIV Uninfected)
· 2weeks ÷ I,R,Z,E daily (14 doses) then
· 6 weeks ÷ I,R,Z,E twice weekly (12 doses)



· PLUS (DOT only)
· -4mo ÷ I,R Twice weekly (36 doses, 18 weeks) or
continuation
phase
Initial
phase
Treatment of
Culture Positive Pulmonary Tuberculosis

÷ Regimens Rated A-III (HIV Uninfected)

· 2 weeks ÷ I,R,Z,E 5x/week (10 doses) then
· 6 weeks ÷ I,R,Z,E twice weekly (12 doses)

÷
÷ PLUS (DOT only)
· -4mo ÷ I,R Twice weekly (36 doses, 18 weeks) or
continuation
phase
Initial
phase
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Treatment of
Culture Positive Pulmonary TB
÷ THRICE WEEKLY ÷ "HONG KONG¨ REGÌMEN
» Regimen Rated BI (HIV uninfected)
÷ Initial phase
· 2mo ÷ I,R,Z,E 3x/week (24 doses, 8weeks)

PLUS

÷ Continuation phase
· 4mo ÷ I,R 3x/wk (54 doses, 18 weeks)
Nucleic Acid Amplification NAAT
· FDA cleared for respiratory specimens
÷ M.tb Direct Test® (MDT) (Gen-Probe®)
÷ also referred to as PCR tests

· DNA probe detects M TB complex RNA directly
in the sputum
÷ >95% sensitive for AFB smear + TB
÷ 55 ÷ 75% of AFB smear ÷ (culture +) patients detected

· Does not distinguish live and dead bacilli

12/28/2011
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CDC Recommendations for NAAT

· "NAAT should be performed on at least one
respiratory specimen from each patient with
signs and symptoms of pulmonary TB for whom
a diagnosis of TB is being considered but has
not yet been established, and for whom the test
result would alter case management or TB
control activities.¨
Why Use A NAAT ?
· Confirms AFB + case as M TB

· If AFB + case is NAAT negative on 2 specimens
÷ Suspect this is not M TB
· Suspend Contact investigation and
· Hold TB treatment unless TB strongly suspected.

· If patient is not strongly suspected as M TB and
is NAAT negative x 2,
÷ Remove from isolation.
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Case Management
· Monthly clinical visit
÷ check response to therapy,
÷ evaluate for toxicity:
· hepatitis, visual acuity, Ishihara Plates
÷ repeat education (document!)

· Monthly laboratory to check liver enzymes, CBC

· Document susceptibility of isolate prior to stopping
ethambutol


Pt educated regarding:
signs/symptoms of visual
and liver toxicity & need
to report these to provider
Case Management

· For pulmonary TB ÷ Monthly sputum until two consecutive
cultures are negative
÷ -2 month sputum is crucial

÷ 80% should convert by 2 months, 95% by 3 months



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Drug Susceptibility Tests
· INH, Rifampin, Ethambutol, and PZA are recommended
for each initial isolate

· Expect results by day 28

· If the private lab does not do susceptibilities, referral
may lead to unnecessary delays

÷ Positive culture should be sent for DST within 24 hrs,
lab should not wait for culture to grow on solid media
Specimen
received
in the lab
Day
At 24 hours,
expect smear
results
0 1
At 48 hours,
expect results
of NAAT or
Molecular DST
2 21 28 42-56 3
At 72 hours,
expect results of
IGRA
When should I consider my specimen delayed?
At 21 days,
expect a culture ID
(TB or not)
At 28 days,
expect 1
st
line
susceptibility results,
expect 2
nd
line 4 weeks
after requested
At 6-8 weeks, expect
the culture to be
finalized if negative
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When Should You Expect the Culture to Turn Positive?
Time to Culture Positive by Presence of Cavitary Lesions
Perrin Int J TB Lung Dis, Dec 2010
When Should You Expect the Culture to Turn Positive?
Time to Culture Positive by Presence of Cavitary Lesions
Perrin Int J TB Lung Dis, Dec 2010
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What About Ethambutol?
· A four drug regimen is recommended until susceptibility
tests are reported

· If treatment is being initiated after drug susceptibility
tests are known and the organisms are susceptible,
ethambutol is not necessary if patient is given both
INH and rifampin

· Ethambutol can be stopped as soon as the lab reports
an isolate susceptible to INH & rifampin.
TBTC STUDY 22: RATE OF FAILURE or
RELAPSE, BY REGIMEN, SPUTUM CULTURE,
AND CHEST RADIOGRAPH
0
5
10
15
20
25
Culture + Culture - Cavitary Non-
Cavitary
23.5
5.6
14.4
2.9
16.7
3.8
8.9
2.5
Rate of Failure/Relapse (%)
HP1
HR2
Positive Negative Cavitary Non-Cavitary
culture at 2 mo Chest radiograph at study entry
Lancet 2002; 360:528.
!"#
%&'( )* +&,-./(0%(-&12(
3456#
758#
859#
!5:#
12/28/2011
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Prolongation of Continuation Phase

Continuation phase increased to 7 mo if initial
CXR is cavitary & culture is positive at 2 mo

· Rational for Extending Therapy
÷ Continuation of PZA for an additional 2 months
was not helpful in drug susceptible disease

÷ Prolongation of continuation phase by 2 months
decreased relapses in silico-tuberculosis from
20% to 2%
Effect of Prolonging Therapy on
Treatment Failure or Relapse
Treatment of Silico-tuberculosis

Outcome SHRZ - 6mo* SHRZ ÷ 8mo*
(n=49) (n=50)
____________________________________
Relapse 20% 2%


* Three times weekly therapy Am Rev Respir Dis 1991;143:262-267
12/28/2011
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End of Therapy (EOT) Cavity:
A Risk Factor for Relapse
Hamilton; Int J Tuber Lung Dis 2008
Independent of
culture results
New Treatment Guidelines
Tailoring Treatment Regimens
· Prolongation of continuation phase
÷ Positive 2 month culture with cavitary disease

÷ Extrapulmonary disease
· Meningitis
· Disseminated disease in children

÷ HIV TB in children and adolescents
ATS, CDC, IDSA: Treatment of Tuberculosis 2003
12/28/2011
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Additional New Treatment Guidelines
Tailoring Treatment Regimens
· Consider - Prolongation of continuation phase when
patient:
÷ Slow to clinically or radiographically respond

÷ Positive 2 month culture OR cavitary disease?

÷ End of therapy (EOT) cavity present

÷ <10% ideal body weight?
Relapse

· Circumstance in which a patient becomes and remains
culture-negative while receiving antituberculosis drugs
but at some point after completion of therapy, either
becomes culture-positive again or experiences clinical
and radiographic deterioration consistent with active
tuberculosis

· Try to identify "WHY¨ your patient relapsed so you can
do it right this time!


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Treatment Guidelines 2003
· "Microbiological Confirmation of Relapse Should be
Pursued Vigorously¨

÷ Confirm relapse bacteriologically

÷ Use DNA fingerprinting to identify new infection
causing the disease versus relapse

÷ Identify drug susceptibility pattern of isolate
Relapsed Tuberculosis
· Most relapses occur within the first 6 ÷ 12 months after
stopping therapy but some occur 5 or more years later

· Nearly all drug susceptible patients who were treated
with a rifamycin and received DOT will relapse with drug
susceptible organisms

÷ Treat with standard RIPE regimen
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Relapsed Tuberculosis
Management Strategies

· If culture & susceptibility studies (those treated in other
countries ) were not done but treatment given by DOT

÷ Usual treatment with RIPE
· Watch carefully for clinical deterioration -
÷ Consider expanding the regimen by adding at least 2 drugs

÷ Consider an expanded regimen if immune suppressed,
significantly ill, or extensive disease

Relapsed Tuberculosis
Management Strategies
· Suspect drug resistance if

÷ Patients treated with self administered therapy
÷ Patient was poorly adherent
÷ Patient deteriorates clinically or radiographically during initial
weeks of treatment

÷ Consider expanded regimen, especially if immune
suppressed
· RIPE plus a fluoroquinolone and an injectable

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Patients at Risk of Relapse

· Who Should We Suspect?


· What Can We Do Differently to Decrease the
Risk?





Treatment Related Risk Factors
for Early Relapse of TB
· Evaluation of 113 cases of relapsed TB when matched with case
controls
÷ Non-cavitary TB, relapse rate: 1.1%
÷ Cavitary TB relapse rates:
· Thrice weekly Rx: 7.8%
· Daily Rx: 3.3%
· Extended thrice weekly: 0.5%
· Extended daily 0.4%
÷ Either intensive phase or both was beneficial


» Chang, Am J Respir Crit Care Med. 2004; 170: 1124-30

12/28/2011
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Treatment Related Risk Factors
for Early Relapse-Dosing Intensity
· Review of trials, 200 cases of relapse, 6 month Rx

· Relapse rates higher when intermittent therapy used
especially in initiation phase
÷ Daily IP, 3 x/wk CP: 1.6%
÷ Daily IP 2x/wk CP: 2.8%
÷ 3/wk IP and CP: 5.0%

· Relapse higher especially with cavitary disease and
positive 2 month cultures
÷ Only 6 month daily or 6 month daily IP and 3/wk CP had
relapse rates <5%



Chang Am J Respir Crit Care Med 2006; Vol 174 p 1153

In the Treatment of TB,
You Get What You Pay For.
· " A consistent theme has begun to appear: more extensive disease
requires more treatment, and the fewer total doses, the higher the risk
that treatment will prove inadequate¨

÷ What should we conclude?
· First: More treatment means more cures

· Second: Programs need to consider some individualization of therapy

· Third: Should not deter us from intermittent therapy but should remind
us of need for sophisticated management based on case-specific
circumstances
÷ Should not be surprised that individuals differ in their response.

» Vernon & Iademarco (CDC) Am J Resp Crit Care Med 2004: 170, pp 1040-41
12/28/2011
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Medical Factors Associated With
Relapse-Dosing Intensity
· Cavitary TB
· Extensive disease on CXR; bilateral infiltrates
· Positive 2 month culture
· Associated medical conditions
÷ Diabetes
÷ HIV
÷ Malabsorption of TB drugs
· Tuberculous lymphadenitis
· Underweight at diagnosis and failure to gain
· Drug resistant disease
· Prior treatment for tuberculosis

Treatment Factors Associated with
Relapse of Tuberculosis
· DOT
· Adherence
· Dosing intensity (Dose itself)
· Duration of therapy
÷ Intensive phase
÷ Continuation phase
÷ Both
· Rifampin containing regimen
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Length of Treatment and Relapse Risk
Johnson; AJRCCM June 09
HIV neg, 2 mo culture neg, Non-Cavitary TB in Uganda.
Risk of Relapse With a Four Month Treatment Regimen
Treatment of TB and Optimal
Dosing Schedules

Kwok Chiu Chang, Chi Chiu Leung,
Jacques Grosset, Wing Wai Yew
Thorax December, 2010
Systematic Review of 17 analytic studies ÷ 9 systematic reviews,
8 controlled studies and 2 case-control studies.
Levels of evidence and grades of recommendations
assigned according to clinical evidence with reference to
Scottish Intercollegiate Guidelines
12/28/2011
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Non HIV related TB (11 studies)

· Suggests that intermittent Rx reduces TB treatment efficacy
as shown by a higher risk of relapse or failure

· Negative impact most prominent in presence of cavities

· Review suggests with standard 6 mo Rx - no significant
difference between daily throughout & daily in initial phase
Level of evidence: 1+
Grade of recommendation: "A"
· Avoid intermittent doses, especially in initial phase
and in presence of cavities


TB With INH Resistance (2 studies)
· Suggests that dosing intermittency reduces TB
treatment efficacy as shown by:
÷ Higher risk of treatment failure, relapse or acquired
drug resistance

Level of evidence 1+
Grade of evidence: "A"
÷ Avoid dosing intermittency, especially in the
initial phase in the presence of INH resistance
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HIV related TB ( 3 studies)

· Suggests intermittent Rx, especially in initial
phase reduces treatment efficacy as shown by
÷ a higher risk of treatment failure, relapse, or
acquired Rifampin resistance

Level of evidence 1+
Grade of recommendation "A"
÷ Avoid intermittency, especially in the initial phase
in HIV TB
Why is the Initial Phase of
Therapy So Important?
12/28/2011
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Importance of the Initiation Phase
· Evidence suggests
÷ Effect of dosing schedules on treatment efficacy is
best harnessed in the initial phase

· Evidence has existed in vitro for several
decades that:
÷ the more rapid the anti-bacterial effect ÷
· the less likely is the emergence of persisters
· and the lower is the risk of relapse.
Importance of Rifampin Especially in the
Initiation Phase


· Rifampin is the only first line TB drug with
putative activity against persisters

· Persisting bacilli are the source of relapses





12/28/2011
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Populations of Mycobacteria
INH
Rifampin
EMB
Rifampin
PZA
Rifampin
Importance of the Initiation Phase
· Rifampin is the only first line TB drug with
putative activity against persisters

· Persisters may revert back and forth to other
subpopulations of bacilli
· Optimizing bactericidal and sterilizing activity early will
minimize overall bacterial load present during
continuation phase




12/28/2011
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Relapsed Tuberculosis - Case Study
Case Study
· 47 yr old male, recurrence of TB
÷ Weight at Diagnosis 117 pounds (<10% IBW)
÷ Two months, 114 pounds
÷ Three months, 114 pounds
÷ Four months, 115 pounds

· Extensive cavitary disease on CXR

· Sputum smear + 5 ! months

· Sputum culture + 3 ! months
What is problem?
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Lack of Weight Gain and Relapse Risk,
TBTC Study 22
· Relapse risk high in those underweight at diagnosis
19.1% versus 4.8%

· Among pts underweight at diagnosis, if weight gain > 5%
after 2 months of treatment:
÷ Relapse risk 18.4% vs. 10.3%
÷ If also cavitary disease: 18.9%
÷ If cavitary and + 2 month culture: 50.5%

» Khan. 2006 Am J Resp & Crit Care Med;174:344-48

Nutrition Risk Score (NRS):
Relation to Respiratory Failure & Death
· Miliary TB (MTB) develops in 1 ÷ 2% of patients and is
associated with acute respiratory failure (ARF) and death

· NRS < 3 is an independent predictor of acute respiratory
failure (ARF) and death
÷ Lower BMI, fewer lymphocytes, lower cholesterol, &
albumin in those who died
÷ 14/56 (25%) patients with Miliary TB developed ARF

Kim, Europ Resp Society 2008
12/28/2011
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Treatment in Special
Situations
Active TB During Pregnancy
· Diagnosis may be difficult
÷ Respiratory symptoms common in late pregnancy
÷ Reluctance to do a CXR
÷ Extra-pulmonary disease is even more difficult

· Outcomes for BOTH mom and baby are
improved with treatment during pregnancy

· Infection control is important at time of delivery if
mom is still infectious


12/28/2011
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Active TB During Pregnancy
· Treatment:
÷ INH, Rifampin, Ethambutol x 9 months
· Stop ethambutol if susceptible to INH and rifampin
÷ PZA only if drug resistance is present
· PZA regarded as safe by most countries in world

· Follow carefully for hepatotoxicity- risk is increased
÷ During pregnancy
÷ Three months postpartum
Delayed Response
Culture Positive at 3 Months
· TB lab should automatically repeat susceptibility
studies on last positive culture check to be sure

· Assess adherence

· Consider serum drug levels

· Evaluate response to therapy
÷ Clinically and radiographically
By the time you know this it is 4 months into therapy!
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"Treatment FaiIure"
Culture Positive at 4 Months
Repeat susceptibility studies
· On last positive culture
· And request on a "new sputum cuIture" now
÷ Serum drug levels if not previously done
÷ Clinical evaluation
Augment therapy
· Add at least two and preferably three new drugs to which
the isolate is likely to be susceptible
· Even if no clinical or radiographic evidence of failure
MMWR Treatment of Tuberculosis 2003; 52
Tuberculosis Drug Serum Level
Monitoring Recommended
· Delayed response to therapy
· Advanced AIDS with evidence of malabsorption
· Seriously ill patient to maximize therapy
· ? Diabetics
· Toxicity evaluation
· Use of second line drugs
· Acquired drug resistance
· Relapse
· Potential for drug-drug interactions
· Renal and hepatic insufficiency

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Management of TST + Persons With an
Abnormal CXR
· Isolated CXR with nodules
and/or fibrotic lesions:

· If no symptoms - wait
÷ Collect sputum culture
÷ Evaluate for symptoms
÷ Repeat CXR

· If CXR stable at 2 ÷ 3
months and cultures are
negative, treat as LTBI
· Isolated CXR with nodules
and/or fibrotic lesions:

÷ If patient has any signs or
symptoms of TB disease:
the patient is a TB
suspect
· Start 4 drugs

÷ Never start a single
drug in a patient with
possible active TB

Culture Negative TB
· TB suspect with positive TST or IGRA
÷ Risk factors for TB
÷ Abnormal CXR
÷ Usually ÷ clinical symptoms

· All cultures are negative

· Classify based on clinical and/or radiograph response to
treatment at 2 months
÷ Clinical or CXR improvement - Culture Negative TB
÷ Treat for 4 months (children and HIV + 6 months)
÷ RIPE for 2 months, then RIE +/- PZA dependent on INH resistance
12/28/2011
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Why Do Doctors Give Patients Moxifloxacin for
a Lower Respiratory Illness?

· LRTIs: A Leading
Cause of Disease
Burden Globally: All
Ages, 2004


· In 2006, pneumonia
was the leading
cause of death from
infectious disease in
the United States


· From Reuters Health
Information:
·
Moxifloxacin
Improves
Outcomes in
Hospitalized
Pneumonia
Patients
Ott, Europ Resp J , Sept 2011
W.C. 12-18-01
Prolonged Positive Smears
· 51 year old male

· Slow clinical and CXR
improvement

· Prolonged conversion of
cultures (10 weeks)

· Prolonged conversion of
smears (7! months)

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Significance of Persistent + AFB Smears
· Review of lab data of 428 patients, 30 with smear
persistently + >20weeks
÷ 23/30 had a negative culture
÷ 7/30 positive culture " treatment failure¨

· Of those with negative cultures - none relapsed
·
· Most received standard therapy for 12 months
÷ PZA was continued for 2-3 months


» Al-Moamary Chest 1999; 116:726-731
W. C. 12-11-2002
Prolonged Positive Smears

· 12 months of RX

· Culture and smear ÷ 20
months after stopping TB
meds

· CXR still extensive
cavitary infiltrates


12/28/2011
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Mycobacterium bovis
· A member of the M TB complex which is what is identified
by all TB labs or PCR

· Similar to other members but is resistant to PZA

· Is associated with extra pulmonary disease and increased
mortality

· Is common in children (> 1 year) along U.S. Mexico border
÷ Non-pasturized milk and cheese ÷ a food borne disease as well as
respiratory
M bovis & Genotyping - Texas
1
3
2
0 1
5
8
10
0%
20%
40%
60%
80%
100%
0
2
4
6
8
10
12
2000 2001 2002 2003 2004 2005 2006 2007
year
# of bovis cases
% of TB genotyped
All M. bovis are resistant to PZA and need treatment
for 9 months with INH and Rifampin +/- EMB
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Management of Treatment Interruptions
· Initial phase of therapy
÷ <14 days ÷complete standard # of doses

÷ >14 days ÷ restart from the beginning

· Continuation phase
÷ >80% doses by DOT ÷ if initial smear÷, may stop

÷ < 80% doses by DOT and/or initial smear +
· Repeat culture
÷ Management based on clinical and bacteriological factors.

TB Research

Impact on Future TB
Treatment
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Rifampin Dose - High is Better

· Higher peak serum concentrations were linked
to
÷ Improved killing of MTB,
÷ Suppression of resistance
÷ Post antibiotic effect

· Short half life not important but peak
concentration was

Gumbo; Antimicrob Agents Chemother, 2007
TB Trial Consortium Study 29
· Part I compare standard therapy (rifampin 10mg/kg) to:
÷ 3 x/wk rifapentine 15mg/kg + Moxi/PZA/EMB
÷ Daily rifampin 15mg/kg + Moxi/PZA/EMB
÷ Daily rifapentine 7.5mg/kg + Moxi/PZA/EMB

· Part II
÷ Increase to rifapentine 20mg/kg 3x/wk,
÷ Daily rifampin 20mg/kg
÷ Rifapentine 10mg/kg

12/28/2011
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TBTC Study 27
Moxifloxin Substituted for Ethambutol
Burman; Am J Resp Crit Care Med 2006
Where to Get More Information
· HEARTLAND NATIONAL TB CENTER
÷ 1-800-TEX LUNG: Medical Consultation and
Technical Assistance Line
÷ Future training courses

· CDC

· TB Educate

· TBresources.com