Recent Advances in Multidrug-Resistant TB of HIV/TB coinfection.2013

Recent Advances in
Multidrug-Resistant TB
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Recent Advances in Multidrug-Resistant TB
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Faculty and Disclosure Information
Richard E. Chaisson, MD
Professor of Medicine,
Epidemiology and International
Health
Johns Hopkins University
Director, Johns Hopkins Center
for AIDS Research and Center
for Tuberculosis Research
Baltimore, Maryland
Richard E. Chaisson, MD, has disclosed that his spouse has
ownership interest in Merck.
Maunank Shah, MD, has no significant financial relationships to
disclose.
Maunank Shah, MD
Assistant Professor
Department of Infectious Disease
Johns Hopkins University
Medical Director
Tuberculosis Program
Baltimore City Health Department
Baltimore, Maryland

Tuberculosis Drug Resistance: Definitions
 Acquired drug resistance
– Selection of resistant mutants by inadequate treatment
 Primary drug resistance
– Disease caused by an organism that was resistant when
infection was acquired
 Multidrug-resistant TB
– Resistance to at least isoniazid and rifampin (and other
rifamycins)
 Extensively drug–resistant TB
– MDR-TB plus resistance to fluoroquinolones and an
injectable agent (amikacin, kanamycin, capreomycin)

Drug-Resistant TB: MDR and XDR
 Drug-resistant TB first arises from improper treatment
– Wrong selection of drugs by doctors or poor adherence to treatment by
patients results in selection of naturally occurring mutants with innate
resistance
 Patients with acquired drug-resistant TB can spread infection to
others, causing primary resistance in their contacts
 In many countries, transmission of drug-resistant TB is now more
common than acquired resistance[1]
 The key prevention strategies for drug-resistant TB are:
– Avoid creating new cases by treating TB properly and thoroughly
– Prevent transmission of infection through early and proper diagnosis and
infection control
1. WHO. 2013. Surveillance of drug resistance in tuberculosis.

MDR-TB: Epidemiology
 In 2012, an estimated 450,000 new cases of MDR-TB emerged
globally[1]
 Among all new cases of TB, 3.6% are estimated to have MDR-
TB[1]
 An estimated 20% of persons with previously treated TB have
MDR-TB[1,2]
 More than one half of the new MDR-TB cases occur in China,
India, and the Russian Federation[1]
 Mortality in MDR-TB patients usually exceeds 10%[3]
 In 2012, MDR-TB caused an estimated 170,000 deaths[1]
1. WHO. 2013. Update on MDR-TB. 2. CDC. MMWR Morb Mortal Wkly Rep. 2013;62:1-12.
3. Wells CD. Curr Infect Dis Rep. 2010;12:192-197.

MDR-TB Among New TB Cases, 1994-2012
WHO. 2013. Surveillance of drug resistance in tuberculosis.

MDR-TB Among Previously Treated TB
Cases, 1994-2013
WHO. 2013. Surveillance of drug resistance in tuberculosis.

Diagnosis of MDR-TB
 Gold-standard test: Culture of patient specimen (sputum) to assess inhibition of M
tuberculosis growth in the presence of antibiotics (phenotypic assay)
 Solid-media assays: Result may not be available for 3-6 wks
 Automated liquid culture systems: Faster and more sensitive than solid-media
cultures; results available in 1-2 wks
 Rapid molecular tests can identify genotypic resistance in 1-2 days
– Xpert TB/RIF identifies M tuberculosis and rifampin resistance using cartridge-based real-time
PCR
– Line-probe assays (eg, Hain GenoType) identify genotypic resistance to both isoniazid and
rifampin
1-2 days 1-2 wks 3-6 wks 4-12 wks
Average Turnaround Time for Diagnostic Tests

WHO Recommendations: Diagnosis of
MDR-TB
 Xpert MTB/RIF should be used as the initial diagnostic test in
individuals suspected of MDR-TB[1]
 However, Xpert MTB/RIF does not eliminate need for
conventional microscopy, culture, and DST to monitor treatment
progress and to detect resistance to drugs other than rifampin[1]
1. WHO. Xpert MTB/RIF system policy statement 2011.
2. Aurum Institute. Managing TB in a new era of diagnostics. 2012.
Xpert
Result[2]
Xpert Positive,
Rifampin
Susceptible
Xpert Positive,
Rifampin Resistant
Xpert Positive,
Rifampin
Unsuccessful
Xpert Negative Xpert
Unsuccessful
Interpretation Drug-sensitive TB Presumed MDR-TB Presumed
drug-sensitive TB
TB unlikely but
further investigation
necessary
No diagnosis
Actions Treat for drug-
sensitive TB;
collect sputum for
microscopy and
culture with DST
Treat with regimen
for MDR-TB; collect
sputum for TB
culture/DST
Treat for drug-
sensitive TB;
collect sputum for
microscopy and
culture with DST
Collect sputum for TB
microscopy and
culture to exclude TB
Collect sputum
for TB
microscopy and
culture to
exclude TB

Performance of Xpert MTB/RIF vs Other
Diagnostic Modalities
Boehme C, et al. Lancet. 2011;377:1495-1505.
Proportion of TB Cases and Resistance Results by Each Method in Culture-Positive Patients
Liquid culture
MTB/RIF test
Solid culture
Microscopy
TBCasesDetected(%)
100
90
80
70
60
50
40
30
20
10
0
1000 20 40 60 80
Days to Detection
100%
90%
89%
67%
Line-probe assay
MTB/RIF test
Phenotypic drug-susceptibility
testing
0 20 40 60 80 100 120 140
Days to Detection
100%
94%
RIFResistanceDetected(%)
100
90
80
70
60
50
40
30
20
10
0

Time to DST Results Halved With MDR
Line Probe Assay in South Africa
Time Period Median Time, Days (IQR) P Value
Before LPA After LPA
1 Sputum collection to lab
receipt of sample
1 (0-1) 0 (0-1) < .001
2 Lab receipt to DST testing 27 (21-34) 19 (12-31) < .001
 Smear positive 26 (21-43) 13 (9-16) < .001
 Smear negative 29 (22-43) 29 (22-42) .497
3 DST testing 9 (2-14) 0 (0-1) < .001
Total Sputum collection to DST
results available
52 (41-77) 26 (11-52) .008
Sputum
collection
Lab receipt
of sputum
DST started DST results
reported
1 2 3
Hanrahan CF, et al. PLoS One. 2012;7:e49898.

Time to MDR Treatment Before and After
Line-Probe Assay in South Africa
From initial patient sputum sample to date of appropriate MDR therapy
Mos to MDR Treatment
80 2 4 6
1.00
0.75
0.50
0.25
0
CumulativeProportionon
MDRTreatment
After LPA
Before LPA (study data)
Before LPA (undetected MDR modeled)
Hanrahan CF, et al. PLoS One. 2012;7:e49898.

Resistance at Start of Second-line TB Therapy
Drug Resistance, n (%)
First-line drugs
 Ethambutol 826 (64.6)
 Streptomycin 881 (69.0)
 4 first-line drugs* 625 (49.0)
Second-line drugs
 Any second-line drug 559 (43.7)
 At least 1 fluoroquinolone 165 (12.9)
Second-line Injectable drugs
 Kanamycin 237 (18.5)
 Amikacin 205 (16.0)
 Capreomycin 152 (12.0)
 At least 1 255 (20.0)
 All 134 (10.5)
Other oral second-line drug
 Ethionamide 249 (19.5)
 Aminosalicylic acid 137 (10.7)
 At least 1 346 (27.1)
XDR-TB 86 (6.7)
PETTS Study: Prevalence of Drug
Resistance in 1278 Pts With MDR-TB
 1278 pts enrolled in several
countries at start of second-line
TB treatment, 2005-2008
 DST done centrally at CDC
 High levels of resistance to
second-line drugs detected
– 43.7% with resistance to
≥ 1 second-line drug
– 20% with resistance to ≥ 1
injectable second-line drug
– 12.9% with resistance to
≥ 1 fluoroquinolone
– 6.7% with XDR-TB
Dalton T, et al. Lancet. 2012;380:1406-1417.
*Isoniazid, rifampin, ethambutol, streptomycin.

Principles of MDR-TB
Treatment

MDR-TB General Principles
 An individualized approach should be undertaken
– Guided by drug susceptibility testing when available
– Assessment of comorbidities that may affect therapy should
be undertaken before therapy
 Never add a single drug to a failing regimen
 Use at least 3-5 previously unused drugs to which an
isolate has in vitro susceptibility
 Supervise treatment to ensure adherence
 Continue treatment for at least 18-24 mos after culture
conversion
WHO. Guidelines for programmatic management of drug-resistant TB. 2011.
Curry International Tuberculosis Center. Drug-resistant tuberculosis: a survival guide for clinicians.

Drugs for MDR-TB
Group 1: First-line oral drugs
Ethambutol
Pyrazinamide
High-dose isoniazid
Group 2: Fluoroquinolones
Levofloxacin
Moxifloxacin
Gatifloxacin
Ofloxacin
Group 3: Injectable drugs
Kanamycin
Amikacin
Capreomycin
Streptomycin
Group 4: Oral bacteriostatic second-line drugs
Ethionamide
Prothionamide
Cycloserine/terizidone
Para-aminosalicylic acid
Group 5: Drugs of unclear efficacy
Clofazimine
Clarithromycin
Amoxicillin-clavulanate
Linezolid
Thiacetazone
Meropenem-clavulanate
Thioridazine
*Other newer drugs
Adapted from: Chang KC, et al. Respirology. 2013;18:8-21.
*Newer drugs will be discussed later in the educational activity.

Building a Treatment Regimen for MDR-TB
Adapted from: Curry International Tuberculosis Center. Drug-resistant tuberculosis: a survival guide for
clinicians. Chang KC, et al. Respirology. 2013;18:8-21.
Step 1: Include any first-line
drugs to which the isolate is
susceptible
Injectables
Kanamycin
Amikacin
Capreomycin
Streptomycin
Step 2: Add a fluoroquinolone
Fluoroquinolone
Levofloxacin
Moxifloxacin
Gatifloxacin
First-line Drugs
Ethambutol
Pyrazinamide
Step 3: Include an
injectable agent
Oral Second-line Drugs
Ethionamide
Prothionamide
Cycloserine/terizidone
Para-aminosalicylic acid
Third-line Drugs
Clofazimine
Clarithromycin
Amoxicillin-clavulanate
Linezolid
Thiacetazone
Meropenem-clavulanate
Thioridazine
Other new drugs
Step 4: Include second-line
drugs until you have 4-6
drugs to which the isolate is
susceptible
Consider third-line drugs if
there are not 4-6 drugs to
which the isolate is
susceptible

Treatment Regimens for MDR-TB
Resistance Pattern Regimen Comments
INH and RIF ± Strept PZA + EMB + FQN + injectable (for
≥ 6 mos) + second-line agent if
extensive disease
Treat 18-24 mos following
conversion
INH, RIF + (PZA or
EMB)
(PZA or EMB) + FQN + 2 second-
line agents + injectable agent (for
first 6 mos)
conversion;
consider additional agents,
high-dose INH
INH, RIF, PZA, EMB FQN + 3 second-line agents +
injectable drug for first 6-12 mos
conversion
INH, RIF, PZA, EMB,
FQN
Injectable + 3 second-line agents +
third-line agents
Treat 24 mos following conversion;
consider high-dose INH,
Surgery
INH, RIF, PZA, EMB,
injectables
FQN + all available second-line
agents; consider any third-line
agents if susceptible
Treat 24 mos following conversion;
consider surgery
Adapted from: Curry International Tuberculosis Center. Drug-resistant tuberculosis: a survival guide for
clinicians.

“Bangladesh” Regimen: Experimental
Short-Course Treatment for MDR-TB
 Controlled trial under way to confirm the efficacy of this regimen
van Deun A, et al. Am J Respir Crit Care Med. 2010;182:684-692.
*Resistance likely for many MDR patients.
Phase Drugs
4-mo intensive phase High-dose INH*
Prothionamide*
Kanamycin
Gatifloxacin
Ethambutol*
Pyrazinamide*
Clofazimine
5-mo continuation phase Gatifloxacin
Ethambutol*
Pyrazinamide*
Clofazimine

Potency and Tolerability of Existing TB
Drugs
Dorman SE, et al. Nat Med. 2007;13:295-298.
Increasing potency,
reliability,
reproducibility of
susceptibility testing
Decreasing
tolerability
First-line
Drugs
Second-line
Drugs
Rifampin
Isoniazid
Pyrazinamide
Ethambutol
Fluoroquinolones
(moxifloxacin, gatifloxacin,
levofloxacin)
Injectable agents
Aminoglycosides (streptomycin,
amikacin, kanamycin)
Polypeptides (capreomycin)
Oral bacteriostatic agents
(ethionamide, protionamide, cycloserine/
terizidone, p-aminosalicylic acid, thiacetazone)
Agents with unclear efficacy (clofazimine,
amoxicillin-clavulanate, clarithromycin, linezolid)

Adverse Effects of MDR-TB Drugs
Drug Toxicities and Adverse Effects
Ethambutol Visual acuity, color vision
Pyrazinamide Hepatotoxicity
Isoniazid Neurologic effects, hepatotoxicity
Injectables Vestibular, renal toxicity, hearing loss
Fluoroquinolones GI, CNS, cardiac toxicities, tendinopathy
Cycloserine/terizidone CNS toxicity, behavioral changes
Ethionamide GI toxicity, hypothyroidism
PAS GI toxicity, hypothyroidism, osteoarticular pain.
Clofazimine Changes in skin and ocular pigmentation, GI effects
Linezolid Thrombocytopenia, neutropenia, neuropathy, metallic taste
Aurum Institute. Managing TB in a new era of diagnostics. 2012.

Newer Drugs for MDR-TB
Prevention Strategies

Bedaquiline
 Oral diarylquinoline
 Target: ATP synthase
– Activity specific to mycobacteria
 Bactericidal activity
comparable to RIF-INH-PZA
in mice
 Sterilizing activity comparable
to rifampin in mice
 Synergy with PZA
 No cross-resistance with other antimycobacterial drugs (INH, RIF,
EMB, PZA, streptomycin, amikacin, or moxifloxacin)
Andreas K, et al. Science. 2005;307:223-227. CDC. MMWR Morb Mortal Wkly Rep. 2013;62:1-12.
Br
N O
(S)
H
O(R) N

C208: Phase II Trial of Bedaquiline for
MDR-TB
 Stage I study: 47 pts with newly
diagnosed pulmonary MDR-TB
randomized to bedaquiline or
placebo in combination with
5-drug second-line TB regimen
– BDQ dose: 400 mg QD for
2 wks, then 200 mg TIW for
6 wks
 BL resistance: pyrazinamide,
65%; ethambutol, 59%;
kanamycin, 8%; ofloxacin, 8%;
ethionamide, 8%
 BDQ reduced time to culture
conversion (HR: 11.8; 95% CI:
2.3-61.3; P = .003)
 Incidence of AEs similar
between arms
– Nausea more frequent in
BDQ vs placebo: 26% vs 4%
(P = .04).Diacon AH, et al. N Engl J Med. 2009;360:2397.
0
0.2
0.4
0.6
0.8
1.0
0 7 42
Culture-PositivePatients(%)
14 21 28 35 49 56
Placebo (n = 24)
Bedaquiline (n = 23)
Days
52%
91%

C208: Phase II Trial of Bedaquiline for
MDR-TB
 Stage II study: 15 sites in Brazil,
India, Latvia, Peru, Philippines,
Russia, South Africa, Thailand
 Pts randomized to receive BDQ
(n = 67) vs placebo (n = 66) for
24 wks with 5-drug BR
– BDQ dose: 400 mg QD for
2 wks, then 200 mg TIW for
22 wks
 After Wk 24, both groups
continued the 5-drug BR to
total of 96 wks
 Culture conversion at Wk 24
significantly higher with
bedaquiline vs placebo
 Cure rate also significantly
higher
WHO. The use of BDQ in treatment of MDR-TB—interim policy guidance. 2013.
Outcome BDQ Placebo P Value
Median time to
sputum conversion,
days (95% CI)
83
(56-97)
125
(98-168)
< .0001
Pts with culture
conversion, %
Wk 24
Wk 72
Wk 120
78.8
71.2
62.1
57.6
56.1
43.9
.008
.069
.035
Proportion cured,
%
57.6 31.8 .003

FDA Bedaquiline Indication
 Approved by FDA in 2012 as part of combination therapy
in adults with pulmonary MDR-TB
– Should be used only when an effective treatment regimen
cannot otherwise be provided[1]
 Recommended dose: 400 mg PO QD for 2 wks, then
200 mg PO TIW, for a total duration of 24 wks
 First drug with novel mechanism approved by FDA for TB
since 1971
Bedaquiline [package insert].

CDC Provisional Guidance on Bedaquiline
 BDQ may be used as a component of TB therapy when an
effective treatment regimen cannot otherwise be provided
– Administer by DOT for 24 wks with food in adults with
laboratory-confirmed pulmonary MDR-TB
– Use on case-by-case basis in children, HIV-positive pts,
pregnant women, pts with extrapulmonary MDR-TB, and pts
with comorbid conditions on concomitant medications
– Use on case-by-case basis for durations > 24 wks
CDC. MMWR Morb Mortal Wkly Rep. 2013;62:1-12.

WHO Interim Guidance on Use of
Bedaquiline
 BDQ may be added to a WHO-recommended regimen in
adult MDR-TB patients under following conditions:
– When an effective treatment regimen containing 4 second-
line drugs in addition to PZA, according to WHO
recommendations, cannot be designed
– When there is documented resistance to any fluoroquinolone
in addition to MDR
– Recommended for adults older than 18 yrs of age under
carefully monitored conditions
WHO. Bedaquiline for MDR-TB. 2013.

Bedaquiline Safety Concerns
 Black box warning: increase in all-cause mortality and
prolongation of QT interval—monitor EKGs[1]
– 30 deaths occurred in the clinical trial program in patients
receiving BDQ vs 6 on placebo[2]
 BDQ should be used with caution with other drugs that
can cause QT interval prolongation and EKGs should be
monitored more often[1]
– Includes clofazimine and fluoroquinolones
 BDQ should not be used with rifampin or rifapentine,
which are strong inducers of CYP3A4[1]
1. Bedaquiline [package insert]. 2. CDC. MMWR Morb Mortal Wkly Rep. 2013;62:1-12.

Bedaquiline Monitoring
 All patients should be monitored wkly for adverse effects
 EKGs should be monitored at baseline and at least 2, 12, and 24 wks after
starting treatment
 Serum potassium, calcium, and magnesium should be measured at baseline
and whenever clinically indicated, especially if QT interval prolongation is
detected
 All patients started should be included in a registry for ongoing monitoring
 Additional notes:
– Bedaquiline should never be used as a single drug
– Bedaquiline has a long terminal half-life of 4-5 mos; should be discontinued before
other drugs in regimen
– Rifamycins and other CYP3A4 inducers reduce bedaquiline concentrations
– Bioavailability is significantly affected by food
CDC. MMWR Morb Mortal Wkly Rep. 2013;62:1-12.

Delamanid (OPC-67683)
 Nitro-dihydro-imidazooxazole
 Derivative of metronidazole
 Inhibits mycolic acid synthesis
 Potent preclinical in vitro and in vivo activity against both
drug-susceptible and drug-resistant strains of TB
Skripconoka V, et al. Eur Respir J. 2013;41:1393-1400.
N
O
O
F
F
FO
OO
O
N+
N
N

Delamanid: Phase II Trial vs Placebo
 Multinational trial of pts with
pulmonary MDR-TB
 Pts randomized to 2 mos of
– Delamanid 100 mg (n = 161)
– Delamanid 200 mg (n = 160)
– Placebo (n = 160)
– Each with WHO BR
 Primary endpoint: sputum
culture conversion at 2 mos
 Delamanid significantly
increased rate of sputum
conversion vs placebo after
2 mos of treatment
 QT prolongation reported
significantly more frequently
with delamanid
 All other AEs mild to moderate
and similar among groupsGler MT, et al. N Engl J Med. 2012;366:2151-2163.
Patients(%)
41.9
29.6
45.4
100
80
60
40
20
0
Delamanid
200 mg
Delamanid
100 mg
Placebo
57/136 37/12564/141
P = .04
P = .008
n/N =
Mycobacterial Growth Indicator Tube
Culture Conversion at Day 57

EMEA Delamanid Recommendation
 In November 2013, the European Committee for Medicinal
Products for Human Use recommended granting a
conditional marketing authorization for delamanid for the
treatment of MDR-TB
 Recommended indication:
– Use as part of an appropriate combination regimen for
pulmonary MDR-TB in adult patients when an effective
treatment regimen cannot otherwise be composed for
reasons of resistance or tolerability
EMEA. Marketing authorization for delamanid. November 2013.

Linezolid
 Oxazolidinone, approved to treat
drug-resistant, Gram-positive bacteria
 Good activity against MDR-TB in vitro and in animal studies
 Use in TB often limited due to long-term toxicities (bone marrow
suppression, neuropathy)
 However, retrospective chart review (2003-2007) of 30 pts (29 with
pulmonary TB) who received linezolid 600 mg QD (plus vitamin B6) as
part of a regimen for MDR-TB concluded[1]
:
– Culture conversion occurred in all pulmonary cases at median of 7 wks
– AEs occurred in only 9 patients, including peripheral and optic neuropathy,
anemia/thrombocytopenia, rash, and diarrhea
– Only 3 patients stopped linezolid treatment because of AEs
1. Schecter GF, et al. Clin Infect Dis. 2010;50:49-55.
F
O
N
N
O
O O
N
H

Linezolid 600 mg QD
immediately*
Linezolid 600 mg QD
delayed by 2 mos*
Pts with sputum-
culture–positive XDR-
TB (no response to
any TB drugs in
previous 6 mos)
(N = 41)
Smear conversion or 4 mos
*All pts remained on background regimen of drugs they were taking before study entry.

Second randomization continued at least 18 mos after smear conversion or after 4 mos on first regimen.
Linezolid 600 mg QD
22 mos
Linezolid 300 mg QD
Lee M, et al. N Engl J Med 2012;367:1508-1518.
Phase II Trial of Linezolid in Patients With
XDR-TB
 Phase II trial in South Korea
 Primary endpoint: time to sputum-culture conversion on solid medium (data
censored 4 mos after study entry)
Linezolid 600 mg QD
Linezolid 300 mg QD

Phase II Trial of Linezolid in Patients With
XDR-TB
 Culture conversion at 4 mos:
– 79% (15/19) in immediate arm
vs 35% (7/20) in delayed arm
(P = .001)
 87% (34/39) with negative
sputum culture within 6 mos
 31 pts (82%) with clinically
significant AEs related to LZD
– 3 pts d/c therapy
 Pts on LZD 300 mg on second
randomization had fewer AEs
 13 pts completed therapy
without relapse
 4 pts acquired LZD resistance
Lee M, et al. N Engl J Med. 2012;367:1508-1518.
1.0
0.8
0.6
0.4
0.2
0
0 30 60 90 120 150 180
Days Since Start of LZDCumulativeProbability
ofConversion
Conversion Probability
According to Time on Treatment

Sutezolid (PNU-100480)
 Oxazolidinone, related to linezolid
 MOA: protein synthesis inhibition[1]
 Like LZD, has a high barrier to
resistance
 More potent than LZD in mice,
whole blood culture
 Efficacy in mice similar to isoniazid and/or rifampin and may be
synergistic with other first-line drugs
 May be safer than LZD
S
N
F
O
N O
OH
N
H
CH3
1. Alffenaar JW, et al. Antimicrob Agents Chemother. 2011;55:1287-1289.

Early Bactericidal Activity of Sutezolid in
HIV+/- Pts With Drug-Susceptible TB
 Significant log CFU reductions with
both sutezolid regimens during the
14-day treatment period
– 600 mg BID: -0.09 log/day
(90% CI: -0.06 to -0.11)
– 1200 mg QD: -0.07 log/day
(90% CI: -0.04 to -0.09)
– Trend toward superior response
with BID dosing
 Both dosing schedules generally
safe and relatively well tolerated
– 7/50 sutezolid-treated pts
experienced ALT increases to
2-3 x ULN, which were
asymptomatic and resolved
spontaneously
Wallis RS, et al. AIDS 2012. Abstract THLBB02. Graphic used with permission.
0
-1
-2
-3
140 2 4 6 8 10 12
Day
ChangeinlogCFU 1200 QD
600 BID
HREZ

PA-824
 PA-824: nitroimidazole-oxazine
– Active in vitro and in mouse
models
 Cross-resistant with delamanid
 High protein binding may render PA-824 less accessible in
cavities of pulmonary TB
 May be useful in combination regimens; synergistic with
other drugs
F
F F
O
O
O
O
ON
N+

Novel Drug Combinations With PA-824
Show Promise in Mouse Models
 PA-824 with moxifloxacin and
pyrazinamide cures TB more
rapidly than the first-line regimen in
mice[1]
 Bedaquiline + PA-824 + sutezolid
may provide a novel 3-drug
backbone for a universally active
short-course regimen[2]
Regimen
(Duration)
Mice Cured, % (n/N)
4 Mos 5 Mos 6 Mos
RIF-INH-PZA (2
mos) + RIF-INH (4
mos)
50
(10/20)
100
(20/20)
100
(20/20)
RIF-MXF-PZA (2
mos) + RIF-MXF (3
mos)
95
(19/20)
100
(20/20)
100
(20/20)
Pa-MXF-PZA (2
mos) + Pa-MXF (4
mos)
100
(20/20)
100
(20/20)
100
(20/20)
Regimen
Relapse, % (n/N) After Tx for
2 Mos 3 Mos 4 Mos
RIF + PZA +
INH
ND
100
(15/15)
64
(9/14)
BDQ + SUT +
CFZ + Pa
93
(14/15)
13
(2/15)
7
(1/15)
BDQ + SUT +
CFZ
87
(13/15)
27
(4/15)
7
(1/14)
BDQ + SUT +
Pa
100
(15/15)
43
(6/14)
0
(0/15)
BDQ + CFZ +
Pa
100
(15/15)
60
(9/15)
33
(5/15)
SUT + CFZ +
Pa
100
(15/15)
100
(15/15)
100
(15/15)
1. Nuermberger EL, et al. Antimicrob Agents
Chemother. 2008;52:1522-1524. 2. Williams K, et al.
Antimicrob Agents Chemother. 2012;56:3114-3120.

HIV-negative or
HIV-positive pts* with
newly diagnosed
pulmonary smear and
culture-positive drug-
sensitive TB
(N = 83)
Day 14
Early Bactericidal Activity of Novel
Combinations of TB Drugs
 Phase II trial in TB-infected pts
Diacon AH, et al. Lancet. 2012;380:986-993.
Bedaquiline + Pyrazinamide
(n = 15)
Bedaquiline + PA-824
(n = 15)
PA-824 + Pyrazinamide
(n = 15)
Rifampin/Isoniazid/Ethambutol/Pyrazinamide
(n = 8)
Bedaquiline
(n = 15)
PA-824 + Pyrazinamide + Moxifloxacin
(n = 15)
*6 HIV-positive subjects.

Early Bactericidal Activity of Novel TB
Regimens
0.5
0
-0.5
-1.0
-1.5
-2.0
-2.5
-3.0
0 142 4 6 8 10 12
Day
LogCFUChangeFromBaseline
Bedaquiline
Bedaquiline + PZA
Bedaquiline + PA-824
RHEZ
PA-824 + PZA
PA-824 + PZA + moxifloxacin
Diacon AH, et al. Lancet. 2012;380:986-993.
Standard-of-
care regimen
Novel PA-824/
PZA/moxifloxacin
regimen

Prevention of MDR-TB
 Prevention of MDR-TB involves adequate, proper treatment of
initial disease to prevent selection of resistance
– Prompt diagnosis with adequate TB treatment under DOT
– Rapid identification of MDR-TB and use of appropriate second-line
regimens
– Avoid further evolution of resistance
– Airborne infection control
– Preventive treatment of TB/HIV coinfection with optimal use of
ART
 Management strategies for established cases mainly rely on
specific alternative treatment regimens complemented with
surgery in carefully selected cases

Preventive Therapy in Contacts of Pts
With MDR-TB in Micronesia
 232 contacts of 5 pts with 2 different MDR-TB strains
 105 with positive TST received preventive therapy
 Strain A: resistant to isoniazid, rifampin, pyrazinamide,
ethambutol, and streptomycin
– Contacts offered fluoroquinolone alone or in combination
with ethionamide
 Strain B: resistant to isoniazid, rifampin, and ethionamide
– Contacts offered fluoroquinolone with ethambutol
 No cases of MDR-TB developed in those treated
– 28 untreated contacts developed MDR-TB
ECDC. Management of contacts of MDR TB and XDR TB patients. 2012.

Conclusions
 Current approaches to MDR-TB therapy are long, with
much toxicity
 Bedaquiline is the first drug with a novel mechanism of
action to be approved by FDA for MDR-TB since 1971
 Delamanid recently approved by European Medicines
Agency
– Both agents indicated only when an effective regimen
cannot otherwise be provided
 Multiple new drugs are in the pipeline
 Successful eradication of MDR-TB will require new drug
regimens with novel drug combinations

Go Online for More CCO
Educational Content on Multidrug-
Resistant TB!
Interactive Virtual Presentation featuring streaming narration of these
slides by expert faculty Richard E. Chaisson, MD, and Maunank Shah,
MD

Recent Advances in Multidrug-Resistant TB of HIV/TB coinfection.2013

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