Professional Documents
Culture Documents
review article
current concepts
Tuberculosis
Alimuddin Zumla, M.D., Ph.D., Mario Raviglione, M.D., Richard Hafner, M.D.,
and C. Fordham von Reyn, M.D.
D
espite the availability of a cheap and effective treatment, tu- From the Department of Infection, Divi-
berculosis still accounts for millions of cases of active disease and deaths sion of Infection and Immunity, Univer-
sity College London Medical School,
worldwide. The disease disproportionately affects the poorest persons in London (A.Z.); STOP TB Department,
both high-income and developing countries.1 However, recent advances in diagnos- World Health Organization, Geneva
tics, drugs, and vaccines and enhanced implementation of existing interventions have (M.R.); the Tuberculosis Clinical Re-
search Branch, Division of AIDS, Nation-
increased the prospects for improved clinical care and global tuberculosis control. al Institute of Allergy and Infectious Dis-
eases, National Institutes of Health,
Bethesda, MD (R.H.); and the Section of
Epidemiol o gy Infectious Disease and International
Health, Geisel School of Medicine at
In 2011, there were 8.7 million new cases of active tuberculosis worldwide (13% Dartmouth, Hanover, NH (C.F.R.). Ad-
of which involved coinfection with the human immunodeficiency virus [HIV]) and dress reprint requests to Dr. Zumla at the
Division of Infection and Immunity, Cen-
1.4 million deaths, including 430,000 deaths among HIV-infected patients1 repre- tre for Clinical Microbiology, 2nd Fl., UCL
senting a slight decrease from peak numbers in the mid-2000s (Fig. 1). It has been Royal Free Campus, Rowland Hill St.,
estimated that there were 310,000 incident cases of multidrug-resistant tuberculo- London NW3 OPE, United Kingdom, or
at a.zumla@ucl.ac.uk.
sis, caused by organisms resistant to at least isoniazid and rifampin, among patients
who were reported to have tuberculosis in 2011 (Fig. 2). More than 60% of these N Engl J Med 2013;368:745-55.
DOI: 10.1056/NEJMra1200894
patients were in China, India, the Russian Federation, Pakistan, and South Africa.1,2 Copyright 2013 Massachusetts Medical Society.
A total of 84 countries have reported cases of extensively drug-resistant tuberculosis,
a subset of multidrug-resistant tuberculosis with added resistance to all fluoroquin
olones plus any of the three injectable antituberculosis drugs, kanamycin, amikacin,
and capreomycin.1-3 Sub-Saharan Africa has the highest rates of active tuberculosis
per capita, driven primarily by the HIV epidemic.1 The absolute number of cases is
highest in Asia, with India and China having the greatest burden of disease glob-
ally.1 In the United States and most Western European countries, the majority of
cases occur in foreign-born residents and recent immigrants from countries in
which tuberculosis is endemic.4-6
Patients with active pulmonary tuberculosis are the source of Mycobacterium tubercu-
losis. In more than 90% of persons infected with M. tuberculosis, the pathogen is
contained as asymptomatic latent infection. Recent studies raise the possibility that
some persons acquire and eliminate acute infection with M. tuberculosis.7 The risk of
active disease is estimated to be approximately 5% in the 18 months after initial in-
fection and then approximately 5% for the remaining lifetime.8 An estimated 2 bil-
lion persons worldwide have latent infection and are at risk for reactivation.1 Con-
tained latent infection reduces the risk of reinfection on repeated exposure,
whereas active tuberculosis is associated with an increased risk of a second episode
of tuberculosis on reexposure (Fig. S1 in the Supplementary Appendix, available
with the full text of this article at NEJM.org).8-10
A
10.0
All cases
HIV-negative
5.0
2.5
HIV-positive
0.0
1990 1995 2000 2005 2010
Drug-resistant strains of M. tuberculosis arise person may result in infection and eventually
from spontaneous chromosomal mutations at a disease (primary resistance). Outbreaks of highly
predictable low frequency. Selection pressure that fatal drug-resistant infection have been docu-
is caused by misuse of antituberculosis drugs, mented in several settings, especially those in
such as monotherapy or the addition of single which the prevalence of HIV infection is high.11-13
drugs to failing regimens, results in the emer- Recent reports describing totally drug-resistant
gence of resistant mutants (acquired resistance). tuberculosis require confirmation.14,15 The fail-
Transmission of such resistant strains to another ure to detect drug resistance results in the pre-
MDR-TB Cases
0299
3002999
300029,999
30,00059,999
60,000
Data not shown
Multiple trials Increased doses of rifampin and rifapentine Higher doses of rifamycins may permit shorter regimens with stan-
dard drugs
Treatment of drug-resistant active disease
Bedaquiline (TMC207) Background therapy for multidrug-resistant disease plus bedaquiline Mycobacterial ATP synthase inhibitor shown to improve sputum
conversion at 8 wk; also to be studied in new regimens for drug-
sensitive tuberculosis
Delamanid (OPC-67683) Background therapy for multidrug-resistant disease plus delamanid A nitroimidazole with activity against replicating bacilli through inhibi-
tion of mycolic acid synthesis; active against nonreplicating bacilli
through generation of reactive nitrogen intermediates; shown to
improve sputum-culture conversion at 8 wk
PA-824 PA-824 combined with moxifloxacin and pyrazinamide is being studied A nitroimidazole with the same mechanism of action as delamanid;
n e w e ng l a n d j o u r na l
in a phase 2b trial (8 wk) for treatment of drug-sensitive and when combined with moxifloxacin and pyrazinamide, has high
of
* A full listing of all trial references or clinical trial numbers is provided in the Supplementary Appendix at NEJM.org. ACTG 5279 denotes Ultra-Short-Course Rifapentine/Isoniazid for the
Prevention of Active Tuberculosis in HIV-Infected Individuals with Latent Tuberculosis Infection, OFLOTUB Randomized, Open-Label, Controlled Trial of a 4-Month Gatifloxacin-Containing
Designed to reduce mortality from undiagnosed tuberculosis in HIV-
Regimen versus Standard Regimen for the treatment of Adult Patients with Pulmonary Tuberculosis, PROMPT Prevention of Early Mortality by Presumptive Tuberculosis Treatment,
tigate targeted use of preventive therapy with
REMEMBER Reducing Early Mortality and Morbidity by Empiric Tuberculosis Treatment, REMox Rapid Evaluation of Moxifloxacin in Tuberculosis, and RIFAQUIN International
isoniazid on a continuous or recurring basis in
persons with HIV infection who have a positive
tuberculin skin test.48
infected patients
positive patients
first 8 weeks after the initiation of tuberculosis but who do not have probable or confirmed tu-
treatment and that patients with a CD4+ cell berculosis (Table 2).
count of less than 50 per cubic millimeter receive
antiretroviral therapy within the first 2 weeks.42 Multidrug-Resistant Tuberculosis
One exception is patients with tuberculous men- The treatment of multidrug-resistant tuberculo-
ingitis, in whom the early initiation of antiretro- sis is based on expert opinion and requires the
viral therapy does not improve outcomes and re- creation of combination drug regimens chosen
sults in an increased risk of adverse events.42 from five hierarchical groups of first-line and
The immune reconstitution inflammatory second-line drugs58,59 (Table S1 in the Supple-
syndrome (IRIS) occurs in at least 10% of HIV- mentary Appendix). Such therapy is associated
infected patients who start antiretroviral therapy with a high risk of intolerance and serious toxic
during tuberculosis treatment. These cases of effects. Regimens may be chosen on a standard-
IRIS include both new cases of active tuberculo- ized or empirical basis and then switched to in-
sis detected after the initiation of antiretroviral dividualized therapy after data regarding drug-
therapy (called unmasking IRIS) and clinical susceptibility testing become available. However,
worsening during tuberculosis treatment after the reliable drug-susceptibility testing is not widely
initiation of antiretroviral therapy (called para- available in regions in which tuberculosis is en-
doxical IRIS).53 The most common manifesta- demic, particularly for second-line drugs. WHO
tions of IRIS are new-onset or worsening respi- treatment guidelines for multidrug-resistant tu-
ratory symptoms and increased lymphadenopathy. berculosis recommend that the intensive phase of
IRIS is more common in patients who have a therapy be administered for at least 8 months.58,59
reduced number of CD4+ cells and those in A fluoroquinolone and an injectable agent should
whom antiretroviral therapy was initiated early routinely be included to provide a regimen with
in the course of tuberculosis treatment, with at least four second-line drugs that will have cer-
rates approaching 50% among patients with a tain or nearly certain effectiveness, as well as
CD4+ cell count of less than 50 per cubic milli- pyrazinamide.
meter who started to receive antiretroviral ther- Such therapy should be administered for at
apy within 4 weeks after the start of tuberculosis least 20 months in patients who have not re-
treatment.53 For antiretroviral therapy in pa- ceived previous treatment for multidrug-resis-
tients with active tuberculosis, regimens with tant tuberculosis and for up to 30 months in
non-nucleoside reverse transcriptase inhibitors those who have received previous treatment. An
are preferred, and efavirenz is the drug of first observational study showed that a shorter regi-
choice.54 men, with treatment given for 9 to 12 months
The use of rifampin significantly reduces se- (the so-called Bangladesh regimen), had accept-
rum concentrations of protease inhibitors.55 able efficacy with fewer adverse reactions60 in a
Studies of the substitution of rifabutin for rifam population with no previous exposure to second-
pin and increased doses of boosted protease in- line drugs. This regimen is being more widely
hibitors to avoid this reduction are under way.55 evaluated in the ongoing Standardized Treat-
Patients with HIV-associated tuberculosis should ment Regimen of Antituberculosis Drugs for
also receive prophylaxis with trimethoprim Patients with Multidrug-Resistant Tuberculosis
sulfamethoxazole. In two clinical trials the (STREAM) trial.61 Since most of the recommend-
Prevention of Early Mortality by Presumptive ed drugs have serious side effects that render
Tuberculosis Treatment (PROMPT) study56 and treatment particularly difficult, expert consulta-
the Reducing Early Mortality and Morbidity by tion is always advised for the treatment of mul-
Empiric Tuberculosis Treatment (REMEMBER) tidrug-resistant tuberculosis (Table S2 in the
study57 investigators are evaluating the use of Supplementary Appendix).
early empirical tuberculosis therapy to reduce Extensively drug-resistant tuberculosis is ex-
the high rate of death among patients living in tremely difficult to diagnose and treat in coun-
tuberculosis-endemic countries who have a CD4+ tries in which the disease is endemic. The condi-
cell count of less than 50 per cubic millimeter tion has been associated with death rates as high
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This appendix has been provided by the authors to give readers additional information about their work.
Supplement to: Zumla A, Raviglione M, Hafner R, von Reyn CF. Tuberculosis. N Engl J Med 2013;368:745-55.
DOI: 10.1056/NEJMra1200894
APPENDIX (WEB SUPPLEMENT)
TABLE S1 Page 3
GROUPS OF FIRST AND SECOND-LINE ANTI-TUBERCULOSIS DRUGS
TABLE S2 Page 4
MDR-TB TREATMENT DRUGS AND RELATED TOXICITIES
TABLE S3 Page 6
CANDIDATE TUBERCULOSIS DRUGS IN CLINICAL TRIALS
FIGURE S1 Page 8
RISKS OF Mycobacterium tuberculosis INFECTION AND DISEASE
FIGURE S2 Page 9
CLASSIFYING THE TUBERCULIN SKIN TEST REACTION
FIGURE S3 Page 10
GLOBAL TB VACCINE PIPELINE
1
Current Concepts
TUBERCULOSIS
ALIMUDDIN ZUMLA,M.D.,Ph.D., MARIO RAVIGLIONE,M.D., RICHARD HAFNER,M.D., AND C. FORDHAM VON REYNM.D.
From the Department of Infection, Center for Clinical Microbiology, Division of Infection and Immunity, University
College London Medical School, University College London, U.K. (A.Z); STOP TB Department, World Health
Organisation, Avenue Appia 20, 1211 Geneva 27, Switzerland (M.R); Tuberculosis Clinical Research Branch, Division of
AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and
Human Services, Bethesda, MD 20892-7628, USA (R.H); Section of Infectious Disease and International Health, Geisel
School of Medicine at Dartmouth, Hanover, NH 03756, USA (C.FvR).
2
TABLE S1
3
TABLE S2
MDR-TB TREATMENT DRUGS AND RELATED TOXICITIES
GROUP DRUG SEVERE OR COMMON TOXICITIES COMMENTS
Group 1 Pyrazinamide (Pza)* - Hepatotoxicity (<1% with current dosing) - WHO guidelines recommend routine use despite
First-line Agents - Hyperuricemia and gout 50% - 70% MDR resistance rates in some regions;
Generally well tolerated - Anorexia, vomiting reliable DST
Ethambutol (Emb)* - Central or peripheral retrobulbar neuritis in - is
Nonot usually
longer available for routine use in MDR-TB
recommended
<1% cases treatment because benefit not been shown
Group 2 Aminoglycosides: with current dosing
- Irreversible ototoxicity (6-18%) and in some - Parenteral administration only
Injectable Agents Kanamycin (Km)* cases may develop months after - Km is preferred due to cost, but if resistance probable,
Amikacin (Amk) discontinuation Cm should be used
Cyclic polypeptide: - Nephrotoxicity - risk increased in elderly, renal - Cross-resistance patterns are variable and
Capreomycin (Cm) impairment, and use with other nephrotoxic complex - local drug choice often made on basis of cost
agents and availability
Group 3 - Generally well tolerated - Optimal Mfx and Lfx doses not definitively established
Fluoroquinolones Moxifloxacin (Mfx)* - GI disturbance - nausea, vomiting, diarrhea - Ofx substantially less potent
- Neurologic disturbance insomnia, - Use of ciprofloxacin is not recommended
Levofloxacin (Lfx) restlessness; In less than 0.5%: agitation,
confusion, depression
Ofloxacin (Ofx) - Dose-related QT prolongation common, so
avoid use with long Q-T syndrome and caution
with other drugs prolonging Q-T interval
Group 4 Ethionamide (Eto) - Frequent GI intolerance anorexia, nausea, - Active against katG mutants, but not inhA and other
Bacteriostatic Second-line vomiting, metallic taste relevant mutations
Agents (in order of Prothionamide (Pto)* - Neurotoxicity: seizures, psychosis, depression - No substantial difference in toxicity between analogues
preference) - Peripheral and optic neuropathy - Divided doses (BID or TID) and/or initial dose ramping
- Hepatotoxicity (2%) over 1-2 weeks may improve tolerance
- Hypothyroidism - Less effective with history of previous MDR- TB
treatment
- Pyridoxine should be added
Cycloserine (Cs) - Common CNS effects: mood changes, - Terizidone may have less CNS toxicity, but not proven
confusion, psychosis, paranoia, aggression, - Dose reduction common
Terizidone (Trd) vertigo, tremor
seizures, paresis, and coma
4
GROUP DRUG SEVERE OR COMMON TOXICITIES COMMENT
S
- High-dose pyridoxine (150-300 mg/day) should
be added
Para-aminosalicylic - Frequent GI intolerance: anorexia, nausea, - Weak static activity only, but helps to prevent
acid (Pas) vomiting, diarrhea emergence of resistance
- Hepatotoxicity approx. 0.5% - Granular form and divided dosing are usually
- Hypothyroidism better tolerated
Group 5 High dose isoniazid - Hepatoxicity Risk increases with age (2% with - Unlikely to have activity against katG mutant
Agents with unclear role in (High-dose Inh)* age > 50y), liver disease, other hepatoxic drugs; strains, but may be active against most inhA
MDR-TB Treatment (use - Rash (2%); mutant strains
only as needed for regimen - Neurotoxicity risk is increased with higher dose, - Pyridoxine should be added
to have at least 4 high- CNS seizure, hallucinations, mental changes,
probability active second- depression;
line drugs) - Peripheral neuropathy, rarely optic neuritis
Clofazimine (Cfz)* - Red to brown skin discoloration with intensity - While role in treatment is not yet clear, has
related to dose and duration; substantial activity in animal models
- Dose-related GI disturbance: nausea, vomiting, - Optimal dosing not established
And cramps - High barrier to resistance development
- Q-T prolongation has been observed, but not - Extremely high/prolonged tissue and macrophage
carefully studied concentrations vs. serum
Linezolid (Lzd) - Nausea, diarrhea, and headache - Has substantial sterilizing activity
- With long-term use:Peripheral neuropathy, - High barrier to resistance
thrombocytopenia, infrequently optic neuropathy - Relatively high cost
- Myelosuppression common; - Dose reduction (600 daily to 300 mg daily)
- Rarely, lactic acidosis, pancreatitis often required to allow continuation
Amoxicillin/Clavulanate - Generally well tolerated - Role in MDR-TB therapy not defined, but some
(Amx/Clv) - GI disturbance related to dose of Clv case reports indicate possible benefit
- Rarely, hypersensitivity/anaphylaxis - Imp/Cln intravenous only
Imipenam/Cilastatin - Emb may be synergistic and increases activity,
(Imp/Cln) even at sub-inhibitory concentrations
Clarithromycin (Clr) - Generally well tolerated; - Potent inhibitor of CYP3A
- GI disturbance common nausea, cramping, - Activity is low, but may synergize with Pza and
diarrhea, abnormal taste activity may be significantly enhanced by Emb,
- Q-T interval prolongation if susceptible
- High lung tissue levels
Abbreviations: DST = Drug susceptibility testing BID = twice daily dosing; TID = Thrice daily dosing
5
2011 WHO guidelines for choice of combination regimens for MDR treatment: Initiate treatment with Pza and four second-line drugs likely to be effective based on patient
treatment history, local resistance and drug use patterns, and available DST of strains from patient or close contacts. Combination should include a fluoroquinolone (preferably Mfx
or Lfx), an injectable drug, and eto (or pto) as first choices, if appropriate. Other drugs from Group 4 should be added in the order listed above to achieve combination goals. If other
drugs are still needed, they are chosen from Group 5, and in that case, use of two Group 5 drugs may be considered. Addition of more drugs has not been demonstrated to add benefit
in treatment of extensive disease. Intensive phase with at least five drugs (including an injecta ble and Pza) is continued for at least 8 months.
Maintenance therapy includes only the other drugs (typically a fluoroquinolone, Eto or Pto, and Cs or Trd). Total duration of therapy is at least 20 months in the absence of prior MDR
treatment, but longer with previous MDR therapy (approximately 28-30 months). If available, DST should be obtained for fluoroquinolones and aminoglycosides. DST for other listed
drugs is not reproducible or reliable (except for detection of inhA and KatG mutations). Regimen changes are made based on clinical and bacteriologic indicators of response and DST
results.
HIV co-infection: All HIV co-infected patients treated for MDR-TB should begin antiretroviral therapy regardless of CD4+ cell count as soon as possible, but within 8 weeks of TB
treatment initiation, and within 2 weeks for those with a CD4+ T cell count of less than 50 per cubic millimeter.
* Drugs included in the (modified) Bangladesh Regimen: Intensive phase consists of at least four months of Pza, Emb, Mfx, Clz, Km, high dose Inh, and Pto.
Maintenance phase includes Pza, Emb, Mfx, and Cfz to complete nine to twelve months total duration.
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TABLE S3
CANDIDATE TUBERCULOSIS DRUGS IN CLINICAL TRIALS
CLASS DRUG TRIAL DEVELOPER MECHANISM OF ACTION COMMENTS
PHASE
Fluoroquinolone Moxifloxacin 3 Bayer/GATB -Inhibition of Topoisomerase IV - Q-T interval prolongation: avoid use with long Q-T
and DNA gyrase syndrome and caution when using with other drugs prolonging Q-T
- Optimal doses not established
Gatifloxacin 3 WHO - Gatifloxacin: More frequent dysglycemia; Not commercially
available at present
Janssen; - Phase III trials to reduce treatment to 4 months:
Levofloxacin generics now - Gatifloxacin (Oflotub III trial) results available mid-2013
2 available - Moxifloxacin REMox trial to be completed late 2014
Nitroimidazole Delamanid 3 Otsuka -For replicating M.tb bacilli - - Q-T interval prolongation
(OPC-67683) inhibition of mycolic acid - Mild antagonism with bedaquiline, probably has no substantial
synthesis effect on sterilizing activity of combination use
-For non-replicating M.tb bacilli - - Delamanid - NDA for accelerated approval has been filed
PA-824 2 GATB generation of highly reactive with EMA; Phase III trial initiated
nitrogen radicals - Phase IIB trial of PA-824 in combination with Pza and Mfx initiated
Oxazolidinone* Sutezolid 2 Pfizer -Inhibition of translation - Whether hematologic and neurologic toxicity will be decreased
(PNU 100480) by binding at the A site of vs. Linezolid is unknown
peptidyl transferase center - Appear to have good sterilizing activity
- High barrier to development of resistance
AZD 5847 Astra
- Sutezolid Phase IIA (EBA) trial completed
2 Zeneca - AZD Phase IIA (EBA) trial now underway
Ethylenediamine SQ109 2 Sequella -Inhibition of MmpL3 transporter - Phase 2b MAMS trial will evaluate four new treatment regimens
of trehalose mycolate across cell including SQ109, an increased dose of Rif, and Mfx, in early 2013
membrane for incorporation into - Appears to have high barrier to development of resistance
cell wall
* Two other oxazoldinones now in late clinical trials for other indications have substantial activity against Mycobacterium tuberculosis: Tedazolid (Trius) and Radezolid (Rib-X)
EBA = Early bactericidal activity. GATB = The Global Alliance for Tuberculosis Drug Development
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FIGURE S1
RISKS OF Mycobacterium tuberculosis INFECTION AND DISEASE
Percentages represent the estimated risk of progression from latent infection to active disease in a general population. The right side of the
Figure depicts the relative risk of developing active tuberculosis after new exposure for subjects with and without prior mycobacterial
experience including BCG, LTBI, or active tuberculosis. The risk of disease after new exposure is shown as 1X for nave subjects and is
higher or lower depending on prior mycobacterial experience.
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FIGURE S2
Note:
Targeted TST programs should be conducted amongst high risk groups
TST reaction may be negative in patients with LTBI
Rule out active TB disease before treating LTBI
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FIGURE S3
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SUPPLEMENTARY REFERENCES TO TABLE 2
REMox -- Controlled Comparison of Two Moxifloxacin Containing Treatment Shortening Regimens in Pulmonary
Tuberculosis (REMoxTB). ClinicalTrials.gov Identifier: NCT00864383.
OFLOTUB III -- A Controlled Trial of a 4-Month Quinolone-Containing Regimen for the Treatment of Pulmonary Tuberculosis
ClinicalTrials.gov Identifier: NCT00216385.
RIFAQUIN -- An international multicentre controlled clinical trial to evaluate high dose RIFApentine and a QUINolone in the
treatment of pulmonary tuberculosis RIFAQUIN. International Standard Randomised Controlled Trial Number
Register Identifier: ISRCTN44153044.
BEDAQUILINE -- (Ref 64 ) -- Diacon AH, Donald PR, Pym A, et al. The diarylquinoline TMC207 for multidrug-resistant tuberculosis.
N Engl J Med. 2009 Jun 4;360(23):2397-405.
BEDAQUILINE -- (Ref 66) -- Diacon AH, Dawson R, von Groote-Bidlingmaier et al. 14-day bactericidal activity of PA-824, bedaquiline,
pyrazinamide, and moxifloxacin combinations: a randomised trial Lancet. 2012 Sep 15;380(9846):986-93.
-- Evaluation of Early Bactericidal Activity in Pulmonary Tuberculosis. ClinicalTrials.gov Identifier: NCT01215851
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DELAMANID -- (Ref 65) -- Gler MT, Skripconoka V, Sanchez-Garavito E, et al. Delamanid for multidrug-resistant pulmonary
tuberculosis. N Engl J Med. 2012 Jun 7;366(23):2151-60.
DELAMANID -- Safety and Efficacy Trial of Delamanid for 6 Months in Patients With Multidrug Resistant Tuberculosis.
ClinicalTrials.gov Identifier: NCT01424670 (Phase 3 trial by Otsuka).
PA-824 -- Diacon AH, Dawson R, du Bois J, et al. Phase II dose-ranging trial of the early bactericidal activity of PA-824. Antimicrob
Agents Chemother. 2012 Jun;56(6):3027-31.
PA-824 -- Singh R, Manjunatha U, Boshoff HI, et al. PA-824 kills nonreplicating Mycobacterium tuberculosis by intracellular NO release.
Science. 2008 Nov 28;322(5906):1392-5.
PA-824 -- (Ref 66) -- Diacon AH, Dawson R, von Groote-Bidlingmaier et al. 14-day bactericidal activity of PA-824, bedaquiline,
pyrazinamide, and moxifloxacin combinations: a randomised trial Lancet. 2012 Sep 15;380(9846):986-93.
PA-824 -- Evaluation of 8 weeks treatment With the Combination of Moxifloxacin, PA-824 and Pyrazinamide in Patients With Drug
Sensitive and Multi Drug-Resistant Pulmonary Tuberculosis (TB). ClinicalTrials.gov Identifier: NCT01498419 (ongoing Phase IIB trial
for the Global Alliances PA-824+PZA+moxifloxacin combination).
PA-824 -- Evaluation of Early Bactericidal Activity in Pulmonary Tuberculosis With Clofazimine (C)-TMC207 (J)-PA-824(Pa)-
Pyrazinamide(Z). ClinicalTrials.gov Identifier: NCT01691534. (Not yet initiated).
LINEZOLID -- (Ref 67) -- Lee M, Lee J, Carroll MW, et al . Linezolid for treatment of chronic extensively drug-resistant tuberculosis. N
Engl J Med. 2012;367(16):1508-18.
SUTEZOLID -- A Study Of PNU-100480 In Newly Diagnosed, Treatment Sensitive Patients With Pulmonary Tuberculosis To Assess Early
Bactericidal Activity (EBA) And Whole Blood Activity (WBA). ClinicalTrials.gov Identifier: NCT01225640
-- Wallis RS, Friedrich SO, Diacon AH, et al. Bactericidal Activity in Sputum and Blood of PNU-100480(Sutezolid,U-480)
and its Major Metabolite (PNU101603,U-603) in Patients with Pulmonary TB. ICAAC 201 abs A-1264.
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AZD5847 -- Phase 2a EBA Trial of AZD5847. ClinicalTrials.gov Identifier: NCT01516203.
SQ-109 -- Dose Escalation Study of SQ109 in Healthy Adult Volunteers. ClinicalTrials.gov Identifier: NCT00866190
-- Dose Escalation Study of SQ109 in Healthy Adult Volunteers, International Consortium for Trials of
Chemotherapeutic Agents in Tuberculosis, 2012 Meeting: http://www.intertb.sgul.ac.uk/2012-meeting.
SQ-109 -- A multiple arm, multiple stage (MAMS), phase 2, open label, randomized, controlled clinical trial to evaluate four
treatment regimens including two doses of SQ109, an increased dose of rifampicin, and moxifloxacin in adult
subjects with newly diagnosed, smear-positive pulmonary tuberculosis - PanACEA-MAMS-TB-01.
Pan-African Clinical Trials Registry Identifier: PACTR201205000383208.
ACTG 5290 -- (Ref 55) -- Rifampin-Based Tuberculosis Treatment Versus Rifabutin-Based Tuberculosis Treatment in HIV.
http://clinicaltrials.gov/ct2/show/NCT01601626.
PROMPT -- (Ref 56) -- Prevention of Early Mortality by Presumptive Tuberculosis (TB) Treatment (PrOMPT).
ClinicalTrials.gov Identifier: NCT01417988.
REMEMBER (ACTG 5274) -- (Ref 57) -- Reducing Early Mortality & Morbidity by Empiric Tuberculosis (TB) Treatment.
AC ClinicalTrials.gov Identifier: NCT01380080.
ACTG 5279 -- Evaluating the Safety and Effectiveness of Short-Course Rifapentine/Isoniazid for the Prevention of Active
Tuberculosis in HIV-Infected Individuals With Latent Tuberculosis Infection. ClinicalTrials.gov Identifier: NCT01404312.
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