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Tratamiento TBC
Tratamiento TBC
Tratamiento TBC
n e w e ng l a n d j o u r na l
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Review Article
DanL. Longo, M.D., Editor
Treatment of Tuberculosis
C.Robert Horsburgh, Jr., M.D., CliftonE. BarryIII, Ph.D.,
and Christoph Lange, M.D.
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A
Bacteria in Sputum (log10 CFU/ml)
Persistentbacillitheory
TR EATMENT
Persistentdiseasetheory
Thick-walled granuloma
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Treatment of Tuberculosis
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An interactive
graphic is available at NEJM.org
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Oral, IV
Oral, IV
Levofloxacin
Moxifloxacin
Amikacin
IM, IV
Oral
Delamanid
Oral
Bedaquiline
Oral, IV
Oral
Oral
Oral, IV
Route
Isoniazid
Rifapentine
Rifabutin
Alternative rifamycins
Rifampin
Rifamycins
Drug
Less likely than rifampin to interact with antiretroviral agents and may be useful in
patients with HIV infection; monitor for hepatotoxicity; dose adjustments may be
necessary in patients receiving interacting drugs (e.g., ART)
A higher dose (13 mg/kg IV in the first 2 wk) improves treatment outcome in TB menin
gitis (low CSF penetration); monitor for hepatotoxicity; dose adjustments may be
necessary in patients receiving interacting drugs (e.g., ART)
Comments
Approved by the EMA for use as part of an appropriate combination regimen for MDR-TB
when an effective treatment regimen is unavailable because of resistance to or un
acceptable adverse effects of other medications; may potentiate QTc-interval prolon
gation when used with other drugs; close monitoring recommended when used with
other drugs that prolong the QTc interval; concurrent use with bedaquiline or moxi
floxacin not recommended
Approved by the FDA and EMA as part of an appropriate combination regimen for
MDR-TB when an effective treatment regimen is unavailable because of resistance to
or unacceptable adverse effects of other medications; may potentiate QTc-interval
prolongation when used with other drugs; close monitoring recommended when
used with other drugs that prolong the QTc interval; concurrent use with delamanid
or moxifloxacin not recommended
May potentiate QTc-interval prolongation when given with other drugs; close monitoring
recommended when used with other drugs that prolong the QTc interval; concurrent
use with bedaquiline or delamanid not recommended
May potentiate QTc-interval prolongation when given with other drugs; close monitoring
recommended when used with other drugs that prolong the QTc interval
MDR-TB: in the absence of a katG S315T mutation, inhA promoter mutations (8A/C, 15T,
16G) confer low-level isoniazid resistance (MIC, <1 mg/liter), and a dose of 1620
mg/kg should be considered; monitor for hepatotoxicity; give with pyridoxine
400 mg daily
Dose in Adults
Treatment of Tuberculosis
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IM, IV
Kanamycin
Amoxicillinclavulanate
Oral, IV
Oral
Pyrazinamide
Oral
Terizidone or cycloserine
Oral, IV
Aminosalicylic acid
Severe adverse events are common with long-term therapy; close monitoring of blood
count and awareness of peripheral neuropathy is mandatory; give with pyridoxine
Companion drug in the WHO first-line regimen but with less sterilizing activity than
rifampin and isoniazid; may induce visual disturbance that can be rapid in onset and
can begin with loss of redgreen discrimination; monitor visual acuity
1015 mg/kg (usually 750 mg as a single Terizidone, the fusion product of two molecules of cycloserine and one molecule of tere
daily dose or in 23 divided doses)
phthalaldehyde, is less toxic than cycloserine; monitor mental status; give with pyri
doxine
1520 mg/kg (usually 750 mg as a single Often not tolerated in combination with aminosalicylic acid; monitor liver and thyroid
daily dose or in 23 divided doses)
function; give with pyridoxine
600 mg daily
of
Oral
Oral, IV
Linezolid
Comments
Dose in Adults
n e w e ng l a n d j o u r na l
Protionamide or ethionamide
Oral, IV
Ethambutol
IM, IV
IM, IV
Capreomycin
Streptomycin
Route
Drug
Table 1. (Continued.)
The
m e dic i n e
* An expanded table that includes doses in children and adverse events is in the Supplementary Appendix, available at NEJM.org. ART denotes antiretroviral therapy, CSF cerebrospinal fluid,
EMA European Medicines Agency, FDA Food and Drug Administration, HIV human immunodeficiency virus, IM intramuscular, IV intravenous, MDR-TB multidrug-resistant tuberculosis,
MIC minimal inhibitory concentration, QTc corrected QT, and WHO World Health Organization.
Some drugs in the oral drugs category may have injectable formulations but are almost always given orally for tuberculosis treatment.
150 mg daily
1000 mg 2 or 3 times/day
In cases of severe skin discoloration, reduce dose to 5 times/wk; monitor QTc interval
Oral
Clofazimine
100200 mg daily
Oral
Clarithromycin
Dose in Adults
Route
Drug
Comments
Treatment of Tuberculosis
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A r e a s of Uncer ta in t y
There are conflicting opinions about many aspects of tuberculosis treatment, largely because of
the paucity of strong evidence. Treatment guidelines have been prepared by the WHO, the International Union against Tuberculosis and Lung
Disease (the Union), and a number of countries,
and these various guidelines reflect this diversity
(see Table S2 in the Supplementary Appendix).30,47-59 In this section, we address some of the
areas in which general consensus is lacking.
Treatment of Drug-Susceptible Tuberculosis
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Recommendations for the treatment of tuberculosis that is resistant only to isoniazid are varied
but similar. All guidelines recommend a regimen consisting of a rifamycin, ethambutol, and
pyrazinamide, with or without a fluoroquinolone, for 6 to 12 months. Rifampin resistance is
rare in the absence of isoniazid resistance, but a
9-month regimen of isoniazid, pyrazinamide,
and streptomycin has been shown to be effective60; however, it can be difficult for patients to
complete 9 months of treatment with an injectable agent. Eighteen-month regimens comprising
isoniazid, pyrazinamide, and ethambutol, with or
without a fluoroquinolone, are also recommended, on the basis of clinical experience. The
WHO and some countries47 recommend a regimen for MDR tuberculosis even in cases of monoresistant (i.e., rifampin-resistant) tuberculosis,
because on the basis of testing with GeneXpert
(Cepheid), many cases of tuberculosis are rifampinresistant and companion susceptibilities are not
known. If the isolate is susceptible to isoniazid
and pyrazinamide, a shorter and less toxic regimen can be used. For MDR tuberculosis, all the
national guidelines surveyed recommend regimens that are individualized on the basis of the
results of drug-susceptibility testing. The WHO47
and the Union52 recommend the use of empirical
regimens (based on prevailing national drugsusceptibility profiles) when susceptibility testing is not available.
Treatment of Tuberculous Meningitis
Treatment of Tuberculosis
ensure adequate drug delivery at the site of infection by either increasing the dose of rifampin
or including in the regimen agents that have
better penetration into cerebrospinal fluid.61
Clinical or laboratory algorithms that could predict which patients will have a response to a
shorter course of treatment and which patients
require a longer course would allow more appropriate targeting of resources and in many
cases would reduce drug toxicity and lessen the
effect of nonadherence to the regimen. Although
clinical factors are inadequate for predicting responses in individual patients, new molecular
techniques have identified some promising potential biomarkers.63
Use of Pharmacokinetic Data to Improve
Regimen Composition
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M. tuberculosis
NADH dehydrogenase
Clofazimine
ATP synthase
Bedaquiline
H+ H+
H+ H+
+
H+ H
Intracellular acidification
Pyrazinamide
Peptidoglycan
Arabinogalactan
Mycolic acids
Amoxicillinclavulanate
Imipenemcilastatin
Meropenemclavulanate
Cycloserine
Terizidone
Ethambutol
Isoniazid
Protionamide or
ethionamide
Delamanid
Amithiozone
Ribosome
Amikacin
Capreomycin
Kanamycin
Streptomycin
Linezolid
Clarithromycin
RNA polymerase
DNA gyrase
Rifabutin
Rifampin
Rifapentine
Levofloxacin
Moxifloxacin
N
H2N
HN
N
H
N
H
OH
CO2-
CO2-
Folate metabolism
Aminosalicylic acid
ity. All these factors combine to make generalization from adult to pediatric treatment a
highly speculative undertaking. Efforts to define
the most effective treatment approaches, including individualization of regimens, doses, and
treatment duration, must be extended to this
important group of patients.
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Treatment of Tuberculosis
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