Transcript M. tuberculosis

The Diagnosis and Therapy of Tuberculosis
During the Past 100 Years
&
Pulmonary and Critical Care Updates
Update in Tuberculosis 2005
호흡기내과
R4 강양일
The Diagnosis and Therapy of
Tuberculosis During
the Past 100 Years
- Centennial Review
Denis A. Mitchison
Medical Microbiology, Department of Cellular and Molecular
Medicine, St. George’s Hospital Medical School, London, United
Kingdom
Am J Respir Crit Care Med Vol 171. pp 699–706, 2005
호흡기내과 R4 강양일

Key steps in the development of modern chemotherapy regimens were the
demonstrations in clinical trials
(1) streptomycin was effective
(2) combination of drugs prevented the emergence of drug-resistant
Mycobacterium tuberculosis
(3) chemotherapy under domiciliary conditions was effective and did not put
family members at risk of infection
(4) patient compliance could be assisted by fully supervised intermittent
regimens, or more effectively
(5) patient compliance could be assisted by shortening treatment by the
introduction of rifampin and pyrazinamide, the two most potent sterilizing
drugs, into the regimens
DIAGNOSIS
Radiography

Fluoroscopy
■

Images on film with use of tomography
■

During the first 30 to 40 years of the twentieth century
Toward the end of the century, computerized axial tomography and
nuclear magnetic resonance tomography
Mass miniature radiography
■
■
■
introduced in the 1940s , for screening for pulmonary disease
pulmonary lesions developed more rapidly than initially envisaged,
radiographic screening for control purposes needed to be done at time
intervals too small to be practical
became sessile in hospitals in developing countries
Bacteriology

bright field examination of direct smears stained by Ziehl-Neelsen method
■ Mainly , Up to the 1950s, rapid and highly specific, low sensitivity

fluorescence microscopy
■ replaced bright field microscopy, 5 times more rapid / more specific

Cultures
■ more sensitive than smears, results more slowly, rarely up to the 1950s
■ Solid slopes of egg yolk media, Lowenstein-Jensen medium
- widely adopted from about 1950 onwards
- liquid medium detoxified with ascitic fluid, but high rates of contamination
■ liquid medium containing antibacterials selective for M. tuberculosis
- greatly improved results
- in 1977, containing radioactive palmitic acid and similar antibacterials
-depended on measuring radioactivity of CO2, widely adopted, too
expensive
■ Alternative methods
-do not contain radioactive compounds, also depend on CO2 production,
now more widely used
-increase the sensitivity, speed up diagnosis

Drug susceptibility testing
■ started in the 1950s, in liquid medium, but later on solid medium
slopes

Rapid molecular methods
■ Identifying mycobacteria, mycobacterial species, for drug susceptibility
testing
■ not yet in wide use (high cost, uncertainty about specificity)
Immunology

Serologic diagnostic methods
■ work well when pts are smear positive
■ much less effective in pts who have minimal disease or where the
disease process cannot be sampled for conventional culture
■ do not perform well in human immunodeficiency virus–infected
subjects
■ Childhood tuberculosis- still difficult to diagnose with certainty

skin tuberculin reaction
■ useful, but low specificity

enzyme-linked immunosorbent spot assay for IFN-r–producing cells
■ Highly sensitive and specific
■ detect any individual who harbors tubercle bacilli whether or not the
disease is active, but too expensive for widespread use
TREATMENT
The Prestreptomycin Era

Attempts to find chemotherapeutic agents for tuberculolsis
■ sanocrysin, gold salt - widely used in Tx, 1925-1935
■ a number of different sulphones - activity in experimental animals, but
never widely used in treatment
■ Vitamin D
■ Nicotinamide

The basis of treatment
■ sanatorium and
■ affected portion of the lung by collapse therapy – thoracoplasty,
artificial pneumothorax
■
Pulmonary tuberculosis was reputed to have a 50% mortality, with
tuberculous meningitis and miliary tuberculosis uniformly fatal
SM

first clinical trial with a randomized intake in the history of medicine
■ started in 1946 by the British Medical Research Council
■ pts with advanced pulmonary disease
– randomized, bed rest alone or bed rest plus 2 g SM daily
■ immediate advantage to the SM arm
most pts developed SM resistant strains
5 yr follow-up => little eventual benefit compared with control arm
Prevention of Drug Resistance
 randomized controlled trial (RCT)
■ acute pulmonary TB with either SM or PAS or with both
■ aim : inhibit SM-resistant mutant bacilli with PAS
■ SM and PAS : far fewer SM-resistant strains than SM alone
Isoniazid and Effective Standard Treatment

Isoniazid (INH), introduced in 1952

RCTs on combinations of INH, SM and PAS
■ 1952 - mid 1960s, British Medical Research Council, the U.S.
Veterans Administration, U.S. Public Health Service, and elsewhere
■ In 1955, the British Medical Research Council
- first national drug resistance survey
- almost all strains with primary resistance : resistant to only one drug
 treatment with initial 3 drug phase lasting 2-3 months, followed by a
continuation phase with 2 drugs was explored first in Scotland and then
internationally
 highly successful, at least 12 months with resulting frequent failures to
complete treatment
 too expensive in drug costs (particularly for PAS)

RCTs in East Africa on thiacetazone (TB1) as a cheaper alternative to PAS

possible use of INH alone was also explored on drug cost grounds
■ because initial INH resistance carried a poor prognosis, the use of INH
in monotherapy has been abandoned

double-drug regimen with INH
■ assess relative merits of other antituberculosis drugs by their ability to
prevent the emergence of INH resistance (Table 2)
■ Rifampin (RMP) : the most effective
SM and ethambutol : little less effective
PAS and TB1 : much less effective
Domiciliary Treatment

In 1956, the Tuberculosis Chemotherapy Center
■ in Madras, India
■ study whether older, standard treatment in hospital or sanatorium
improved results of chemotherapy
■ all received INH/PAS for 1 yr => randomly Tx in sanatorium or at home
■ similar result in the two arms of the study
■ family contacts : no more liable to develop TB than those treated at
home
 widespread closure of TB beds and the spread of domiciliary treatment
 problem of how to assure regular drug taking during a year of domiciliary
treatment was immediately evident
 investigated in two ways
(1) by the use of regimens with drugs given fully supervised in widely
intermittent frequencies to make supervision easier, and
(2) by shortening the duration of treatment
Intermittent Regimens

In vitro and in experimental TB of the guinea pig by Jean Dickinson

RCTs at the Tuberculosis Chemotherapy Center, Madras
■ SM/INH, once or twice weekly
■ INH : given efficiently twice weekly
■ SM : limited efficacy when given intermittently as the dose size could
not be increased in intermittent regimens
■ Ethambutol : effective in preventing failure in intermittent regimens,
but high relapse rates
■ RMP : given intermittently with excellent effect, but higher dose
sizes required produced an immunologic “flu” reaction
Laboratory Studies on Shortening Chemotherapy

murine model, therapy with standard drugs (INH,SM, PAS)
■ initial fall in viable counts => leveled out, difficult to sterilize organs
(Figure 2)
■ PZA added => counts continued downwards => all organ cultures (-)
■ PZA : good sterilizing drug
■ bacilli in a non-culturable form, relapses eventually

In vitro experiments, at the Pasteur Institute, Paris
■ hypothesis (Figure 3) : activities of different drugs, on basis of presence
of widely different growth rates within bacterial
population at start of Tx
■ high sterilizing activity of RMP
Short-course Chemotherapy
 Multicenter RCT, East Africa in 1970
■ All pts in hospital throughout Tx to be sure that their Tx was actually taken
■ random 6-month regimens (1) daily SM + INH (SH) (2) SH + RMP (3) SH + PZA
(4) SH + TB1, given for 12 months as a control
■ After completion of Tx, monthly bacteriology f/u for 24 months
■ primary endpoint : rate of relapse during follow-up
■ secondary endpoint : proportion of pts who had positive sputum culture at 8wks
■ (Table 3) : great reduction in relapse rates in the regimens containing
RMP and PZA, slight superiority of the regimen with RMP
H = isoniazid
R= rifampin
S=streptomycin
Z=pyrazinamide
Synergistic Sterilizing Activity of RMP and PZA

addition of RMP (Table 4), or PZA (Table 5)
■ proportion of pts with a positive 2-month sputum culture ↓
■ relapse rate ↓
■ indicating improved sterilizing activity

addition of RMP to regimen containing PZA or PZA to regimen containing
RMP (Tables 4 and 5)
■ sterilizing activity ↑
■ synergistic sterilizing activity of these two drugs
Division of Regimens into an Initial Intensive Phase Followed by a
Continuation Phase

viable bacterial populations - largest at the start of Tx, resistant mutants
■ greatest number of drugs during initial phase : prevent resistant strains
emerging
■ fewer drugs in continuation phase : risk or drug resistance – smaller
■
■
in East Africa : RMP and PZA, first 1 or 2 months of therapy
Regimens with 2-month intensive phase : lower relapse rates than 1mon.
PZA is Only Active During the Intensive Phase

Three RCTs (Figure 4)
■
PZA sterilizes only during the intensive phase
Steroids in Chemotherapy

in Madras, addition of high dosage steroids during the start of Tx
■ not alter the speed of bacterial clearance during Tx nor relapse rates

highly protuberculous in the mouse, steroids with chemotherapy
■ Failed to demonstrate any increase in bactericidal activity

waking up dormant bacilli, can be killed more efficiently: unlikely to work

Steroids may however be used to suppress inflammation
Modern Regimen of Chemotherapy

Two regimens from the numerous RCTs

6-month regimen (2SHRZ/4HR)
■ pioneered in Singapore, its efficacy and low toxicity confirmed by later
studies in other countries
■ now widely used with ethambutol substituted for SM (2EHRZ/4RH) to
avoid transmission of human immunodeficiency virus

8-month regimen (2SHRZ/6TH)
■ used a minimum of RMP and PZA because of their original high cost
■ in pts with an human immunodeficiency virus infection, StevensJohnson syndrome due to TB1 => substitution of ethambutol for TB1
(2EHRZ/6EH), as well as for SM
■ recent RCT => 8-month regimen is distinctly inferior to the 6-month
regimen with RMP throughout
Tuberculosis in Organs Other Than the Lungs

lesions do not communicate with the air (spinal TB, glandular disease)
■ exellent results : 6month, 2 drug regimen of INH, RMP

tuberculous meningitis
■
■
blood–brain barrier
: prevents penetration into CSF by SM and EMB
once initial inflammation has subsided
=> not really necessary because of a small bacterial population
INH, RMP, and PZA
: effective, except in infections with strains resistant to INH and RMP
Role of Individual Drugs in Chemotherapy

RMP and PZA
■ major role in shortening the duration of chemotherapy
■ current 6-month regimen (2EHRZ/4RH)
■
■
RMP : slightly more effective overall
PZA : most effective sterilizing action during the intensive phase
■
similarity in relapse rates of pts with strains that are resistant just to INH
and those that are sensitive (Table 6)
New Antituberculosis Drugs

Fluoroquinolones, PA 824 and the diarylquinoline R207910
■ could shorten Tx period from current 6 months to 4 months or less
■ treatment of pts with multi–drug-resistant tuberculosis
■
■
tested for activity in human disease by early bactericidal activity method
titration of the dose size in EBA study => “therapeutic margin” (Figure 5)

Surrogate markers (Table 7)
■
Preclinical assessments : studies of bactericidal activity of drugs in models
of in vitro bacterial persistence, or long-term
experiments in the mouse
■
clinical study: first 2 months of Tx in which one arm contains new drug X
Pulmonary and Critical Care Updates
- Update in Tuberculosis 2005
Wing Wai Yew and Chi Chiu Leung
Tuberculosis and Chest Unit, Grantham Hospital; and
Tuberculosis Service, Department of Health, Hong Kong, China
Am J Respir Crit Care Med Vol 173. pp 491–498, 2006
PATHOGENESIS AND IMMUNITY OF TUBERCULOSIS
 genomic alterations of Mycobacterium tuberculosis

phospholipase C gene

Talarico and colleagues
■
■
■
genetic diversity of four M. tuberculosis phospholipase C - encoding
genes (plcA, plcB, plcC, and plcD) as a result of IS6110 insertions and
associated deletions among 106 clinical isolates from Turkey
proportions of isolates with interruptions
: plcA 3.8%, plcB 1.9%, plcC 3.8%, plcD gene 38%
likely greater importance of the plcD gene over the other
phospholipase C - encoding components

Yang and coworkers
■
■
■
■
■
■
■
relevance of mycobacterial phospholipase C gene D (plcD) mutations in
clinical presentation of TB
496 well-characterized clinical isolates of M. tuberculosis, 147 (30%)
regional interruptions (insertions or insertions + deletions) of gene
Pts infected with the plcD mutant types : twice extrathoracic disease
275 isolates with distinct DNA fingerprint patterns: same association
extrathoracic TB into 3 categories : strong association of plcD mutations
with isolated extrathoracic organ involvement, marginal association with
disseminated disease, no association with extrathoracic lymphadenitis
plcD gene of M. tuberculosis might be potentially involved in the
pathogenesis of TB, with resultant variation in its clinical presentation
further pursuit of possible gene targets for functional studies in the hope of
identifying M. tuberculosis virulence factors
 Granuloma formation and cavitation


key phenomena in pathogenesis of tuberculosis
synthetic matrix metalloproteinase inhibitor
: promote granuloma formation in murine model

Elkington and coworkers
■ gene expression of matrix metalloproteinases (MMPs), disintegrin,
metalloproteinase families, tissue inhibitors of MP in M. tuberculosisinfected human macrophages by reverse transcriptase PCR
■ Gene expression and secretion of MMP-1 and MMP-7 : upregulated by M.
tuberculosis, with no increase in tissue inhibitors of MP
■ macrophages : express MMP-1 and MMP-7 adjacent to tissue destruction
■ MMP-1: M. tuberculosis–specific and prostaglandin-dependent
■ BCG : increase MMP-7 gene expression/secretion, not upregulate MMP-1
■
■
increased MMP-1 expression in M. tuberculosis–infected macrophages
: key step in formation of pulmonary cavities
Modulation of excessive MMP-1 activity
: therapeutic target to ameliorate immunopathology of TB
 alveolar macrophages, CD4, CD8 T cells

interact in containment of microbe, immunopathogenesis of tuberculosis

CD4 T cells
■ pivotal in protective immunity against M. tuberculosis

CD8 T cells
■ killer cells by lysing bacilli-infected macrophages via a Fas-Independent
granule exocytosis pathway
■ Fas-FasL interaction : apoptotic death of M. tuberculosis-Infected target cells
■ M. tuberculosis specificity, recognize mycobacterial antigens,
production of IFN-r / TNF-α on stimulation with M. tuberculosis

Carranza and coworkers
■ M. tuberculosis growth control by alveolar macrophages and autologous
blood CD4 and CD8 T cells
■ healthy household contacts: CD8 T cells significantly increased control of
bacillary growth by autologous alveolar macrophages
■ unexposed community contacts: no CD8 T cells to growth control
■ two groups: no CD4 T cells to increase bacillary growth control
■ no correlation between IFN-r and NO concentrations and growth control
of M. tuberculosis by alveolar macrophages and CD8 T cells
■ circulating M. tuberculosis-specific CD8 effector T cells of host
: expanded systemically after bacillary exposure, recruitment of M.
tuberculosis-specific CD8 T cells from blood to local sites of
inflammation in lungs => important role in control of initial infection
■ useful insights relevant to the development of vaccines and other
immunotherapeutic strategies

Roy and coworkers
■ M. tuberculosis-infected mice with single cycle of high-dose i.v. Ig
: reduced bacillary loads in the spleen and lungs
■ T cells infiltrating the lungs: small increases in CD8, not CD4 T-cell

Irwin and coworkers
■ antigen-specific CD8 T cells in lungs of mice immunized with TB vaccine
candidate Mtb72F
■ CD8 T cells recognizing an immunodominant Mtb32-specific epitope
: detected in significant numbers over the course of infection in mice
exposed to low-dose aerosol challenge with M. tuberculosis, prior
vaccination substantially increased the number of these cells at early
time points in lungs
■ Effector cells : demonstrated by secretion of IFN-r, granzyme B
■ as the infection progressed, many activated CD8 T cells down-regulated
expression of CD45RB and up-regulated expression of IL-7 receptor α
chain, indicating their transition to a memory state
■ M. tuberculosis-specific CD8 T cells can be targeted by vaccination with
the Mtb72F polyprotein

Dheda and coworkers
■ in vivo and in vitro studies of IL-4δ2 in pulmonary tuberculosis
■ objective : evaluate the levels of mRNA encoding IL-4 and IL-4δ2
: their relationship to clinical and Tx parameters in cells from
BAL and blood of pts with pulmonary TB
■
■
IL-4δ2, IL-4, IFN-r, soluble CD30 level: by PCR and immunoassays
29 pts with TB vs. control lacking responses to M. tuberculosis-specific Ag
■
■
■
TB pts: higher levels of mRNA for IL-4, IL-4δ2 in T-cell and non–T-cell
control subjects: low levels of IL-4 and IL-4δ2 mRNA, mainly by non–T cell
Radiologic extent of disease: correlated with IL-4/IFN-r ratio, soluble CD30
■
anti-TB chemotherapy => IL-4 mRNA (unchanged levels) ,
IL-4δ2 levels (increased in parallel with IFN-r)
■
immunologic response driven by M. tuberculosis Ag// IL-4 and IL-4δ2
: important in pathogenesis of tuberculosis
IL-4/IL-4δ2 ratio
: altered by treatment, possible marker of disease activity
■

Rook and coworkers
■ geographic variation in efficacy of BCG might be related to presence
of a cross-reactive background Th2-like response (probably
attributable to exposure of mother and infant to helminthes and
environmental mycobacteria) that stops M. tuberculosis from being
pushed into latent state by protective Th1 response ?
■
■

successful vaccine, rather than concentrating solely on Th1 response,
might need to suppress the preexisting subversive Th2-like component
Other means of addressing the Th1 and Th2 balance were also
explored by investigators worldwide
Silva and coworkers
■ Immunotherapy with plasmid DNA encoding the Mycobacterium leprae
65-kD heat-shock protein in association with anti-tuberculosis
chemotherapy
: more rapid and efficient form of Tx for murine TB
■
This adjunctive immunomodulation may have a potential role
in shortening the duration of chemotherapy
DIAGNOSIS OF TUBERCULOSIS INFECTION
 IFN-r release tests
■
might improve specificity and sensitivity in diagnosis of latent tuberculosis
infection as compared with conventional TST

The QuantiFeron-TB Gold (QFT-Gold; Cellestis Ltd., Victoria, Australia)
■ promising results in selected groups of study subjects
■ unclear whether this test would perform well in unselected pt population
independently evaluated for possible tuberculosis infection

Ferrara and coworkers
■ QFT-Gold test in unselected pts for its agreement with TST
■ 68/318pts (21.4%) : indeterminate test results, with significant
overrepresentation among pts negative TST (28.9% vs 6.6%)
■ QFT-Gold indeterminate results : more frequently among pts receiving
immunosuppressive therapy
■ After exclusion of indeterminate results, the concordance between QFTGold and TST was significantly lower in BCG-vaccinated pts
■ 11 pts with active TB: QFT-Gold more positive results than TST
■ QFT-Gold test: feasible for routine hospital use in diagnosing tb infection

Ravn and coworkers
■ Quantiferon-TB RD1 (QFT-RD1) test, using M. tuberculosis-specific Ag, in
diagnosis of active tuberculosis
■ sensitivity of QFT-RD1 : 85%, higher than microscopy(42%)/ culture(59%)
■ test for tuberculosis infection rather than disease itself
■ Positive result is difficult to interpret in areas with a high background
prevalence of latent TB infection

FDA
■ approved the QFTGold test
■ evaluating the enzyme-linked immunospot (ELISPOT) assay

ELISPOT test
■ detects individual cytokine-producing T cells
■ marketed as the T SPOT-TB test (Oxford Immunotec, Oxford, UK)

Shams and coworkers
■
■
■
■
■
■
ELISPOT vs. TST, for detecting latent TB infection in contacts of pts with TB
Because of the absence of a gold standard for latent tuberculosis infection,
sensitivity and specificity of ELISPOT and TST could not be directly measured
latent TB infection by contact score (quantified exposure to and infectiousness
of the index case), relationship of contact score to ELISPOT and TST results
positive ELISPOT and TST: increased significantly with rising contact scores
contact score: more strongly related to the ELISPOT than to the TST results,
not statistically significant difference d/t limited sample size
BCG-vaccinated pt: significantly more positive TST than positive ELISPOT
■
ELISPOT : at least as sensitive as TST for diagnosis of latent TB infection in
contacts of pts with TB, more specific than TST in BCG-vaccinated subjects
■
This improved specificity : corroborates the results of study conducted in
endemic tropical setting
=> potential value in reducing the number of falsepositive diagnoses, thus saving unwarranted Tx
with cost and toxicity

study in Korea with intermediate tuberculosis burden
■ whole-blood IFN-r assay : better indicator of risk of M. tuberculosis
infection than TST in a BCG-vaccinated population

study of children with the clinical diagnosis of tuberculosis
■ detectable response to M. tuberculosis-specific Ag, ESAT-6, or culture
filtrate protein 10 (CFP-10)
: 70% of subjects, more frequently in those with culture-proven disease
■ M. tuberculosis-specific ELISPOT testing
: promising tool for diagnosis of TB in children,
as its interpretation is less likely affected by the lower background
prevalence of latent TB infection in child
■ Another study
: Use of combined peptide spot counts and fusion protein of ESAT6/CFP-10 could improve the sensitivity of testing for optimal diagnosis
of latent tuberculosis infection

Recent study from Gambia
■ quantitative purified protein derivative (PPD) skin test and PPD
ELISPOT, in healthy household contacts of index pts with smear/culture-positive TB
■ in ESAT-6-/ CFP-10-positive subjects
=> Both PPD skin test reaction size and PPD ELISPOT count
: larger
=> only ELISPOT count : sensitive to the exposure gradient
■ number of positive spots increased significantly with exposure,
thus implicating its potential value in reflecting the infectious load in
recent exposure

One recent report
■ ELISPOT test could perform well in diagnosing TB infection among
HIV-positive subjects, including those with low CD4 T-lymphocyte
count
TREATMENT OF TUBERCULOSIS

rifapentine (RPE)
■ RPE 600 mg once weekly : higher relapse rates of TB than thriceweekly or twice-weekly rifampin (RMP)
■ in HIV-positive subjects, monoresistance to rifamycin could emerge
when these pts relapsed after RPE Tx

Sirgel and coworkers
■ early bactericidal activity (EBA) & pharmacokinetics of RPE, RMP
■ objective : determine the dose size of RPE that could provide
adequate drug exposure to prevent mycobacterial regrowth
■ initial 5 d of Tx, 123 pts with newly diagnosed, previously untreated,
and strongly smear-positive pulmonary TB in South Africa
■ randomly Tx groups
: (1) RPE 300 mg qd, (2) RPE 600 mg qd, (3) RPE 900 mg qd,
(4) RPE 1,200 mg qd, (5) RMP 150 mg for five daily doses,
(6) RMP 300 mg for five daily doses, or (7) RMP 600 mg for five
daily doses
■
■
■
■
EBAs for both rifamycins : quite similar
=> linear relationship to log dose at lower doses and
curvilinear response at higher doses, with a likely plateau
at 1,136 mg for RPE
1,200-mg dose of RPE : improve response, prevent regrowth
difficult to assume that measures of EBA can adequately guide the dosing
of a rifamycin that has a predominant effect on dormant bacilli or persisters
validated surrogate markers are urgently needed to assess the sterilizing
potential of drugs currently in use or under development

rifabutin-based therapy
■ RMP: well-documented interaction with some highly active antiretroviral
agents, especially HIV protease inhibitors
■ much less effect due to its lower enzyme inducing activity on cytochrome
P450 family
■ better choice for treatment of HIV-tuberculosis

Burman and coworkers
■ pts with culture-positive TB, treated with 2 mo of rifabutin, isoniazid,
pyrazinamide, and ethambutol (daily, thrice weekly, or twice weekly)
followed by 4 mo of twice-weekly rifabutin plus isoniazid
■ Most pts : advanced HIV disease
■ 9 pts (5.3%) : treatment failure or relapse
■ 8/9 pts (89%) : M. tuberculosis isolates with acquired rifamycin resistance,
associated with low CD4 lymphocyte count (<100/mm3)
■ intermittent rifabutin-based therapy for HIV-related TB
: high risk of failure or relapse in presence of significant
immunosuppression

A study undertaken in New York City furnished
■ HIV-infected pts treated with a RMP-based regimen alone
: higher risk of relapse and acquired RMP resistance if intermittent
dosing of RMP was started during intensive phase of treatment
■ Association: pts with CD4 cell counts <100 cu/mm
■ risk for acquired rifamycin resistance among HIV-infected pts with TB
: not rifamycin used but rifamycin dosing schedule in intensive
phase of treatment

Weiner and coworkers
■ pts with HIV and TB, after adjustment for CD4 T-cell count,
mean rifabutin drug exposure was significantly lower in those with
failure or relapse associated with acquired rifamycin-resistant
mycobacteria (ARR failure or relapse) than those without
■ median isoniazid drug exposure was not significantly associated with
ARR failure or relapse
■ in multivariate logistic regression model: adjusted for rifabutin drug
exposure, a lower isoniazid drug exposure was also associated with
ARR failure or relapse
■ lower plasma concentrations of rifabutin, and perhaps isoniazid,
were associated with ARR (acquired rifamycin-resistant mycobacteria)
failure or relapse in pts with TB and HIV infection treated with twiceweekly anti-tuberculosis therapy

Ethambutol
■ Ocular toxicity, especially in the elderly population

retrospective analysis by Griffith and coworkers
■ pts enrolled in six prospective treatment protocols for M. avium
complex lung disease that included ethambutol, 50 pts (22%) were
known to have preexisting ocular disease
■ While receiving ethambutol, 42% of pts consulted an ophthalmologist,
and 10% stopped ethambutol, at least temporarily
■ 8/ 139 (6%) on daily therapy => ethambutol-related ocular toxicity,
0/ 90 (0%) on intermittent therapy => no problem
■ All pts with such ocular toxicity developed symptoms between
outpatient clinic appointments ; none were diagnosed with routine
visual acuity and color vision testing
■ All pts returned to baseline ocular status after discontinuation of EMB
■ limitations of this study
: visual examination was not performed routinely
: no single diagnostic test of ethambutol toxicity

prospective study by Goyal and colleagues
■ Visual parameters: best-corrected visual acuity, papillary reactions,
optic disc changes, color vision, contrast sensitivity, pupil cycle time,
visual field charting, and visual evoked potential => examined on a
monthly
■ Ethambutol-induced toxicity : 10% of patients
■ maximum visual recovery : first 6 to 8 wks after stopping ethambutol
■ Visual recovery : complete in only one pt, partial in the other two pts

earlier analysis from Great Britain
■ 8 out of 10 pts with ocular toxicity were picked up as a result of routine
eye examinations at follow-up appointments and only two of these pts
were symptomatic
■ appropriate to monitor visual acuity and color discrimination during the
course of ethambutol therapy
■ Intermittent therapy with ethambutol : safer than daily therapy in terms
of ocular toxicity and this merits further evaluation

animal studies, RPE
■ long-acting cyclopentyl rifamycin
■ currently used together with INH during once-weekly continuation Tx
for pulmonary TB
■ HIV-positive pts, those with cavitary disease
: higher rates of Tx failure or relapse, risk of acquired rifamycin
monoresistance
■ once-weekly INH and RPE
: less active than thrice- or twice-weekly Tx
■
Increase of the once weekly dose of RPE from 10 to 15 mg/kg
: significantly improve the pharmacokinetic parameters of the drug

animal studies, moxifloxcin
■ 8-methoxy fluoroquinolone, long half-life and potent bactericidal and
good sterilizing activities
■

reduce the time to culture conversion in murine TB, producing a stable
cure (without relapse) in the same animal model
Rosenthal and coworkers, murine model of tuberculosis
■ sterilizing activity of once-weekly moxifloxacin plus RPE (15 mg/kg)
: significantly greater than that twice-weekly regimen of INH plus RMP
■ efficacy : once-weekly INH + RPE continuation Tx
< moxifloxacin + RPE(15 mg/kg)

9-mo daily monotherapy with isoniazid
■ Currently recommended as first-line Tx for latent TB infection
■ Alternatively, 4-mo course of daily RMP, but efficacy remained untested

priorities for developing better Tx of latent TB infection
■ evaluating regimens
(1) administered for a shorter duration and/or wider intervals and
(2) effective against MDR- M. tuberculosis
■ RPE, the long-acting rifamycin : considerable appeal
■ empiric therapy of latent TB infection after exposure to MDR- TB
: PZA + either EMB or fluoroquinolone for 6-12 mo,
but pertinent clinical data in support of this treatment are lacking

Nuermberger and coworkers
■ several new Tx regimens for latent TB infection using a previously
validated murine model comprising mice immunized with M. bovis BCG to
augment host immunity before infection with M. tuberculosis H37Rv
■ 3-mo once-weekly RPE-containing regimens vs. 6-mo moxifloxacincontaining regimens vs. INH monotherapy control regimens
■ 3-mo once-weekly regimens of RPE + either isoniazid or moxifloxacin
: active as daily INH for 6 - 9 mo
■ 6-mo daily moxifloxacin + PZA, EMB or ethionamide
: more active than PZA + EMB
: regimen recommended for therapy for possible latent TB infection after
exposure to MDR- TB
■ moxifloxacin + experimental nitroimidazopyran PA-824
: especially active
■ Hsp65 DNA vaccine alone had no anti-tuberculosis effect in murine model,
but augment the mycobactericidal activity of moxifloxacin
■
RPE, moxifloxacin, therapeutic DNA vaccination
: might have the potential to improve on current therapy for latent TB
infection