mg/L could be considered as a clinical breakpoint for moxifloxacin, provided
other investigators can confirm our findings.
PMID: 20332195 [PubMed - in process]
3. Vaccine. 2010 Apr 30;28(20):3571-81. Epub 2010 Mar 11.
Ag85B-ESAT-6 adjuvanted with IC31 promotes strong and long-lived Mycobacterium
tuberculosis specific T cell responses in naïve human volunteers.
van Dissel JT, Arend SM, Prins C, Bang P, Tingskov PN, Lingnau K, Nouta J,
Leiden University Medical Center, Department of Infectious Diseases, Leiden, The
Netherlands. j.t.van_dissel@lumc.nl
Though widely used, the BCG vaccine has had little apparent effect on rates of
adult pulmonary tuberculosis. Moreover, the risk of disseminated BCG disease in
immunocompromised individuals means that improved TB vaccines ideally need to be
able to efficiently prime mycobacterially-naïve individuals as well as boost
individuals previously vaccinated with BCG. Protective immunity against
Mycobacterium tuberculosis is thought to depend on the generation of a Th1-type
cellular immune response characterized by interferon-gamma (IFN-gamma)
production. In the present study, we monitored safety and IFN-gamma responses in
healthy TB-naïve humans receiving an entirely novel vaccine, composed of the
fusion protein Ag85B-ESAT-6, administered at 0 and 2 months either as recombinant
protein alone or combined with two concentrations of the novel adjuvant IC31.
Vaccination did not cause local or systemic adverse effects besides transient
soreness at the injection site, but it elicited strong antigen-specific T cell
responses against H1 and both the Ag85B and the ESAT-6 components. These strong
responses persisted through 2.5 years of follow-up, indicating the induction of a
substantial memory response in the vaccine recipients. (c) 2010 Elsevier Ltd. All
rights reserved.
PMID: 20226890 [PubMed - in process]
4. Cell. 2010 Mar 5;140(5):731-43.
Genome-wide analysis of the host intracellular network that regulates survival of
Mycobacterium tuberculosis.
Kumar D, Nath L, Kamal MA, Varshney A, Jain A, Singh S, Rao KV.
Immunology Group, International Centre for Genetic Engineering and Biotechnology,
Aruna Asaf Ali Marg, New Delhi 110067, India.
We performed a genome-wide siRNA screen to identify host factors that regulated
pathogen load in human macrophages infected with a virulent strain of
Mycobacterium tuberculosis. Iterative rounds of confirmation, followed by
validation, identified 275 such molecules that were all found to functionally
associate with each other through a dense network of interactions. This network
then yielded to a molecular description of the host cell functional modules that
were both engaged and perturbed by the pathogen. Importantly, a subscreen against
a panel of field isolates revealed that the molecular composition of the host
interface varied with both genotype and the phenotypic properties of the
pathogen. An analysis of these differences, however, permitted identification of
those host factors that were invariantly involved, regardless of the
diversification in adaptive mechanisms employed by the pathogen. Interestingly,
these factors were found to predominantly function through the regulation of
autophagy. (c) 2010 Elsevier Inc. All rights reserved.
PMID: 20211141 [PubMed - indexed for MEDLINE]
5. Tuberculosis (Edinb). 2010 Mar;90(2):71-83. Epub 2010 Mar 4.
Current findings, challenges and novel approaches in human genetic susceptibility
to tuberculosis.
Möller M, Hoal EG.
Molecular Biology and Human Genetics, MRC Centre for Molecular and Cellular
Biology and the DST/NRF Centre of Excellence for Biomedical TB Research, Faculty
of Health Sciences, P.O. Box 19063, Stellenbosch University, Tygerberg 7505,
South Africa.
The evidence for a human genetic component in susceptibility to tuberculosis (TB)
is incontrovertible. Quite apart from studies of rare disease events illustrating
the importance of key genes in humans and animals, TB at the population level is
also influenced by the genetics of the host. Heritability of disease concordance
and immune responses to mycobacterial antigens has been clearly shown, and ranges
up to 71%. Linkage studies, designed to identify major susceptibility genes in a
disease, have produced a number of candidate loci but few, except for regions on
chromosome 5p15, 20p and 20q, have been replicated. The region on 5p15 regulates
the intensity of the response to the tuberculin skin test, and another locus on
11p14 appears to control resistance to the bacterium. In addition, numerous genes
and pathways have been implicated in candidate gene association studies, with
validation of polymorphisms in IFNG, NRAMP1, and NOS2A and equivocal results for
IL10, CCL2, DC-SIGN, P2RX7, VDR, TLR2, TLR9 and SP110. Other more recently
researched candidate genes such as TNFRSF1B remain to be validated, preferably in
meta-analyses. New approaches have provided early evidence for the importance of
gene-gene interactions in regulating resistance to disease, and also the prospect
that applying host genetics in the field of vaccinomics could lead to a more
targeted approach in designing interventions to aid the human immune system in
combating mycobacteria. Genome-wide association studies and admixture mapping are
approaches that remain to be applied to TB, and it is not clear, as is the case
with other complex diseases, how much of the heritability of the TB
susceptibility phenotype will be determined by multiple genes of small effect
versus rare variants with disproportionately large effects.
PMID: 20206579 [PubMed - in process]
6. J Mol Biol. 2010 Apr 23;398(1):54-65. Epub 2010 Mar 3.
Unusual conformation of the SxN motif in the crystal structure of
penicillin-binding protein A from Mycobacterium tuberculosis.
Fedarovich A, Nicholas RA, Davies C.
Department of Biochemistry and Molecular Biology, Medical University of South
Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA.
PBPA from Mycobacterium tuberculosis is a class B-like penicillin-binding protein
(PBP) that is not essential for cell growth in M. tuberculosis, but is important
for proper cell division in Mycobacterium smegmatis. We have determined the
crystal structure of PBPA at 2.05 A resolution, the first published structure of
a PBP from this important pathogen. Compared to other PBPs, PBPA has a relatively
small N-terminal domain, and conservation of a cluster of charged residues within
this domain suggests that PBPA is more related to class B PBPs than previously
inferred from sequence analysis. The C-terminal domain is a typical
transpeptidase fold and contains the three conserved active-site motifs
characteristic of penicillin-interacting enzymes. Whilst the arrangement of the
SxxK and KTG motifs is similar to that observed in other PBPs, the SxN motif is
markedly displaced away from the active site, such that its serine (Ser281) is
not involved in hydrogen bonding with residues of the other two motifs. A
disulfide bridge between Cys282 (the "x" of the SxN motif) and Cys266, which
resides on an adjacent loop, may be responsible for this unusual conformation.
Another interesting feature of the structure is a relatively long connection
between beta 5 and alpha 11, which restricts the space available in the active
site of PBPA and suggests that conformational changes would be required to
accommodate peptide substrate or beta-lactam antibiotics during acylation.
Finally, the structure shows that one of the two threonines postulated to be
targets for phosphorylation is inaccessible (Thr362), whereas the other (Thr437)
is well placed on a surface loop near the active site. (c) 2010 Elsevier Ltd. All
rights reserved.
PMCID: PMC2854034 [Available on 2011/4/23]
PMID: 20206184 [PubMed - indexed for MEDLINE]
7. J Immunol. 2010 Apr 1;184(7):3326-30. Epub 2010 Mar 3.
Caspase-1 independent IL-1beta production is critical for host resistance to
mycobacterium tuberculosis and does not require TLR signaling in vivo.
Mayer-Barber KD, Barber DL, Shenderov K, White SD, Wilson MS, Cheever A, Kugler
D, Hieny S, Caspar P, Núñez G, Schlueter D, Flavell RA, Sutterwala FS, Sher A.
Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of
Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
20892, USA.
To investigate the respective contributions of TLR versus IL-1R mediated signals
in MyD88 dependent control of Mycobacterium tuberculosis, we compared the outcome
of M. tuberculosis infection in MyD88, TRIF/MyD88, IL-1R1, and IL-1beta-deficient
mice. All four strains displayed acute mortality with highly increased pulmonary
bacterial burden suggesting a major role for IL-1beta signaling in determining
the MyD88 dependent phenotype. Unexpectedly, the infected MyD88 and
TRIF/MyD88-deficient mice, rather than being defective in IL-1beta expression,
displayed increased cytokine levels relative to wild-type animals. Similarly,
infected mice deficient in caspase-1 and ASC, which have critical functions in
inflammasome-mediated IL-1beta maturation, showed unimpaired IL-1beta production
and importantly, were considerably less susceptible to infection than IL-1beta
deficient mice. Together our findings reveal a major role for IL-1beta in host
resistance to M. tuberculosis and indicate that during this infection the
cytokine can be generated by a mechanism that does not require TLR signaling or
caspase-1.
PMID: 20200276 [PubMed - in process]
8. Tuberculosis (Edinb). 2010 Mar;90(2):145-51. Epub 2010 Feb 26.
Breath biomarkers of active pulmonary tuberculosis.
Phillips M, Basa-Dalay V, Bothamley G, Cataneo RN, Lam PK, Natividad MP,
Menssana Research Inc., 1 Horizon Road, Suite 1415, Fort Lee, NJ 07024-6510, USA.
mphillips@menssanaresearch.com
BACKGROUND: Volatile organic compounds (VOCs) in breath may contain biomarkers of
active pulmonary tuberculosis derived from the infectious organism (metabolites
of Mycobacterium tuberculosis) and from the infected host (products of oxidative
stress). METHODS: We analyzed breath VOCs in 226 symptomatic high-risk patients
in USA, Philippines, and UK, using gas chromatography/mass spectroscopy.
Diagnosis of disease was based on sputum culture, smear microscopy, chest
radiography and clinical suspicion of tuberculosis (CSTB). Chromatograms were
converted to a series of 8s overlapping time slices. Biomarkers of active
pulmonary tuberculosis were identified with a Monte Carlo analysis of time-slice
alveolar gradients (abundance in breath minus abundance in room air). RESULTS:
Breath VOCs contained apparent biomarkers of active pulmonary tuberculosis
comprising oxidative stress products (alkanes and alkane derivatives) and
volatile metabolites of M. tuberculosis (cyclohexane and benzene derivatives).
Breath biomarkers identified active pulmonary tuberculosis with C-statistic (area
under curve of receiver operating characteristic)=0.85 (i.e. 85% overall
accuracy, sensitivity=84.0%, specificity=64.7%) when sputum culture, microscopy,
and chest radiography were either all positive or all negative. Employing a
single criterion of disease, C-statistic=0.76 (smear microscopy), 0.68 (sputum
culture), 0.66 (chest radiography) and 0.65 (CSTB). CONCLUSION: A breath test
identified apparent biomarkers of active pulmonary tuberculosis with 85% accuracy
in symptomatic high-risk subjects.
PMID: 20189456 [PubMed - in process]
9. Tuberculosis (Edinb). 2010 Mar;90(2):135-42. Epub 2010 Feb 25.
Experimental tuberculosis: designing a better model to test vaccines against
tuberculosis.
Morais Fonseca D, Rosada RS, e Paula MO, Wowk PF, Franco LH, Soares EG, Silva CL,
Núcleo de Pesquisas em Tuberculose, Departamento de Bioquímica e Imunologia,
Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Av.
Bandeirantes, 3900, CEP 14049-900 Ribeirão Preto, SP, Brazil.
denise@cpt.fmrp.usp.br
Experimental models of infection are good tools for establishing immunological
parameters that have an effect on the host-pathogen relationship and also for
designing new vaccines and immune therapies. In this work, we evaluated the
evolution of experimental tuberculosis in mice infected with increasing bacterial
doses or via distinct routes. We showed that mice infected with low bacterial
doses by the intratracheal route were able to develop a progressive infection
that was proportional to the inoculum size. In the initial phase of disease, mice
developed a specific Th1-driven immune response independent of inoculum
concentration. However, in the late phase, mice infected with higher
concentrations exhibited a mixed Th1/Th2 response, while mice infected with lower
concentrations sustained the Th1 pattern. Significant IL-10 concentrations and a
more preeminent T regulatory cell recruitment were also detected at 70 days
post-infection with high bacterial doses. These results suggest that mice
infected with higher concentrations of bacilli developed an immune response
similar to the pattern described for human tuberculosis wherein patients with
progressive tuberculosis exhibit a down modulation of IFN-gamma production
accompanied by increased levels of IL-4. Thus, these data indicate that the
experimental model is important in evaluating the protective efficacy of new
vaccines and therapies against tuberculosis.
PMID: 20188631 [PubMed - in process]
10. Eur J Clin Pharmacol. 2010 Mar;66(3):261-7.
Is there any difference between acetylator phenotypes in tuberculosis patients
and healthy subjects?
Khalili H, Dashti-Khavidaki S, Amini M, Mahjub R, Hajiabdolbaghi M.
Department of Pharmacotherapy, Tehran University of Medical Sciences, Iran.
khalilih@tums.ac.ir
BACKGROUND AND PURPOSE: Many studies have been done to determine the distribution
of acetylator phenotypes among populations of different geographic origin. The
goal of this study was to investigate the acetylator phenotypes of the Iranian
population and compare them between tubercular patients and healthy subjects.
METHODS: The study population consisted of two groups; the first group included
100 newly diagnosed tubercular patients and the second group consisted of 100
healthy subjects. Acetylator phenotype was determined from the metabolic ratio of
acetyl-isoniazid to isoniazid in the plasma samples. Metabolic ratio was used to
classify subjects as slow (= or < 0.70) or fast acetylators (>0.70). RESULTS: In
the tubercular patients, the frequencies of slow and fast acetylator phenotypes
were 62 and 38%, respectively. Of the healthy individuals, 45% were found to be
slow acetylators and the remaining 55% were fast acetylators. CONCLUSION: It
seems that tubercular patients metabolize isoniazid more slowly than healthy
individuals.
PMID: 20187288 [PubMed - in process]
11. Lancet Infect Dis. 2010 Mar;10(3):176-83.
Tuberculosis and air travel: a systematic review and analysis of policy.
Abubakar I.
University of East Anglia, Norwich, UK. i.abubakar@uea.ac.uk
WHO international guidelines for the control of tuberculosis in relation to air
travel require-after a risk assessment-tracing of passengers who sat for longer
than 8 h in rows adjacent to people with pulmonary tuberculosis who are smear
positive or smear negative. A further recommendation is that all commercial air
travel should be prohibited until the person has two consecutive negative sputum
smears for drug-susceptible tuberculosis or two consecutive cultures for
multidrug-resistant tuberculosis. In this Review I examine the evidence put
forward to support these recommendations and assess whether such an approach is
justifiable. A systematic review identified 39 studies of which 13 were included.
The majority of studies found no evidence of transmission. Only two studies
reported reliable evidence of transmission. The analysis suggests that there is
reason to doubt the value of actively screening air passengers for infection with
Mycobacterium tuberculosis and that the resources used might be better spent
addressing other priorities for the control of tuberculosis. 2010 Elsevier Ltd.
All rights reserved.
PMID: 20185096 [PubMed - indexed for MEDLINE]
12. J Infect Dis. 2010 Mar 15;201(6):881-8.
Mutations in extensively drug-resistant Mycobacterium tuberculosis that do not
code for known drug-resistance mechanisms.
Motiwala AS, Dai Y, Jones-López EC, Hwang SH, Lee JS, Cho SN, Via LE, Barry CE,
Division of Infectious Disease, Department of Medicine, and the Ruy V. Lourenço
Center for the Study of Emerging and Reemerging Pathogens, New Jersey Medical
School, University of Medicine and Dentistry of New Jersey, Newark, NJ 07103,
USA.
BACKGROUND: Highly lethal outbreaks of multidrug-resistant (MDR) and extensively
drug-resistant (XDR) tuberculosis are increasing. Whole-genome sequencing of
KwaZulu-Natal MDR and XDR outbreak strains prevalent in human immunodeficiency
virus (HIV)-infected patients by the Broad Institute identified 22 novel
mutations which were unique to the XDR genome or shared only by the MDR and XDR
genomes and not already known to be associated with drug resistance. METHODS: We
studied the 12 novel mutations which were not located in highly-repetitive genes
to identify mutations that were truly associated with drug resistance or were
likely to confer a specific fitness advantage. RESULTS: None of these mutations
could be found in a phylogenetically and geographically diverse set of
drug-resistant and drug-susceptible Mycobacterium tuberculosis isolates,
suggesting that these mutations are unique to the KZN clone. Examination of the
600-basepair region flanking each mutation revealed 26 new mutations. We searched
for a convergent evolutionary signal in the new mutations for evidence that they
emerged under selective pressure, consistent with increased fitness. However, all
but 1 rare mutation were monophyletic, indicating that the mutations were markers
of strain phylogeny rather than fitness or drug resistance. CONCLUSIONS: Our
results suggest that virulent XDR tuberculosis in immunocompromised HIV-infected
patients can evolve without generalizable fitness changes or other XDR-specific
mutations.
PMCID: PMC2826498 [Available on 2011/3/15]
PMID: 20136412 [PubMed - indexed for MEDLINE]
13. Proc Natl Acad Sci U S A. 2010 Mar 16;107(11):5154-9. Epub 2010 Jan 20.
Lsr2 is a nucleoid-associated protein that targets AT-rich sequences and
virulence genes in Mycobacterium tuberculosis.
Gordon BR, Li Y, Wang L, Sintsova A, van Bakel H, Tian S, Navarre WW, Xia B,
Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8,
Canada.
Bacterial nucleoid-associated proteins play important roles in chromosome
organization and global gene regulation. We find that Lsr2 of Mycobacterium
tuberculosis is a unique nucleoid-associated protein that binds AT-rich regions
of the genome, including genomic islands acquired by horizontal gene transfer and
regions encoding major virulence factors, such as the ESX secretion systems, the
lipid virulence factors PDIM and PGL, and the PE/PPE families of antigenic
proteins. Comparison of genome-wide binding data with expression data indicates
that Lsr2 binding results in transcriptional repression. Domain-swapping
experiments demonstrate that Lsr2 has an N-terminal dimerization domain and a
C-terminal DNA-binding domain. Nuclear magnetic resonance analysis of the
DNA-binding domain of Lsr2 and its interaction with DNA reveals a unique
structure and a unique mechanism that enables Lsr2 to discriminately target
AT-rich sequences through interactions with the minor groove of DNA. Taken
together, we provide evidence that mycobacteria have employed a structurally
distinct molecule with an apparently different DNA recognition mechanism to
achieve a function similar to the Enterobacteriaceae H-NS, likely coordinating
global gene regulation and virulence in this group of medically important
bacteria.
PMCID: PMC2841939
PMID: 20133735 [PubMed - in process]
14. Int J Tuberc Lung Dis. 2010 Mar;14(3):347-55.
Effector memory T-cells dominate immune responses in tuberculosis treatment:
antigen or bacteria persistence?
Tapaninen P, Korhonen A, Pusa L, Seppälä I, Tuuminen T.
Department of Bacteriology and Immunology, University of Helsinki, Helsinki,
Finland. pekka.tapaninen@helsinki.fi
OBJECTIVE: To compare ex vivo immunological responses upon stimulation of
lymphocytes with Mycobacterium tuberculosis-specific antigens in three groups: 1)
subjects diagnosed with tuberculosis (TB) in the early 1940s and 1950s but who
did not receive anti-tuberculosis chemotherapy (n = 5), 2) subjects treated with
anti-tuberculosis agents prior to the rifampicin (RMP) era (n = 26) and 3)
subjects who received RMP as a part of modern combination therapy (n = 7).
DESIGN: A total of 38 healthy subjects, mean age 70 +/- 13 years, with a history
of previously treated TB were recruited. Peripheral blood mononuclear cells were
collected and analysed as a batch by ELISpot. Representative samples with high
reactivities were further immunophenotypically characterised. RESULTS: No
differences between the studied groups were detected with regard to the
frequencies of reactive lymphocytes. The dominant immunophenotypic profile of the
representative responders, irrespective of the treatment schemes, was
CD4+CD45RO+CD45RA-CD27-CD28-CCR7-, compatible with the fast reacting effector
memory T-cell lineage (T(EM)). CONCLUSION: Specific T(EM) cells persist even in
subjects treated for TB decades ago with modern anti-tuberculosis chemotherapy.
Additional studies are needed to address the question of what drives the survival
of T(EM) after adequate treatment: persistence of antigens or bacteria.
PMID: 20132627 [PubMed - in process]
15. Int J Tuberc Lung Dis. 2010 Mar;14(3):269-74.
Global policies and practices for managing persons exposed to multidrug-resistant
tuberculosis.
Cain KP, Nelson LJ, Cegielski JP.
Division of Tuberculosis Elimination, and Epidemic Intelligence Service, Centers
for Disease Control and Prevention, Atlanta, Georgia, USA. kcain@cdc.gov
SETTING: In the 1960s, treatment for latent tuberculosis infection (LTBI) with
isoniazid proved to be so effective, safe, and inexpensive that research into
alternative treatments virtually ceased. Now that multidrug-resistant
tuberculosis (MDR-TB) is widespread, no data are available to guide the
management of persons exposed to MDR-TB (contacts). METHODS: We surveyed National
TB Program directors and MDR-TB program managers about current practices for
managing MDR-TB contacts in countries with an MDR-TB prevalence of >2% in new
patients and those with programs for managing MDR-TB. RESULTS: Of 35 countries
that met the survey criteria, 25 (71%) responded; 24 of these (96%) have a
guideline for managing TB contacts. Of these, 19 (76%) usually or always
evaluated contacts and treated LTBI. In contrast, 10 (40%) countries reported
having a guideline for managing MDR-TB contacts, 11 (44%) usually or always
evaluated MDR-TB contacts, and 9 (36%) treated LTBI. Only two (8%) used a regimen
that has activity against MDR-TB. Lack of evidence or guidelines was the main
reason for not treating MDR-TB contacts. CONCLUSIONS: Management of MDR-TB
contacts is inconsistent and ineffective due to lack of evidence-based
guidelines. There is an urgent need to generate evidence to guide policy.
PMID: 20132616 [PubMed - in process]
16. Protein Sci. 2010 Mar;19(3):458-74.
Isoniazid-resistance conferring mutations in Mycobacterium tuberculosis KatG:
catalase, peroxidase, and INH-NADH adduct formation activities.
Cade CE, Dlouhy AC, Medzihradszky KF, Salas-Castillo SP, Ghiladi RA.
Department of Chemistry, North Carolina State University, Raleigh, North Carolina
27695-8204, USA.
Mycobacterium tuberculosis catalase-peroxidase (KatG) is a bifunctional
hemoprotein that has been shown to activate isoniazid (INH), a pro-drug that is
integral to frontline antituberculosis treatments. The activated species,
presumed to be an isonicotinoyl radical, couples to NAD(+)/NADH forming an
isoniazid-NADH adduct that ultimately confers anti-tubercular activity. To better
understand the mechanisms of isoniazid activation as well as the origins of
KatG-derived INH-resistance, we have compared the catalytic properties (including
the ability to form the INH-NADH adduct) of the wild-type enzyme to 23 KatG
mutants which have been associated with isoniazid resistance in clinical M.
tuberculosis isolates. Neither catalase nor peroxidase activities, the two
inherent enzymatic functions of KatG, were found to correlate with isoniazid
resistance. Furthermore, catalase function was lost in mutants which lacked the
Met-Tyr-Trp crosslink, the biogenic cofactor in KatG which has been previously
shown to be integral to this activity. The presence or absence of the crosslink
itself, however, was also found to not correlate with INH resistance. The KatG
resistance-conferring mutants were then assayed for their ability to generate the
INH-NADH adduct in the presence of peroxide (t-BuOOH and H(2)O(2)), superoxide,
and no exogenous oxidant (air-only background control). The results demonstrate
that residue location plays a critical role in determining INH-resistance
mechanisms associated with INH activation; however, different mutations at the
same location can produce vastly different reactivities that are
oxidant-specific. Furthermore, the data can be interpreted to suggest the
presence of a second mechanism of INH-resistance that is not correlated with the
formation of the INH-NADH adduct.
PMID: 20054829 [PubMed - in process]
17. Antimicrob Agents Chemother. 2010 Mar;54(3):1068-74. Epub 2009 Dec 28.
Pharmacokinetics of antituberculosis drugs in pulmonary tuberculosis patients
with type 2 diabetes.
Ruslami R, Nijland HM, Adhiarta IG, Kariadi SH, Alisjahbana B, Aarnoutse RE, van
Department of Pharmacology, Faculty of Medicine, Padjadjaran University, Jl.
Prof. Eijkman no. 38, Bandung 40161, West Java, Indonesia. n.ruslami@gmail.com
Altered pharmacokinetics of antituberculosis drugs may contribute to an increased
risk of tuberculosis treatment failure for diabetic patients. We previously found
that rifampin exposure was 2-fold lower in diabetic than in nondiabetic
tuberculosis patients during the continuation phase of treatment. We now examined
the influence of diabetes on the pharmacokinetics of antituberculosis drugs in
the intensive phase of tuberculosis treatment, and we evaluated the effect of
glycemic control. For this purpose, 18 diabetic and 18 gender- and body
weight-matched nondiabetic tuberculosis patients were included in an Indonesian
setting. Intensive pharmacokinetic sampling was performed for rifampin,
pyrazinamide, and ethambutol at steady state. The bioavailability of rifampin was
determined by comparing rifampin exposure after oral versus intravenous
administration. Pharmacokinetic assessments were repeated for 10 diabetic
tuberculosis patients after glycemic control. No differences in the areas under
the concentration-time curves of the drugs in plasma from 0 to 24 h postdose
(AUC(0-24)), the maximum concentrations of the drugs in plasma (C(max)), the
times to C(max) (T(max)), and the half-lives of rifampin, pyrazinamide, and
ethambutol were found between diabetic and nondiabetic tuberculosis patients in
the intensive phase of tuberculosis treatment. For rifampin, oral bioavailability
and metabolism were similar in diabetic and nondiabetic patients. The
pharmacokinetic parameters of antituberculosis drugs were not correlated with
blood glucose levels or glucose control. We conclude that diabetes does not alter
the pharmacokinetics of antituberculosis drugs during the intensive phase of
tuberculosis treatment. The reduced exposure to rifampin of diabetic patients in
the continuation phase may be due to increased body weight and possible
differences in hepatic induction. Further research is needed to determine the
cause of increased tuberculosis treatment failure among diabetic patients.
PMCID: PMC2825975 [Available on 2010/9/1]
PMID: 20038625 [PubMed - in process]
18. Antimicrob Agents Chemother. 2010 Mar;54(3):1022-8. Epub 2009 Dec 28.
Rates and mechanisms of resistance development in Mycobacterium tuberculosis to a
novel diarylquinoline ATP synthase inhibitor.
Huitric E, Verhasselt P, Koul A, Andries K, Hoffner S, Andersson DI.
Swedish Institute for Infectious Disease Control, Solna, Sweden.
R207910 (also known as TMC207) is an investigational drug currently in clinical
studies for the treatment of multidrug-resistant (MDR) tuberculosis. It has a
high degree of antimycobacterial activity and is equally effective against
drug-susceptible and MDR Mycobacterium tuberculosis isolates. In the present
study, we characterized the development of resistance to R207910 in vitro.
Ninety-seven independent R207910-resistant mutants were selected from seven
different clinical isolates of M. tuberculosis (three drug-susceptible and four
MDR isolates) at 10x, 30x, and 100x the MIC. At a concentration of 0.3 mg/liter
(10x the MIC), the mutation rates ranged from 4.7 x 10(-7) to 8.9 x 10(-9)
mutations per cell per division, and at 1.0 mg/liter (30x the MIC) the mutation
rate ranged from 3.9 x 10(-8) to 2.4 x 10(-9). No resistant mutants were obtained
at 3 mg/liter (100x the MIC). The level of resistance ranged from 0.12 to 3.84
mg/liter for the mutants identified; these concentrations represent 4- to
128-fold increases in the MICs. For 53 of the resistant mutants, the atpE gene,
which encodes a transmembrane and oligomeric C subunit of the ATP synthase and
which was previously shown to be involved in resistance, was sequenced. For 15/53
mutants, five different point mutations resulting in five different amino acid
substitutions were identified in the atpE gene. For 38/53 mutants, no atpE
mutations were found and sequencing of the complete F0 ATP synthase operon (atpB,
atpE, and atpF genes) and the F1 ATP synthase operon (atpH, atpA, atpG, atpD, and
atpC genes) from three mutants revealed no mutations, indicating other,
alternative resistance mechanisms. Competition assays showed no measurable
reduction in the fitness of the mutants compared to that of the isogenic wild
types.
PMCID: PMC2825986
PMID: 20038615 [PubMed - in process]
19. J Control Release. 2010 Mar 19;142(3):339-46. Epub 2009 Nov 29.
Delivery of rifampicin-PLGA microspheres into alveolar macrophages is promising
for treatment of tuberculosis.
Hirota K, Hasegawa T, Nakajima T, Inagawa H, Kohchi C, Soma G, Makino K, Terada
H.
Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki
Noda, Chiba 278-8510, Japan.
Inhalation delivery of poly(lactic-co-glycolic) acid (PLGA) microspheres (MS)
loaded with the anti-tuberculosis agent rifampicin (RFP-PLGA MS) to alveolar
macrophage (M phi) cells could be an effective drug delivery system for the
treatment of tuberculosis. To examine this possibility, we studied (1) the
bactericidal effect of RFP-PLGA MS on Mycobacterium bovis Bacillus
Calmette-Guérin (BCG)-infected rat alveolar M phi NR8383 cells, and (2) changes
in the biochemical events induced in these cells by the uptake of RFP-PLGA MS.
The amount of intracellular RFP imported into the M phi s by RFP-PLGA MS
containing 0.25 and 2.50 microg RFP/mL was more than twice and ten times,
respectively, than that attained with 5.00 microg/mL of RFP solution; and the MS
exerted more potent bactericidal effect on BCG inside M phi cells than 5.00
microg RFP/mL solution after incubation for 7 days. RFP-PLGA MS little affected
the viability of M phi cells, whereas the polystyrene latex (PSL) MS used as a
reference decreased it significantly. RFP-PLGA MS did not stimulate the
production of tumor necrosis factor-alpha (TNF-alpha), nitric oxide,
interleukin-10 (IL-10), and transforming growth factor-beta1 (TGF-beta1) by the M
phi cells, whereas PSL MS stimulated all of these mediators except IL-10. We
conclude that RFP-PLGA MS are bio-safe microspheres due to their "silent" nature
when taken into M phi cells and that they are promising for the treatment of
tuberculosis by pulmonary inhalation. (c) 2009 Elsevier B.V. All rights reserved.
PMID: 19951729 [PubMed - in process]
20. Adv Drug Deliv Rev. 2010 Mar 18;62(4-5):547-59. Epub 2009 Nov 13.
New old challenges in tuberculosis: potentially effective nanotechnologies in
drug delivery.
Sosnik A, Carcaboso AM, Glisoni RJ, Moretton MA, Chiappetta DA.
The Group of Biomaterials and Nanotechnology for Improved Medicines (BIONIMED),
Department of Pharmaceutical Technology, Faculty of Pharmacy and Biochemistry,
University of Buenos Aires, Buenos Aires CP1113, Argentina. alesosnik@gmail.com
Tuberculosis (TB) is the second most deadly infectious disease. Despite
potentially curative pharmacotherapies being available for over 50 years, the
length of the treatment and the pill burden can hamper patient lifestyle. Thus,
low compliance and adherence to administration schedules remain the main reasons
for therapeutic failure and contribute to the development of multi-drug-resistant
(MDR) strains. Pediatric patients constitute a high risk population. Most of the
first-line drugs are not commercially available in pediatric form. The design of
novel antibiotics attempts to overcome drug resistance, to shorten the treatment
course and to reduce drug interactions with antiretroviral therapies. On the
other hand, the existing anti-TB drugs are still effective. Overcoming
technological drawbacks of these therapeutic agents as well as improving the
effectiveness of the drug by targeting the infection reservoirs remains the
central aims of Pharmaceutical Technology. In this framework, nanotechnologies
appear as one of the most promising approaches for the development of more
effective and compliant medicines. The present review thoroughly overviews the
state-of-the-art in the development of nano-based drug delivery systems for
encapsulation and release of anti-TB drugs and discusses the challenges that are
faced in the development of a more effective, compliant and also affordable TB
pharmacotherapy. Copyright 2009 Elsevier B.V. All rights reserved.
PMID: 19914315 [PubMed - in process]
21. Eur Respir J. 2010 Mar;35(3):606-13. Epub 2009 Aug 28.
Newer fluoroquinolones for treating respiratory infection: do they mask
tuberculosis?
Chang KC, Leung CC, Yew WW, Lau TY, Leung WM, Tam CM, Lam HC, Tse PS, Wong MY,
Centre for Health Protection, Dept of Health, Hong Kong SAR, China.
kc_chang@dh.gov.hk
Possible masking of tuberculosis (TB) in treatment of community-acquired
respiratory infection by newer fluoroquinolones has not been examined in
randomised controlled trials. We undertook a randomised, open-label controlled
trial involving adults with community-acquired pneumonia or infective
exacerbation of bronchiectasis encountered in government chest clinics in Hong
Kong. 427 participants were assigned by random permutated blocks of 20 to receive
either amoxicillin clavulanate (n = 212) or moxifloxacin (n = 215). Participants
were followed for 1 yr for active pulmonary TB. Excluding three participants with
positive baseline culture, 13 developed active pulmonary TB: 10 (4.8%) out of 210
were given amoxicillin clavulanate, and three (1.4%) out of 214 were given
moxifloxacin. The difference was significant by both proportion and time-to-event
analysis. Post hoc analysis showed a significant decrease in the proportion with
active pulmonary TB from 4.8% to 2.4% and 0% among participants given amoxicillin
clavulanate (n = 210), moxifloxacin for predominantly 5 days (n = 127) and 10
days (n = 87), respectively. The log rank test for trend also showed a
significant difference between the three subgroups. Regression models reaffirmed
the linear effect; the adjusted odds ratio (95% confidence interval) of active
pulmonary TB after moxifloxacin exposure up to predominantly 10 days was 0.3
(0.1-0.9). Newer fluoroquinolones appear to mask active pulmonary TB.
PMID: 19717477 [PubMed - in process]
