scholarly journals Lung Tissue Concentrations of Pyrazinamide among Patients with Drug-Resistant Pulmonary Tuberculosis

2017 ◽  
Vol 61 (6) ◽  
Author(s):  
Russell R. Kempker ◽  
M. Tobias Heinrichs ◽  
Ketino Nikolaishvili ◽  
Irina Sabulua ◽  
Nino Bablishvili ◽  
...  
Keyword(s):  
Pulmonary Tuberculosis ◽  
Lung Tissue ◽  
Ex Vivo ◽  
Inverse Correlation ◽  
Drug Resistant ◽  
Tissue Penetration ◽  
Serum Samples ◽  
Tissue Samples ◽  
Content Type ◽  
Antituberculosis Treatment

ABSTRACT Improved knowledge regarding the tissue penetration of antituberculosis drugs may help optimize drug management. Patients with drug-resistant pulmonary tuberculosis undergoing adjunctive surgery were enrolled. Serial serum samples were collected, and microdialysis was performed using ex vivo lung tissue to measure pyrazinamide concentrations. Among 10 patients, the median pyrazinamide dose was 24.7 mg/kg of body weight. Imaging revealed predominant lung lesions as cavitary (n = 6 patients), mass-like (n = 3 patients), or consolidative (n = 1 patient). On histopathology examination, all tissue samples had necrosis; eight had a pH of ≤5.5. Tissue samples from two patients were positive for Mycobacterium tuberculosis by culture (pH 5.5 and 7.2). All 10 patients had maximal serum pyrazinamide concentrations within the recommended range of 20 to 60 μg/ml. The median lung tissue free pyrazinamide concentration was 20.96 μg/ml. The median tissue-to-serum pyrazinamide concentration ratio was 0.77 (range, 0.54 to 0.93). There was a significant inverse correlation between tissue pyrazinamide concentrations and the amounts of necrosis (R = −0.66, P = 0.04) and acid-fast bacilli (R = −0.75, P = 0.01) identified by histopathology. We found good penetration of pyrazinamide into lung tissue among patients with pulmonary tuberculosis with a variety of radiological lesion types. Our tissue pH results revealed that most lesions had a pH conducive to pyrazinamide activity. The tissue penetration of pyrazinamide highlights its importance in both drug-susceptible and drug-resistant antituberculosis treatment regimens.

scholarly journals Heightened Systemic Levels of Neutrophil and Eosinophil Granular Proteins in Pulmonary Tuberculosis and Reversal following Treatment

2018 ◽  
Vol 86 (6) ◽  
Author(s):  
Kadar Moideen ◽  
Nathella Pavan Kumar ◽  
Dina Nair ◽  
Vaithilingam V. Banurekha ◽  
Ramalingam Bethunaickan ◽  
...  
Keyword(s):  
Pulmonary Tuberculosis ◽  
Plasma Levels ◽  
Eosinophil Cationic Protein ◽  
Proteinase 3 ◽  
Cationic Protein ◽  
Indirect Measure ◽  
Content Type ◽  
Immune Effector ◽  
Effector Cells ◽  
Antituberculosis Treatment

ABSTRACT Granulocytes are activated during Mycobacterium tuberculosis infection and act as immune effector cells, and granulocyte responses are implicated in tuberculosis (TB) pathogenesis. Plasma levels of neutrophil and eosinophil granular proteins provide an indirect measure of degranulation. In this study, we wanted to examine the levels of neutrophil and eosinophil granular proteins in individuals with pulmonary tuberculosis (PTB) and to compare them with the levels in individuals with latent TB (LTB). Hence, we measured the plasma levels of myeloperoxidase (MPO), neutrophil elastase, proteinase 3, major basic protein (MBP), eosinophil-derived neurotoxin (EDN), eosinophil cationic protein (ECP), and eosinophil peroxidase (EPX) in these individuals. Finally, we also measured the levels of all of these proteins in PTB individuals following antituberculosis treatment (ATT). Our data reveal that PTB individuals are characterized by significantly higher plasma levels of MPO, elastase, proteinase 3, as well as MBP and EDN in comparison to those in LTB individuals. Our data also reveal that ATT resulted in the reversal of all of these changes, indicating an association with TB disease. Finally, our data show that the systemic levels of MPO and proteinase 3 can significantly discriminate PTB from LTB individuals. Thus, our data suggest that neutrophil and eosinophil granular proteins could play a potential role in the innate immune response and, therefore, the pathogenesis of pulmonary TB.

scholarly journals Development of anEx VivoTissue Platform To Study the Human Lung Response to Coxiella burnetii

2016 ◽  
Vol 84 (5) ◽  
pp. 1438-1445 ◽  
Author(s):  
Joseph G. Graham ◽  
Caylin G. Winchell ◽  
Richard C. Kurten ◽  
Daniel E. Voth
Keyword(s):  
Coxiella Burnetii ◽  
Lung Tissue ◽  
Human Lung ◽  
Q Fever ◽  
Ex Vivo ◽  
Parasitophorous Vacuole ◽  
Inflammasome Activation ◽  
Human Lung Tissue ◽  
Content Type

Coxiella burnetiiis an intracellular bacterial pathogen that causes human Q fever, an acute debilitating flu-like illness that can also present as chronic endocarditis. Disease typically occurs following inhalation of contaminated aerosols, resulting in an initial pulmonary infection. In human cells,C. burnetiigenerates a replication niche termed the parasitophorous vacuole (PV) by directing fusion with autophagosomes and lysosomes.C. burnetiirequires this lysosomal environment for replication and uses a Dot/Icm type IV secretion system to generate the large PV. However, we do not understand howC. burnetiievades the intracellular immune surveillance that triggers an inflammatory response. We recently characterized human alveolar macrophage (hAM) infectionin vitroand found that avirulentC. burnetiitriggers sustained interleukin-1β (IL-1β) production. Here, we evaluated infection ofex vivohuman lung tissue, defining a valuable approach for characterizingC. burnetiiinteractions with a human host. Within whole lung tissue,C. burnetiipreferentially replicated in hAMs. Additionally, IL-1β production correlated with formation of an apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC)-dependent inflammasome in response to infection. We also assessed potential activation of a human-specific noncanonical inflammasome and found that caspase-4 and caspase-5 are processed during infection. Interestingly, although inflammasome activation is closely linked to pyroptosis, lytic cell death did not occur followingC. burnetii-triggered inflammasome activation, indicating an atypical response after intracellular detection. Together, these studies provide a novel platform for studying the human innate immune response toC. burnetii.

scholarly journals ComparativeEx VivoActivity of Novel Endoperoxides in Multidrug-Resistant Plasmodium falciparum and P. vivax

2012 ◽  
Vol 56 (10) ◽  
pp. 5258-5263 ◽  
Author(s):  
Jutta Marfurt ◽  
Ferryanto Chalfein ◽  
Pak Prayoga ◽  
Frans Wabiser ◽  
Grennady Wirjanata ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Antimalarial Activity ◽  
Ex Vivo ◽  
Drug Susceptibility ◽  
Multidrug Resistant ◽  
Intrinsic Activity ◽  
Drug Resistant ◽  
The Novel ◽  
Content Type ◽  
Artemisinin Derivatives

ABSTRACTThe declining efficacy of artemisinin derivatives againstPlasmodium falciparumhighlights the urgent need to identify alternative highly potent compounds for the treatment of malaria. In Papua Indonesia, where multidrug resistance has been documented against bothP. falciparumandP. vivaxmalaria, comparativeex vivoantimalarial activity againstPlasmodiumisolates was assessed for the artemisinin derivatives artesunate (AS) and dihydroartemisinin (DHA), the synthetic peroxides OZ277 and OZ439, the semisynthetic 10-alkylaminoartemisinin derivatives artemisone and artemiside, and the conventional antimalarial drugs chloroquine (CQ), amodiaquine (AQ), and piperaquine (PIP).Ex vivodrug susceptibility was assessed in 46 field isolates (25P. falciparumand 21P. vivax). The novel endoperoxide compounds exhibited potentex vivoactivity against both species, but significant differences in intrinsic activity were observed. Compared to AS and its active metabolite DHA, all the novel compounds showed lower or equal 50% inhibitory concentrations (IC50s) in both species (median IC50s between 1.9 and 3.6 nM inP. falciparumand 0.7 and 4.6 nM inP. vivax). The antiplasmodial activity of novel endoperoxides showed different cross-susceptibility patterns in the twoPlasmodiumspecies: whereas theirex vivoactivity correlated positively with CQ, PIP, AS, and DHA inP. falciparum, the same was not apparent inP. vivax. The current study demonstrates for the first time potent activity of novel endoperoxides against drug-resistantP. vivax. The high activity against drug-resistant strains of bothPlasmodiumspecies confirms these compounds to be promising candidates for future artemisinin-based combination therapy (ACT) regimens in regions of coendemicity.

scholarly journals Sensitive and Specific Enzyme-Linked Immunosorbent Assay for Detecting Serum Antibodies against Mycobacterium avium subsp. paratuberculosis in Fallow Deer

2014 ◽  
Vol 21 (8) ◽  
pp. 1077-1085 ◽  
Author(s):  
José M. Prieto ◽  
Ana Balseiro ◽  
Rosa Casais ◽  
Naiara Abendaño ◽  
Liam E. Fitzgerald ◽  
...  
Keyword(s):  
Immunosorbent Assay ◽  
Mycobacterium Avium ◽  
Cost Effective ◽  
Fallow Deer ◽  
Enzyme Linked Immunosorbent Assay ◽  
Serum Samples ◽  
Igg Antibody ◽  
Tissue Samples ◽  
Content Type ◽  
Mycobacterium Avium Subsp Paratuberculosis

ABSTRACTThe enzyme-linked immunosorbent assay (ELISA) is the diagnostic test most commonly used in efforts to control paratuberculosis in domestic ruminants. However, commercial ELISAs have not been validated for detecting antibodies againstMycobacterium aviumsubsp.paratuberculosisin wild animals. In this study, we compared the sensitivities and specificities of five ELISAs using individual serum samples collected from 41 fallow deer with or without histopathological lesions consistent with paratuberculosis. Two target antigenic preparations were selected, an ethanol-treated protoplasmic preparation obtained from a fallow deerM. aviumsubsp.paratuberculosisisolate (ELISAs A and B) and a paratuberculosis protoplasmic antigen (PPA3) (ELISAs C and D). Fallow deer antibodies bound to the immobilized antigens were detected by using a horseradish peroxidase (HRP)-conjugated anti-fallow deer IgG antibody (ELISAs A and C) or HRP-conjugated protein G (ELISAs B and D). A commercially available assay, ELISA-E, which was designed to detectM. aviumsubsp.paratuberculosisantibodies in cattle, sheep, and goats, was also tested. Although ELISAs A, C, and E had the same sensitivity (72%), ELISAs A and C were more specific (100%) for detecting fallow deer with lesions consistent with paratuberculosis at necropsy than was the ELISA-E (87.5%). In addition, the ELISA-A was particularly sensitive for detecting fallow deer in the latent stages of infection (62.5%). The antibody responses detected with the ELISA-A correlated with both the severity of enteric lesions and the presence of acid-fast bacteria in gut tissue samples. In summary, our study shows that the ELISA-A can be a cost-effective diagnostic tool for preventing the spread of paratuberculosis among fallow deer populations.

Functional assessment and phenotypic heterogeneity of SFTPA1 and SFTPA2 mutations in interstitial lung diseases and lung cancer

2020 ◽  
Vol 56 (6) ◽  
pp. 2002806 ◽  
Author(s):  
Marie Legendre ◽  
Afifaa Butt ◽  
Raphaël Borie ◽  
Marie-Pierre Debray ◽  
Diane Bouvry ◽  
...  
Keyword(s):  
Lung Transplantation ◽  
Lung Tissue ◽  
Lung Diseases ◽  
Ex Vivo ◽  
Phenotypic Expression ◽  
Surfactant Protein ◽  
Interstitial Lung Diseases ◽  
Incomplete Penetrance ◽  
Tissue Samples

IntroductionInterstitial lung diseases (ILDs) can be caused by mutations in the SFTPA1 and SFTPA2 genes, which encode the surfactant protein (SP) complex SP-A. Only 11 SFTPA1 or SFTPA2 mutations have so far been reported worldwide, of which five have been functionally assessed. In the framework of ILD molecular diagnosis, we identified 14 independent patients with pathogenic SFTPA1 or SFTPA2 mutations. The present study aimed to functionally assess the 11 different mutations identified and to accurately describe the disease phenotype of the patients and their affected relatives.MethodsThe consequences of the 11 SFTPA1 or SFTPA2 mutations were analysed both in vitro, by studying the production and secretion of the corresponding mutated proteins and ex vivo, by analysing SP-A expression in lung tissue samples. The associated disease phenotypes were documented.ResultsFor the 11 identified mutations, protein production was preserved but secretion was abolished. The expression pattern of lung SP-A available in six patients was altered and the family history reported ILD and/or lung adenocarcinoma in 13 out of 14 families (93%). Among the 28 SFTPA1 or SFTPA2 mutation carriers, the mean age at ILD onset was 45 years (range 0.6–65 years) and 48% underwent lung transplantation (mean age 51 years). Seven carriers were asymptomatic.DiscussionThis study, which expands the molecular and clinical spectrum of SP-A disorders, shows that pathogenic SFTPA1 or SFTPA2 mutations share similar consequences for SP-A secretion in cell models and in lung tissue immunostaining, whereas they are associated with a highly variable phenotypic expression of disease, ranging from severe forms requiring lung transplantation to incomplete penetrance.

scholarly journals Pharmacokinetics of Tulathromycin in Healthy and Neutropenic Mice Challenged Intranasally with Lipopolysaccharide from Escherichia coli

2012 ◽  
Vol 56 (8) ◽  
pp. 4078-4086 ◽  
Author(s):  
N. Villarino ◽  
S. A. Brown ◽  
T. Martín-Jiménez
Keyword(s):  
Escherichia Coli ◽  
Lung Tissue ◽  
Intranasal Administration ◽  
Positive Influence ◽  
Time Profile ◽  
Sampling Time ◽  
Tissue Concentrations ◽  
Tissue Samples ◽  
Content Type ◽  
E Coli

ABSTRACTTulathromycin represents the first member of a novel subclass of macrolides, known as triamilides, approved to treat bovine and swine respiratory disease. The objectives of the present study were to assess the concentration-versus-time profile of tulathromycin in the plasma and lung tissue of healthy and neutropenic mice challenged intranasally with lipopolysaccharide (LPS) fromEscherichia coliO111:B4. BALB/c mice were randomly allocated into four groups of 40 mice each: groups T-28 (tulathromycin at 28 mg/kg of body weight), T-7, T7-LPS, and T7-LPS-CP (cyclophosphamide). Mice in group T-28 were treated with tulathromycin at 28 mg/kg subcutaneously (s.c.) (time 0 h). The rest of the mice were treated with tulathromycin at 7 mg/kg s.c. (time 0 h). Animals in dose groups T-7-LPS and T7-LPS-CP received a single dose ofE. coliLPS intranasally at −7 h. Mice in group T7-LPS-CP were also rendered neutropenic with cyclophosphamide (150 mg/kg intraperitoneally) prior to the administration of tulathromycin. Blood and lung tissue samples were obtained from 5 mice from each dose group at each sampling time over 144 h after the administration of tulathromycin. There were not statistical differences in lung tissue concentrations among groups T-7, T-7-LPS, and T7-LPS-CP. For all dose groups, the distribution of tulathromycin in the lungs was rapid and persisted at relatively high levels during 6 days postadministration. The concentration-versus-time profile of tulathromycin in lung tissue was not influenced by the intranasal administration ofE. coliLPS. The results suggest that in mice, neutrophils may not have a positive influence on tulathromycin accumulation in lung tissue when the drug is administered during either a neutrophilic or a neutropenic state.

scholarly journals Antitubercular Activity of Disulfiram, an Antialcoholism Drug, against Multidrug- and Extensively Drug-Resistant Mycobacterium tuberculosis Isolates

2012 ◽  
Vol 56 (8) ◽  
pp. 4140-4145 ◽  
Author(s):  
Yasuhiro Horita ◽  
Takemasa Takii ◽  
Tetsuya Yagi ◽  
Kenji Ogawa ◽  
Nagatoshi Fujiwara ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Antitubercular Activity ◽  
Clinical Isolates ◽  
Drug Resistant ◽  
Drug Resistant Tuberculosis ◽  
Content Type ◽  
Resistant Tuberculosis ◽  
Extensively Drug Resistant

ABSTRACTThe antimycobacterial activities of disulfiram (DSF) and diethyldithiocarbamate (DDC) against multidrug- and extensively drug-resistant tuberculosis (MDR/XDR-TB) clinical isolates were evaluatedin vitro. Both DSF and DDC exhibited potent antitubercular activities against 42 clinical isolates ofM. tuberculosis, including MDR/XDR-TB strains. Moreover, DSF showed remarkable bactericidal activityex vivoandin vivo. Therefore, DSF might be a drug repurposed for the treatment of MDR/XDR-TB.

scholarly journals Developing Synergistic Drug Combinations To Restore Antibiotic Sensitivity in Drug-Resistant Mycobacterium tuberculosis

2021 ◽  
Vol 65 (5) ◽  
Author(s):  
Charles Omollo ◽  
Vinayak Singh ◽  
Elizabeth Kigondu ◽  
Antonina Wasuna ◽  
Pooja Agarwal ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Efflux Pump ◽  
Ex Vivo ◽  
Antibiotic Sensitivity ◽  
Infectious Agent ◽  
Drug Combinations ◽  
Major Facilitator Superfamily ◽  
Drug Resistant ◽  
Content Type

ABSTRACT Tuberculosis (TB) is a leading global cause of mortality owing to an infectious agent, accounting for almost one-third of antimicrobial resistance (AMR) deaths annually. We aimed to identify synergistic anti-TB drug combinations with the capacity to restore therapeutic efficacy against drug-resistant mutants of the causative agent, Mycobacterium tuberculosis. We investigated combinations containing the known translational inhibitors, spectinomycin (SPT) and fusidic acid (FA), or the phenothiazine, chlorpromazine (CPZ), which disrupts mycobacterial energy metabolism. Potentiation of whole-cell drug efficacy was observed in SPT-CPZ combinations. This effect was lost against an M. tuberculosis mutant lacking the major facilitator superfamily (MFS) efflux pump, Rv1258c. Notably, the SPT-CPZ combination partially restored SPT efficacy against an SPT-resistant mutant carrying a g1379t point mutation in rrs, encoding the mycobacterial 16S rRNA. Combinations of SPT with FA, which targets the mycobacterial elongation factor G, exhibited potentiating activity against wild-type M. tuberculosis. Moreover, this combination produced a modest potentiating effect against both FA-monoresistant and SPT-monoresistant mutants. Finally, combining SPT with the frontline anti-TB agents, rifampicin (RIF) and isoniazid, resulted in enhanced activity in vitro and ex vivo against both drug-susceptible M. tuberculosis and a RIF-monoresistant rpoB S531L mutant. These results support the utility of novel potentiating drug combinations in restoring antibiotic susceptibility of M. tuberculosis strains carrying genetic resistance to any one of the partner compounds.

scholarly journals Field Application of Serodiagnostics To Identify Elephants with Tuberculosis prior to Case Confirmation by Culture

2012 ◽  
Vol 19 (8) ◽  
pp. 1269-1275 ◽  
Author(s):  
Konstantin P. Lyashchenko ◽  
Rena Greenwald ◽  
Javan Esfandiari ◽  
Susan Mikota ◽  
Michele Miller ◽  
...  
Keyword(s):  
Diagnostic Algorithm ◽  
Antibody Test ◽  
Field Application ◽  
Antibody Detection ◽  
Test Accuracy ◽  
Serum Samples ◽  
Tissue Samples ◽  
Content Type ◽  
Treatment Information ◽  
Posttreatment Period

ABSTRACTThree serologic methods for antibody detection in elephant tuberculosis (TB), the multiantigen print immunoassay (MAPIA), ElephantTB STAT-PAK kit, and DPP VetTB test, were evaluated using serial serum samples from 14 captive elephants infected withMycobacterium tuberculosisin 5 countries. In all cases, serological testing was performed prior to the diagnosis of TB by mycobacterial culture of trunk wash or tissue samples collected at necropsy. All elephants produced antibody responses toM. tuberculosisantigens, with 13/14 recognizing ESAT-6 and/or CFP10 proteins. The findings supported the high serodiagnostic test accuracy in detecting infections months to years beforeM. tuberculosiscould be isolated from elephants. The MAPIA and/or DPP VetTB assay demonstrated the potential for monitoring antimycobacterial therapy and predicting TB relapse in treated elephants when continuously used in the posttreatment period. History of exposure to TB and past treatment information should be taken into consideration for proper interpretation of the antibody test results. Data suggest that the more frequent trunk wash culture testing of seropositive elephants may enhance the efficiency of the TB diagnostic algorithm, leading to earlier treatment with improved outcomes.

Sign in / Sign up

Export Citation Format

Share Document