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Concept: Tuberculosis treatment

186

Background Drug-resistant tuberculosis threatens recent gains in the treatment of tuberculosis and human immunodeficiency virus (HIV) infection worldwide. A widespread epidemic of extensively drug-resistant (XDR) tuberculosis is occurring in South Africa, where cases have increased substantially since 2002. The factors driving this rapid increase have not been fully elucidated, but such knowledge is needed to guide public health interventions. Methods We conducted a prospective study involving 404 participants in KwaZulu-Natal Province, South Africa, with a diagnosis of XDR tuberculosis between 2011 and 2014. Interviews and medical-record reviews were used to elicit information on the participants' history of tuberculosis and HIV infection, hospitalizations, and social networks. Mycobacterium tuberculosis isolates underwent insertion sequence (IS)6110 restriction-fragment-length polymorphism analysis, targeted gene sequencing, and whole-genome sequencing. We used clinical and genotypic case definitions to calculate the proportion of cases of XDR tuberculosis that were due to inadequate treatment of multidrug-resistant (MDR) tuberculosis (i.e., acquired resistance) versus those that were due to transmission (i.e., transmitted resistance). We used social-network analysis to identify community and hospital locations of transmission. Results Of the 404 participants, 311 (77%) had HIV infection; the median CD4+ count was 340 cells per cubic millimeter (interquartile range, 117 to 431). A total of 280 participants (69%) had never received treatment for MDR tuberculosis. Genotypic analysis in 386 participants revealed that 323 (84%) belonged to 1 of 31 clusters. Clusters ranged from 2 to 14 participants, except for 1 large cluster of 212 participants (55%) with a LAM4/KZN strain. Person-to-person or hospital-based epidemiologic links were identified in 123 of 404 participants (30%). Conclusions The majority of cases of XDR tuberculosis in KwaZulu-Natal, South Africa, an area with a high tuberculosis burden, were probably due to transmission rather than to inadequate treatment of MDR tuberculosis. These data suggest that control of the epidemic of drug-resistant tuberculosis requires an increased focus on interrupting transmission. (Funded by the National Institute of Allergy and Infectious Diseases and others.).

Concepts: HIV, AIDS, Immune system, Infectious disease, Tuberculosis, South Africa, Tuberculosis treatment, Extensively drug-resistant tuberculosis

171

In Uganda, isoniazid plus ethambutol is used for 6 months (6HE) during the continuation treatment phase of new tuberculosis (TB) cases. However, the World Health Organization (WHO) recommends using isoniazid plus rifampicin for 4 months (4HR) instead of 6HE. We compared the impact of a continuation phase using 6HE or 4HR on total cost and expected mortality from the perspective of the Ugandan national health system.

Concepts: Health economics, Costs, Tuberculosis, World Health Organization, Pharmacoeconomics, Tuberculosis treatment, Isoniazid, Ethambutol

169

Badgers are involved in the transmission to cattle of bovine tuberculosis (TB), a serious problem for the UK farming industry. Cross-sectional studies have shown an association between bite wounds and TB infection in badgers which may have implications for M. bovis transmission and control, although the sequence of these two events is unclear. Transmission during aggressive encounters could potentially reduce the effectiveness of policies which increase the average range of a badger and thus its opportunities for interaction with other social groups.

Concepts: Tuberculosis, Mycobacterium, Cattle, Mycobacterium bovis, Bacillus Calmette-Guérin, Tuberculosis treatment, Badger

36

Tuberculosis is epidemic among workers in South African gold mines. We evaluated an intervention to interrupt tuberculosis transmission by means of mass screening that was linked to treatment for active disease or latent infection.

Concepts: HIV, Epidemiology, Cancer, Infectious disease, Tuberculosis, Gold, Tuberculosis treatment, Isoniazid

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Effective management of infectious disease relies upon understanding mechanisms of pathogen transmission. In particular, while models of disease dynamics usually assume transmission through direct contact, transmission through environmental contamination can cause different dynamics. We used Global Positioning System (GPS) collars and proximity-sensing contact-collars to explore opportunities for transmission of Mycobacterium bovis [causal agent of bovine tuberculosis] between cattle and badgers (Meles meles). Cattle pasture was badgers' most preferred habitat. Nevertheless, although collared cattle spent 2914 collar-nights in the home ranges of contact-collared badgers, and 5380 collar-nights in the home ranges of GPS-collared badgers, we detected no direct contacts between the two species. Simultaneous GPS-tracking revealed that badgers preferred land > 50 m from cattle. Very infrequent direct contact indicates that badger-to-cattle and cattle-to-badger M. bovis transmission may typically occur through contamination of the two species' shared environment. This information should help to inform tuberculosis control by guiding both modelling and farm management.

Concepts: Infectious disease, Microbiology, Tuberculosis, Mycobacterium, Cattle, Mycobacterium bovis, Global Positioning System, Tuberculosis treatment

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We report the high-pressure response of three forms (α, δ, and γ) of pyrazinamide (C5H5N3O, PZA) by in situ Raman spectroscopy and synchrotron X-ray diffraction techniques with a pressure of about 14 GPa. These different forms are characterized by various intermolecular bonding schemes. High-pressure experimental results show that the γ phase undergoes phase transition to the β phase at a pressure of about 4 GPa, whereas the other two forms retain their original structures at a high pressure. We propose that the stabilities of the α and δ forms upon compression are due to the special dimer connection that these forms possess. On the other hand, the γ form, which does not have this connection, prefers to transform to the closely related β form when pressure is applied. The detailed mechanism of the phase transition together with the stability of the three polymorphs is discussed by taking molecular stacking into account.

Concepts: Spectroscopy, Diffraction, X-ray, Chemical bonding, Raman spectroscopy, X-ray crystallography, Tuberculosis treatment, Pyrazinamide

28

BACKGROUND: Intensified antibiotic treatment might improve the outcome of tuberculous meningitis. We assessed pharmacokinetics, safety, and survival benefit of several treatment regimens containing high-dose rifampicin and moxifloxacin in patients with tuberculous meningitis in a hospital setting. METHODS: In an open-label, phase 2 trial with a factorial design in one hospital in Indonesia, patients (aged >14 years) with tuberculous meningitis were randomly assigned to receive, according to a computer-generated schedule, first rifampicin standard dose (450 mg, about 10 mg/kg) orally or high dose (600 mg, about 13 mg/kg) intravenously, and second oral moxifloxacin 400 mg, moxifloxacin 800 mg, or ethambutol 750 mg once daily. All patients were given standard-dose isoniazid, pyrazinamide, and adjunctive corticosteroids. After 14 days of treatment all patients continued with standard treatment for tuberculosis. Endpoints included pharmacokinetic analyses of the blood and cerebrospinal fluid, adverse events attributable to tuberculosis treatment, and survival. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01158755. FINDINGS: 60 patients were randomly assigned to receive rifampicin standard dose (12 no moxifloxacin, ten moxifloxacin 400 mg, and nine moxifloxacin 800 mg) and high dose (ten no moxifloxacin, nine moxifloxacin 400 mg, and ten moxifloxacin 800 mg). A 33% higher dose of rifampicin, intravenously, led to a three times higher geometric mean area under the time-concentration curve up to 6 h after dose (AUC(0-6); 78·7 mg.h/L [95% CI 71·0-87·3] vs 26·0 mg.h/L [19·0-35·6]), maximum plasma concentrations (C(max); 22·1 mg/L [19·9-24·6] vs 6·3 mg/L [4·9-8·3]), and concentrations in cerebrospinal fluid (0·60 mg/L [0·46-0·78] vs 0·21 mg/L [0·16-0·27]). Doubling the dose of moxifloxacin resulted in a proportional increase in plasma AUC(0-6) (31·5 mg.h/L [24·1-41·1] vs 15·1 mg.h/L [12·8-17·7]), C(max) (7·4 mg/L [5·6-9·6] vs 3·9 mg/L [3·2-4·8]), and drug concentrations in the cerebrospinal fluid (2·43 mg/L [1·81-3·27] vs 1·52 mg/L [1·28-1·82]). Intensified treatment did not result in increased toxicity. 6 month mortality was substantially lower in patients given high-dose rifampicin intravenously (ten [35%] vs 20 [65%]), which could not be explained by HIV status or severity of disease at the time of presentation (adjusted HR 0·42; 95% CI 0·20-0·91; p=0·03). INTERPRETATION: These data suggest that treatment containing a higher dose of rifampicin and standard-dose or high-dose moxifloxacin during the first 2 weeks is safe in patients with tuberculous meningitis, and that high-dose intravenous rifampicin could be associated with a survival benefit in patients with severe disease. FUNDING: Royal Dutch Academy of Arts and Sciences, Netherlands Foundation for Scientific Research, and Padjadjaran University, Bandung, Indonesia.

Concepts: Tuberculosis, Cerebrospinal fluid, Meningitis, Tuberculous meningitis, Lumbar puncture, Tuberculosis treatment, Pyrazinamide, Rifampicin

28

Standard tuberculosis (TB) treatment includes an initial regimen containing drugs that are both rapidly bactericidal (isoniazid) and sterilizing (rifampin and pyrazinamide), and ethambutol to help prevent the emergence of drug resistance. Antagonism between isoniazid and pyrazinamide has been demonstrated in a TB treatment mouse model. Because isoniazid’s bactericidal activity is greatest during the initial two treatment days, we hypothesized that removing isoniazid after the second day would increase the effectiveness of the standard regimen. To test this hypothesis, we developed a mouse model to measure the early bactericidal activity (EBA) of drug regimens designed to analyze the essentiality of both isoniazid and pyrazinamide during the first 14 d of therapy. Our results clearly indicate that discontinuation of isoniazid after the second day of treatment increases the EBA of standard therapy in the mouse model, whereas omitting pyrazinamide during the first 14 d was detrimental. Substitution of moxifloxacin for isoniazid on day 3 did not increase the EBA compared with only removing isoniazid after day 2. Our data show that a mouse model can be used to analyze the EBA of TB drugs, and our findings support pursuing clinical trials to evaluate the possible benefit of removing isoniazid after the first 2 treatment days.

Concepts: Pharmacology, Tuberculosis, Murinae, Tuberculosis treatment, Pyrazinamide, Rifampicin, Isoniazid, Ethambutol

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It is often necessary to include WHO Group 5 drugs in the treatment of extensively drug-resistant TB (XDR-TB) and fluoroquinolone-resistant multidrug-resistant tuberculosis (MDR-TB). As clinical evidence about use of Group 5 drugs is scarce, we conducted a systematic review using published individual patient data. We searched PubMed and OvidSP through 7 April 2013 for publications in English to assemble a cohort with fluoroquinolone-resistant MDR-TB treated with Group 5 drugs. Favorable outcome was defined as sputum culture conversion, cure, or treatment completion in the absence of death, default, treatment failure, or relapse. A cohort of 194 patients was assembled from 20 articles involving 12 geographical regions. In descending order of frequency, linezolid was used in 162 (84%), macrolides in 84 (43%), clofazimine in 65 (34%), amoxicillin with clavulanate in 56 (29%), thioridazine in 18 (9%), carbapenem in 16 (8%), and high-dose isoniazid in 16 (8%). Cohort analysis with robust Poisson regression models and random-effects meta-analysis similarly suggested that linezolid use significantly increased the probability (95% confidence interval) of favorable outcome by 57% (10%, 124%) and 55% (10%, 121%), respectively. Defining significant associations by risk ratios ≥ 1.2 or ≤ 0.9, neither cohort analysis nor meta-analysis demonstrated any significant add-on benefit from the use of other Group 5 drugs on outcome of patients treated with linezolid, although selection bias might have underestimated their effects. Our findings substantiated use of linezolid in the treatment of XDR-TB or fluoroquinolone-resistant MDR-TB, and calls for further studies to evaluate the roles of other Group 5 drugs.

Concepts: Regression analysis, Evidence-based medicine, Antibiotic resistance, Relative risk, Tuberculosis, Multi-drug-resistant tuberculosis, Tuberculosis treatment, Extensively drug-resistant tuberculosis

24

Mycobacterium tuberculosis causes the majority of tuberculosis (TB) cases in humans; however, in developing countries, human TB caused by M. bovis may be frequent but undetected. Human TB caused by M. bovis is considered a zoonosis; transmission is mainly through consumption of unpasteurized dairy products, and it is less frequently attributed to animal-to-human or human-to-human contact. We describe the trends of M. bovis isolation from human samples and first-line drug susceptibility during a 15-year period in a referral laboratory located in a tertiary care hospital in Mexico City.

Concepts: Tuberculosis, Mycobacterium, Mycobacterium tuberculosis, Mycobacterium bovis, Bacillus Calmette-Guérin, Pasteurization, Tuberculosis treatment, Zoonosis