A systematic review on the effect of diabetes mellitus on the pharmacokinetics of TB drugs.

The coexistence of TB and diabetes mellitus (DM) (TB-DM) is associated with an increased risk of treatment failure, death, delayed culture conversion, and drug resistance. Because plasma concentrations may influence clinical outcomes, we evaluated the evidence on the pharmacokinetic (PK) of TB drugs in individuals with DM to guide management.We performed a systematic review and meta-analysis through searches of major databases from 1946 to 6 July 2023. PROSPERO (CRD42022323566).Of 4,173 potentially relevant articles, we identified 16 studies assessing rifampicin (RIF) PK, 9 on isoniazid (INH), 8 on pyrazinamide (PZA), and 3 on ethambutol (EMB). Two studies reported on second-line anti-TB drugs. According to our meta-analysis, RIF time to maximum concentration (Tmax) was significantly prolonged in patients with DM compared with non-DM patients. We found no significant differences for RIF Cmax, area under the curve (AUC) 0-24 or drug concentration at 2 h (C2h), INH C2h, PZA C2h, PZA Tmax, and EMB Tmax. Although RIF C2h was slightly reduced in patients with TB-DM, this finding was not statistically significant.This review comprehensively examines the impact of DM on the PK of TB drugs. We observed significant heterogeneity among the studies. Given the association between lower plasma concentrations and poor clinical outcomes among patients with DM, we recommend a higher dose limit to compensate for the larger body weight of patients with DM..

First Evidence of Axial Shape Asymmetry and Configuration Coexistence in

The excited states of N=44 ^{74}Zn were investigated via γ-ray spectroscopy following ^{74}Cu ß decay. By exploiting γ-γ angular correlation analysis, the 2_{2}^{+}, 3_{1}^{+}, 0_{2}^{+}, and 2_{3}^{+} states in ^{74}Zn were firmly established. The γ-ray branching and E2/M1 mixing ratios for transitions deexciting the 2_{2}^{+}, 3_{1}^{+}, and 2_{3}^{+} states were measured, allowing for the extraction of relative B(E2) values. In particular, the 2_{3}^{+}→0_{2}^{+} and 2_{3}^{+}→4_{1}^{+} transitions were observed for the first time. The results show excellent agreement with new microscopic large-scale shell-model calculations, and are discussed in terms of underlying shapes, as well as the role of neutron excitations across the N=40 gap. Enhanced axial shape asymmetry (triaxiality) is suggested to characterize ^{74}Zn in its ground state. Furthermore, an excited K=0 band with a significantly larger softness in its shape is identified. A shore of the N=40 "island of inversion" appears to manifest above Z=26, previously thought as its northern limit in the chart of the nuclides.

First Direct Measurement of an Astrophysical p-Process Reaction Cross Section Using a Radioactive Ion Beam.

We have performed the first direct measurement of the ^{83}Rb(p,γ) radiative capture reaction cross section in inverse kinematics using a radioactive beam of ^{83}Rb at incident energies of 2.4 and 2.7A MeV. The measured cross section at an effective relative kinetic energy of E_{cm}=2.393 MeV, which lies within the relevant energy window for core collapse supernovae, is smaller than the prediction of statistical model calculations. This leads to the abundance of ^{84}Sr produced in the astrophysical p process being higher than previously calculated. Moreover, the discrepancy of the present data with theoretical predictions indicates that further experimental investigation of p-process reactions involving unstable projectiles is clearly warranted.

Secondary data analysis investigating effects of marine omega-3 fatty acids on circulating levels of leptin and adiponectin in older adults.

BACKGROUND: Higher leptin and lower adiponectin levels have been linked to progressing systemic inflammation and diseases of aging. Among older adults with obesity and an inflammatory conditions, we quantified effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) supplementation on leptin, adiponectin, and the leptin-to-adiponectin ratio (LAR). We also examined associations among adipokine and cytokine levels. METHODS: Using a randomized, double-blind, placebo-controlled design, participants (mean age 61.3 ± 2.1) received 1.5 g EPA + 1.0 g DHA (n = 14) or mineral oil (n = 18) daily. Plasma adipokine and cytokine levels were quantified by electrochemiluminescence at all study intervals. RESULTS: While no between-group differences were detected, there was a reduction in the LAR (by 23%, p=.065) between weeks 4 and 8 among the EPA+DHA group. Adiponectin levels were negatively associated with IL-1ß levels at week 4 (p=.02) and TNF-α levels at week 8 (p=.03). CONCLUSION: Potential benefits of EPA+DHA supplementation among aging populations warrant further study.

A partially randomised trial of pretomanid, moxifloxacin and pyrazinamide for pulmonary TB.

BACKGROUND: Treatment for TB is lengthy and toxic, and new regimens are needed.METHODS: Participants with pulmonary drug-susceptible TB (DS-TB) were randomised to receive: 200 mg pretomanid (Pa, PMD) daily, 400 mg moxifloxacin (M) and 1500 mg pyrazinamide (Z) for 6 months (6Pa200MZ) or 4 months (4Pa200MZ); 100 mg pretomanid daily for 4 months in the same combination (4Pa100MZ); or standard DS-TB treatment for 6 months. The primary outcome was treatment failure or relapse at 12 months post-randomisation. The non-inferiority margin for between-group differences was 12.0%. Recruitment was paused following three deaths and not resumed.RESULTS: Respectively 4/47 (8.5%), 11/57 (19.3%), 14/52 (26.9%) and 1/53 (1.9%) DS-TB outcomes were unfavourable in patients on 6Pa200MZ, 4Pa200MZ, 4Pa100MZ and controls. There was a 6.6% (95% CI -2.2% to 15.4%) difference per protocol and 9.9% (95%CI -4.1% to 23.9%) modified intention-to-treat difference in unfavourable responses between the control and 6Pa200MZ arms. Grade 3+ adverse events affected 68/203 (33.5%) receiving experimental regimens, and 19/68 (27.9%) on control. Ten of 203 (4.9%) participants on experimental arms and 2/68 (2.9%) controls died.CONCLUSION: PaMZ regimens did not achieve non-inferiority in this under-powered trial. An ongoing evaluation of PMD remains a priority.

VA Home Based Primary Care Teams: Partnering with and Acting as Caregivers for Veterans.

The U.S. Department of Veterans Affairs' Home-Based Primary Care (HBPC) Interdisciplinary Team (IDT) provides in-home, primary care for medically complex Veterans. This study explores how HBPC and Veterans' caregivers partner to provide care. Interviews, focus groups, and field observations were conducted during eight HBPC site visits. Qualitative thematic analysis was performed. Caregivers/IDT member partnerships are important to care. Effective partnerships include: ease of communication; caregiver-centered support; and when no caregiver is present, IDTs providing more monitoring/services to Veterans and connection to community services. As this model expands, understanding dynamics between IDT members and caregivers will optimize the success of HBPC programs.

Viscoelastic haemostatic assay augmented protocols for major trauma haemorrhage (ITACTIC): a randomized, controlled trial.

PURPOSE: Contemporary trauma resuscitation prioritizes control of bleeding and uses major haemorrhage protocols (MHPs) to prevent and treat coagulopathy. We aimed to determine whether augmenting MHPs with Viscoelastic Haemostatic Assays (VHA) would improve outcomes compared to Conventional Coagulation Tests (CCTs). METHODS: This was a multi-centre, randomized controlled trial comparing outcomes in trauma patients who received empiric MHPs, augmented by either VHA or CCT-guided interventions. Primary outcome was the proportion of subjects who, at 24 h after injury, were alive and free of massive transfusion (10 or more red cell transfusions). Secondary outcomes included 28-day mortality. Pre-specified subgroups included patients with severe traumatic brain injury (TBI). RESULTS: Of 396 patients in the intention to treat analysis, 201 were allocated to VHA and 195 to CCT-guided therapy. At 24 h, there was no difference in the proportion of patients who were alive and free of massive transfusion (VHA: 67%, CCT: 64%, OR 1.15, 95% CI 0.76-1.73). 28-day mortality was not different overall (VHA: 25%, CCT: 28%, OR 0.84, 95% CI 0.54-1.31), nor were there differences in other secondary outcomes or serious adverse events. In pre-specified subgroups, there were no differences in primary outcomes. In the pre-specified subgroup of 74 patients with TBI, 64% were alive and free of massive transfusion at 24 h compared to 46% in the CCT arm (OR 2.12, 95% CI 0.84-5.34). CONCLUSION: There was no difference in overall outcomes between VHA- and CCT-augmented-major haemorrhage protocols.

Clinical perspectives in integrating whole-genome sequencing into the investigation of healthcare and public health outbreaks - hype or help?

Outbreaks pose a significant risk to patient safety as well as being costly and time consuming to investigate. The implementation of targeted infection prevention and control measures relies on infection prevention and control teams having access to rapid results that detect resistance accurately, and typing results that give clinically useful information on the relatedness of isolates. At present, determining whether transmission has occurred can be a major challenge. Conventional typing results do not always have sufficient granularity or robustness to define strains unequivocally, and sufficient epidemiological data are not always available to establish links between patients and the environment. Whole-genome sequencing (WGS) has emerged as the ultimate genotyping tool, but has not yet fully crossed the divide between research method and routine clinical diagnostic microbiological technique. A clinical WGS service was officially established in 2014 as part of the Scottish Healthcare Associated Infection Prevention Institute to confirm or refute outbreaks in hospital settings from across Scotland. This article describes the authors' experiences with the aim of providing new insights into practical application of the use of WGS to investigate healthcare and public health outbreaks. Solutions to overcome barriers to implementation of this technology in a clinical environment are proposed.

How mechanistic in silico modelling can improve our understanding of TB disease and treatment.

TB is one of the top 10 causes of death worldwide and the leading cause of death from a single infectious agent. Decreasing the length of time for TB treatment is an important step towards the goal of reducing mortality. Mechanistic in silico modelling can provide us with the tools to explore gaps in our knowledge, with the opportunity to model the complicated within-host dynamics of the infection, and simulate new treatment strategies. Significant insight has been gained using this form of modelling when applied to other diseases - much can be learned in infection research from these advances.

Multiple organ dysfunction after trauma.

BACKGROUND: The nature of multiple organ dysfunction syndrome (MODS) after traumatic injury is evolving as resuscitation practices advance and more patients survive their injuries to reach critical care. The aim of this study was to characterize contemporary MODS subtypes in trauma critical care at a population level. METHODS: Adult patients admitted to major trauma centre critical care units were enrolled in this 4-week point-prevalence study. MODS was defined by a daily total Sequential Organ Failure Assessment (SOFA) score of more than 5. Hierarchical clustering of SOFA scores over time was used to identify MODS subtypes. RESULTS: Some 440 patients were enrolled, of whom 245 (55·7 per cent) developed MODS. MODS carried a high mortality rate (22·0 per cent versus 0·5 per cent in those without MODS; P < 0·001) and 24·0 per cent of deaths occurred within the first 48 h after injury. Three patterns of MODS were identified, all present on admission. Cluster 1 MODS resolved early with a median time to recovery of 4 days and a mortality rate of 14·4 per cent. Cluster 2 had a delayed recovery (median 13 days) and a mortality rate of 35 per cent. Cluster 3 had a prolonged recovery (median 25 days) and high associated mortality rate of 46 per cent. Multivariable analysis revealed distinct clinical associations for each form of MODS; 24-hour crystalloid administration was associated strongly with cluster 1 (P = 0·009), traumatic brain injury with cluster 2 (P = 0·002) and admission shock severity with cluster 3 (P = 0·003). CONCLUSION: Contemporary MODS has at least three distinct types based on patterns of severity and recovery. Further characterization of MODS subtypes and their underlying pathophysiology may lead to future opportunities for early stratification and targeted interventions.

ANTECEDENTES: La naturaleza del síndrome de disfunción orgánica múltiple (Multiple Organ Dysfunction Syndrome, MODS) resultante de un traumatismo está evolucionando a medida que avanzan las prácticas de reanimación y más pacientes sobrevive a las lesiones y pueden recibir cuidados críticos. El objetivo de este estudio fue caracterizar los subtipos actuales MODS en atención crítica de trauma a nivel poblacional. MÉTODOS: Los pacientes adultos ingresados en unidades de cuidados intensivos de trauma se incluyeron en este estudio de prevalencia puntual de 4 semanas. MODS se definió como una puntuación total diaria de la escala de Evaluación de Fallo Orgánico Secuencial (Sequential Organ Failure Assessment, SOFA) > 5. Se utilizó el agrupamiento jerárquico de las puntuaciones SOFA a lo largo del tiempo para determinar los subtipos MODS. RESULTADOS: Se incluyeron 440 pacientes, de los cuales 245 (56%) presentaron MODS. MODS conllevó una alta mortalidad (22% versus 1%, P < 0,001) y 24% de las muertes fueron precoces, durante las primeras 48 horas tras el traumatismo. Se identificaron tres patrones de MODS, estando todos presentes al ingreso. En el tipo 1, MODS se resolvió de forma temprana, con una mediana de tiempo de recuperación de 4 días y una mortalidad del 14%. El tipo 2 presentaba un tiempo de recuperación retardado (mediana 13 días) y una mortalidad del 35%. El tipo 3 presentaba un tiempo de recuperación prolongado (mediana 25 días) y una mortalidad asociada alta del 46%. El análisis multivariable reveló asociaciones clínicas diferentes para cada tipo de MODS, con la administración de cristaloides durante 24 horas fuertemente asociada al tipo 1 (P < 0,001); el traumatismo craneal al tipo 2 (P < 0,01); y la gravedad del shock al ingreso al tipo 3 (P < 0,01). CONCLUSIÓN: Los MODS actuales presentan al menos tres tipos distintos basados en patrones de gravedad y recuperación. La caracterización de los subtipos de MODS y su fisiopatología subyacente puede contribuir a futuras oportunidades de estratificación temprana e intervenciones dirigidas.

Intravascular catheter migration: A cross-sectional and health-economic comparison of adhesive and subcutaneous engineered stabilisation devices for intravascular device securement.

The Infusional Services Team at a large cancer centre in Belfast, Northern Ireland, performed a cross-sectional analysis of two catheter securement technologies to address an area of frequent, but underestimated concern - peripherally inserted central catheter migration and dislodgement. Healthcare practitioner and patient feedback, along with economic impact, were assessed. The costs associated with catheter replacement during the adhesive device group study period were calculated using an average cost per insertion, based on material costs required for the procedure. Other factors were the replacement cost of the adhesive engineered securement device with each dressing change. In the subcutaneous securement group, the material costs were adjusted for use of the subcutaneous device as it remained in situ for the duration of the catheters' dwell time. This review found that subcutaneous securement offers both patient and facilities a safe, effective and economical alternative for device securement with patients who are unable to tolerate or have successful securement with adhesive securement devices. The use of subcutaneous devices provided for reduced risks for peripherally inserted central catheters in terms of dislodgement, migration or malposition, alleviating the potential risks to develop catheter-related thrombosis and device-related infection.

Gender differences in tuberculosis treatment outcomes: a post hoc analysis of the REMoxTB study.

BACKGROUND: In the REMoxTB study of 4-month treatment-shortening regimens containing moxifloxacin compared to the standard 6-month regimen for tuberculosis, the proportion of unfavourable outcomes for women was similar in all study arms, but men had more frequent unfavourable outcomes (bacteriologically or clinically defined failure or relapse within 18 months after randomisation) on the shortened moxifloxacin-containing regimens. The reason for this gender disparity in treatment outcome is poorly understood. METHODS: The gender differences in baseline variables were calculated, as was time to smear and culture conversion and Kaplan-Meier plots were constructed. In post hoc exploratory analyses, multivariable logistic regression modelling and an observed case analysis were used to explore factors associated with both gender and unfavourable treatment outcome. RESULTS: The per-protocol population included 472/1548 (30%) women. Women were younger and had lower rates of cavitation, smoking and weight (all p < 0.05) and higher prevalence of HIV (10% vs 6%, p = 0.001). They received higher doses (mg/kg) than men of rifampicin, isoniazid, pyrazinamide and moxifloxacin (p ≤ 0.005). There was no difference in baseline smear grading or mycobacterial growth indicator tube (MGIT) time to positivity. Women converted to negative cultures more quickly than men on Lowenstein-Jensen (HR 1.14, p = 0.008) and MGIT media (HR 1.19, p < 0.001). In men, the presence of cavitation, positive HIV status, higher age, lower BMI and 'ever smoked' were independently associated with unfavourable treatment outcome. In women, only 'ever smoked' was independently associated with unfavourable treatment outcome. Only for cavitation was there a gender difference in treatment outcomes by regimen; their outcome in the 4-month arms was significantly poorer compared to the 6-month treatment arm (p < 0.001). Women, with or without cavities, and men without cavities had a similar outcome on all treatment arms (p = 0.218, 0.224 and 0.689 respectively). For all other covariate subgroups, there were no differences in treatment effects for men or women. CONCLUSIONS: Gender differences in TB treatment responses for the shorter regimens in the REMoxTB study may be explained by poor outcomes in men with cavitation on the moxifloxacin-containing regimens. We observed that women with cavities, or without, on the 4-month moxifloxacin regimens had similar outcomes to all patients on the standard 6-month treatment. The biological reasons for this difference are poorly understood and require further exploration.

Pretreatment chest x-ray severity and its relation to bacterial burden in smear positive pulmonary tuberculosis.

BACKGROUND: Chest radiographs are used for diagnosis and severity assessment in tuberculosis (TB). The extent of disease as determined by smear grade and cavitation as a binary measure can predict 2-month smear results, but little has been done to determine whether radiological severity reflects the bacterial burden at diagnosis. METHODS: Pre-treatment chest x-rays from 1837 participants with smear-positive pulmonary TB enrolled into the REMoxTB trial (Gillespie et al., N Engl J Med 371:1577-87, 2014) were retrospectively reviewed. Two clinicians blinded to clinical details using the Ralph scoring system performed separate readings. An independent reader reviewed discrepant results for quality assessment and cavity presence. Cavitation presence was plotted against time to positivity (TTP) of sputum liquid cultures (MGIT 960). The Wilcoxon rank sum test was performed to calculate the difference in average TTP for these groups. The average lung field affected was compared to log 10 TTP by linear regression. Baseline markers of disease severity and patient characteristics were added in univariable regression analysis against radiological severity and a multivariable regression model was created to explore their relationship. RESULTS: For 1354 participants, the median TTP was 117 h (4.88 days), being 26 h longer (95% CI 16-30, p < 0.001) in patients without cavitation compared to those with cavitation. The median percentage of lung-field affected was 18.1% (IQR 11.3-28.8%). For every 10-fold increase in TTP, the area of lung field affected decreased by 11.4%. Multivariable models showed that serum albumin decreased significantly as the percentage of lung field area increased in both those with and without cavitation. In addition, BMI and logged TTP had a small but significant effect in those with cavitation and the number of severe TB symptoms in the non-cavitation group also had a small effect, whilst other factors found to be significant on univariable analysis lost this effect in the model. CONCLUSIONS: The radiological severity of disease on chest x-ray prior to treatment in smear positive pulmonary TB patients is weakly associated with the bacterial burden. When compared against other variables at diagnosis, this effect is lost in those without cavitation. Radiological severity does reflect the overall disease severity in smear positive pulmonary TB, but we suggest that clinicians should be cautious in over-interpreting the significance of radiological disease extent at diagnosis.

Liver toxicity associated with tuberculosis chemotherapy in the REMoxTB study.

BACKGROUND: Drug-induced liver injury (DILI) is a common complication of tuberculosis treatment. We utilised data from the REMoxTB clinical trial to describe the incidence of predisposing factors and the natural history in patients with liver enzyme levels elevated in response to tuberculosis treatment. METHODS: Patients received either standard tuberculosis treatment (2EHRZ/4HR), or a 4-month regimen in which moxifloxacin replaced either ethambutol (isoniazid arm, 2MHRZ/2MHR) or isoniazid (ethambutol arm, 2EMRZ/2MR). Hepatic enzymes were measured at 0, 2, 4, 8, 12 and 17 weeks and as clinically indicated during reported adverse events. Patients included were those receiving at least one dose of drug and with two or more hepatic enzyme measurements. RESULTS: A total of 1928 patients were included (639 2EHRZ/4HR, 654 2MHRZ/2MHR and 635 2EMRZ/2MR). DILI was defined as peak alanine aminotransferase (ALT) ≥ 5 times the upper limit of normal (5 × ULN) or ALT ≥ 3 × ULN with total bilirubin > 2 × ULN. DILI was identified in 58 of the 1928 (3.0%) patients at a median time of 28 days (interquartile range IQR 14-56). Of 639 (6.4%) patients taking standard tuberculosis therapy, 41 experienced clinically significant enzyme elevations (peak ALT ≥ 3 × ULN). On standard therapy, 21.1% of patients aged >55 years developed a peak ALT/aspartate aminotransferase (AST) ≥ 3 × ULN (p = 0.01) and 15% of HIV-positive patients experienced a peak ALT/AST ≥ 3 × ULN compared to 9% of HIV-negative patients (p = 0.160). The median peak ALT/AST was higher in isoniazid-containing regimens vs no-isoniazid regimens (p < 0.05), and lower in moxifloxacin-containing arms vs no-moxifloxacin arms (p < 0.05). Patients receiving isoniazid reached a peak ALT ≥ 3 × ULN 9.5 days earlier than those on the ethambutol arm (median time of 28 days vs 18.5 days). Of the 67 Asian patients with a peak ALT/AST ≥ 3 × ULN, 57 (85.1%) were on an isoniazid-containing regimen (p = 0.008). CONCLUSIONS: Our results provide evidence of the risk of DILI in tuberculosis patients on standard treatment. Older patients on standard therapy, HIV-positive patients, Asian patients and those receiving isoniazid were at higher risk of elevated enzyme levels. Monitoring hepatic enzymes during the first 2 months of standard therapy detected approximately 75% of patients with a peak enzyme elevation ≥3 × ULN, suggesting this should be a standard of care. These results provide evidence for the potential of moxifloxacin in hepatic sparing.

Trends in rotavirus from 2001 to 2015 in two paediatric hospitals in Atlanta, Georgia.

We compared rotavirus detection patterns before (2001-2006) and after (2008-2015) rotavirus vaccine introduction. We also compared rotavirus detection patterns in odd (2009, 2011, 2013, 2015) and even (2008, 2010, 2012, 2014) years post-vaccine separately. Results of stool rotavirus antigen testing from inpatient, outpatient and emergency department encounters from July 2000 to July 2015 at two paediatric hospital laboratories in Atlanta, Georgia were reviewed. Post-vaccine, rotavirus detection declined (30.2% vs. 13.7% (overall 54.6% decline, P <0.001)), occurred more frequently outside the rotavirus season (19.8% vs. 3.5%; P < 0.001), and was more common among older children (26 vs. 13 median months of age; P < 0.001). During odd years post-vaccine, rotavirus detection was significantly higher than even years (20.2% vs. 6.4%; P < 0.001). Rotavirus detection declined substantially and developed a biennial pattern in the post-vaccine era. The intensity and temporality of rotavirus detection in odd years post-vaccine resembled that observed pre-vaccine, although considerably reduced in magnitude.

Pseudomonas aeruginosa intensive care unit outbreak: winnowing of transmissions with molecular and genomic typing.

BACKGROUND: Pseudomonas aeruginosa healthcare outbreaks can be time consuming and difficult to investigate. Guidance does not specify which typing technique is most practical for decision-making. AIM: To explore the usefulness of whole-genome sequencing (WGS) in the investigation of a P. aeruginosa outbreak, describing how it compares with pulsed-field gel electrophoresis (PFGE) and variable number tandem repeat (VNTR) analysis. METHODS: Six patient isolates and six environmental samples from an intensive care unit (ICU) positive for P. aeruginosa over two years underwent VNTR, PFGE and WGS. FINDINGS: VNTR and PFGE were required to fully determine the potential source of infection and rule out others. WGS results unambiguously distinguished linked isolates, giving greater assurance of the transmission route between wash-hand basin water and two patients, supporting the control measures employed. CONCLUSION: WGS provided detailed information without the need for further typing. When allied to epidemiological information, WGS can be used to understand outbreak situations rapidly and with certainty. Implementation of WGS in real-time would be a major advance in day-to-day practice. It could become a standard of care as it becomes more widespread due to its reproducibility and lower costs.

Pharmacokinetics, Tolerability, and Bacteriological Response of Rifampin Administered at 600, 900, and 1,200 Milligrams Daily in Patients with Pulmonary Tuberculosis.

In a multiple-dose-ranging trial, we previously evaluated higher doses of rifampin in patients for 2 weeks. The objectives of the current study were to administer higher doses of rifampin for a longer period to compare the pharmacokinetics, safety/tolerability, and bacteriological activity of such regimens. In a double-blind, randomized, placebo-controlled, phase II clinical trial, 150 Tanzanian patients with tuberculosis (TB) were randomized to receive either 600 mg (approximately 10 mg/kg of body weight), 900 mg, or 1,200 mg rifampin combined with standard doses of isoniazid, pyrazinamide, and ethambutol administered daily for 2 months. Intensive pharmacokinetic sampling occurred in 63 patients after 6 weeks of treatment, and safety/tolerability was assessed. The bacteriological response was assessed by culture conversion in liquid and solid media. Geometric mean total exposures (area under the concentration-versus-time curve up to 24 h after the dose) were 24.6, 50.8, and 76.1 mg · h/liter in the 600-mg, 900-mg, and 1,200-mg groups, respectively, reflecting a nonlinear increase in exposure with the dose (P < 0.001). Grade 3 adverse events occurred in only 2 patients in the 600-mg arm, 4 patients in the 900-mg arm, and 5 patients in the 1,200-mg arm. No significant differences in the bacteriological response were observed. Higher daily doses of rifampin (900 and 1,200 mg) resulted in a more than proportional increase in rifampin exposure in plasma and were safe and well tolerated when combined with other first-line anti-TB drugs for 2 months, but they did not result in improved bacteriological responses in patients with pulmonary TB. These findings have warranted evaluation of even higher doses of rifampin in follow-up trials. (This study has been registered at ClinicalTrials.gov under identifier NCT00760149.).

Defining dormancy in mycobacterial disease.

Tuberculosis remains a threat to global health and recent attempts to shorten therapy have not succeeded mainly due to cases of clinical relapse. This has focussed attention on the importance of "dormancy" in tuberculosis. There are a number of different definitions of the term and a similar multiplicity of different in vitro and in vivo models. The danger with this is the implicit assumption of equivalence between the terms and models, which will make even more difficult to unravel this complex conundrum. In this review we summarise the main models and definitions and their impact on susceptibility of Mycobacterium tuberculosis. We also suggest a potential nomenclature for debate. Dormancy researchers agree that factors underpinning this phenomenon are complex and nuanced. If we are to make progress we must agree the terms to be used and be consistent in using them.