The history of the development of modern chemotherapy for tuberculosis (TB), largely due to the British Medical Research Council, is first described. There is a current need to shorten the duration ...of treatment and to prevent and cure drug-resistant disease. These aims will only be
achieved if the way in which multidrug treatment prevents resistance from emerging and the reasons for the very slow response to chemotherapy are understood. Consideration of mutation rates to resistance and the size of bacterial populations in lesions makes it very unlikely that resistance
would emerge spontaneously, leaving irregularity in drug taking and inadequate dosage as the main reasons for its occurrence. Slow response to treatment seems due to the presence of persister populations whose natural history is only partly known. In the future, we need to explore the persister
state in patients and in experimental murine TB, and to take it into account in the design of future mouse experiments. The activity of rifamycins and pyrazinamide is being increased by a rise in rifamycin dosage and the inhalation of pyrazinoic acid. New drugs are gradually being brought
into use, initially TMC207 and the nitroimadazoles, PA824 and OPC67683. They will need to be tested in new combination regimens for drug-susceptible and multi- and extensively drug-resistant disease.
SETTING: Current treatment for pulmonary tuberculosis (TB) might be shortened by the incorporation of fluoroquinolones (FQs).OBJECTIVES: A Phase II study aimed to assess the sterilising activities of ...three novel regimens containing FQs before a Phase III trial of a 4-month regimen
containing gatifloxacin (GFX).DESIGN: A total of 217 newly diagnosed smear-positive patients were randomly allocated to one of four regimens: isoniazid (INH), pyrazinamide and rifampicin (RMP) with either ethambutol, GFX, moxifloxacin (MFX) or ofloxacin (OFX) for 2 months. At the end of
the study, RMP and INH were given for 4 months. The rates of elimination of Mycobacterium tuberculosis were compared in the regimens using non-linear mixed effects modelling of the serial sputum colony counts (SSCC) during the first 8 weeks.RESULTS: After adjustment for covariates,
MFX substitution appeared superior during the early phase of a bi-exponential fall in colony counts, but significant and similar acceleration of bacillary elimination during the late phase occurred with both GFX and MFX (P = 0.002). Substitution of OFX had no effect. These findings
were supported by estimates of time to conversion, using Cox regression, but there were no significant differences in proportions culture-negative at 8 weeks.CONCLUSIONS: GFX and MFX improve the sterilising activity of regimens and might shorten treatment; their progression into Phase
III trials therefore seems warranted.
Pyrazinamide (PZA) is an important sterilising tuberculosis drug that helps to shorten the duration of current chemotherapy regimens for tuberculosis. When first discovered, it had activity in murine ...tuberculosis but no apparent in vitro activity, and its subsequent use in treatment depended largely on classic experiments at Cornell University, which showed its requirement for an acid pH for activity and its sterilising activity in the mouse. Recent studies have shown that PZA enters Mycobacterium tuberculosis by passive diffusion, is converted to pyrazinoic acid (POA) by nicotinamidase/pyrazinamidase (PZase) and is then excreted by a weak efflux pump. Protonated POA (HPOA) is reabsorbed into the bacilli under acid conditions and accumulates because the efflux pump is inefficient, causing cellular damage. Unlike other antibacterials, PZA has no defined target of action. PZA is more active against old than against actively growing cultures, probably because the energy production and efflux pump would be slowed down by low bacterial metabolism. This review deals with the activity of PZA in vitro, in macrophages and in animal models. It describes the evidence from clinical trials that it is an effective sterilising drug that acts synergistically with rifampicin. The highly diverse mutations in the PZase gene (pncA) that lead to loss of PZase activity cause PZA resistance. Methods for susceptibility determination either as tests against PZA or nicotinamide in liquid and solid media, as tests for PZase activity or for mutations in pncA, are reviewed.
Obesity and eating disorders are often studied and treated separately. While the increases in obesity prevalence are well known, examination of its co-occurrence with eating disorders, a problem also ...of public health concern, is important because eating disorder behaviors are known to contribute to obesity onset and maintenance, and vice versa.
Data from large cross-sectional representative statewide community samples of people in the years of 1995 (n=3001), 2005 (n=3047) and 2015 (n=3005) were analyzed. Data were collected using a structured, self-report interview that included demographic, health-related, weight, height and eating disorder behavior questions. Eating behavior questions assessed binge eating, very strict dieting/fasting and purging, and were derived from the Eating Disorder Examination. Logistic regression analyses were conducted comparing prevalence of obesity, eating disorder behaviors and their co-occurrence.
The prevalence of obesity or binge eating, or obesity with comorbid binge eating, each increased significantly from 1995 to 2005 (P<0.001 for each comparison) and continued to increase significantly from 2005 to 2015 (P<0.001 for each comparison). The highest increases from 1995 to 2015 were in the prevalence of obesity with comorbid binge eating (7.3-fold), or obesity with comorbid very strict dieting/fasting (11.5-fold). The prevalence of very strict dieting/fasting also increased significantly from 1995 to 2015 (3.8-fold). The prevalence of purging, or obesity with comorbid purging, did not change significantly from 1995 to 2015.
There were statewide increases during the 20 years from 1995 to 2015 in the independent prevalence of obesity, binge eating and very strict dieting/fasting, and even higher increases in the prevalence of obesity with comorbid binge eating, and obesity with comorbid very strict dieting/fasting. These findings support the need for more integrated approaches to both the prevention and treatment of obesity and eating disorder behaviors, namely binge eating and very strict dieting/fasting.
During the course of chemotherapy, certain drugs are predominant in their bactericidal activities. Isoniazid is responsible for an initial kill of about 95% of organisms during the first 2 days of ...treatment. Its bactericidal role is then replaced by rifampicin and pyrazinamide during
the intensive phase. In the continuation phase with an isoniazid/rifampicin regimen, rifampicin is the only effective drug against persisters, as shown by the similarity of response by patients with initially isoniazid-resistant or sensitive strains. If the continuation phase regimen does
not contain rifampicin but does contain isoniazid, the dominant bactericidal drug is isoniazid. In this case, the response of patients with initial isoniazid resistance is appreciably less good than in those with sensitive organisms. The review suggests exploration in randomised control trials
of a continuation phase of rifampicin (or rifapentine) alone. It also suggests the importance of the dose size of rifampicin and the need for exploring a higher dose. Finally, it emphasises the importance of finding drugs that act on persisting organisms that are phenotypically but not genetically
resistant to rifampicin.
Objective
Although findings suggest that binge eating is becoming increasingly normative, the ‘clinical significance’ of this behaviour at a population level remains uncertain. We aimed to assess the ...time trends in binge‐eating prevalence and burden over 18 years.
Method
Six cross‐sectional face‐to‐face surveys of the Australian adult population were conducted in 1998, 2005, 2008, 2009, 2014, and 2015 (Ntotal = 15 126). Data were collected on demographics, 3‐month prevalence of objective binge eating (OBE), health‐related quality of life, days out of role, and distress related to OBE.
Results
The prevalence of OBE increased six‐fold from 1998 (2.7%) to 2015 (13.0%). Health‐related quality of life associated with OBE improved from 1998 to 2015, where it more closely approximated population norms. Days out of role remained higher among participants who reported OBE, although decreased over time. Half of participants who reported weekly (56.6%) and twice‐weekly (47.1%) OBE reported that they were not distressed by this behaviour. However, the presence of distress related to OBE in 2015 was associated with greater health‐related quality‐of‐life impairment.
Conclusion
As the prevalence of binge eating increases over time, associated disability has been decreasing. Implications for the diagnosis of disorders associated with binge eating are discussed.
We have reviewed the results from 15 tuberculosis treatment trials initiated by the British Medical Research Council between 1970 and 1983 in Africa and East Asia. Of 574 relapses, 447 (78%) occurred ...within 6 months of stopping treatment and 525 (91%) within 12 months. We suggest that
investigators should consider terminating follow-up after the last enrolled patient completes 6 months following treatment, while continuing to follow patients enrolled earlier until that time. Compared to following all patients to 24 months, the total trial duration could be reduced by 18
months, with no increase in patient numbers in a non-inferiority design.
SETTING: Clinical trials and the behaviour of bacterial persisters.OBJECTIVE: To explain why the efficacies of isoniazid (INH) and rifamycins during the treatment of tuberculosis (TB) are related not ...to the area under the curve (AUC)/minimum inhibitory concentration (MIC), but to
peak drug concentrations.DESIGN: We examined the response in clinical trials with patients treated with INH alone and divided into slow and rapid acetylators of INH.RESULTS: The efficacy of INH is best related to peak concentrations, as repeated peaks can kill low-degree resistant
mutants. A similar process might result in repeated peak concentrations of rifamycins killing low-tolerance persisters.CONCLUSIONS: If the efficacy of rifamycins is best related to peak concentrations, we can explain the discrepancy between mouse studies on daily rifapentine (RPT) and
the failure to accelerate elimination of TB from sputum in the TBTC Study 29A, as daily RPT greatly increases the AUC but not the peak concentrations. High dosage rifampicin may be better able than RPT to cause high peaks.
Fear of negative evaluation has been linked with weight/shape concerns among adults, however, similar research among adolescents is lacking. We investigated the relationship between fear of negative ...evaluation and weight/shape concerns, including the moderating roles of gender and body mass index (BMI) in adolescents. Participant were 4045 Australian adolescents (53.7% girls) aged 11–19 years (
M
age
= 14 years 11 months), who completed a self-report questionnaire about weight/shape concerns, fear of negative evaluation, and weight and height. Results showed a positive association between fear of negative evaluation and weight/shape concerns, with the association being stronger among girls. Furthermore, the association between fear of negative evaluation and weight/shape concerns was stronger among adolescents with higher BMIs, especially so for boys. These results highlight the role of fear of negative evaluation in weight/shape concerns and suggest potential avenues for prevention programs.
Summary While we wait for improved new anti-tuberculosis drugs, the main aim for improving current treatment should be to optimize the use of the two current drugs, rifampicin and the pro-drug ...pyrazinamide, which are responsible to a similar extent for the entire sterilizing activity of current therapy. The rifamycin activity could be improved by increasing the dose size of rifampicin or by daily dosing with long acting rifapentine. Increasing the dose size of pyrazinamide is limited by toxicity but an alternative approach is to use inhalation with pyrazinoic acid, as an adjunct to standard oral therapy. This would acidify pulmonary lesions, thus increasing the bactericidal activity of the orally administered pyrazinamide. Because pyrazinoic acid is the active moiety, it should also increase overall pyrazinamide activity and, because most resistance arises in the pncA gene that converts pyrazinamide to pyrazinoic acid, it should act on most pyrazinamide resistant strains. Inhalation technology allows delivery of drug to lesions rapidly and without first pass toxicity. The properties of drug containing microparticles and nanoparticles during inhalation and storage are reviewed. Spray-dried larger Trojan particles in which the smaller encapsulated particles can reside should be able to improve localisation within alveoli and avoid some storage problems.
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