A cough that doesn’t fit the mould Lee, Mihye; Brindle, Richard
Clinical medicine (London, England),
June 2016, 2016-06-00, 20160601, Letnik:
16, Številka:
3
Journal Article
Summary
Background HIV infection is a major risk factor for pneumococcal disease in industrialised countries. Although both are common infections in sub-Saharan Africa, few studies have investigated ...the importance of this interaction. We have followed up a cohort of female sex-workers in Nairobi and report here on the extent of invasive pneumococcal disease.
Methods A well-established cohort of low-class female sex-workers, based around a community clinic, was followed up from October, 1989, to September, 1992. 587 participants were HIV positive and 132 remained HIV negative. Set protocols were used to investigate common presentations. Cases were identified clinically and radiographically. Streptococcus pneumoniae and other pathogens were diagnosed by culture.
Findings Seventy-nine episodes of invasive pneumococcal disease were seen in the 587 HIV-positive women compared with one episode in the 132 seronegative women (relative risk 17·8, 95% Cl 2·5 to 126·5). In seropositive women the incidence rate was 42·5 per 1000 person-years and the recurrence rate was 264 per 1000 person-years. By serotyping, most recurrent events were re-infection. A wide spectrum of HIV-related pneumococcal disease was seen: only 56% of cases were pneumonia; sinusitis was seen in 30% of cases, and occult bacteraemia, a novel adult presentation, in 11%. Despite forty-two bacteraemic episodes, no deaths were attributable to Strep pneumoniae. At first presentation the mean CD4 cell count was 302/μL (SD 191) and was 171/μL (105) for recurrent episodes. During acute Strep pneumoniae infection the CD4 cell count was reversibly suppressed (mean fall in sixteen episodes, 105/μL 123). The neutrophil response to acute infection was blunted and was correlated with CD4 count (r=0·50, 95% Cl 0·29 to 0·66). Strep pneumoniae caused more disease, at an earlier stage of HIV immunosuppression, than Mycobacterium tuberculosis or non-typhi salmonellae.
Interpretation Our study highlights the importance of the pneumococcus as an early but readily treatable complication of HIV infection in sub-Saharan Africa.
Since the sterilising activity of new antituberculosis drugs is difficult to assess by conventional phase III studies, surrogate methods related to eventual relapse rates are required.
A suitable ...method is suggested by a retrospective analysis of viable counts of Mycobacterium tuberculosis in 12-hr sputum collections from 122 newly diagnosed patients with pulmonary tuberculosis in Nairobi, done pretreatment and at 2, 7, 14 and 28 days. Treatment was with isoniazid and streptomycin, supplemented with either thiacetazone (SHT) or rifampicin + pyrazinamide (SHRZ).
During days 0-2, a large kill due to isoniazid occurred, unrelated to treatment or HIV status; thereafter it decreased exponentially. SHRZ appeared to have greater sterilising activity than SHT during days 2-7 (p = 0.044), due to rifampicin, and during days 14-28, probably due mainly to pyrazinamide. The greatest discrimination between SHRZ and SHT treatments was found between regression estimates of kill over days 2-28 (p = 0.0005) in patients who remained positive up to 28 days with homogeneous kill rates. No associations were found between regression estimates and the age, sex, and extent of disease or cavitation. An increased kill in HIV seropositive patients, unrelated to the treatment effect, was evident during days 2-28 (p = 0.007), mainly during days 2-7.
Surrogate marker studies should either be in small groups treated with monotherapy during days 2 to about 7 or as add-ons or replacements in isoniazid-containing standard regimens from days 2 to 28 in large groups.
Summary
Background
Ondansetron may be beneficial in irritable bowel syndrome with diarrhoea (IBS‐D).
Aim
To conduct a 12‐week parallel group, randomised, double‐blind, placebo‐controlled trial of ...ondansetron 4 mg o.d. (titrated up to 8 mg t.d.s.) in 400 IBS‐D patients. Primary endpoint: % responders using the Food and Drug Administration (FDA) composite endpoint. Secondary and mechanistic endpoints included stool consistency (Bristol Stool Form Scale) and whole gut transit time (WGTT). After literature review, results were pooled with other placebo‐controlled trials in a meta‐analysis to estimate relative risks (RR), 95% confidence intervals (CIs) and number needed to treat (NNT).
Results
Eighty patients were randomised. On intention‐to‐treat analysis, 15/37 (40.5%; 95% CI 24.7%–56.4%) met the primary endpoint on ondansetron versus 12/43 (27.9%; 95% CI 14.5%–41.3%) on placebo (p = 0.19). Ondansetron improved stool consistency compared with placebo (adjusted mean difference − 0.7; 95% CI −1.0 to−0.3, p < 0.001). Ondansetron increased WGTT between baseline and week 12 (mean (SD) difference 3.8 (9.1) hours, versus placebo −2.2 (10.3) hours, p = 0.01). Meta‐analysis of 327 patients from this, and two similar trials, demonstrated ondansetron was superior to placebo for the FDA composite endpoint (RR of symptoms not responding = 0.86; 95% CI 0.75–0.98, NNT = 9) and stool response (RR = 0.65; 95% CI 0.52–0.82, NNT = 5), but not abdominal pain response (RR = 0.95; 95% CI 0.74–1.20).
Conclusions
Although small numbers meant the primary endpoint was not met in this trial, when pooled with other similar trials meta‐analysis suggests ondansetron improves stool consistency and reduces days with loose stool and urgency.
Trial registration – http://www.isrctn.com/ISRCTN17508514
Objectives To establish whether local practice review and national methicillin-resistant Staphylococcus aureus (MRSA) treatment guidelines have increased the survival of patients with MRSA ...bacteraemia. Methods A multisite retrospective analysis of survival of patients with MRSA bacteraemia, which included patients from March 1995 to December 2008. Periods before and after the publication of UK guidelines were compared. Results Data were analysed for 1675 patients with a mean age of 69.8 years. Survival for the period up to and including 2003 was 64.3%, and was 62.8% for both 2004–2005 and 2006–2008. Conclusions No significant difference in survival in relation to local practice review or the publication of national guidelines was detected.
Most patients with irritable bowel syndrome (IBS) are managed in primary care. When first-line therapies for IBS are ineffective, the UK National Institute for Health and Care Excellence guideline ...suggests considering low- dose tricyclic antidepressants as second-line treatment, but their effectiveness in primary care is unknown, and they are infrequently prescribed in this setting.
This randomised, double-blind, placebo-controlled trial (Amitriptyline at Low-Dose and Titrated for Irritable Bowel Syndrome as Second-Line Treatment ATLANTIS) was conducted at 55 general practices in England. Eligible participants were aged 18 years or older, with Rome IV IBS of any subtype, and ongoing symptoms (IBS Severity Scoring System IBS-SSS score ≥75 points) despite dietary changes and first-line therapies, a normal full blood count and C-reactive protein, negative coeliac serology, and no evidence of suicidal ideation. Participants were randomly assigned (1:1) to low-dose oral amitriptyline (10 mg once daily) or placebo for 6 months, with dose titration over 3 weeks (up to 30 mg once daily), according to symptoms and tolerability. Participants, their general practitioners, investigators, and the analysis team were all masked to allocation throughout the trial. The primary outcome was the IBS-SSS score at 6 months. Effectiveness analyses were according to intention-to-treat; safety analyses were on all participants who took at least one dose of the trial medication. This trial is registered with the ISRCTN Registry (ISRCTN48075063) and is closed to new participants.
Between Oct 18, 2019, and April 11, 2022, 463 participants (mean age 48·5 years SD 16·1, 315 68% female to 148 32% male) were randomly allocated to receive low-dose amitriptyline (232) or placebo (231). Intention-to-treat analysis of the primary outcome showed a significant difference in favour of low-dose amitriptyline in IBS-SSS score between groups at 6 months (–27·0, 95% CI –46·9 to –7·10; p=0·0079). 46 (20%) participants discontinued low-dose amitriptyline (30 13% due to adverse events), and 59 (26%) discontinued placebo (20 9% due to adverse events) before 6 months. There were five serious adverse reactions (two in the amitriptyline group and three in the placebo group), and five serious adverse events unrelated to trial medication.
To our knowledge, this is the largest trial of a tricyclic antidepressant in IBS ever conducted. Titrated low-dose amitriptyline was superior to placebo as a second-line treatment for IBS in primary care across multiple outcomes, and was safe and well tolerated. General practitioners should offer low-dose amitriptyline to patients with IBS whose symptoms do not improve with first-line therapies, with appropriate support to guide patient-led dose titration, such as the self-titration document developed for this trial.
National Institute for Health and Care Research Health Technology Assessment Programme (grant reference 16/162/01).
Abstract
Background
Although cellulitis is a relatively common skin infection, there remains uncertainty about management, particularly the length and route of antimicrobials required. Further ...information on the symptomatology and biomarker changes associated with cellulitis over time would guide clinicians and patients as to the expected natural history.
Methods
We extracted data from a randomized clinical trial (NCT01876628) of clindamycin as adjunctive therapy in cellulitis to illustrate the evolution of local parameters (pain, swelling, local erythema, and warmth) and the resolution of biomarkers over time.
Results
Data from 247 individuals with mild to moderate unilateral lower limb cellulitis, who attended at least 1 face-to-face interview following recruitment, were used to examine response dynamics. Although there was a local improvement in swelling, warmth, erythema, and pain by day 5 compared with baseline, some individuals still had evidence of local inflammation at 10 days. Most biomarkers demonstrated a return to normal by day 3, although the initial fall in albumin only returned to baseline by day 10.
Conclusions
Although there was initial resolution, a significant number of individuals still had local symptoms persisting to day 10 and beyond. Clinicians can use these data to reassure themselves and their patients that ongoing local symptoms and signs after completion of antibiotic treatment do not indicate treatment failure or warrant extension of the initial antibiotic treatment or a change in antibiotic class or mode of administration.
Using data routinely collected during a clinical trial we describe the natural history of antibiotic-treated lower limb cellulitis. Importantly, a significant number of individuals still have local symptoms that persist up to 10 days and beyond.
These evidence-based guidelines are an updated version of those published in 2006. They have been produced after a literature review of the treatment and prophylaxis of methicillin-resistant ...Staphylococcus aureus (MRSA). The guidelines aim to complement those recently published for the antibiotic treatment of common and emerging community-onset MRSA infections in the UK. The guidelines have reviewed and updated, where appropriate, previous recommendations, taking into account any changes in the UK epidemiology of MRSA, ongoing national surveillance data and the value of new antistaphylococcal agents licensed for use in UK practice. Emerging therapies that have not been licensed for UK use are not reviewed, but their future potential role has been mentioned where deemed appropriate. Recommendations are given for the treatment of common infections caused by MRSA, elimination of MRSA from carriage sites and prophylaxis of surgical site infection.
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