Our primary goal has been to discover leukotriene biosynthesis inhibitors with characteristics that are appropriate for use as clinical agents. The success of the use of zileuton in the treatment of asthma led us to explore further the use of the N-hydroxyurea class of 5-lipoxygenase inhibitors as longer-acting compounds with good lung penetration. A variety of in vitro and in vivo methods were used to evaluate a large number of compounds, from which ABT-761 [(R)-N-(3-(5-(4-fluorophenylmethyl)thien-2-yl)-1-methyl-2-pr opynyl)-N-hydroxyurea] was selected for study. ABT-761 exhibited potent and selective inhibition of leukotriene formation both in vitro and in vivo. More importantly, the compound potently inhibited antigen-induced bronchospasm in guinea pigs when given either prophylactically or therapeutically. In addition, ABT-761 was a potent inhibitor of eosinophil influx into the lungs of Brown Norway rats. These data provide added support for the role of leukotrienes in both bronchospasm and eosinophilic inflammation and characterize ABT-761 as a particularly potent inhibitor of leukotrienes formed in pulmonary tissues. These data combined with the excellent pharmacokinetic characteristics of the compound indicate its potential use in the treatment of leukotriene-dependent human disease.
To evaluate adherence to antibiotic recommendations for the treatment of pneumonia in patients who receive long-term care and to assess outcomes associated with these recommendations.
A prospective cohort study.
Twenty-two facilities that provide long-term care in southern Ontario.
Older adults treated with antibiotics for a presumptive diagnosis of pneumonia and those with radiologically confirmed pneumonia
Over a 12-month period, older patients who were treated with antibiotics for presumptive pneumonia were prospectively identified. A random sample of these antibiotic courses (646 courses in 638 patients) was reviewed using a standardized data collection form, and demographic and clinical data were collected. Antibiotic courses were classified according to Canadian and American Thoracic Society antibiotic recommendations for pneumonia. In patients with radiologically confirmed pneumonia, the effect of adherence to these recommendations on mortality and persistence of symptoms was assessed.
Only 27.6% (178 of 646) of antibiotic prescriptions evaluated met antibiotic recommendations for nursing-home-acquired pneumonia, and the proportion meeting these varied greatly by facility, ranging from 0% to 53% (median 31%). For patients with radiologically confirmed pneumonia, age (adjusted odds ratio [OR] 1.6, 95% confidence interval [CI] 1.0-2.4, per increase in 10 yr, p = 0.02), sex (adjusted OR 3.0, 95% CI 1.1-8.0, p = 0.03), and adherence to recommended antibiotics (OR 3.0, 95% CI 1.3-7.2, p = 0.01) were associated with death. Adherence to the recommended antibiotics was also associated with adverse reactions, which occurred in 10% of prescriptions meeting the recommendations (OR 2.4, 95% CI 1.3-4.6, p = 0.01).
Adherence to recommended guidelines for antibiotic treatment was low and highly variable among study facilities. Use of recommended antibiotic regimens was associated with increased adverse events and worse outcomes in patients with radiologically confirmed pneumonia.
Management guidelines for acute community acquired pneumonia vary considerably. The objective is to estimate by a retrospective study the uniformity of the recommendations for the management of patients and the choice of initial empirical antibiotic therapy.
Eight English and French language guidelines published between 1998 and 2001 were identified by a search of the literature. They were applied retrospectively to a sample of 101 patients admitted to a university hospital in 2000 with a diagnosis of pneumonia.
Hospital admission was advocated for between 61% and 95% and admission to intensive care for between 8% and 35% of the patients, depending on the guidelines under consideration. The actual management conformed to that advocated for between 34% and 94% of the patients (kappa=0.27 [0,19; 0,34]). Compliance of the empirical antibiotic therapy (drug, dose, mode of administration) with the recommendations varied from 0% to 68% of the patients depending on the guidelines considered (kappa=0.01 [-0,10; 0,12]).
The heterogeneity of the guidelines is manifest by important variations in the recommendations for management and initial empirical therapy. These differences are due, in part, to a paucity of evidence based data upon which to base the guidelines. It would appear essential to harmonise the guidelines in a way that is appropriate for the country of their intended use.
Comment In: Rev Mal Respir. 2003 Dec;20(6 Pt 1):841-314743083
A comprehensive study was undertaken to examine morbidity due nosocomial pneumonia. An epidemiological survey demonstrated a growth in morbidity and mortality from this disease among the adult population of the Republic of Tatarstan. Pharmacological and epidemiological survey indicated that antibacterial therapy was in conformity with the federal protocols in 43.9% of cases, revealed the optimization of the use of antibacterial agents after introduction of the federal standards. At the same time the low social status of patients dying from pneumonia was accompanied by their appeal for medical aid, which leads to late hospitalization and untimely intensive therapy.
Appropriate antibiotic prescribing is associated with favourable levels of antimicrobial resistance (AMR) and clinical outcomes. Most intervention studies on antibiotic prescribing originate from settings with high level of AMR. In a Norwegian hospital setting with low level of AMR, the literature on interventions for promoting guideline-recommended antibiotic prescribing in hospital is scarce and requested. Preliminary studies have shown improvement potentials regarding antibiotic prescribing according to guidelines. We aimed to promote appropriate antibiotic prescribing in patients with community-acquired pneumonia (CAP) and acute exacerbations of chronic obstructive pulmonary disease (AECOPD) at a respiratory medicine department in a Norwegian University hospital. Our specific objectives were to increase prescribing of appropriate empirical antibiotics, reduce high-dose benzylpenicillin and reduce total treatment duration.
We performed an audit and feedback intervention study, combined with distribution of a recently published pocket version of the national clinical practice guideline. We included patients discharged with CAP or AECOPD and prescribed antibiotics during hospital stay, and excluded those presenting with aspiration, nosocomial infection and co-infections. The pre- and post-intervention period was 9 and 6 months, respectively. Feedback was provided orally to the department physicians at an internal-educational meeting. To explore the effect of the intervention on appropriate empirical antibiotics and mean total treatment duration we applied before-after analysis (Student's t-test) and interrupted time series (ITS). We used Pearson's ?2 to compare dose changes.
In the pre-and post-intervention period we included 253 and 155 patients, respectively. Following the intervention, overall mean prescribing of appropriate empirical antibiotics increased from 61.7 to 83.8 % (P
Pneumococci are a leading cause of bacterial meningitis and bacteraemia, as well as pneumonia, otitis media and sinusitis in childhood. These organisms recently have shown a dramatic increase in antibiotic resistance. Penicillin-resistant pneumococci are of special concern as they are often resistant to other unrelated antibiotics. This is of particular significance to Aboriginal children who have among the highest rates of pneumococcal infection in the world. Laboratories should now test all invasive pneumococcal isolates for penicillin and third generation cephalosporin resistance. Local treatment guidelines are required for pneumococcal infections, especially for meningitis, taking into account the prevalence of resistant strains within the community. At present, penicillin and amoxycillin remain the drugs of choice for pneumococcal infections, with the exception of meningitis where initial empirical therapy must be with a third generation cephalosporin. Judicious antibiotic use, which avoids over-prescribing and unnecessary use of broad-spectrum agents, improved living standards in underprivileged communities and introduction of an effective conjugate vaccine, able to reduce the rates of pneumococcal infection and hopefully colonization, may limit the spread of resistant strains.
Benzylpenicillin versus wide-spectrum beta-lactam antibiotics as empirical treatment of Haemophilus influenzae-associated lower respiratory tract infections in adults; a retrospective propensity score-matched study.
There is consensus that definitive therapy for infections with H. influenzae should include antimicrobial agents with clinical breakpoints against the bacterium. In Scandinavia, benzylpenicillin is the recommended empirical treatment for community-acquired pneumonia (CAP) except in very severe cases. However, the effect of benzylpenicillin on H. influenzae infections has been debated. The aim of this study was to compare the outcomes of patients given benzylpenicillin with patients given wide-spectrum beta-lactams (WSBL) as empirical treatment of lower respiratory tract H. influenzae infections requiring hospital care. We identified 481 adults hospitalized with lower respiratory tract infection by H. influenzae, bacteremic and non-bacteremic. Overall, 30-day mortality was 9% (42/481). Thirty-day mortality, 30-day readmission rates, and early clinical response rates were compared in patients receiving benzylpenicillin (n?=?199) and a WSBL (n?=?213) as empirical monotherapy. After adjusting for potential confounders, empirical benzylpenicillin treatment was not associated with higher 30-day mortality neither in a multivariate logistic regression (aOR 2.03 for WSBL compared to benzylpenicillin, 95% CI 0.91-4.50, p?=?0.082), nor in a propensity score-matched analysis (aOR 2.14, 95% CI 0.93-4.92, p?=?0.075). Readmission rates did not significantly differ between the study groups, but early clinical response rates were significantly higher in the WSBL group (aOR 2.28, 95% CI 1.21-4.31, p?=?0.011), albeit still high in both groups (84 vs 81%). In conclusion, despite early clinical response rates being slightly lower for benzylpenicillin compared to WSBL, we found no support for increased mortality or readmission rates in patients empirically treated with benzylpenicillin for lower respiratory tract infections by H. influenzae.