The first macrolide, erythromycin A, demonstrated broad-spectrum antimicrobial activity and was used primarily for respiratory and skin and soft tissue infections. Newer 14-, 15- and 16-membered ring macrolides such as clarithromycin and the azalide, azithromycin, have been developed to address the limitations of erythromycin. The main structural component of the macrolides is a large lactone ring that varies in size from 12 to 16 atoms. A new group of 14-membered macrolides known as the ketolides have recently been developed which have a 3-keto in place of the L-cladinose moiety. Macrolides reversibly bind to the 23S rRNA and thus, inhibit protein synthesis by blocking elongation. The ketolides have also been reported to bind to 23S rRNA and their mechanism of action is similar to that of macrolides. Macrolide resistance mechanisms include target site alteration, alteration in antibiotic transport and modification of the antibiotic. The macrolides and ketolides exhibit good activity against Gram-positive aerobes and some Gram-negative aerobes. Ketolides have excellent activity versus macrolide-resistant Streptococcus spp. Including mefA and ermB producing Streptococcus pneumoniae. The newer macrolides, such as azithromycin and clarithromycin, and the ketolides exhibit greater activity against Haemophilus influenzae than erythromycin. The bioavailability of macrolides ranges from 25 to 85%, with corresponding serum concentrations ranging from 0.4 to 12 mg/L and area under the concentrationtime curves from 3 to 115 mg/L ⋅ h. Half-lives range from short for erythromycin to medium for clarithromycin, roxithromycin and ketolides, to very long for dirithromycin and azithromycin. All of these agents display large volumes of distribution with excellent uptake into respiratory tissues and fluids relative to serum. The majority of the agents are hepatically metabolised and excretion in the urine is limited, with the exception of clarithromycin. Clinical trials involving the macrolides are available for various respiratory infections. In general, macrolides are the preferred treatment for communityacquired pneumonia and alternative treatment for other respiratory infections. These agents are frequently used in patients with penicillin allergies. The macrolides are well-tolerated agents. Macrolides are divided into 3 groups for likely occurrence of drug-drug interactions: group 1 (e.g. erythromycin) are frequently involved, group 2 (e.g. clarithromycin, roxithromycin) are less commonly involved, whereas drug interactions have not been described for group 3 (e.g. azithromycin, dirithromycin). Few pharmacoeconomic studies involving macrolides are presently available. The ketolides are being developed in an attempt to address the increasingly prevalent problems of macrolide-resistant and multiresistant organisms.

Review of macrolides and ketolides: focus on respiratory tract infections

Background
Antibiotics provide only modest benefit in treating sore throat, although effectiveness increases in participants with positive throat swabs for group A beta-haemolytic streptococci (GABHS). It is unclear which antibiotic is the best choice if antibiotics are indicated.

Objectives
To assess the evidence on the comparative efficacy of different antibiotics in: (a) alleviating symptoms (pain, fever); (b) shortening the duration of the illness; (c) preventing relapse; and (d) preventing complications (suppurative complications, acute rheumatic fever, post-streptococcal glomerulonephritis). To assess the evidence on the comparative incidence of adverse effects and the risk-benefit of antibiotic treatment for streptococcal pharyngitis.

Search methods
We searched CENTRAL (2016, Issue 3), MEDLINE Ovid (1946 to March week 3, 2016), Embase Elsevier (1974 to March 2016), and Web of Science Thomson Reuters (2010 to March 2016). We also searched clinical trials registers.

Selection criteria
Randomised, double-blind trials comparing different antibiotics and reporting at least one of the following: clinical cure, clinical relapse, or complications or adverse events, or both.

Data collection and analysis
Two review authors independently screened trials for inclusion, and extracted data using standard methodological procedures as recommended by Cochrane. We assessed risk of bias of included studies according to the methods outlined in the Cochrane Handbook for Systematic Reviews of Interventions and used the GRADE tool to assess the overall quality of evidence for the outcomes.

Main results
We included 19 trials (5839 randomised participants); seven compared penicillin with cephalosporins, six compared penicillin with macrolides, three compared penicillin with carbacephem, one trial compared penicillin with sulphonamides, one trial compared clindamycin with ampicillin, and one trial compared azithromycin with amoxicillin in children. All included trials reported clinical outcomes. Reporting of randomisation, allocation concealment, and blinding was poor in all trials. The overall quality of the evidence assessed using the GRADE tool was low for the outcome 'resolution of symptoms' in the intention-to-treat (ITT) analysis and very low for the outcomes 'resolution of symptoms' of evaluable participants and for adverse events. We downgraded the quality of evidence mainly due to lack of (or poor reporting of) randomisation or blinding, or both, heterogeneity, and wide confidence intervals (CIs).

There was a difference in symptom resolution in favour of cephalosporins compared with penicillin (evaluable patients analysis odds ratio (OR) for absence of resolution of symptoms 0.51, 95% CI 0.27 to 0.97; number needed to treat to benefit (NNTB) 20, N = 5, n = 1660; very low quality evidence). However, this was not statistically significant in the ITT analysis (OR 0.79, 95% CI 0.55 to 1.12; N = 5, n = 2018; low quality evidence). Clinical relapse was lower for cephalosporins compared with penicillin (OR 0.55, 95% CI 0.30 to 0.99; NNTB 50, N = 4, n = 1386; low quality evidence), but this was found only in adults (OR 0.42, 95% CI 0.20 to 0.88; NNTB 33, N = 2, n = 770). There were no differences between macrolides and penicillin for any of the outcomes. One unpublished trial in children found a better cure rate for azithromycin in a single dose compared to amoxicillin for 10 days (OR 0.29, 95% CI 0.11 to 0.73; NNTB 18, N = 1, n = 482), but there was no difference between the groups in ITT analysis (OR 0.76, 95% CI 0.55 to 1.05; N = 1, n = 673) or at long-term follow-up (evaluable patients analysis OR 0.88, 95% CI 0.43 to 1.82; N = 1, n = 422). Children experienced more adverse events with azithromycin compared to amoxicillin (OR 2.67, 95% CI 1.78 to 3.99; N = 1, n = 673). Compared with penicillin carbacephem showed better symptom resolution post-treatment in adults and children combined (ITT analysis OR 0.70, 95% CI 0.49 to 0.99; NNTB 14, N = 3, n = 795), and in the subgroup analysis of children (OR 0.57, 95% CI 0.33 to 0.99; NNTB 8, N = 1, n = 233), but not in the subgroup analysis of adults (OR 0.75, 95% CI 0.46 to 1.22, N = 2, n = 562). Children experienced more adverse events with macrolides compared with penicillin (OR 2.33, 95% CI 1.06 to 5.15; N = 1, n = 489). Studies did not report on long-term complications so it was unclear if any class of antibiotics was better in preventing serious but rare complications.

Authors' conclusions
There were no clinically relevant differences in symptom resolution when comparing cephalosporins and macrolides with penicillin in the treatment of GABHS tonsillopharyngitis. Limited evidence in adults suggests cephalosporins are more effective than penicillin for relapse, but the NNTB is high. Limited evidence in children suggests carbacephem is more effective than penicillin for symptom resolution. Data on complications are too scarce to draw conclusions. Based on these results and considering the low cost and absence of resistance, penicillin can still be regarded as a first choice treatment for both adults and children. All studies were in high-income countries with low risk of streptococcal complications, so there is need for trials in low-income countries and Aboriginal communities where risk of complications remains high.

https://biblio.ugent.be/publication/8551618/file/8551619.pdf

Different antibiotic treatments for group A streptococcal pharyngitis

Aloe vera has wide spread use in health products, and despite several reports on the whole plant and inner gel, little work has been performed on the leaf exudate. Our aim was to evaluate the in vitro efficacy of Aloe vera leaf exudate (AVL) in leishmaniasis. Irrespective of the disease manifestation, promastigotes from strains responsible for cutaneous, mucocutaneous, and visceral leishmaniasis were susceptible to AVL and their IC(50) ranged from 100 to 180 microg/ml. In axenic amastigotes cultured from a L. donovani strain 2001 responsible for visceral leishmaniasis, the IC(50) was 6.0 microg/ml. AVL caused activation of host macrophages evident by an increased release of members of reactive oxygen species that was attenuated by preincubation with free radical scavengers. Collectively, our data indicates that AVL, via its direct leishmanicidal activity which can be further enhanced by activation of host macrophages, is an effective antileishmanial agent meriting further pharmacological investigations.

In vitro antileishmanial activity of Aloe vera leaf exudate: a potential herbal therapy in leishmaniasis.

In a meta-analysis of two identically designed, well-controlled, randomized, double-blind clinical trials, we compared 5 days of dirithromycin with 7 days of erythromycin for acute exacerbations of chronic bronchitis. Five hundred and thirty-one patients were randomized to receive dirithromycin (500 mg od) for 5 days and 526 patients were randomized to receive erythromycin (250 mg qid) for 7 days. Clinical and bacteriological responses were assessed 3-5 days after therapy and at termination from the study. Adverse events were collected from both groups and compared with each other, before and after treatment. Of the 690 patients clinically appraisable at the post-therapy visit, 298 (84.2%) dirithromycin-treated patients and 270 (80.4%) erythromycin-treated patients showed a favourable response. At termination, 273 (77.1%) dirithromycin-treated patients and 243 (72.3%) erythromycin-treated patients showed a favourable response. The microbiological cure was equivalent in the two groups (75% of dirithromycin-treated patients and 74.1% of erythromycin-treated patients showed a favourable response at termination). After therapy, dirithromycin was as effective as erythromycin in eradicating Streptococcus pneumoniae (77.8% vs 90.9%), Haemophilus influenzae (71.7% vs 72.2%), Moraxella catarrhalis (93.3% vs 88.9%) and Staphylococcus aureus (81.8% vs 82.1%). Although not statistically significant, fewer dirithromycin-treated patients reported adverse events than did erythromycin-treated patients. Nausea (6.8% vs 7.8%), headache (7.3% vs 8.2%) and diarrhoea (6.6% vs 9.5%) were the most frequently reported adverse events in both groups. In the treatment of acute exacerbations of chronic bronchitis, 5 days of dirithromycin is as effective as 7 days of erythromycin.

Five-day dirithromycin therapy is as effective as seven-day erythromycin therapy for acute exacerbations of chronic bronchitis

There are many examples of physicians using treatments inappropriately, despite clear evidence about the circumstances under which the benefits of such treatments outweigh their harms. When such over- or under- use of treatments occurs for common diseases, the burden to the healthcare system and risks to patients can be substantial. We propose that a major contributor to inappropriate treatment may be how clinicians judge the likelihood of important treatment outcomes, and how these judgments influence their treatment decisions. The current study will examine the role of judged outcome probabilities and other cognitive factors in the context of two clinical treatment decisions: 1) prescription of antibiotics for sore throat, where we hypothesize overestimation of benefit and underestimation of harm leads to over-prescription of antibiotics; and 2) initiation of anticoagulation for patients with atrial fibrillation (AF), where we hypothesize that underestimation of benefit and overestimation of harm leads to under-prescription of warfarin. For each of the two conditions, we will administer surveys of two types (Type 1 and Type 2) to different samples of Canadian physicians. The primary goal of the Type 1 survey is to assess physicians' perceived outcome probabilities (both good and bad outcomes) for the target treatment. Type 1 surveys will assess judged outcome probabilities in the context of a representative patient, and include questions about how physicians currently treat such cases, the recollection of rare or vivid outcomes, as well as practice and demographic details. The primary goal of the Type 2 surveys is to measure the specific factors that drive individual clinical judgments and treatment decisions, using a 'clinical judgment analysis' or 'lens modeling' approach. This survey will manipulate eight clinical variables across a series of sixteen realistic case vignettes. Based on the survey responses, we will be able to identify which variables have the greatest effect on physician judgments, and whether judgments are affected by inappropriate cues or incorrect weighting of appropriate cues. We will send antibiotics surveys to family physicians (300 per survey), and warfarin surveys to both family physicians and internal medicine specialists (300 per group per survey), for a total of 1,800 physicians. Each Type 1 survey will be two to four pages in length and take about fifteen minutes to complete, while each Type 2 survey will be eight to ten pages in length and take about thirty minutes to complete. This work will provide insight into the extent to which clinicians' judgments about the likelihood of important treatment outcomes explain inappropriate treatment decisions. This work will also provide information necessary for the development of an individualized feedback tool designed to improve treatment decisions. The techniques developed here have the potential to be applicable to a wide range of clinical areas where inappropriate utilization stems from biased judgments.

/pdf/do-physician-outcome-judgments-and-judgment-biases-1w0pcftvgu.pdf

Do physician outcome judgments and judgment biases contribute to inappropriate use of treatments? Study protocol

In the treatment of group A beta-hemolytic streptococcal pharyngitis, penicillin is the drug of choice and erythromycin is the alternative. In a double-blind, randomized study, dirithromycin, a new macrolide, was compared with penicillin for the treatment of streptococcal pharyngitis. Of 121 patients who were treated with dirithromycin, 96.7% manifested a favorable clinical response, and of 136 patients treated with penicillin, 94.2% manifested a favorable clinical response. Streptococci were eradicated from the pharynges of 85.3% of 116 dirithromycin-treated patients and 82.5% of 126 penicillin-treated patients who returned for follow-up. There were no statistically significant differences in efficacy between the two groups. The incidence of abdominal symptoms was higher in dirithromycin-treated patients. Being as efficacious as penicillin and having the advantages over erythromycin of once-daily dosing and the lack of drug interactions, dirithromycin is an alternative to penicillin in the treatment of streptococcal pharyngitis for patients 12 years of age and older.

Comparison of dirithromycin and penicillin for treatment of streptococcal pharyngitis.

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Comparison of dirithromycin and penicillin for treatment of streptococcal pharyngitis.