Azithromycin studies

O Doherty, B. (1996). Azithromycin versus penicillin V in the treatment of paediatric patients with acute streptococcal pharyngitis/tonsillitis. Paediatric Azithromycin Study Group. Eur. J. Clin. Microbiol. Infect. Dis. 15, 718-724. 

Felstead, S. J., Daniel, R., and European Azithromycin Study Group (1991). Short-course treatment of sinusitis and other upper respiratory tract infections with azithromycin A comparison with erythromycin and amoxycillin. J. Int. Med. Res. 19, 363-372. 

In a recent study, Walters et al. [141] described the occurrence and loss of several PhC from biosolid-soil mixtures exposed at ambient outdoor conditions for 3 years. Some compounds showed no detectable loss over the monitoring period, including diphenhydramine, fluoxetine, thiabendazole and triclosan, while half-life estimates ranging from 182 to 3,466 days were determined for others such as azithromycin, carbamazepine, ciprofloxacin, doxycycline, tetracycline, 4-epitetracycline, gemfibrozil, norfloxacin and triclosan. These findings highlight the potential use of T. versicolor to reduce the impact of biosolids once released to the environment, which could reduce the concentrations of PhC in much shorter periods of treatment. 

Clindamycin (see Chapter 44) is slowly active against erythrocytic schizonts and can be used after treatment courses of quinine, quinidine, or artesunate in those for whom doxycycline is not recommended, such as children and pregnant women. Azithromycin (see Chapter 44) also has antimalarial activity and is now under study as an alternative chemoprophylactic drug. Antimalarial activity of fluoroquinolones has been demonstrated, but efficacy for the therapy or chemoprophylaxis of malaria has been suboptimal. 

Cethromycin (ABT-773) 39 (Advanced Life Sciences) had an NDA filed in October 2008 for the treatment of CAP.67 Advanced Life Sciences is also evaluating cethromycin 39 against other respiratory tract infections and in pre-clinical studies as a prophylactic treatment of anthrax post-exposure. Cethromycin 3968 70 is a semi-synthetic ketolide derivative of erythromycin 4071 originally synthesised by Abbott Laboratories,72 which like erythromycin 40, inhibits bacterial protein synthesis through binding to the peptidyl-transferase site of the bacterial 50S ribosomal subunit. Important macrolide antibiotics in clinical use today include erythromycin 40 itself, clarithromycin, azithromycin and, most recently, telithromycin (launched in 2001). 

In an open, randomized, crossover, pharmacokinetic and pharmacodynamic study in 12 healthy volunteers who took clarithromycin 250 mg bd for 5 days, azithromycin 500 mg/day for 3 days, or no pretreatment, followed by a single dose of midazolam (15 mg), clarithromycin increased the AUC of midazolam by over 3.5 times and the mean duration of sleep from 135 to 281 minutes (69). In contrast, there was no change with azithromycin, suggesting that it is much safer for co-administration with midazolam. 

In a randomized, double-bhnd, pharmacokinetic-pharmacodynamic study, 12 volunteers took placebo or triazolam 0.125 mg orally, together with placebo, azithromycin, erythromycin, or clarithromycin. The apparent oral clearance of triazolam was significantly reduced by erythromycin and clarithromycin. The peak plasma concentration was correspondingly increased, and the half-life was prolonged. The effects of triazolam on dynamic measures were nearly identical when triazolam was given with placebo or azithromycin, but benzodiazepine agonist effects were enhanced by erythromycin and clarithromycin (23). 

Formation of this carbinolamine bond is revealed by the continuous electron density that connects the aldehyde group of the antibiotic to Hm A2103 in the unbiased electron density maps obtained for each of the 16-membered macrolides studied to date, each of which has an aldehyde group extending from C6. Not surprisingly, that continuous electron density feature is absent in the unbiased electron density map calculated for the structure of the 15-membered macrolide azithromycin which has no aldehyde group at C6. The electron density feature is consistent with formation of a carbinolamine bond and not with a SchifFbase, consistent with the expected chemical reactivity between exocyclic amines and aldehydes (Fig. 4.9) [21]. 

Tabbara KF, Abu-el-Asrar A, al-Otnare O, et al. Single dose azithromycin in the treatment of trachoma. A randomized controlled study. Ophthalmology 1996 103 842-846. 

Two other agents show promise in treatment of ocular toxoplasmosis. Atovaquone, primarily used for mild to moderate episodes of Pneumocystis carinii pneumonia, has been effective in small series of patients with toxoplasmosis. It appears to have activity against both tachy-zoites and tissue cysts. More recent studies on atovaquone in toxoplasmosis are limited to murine models, and no further reports on this drug therapy in humans have been published. Azithromycin, a macrolide antibiotic, is efficacious against T. gondii and can also kill tissue cysts. A randomized study of 46 patients compared the combinations of azithromycin plus pyrimethamine versus pyrimethamine plus sulfadiazine in treatment of ocular toxoplasmosis efficacy was similar, but the azithromycin/ pyrimethamine regimen caused less adverse effects. 

Human babesiosis has been traditionally treated with quinine plus clindamycin, a combination that has been compared with atovaquone plus azithromycin in a randomized, multicenter, unblinded study (7). The treatments... 

The tolerabihty of azithromycin oral suspension, 10 mg/ kg od for 3 days, has been assessed in children in a review of 16 multicenter studies (7). Of 2425 patients, 1213 received azithromycin and 1212 received other drugs. The incidence of treatment-related adverse events was significantly lower in those who took azithromycin, while withdrawal rates were similar. There were significantly fewer gastrointestinal events with azithromycin and their duration was significantly shorter. 

Torsade de pointes and cardiorespiratory arrest have been reported in a patient with congenital long QT syndrome who took azithromycin (20). In a prospective study of 47 previously healthy people, there was a modest statistically insignificant prolongation of the QT interval without clinical consequences after the end of a course of azithromycin 3 g/day for 5 days (21). 

Azithromycin can cause ototoxicity. In one study, 8 (17%) of 46 HIV-positive patients had probable (n = 6) or possible (n = 2) ototoxicity with azithromycin (22). The effects were... 

The effects of combining azithromycin and rifabutin have been studied in 50 subjects with or without HIV infection, of whom 19 took azithromycin 1200 mg/day and rifabutin 600 mg/day, and 31 took azithromycin 600 mg/day and rifabutin 300 mg/day (28). Neutropenia was the most common adverse event, in 33 of 50 subjects. Low-grade nausea, diarrhea, fatigue, and headache were also common, and most subjects had more than one type of event. There was no significant pharmacokinetic interaction between the two drugs. 

In a review of 12 clinical studies most of the adverse events in those taking azithromycin affected the gastrointestinal system, and were reported in 138 (8.5%) azithromycin-treated patients (29). Abdominal pain, diarrhea, nausea, and vomiting were the most frequently reported gastrointestinal adverse events. 

The effects of azithromycin 250 mg/day on the pharmacokinetics of desloratadine 5 mg/day and fexofenadine 60 mg bd have been studied in a parallel-group, third-party-blind, multiple-dose, randomized, placebo-controlled study (46). There were small increases (under 15%) in the mean plasma concentrations of desloratadine. In contrast, peak fexofenadine concentrations were increased by 69% and the AUC by 67%. There were no changes in the electrocardiogram. 

The potential interaction of azithromycin with terfenadine has been evaluated in a randomized, placebo-controlled study in 24 patients who took terfenadine plus azithromycin or terfenadine plus placebo (52). Azithromycin did not alter the pharmacokinetics of the active carboxylate metabolite of terfenadine or the effect of terfenadine on the QT interval. 

In two double-blind, randomized, placebo-controlled studies there was no inhibition of the metabolism of theophylline by azithromycin (53,54). However, there has been a report of reduced theophylline concentrations after withdrawal of azithromycin (55). The authors concluded that the mechanism of interaction was best explained by concomitant induction and inhibition of theophylline metabolism by azithromycin, followed by increased availability of unbound enzyme sites as azithromycin was cleared from the system. 

Jacobson JM, Hafner R, Remington J, Farthing C, Holden-Wiltse J, Bosler EM, Harris C, Jayaweera DT, Roque C, Luft BJ ACTG 156 Study Team. Dose-escalation, phase I/II study of azithromycin and pyrimethamine for the treatment of toxoplasmic encephalitis in AIDS. AIDS 2001 15(5) 583-9. 

Hafner R, Bethel J, Standiford HC, Follansbee S, Cohn DL, Polk RE, Mole L, Raasch R, Kumar P, Mushatt D, Drusano G DATRI (X)1B Study Group. Tolerance and pharmacokinetic interactions of rifabutin and azithromycin. Antimicrob Agents Chemother 2001 45(5) 1572-7. 

Gupta S, Banfield C, Kantesaria B, Marino M, Clement R, Affrime M, Batra V. Pharmacokinetic and safety profile of desloratadine and fexofenadine when coadministered with azithromycin a randomized, placebo-controlled, parallel-group study. Clin Ther 2001 23(3) 451-66. 

The effect of co-administration of azithromycin on plasma concentrations of desloratadine has been examined in a randomized third-party-blind, placebo-controlled, parallel-group study in 90 healthy volunteers (18). An initial loading dose of azithromycin (500 mg) was given on day 3, followed by 250 mg od for 4 days. Concomitant azithromycin had little effect (<15%) on either the C ax or AUC of desloratadine, and there were no statistically significant increases in the PR, QT, QTc interval, QRS complex duration, or ventricular rate after administration of desloratadine with or without azithromycin. 

In a large study vaginitis and vulvitis were detected by prescription event monitoring in a significantly higher proportion of women taking fluoroquinolones than women taking azithromycin or cefixime (19). 

The most prominent adverse reaction of the lincosamides is diarrhea, which varies from mildly loose bowel movements to life-threatening pseudomembranous colitis (see monograph on Beta-lactam antibiotics). Almost all antimicrobial drugs have been associated with severe diarrhea and colitis however, lincomycin and clindamycin have been particularly incriminated. The incidence of clindamycin-induced diarrhea in hospital is 23%. Diarrhea resolves promptly after withdrawal in most cases. It seems to be dose-related and may result from a direct action on the intestinal mucosa. Severe colitis due to C. difficile is not dose-related and occurs in 0.01-10% of recipients. Clustering of cases in time and place suggests the possibility of cross-infection. Even low doses of clindamycin, in some cases after topical administration, can cause marked alterations in several intestinal functions related to bowel flora (23). There was reduced susceptibility of C. difficile to clindamycin in 80% of French isolates in 1997 (24). Lincomycin was among the antibiotics that were most often associated with the development of antibiotic-associated diarrhea in a Turkish study of 154 patients other associated antibiotics were azithromycin and ampicillin (25). 

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