Macrolides and ketolides: azithromycin, clarithromycin, telithromycin

The advanced macrolides, azithromycin and clarithromycin, and the ketolide telithromycin are structural analogues of erythromycin. They have several distinct advantages when compared with erythromycin including enhanced spectrum of activity, more favorable pharmacokinetics and pharmacodynamics, once daily administration, and improved tolerability. This article reviews the pharmacokinetics, antimicrobial activity, clinical use, and adverse effects of these antimicrobial agents.     

Macrolides,ketolides and streptogramins

Macrolides, ketolides and streptogramins are three families of antibiotics with different chemical structures, sharing the same mechanism of action. All three bind to distinct bases of the peptidyl transferase center of ARNr 23S. Their antibacterial spectrum practically overlaps, but dissimilarities in affinity and/or number of binding sites determine differences in the intensity of their antibacterial effects (bacteriostatic or bactericidae) and in their activity against strains with acquired resistance mechanisms. These agents are active against the majority of gram-positive microorganisms and many intracellular microorganisms for growth. Over the last five years in our country, the percentage of macrolide-resistant pneumococci and S. pyogenes strains has increased substantially. Telithromycin (ketolide) and Synercid (streptogramin) have shown maintained activity against these strains. Macrolides, ketolides and streptogramins are metabolized in the liver through CYP 3A4 and they can partially block the activity of the enzyme, interfering with the metabolism of other drugs that use the same metabolic pathway. There is little elimination through the urine, with the exception of clarithromycin. High concentrations are reached in the cellular cytoplasm, but they do not diffuse to the CSF. These agents are included among class B drugs for use during pregnancy. Tolerance to macrolides and telithromycin is good and they have few associated adverse effects. The main clinical indication for these drugs is in empirical treatment of mild to moderate, community-acquired, upper and lower respiratory tract infections. Synercid is indicated in the treatment of infections due to methicillin-resistant staphylococci and glycopeptide-resistant enterococci.     

Azithromycin Triple Therapy for Helicobacter pylori Infection: Azithromycin, Tetracycline, and Bismuth

Background : Azithromycin is new acid-stable macrolide that achieves 10- to 40-fold higher tissue levels than erythromycin after oral dosing. Important to note, the tissue half-life of azithromycin is measured in days instead of hours. Method : We evaluated two new triple therapies for Helicobacter pylori infection in which azithromycin was substituted for metronidazole either as 250 mg b.l.d . or t.l.d . along with tetracycline 500 mg q.ld . and bismuth subsalicylate 2 tablets q.l.d . for 14 days. H. pylori status was determined by histology before and 6 wk or more after therapy. Results : Thirty men with documented H. pylori peptic ulcers completed therapy. Twenty-one also received ranitidine (300 mg in the evening) along with the antimicrobial therapy. H. pylori infection was successfully treated in 15 (50%) (95% CI = 31-69%). The cure rate was significantly higher with the 250-mg-t.i.d .-azithromycin dosage regime (83%) (95% CI = 52-98%) compared to the 250-mg-b.i.d .-dosage regime (28%) (95% CI = 10-53%) ( p < 0.01). Troublesome side effects were experienced by the majority of those receiving azithromycin t.l.d. Conclusion : We conclude that although 750 mg or more of azithromycin might eventually be able to replace metronidazole or clarithromycin in standard triple therapy, additional studies are required to identify a regime that is both effective and tolerable.     

Macrolides, quinolones and amoxicillin/clavulanate for chronic bronchitis: a meta-analysis.

The comparative effectiveness and safety of macrolides, quinolones and amoxicillin/clavulanate (A/C) for the treatment of patients with acute bacterial exacerbation of chronic bronchitis (ABECB) was evaluated in the present study. PubMed, Current Contents and the Cochrane Central Register of Controlled Trials were searched to identify relevant randomised controlled trials (RCTs). In total, 19 RCTs (20 comparisons) were included in the present analysis. There was no difference regarding treatment success in intention-to-treat and clinically evaluable patients between macrolides and quinolones, A/C and quinolones or A/C and macrolides. The treatment success in microbiologically evaluable patients was lower for macrolides compared with quinolones (odds ratio (OR) 0.47, 95% confidence interval (CI) 0.31-0.69). Fewer quinolone-recipients experienced a recurrence of ABECB after resolution of the initial episode compared with macrolide-recipients during the 26-week period following therapy. Adverse effects in general were similar between macrolides and quinolones. Administration of A/C was associated with more adverse effects (mainly diarrhoea) than quinolones (OR 1.36, 95% CI 1.01-1.85). Macrolides, quinolones and amoxicillin/clavulanate may be considered equivalent for the treatment of patients with an acute bacterial exacerbation of chronic bronchitis in terms of short-term effectiveness. Quinolones are associated with better microbiological success and fewer recurrences of acute bacterial exacerbation of chronic bronchitis than macrolides, while amoxicillin/clavulanate is associated with more adverse effects than both comparators.     

Immune Agranulocytosis and Clarithromycin

Previous in vitro studies suggest that erythrocytes may be a source of nitric oxide (NO) produced by nitric oxide synthase (NOS) or by oxyhemoglobin-mediated oxidation of hydroxyurea (HU). This study was performed to determine the roles of HU and NOS in the production of NO by normal and sickle erythrocytes. Red blood cells (RBCs) from normal adult hemoglobin (HbAA) and homozygous sickle cell subjects (HbSS) were incubated with PBS containing 0.2 mM hydrogen peroxide (control) for 2 h at 37°C in the presence and absence of L-arginine, the substrate for NOS, and with L-arginine plus HU in the presence and absence of L-NMMA, a specific inhibitor of NOS. The nitrate and nitrite metabolites of NO, expressed as [NOx], were measured. [NOx] in the HbAA and HbSS RBC cultures was not significantly different in the presence and absence of 1.0 mM L-arginine (p > 0.1). [NOx] in the HbAA and HbSS cultures treated with a clinically relevant dose of HU (1.0 mM) plus 1.0 mM L-arginine was significantly greater than that in controls incubated with PBS and with L-arginine p < 0.01. However, [NOx] in the HbAA and HbSS cultures treated with 50 μg/ml L-NMMA was not significantly different than that in the cultures treated with HU plus L-arginine in the absence of L-NMMA. These findings suggest that NOx production by erythrocytes may be increased by treatment with HU and may not be decreased by inhibiting NOS. Therefore, we conclude that a therapeutic dose of HU may increase the plasma concentration of NO by a mechanism that does not require erythrocytes NOS activity     

Clarithromycin, Tetracycline, and Bismuth: A New Non-Metronidazole Therapy for Helicobacter pylori Infection

Objective: Metronidazole resistance has become an increasing problem that has limited the usefulness of the original triple therapy. Our objective was to evaluate clarithromycin, a new macrolide compound active against Helicobacter pylori. Methods: We evaluated a new clarithromycin triple therapy for H. pylori infection consisting of the combination of clarithromycin (500 mg t.i.d .), tetracycline (500 mg q.i.d .), and bismuth subsalicylate tablets (2 q.i.d.) for 14 days. Patients with ulcer also received concomitant ranitidine, 300 mg after the evening meal, for 6 wk. Results: Thirty men with documented H. pylori infection were studied; 29 had peptic ulcer disease. Seven had previously failed antimicrobial therapy, including three with metronidazole-based triple therapy. H. pylori status was determined by histology. H. pylori status and ulcer status were evaluated 4 wk after the end of antimicrobial therapy. The ulcer was healed in 90%. The H. pylori infection was cured in 93%, including all three patients who previously failed metronidazole-based triple therapy. Conclusion: We conclude that the combination of clarithromycin, tetracycline, and bismuth is an effective new therapy for treatment of H. pylori infection.     

One-Week Triple Therapy With Ranitidine Bismuth Citrate, Clarithromycin and Metronidazole Versus Two-Week Dual Therapy With Ranitidine Bismuth Citrate and Clarithromycin for Helicobacter pylori Infection: A Randomized, Clinical Trial

Objective: The aim of this study was to compare the efficacy and side effects of 1-wk triple therapy with ranitidine bismuth citrate (RBC) 400 mg b.i.d. , clarithromycin 500 mg b.i.d. , and metronidazole 500 mg b.i.d. , to 2-wk dual therapy with RBC 400 mg b.i.d. and clarithromycin 500 mg b.i.d. for H. pylori infection in a randomized, clinical trial.
Methods: Patients (18–80 yr) with a culture proven H. pylori infection were randomized to one of these regimens. Side effects were scored on a semiquantitative scale. Endoscopy was performed ≥4 wk after treatment. Antral biopsy samples were taken for hematoxylin-eosin stain (HE), rapid urease test, and culture and corpus samples for culture and HE. Two weeks after the endoscopy, a ¹³C-urea breath test was performed. Eradication failure was defined as detection of H. pylori by culture or by at least two other tests.
Results: A total of 104 patients, 54 men, age 54 ± 14 yr, (36 duodenal ulcer, 16 gastric ulcer, and 52 functional dyspepsia) were included. Gender, age, and diagnosis were comparable in both groups. Fourteen of 52 patients in both triple and dual therapy, respectively, had significant side effects, but all patients completed the course. Eradication results were 49 of 52 (94%; 95% CI: 84–99%) and 50 of 52 (96%; 95% CI: 87–100%) on intention to treat analysis and 44 of 46 (96%; 95% CI: 85–99%) and 48 of 49 (98%; 95% CI: 89–100%) on per protocol analysis for triple and dual therapy respectively.
Conclusion: Both regimens are very effective and well tolerated in the treatment of H. pylori infection. The triple regimen has the advantage of being shorter.     

奥美拉唑和克拉霉素及阿莫西林三联疗法治疗肝源性溃疡疗效观察

目的观察奥美拉唑、克拉霉素、阿莫西林三联疗法治疗肝源性溃疡的疗效。方法经胃镜确诊的肝源性溃疡患者58例,随机分为治疗组(31例)和对照组(27例)。两组患者均给予综合治疗。治疗组患者给予奥美拉唑20mg,口服,2次/d;克拉霉素500mg,口服,2次/d;阿莫西林1000mg,口服,2次/d。对照组单用奥美拉唑20mg,口服,2次/d。十二指肠溃疡治疗2周,胃溃疡治疗3周。疗程结束后,用内窥镜观察溃疡愈合情况。结果治疗组和对照组溃疡愈合率分别为87.0%和55.5%,差异有统计学意义(P<0.01);治疗后6个月和12个月,治疗组溃疡复发率分别为14.8%和18.5%,对照组分别为33.3%和40.0%,差异均有统计学意义(P<0.01)。结论奥美拉唑、克拉霉素、阿莫西林三联疗法治疗肝源性溃疡临床效果显著。     

Macrolides: A Canadian Infectious Disease Society position paper.

Since the introduction of erythromycin in 1965, no new compounds from the macrolide antimicrobial class were licensed in Canada until the 1990s. Clarithromycin and azithromycin, since their introduction, have become important agents for treating a number of common and uncommon infectious diseases. They have become prime agents in the treatment of respiratory tract infections, and have revolutionized the management of both genital chlamydial infections, by the use of single-dose therapy with azithromycin, and nontuberculous mycobacterial infections, by the use of clarithromycin. The improvement of clarithromycin and azithromycin over the gastrointestinal intolerability of erythromycin has led to supplanting the use of the latter for many primary care physicians. Unfortunately, the use of these agents has also increased the likelihood for misuse and has raised concerns about a resultant increase in the rates of macrolide resistance in many important pathogens, such as Streptococcus pneumoniae. This paper reviews the pharmacology and evidence for the current indications for use of these newer agents, and provides recommendations for appropriate use.     

Clarithromycin in the treatment of RSV bronchiolitis: a double-blind, randomised, placebo-controlled trial.

Respiratory syncytial virus (RSV) bronchiolitis is the most common lower respiratory tract infection in infancy. To date, there is no effective therapy for RSV bronchiolitis. In order to investigate the efficacy of clarithromycin in the treatment of RSV bronchiolitis, the present authors conducted a randomised, double-blind, placebo-controlled trial comparing clarithromycin with placebo in 21 infants with a diagnosis of RSV bronchiolitis. The infants were randomised to receive clarithromycin or placebo daily for 3 weeks. Levels of interleukin (IL)-4, IL-8, eotaxin, and interferon-gamma were determined in plasma, before and after treatment, using ELISA. Six months after treatment, parents were surveyed as to whether their child had experienced wheezing within the previous 6 months. Treatment with clarithromycin was associated with a statistically significant reduction in the length of hospital stay, the duration of need for supplemental oxygen and the need for beta(2)-agonist treatment. There were significant decreases in plasma IL-4, IL-8 and eotaxin levels after 3 weeks of treatment with clarithromycin. Readmission to the hospital within 6 months after discharge was significantly lower in the clarithromycin group. In conclusion, clarithromycin has statistically significant effects on the clinical and laboratory findings in respiratory syncytial virus bronchiolitis. Therefore, clarithromycin treatment may be helpful in reducing the short-term effects of respiratory syncytial virus bronchiolitis.