Several macrolides have been reported to cause QT prolongation and ventricular arrhythmias such as torsades de pointes. To clarify the underlying ionic mechanisms, we examined the effects of six ...macrolides on the human ether-a-go-go-related gene (HERG)-encoded potassium current stably expressed in human embryonic kidney-293 cells. All six drugs showed a concentration-dependent inhibition of the current with the following IC(50) values: clarithromycin, 32.9 microM; roxithromycin, 36.5 microM; erythromycin, 72.2 microM; josamycin, 102.4 microM; erythromycylamine, 273.9 microM; and oleandomycin, 339.6 microM. A metabolite of erythromycin, des-methyl erythromycin, was also found to inhibit HERG current with an IC(50) of 147.1 microM. These findings imply that the blockade of HERG may be a common feature of macrolides and may contribute to the QT prolongation observed clinically with some of these compounds. Mechanistic studies showed that inhibition of HERG current by clarithromycin did not require activation of the channel and was both voltage- and time-dependent. The blocking time course could be described by a first-order reaction between the drug and the channel. Both binding and unbinding processes appeared to speed up as the membrane was more depolarized, indicating that the drug-channel interaction may be affected by electrostatic responses.
Objective
To investigate the transplacental transfer of the macrolide antibiotics erythromycin, roxithromycin and azithromycin.
Methods
Twenty‐one term placentas were obtained with maternal consent ...immediately after delivery and a two‐hour nonrecirculating perfusion of a single placental cotyledon was performed. Erythromycin (2 μg/mL), roxithromycin (2 μg/mL) and azithromycin (0.3 μg/mL) were infused to the maternal inflow at a constant rate, with antipyrine as a reference compound, and their appearance in the fetal circulation was followed. Drug concentrations were measured by high performance liquid chromatography for 120 min.
Results
The mean transplacental transfers (TPTss) for erythromycin, roxithromycin and azithromycin were 3.0%, 4.3% and 2.6%, respectively, calculated as the ratio between the steady state concentrations in fetal venous and maternal arterial sides. Similar results were obtained when the TPT was calculated as the absolute amount of drug transferred across the placenta during 2‐hour perfusion (TPTA). No significant differences were found among the three macrolides in TPTSS (P= 0.39) or TPTA (P= 0.35). The TPTSS of erythromycin, roxithromycin and azithromycin were 41%, 35% and 32% of the freely diffusable reference compound antipyrine, respectively. Steady state was reached in 60 minutes in each perfusion indicating sufficient perfusion time.
Conclusion
The limited transplacental transfer of erythromycin, roxithromycin and azithromycin suggests compromised efficacy in the treatment of fetal infections. On the other hand, the placenta seems to produce an effective barrier reducing the fetal exposure when these three macrolides are used to treat maternal infections.
2 McMaster University,
Department of Biology, Hamilton, Ontario, Canada L8S 4K1; and
1 Department of Biological
Sciences, Hatherly Laboratories, University of Exeter,
Exeter, United Kingdom EX4 4PS
...The branchial uptake mechanism of the
nonessential heavy metal silver from very dilute media by the gills of
freshwater rainbow trout was investigated. At concentrations >36 nM
AgNO 3 , silver rapidly entered the
gills, reaching a peak at 1 h, after which time there was a
steady decline in gill silver concentration and a resulting increase in
body silver accumulation. Below 36 nM AgNO 3 , there was only a very
gradual increase in gill and body silver concentration over the 48-h
exposure period. Increasing water sodium concentration
(Na + ; 0.05 to 21 mM)
significantly reduced silver uptake, although, in contrast, increasing
ambient Ca 2+ or
K + up to 10 mM did
not reduce silver uptake. Kinetic analysis of silver uptake at varying
Na + showed a
significant decrease in maximal silver transport capacity (173 ± 34 pmol · g 1 · h 1 at 0.1 mM
Na + compared with 35 ± 9 at 13 mM
Na + )
and only a slight decrease in the affinity for silver transport ( K m ; 55 ± 27 nM at 0.1 mM Na +
compared with 91 ± 47 nM at 13 mM
Na + ). Phenamil (a
specific blocker of Na + channels),
at a concentration of 100 µM, blocked
Na + uptake by 78% of control
values (58% after washout), and bafilomycin A 1 (a specific blocker of V-type
ATPase), at a concentration of 2 µM, inhibited
Na + uptake by 57% of control
values, demonstrating the presence of a proton-coupled
Na + channel in the apical membrane
of the gills. Phenamil (after washout) and bafilomycin
A 1 also blocked silver uptake by
62 and 79% of control values, respectively, indicating that
Ag + is able to enter the apical
membrane via the proton-coupled
Na + channel.
silver transport; teleost; sodium channel; phenamil; bafilomycin
A 1
The Alexander Project was established in 1992 to examine the antimicrobial susceptibility of community-acquired lower respiratory tract bacterial pathogens to a range of compounds. Since then it has ...expanded both geographically and in the number of antimicrobial agents tested. Within Europe, the most recent data have confirmed that the prevalence of penicillin resistance among isolates of Streptococcus pneumoniae is high in France and Spain, with both intermediate (MIC 0.12-1 mg/L) and resistant (MIC > or = 2 mg/L) phenotypes, and combined resistance rates of >50%. Macrolide resistance is increasing generally both among penicillin-resistant and penicillin-susceptible isolates of S. pneumoniae and its prevalence now exceeds that of penicillin resistance, overall (16.5% and 10.4%, respectively, in 1996; 21.9% and 14.1% in 1997; 16.5% and 11.6% in 1998). Beta-lactamase production was the principal mechanism of resistance observed among isolates of Haemophilus influenzae and Moraxella catarrhalis.
Macrolide resistance in Streptococcus pneumoniae has been associated with two main mechanisms: target modification by Erm methyltransferases and efflux by macrolide pumps. The ketolide ABT-773, which ...has a 3-keto group and no L-cladinose sugar, represents a new class of drugs with in vitro activity against a variety of resistant bacteria. Several approaches were undertaken to understand how ABT-773 was able to defeat resistance mechanisms. We demonstrated tighter ribosome binding of ABT-773 than erythromycin. We also showed that ABT-773 (i) accumulated in macrolide-sensitive S. pneumoniae at a higher rate than erythromycin, (ii) was able to bind with methylated ribosomes, though at lower affinities than with wild-type ribosomes, and (iii) accumulated in S. pneumoniae strains with the efflux-resistant phenotype.
Recent semi-synthetic studies of erythromycin A culminated in the discovery of two ketolide drug candidates, HMR-3647 and ABT-773, for the treatment of community-acquired bacterial infections caused ...by both macrolide- and β-lactam-susceptible and -resistant S. pneumoniae, gram negative bacteria, and intracellular atypical pathogens. The discovery of ketolides has rekindled interest in macrolides, and recent efforts have also led to a novel class of 4"-carbamates with activity against macrolide-resistant organisms. This review is an account of recent developments on ketolides and macrolides in terms of both chemistry and antibacterial activity.
The azalide antibiotic azithromycin and the newer macrolides, such as clarithromycin, dirithromycin and roxithromycin, can be regarded as ‘advanced-generation’ macrolides compared with erythromycin, ...the first macrolide used clinically as an antibiotic. Their pharmacokinetics are characterized by a combination of low serum concentrations, high tissue concentrations and, in the case of azithromycin, an extended tissue elimination half-life. Azithromycin is particularly noted for high and prolonged concentrations at the site of infection. This allows once-daily dosing for 3 days in the treatment of respiratory tract infections, in contrast to longer dosage periods required for erythromycin, clarithromycin, roxithromycin and agents belonging to other classes of antibiotics. The spectrum of activity of the advanced-generation macrolides comprises Gram-positive, atypical and upper respiratory anaerobic pathogens. Azithromycin and the active metabolite of clarithromycin also demonstrate activity against community-acquired Gram-negative organisms, such as
Haemophilus influenzae. Advanced-generation macrolides, and in particular azithromycin, are highly concentrated within polymorphonuclear leucocytes, which gravitate by chemotactic mechanisms to sites of infection. Following phagocytosis of the pathogens at the infection site, they are exposed to very high, and sometimes cidal, intracellular concentrations of antibacterial agent. Pharmacodynamic models and susceptibility breakpoints derived from studies with other classes of drugs, such as the β-lactams and aminoglycosides, do not adequately explain the clinical utility of antibacterial agents that achieve high intracellular concentrations. In the case of azithromycin, attention should focus on tissue pharmacokinetic and pharmacodynamic concepts.
Fourteen-membered macrolides (e.g. clarithromycin and erythromycin), but not 16-membered macrolides (e.g. josamycin), are effective in diffuse panbronchiolitis. However, there are no studies that ...have compared the effects of 14- and 16-membered macrolide antibiotics on biofilm formation. Treatment with high-dose clarithromycin (100 mg/kg) resulted in a significant decrease in the number of viable bacteria in an experimental murine model. Josamycin at a dose of up to 100 mg/kg had no effect on the number of viable bacteria in the lung. Our results may explain, at least in part, the clinical efficacy of 14-membered macrolide antibiotics in patients with chronic pneumonia caused by Pseudomonas aeruginosa.
Background:
Clarithromycin is a semisynthetic macrolide that exhibits broad-spectrum activity against gram-positive, gram-negative, and atypical respiratory tract and skin/skin structure pathogens,
...Mycobacterium species, and
Helicobacter pylori. It is indicated for the treatment of a wide variety of respiratory and dermatologic infections in children and adults as well as prophylaxis and treatment of
Mycobacterium avium complex infection and peptic ulcers due to
H pylori.
Objective:
In this article, we review the results of 3 studies of the steady-state pharmacokinetic profiles of clarithromycin and 14(
R)-hydroxy-clarithromycin after multiple oral once-daily doses of 500-mg extended-release (ER) clarithromycin tablets. We also review the drug tolerability in 2 phase III comparative clinical trials of immediate-release (IR) and ER clarithromycin conducted in adults with acute maxillary sinusitis (AMS) and acute exacerbation of chronic bronchitis (AECB).
Methods:
In the 3 pharmacokinetic studies, multiple-dose regimens of clarithromycin IR (one 250-mg or 500-mg tablet twice daily) and clarithromycin ER (one or two 500-mg tablets once daily), administered to healthy male and female volunteers, were evaluated. The effect of administration in nonfasting versus fasting conditions was assessed as well. Tolerability information was collected from each adult patient enrolled in phase III efficacy studies conducted to support the application for US Food and Drug Administration approval for the treatment of AMS and AECB. Regimens evaluated were 500 mg IR clarithromycin tablets twice daily or 1000 mg (2 × 500 mg) ER clarithromycin tablets once daily for 7 days (AECB) or 14 days (AMS).
Results:
Bioavailability of the ER clarithromyin tablet administered with food was equivalent to that of the reference IR tablet, based on area under the plasma concentration-time curve (AUC) for both parent compound and active metabolite. The bioavailability of the ER tablet was 30% lower (based on clarithromycin AUC) when administered under fasting versus nonfasting conditions. Compared with the IR tablet, administration of the ER tablet resulted in significantly lower (
P < 0.05) clarithromycin peak plasma concentration (C
max), delayed time to C
max, and lower degree of concentration fluctuation, confirming its in vivo extended-release characteristics. The most frequently reported adverse events (AEs) in the phase III clinical trials were diarrhea, abnormal taste, and nausea and were generally mild or moderate. The incidence of AEs was comparable for the 2 formulations. The severity of gastrointestinal AEs was significantly less for the ER formulation than for the IR formulation (
P = 0.018), as was the frequency of premature study discontinuation due to gastrointestinal AEs or abnormal taste (
P = 0.004).
Conclusions:
The results from the 3 pharmacokinetic studies reviewed demonstrate the bioequivalence of the ER and IR formulations and support the use of this clarithromycin ER formulation in a once-daily dosing regimen in phase III clinical trials. The ER tablet should be taken with food to maximize bioavailability. The results of 2 phase III comparative clinical efficacy and safety trials of clarithromycin ER tablets versus IR tablets in AMS and AECB confirm the good tolerability of the ER formulation.
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