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Down-regulation of motilin receptors on rabbit colon myocytes by chronic oral erythromycin.

Acutely, erythromycin stimulates colonic smooth muscle contraction via action on motilin receptors, but the effects of chronic erythromycin exposure are unknown. Thus contraction and motilin binding studies were performed on rabbit colonic smooth muscle after 2 weeks of oral erythromycin ethyl succinate (25 mg/kg, twice a day). Isolated colon myocytes from untreated rabbits contracted to erythromycin with an EC50 of 30 +/- 17 pM and peak shortening of 24.1 +/- 0.8% at 10 nM. Motilin evoked similar contractions with an EC50 of 63 +/- 13 pM and peak shortening of 26.8 +/- 0.9% at 10 nM. Myocytes from treated rabbits exhibited reduced contractile responses to erythromycin with an EC50 of 203 +/- 27 pM (P < .002) and decreased peak shortening to 20.1 +/- 2.9% at 100 nM (P < .05). Motilin responses were also blunted [EC50 of 326 +/- 16 pM, peak shortening of 16.2 +/- 1.2% at 1 microM (P < .002)]. [125I]motilin binding to untreated colon smooth muscle homogenates was saturable and specific with a Kd of 0.53 +/- 0.10 nM and a Bmax of 48 +/- 6 fmol/mg protein. Muscle from treated rabbits exhibited no change in motilin receptor affinity (Kd = 0.50 +/- 0.08 nM) but showed a 63% reduction in receptor density (Bmax = 18 +/- 4 fmol/mg protein; P < .03). In conclusion, chronic erythromycin administration results in decreased contractile potency and efficacy of motilin and erythromycin on colonic myocytes, associated with decreased motilin receptor density but no change in receptor affinity. Thus chronic erythromycin exposure leads to tolerance to its colonic smooth muscle motor effects via motilin receptor down-regulation.

Administration, Oral↗

The effect of erythromycin on motility of the duodenum, sphincter of Oddi, and gallbladder in the prairie dog.

BACKGROUND: Interdigestive motility of the stomach, duodenum, sphincter of Oddi, and gallbladder is mediated through the migrating myoelectric complex and the action of motilin. Erythromycin, a motilin agonist, has recently been studied as a gastrointestinal and biliary prokinetic agent. We hypothesized that erythromycin would increase interdigestive duodenal and sphincter of Oddi motility in a dose-dependent manner. METHODS: In 10 anesthetized prairie dogs we determined the motility responses of the duodenum, sphincter of Oddi, and gallbladder to erythromycin infusion during a three-log dosing regimen and correlated activity with serum concentrations of the drug. RESULTS: Erythromycin administered at 0.01 and 0.1 mg/kg had no effect on duodenal or sphincter motility. At 1.0 and 10 mg/kg, duodenal motility index increased by 451% +/- 114% and 1070% +/- 480%, respectively, when compared with baseline values, (p < 0.05). Sphincter of Oddi motility index increased by 122% +/- 38% and 323% +/- 99%, respectively, at these same doses of erythromycin (p < 0.05). Gallbladder pressure did not change significantly during erythromycin infusion. Erythromycin serum concentration at 1.0 mg/kg was 1.0 +/- 0.7 micrograms/ml. CONCLUSIONS: These data suggest that erythromycin stimulates interdigestive motility of the duodenum and sphincter of Oddi in a dose-dependent manner at otherwise subtherapeutic concentrations of the drug.

Animals↗

Effect of erythromycin on Haemophilus influenzae endotoxin-induced release of IL-6, IL-8 and sICAM-1 by cultured human bronchial epithelial cells.

Although several studies have demonstrated that low-dose, long-term erythromycin treatment is effective in the management of patients with chronic lower respiratory tract infections, such as chronic bronchitis, bronchiolitis and bronchiectasis, the mechanisms underlying the action of erythromycin are not clear. We have cultured human bronchial epithelial cells (HBEC) as explant cultures from surgical tissue, and have investigated the effect of erythromycin on H. influenzae endotoxin (HIE)-induced release of inflammatory mediators in these cultures. Confluent epithelial cell cultures were incubated with 100 micrograms.mL-1 HIE +/- 0.1-10 micrograms.mL-1 erythromycin and were investigated for interleukin-6 (IL-6), interleukin-8 (IL-8) and soluble intercellular adhesion molecule-1 (sICAM-1) released into the culture medium after 24 h. HIE significantly increased the release of IL-6 from 3.9 +/- 1.5 pg.micrograms-1 cellular protein (in control untreated cultures) to 12.1 +/- 1.5 pg.micrograms-1 cellular protein, and IL-8 from 83.7 +/- 8.2 pg.micrograms-1 cellular protein (in control cultures) to 225.7 +/- 44.8 pg.micrograms-1 cellular protein. Similarly, HIE led to a significantly greater release of sICAM-1 from 0.04 +/- 0.01 ng.microgram-1 cellular protein, in control cultures, to 3.8 +/- 0.9 ng.microgram-1 cellular protein. Incubation of the epithelial cultures in the presence of 0.1-10 micrograms.mL-1 erythromycin significantly blocked the HIE-induced release of IL-6, IL-8, and sICAM-1, at all concentrations of erythromycin investigated. Erythromycin also attenuated neutrophil chemotaxis and adhesion to human endothelial cells, mediated by incubation with conditioned medium obtained from HIE-exposed epithelial cell cultures, in vitro. These results suggest that H. influenzae-induced release of inflammatory mediators from airway epithelial cells could contribute to chronic airway inflammation, and that this effect may be modulated by treatment with erythromycin.

Anti-Bacterial Agents↗

Erythromycin in the Treatment of Diabetic Gastroparesis.

The macrolide antibiotic erythromycin has been known to be associated with increased gastrointestinal motility since its introduction more than 35 years ago. Investigators have, thus, sought to take advantage of this side effect in patients with gastric stasis secondary to long-standing insulin-dependent diabetes mellitus (IDDM). The hormone motilin induces phase 3 contractions of the migrating motor complex (MMC) to induce peristalsis and facilitate gastric emptying in normal subjects. Patients with diabetic gastroparesis lack adequate phase 3 activity to effectively empty gastric contents. Exogenous motilin administered to animals and patients with diabetic gastroparesis has proven useful for promoting gastric emptying. However, motilin is expensive to produce and must be given intravenously. Erythromycin has been shown to induce premature phase 3 activity via stimulation of motilin receptors, so investigators evaluated its efficacy for the treatment of diabetic gastroparesis. Early studies in animals with experimental gastroparesis indicated that erythromycin may be a useful prokinetic agent. Human studies of both intravenous erythromycin and chronic oral erythromycin in patients with diabetic gastroparesis resistant to other prokinetic agents showed that gastric retention was indeed reduced and symptomatic improvement achieved. Even though erythromycin lost some of its prokinetic activity with chronic oral dosing, gastric retention was still significantly reduced compared to placebo or baseline. Although prokinetic agents like metoclopramide, domperidone and cisapride are effective for the treatment of patients with diabetic gastroparesis, tachyphylaxis and adverse effects are obstacles to their use. Erythromycin appears to be both effective and well tolerated in clinical studies. At this time it should be reserved for the treatment of patients with diabetic gastroparesis who are resistant to or intolerant of other prokinetic agents. Future research on erythromycin's long-term safety and comparative efficacy will further define its role.

Journal Article↗

Streptococcal pharyngitis therapy. A comparison of two erythromycin formulations.

The recommended dosage of erythromycin, without regard to the formulation prescribed, for children with streptococcal pharyngitis is 30 to 40 mg/kg/day. We previously reported an acceptable streptococcal eradication rate among patients with pharyngitis treated with erythromycin estolate, 20 mg/kg/day. In this study, an extension of the earlier one, the efficacy of this same dosage of erythromycin estolate was compared with a 40 mg/kg/day dosage of erythromycin ethylsuccinate. Streptococcal eradication rates were nearly identical in the two groups of patients. The efficacy of erythromycin estolate at a dosage lower than that recommended for children is most likely explained on pharmacologic grounds: better absorption and higher levels in serum and tissue than those achieved with other erythromycin formulations. It seems rational to calculate required dosages of erythromycin on the basis of the formulation being administered.

Antibodies, Bacterial↗

Erythromycin estolate impairs the mitochondrial and microsomal calcium homeostasis: correlation with hepatotoxicity.

The effects of erythromycin estolate, a well known hepatotoxic macrolide antibiotic, on isolated rat hepatocyte viability and on subcellular Ca2+ transport have been investigated. Erythromycin estolate (0.5 mM), but not erythromycin base and erythromycin ethylsuccinate, induced 100% cell death after 60 min incubation, and caused maximal inhibition of mitochondrial and microsomal Ca2+ sequestration activities at 0.1 mM concentration. Sodium lauryl sulphate, which is the surfactant moiety of the erythromycin estolate molecule, caused effects similar to those exhibited by erythromycin estolate. Disorders of the intracellular calcium homeostasis seem to play a role in the lauryl sulphate-mediated hepatotoxic action of erythromycin estolate.

Animals↗

The penetration of erythromycin into Waldeyer's ring--tonsil and adenoid tissue.

Erythromycin ethylsuccinate was given orally (30-60 mg/kg/day) to 72 otherwise healthy children for different intervals before adenoidectomy. The concentration of erythromycin was assessed in homogenized tissue, in whole blood and in plasma, making it possible to calculate blood-free tissue levels. The tissue levels (1.5-2.0 mg/l) were the same as the plasma levels. Six patients with chronic tonsillitis were given 1000 mg erythromycin ethylsuccinate via a gastric tube, and tonsillectomy à froid was performed three to five hours later. This unusual mode of administration was chosen to avoid tonsil surface contamination, which might cause artificially high values. The concentration of erythromycin was assessed as described above. The levels of erythromycin in the tonsil tissue were the same as the concomitant plasma levels. Erythromycin has been shown to penetrate into adenoid and tonsil tissue and to attain levels similar to the simultaneous plasma levels. It may be inferred from this study that erythromycin penetrates into other lymphatic localities to the same degree.

Adenoidectomy↗

Cefadroxil monohydrate versus erythromycin in paediatric patients.

Cefadroxil monohydrate, an oral cephalosporin with a long half-life, was compared to erythromycin estolate for efficacy in treating upper respiratory tract infections in children. The study was carried out on forty patients, twenty receiving cefadroxil and twenty receiving erythromycin. Each drug was dosed at 50 mg/kg/day and was given every 12 hours in two equally divided doses. The complete cure rate was 95% for the cefadroxil group and 80% for the erythromycin group. Two patients originally in the erythromycin test group showed no improvement either bacteriologically or clinically after 3 days of treatment. It was found that these patients harboured S. aureus which had become resistant to erythromycin during the course of therapy. Both patients were shifted to cefadroxil treatment and achieved complete cures. Two patients in the erythromycin group and one in the cefadroxil group were diagnosed as having scarlet fever. All three responded clinically, yet cultures from the two treated with erythromycin showed persistence of bacteria while the one treated with cefadroxil proved to be cured both clinically and bacteriologically.

Cefadroxil↗

Comparison of two oral forms of erythromycin in the treatment of acute respiratory tract infections. A multicentre general practice study.

A total of 1244 patients with acute upper or lower respiratory tract infection were randomized to receive, twice daily for 7 days, either capsules of enteric-coated pellets of erythromycin base at a dose of 1 g/day or erythromycin ethylsuccinate tablets at a dose of 2 g/day in a single-blind, multicentre study. The efficacy of each formulation was similar, with about 90% of patients who had completed at least 5 days of treatment being reported as either cured or improved. Gastro-intestinal symptoms were the most commonly reported side-effects, being significantly more frequent in patients receiving erythromycin base. Gastro-intestinal intolerance was also the main reason for discontinuing either treatment, although it was a significantly more frequent reason in patients given erythromycin base. This study indicates that both formulations of erythromycin are highly effective for routine, empirical treatment of acute respiratory tract infections. Erythromycin base, however, appears to be less well tolerated than erythromycin ethylsuccinate.

Acute Disease↗

Absorption of erythromycin. A cross-over study in healthy volunteers.

The absorptions of 6 erythromycin preparations were compared in a cross-over study in healthy humans. In a single-dose study, 500 mg of each preparation was, after an overnight fast, given to 10 volunteers. The two enterosoluble preparations of erythromycin base studied were absorbed slowly, and the peak serum concentration (1.5-2 mg/l) was achieved only at 4 h. The absorption of the stearates was quick, but especially one of them was poorly absorbed, the serum concentration being always below 1 mg/l. Both of the two estolates gave highest apparent concentrations, and the maximum serum level (2-2.5 mg/l) was achieved at 2 h, but the concentration of active erythromycin remains unknown. In the second part of the study, two erythromycin stearates and one base preparation were given at 6-h interval in a cross-over fashion, each for 4 days. On the 4th day, blood samples were analyzed. The erythromycin base gave higher serum concentrations than did the two stearates, which were equivalent. It seems doubtful that the erythromycin stearate at the dose of 250 mg every 6th hour would give satisfactory serum levels of erythromycin which would be effective against most bacteria during the whole treatment.

Biopharmaceutics↗

Azithromycin vs cefuroxime plus erythromycin for empirical treatment of community-acquired pneumonia in hospitalized patients: a prospective, randomized, multicenter trial.

OBJECTIVE: To compare the efficacy and safety of azithromycin dihydrate monotherapy with those of a combination of cefuroxime axetil plus erythromycin as empirical therapy for community-acquired pneumonia in hospitalized patients. METHODS: Patients were enrolled in a prospective, randomized, multicenter study. The standard therapy of cefuroxime plus erythromycin was consistent with the American Thoracic Society, Canadian Community-Acquired Pneumonia Consensus Group, and Infectious Disease Society of America consensus guidelines. The doses were intravenous azithromycin (500 mg once daily) followed by oral azithromycin (500 mg once daily), intravenous cefuroxime (750 mg every 8 hours), followed by oral cefuroxime axetil (500 mg twice daily), and erythromycin (500-1000 mg) intravenously or orally every 6 hours. Randomization was stratified by severity of illness and age. Patients who were immunosuppressed or residing in nursing homes were excluded. RESULTS: Data from 145 patients (67 received azithromycin and 78 received cefuroxime plus erythromycin) were evaluable. Streptococcus pneumoniae and Haemophilus influenzae were isolated in 19% (28/145) and 13% (19/145), respectively. The atypical pathogens accounted for 33% (48/145) of the etiologic diagnoses; Legionella pneumophila, Chlamydia pneumoniae, and Mycoplasma pneumoniae were identified in 14% (20/ 145), 10% (15/145), and 9% (13/145), respectively. Clinical cure was achieved in 91% (61/67) of the patients in the azithromycin group and 91% (71/78) in the cefuroxime plus erythromycin group. Adverse events (intravenous catheter site reactions, gastrointestinal tract disturbances) were significantly more common in patients who received cefuroxime plus erythromycin (49% [30/78]) than in patients who received azithromycin (12% [8/67]) (P<.001). CONCLUSIONS: Treatment with azithromycin was as effective as cefuroxime plus erythromycin in the empirical management of community-acquired pneumonia in immunocompetent patients who were hospitalized. Azithromycin was well tolerated.

Anti-Bacterial Agents↗

Very early exposure to erythromycin and infantile hypertrophic pyloric stenosis.

OBJECTIVE: To assess the link between very early erythromycin exposure and pyloric stenosis in young infants. DESIGN: Retrospective cohort study. PARTICIPANTS AND METHODS: Medicaid or TennCare (Tennessee's program for Medicaid enrollees and uninsured individuals) births in Tennessee from 1985 to 1997. Cases of infants with a hospital discharge diagnosis of pyloric stenosis and an associated surgical procedure code were used. Erythromycin exposure and other antibiotic exposure between 3 and 90 days of life were identified from prescription files. MAIN OUTCOME MEASURES: Hospital discharge diagnosis of pyloric stenosis, and an associated surgical procedure code. RESULTS: Of 933 239 births in Tennessee during the study period, 314 029 were enrolled in Medicaid. Among these infants, 804 (2.6/1000 infants) met the criteria for pyloric stenosis. Very early exposure to erythromycin (between 3 and 13 days of life) was associated with a nearly 8-fold increased risk of pyloric stenosis (adjusted incident rate ratio, 7.88; 95% confidence interval, 1.97-31.57). No increased risk of pyloric stenosis was seen in infants exposed to erythromycin after 13 days of life or in infants exposed to antibiotics other than erythromycin. CONCLUSIONS: The significant increase in pyloric stenosis in children with very early exposure to erythromycin is consistent with reports of other investigators. The risks and benefits of erythromycin should be weighed carefully prior to initiating such therapy in young infants.

Anti-Bacterial Agents↗

Oral erythromycin prophylaxis vs watchful waiting in caring for newborns exposed to Chlamydia trachomatis.

BACKGROUND: Chlamydia trachomatis exposure at birth may cause conjunctivitis or pneumonia. Until recently, a course of oral erythromycin prophylaxis was recommended for C trachomatis-exposed neonates. However, recognition of an association between erythromycin and pyloric stenosis prompted a change to a watchful waiting recommendation under which only infants who develop symptomatic C trachomatis infection are treated with oral erythromycin. OBJECTIVE: To compare erythromycin prophylaxis with watchful waiting for a hypothetical cohort of 100 000 neonates exposed to C trachomatis. METHODS: In a decision tree, potential outcomes were C trachomatis conjunctivitis, C trachomatis pneumonia (which could require inpatient or outpatient therapy), no clinical disease, and pyloric stenosis. Published data were reviewed to derive probability point estimates and ranges. Estimated charges served as outcome measures. RESULTS: Watchful waiting is less expensive than erythromycin prophylaxis ($15.1 million vs $28.3 million); prophylaxis prevents 5986 cases of C trachomatis pneumonia, including 1197 hospital admissions, but causes 3284 pyloric stenosis cases. (For every 30 infants given oral erythromycin prophylaxis, one additional case of pyloric stenosis would be expected to occur, and approximately 1.8 cases of C trachomatis pneumonia would be prevented.) In sensitivity analyses, if more than 3.4% of exposed neonates are hospitalized for C trachomatis pneumonia, prophylaxis becomes favored. CONCLUSIONS: This study supports the watchful waiting recommendation for asymptomatic C trachomatis-exposed neonates. However, there are wide plausible ranges for pyloric stenosis risk after erythromycin administration and for the incidence of C trachomatis pneumonia severe enough to require hospitalization; under some combinations of these rates, prophylaxis could be favored.

Anti-Bacterial Agents↗

The effects of erythromycin on theophylline elimination in normal males.

The effects of three erythromycin preparations on theophylline elimination kinetics were examined in 23 male subjects. Subjects received 6 mg/kg of the theophylline elixir orally and elimination kinetics were determined. The population was then randomized to receive either a lactose placebo, erythromycin base, erythromycin stearate, or erythromycin ethylsuccinate. Each 250-mg preparation was given four times a day for six days. On day seven, a repeat kinetic study was performed. The mean theophylline half-life of controls was 7.8 +/- 2.6 hours. The half-life increased significantly in all erythromycin treatment groups. The increase for the base, stearate, and ethylsuccinate groups was 51.7, 21.3, and 60.3 per cent, respectively. The total body theophylline clearance decreased significantly in all treatment groups. This was not associated with biochemical evidence of hepatitis. Three of four smokers who received erythromycin manifested no increase in theophylline half-life, in contrast to one of 13 nonsmokers. There was no difference in the percentage theophylline bound to serum protein for any of the erythromycin treatment groups or controls as determined by ultracentrifugation.

Adult↗

Effect of a high-fat meal on the bioavailability of a polymer-coated erythromycin particle tablet formulation.

The effect of food on the relative bioavailability of an erythromycin particles-in-tablet formulation was studied in 27 healthy volunteers, using a four-way, crossover study design with the following treatments: one or two erythromycin capsules USP (Eryc, Parke-Davis), or one polymer-coated erythromycin particles-in-tablet (PCE, Abbott) administered fasting or with a high-fat meal. Under fasting conditions the erythromycin particles-in-tablet and erythromycin capsule formulations are bioequivalent based on similar tmax and dose-normalized Cmax and AUC values. The rate and extent of absorption from the particles-in-tablet formulation, however, are dramatically reduced following administration with a meal. Mean Cmax and AUC values decreased by 73% and 72%, respectively, and seven subjects had no detectable erythromycin plasma concentrations for 16 hours following administration of the particles-in-tablet formulation with the high-fat meal. Greater than 40% of the subjects had nonfasting Cmax and AUC values that were less than 10% of those values following administration of the dose fasting. Cmax and AUC values in nonfasting subjects were within 75% to 125% of fasting values in only two and one of 27 subjects, respectively. The erythromycin particles-in-tablet formulation therefore should not be administered with meals.

Adult↗

Evaluation of a potential interaction between erythromycin and glyburide in diabetic volunteers.

The effects of erythromycin on the pharmacokinetics and pharmacodynamics of glyburide were evaluated in 12 patients with non-insulin-dependent diabetes mellitus (fasting blood glucose levels 140-280 mg/dL), who received 4 days of treatment with erythromycin base (333 mg administered orally every 8 hr) and a control treatment in a randomized crossover design; 5 mg glyburide was administered on day 4 of each study period. Serum glyburide concentrations were determined by high-performance liquid chromatography. Peak serum glyburide concentrations were increased by 18%, and mean time to peak glyburide concentrations (Tmax) decreased from 4.9 to 3.0 hours during erythromycin treatment; only the difference in Tmax was statistically significant. No significant effects on glyburide clearance were observed. No significant differences in glucose clearance after carbohydrate loads were observed between erythromycin + glyburide and glyburide treatments. These data show that oral erythromycin base treatment does not affect glyburide metabolism but does affect the rate of glyburide absorption. This effect may be mediated by the stimulation of gastric motility by erythromycin. The clinical significance of the effects of erythromycin on glyburide kinetics appears to be minimal, based on the determinations of serum glucose concentrations.

Adult↗

The effect of erythromycin on the CYP3A component of sertindole clearance in healthy volunteers.

The effect of erythromycin on the pharmacokinetic disposition of oral sertindole, a new antipsychotic compound, was investigated. Ten subjects who completed the study received a single 4-mg dose of sertindole without or with concomitant erythromycin 250 mg taken orally 4 times daily. Coadministration of sertindole and erythromycin led to a 33% decrease (P < 0.05) in mean (+/- SD) time to reach maximum plasma concentration (tmax) value and a 15% elevation (P < 0.05) in the mean maximum plasma concentration (Cmax) value of sertindole. The mean area under the concentration-time curve (AUC) value of sertindole did not change significantly in the presence of erythromycin (alone: 159 +/- 111 ng.hr/mL, in combination: 179 +/- 144 ng.hr/mL, P > 0.05). The presence of erythromycin also significantly increased the dehydrosertindole Cmax and AUC means by 16% and 21%, respectively, possibly due to inhibition of the CYP3A metabolic isozyme responsible for the elimination of this metabolite. The rate of absorption of sertindole and the rate of appearance of dehydrosertindole in the systemic circulation after a 4-mg sertindole single dose were slightly enhanced by concomitant dosing of erythromycin. In conclusion, there is a small but noticeable effect of erythromycin on the pharmacokinetic disposition of sertindole. The effects are believed to have little clinical significance.

Administration, Oral↗

Tetracycline and erythromycin distribution in pathological lungs of humans and rat.

Tetracycline and erythromycin concentrate highly in pulmonary tissues in humans as well as in the rat. Their binding to the lung, whatever the species and the pathological state, is weak. Their intrapulmonary concentrations could be explained by a passive diffusion which depends on the pH variation between the intra- and extratissue compartments, the percentage of un-ionized form present, and their liposolubility. The importance of retention of tetracycline and erythromycin by plasma proteins is demonstrated by the decrease of their pulmonary index of penetration (IP, the intra- and extratissue concentrations ratio). The IP values are, respectively, 1.09 and 1.23 for tetracycline and erythromycin. These concentrations are in excess of their minimal inhibitory concentrations for bacteria responsible for pneumopathies. The lung homogenate binding of these antibiotics is weak (5% for erythromycin and 33% for tetracycline), corresponding to a nonsaturable binding to three main subcellular fractions (nucleus, mitochondria, and cytosol). Tetracycline has the same penetration in healthy or cancerous human lungs, whereas erythromycin presents a decreased IP in cancerous tissue. However, the binding of these antibiotics to healthy or cancerous lung homogenates is similar. So, the structure of cancerous cells is solely responsible for this modification of erythromycin penetration. The intrapulmonary concentration of tetracycline is increased in rat lungs infected by Legionella pneumophila. This modification is due to a great bacteria retention. In contrast, erythromycin possesses the same IP in healthy and infected rat lungs.

Animals↗