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Erythromycin gastrokinetic activity is partially vagally mediated.

Erythromycin overcomes postvagotomy gastroparesia in patients without a distal stomach and functional pylorus. We investigate the role of the vagus in gastric emptying increased by erythromycin, using a model that preserves the physiology of the distal stomach and pylorus. The effects of erythromycin lactobionate (10 mg/kg) on transpyloric flow pattern and pyloric resistance were evaluated during repetitive bilateral vagal cooling in anesthetized pigs. Vagal cooling during erythromycin infusion produced a marked decreased of pyloric outflow (23 +/- 1.1 vs 50 +/- 2.6 ml/min) related to a reduced stroke volume of the flow pulses (7.8 +/- 3.31 vs. 14.1 +/- 2.44 ml). The amplitude and frequency of gastric and duodenal pressure events were unchanged or slightly reduced during vagal cooling. The smaller stroke volume of flow pulse was the consequence of increased pyloric resistance (6.2 +/- 1.98 vs. 2.3 +/- 0.21 mmHg.ml-1.s), which is associated with changes in the temporal relationship between a pyloric pressure event and flow pulse. In conclusion, erythromycin activity on the pylorus requires the integrity of vagal pathways. Enhancement of gastric outflow by erythromycin is also modulated by the vagus, since pyloric resistance was able to overcome increased gastric motility.

Animals↗

Effects of organic anions and vinblastine on biliary excretion of erythromycin in rats.

Since little is known about the mechanism of biliary excretion of cationic drugs, biliary excretion of erythromycin was studied in rats. Infusion of sulfobromophthalein and taurocholate significantly decreased biliary erythromycin excretion, whereas infusion of dibromosulfophthalein, cefpiramide, ursodeoxycholate-3-O-glucuronide and taurolithocholate-3-sulfate had no effect on biliary excretion of erythromycin. Vinblastine significantly inhibited biliary erythromycin excretion. Phenothiazine treatment significantly increased biliary erythromycin excretion. However, erythromycin infusion did not affect biliary vinblastine excretion. These findings indicate a multiplicity of biliary excretory pathways for organic cations; at least one additonal pathway may exist for organic cations apart from P-glycoprotein.

Animals↗

The effect of erythromycin on mucociliary transportability and rheology of cystic fibrosis and bronchiectasis sputum.

BACKGROUND: Erythromycin has been shown to diminish sputum production in hypersecretory states by a mechanism that is still unclear. OBJECTIVES AND METHODS: We have investigated the effect of erythromycin on the ciliary transportability of cystic fibrosis and non-cystic fibrosis bronchiectasis sputum in vitro using the mucus-depleted bovine trachea. RESULTS: Additional erythromycin in concentrations up to 20 microg/g did not significantly alter the ciliary transportability of sputum from 6 cystic fibrosis and 6 bronchiectasis patients. Sputum viscoelasticity measured with parallel-plate rheology was also little changed. These erythromycin concentrations also had little effect on the beating frequency of bovine tracheal cilia. CONCLUSIONS: These results suggest that the presence of erythromycin in sputum neither alters the physical properties of the gel nor the activity of cilia. The clinical effects of erythromycin on pulmonary hypersecretory states therefore have another explanation.

Anti-Bacterial Agents↗

The effect of erythromycin on the disposition kinetics of warfarin.

Erythromycin is generally regarded as innocuous in regard to adverse interactions with other drugs. Recently, however, its potentiation of theophylline and warfarin has been reported. The present investigation defined more specifically the kinetics of the interaction between erythromycin and warfarin. Warfarin kinetics were evaluated in 12 normal subjects who took a single 1 mg/kg dose of warfarin with and without erythromycin. Erythromycin (250 mg p.o.) every 6 h for 8 days decreased warfarin clearance by 14% (p less than 0.001). Warfarin's apparent volume of distribution was not affected. Further, the effect of erythromycin was greatest among subjects whose control phase warfarin clearance was relatively slow, and least among those whose control phase warfarin clearance was relatively fast. The magnitude of the decrease in warfarin clearance correlated negatively with control warfarin clearance (r = -0.89, p less than 0.005). These data are consistent with the interpretation that erythromycin can potentiate warfarin-induced hypoprothrombinemia by slowing warfarin clearance.

Adult↗

Josamycin: interpretation of inhibition zones with the Bauer-Kirby agar disk diffusion test as compared with erythromycin.

A total of 432 clinical isolates of Staphylococcus aureus (128), coagulase-negative staphylococci (123), group A and B beta-hemolytic streptococci (61), group D streptococci (30), Streptococcus penumoniae (29), Haemophilus influenzae (19), Haemophilus parainfluenzae (12), and Legionella pneumophila (30) were examined with the agar dilution and Bauer-Kirby agar disk diffusion tests for susceptibility to josamycin as compared with erythromycin. On a weight-for-weight basis, erythromycin was more active than josamycin against all bacterial species, including L. pneumophila. Josamycin inhibited 18 of 23 S. aureus and 11 of 16 coagulase-negative staphylococcal strains resistant to erythromycin. Utilizing minimal inhibitory concentrations (MIC) breakpoints of less than or equal to 2 micrograms/ml (sensitive), 4 microgram/ml (intermediate) and of greater than or equal to 8 micrograms/ml (resistant), and inhibition zone criteria of greater than or equal to 18 mm diameter (sensitive), 14-17 mm (intermediate), and less than or equal to 13 mm (resistant), and excluding L. pneumophila, there was good correlation between erythromycin MIC and corresponding disk diffusion data for staphylococci and streptococci, but not for Haemophilus species. In comparison, josamycin yielded a significant number of minor discrepant data for group D streptococci and Haemophilus species. It is suggested that erythromycin and josamycin should not be tested against Haemophilus species, and that josamycin should be excluded from test batteries against enterococci. Erythromycin-resistant staphylococci require separate testing with josamycin.

Anti-Bacterial Agents↗

Erythromycin blocks the rapid component of the delayed rectifier potassium current and lengthens repolarization of guinea pig ventricular myocytes.

BACKGROUND: Administration of erythromycin to humans has been associated with lengthening of cardiac repolarization and even proarrhythmia. The objectives of our study were to describe effects of erythromycin on repolarization of isolated hearts and to determine effects of the drug on major K+ currents involved in cardiac repolarization. METHODS AND RESULTS: A first set of experiments was conducted in isolated, buffer-perfused guinea pig hearts electrically stimulated at a basic cycle length of 250 ms. In this model, erythromycin 10(-4) mol/L increased monophasic action potential duration measured at 90% repolarization (MAPD90) by 40 +/- 7 ms. Increase in MAPD90 was reproducibly observed in seven hearts studied. To study the mechanism of these effects on cardiac repolarization, a second set of experiments was performed in isolated guinea pig ventricular myocytes using the whole cell configuration of the patch-clamp technique. In these cells, erythromycin 10(-4) mol/L decreased by about 40% (P < .05 versus baseline) the time-dependent outward K+ current elicited by short depolarizations (250 ms) to low depolarizing voltages (-20 to 0 mV). In contrast, the drug was without significant effects on the time-dependent K+ current elicited by long pulses (5000 ms) to high depolarizing voltages (+10 to +50 mV), on the time-independent background current (mostly IKl), and on the slow inward calcium current. CONCLUSIONS: The outward time-dependent K+ current blocked by erythromycin in isolated guinea pig ventricular myocytes had characteristics similar to those described for IKr. Selective block of this component of IK gives an explanation for the effects of erythromycin on cardiac repolarization. These effects were observed at clinically relevant concentrations reached after intravenous administration of the drug and warn for potential interactions with other action potential-lengthening drugs.

Animals↗

Effects of erythromycin on the rabbit pleura: its potential role as a pleural sclerosant.

Tetracycline (TCN) has been considered the agent of choice for pleurodesis in patients with symptomatic malignant pleural effusions and recurrent pneumothoraces. However, the intravenous form of TCN used for pleurodesis is no longer available. Erythromycin, like TCN, often produces irritation when administered intravenously. In view of these irritant properties, we tested the effect of erythromycin as a pleural sclerosant in rabbits as compared with TCN. Normal saline was used as a control. Adult rabbits weighing 2.5 to 3.0 kg underwent sterile placement of a silastic pleural tube in the right pleural space. Erythromycin (n = 17) or TCN (n = 6), each in doses of 35 mg/kg in 2 ml saline, was administered via the tube. Control animals (n = 6) received 2 ml saline. The chest tubes were left in place for removal of pleural fluid and to maintain lung expansion. Animals were killed 8 d after receiving the various treatments, and their pleural surfaces were examined grossly and histologically. Numerous adhesions were present between the visceral and parietal pleurae in all animals receiving erythromycin and TCN, but not in those receiving saline. On light microscopy, pleurae treated with erythromycin or TCN were histologically identical, showing inflammation, edema, and fibroblast proliferation in the submesothelial tissues. The saline-treated animals had a normal pleura. Because erythromycin produced pleural inflammation and adhesions within 8 d of treatment, we propose that it may have a potential role as a pleural sclerosant.

Animals↗

Erythromycin inhibits respiratory glycoconjugate secretion from human airways in vitro.

Erythromycin and other antibiotics have been used empirically in the treatment of patients with chronic obstructive pulmonary disease (COPD). We studied whether this empirical role of antibiotics might not be related to a possible direct effect on respiratory glycoconjugate (RGC) secretion. The effect of erythromycin on RGC secretion and hypersecretion was studied in an in vitro preparation of human airways that were secreting [3H]glucosamine respiratory glycoconjugate (RGC), and on a human endometrial adenocarcinoma cell line secreting a glycoconjugate (tumor glycoconjugate = TGC) chemically similar to the RGC secreted by the airways. Erythromycin at 10(-5) M reduced RGC secretion by 35 +/- 4% (n = 9, p less than 0.001) in both human airways and the adenocarcinoma cells, and was increasingly active in the pharmacologic range of 10(-7) to 10(-4) M. The inhibitory effect of erythromycin was maximal within 16 h and was still evident 34 h after incubation. Erythromycin was noted to reduce both spontaneous (baseline) and stimulated RGC secretion (by histamine and methacholine) from airways in culture. The blocking effect appeared to be more selective for histamine than methacholine. These effects were not associated with any toxicity to the tissues and were not associated with the inhibition of protein synthesis. Dexamethasone also inhibited RGC release in both assay systems and exhibited dose-related effects in the physiologic ranges (10(-9) to 10(-5) M). When administered together, erythromycin and dexamethasone had an additive inhibitory effect on RGC secretion (68.0 +/- 3.0%, n = 7, p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Anti-Bacterial Agents↗

The effect of erythromycin and clarithromycin on the pharmacokinetics of intravenous digoxin in healthy volunteers.

Several case reports have suggested an interaction between digoxin and macrolide antibiotics. The authors investigated the effect of erythromycin and clarithromycin on the pharmacokinetics of intravenously administered digoxin (0.5 mg) in healthy subjects. Nine male subjects participated in three studies (digoxin alone, digoxin with erythromycin, and digoxin with clarithromycin). Subjects took erythromycin (800 mg per day) or clarithromycin (400 mg per day) on the day before digoxin dosing and during the kinetic study, Neither of the macrolides affected serum digoxin concentration-time curves. However, more than 1.3-fold increases in urinary digoxin excretions were observed during erythromycin and clarithromycin coadministration compared with digoxin alone. There were significant differences in renal clearance between macrolide coadministration and the control condition (digoxin alone: 98.4 ml/min; digoxin with erythromycin: 137.3 ml/min; digoxin with clarithromycin: 133.6 ml/min). In conclusion, neither erythromycin nor clarithromycin has a significant effect on serum digoxin disposition after an intravenous administration. Renal digoxin excretion is not inhibited but rather enhanced by both macrolides.

Administration, Oral↗

Erythromycin ototoxicity: analysis and conclusions based on 22 case reports.

Although the majority of patients receiving erythromycin experience no hearing loss, certain patients are susceptible. Erythromycin ototoxicity data were analyzed on 20 patients from 13 reports in the English language literature as well as on two patients from the University of Missouri-Columbia. Patients were classified with respect to age, sex, premorbid diagnosis, renal/hepatic function, type of erythromycin used, dosage, duration of therapy, and route of administration. The following auditory effects were considered: onset of symptoms, degree and configuration of hearing loss, and recovery of hearing. The factors which, when combined with the use of high-dose erythromycin (greater than or equal to 2 gm/day), might place patients at risk for erythromycin ototoxicity are preexisting renal or hepatic disease, age (elderly), and perhaps being female. With knowledge of the predisposing factors and auditory effects, the clinician can more easily recognize hearing loss caused by erythromycin and properly counsel referring physicians and affected patients.

Adult↗

Erythromycin base-induced rash and liver function disturbances.

OBJECTIVE: To report a case of erythromycin base-induced rash and liver function disturbances. CASE SUMMARY: A patient with erythema nodosum and high antistreptolysin-O titers was treated with erythromycin on the assumption that occult streptococcal infection was the cause of the erythema nodosum. Forty-eight hours after the initiation of therapy the patient developed fever, severe generalized rash, pruritus, and cholestatic and hepatocellular liver function disturbances. Extensive evaluation to determine the cause of liver function disturbances was unrevealing. Marked improvement was noticed within days after cessation of erythromycin. DISCUSSION: Case reports in the literature on the adverse effects of erythromycin and its derivatives were reviewed. The possible immunologic mechanism involved is postulated. CONCLUSIONS: Erythromycin base must be added to the list of erythromycin derivatives that can cause rash and liver function disturbances. The concomitant appearance of fever, rash, jaundice, and liver function disturbances raises the possibility of hypersensitivity as the mechanism for the liver disturbances.

Adult↗

In vivo pharmacodynamic evaluation of clarithromycin in comparison to erythromycin.

The efficacy of various dosing regimens of clarithromycin and erythromycin against recently isolated Streptococcus pneumoniae strains was determined in vivo using two animal infection models (mouse peritonitis and thigh infection). For the thigh infection model, mice received a total dose of 4 mg/Kg of either clarithromycin or erythromycin, as a single total dose or divided into 2, 4 or 8 doses/24h. After 24h of therapy S. pneumoniae organisms were killed at 2.06 to 4.03 log10 CFU/thigh by clarithromycin and the one- or two-dose regimens were significantly more effective than the four- or eight-dose regimens. Organism killing following 24h of therapy with erythromycin ranged from 1.13 to 2.31 log10 CFU/thigh, with the one- or two-dose regimens significantly less effective than the four- or eight-dose regimens. In the mouse survival study, the same dose of either clarithromycin or erythromycin was given as a single total dose or divided into two or four doses with dosing intervals of 4 and 2-times the t1/2 respectively. The results obtained in this model show that there is a significant difference in survival when clarithromycin is administered less frequently (4% deaths for the one-dose regimen in comparison to 40% deaths with the four-dose regimen, P < 0.01, Chi-square test). With erythromycin there was a trend for increased survival with the multiple-dose regimen, with significantly higher survival when concentrations exceeding the MIC were maintained for a longer time period. These results indicate that the time during which serum concentrations exceeding the MIC value of the pathogen is an important parameter for efficacy for erythromycin. On the contrary, results with both animal models demonstrate that bacterial killing and survival are significantly higher among clarithromycin-treated mice when the antibiotic is administered less frequently and the highest Cmax/MIC ratio is achieved.

Animals↗

Failure of erythromycin to eliminate airway colonization with ureaplasma urealyticum in very low birth weight infants.

BACKGROUND: Airway colonization of mechanically ventilated very low birth weight infants (birth weight < 1500 grams) by Ureaplasma urealyticum (Uu) is associated with an increased risk of bronchopulmonary dysplasia (BPD). While Uu is sensitive to erythromycin in vitro, the efficacy of intravenous (IV) erythromycin to eliminate Uu from the airways has not been studied. METHODS: 17 very low birth weight infants with Uu positive tracheal aspirate (TA) cultures were randomized to either 5 (8 infants) or 10 days (9 infants) of IV erythromycin lactobionate (40 mg/kg/day in 3 divided doses). Tracheal aspirate cultures for Uu were performed on days 0, 5, 10 and 15. RESULTS: Intravenous erythromycin failed to eliminate airway colonization in a large proportion of infants regardless of whether they received 5 or 10 days of treatment. Ureaplasma urealyticum was isolated from 4/15 (27%) of TAs obtained at 5 days, 5/12 TAs (42%) obtained at 10 days and 6/11(55%) TAs obtained at 15 days (combined group data). CONCLUSIONS: Erythromycin administered IV does not eliminate Uu from the airways in a large proportion of infants. Failure of erythromycin to eliminate Uu from the airways may contribute to the lack of efficacy of this drug in reducing the incidence of BPD in very low birth weight infants.

Anti-Bacterial Agents↗

Compound cardiac toxicity of oral erythromycin and verapamil.

OBJECTIVE: To report a case of complete atrioventricular (AV) block and QTc prolongation following coadministration of high-dose verapamil and erythromycin. CASE SUMMARY: A 79-year-old white woman was admitted to the hospital due to extreme fatigue and dizziness. On admission, heart rate was 40 beats/min and blood pressure was 80/40 mm Hg. An electrocardiogram showed complete atrioventricular (AV) block, escape rhythm of 50 beats/min, and QTc prolongation 583 msec. This event was attributed to concomitant treatment with verapamil 480 mg/d and erythromycin 2,000 mg/d, which was prescribed one week before admission. DISCUSSION: This is the first case published describing complete AV block and prolongation of QTc following coadministration of erythromycin and verapamil. CYP3A4 is the main isoenzyme responsible for metabolism of erythromycin and verapamil. Both drugs are potent inhibitors of CYP3A4 and of P-glycoprotein; this may be the basis for the pharmacokinetic interaction between erythromycin and verapamil. In addition to being a woman, our patient had other risk factors for QT prolongation: slow baseline heart rate (probably induced by verapamil), left-ventricular hypertrophy, and possibly ischemic heart disease. CONCLUSIONS: This life-threatening arrhythmia was probably the result of a pharmacokinetic and/or pharmacodynamic interaction of high-dose verapamil and erythromycin.

Aged↗

Erythromycin does not directly affect neutrophil functions.

To determine whether erythromycin could affect neutrophil functions, we measured N-formyl-methionyl-leucyl-phenylalanine (FMLP)-induced chemotaxis and superoxide generation of neutrophils in the presence of erythromycin at various concentrations. Erythromycin had no effect on either of them. We further confirmed that intracellular free calcium concentration ([Ca2+]i) was not influenced by FMLP stimulation in the presence of erythromycin. Our results indicate that erythromycin has no direct effects on neutrophil functions in vitro, although it is reported that erythromycin inhibits the local migration of neutrophils in the small airways of subjects with asthma.

Asthma↗

Cost-effectiveness of IV-to-oral switch therapy: azithromycin vs cefuroxime with or without erythromycin for the treatment of community-acquired pneumonia.

STUDY OBJECTIVE: To conduct a cost-effectiveness analysis of IV-to-oral regimens of azithromycin vs cefuroxime with or without erythromycin in the treatment of patients hospitalized with community-acquired pneumonia (CAP). PATIENTS: Of the 268 evaluable patients enrolled into a randomized, multicenter clinical trial of adults, 266 patients had sufficient data to be included in this cost-effectiveness analysis. One hundred thirty-six patients received azithromycin, and 130 patients received cefuroxime with or without erythromycin. METHODS: A pharmacoeconomic analysis from the hospital provider perspective was conducted. Health-care resource utilization was extracted from the clinical database and converted to national reference costs. Decision analysis was used to structure and characterize outcomes. Sensitivity analyses were performed, and statistics were applied to the cost-effectiveness ratios. RESULTS: The clinical success and adverse event rates and antibiotic-related length of stay were 78%, 11.8%, and 5.8 days for the azithromycin group and 75%, 20.7%, and 6.4 days for the group receiving cefuroxime with or without erythromycin, respectively. Geometric mean treatment costs were 4,104 US dollars (95% confidence interval [CI], 3,874 to 4,334 US dollars) for the azithromycin group, and 4,578 US dollars (95% CI, 4,319 to 4,837 US dollars) for the group receiving cefuroxime with or without erythromycin (p = 0.06). The cost-effectiveness ratios were 5,265 US dollars per expected cure for the azithromycin group, and 6,145 US dollars per expected cure for group receiving cefuroxime with or without erythromycin (p = 0.05). CONCLUSIONS: Despite a higher per-dose purchase price, overall costs with azithromycin tended to be lower due to decreased duration of therapy, lower preparation and administration costs, and reduced hospital length of stay. As empiric therapy, azithromycin monotherapy was cost-effective compared to cefuroxime with or without erythromycin for patients hospitalized with CAP who have no underlying cardiopulmonary disease, and no risk factors for either drug-resistant pneumococci or enteric Gram-negative pathogens.

Administration, Oral↗

The effect of erythromycin on bile excretion and proximal small bowel motility following divided gastric bypass surgery: a prospective randomized placebo-controlled trial.

BACKGROUND: No conclusive data exists supporting the use of any prokinetic agent in the postoperative setting. The study was designed to examine the effect of erythromycin on small bowel motility in a placebo-controlled trial of post gastric bypass patients utilizing a standardized nuclear medicine test. METHODS: A consecutive series of 21 patients undergoing elective gastric bypass surgery for morbid obesity between September 1999 and March 2001 were enrolled in this prospective double-blind randomized controlled trial. Standard open, divided gastric bypass was performed. Patients were randomized to receive either erythromycin 250 mg i. v. (11 patients) or placebo (10 patients) every 8 hours. On postoperative day 2, a hepatic iminodiacetic acid (HIDA) scan was obtained. Tracer movement through the biliary tree and proximal small bowel was quantified and compared. RESULTS: Tracer clearance from the liver and biliary tree was no different between groups from time of injection through 1 hour. Tracer material clearance from the duodenum into the jejunum was no different between the erythromycin and control groups at 1 hour, 37% +/- 13% and 37% +/- 22% respectively (P = 0.95). At 4 hours, clearance was greater in the erythromycin group, 77% +/- 6%, compared to control, 60% +/- 20% (P = 0.036). The rate of tracer change between hour 1 and 4 (slope) was steeper in the erythromycin group (P = 0.048). CONCLUSIONS: Erythromycin increases intestinal transit in the postoperative setting.

Bile↗

Adsorption and clay-catalyzed degradation of erythromycin A on homoionic clays.

Erythromycin has been widely used in food-producing animals and in humans, and is frequently detected as an organic pollutant in U.S. streams. In batch experiments with homoionic clays, the Freundlich isotherms were determined at 10 and 25 degrees C. The adsorption of erythromycin A was strongly influenced by clay type, exchanged cations, the pH of the bulk solutions, and the acidity of clay surfaces. The formation of clay-erythromycin A complexes was thermodynamically favorable except for K+- and Fe3+-exchanged montmorillonites, since the reactions were exothermic (deltaH(o) > 0) and the systems became stable (deltaS(o) > 0). Clays catalyzed the erythromycin A degradation by the hydrolysis of the neutral sugar and the multiple dehydrations. The surface acidity of clay surface enhanced the rate of clay-catalyzed degradation of erythromycin A. In addition, the Fe3+-exchanged clay minerals seemed to have an electrostatic interaction with the erythromycin A molecule, by which the hydrolysis of the neutral sugar was influenced.

Adsorption↗