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Erythromycin as a prokinetic agent: a prospective, randomized, controlled study of efficacy in nasoenteric tube placement.

OBJECTIVES: Erythromycin, a macrolide antibiotic, has been shown to mimic the effects of the polypeptide motilin in the gastrointestinal tract. To determine whether erythromycin ethylsuccinate elixir would facilitate the transpyloric passage of a standard nasoenteric feeding tube once the tube was placed into the stomach, 20 patients were randomized to receive erythromycin or standard therapy. METHODS: Twenty patients (ages 45-78), mean age 63 yr, all male, had 43-inch nasoenteric tubes placed and were randomized to receive erythromycin ethylsuccinate elixir (400 mg/5 ml per os every 8 h for three doses) through the feeding tube or to receive standard therapy that involved no drug intervention. RESULTS: Three placements resulted in immediate transpyloric passage. This represented 3/21 (14%) with immediate passage. One patient dropped out after initial tube placement. The remaining 17 patients had initial tube placement in the stomach; of these, eight were randomized to receive erythromycin and nine to receive standard therapy. Six of the eight nasoenteric tubes in the erythromycin group achieved transpyloric passage in 1 day. Zero of the nine nasoenteric tubes in the standard therapy group achieved transpyloric passage in 1 day (p = 0.0023, Fisher's exact test). CONCLUSION: This study demonstrates that erythromycin ethylsuccinate elixir improves the success of transpyloric feeding tube passage in 1 day and is superior to the standard therapy, which consists of no drug intervention.

Enteral Nutrition↗

Erythromycin, motilin, and the esophagus.

BACKGROUND: Motilin induces phase III activity of the gastroesophageal tract. Erythromycin has a motilin-like effect on the stomach, but possible esophageal effects have not been evaluated and are the focus of our investigation. METHODS: Esophageal manometry was performed in 11 healthy volunteers before and after intravenous infusion of 500 mg erythromycin. Values are expressed as means +/- SEM. RESULTS: Lower esophageal sphincter (LES) pressure increased from 21.1 +/- 2.6 mm Hg at baseline to 37.5 +/- 3.8 mm Hg after erythromycin infusion (p < 0.0001). Erythromycin did not affect LES length, esophageal body contraction amplitude, duration or velocity, or the upper esophageal sphincter. Serum motilin levels decreased from 96.4 +/- 10.9 pmol/L to 81.8 +/- 10.9 pmol/L (p < 0.01) after erythromycin administration. CONCLUSIONS: Erythromycin profoundly stimulates the normal human LES. This is a direct motilin agonist-like effect and is not mediated by release of endogenous motilin. Erythromycin has no important effect on the esophageal body or the upper esophageal sphincter.

Adult↗

Erythromycin accelerates gastric emptying of indigestible solids and transpyloric migration of the tip of an enteral feeding tube in fasting and fed states.

Erythromycin has been shown to initiate gastric interdigestive migrating motor complexes, which are the motor events responsible for gastric emptying of indigestible solids. Hence, erythromycin should also accelerate gastric emptying of indigestible particles and facilitate transpyloric migration of the tip of an enteral feeding tube. Accordingly, we assessed the effect of erythromycin on these events, using a single-blind crossover study. Healthy subjects were nasally intubated with an enteral feeding tube. For fasting studies, the subjects remained fasted; in the fed studies, the subjects were fed a cheeseburger and fries after placement of the feeding tube. Then, ten 1-cm radiopaque plastic segments were swallowed by each subject, followed by an iv infusion of either erythromycin (200 mg over 20 min) or saline. Abdominal x-rays were then taken at regular intervals to document the location of the tube tip and the plastic segments. Erythromycin significantly shortened gastric emptying time of the indigestible particles during both fasting and fed states. Erythromycin also accelerated transpyloric migration of the tip of the feeding tube in both fasting and fed states. Hence, erythromycin can be beneficial when placement of a feeding tube in the small intestine is clinically desired.

Adult↗

The effect of erythromycin in gastric emptying of solids and hypertonic liquids in healthy subjects.

We report our study of the effect of erythromycin on gastric emptying of solid and liquid meals in 10 healthy subjects. On different occasions, subjects consumed either a radiolabeled 50% glucose solution, or a radiolabeled standard solid meal after placebo, and after receiving 200 mg of erythromycin intravenously. Erythromycin accelerated the gastric emptying of the hypertonic liquid meal by significantly decreasing the duration of lag phase (p < 0.0001), by significantly increasing the emptying rate at the postlag period (p < 0.001), and by significantly decreasing the duration of the postlag period (p < 0.0001) and the meal remaining in the stomach at 15 (p < 0.05), 30 (p < 0.001), and 60 (p < 0.01) min postprandially. In addition, erythromycin administration induced a significant plasma fall at 15 (p < 0.05) and 30 (p < 0.01) min and a significant increase in pulse rate at 15 and 30 min (p < 0.01) after consumption of the hypertonic glucose solution, whereas three subjects experienced symptoms suggesting dumping syndrome. Furthermore, erythromycin administration enhanced the gastric emptying of solids by almost abolishing the duration of lag phase (p < 0.0001) and by reducing the overall t1/2 of emptying (p < 0.0001), whereas less food was retained in the stomach at 60 (p < 0.001) and 120 (p < 0.0001) min postprandially. Conversely, the postlag t1/2 of the solid meal emptying was not affected by erythromycin, as compared to placebo. We conclude that erythromycin has gastrokinetic properties, affecting the gastric emptying of both liquids and solids.

Adult↗

Sufentanil disposition. Is it affected by erythromycin administration?

BACKGROUND: Because oral erythromycin administration has been associated with reduced elimination of alfentanil, suspicion has been raised about related opioids with similar metabolic pathways. A controlled crossover study of sufentanil pharmacokinetics was undertaken to resolve this issue. METHODS: Six subjects had measurements of plasma concentrations for 9 h after intravenous administration of sufentanil (3 micrograms/kg). Each subject was studied following no erythromycin (control) and after 1- and 7-day courses of erythromycin base. RESULTS: Plasma concentrations during the 9 h of measurement were similar before and after erythromycin. Terminal half-life and clearance and distribution volume did not change significantly among treatment groups. Values measured after 7 days of erythromycin were similar to controls. CONCLUSIONS: Prior administration of erythromycin does not alter pharmacokinetics of sufentanil in the 9 h following sufentanil administration. Thus, there are no apparent clinical consequences of prior or concomitant erythromycin administration in patients receiving sufentanil for procedures of 9 h or less.

Adult↗

Double-blind randomized study comparing amoxicillin and erythromycin for the treatment of Chlamydia trachomatis in pregnancy.

OBJECTIVE: To compare the efficacy and patient tolerance of amoxicillin to that of erythromycin in the treatment of lower genital tract chlamydia infections during pregnancy. METHODS: A double-blind, randomized study was conducted comparing oral amoxicillin 500 mg three times daily versus oral erythromycin 500 mg four times daily for 7 days. One hundred forty-three women with positive cervical cultures for chlamydia at less than 36 weeks' gestation were enrolled. A test-of-cure culture was obtained 4 weeks after entry into the study and side effects were assessed. Success of the regimen was defined as completing the course of medication and having a negative test-of-cure culture. RESULTS: Thirty of the 65 women in the erythromycin group (46.1%) developed symptoms while taking the medication and 15 of them were unable to continue treatment (23.1%). In contrast, five of the 65 women (7.7%) in the amoxicillin group became symptomatic, with only one of these patients intolerant of the side effects (1.5%) (P < .001). Of the 50 patients in the erythromycin group who were able to complete their course of medication, only three had a positive test of cure (6.0%). In comparison, nine of the 64 patients (14.1%) taking amoxicillin who completed their course had positive cultures at test of cure. This difference was not statistically significant (P = .14). Forty-seven of the 65 patients (72.3%) in the erythromycin group successfully completed their regimen, compared to 55 of the 65 women (84.6%) in the amoxicillin group. This difference was not statistically significant. CONCLUSIONS: These findings suggest that amoxicillin is a reasonable alternative for the treatment of chlamydia in pregnant patients intolerant to erythromycin. The incidence of side effects and intolerance to therapy for amoxicillin are less than those for erythromycin.

Adult↗

QTc-interval prolongation associated with slow intravenous erythromycin lactobionate infusions in critically ill patients: a prospective evaluation and review of the literature.

Intravenous erythromycin has recently been associated with significant QTc interval prolongation, torsades de pointes, and sudden cardiac death. The prolonged the QTc interval attributed to erythromycin typically is associated with rapid infusion rates in excess of 10 mg/minute. We prospectively assessed the relationship between QTc interval prolongation and erythromycin administration by slow intravenous infusion (mean rate 8.9 +/- 3.5 mg/minute, range 3.9-16.7 mg/minute). Electrocardiographic (ECG) rhythm strips were prospectively obtained in 44 critically ill patients receiving intravenous antibiotics (22 received erythromycin and 22 ceftazidime, cefuroxime, cefotaxime, ceftriaxone, or ampicillin-sulbactam as controls). The ECG recordings were obtained immediately before and within 15 minutes after drug infusions. Only the first available set of ECG strips were evaluated. Two controls had evidence of hepatic dysfunction; no patients receiving erythromycin did. The QTc interval was calculated using Bazett's formula by two blinded investigators. For controls, mean +/- 1 SD (range) QTc intervals were 423 +/- 96 (300-550) msec at baseline and 419 +/- 96 (280-610) msec after infusion (p = 0.712). In contrast, in the erythromycin group, the interval was significantly prolonged from 524 +/- 105 (360-810) msec at baseline to 555 +/- 134 (400-980) msec after infusion (p = 0.034). No patients experienced a dysrhythmia as a consequence of erythromycin infusion. Despite slow rates of infusion, QTc interval prolongation was significant. The clinical importance of this finding remains to be determined.

Adult↗

In vitro activity of telithromycin against mefA and ermB erythromycin-resistant viridans streptococci isolated from bacteremia of oral origin in Spain.

Erythromycin-resistant viridans streptococci are often responsible of bacteremias following dental manipulations. The aim of this study was to evaluate the in vitro activity of telithromycin against erythromycin-susceptible and erythromycin-resistant viridans streptococci. Venous blood samples were collected from 84 patients, 30 s after dental extractions. Viridans streptococci were identified by conventional microbiological techniques. A set of 36 viridans streptococci were selected to investigate the in vitro activity of telithromycin by the agar dilution method. Macrolide resistance genes were amplified with specific primers for the mefA and ermB genes and visualized by electrophoresis. For erythromycin-susceptible viridans streptococci, telithromycin minimal inhibitory concentration90 (MIC90) was <0.008 microg/ml. For erythromycin-resistant viridans streptococci, telithromycin MIC90 was 1 microg/ml. The MIC90 to telithromycin of the mefA-positive and ermB-negative viridans streptococci was lower than that of the mefA-negative and ermB-positive viridans streptococci (0.128 microg/ml versus 1 microg/ml). The in vitro activity of telithromycin was high, irrespective of the erythromycin susceptibility and the mechanism of erythromycin resistance identified.

Anti-Bacterial Agents↗

Erythromycin therapy for streptococcal pharyngitis.

Streptococcal eradication rates of 86% were demonstrated in 97 patients seen on day 14 and in 73 patients seen on both days 14 and 28 after a ten-day course of erythromycin estolate therapy given at a dosage of 20 mg/kg/day, administered in two equal doses. The efficacy of this regimen compares favorably with other results in which this and other erythromycin preparations have been employed at higher doses, usually in the range of 30 to 50 mg/kg/day. Our reported effectiveness at a lower than usual dose of erythromycin is probably explained by the following factors: the known susceptibility of group A streptococci to low concentrations of erythromycin, the uniform absorption of the estolate formulation of erythromycin, and adequate compliance in adhering to the treatment regimen by the majority of our patients. This dosage schedule of erythromycin is simple to administer; and a reduction by half of the total dose usually recommended provides an economical advantage for patients.

Erythromycin↗

Comparative efficacy and toxicity of roxithromycin and erythromycin ethylsuccinate in the treatment of streptococcal pharyngitis in adults.

Roxithromycin is a novel oxime ether derivative of erythromycin. Previous studies have demonstrated similar in-vitro activity for roxithromycin and erythromycin. Roxithromycin has improved pharmacokinetic properties and may be a useful alternative agent for infections where erythromycin is indicated. We compared the efficacy and toxicity of roxithromycin and erythromycin ethylsuccinate in the treatment of streptococcal pharyngitis in adults. We also assessed compliance with treatment between the two agents. Roxithromycin and erythromycin ethylsuccinate were equally effective in resolving the symptoms and signs of pharyngitis. Erythromycin ethylsuccinate was superior to roxithromycin in achieving microbiological cure (90% vs. 33%, respectively). No differences were observed in toxicity or compliance with treatment between the two agents. Based on this prespective clinical trial, roxithromycin is not considered to be an acceptable alternative agent for acute streptococcal pharyngitis in adults.

Adolescent↗

Evaluation of pertussis treatment with erythromycin ethylsuccinate and stearate according to age.

Although erythromycin estolate has been fully assessed for pertussis treatment, the evaluation of erythromycin ethylsuccinate and stearate, the main erythromycin preparations used in Japan and the US, is inadequate. We evaluated these preparations to establish an appropriate treatment for pertussis according to age. Sixty-six patients with culture-confirmed pertussis were treated with erythromycin administered at a dosage of 40-50 mg/kg/day (maximum, 1.2 g/day). Negative culture was obtained in 39% (15/38) of patients aged 0-2 years within one week and in 71% (27/38) within two weeks, in 78% (7/9) of those aged 3-15 years within one week and in 100% (9/9) within two weeks. All 12 adult patients had a negative culture within one week. The efficacy of erythromycin for the eradication of B. pertussis was significantly lower in children aged 0-2 years than in older children. In conclusion, it is desirable to administer erythromycin for three weeks to children aged 0-2 years, two weeks to those aged 3-15 years and one week to adults.

Administration, Oral↗

Studies on the interaction of fermentation and microfiltration operations: erythromycin recovery from Saccharopolyspora erythraea fermentation broths.

Changes in fermentation media not only affect the performance of the fermentation itself (with regard to the kinetics of biomass and product formation and the yields obtained) but also the initial product-recovery operations downstream of the fermentor. In this work, microfiltration experiments to remove Saccharopolyspora erythraea biomass from fermentation broth and to recover erythromycin were carried out using two fundamentally different media; a soluble complex medium (SCM) and an oil-based process medium (OBM). Small-scale batch fermentations of 14-L working volume were carried out in triplicate using both media. Broth samples were taken from each fermentation at regular intervals from the end of the exponential-growth phase onwards. These were then processed using a Minitan II (acrylic), tangential crossflow-filtration module, fitted with a single 60 cm(2) Durapore hydrophilic 0.2 microm membrane, operated in concentration mode. The OBM fermentations produced higher titers of erythromycin but required longer fermentation times due to increased lag phases and slower maximum-growth rates. The OBM also increased the loading on the membrane; at maximum product titers residual oil concentrations of 3 g. L(-1), antifoam concentrations of 2 g. L(-1) and flour concentrations estimated at approximately 10 g/L(-1) were typical. It was found that both the permeate flux and erythromycin transmission were affected by the choice of medium. The OBM had significantly lower values for both parameters (12.8 Lm(-2) h(-1) and 89.6% respectively) than the SCM (35.9 Lm(-2) h(-1) and 96.7% respectively) when the fermentations were harvested at maximum erythromycin titers. Transmission of erythromycin stayed approximately constant as a function of fermentation time for both media, however, for the OBM the permeate flux decreased with time which correlated with an increase in broth viscosity. The relatively poor microfiltration performance of the OBM medium was, however, offset by the higher titers of erythromycin that were achieved during the fermentation. The filtration characteristics of the SCM broth did not show any correlation with either broth viscosity or fermentation time. Image-analysis data suggested that there was a correlation between hyphal morphology (main hyphal length) and permeate flux (no such correlation was found for the OBM broth). Moreover, it has been shown for the OBM broth that the residual flour had a profound effect on the microfiltration characteristics. The influence of the residual flour was greater than that imposed by the morphology and concentration of the biomass. The understanding of the factors governing the interaction of the fermentation and microfiltration operations obtained in this work provides a first step towards optimization of the overall process sequence.

Biomass↗

Determination of erythromycin and related substances in enteric-coated tablet formulations by reversed-phase liquid chromatography.

An isocratic method for the identification and quantitation of erythromycin and related substances in enteric-coated tablet formulations using high-performance liquid chromatography (HPLC) with ultraviolet (UV) detection at 205 nm is described. A novel method for sample preparation using a molecular weight centrifuge filter to reduce the interferences observed from polymeric tablet coating material is also presented. Erythromycin HPLC assays are best run at high pH; therefore, various polymer columns were evaluated. The resulting HPLC method that was developed has several advantages over current pharmacopeial assay methods for enteric-coated erythromycin tablets. Comparative data from both methods for the same batch of EryTab tablets are presented. The method can also be applied to various other erythromycin formulations, including particle-coated tablets, erythromycin stearate tablets, and erythromycin ethylsuccinate suspensions and fermentation broths. A C18 Polymeric column is used with a mobile phase composition of 0.02 M potassium phosphate dibasic buffer (pH 9): acetonitrile (60:40) and flow rate of 1 mL/min. This method is more sensitive, specific, and rugged than the pharmacopeial method.

Chemistry, Pharmaceutical↗

Determination of erythromycin A in salmon tissue by liquid chromatography with ion-spray mass spectrometry.

A reverse-phase liquid chromatography/mass spectrometry (LC/MS) method, incorporating gradient elution, is described for the characterization of residual erythromycin A and its metabolites in salmon tissue. The method uses ion-spray, a mild atmospheric pressure ionization technique which provides an abundant protonated molecule well suited for selected ion monitoring experiments. Tandem mass spectrometry (MS/MS) using collision-induced dissociation was used to provide structural information. The LC/MS method was tested for the analysis of salmon tissue spiked with erythromycin A at levels between 0.01 and 1 p.p.m. A simple extraction and clean-up procedure, slightly modified from that described by Takatsuki et al. (J. Assoc. Off. Anal. Chem. 70, 708 (1987)), was used in this work. Using selected ion and selected reaction monitoring techniques, the LC/MS and LC/MS/MS methods provided detection limits of < 10 and 50 ng g-1, respectively. Confirmatory full-scan LC/MS and LC/MS/MS spectra were obtained at the 0.5 and 1 microgram g-1 levels, respectively. Using a combination of these techniques, the presence of residual erythromycin A was confirmed in the tissue of fish administered medicated feed containing the antibiotic. In addition, several metabolites and degradation products of erythromycin A, including anhydro-erythromycin and N-demethyl-erythromycin, were detected and where possible confirmed by comparison with authentic compounds. Although this analytical method has been shown to afford the necessary sensitivity and precision, application of these techniques to high-throughput quantitative analyses will require development of an improved clean-up procedure and preferably also of a suitable surrogate internal standard.

Animals↗

Differential regulation of liver P-450III cytochromes in choline-deficient rats: implications for the erythromycin breath test as a parameter of liver function.

Progressive liver fibrosis in rats develops when they are fed a diet deficient in choline. This diet also results in a pronounced and selective decrease in the liver microsomal content of a phase I drug-metabolizing enzyme belonging to the cytochrome P-450III gene family. Because P-450III cytochromes characteristically catalyze the N-demethylation of erythromycin, we believed that the production of breath CO2 from erythromycin would be dramatically reduced in choline-deficient rats. However, when 12 choline-deficient rats were compared with 9 control rats, the reduction in CO2 production from erythromycin (mean decrease 71%) was essentially identical to that from aminopyrine (mean decrease 69%), a substrate believed to be metabolized normally by the hepatocyte in fibrotic liver disease. Furthermore, we found that the relative erythromycin and aminopyrine demethylase activities were comparable when measured in vitro in liver microsomes prepared from the choline-deficient rats. To determine the molecular basis for the erythromycin demethylase activity in the choline-deficient rats, the liver microsomes were subjected to immunoblot analysis using a variety of polyclonal and monoclonal antibodies capable of distinguishing individual P-450III-related proteins. Our studies confirm that a major erythromycin demethylase belonging to the P-450III family, termed P-450p, was greatly reduced in the choline-deficient rat liver. However, the specific concentration of a second P-450p-related protein was essentially normal and that of a third P-450p-related protein was actually increased in the choline-deficient rat liver.(ABSTRACT TRUNCATED AT 250 WORDS)

Aminopyrine↗

Evaluation of the potential interaction between felbamate and erythromycin in patients with epilepsy.

Effects of erythromycin on hepatic CYP450 3A4 isozymes can profoundly influence the metabolism of many therapeutic agents. An open-label, randomized, two-period, crossover study was therefore conducted to evaluate the pharmacokinetics of felbamate before and after a concurrent 10-day regimen (333 mg three times daily) of erythromycin. Patients were receiving either 3,000 or 3,600 mg/day felbamate monotherapy for treatment of epilepsy. Mean dose-normalized values for maximum concentration (Cmax) and area under the concentration-time curve (AUC tau) of felbamate were not statistically different in patients taking felbamate as monotherapy than in patients after erythromycin coadministration. Estimates of time to Cmax (tmax), minimum concentration (Cmin), apparent clearance (Cl/kg), average concentration (Cav), and degree of fluctuation (DFss) were likewise unchanged. The incidence of mild and moderate adverse events increased during coadministration of the two drugs. Because patients with epilepsy can not be treated with erythromycin alone, it could not be determined whether the adverse events were attributable to erythromycin or to the combination of the two drugs. Steady-state pharmacokinetic parameters of felbamate were not influenced by erythromycin coadministration.

Adult↗

Erythromycin and motilin stimulate sphincter of Oddi motility and inhibit trans-sphincteric flow in the Australian possum.

The actions of erythromycin lactobionate and porcine motilin on trans-sphincteric flow and simultaneous sphincter of Oddi motility were studied in 15 anaesthetized Australian Brush-tailed possums (Trichosurus vulpecula). Erythromycin (25-200 micrograms/kg) and motilin (25-200 ng/kg) were administered as graded doses by close intraarterial injection. Trans-sphincteric flow was measured as inflow and outflow. Both motilin and erythromycin decreased trans-sphincteric inflow (both P < 0.0001) and outflow (P < 0.0001 and P = 0.0017 respectively) in a dose-dependent manner. The highest dose of each agent abolished trans-sphincteric flow. These agents increased sphincter of Oddi phasic contraction frequency and basal pressure up to 2 and 3 fold respectively (P < 0.05). The amplitude of the sphincter of Oddi phasic contractions were not influenced in any consistent fashion by either agent. The durations of the responses (trans-sphincteric inflow) elicited by erythromycin and motilin were dose dependent (P = 0.0225 and P = 0.0001 respectively). The actions of erythromycin (200 micrograms/kg) or motilin (100 ng/kg) on trans-sphincteric flow and sphincter of Oddi motility were not influenced by neural blockade with tetrodotoxin. These findings support the hypothesis that erythromycin acts as a motilin agonist and both substances increase the resistance to flow through the sphincter of Oddi by raising the basal pressure and frequency of contractions.

Animals↗

Inhibitory action of erythromycin on bacteriophage SPO1 multiplication in sporulating cells of Bacillus subtilis 168.

Erythromycin (2--4 microgram/ml) was found to inhibit specifically multiplication of SPO1 in sporulating cells of an erythromycin-resistant, conditional asporogenous mutant of Bacillus subtilis 168 thy- trp-, Ery1040. In contrast, streptomycin (150--200 microgram/ml) which inhibits protein synthesis to a similar extent as erythromycin did not inhibit SPO1 multiplication severely, suggesting that the inhibition of SPO1 multiplication by erythromycin is not caused by an overall inhibition of protein synthesis. Neither phage DNA synthesis nor phage messenger RNA synthesis was affected appreciably under these conditions. However, the synthesis of three phage proteins that are synthesized 15 min after infection was preferentially inhibited by erythromycine. In addition, the inhibition of SPO1 multiplication has been correlated with the stimulation of host stable RNA synthesis exhibited by erythromycin. Possible mechanisms for the inhibition of SPO1 multiplication in Ery1040 cells are discussed.

Bacillus subtilis↗