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Single-dose ciprofloxacin versus 12-dose erythromycin for childhood cholera: a randomised controlled trial.

BACKGROUND: Single-dose ciprofloxacin is effective for the treatment of severe cholera in adults. We assessed whether single-dose ciprofloxacin would be as effective as 3-day, 12-dose erythromycin in achieving clinical cure in children with severe cholera. METHODS: We did a randomised, open label, controlled trial in children age 2-15 years with V cholerae O1 or O139 present in stool on dark-field microscopy. Children received either a single 20 mg/kg dose of ciprofloxacin (n=90) or 12.5 mg/kg of erythromycin (n=90) every 6 h for 3 days, and remained in hospital for 5 days. The primary outcome was clinical success of treatment, defined as cessation of watery stools within 48 h of start of drug treatment. Analysis was per protocol. This study is registered with the ClinicalTrials.gov Protocol Registration System at http://www.clinicaltrials.gov (registration number NCT 00142272) [corrected] FINDINGS: Of 180 children randomised 162 completed the study. Treatment was clinically successful in 60% (47/78) of children treated with ciprofloxacin and in 55% (46/84) of those treated with erythromycin (difference 5% [95% CI -10 to 21]). Children receiving ciprofloxacin vomited less often (58%vs 74%; difference 16% [2 to 30]), had fewer stools (15 vs 21; 6 [0 to 9]), and less stool volume (152 vs 196 mL/kg; 43 mL/kg [13 to 87]) than those receiving erythromycin. Bacteriological failure was more common in ciprofloxacin-treated patients (58%vs 30%; 28% [13 to 43]) than erythromycin-treated patients. INTERPRETATION: Single-dose ciprofloxacin achieves clinical outcomes similar to, or better than, those achieved with 12-dose erythromycin treatment in childhood cholera, but is less effective in eradicating V cholerae from stool.

Adolescent↗

Serum erythromycin levels in pregnancy.

Erythromycin is the recommended therapy for pregnant women with chlamydial infection. Despite the fact that this drug has been available since 1952, relatively little is known about its pharmacokinetic behavior in pregnant women, and no investigations have been conducted in women who were in the third trimester of pregnancy. In this study, 10 women were treated with erythromycin for chlamydial infection during pregnancy; 7 of these women were in the third trimester of pregnancy, and 3 were in the second trimester. Serum samples were obtained at 0.5, 1, 2, 3, and 4 hours after a 500-mg oral dose of erythromycin base and were analyzed to determine absorption and peak serum levels of erythromycin. Results indicated that absorption was delayed and serum levels were diminished in comparison with values reported in the literature for patients in the second trimester of pregnancy. In 2 women, erythromycin serum levels were not detectable at any time during the 4 hours of the study; these 2 women also experienced the most severe gastrointestinal symptoms. Although the size of our study population was small and certainly not definitive, the data suggest that in patients in the third trimester of pregnancy, severe adverse gastrointestinal events may forewarn of subtherapeutic plasma concentrations of erythromycin, which could have consequences for the treatment outcome.

Adolescent↗

A population-based case-control teratologic study of oral erythromycin treatment during pregnancy.

The objective of the study was to evaluate the human teratogenic potential of oral erythromycin treatment during pregnancy in the population-based dataset of the Hungarian Case-Control Surveillance of Congenital Abnormalities, 1980-1996. Of 38,151 pregnant women who had newborn infants without any congenital abnormalities (population control group), 172 (0.5%) had received erythromycin, while of 22,865 pregnant women who had newborns or fetuses with congenital abnormalities, 113 (0.5%) had been treated with erythromycin (crude OR with 95% Cl = 1.1, 0.9-1.4). The case-control pair analysis did not indicate a teratogenic potential of erythromycin during the second through third months of gestation, i.e., in the critical period for most major congenital abnormalities. The frequency of maternal erythromycin treatments during the second-third months of pregnancy was also not higher in different congenital abnormality groups compared with the rate of the total control group as referent. Thus, treatment with oral erythromycin during pregnancy did not present detectable teratogenic risk to the fetus.

Abnormalities, Drug-Induced↗

Activity of the ketolide telithromycin (HMR-3647) against erythromycin-susceptible and -resistant pneumococci isolated in the UK.

The novel ketolide telithromycin (formerly HMR-3647) was tested against a collection of pneumococci of varying sensitivity to erythromycin and clindamycin, isolated in geographically diverse UK hospitals. Telithromycin was highly active against erythromycin-susceptible pneumococci, the MIC(90) being 0.015 mg/l. Erythromycin-resistant pneumococci that contained the ermB gene, either alone or together with the mefE gene, were cross-resistant to other macrolides and to clindamycin, while erythromycin-resistant pneumococci that contained only the mefE gene were cross-resistant to azithromycin, clarithromycin and roxithromycin but remained susceptible to josamycin and clindamycin. Telithromycin was active against erythromycin-resistant pneumococci irrespective of their mechanism of macrolide resistance, although the MIC(90) (0.25 mg/l) was higher than that seen with erythromycin-sensitive isolates. Telithromycin thus appears to be a potentially useful drug in settings where pneumococcal resistance to macrolides is prevalent.

Anti-Bacterial Agents↗

Audit of the use of erythromycin in the treatment of community-acquired lower respiratory infections.

The British Thoracic Society (BTS) guidelines for the treatment of community-acquired pneumonia recommend initial therapy with a betalactam antibiotic, with the addition of erythromycin if there are features of an atypical pneumonia. To see if these guidelines were being followed, a prospective study was undertaken of all adult patients admitted to hospital over a 3-month period who were given erythromycin for a community-acquired lower respiratory tract infection. Erythromycin was given to 62 patients who could be fully assessed. Continued prescription of erythromycin was justified in 10 (16%)--two patients with penicillin allergy, two with M. catarrhalis infection and one patient with legionnaires disease. Five patients had infections severe enough on admission to warrant combined therapy in line with the BTS recommendations. Five patients had erythromycin stopped on day 2. Erythromycin was prescribed on admission and continued unnecessarily in 47/62 patients, showing that the BTS recommendations are not being followed correctly.

Adult↗

Dental anxiety and the absorption of orally administered erythromycin stearate.

Erythromycin stearate is an acid labile antibiotic, therefore fear and apprehension, which are known to affect gastric motility, may produce erratic absorption resulting in lower serum levels. The mean (SD) serum erythromycin concentration 75 minutes after a 1.5 gm oral dose of erythromycin stearate to 45 patients was 8.7 (4.8) mg/L and ranged widely from 0.4 to 20.5 mg/L. The serum concentration of erythromycin was below therapeutic levels (1.0 mg/L) in two patients. No significant association was found between anxiety and serum levels of erythromycin when age, gender, and gastric distress were taken into account. It is concluded that dental anxiety may indirectly influence the uptake of oral erythromycin stearate; but this relationship is complex, and there is no evidence from this study that increased dental anxiety decreases the uptake of the drug.

Adult↗

Overproduction and characterization of the erythromycin C-12 hydroxylase, EryK.

Hydroxylation of C-12 is one of the final steps in the biosynthesis of erythromycin A (ErA). A point of uncertainty in the erythromycin pathway has been whether the C-12 hydroxylase operates on each of two possible substrates, erythromycin B (ErB) and erythromycin D (ErD). Stassi et al. have cloned the gene, designated eryK, which encodes the P-450 monooxygenase responsible for erythromycin C-12 hydroxylation in Saccharopolyspora erythraea [Stassi, D., Donadio, S., Staver, M. J., & Katz, L. (1993) J. Bacteriol. 175, 182-189]. We report the overproduction of EryK in Escherichia coli as insoluble inclusion bodies; the solubilization, refolding, and reconstitution of active holo-EryK; and kinetic confirmation of a 1200-1900-fold preference of the enzyme for ErD over the alternative C-12 hydroxylase substrate ErB. Our results indicate that ErB is a shunt metabolite in the erythromycin biosynthetic pathway.

Amino Acid Sequence↗

Differential interaction of erythromycin with cytochromes P450 3A1/2 in the endoplasmic reticulum: a CO flash photolysis study.

The kinetics of CO binding to cytochromes P450, measured by the flash photolysis technique, were used to probe the interaction of erythromycin with cytochromes P450 in rat liver microsomes. Addition of erythromycin generates substrate difference spectra using microsomes from rats treated with phenobarbital or dexamethasone but not from untreated rats, showing that it binds to P450s induced by these agents. In contrast, erythromycin and/or a monoclonal antibody to P450 3A1/2 accelerated CO binding to microsomes from rats treated with phenobarbital but had no effect on microsomes from untreated or dexamethasone-treated rats. Based on the differential amounts and inducibilities of the P450 3A1 and 3A2 forms in these microsomal samples, these results indicate that erythromycin increased the rate for P450 3A2 but not P450 3A1. The divergent effects of erythromycin on these P450s, which exhibit 89% sequence similarity, were consistent with a model of the P450 substrate binding site in which erythromycin forms a more rigid complex with P450 3A1 than P450 3A2. These results demonstrate the sensitivity of P450 conformation/dynamics to substrate binding, and show that CO binding kinetics can distinguish among closely related P450s in a microsomal environment.

Animals↗

Improved erythromycin production in a genetically engineered industrial strain of Saccharopolyspora erythraea.

An industrial erythromycin production strain of Saccharopolyspora erythraea spp. was used to demonstrate that careful genetic engineering can significantly improve productivity. The chromosomally integrated Vitreoscilla hemoglobin gene (vhb) was shown to enhance the final titer of erythromycin by some 70% compared to the original S. erythraea spp. Overall, specific erythromycin yields were about 2.5 g of erythromycin/g of total protein for S. erythraea::vhb but <1 for the S. erythraea spp. The maximum rates of biosynthesis were 57.5 mg of erythromycin/(L/h) and 24.3 mg/(L/h) for the recombinant strain S. erythraea::vhb and S. erythraea spp., respectively. Overall space-time yield was 100% higher for the S. erythraea::vhb fermentation (1.1 g of erythromycin/(L/day)) than for the S. erythraea spp. fermentation (0. 56 g of erythromycin/(L/day)). The genetic stability of the recombinant strain was high, and no selective pressure was needed throughout the cultivations. Expression of functional Vitreoscilla hemoglobin throughout the cultivations was verified by CO difference spectrum assays.

Bacterial Proteins↗

Influence of the antibiotic erythromycin on anaerobic treatment of a pharmaceutical wastewater.

A laboratory-scale anaerobic sequencing batch reactor was used to treat a model substrate mixture representing pharmaceutical wastewater at an organic loading rate of 2.9 g COD/(L d). After reaching stable operation the reactor was first exposed to low (1 mg/L) and, subsequently, to high (200 mg/L) concentrations of the antibiotic erythromycin. The addition of low levels of erythromycin resulted in a significant but limited reduction of biogas production by 5% and the higher level of erythromycin did not impact biogas production further, suggesting that a substantial fraction of the microbial populations in the ASBR were resistant to the antibiotic. Effluent soluble COD could not be accounted for in measured volatile fatty acids, perhaps suggesting the production of soluble microbial products. In batch tests evaluating the specific methanogenic activity, conversion of the model substrate mixture was only slightly affected by the presence of erythromycin. However, the conversion of butyric acid was inhibited when erythromycin was present. After 47 days of exposure to erythromycin, the conversion of butyric acid was inhibited to a lesser extent, suggesting the development of antibiotic resistance in the biomass. Exposure to antibiotics can affect specific substrate degradation pathways, leading to the accumulation of volatile fatty acids, soluble microbial products, and potentially to overall system instabilities.

Anti-Bacterial Agents↗

Effect of meal and intravenous erythromycin on manometric and electrogastrographic measurements of gastric motor and electrical activity.

Electrogastrography (EGG) measures, on the skin surface, the myoelectrical activity attributable to gastric smooth muscle cells. The physiological significance of signal amplitude and variation has not been clearly established. The increased signal amplitude after eating a meal may be related to increased contractile activity or to gastric distension. This study investigates the effect of increased gastric motor activity, unaccompanied by gastric distension, on the EGG recording and compares it to the effect of a meal. Nine children (3 months to 15 years old), were assessed by antroduodenal manometry for chronic intestinal pseudoobstruction (N = 5), chronic vomiting (N = 2), and abdominal distension (N = 2). Synchronized EGG recording was performed simultaneously. During the study, four children were given a meal and five were given intravenous erythromycin 3 mg/kg over 1 hr. The ratio of the antral motor index (MI = number of waves x sum of amplitudes) determined 1 hr before a meal (or erythromycin) to that determined 1 hr after a meal (or during intravenous erythromycin) was calculated. The ratio of the running total spectrum power of the electrical signal at the same times was also calculated. Antral MI increased after a meal [MI ratio (mean +/- SE) 5.33 +/- 2.2] and after intravenous erythromycin (MI ratio: 9.36 +/- 2.6). The amplitude of the electrical activity also increased after the meal [power ratio (mean +/- SE) 3.01 +/- 0.65] and after intravenous erythromycin (power ratio: 1.23 +/- 0.39), but the increase was greater after the meal (P < 0.05 vs intravenous erythromycin). No correlation was found between antral MI ratio and running total spectrum power ratio. In conclusion, the increased amplitude of the gastric electrical activity recorded by the EGG after a meal seems to be only partly due to the increase in antral motor activity. The increase in power is also related to gastric distension.

Adolescent↗

Heterogeneity of CYP3A isoforms metabolizing erythromycin and cortisol.

The N-demethylation of erythromycin and 6 beta-hydroxylation of cortisol are both functions of the glucocorticoid-inducible CYP3A in human liver microsomes. To determine whether 6 beta-hydroxylation and erythromycin N-demethylation are catalyzed by similar or distinct CYP3A isoforms, erythromycin N-demethylase activity, as reflected by the recently described 14[C]-erythromycin breath test, was compared with urinary 6 beta-hydroxycortisol/cortisol ratios, a measure of cortisol 6 beta-hydroxylase activity, in nine patients. Erythromycin N-demethylation varied fourfold and 6 beta-hydroxycortisol/cortisol ratios varied sevenfold among the subjects; no correlation was found between these activities (r2 = 0.065). New noninvasive tests of CYP3A strongly suggest cortisol 6 beta-hydroxylation and erythromycin N-demethylation are performed by distinct CYP3A isoforms.

Aged↗

A potentially hazardous interaction between erythromycin and midazolam.

Interaction between erythromycin and midazolam was investigated in two double-blind, randomized, crossover studies. In the first study, 12 healthy volunteers were given 500 mg erythromycin three times a day or placebo for 1 week. On the sixth day, the subjects ingested 15 mg midazolam. In the second study, midazolam (0.05 mg/kg) was given intravenously to six of the same subjects, after similar pretreatments. Plasma samples were collected, and psychomotor performance was measured. Erythromycin increased the area under the midazolam concentration-time curve after oral intake more than four times (p < 0.001) and reduced clearance of intravenously administered midazolam by 54% (p < 0.05). In psychomotor tests (e.g., saccadic eye movements), the interaction between erythromycin and orally administered midazolam was statistically significant (p < 0.05) from 15 minutes to 6 hours. Metabolism of both erythromycin and midazolam by the same cytochrome P450IIIA isozyme may explain the observed pharmacokinetic interaction. Prescription of midazolam for patients receiving erythromycin should be avoided or the dose of midazolam should be reduced by 50% to 75%.

Administration, Oral↗

Extraction-spectrofluorimetric method for the determination of erythromycin and its esters in pharmaceutical formulations using manual and flow-injection procedures.

A sensitive and rapid extraction-spectrofluorimetric method for the determination of erythromycin, based on the formation of an ion pair with Erythrosine B, is described. The calibration graph resulting from the measurement of the fluorescence of the chloroform extract (10 cm3) at 560 nm with excitation at 544 nm is linear over the range 10-600 micrograms of erythromycin per 20 cm3 of total volume of aqueous phase, with a relative standard deviation (RSD) of 1.5% for 3.7 micrograms cm-3 erythromycin. The method can be successfully adapted to an unsegmented flow system, the peak height being proportional to erythromycin concentration over the range 0.65-5.88 micrograms of erythromycin per 400 mm3 of sample solution injected. Up to 45 samples h-1 can be processed with an RSD of 2.9-3.8%. Manual and flow-injection methods were satisfactorily applied to the determination of erythromycin in pharmaceutical preparations.

Erythromycin↗

Could oral erythromycin optimize high energy continuous enteral nutrition?

BACKGROUND: Intravenous erythromycin has previously been reported to stimulate gastric emptying, to inhibit gastric acid secretion and to stimulate pancreatic secretion during continuous gastric infusion of a liquid diet in healthy volunteers. AIM: The aim of this study was to evaluate the effects of oral erythromycin (160 mg/h) on gastrointestinal function under these conditions in seven healthy subjects. METHOD: This randomized double-blind cross-over study measured the gastric emptying rate of nutrients, gastric acid secretion, gastric pH, jejunal flow rate as well as biliopancreatic secretion and duodeno-caecal transit time during a 19.9 kJ/min continuous infusion of a nutrient solution (4.18 kJ/mL) in the antrum over a 6-h period by a perfusion method. RESULTS: The nutrition was well tolerated except by one subject with placebo perfusion. During the 6-period, total gastric volume and gastric volume of nutrient decreased during erythromycin administration by 22 +/- 8 and 22 +/- 6%, respectively. Gastric acid secretion was not modified by erythromycin. Lipase and bile salt outputs were significantly higher with erythromycin. The duodeno-caecal transit time was not statistically different with drug and placebo (169 +/- 15 and 146 +/- 19 min, respectively). CONCLUSION: During continuous gastric infusion of a liquid diet, the effect of oral erythromycin on gastric emptying could be useful to optimize cyclic enteral nutrition or to enhance the tolerance of enteral nutrition.

Administration, Oral↗

Which form of erythromycin should be used to treat gastroparesis? A pharmacokinetic analysis.

BACKGROUND: Erythromycin is a macrolide antibiotic that exhibits prokinetic effects. It has been shown to enhance antral contractility and accelerates gastric emptying rates, primarily by stimulating motilin receptors. AIM: To determine the optimal dosage form of erythromycin for use as a prokinetic agent. METHODS: Eight normal volunteers and three patients with documented gastroparesis ingested 250 mg erythromycin in tablet. suspension and intravenous forms. Serum erythromycin levels were determined at frequent intervals. These data were plotted vs. time and analysed for lag time, time to maximum concentration (tmax), maximum concentration (Cmax) and bioavailability (F). RESULTS: The absorption kinetics of the erythromycin suspension was notable for short lag times and early tmax, while lag times and tmax were delayed with the tablet form. Median lag time was 15 min for the suspension vs. 90 min for the tablet (P < 0.005). Median tmax for the suspension was 45 min vs. 180 min for the tablet (P < 0.005). A non-significant decrease in F was seen with the suspension compared to the tablet (P = 0.12). CONCLUSION: Based on the kinetic data from this study, erythromycin suspension is the ideal dosage form for administration of this drug as a prokinetic agent.

Administration, Oral↗

Review article: erythromycin as a prokinetic agent in infants and children.

Erythromycin has been used as an antibiotic for more than four decades, but only in the last 10 years have other therapeutic benefits of this agent been exploited. Animal and human studies have demonstrated a prokinetic effect on the gastrointestinal tract at sub-antimicrobial doses (typically a quarter or less of the antibiotic dose). A limited number of studies have been performed in children to investigate this action. A review of this literature is particularly pertinent given the frequency of clinical problems related to gastrointestinal dysmotility in children and the limited availability of prokinetic agents in paediatric practice, compounded by the recent withdrawal of cisapride. The prokinetic effects of erythromycin have been investigated in infants with dysmotility associated with prematurity, in low birth-weight infants recovering from abdominal surgery, and in older children with a variety of other gastrointestinal disorders. Only one randomized placebo-controlled trial has been conducted. All except one of these studies have shown a beneficial effect of erythromycin in either promoting tolerance of enteral feeds or enhancing a measured index of gastrointestinal motility. Erythromycin appears to be equally effective when given orally (as ethylsuccinate or estolate) or intravenously (as lactobionate). Significantly, no serious adverse effects have been reported in studies in which erythromycin has been used for its prokinetic effects, although fatal reactions have followed the intravenous administration of erythromycin to neonates in antibiotic doses.

Administration, Oral↗

Effects of erythromycin on human colonic circular muscle in idiopathic chronic constipation.

BACKGROUND: Erythromycin has been shown to have profound prokinetic effects on the gastrointestinal tract of humans and animals, probably through its action on endogenous motilin receptors. The purpose of this study was to determine both the direct and indirect effects ('off contraction') of erythromycin and motilin on ex vivo circular muscle strips of the distal colon from patients with or without idiopathic chronic constipation (ICC). MATERIALS AND METHODS: Cumulative concentrations of erythromycin (1-20 microM) and motilin (0.05-1 microM) were tested in both control and ICC preparations in order to evaluate the direct drugs effect. A range doses of both erythromycin (0.5-10 microM) and motilin (0.05-0.5 microM) were tested on their ability to affect the off-contraction that follows the typical inhibitory response evoked by low frequencies of Electrical Field Stimulation (EFS) (1-5 Hz, 20 V, 1 msec pulse trains lasting 1 min). RESULTS: The direct effect of both erythromycin and motilin was a slight increase (less than 10% of the maximal ACh-induced contraction) in the basal tension, with no dose-response relationship. The off-contraction, evoked by EFS, was not affected by drugs pretreament in control preparations. Conversely, in ICC preparations both drugs significantly increased the off-contraction (about 30%). CONCLUSIONS: Erythromycin causes mainly an indirect contractile effect in circular muscle strips from ICC patients. This effect may be related to the activation of inhibitory neuronal motilin receptors. This activation might potentiate NANC relaxation, proportionally increasing the circumferential reflex contraction that follows the EFS-induced relaxation.

Adult↗