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Induction of clindamycin resistance in erythromycin-resistant, clindamycin susceptible and methicillin-resistant clinical Staphylococcal isolates.

OBJECTIVES: To demonstrate the in vitro ability of erythromycin to induce clindamycin in erythromycin resistant and clindamycin susceptible clinical isolates of Staphylococci. METHODS: We studied 291 clinical isolates of erythromycin-resistant (ER-R) clindamycin-susceptible Staphylococci (CL-S) at Almana General Hospitals, Al-Khobar, Dammam, Saudi Arabia during the period from June 2004 to May 2005. The isolates included 70 Staphylococcus aureus, 81 Methicillin Resistant Staphylococcus aureus (MRSA) and 140 coagulase-negative Staphylococci (CNS). We examined these isolates for inducible clindamycin resistance (ICR) by erythromycin induction test using double disc susceptibility test (D-test). Strains producing ICR show flattening of the clindamycin disc zone adjacent to the erythromycin disc. RESULTS: Of the 291 ER Staphylococci studied, 82 (28%) demonstrated constitutive clindamycin resistance [2 (2.9%) S. aureus, 43 (53%) MRSA and 37 (26%) CNS]. Inducible clindamycin resistance was demonstrated in 113 (38.8%) of Staphylococcal isolates, including 84 (28.9%) from adult patients and 29 (10%) from pediatric patients. The incidence of ICR was 49 (70%) for S. aureus, 35 (43%) for MRSA and 29 (20.7)% for CNS. Overall, 96 (33%) of the isolates remained susceptible to clindamycin and were negative for clindamycin induction [19 (27%) S. aureus, 3 (3.7%) MRSA and 74 (52.8%) CNS]. CONCLUSION: We conclude that a significant number of ER-R CL-S staphylococcal isolates studied were positive for ICR. These isolates should be reported as clindamycin resistant. Given the high rate of inducible resistance to clindamycin in the staphylococcal isolates, we recommend that microbiology laboratories perform erythromycin induction test on all ER-R CL-S staphylococcal isolates prior to reporting clindamycin susceptibility.

Clindamycin↗

Erythromycin synergism with essential and trace elements.

In order to establish the role of various essential and trace element complexation on the antibacterial activity of various macrolide antibiotics, the synergistic or antagonistic behavior of erythromycin metal complexes have been studied and compared with the parent drug. Metal complexes of erythromycin with magnesium, calcium, chromium, manganese, iron, cobalt, nickel, copper, zinc and cadmium have been investigated for their antibacterial activity and compared with erythromycin by observing the changes in minimum inhibitory concentration (MIC) and by measuring the zone of inhibition of complexes against both Gram-negative and Gram-positive microorganisms. Various microorganisms used were Staphylococcus aureus, Enterococcus faecalis, Escherichia coli, Salmonella typhi, Proteus vulgaris, Shigella dysentery, Klebsiella pneumoniae and Staphylococcus epidermidis. For MIC observation, serial dilution method was employed and zone sizes were determined by diffusion disk method. Our investigations reveal that formation of erythromycin complexes result in synergistic effect i.e., antimicrobial activity of complexes of erythromycin increases with respect to parent erythromycin drug and MIC of drug metal complexes decreased.

Anti-Bacterial Agents↗

[Effect of erythromycin on apoptosis of epithelial cell in nasal polyps].

OBJECTIVE: To study the effect of erythromycin on apoptosis and expression of Bax and Bcl-2 of epithelial cell in nasal polyps. METHODS: Epithelial cells from thirty nasal polyps and fifteen inferior turbinates were cultured in Dulbecco Eagle and Ham F12 (1:1) and divided into two groups (one group were treated with Erythromycin). Apoptosis was detected by terminal deoxynucleotidyl transferase mediated dUTP nick end labeling and expression of Bcl-2 and Bax detected by immunohistochemistry at 1, 3, 5 days after culture. RESULTS: The apoptosis indexes (AI) of epithelial cell in nasal polyps after cultured for 1, 3, 5 days with erythromycin were (33.23 +/- 6.50)%, (38.21 +/- 7.22)% and (52.63 +/- 7.86)% respectively. The AI of epithelial cell in inferior turbinates were (31.02 +/- 5.60)%, (32.13 +/- 7.15)% and (39.64 +/- 7.48)% respectively. There was significant difference between two groups at 5 day after culture (P < 0.05). Expression of Bax and Bcl-2 of epithelial cell was significantly higher in nasal polyps than that in inferior turbinates (P < 0.01). Expression of Bax of epithelial cell cultured with erythromycin was significantly higher than that in the controls (P < 0.05). Apoptosis was clearly promoted after 5 day culture with Erythromycin (P < 0.05). CONCLUSIONS: Erythromycin promoted expression of Bax and apoptosis of epithelial cell in nasal polyps.

Adolescent↗

Controlled release microspheres based on Eudragit L100 for the oral administration of erythromycin.

The use of Eudragit L100, a copolymer based on methacrylic acid and methacrylic acid methyl ester, in preparing erythromycin microspheres is described. The microspheres were simply prepared in liquid paraffin by solidifying an Eudragit L100 in ethanol solution. When gelatin was incorporated in the solidifying solution, the resultant microspheres were more spherical and had a smooth surface. The size of the microspheres could be controlled by varying the Eudragit L100 concentration in ethanol, and erythromycin was incorporated with 60-70% efficiency. The degradation of erythromycin by acid was markedly protected when the erythromycin microspheres were coated with the polymer. The in vitro release rate of erythromycin from the microspheres was also modified by the coating process. The feasibility of preparing formulations of erythromycin for oral administration, which release the drug at a controlled rate, and protect the drug from gastric acid, is thus demonstrated.

Acrylic Resins↗

Effect of erythromycin on tricyclic antidepressant metabolism.

Macrolide antibiotics such as erythromycin have been found to impair the hepatic metabolism of carbamazepine. In addition, recent studies have shown that intestinal flora can N-demethylate tricyclic antidepressants, suggesting that the human gut may be a possible site of extrahepatic drug metabolism. Therefore, we conducted a study to determine whether the concurrent use of erythromycin might influence the metabolism and steady-state plasma concentrations of tricyclic antidepressants. Six days of erythromycin administration caused no systematic change in either the parent tricyclic or its metabolite(s). Thus, the short term concurrent use of erythromycin does not appear to alter hepatic or gut flora tricyclic metabolism to an appreciable extent. Nevertheless, prior reports of altered carbamazepine kinetics by erythromycin should increase the physician's awareness of a possible drug interaction when erythromycin is used concurrently with a tricyclic antidepressant.

Adult↗

Serum and tissue concentrations of erythromycin in calves with induced pneumonic pasteurellosis.

The effects of pneumonia on the pharmacokinetics of erythromycin administered IM and the tissue concentration changes with time were evaluated in 2-month-old calves. Pneumonia was induced by injection of Pasteurella haemolytica cultures through the thoracic wall into each lung. Six days prior to induction of pneumonia, erythromycin (15 mg/kg) was administered in a single IM dose. Erythromycin was administered again 48, 72, and 96 hours after injection of P haemolytica. On the third day of erythromycin administration (96 hours), the calves were serially euthanatized in groups of 4 calves each at 2, 5, 8, 12, 18, and 24 hours after the final dose was given. Tissue concentrations of erythromycin in kidney, liver, lung, muscle, CSF, and serum were determined. Neither the serum concentrations nor the overall pharmacokinetic values were significantly (P less than or equal to 0.05) changed by pneumonia. The concentrations of erythromycin were maximal at 5 hours for liver, muscle, and serum and at 8 hours for CSF, kidney, and lung. Serum and muscle concentrations were similar, whereas concentrations in CSF were lower than in serum and higher in kidney, liver, and lung. The lung/serum ratios were approximately 2.5 to 3 at 8 through 24 hours after IM administration. The peak concentration in lung was approximately 6 micrograms/g at 8 hours.

Animals↗

Protein components of the erythromycin binding site in bacterial ribosomes.

Two derivatives of erythromycin have been prepared carrying either an aryl azide or a 4-nitroguaiacol as a photoreactive group. Both derivatives bind to the specific erythromycin ribosomal site as shown by saturation and competition studies. The derivatives were isotopically labeled either with tritium or with 125I, and radioactivity is covalently incorporated to the ribosome upon irradiation at the appropriate wavelength. The ribosomal proteins labeled were identified by either mono- and two-dimensional gel electrophoresis or high performance liquid chromatography. It has been found that protein L22 is the protein mainly, and under some conditions exclusively, labeled by the erythromycin derivatives. These results were confirmed using ribosomes from erythromycin-resistant mutants having a protein L22 with modified electrophoretical mobility. Protein L15 is also labeled in both cases, and the aromatic azide derivative labels to a lesser extent proteins L2 and L4. Competition experiments with erythromycin indicate that labeling in protein L22, and probably in L15, is specific, while the specificity of labeling in proteins L2 and L4 is questionable. These results indicate that the erythromycin derivatives label different ribosomal proteins than the spiramycin type of macrolides (Tejedor, F., and Ballesta, J.P.G. (1985) Biochemistry 24, 467) suggesting that the binding sites of both macrolide types are probably not identical.

Binding Sites↗

Effect on birth weight of erythromycin treatment of pregnant women.

To test the hypothesis that treatment with antibiotics prevents low birth weight, pregnant women whose vaginal cultures contained Ureaplasma urealyticum or Mycoplasma hominis (or both) and who gave written informed consent were treated with one of the following: identical looking capsules containing 250 mg of either erythromycin estolate or stearate (active against U urealyticum), or 150 mg of clindamycin hydrochloride (active against M hominis), or placebo, four times daily for six weeks in a randomized double-blind study. Treatment with clindamycin had no effect. Treatment with erythromycin initiated during the second trimester had no effect on mean birth weight or on the frequency of low-birth-weight infants. In contrast, women whose treatment with erythromycin was initiated in the third trimester gave birth to infants with a heavier mean birth weight (3331 g) than infants born to placebo-treated women (3187 g) (P = .042). Similarly, in women whose erythromycin was begun during the third trimester, the birth rate of infants weighing 2500 g or less was 3%, whereas in women treated with placebo, the birth rate for low-birth-weight infants was 12% (P = .047). These data suggest that treatment with erythromycin during the third trimester prevents low birth weight in mycoplasma-colonized pregnant women. Whether the effect is due solely to the action of erythromycin on U urealyticum is uncertain.

Birth Weight↗

Treatment of Chlamydia trachomatis infections: comparison of 1- and 2-g doses of erythromycin daily for seven days.

Erythromycin is recommended as the alternative to tetracyclines for the treatment of Chlamydia trachomatis infections. However, the usual dose of erythromycin (2 g daily for a week) is frequently associated with gastrointestinal side effects. The goal of this study was to determine whether 1 g of erythromycin daily for a week would be as effective as the 2-g daily dose but without the adverse gastrointestinal effects associated with the larger dose. A total of 114 patients were entered into a randomized double-blind study; 76 patients completed treatment, 13 patients discontinued treatment because of adverse effects, and 25 failed to complete therapy or to return after treatment was initiated. Twelve (27%) of the 45 patients treated with 1 g of erythromycin had cultures positive for C. trachomatis after therapy, as compared with three (10%) of 31 patients treated with a 2-g dose. Only 34% of those treated with 1 g of erythromycin developed adverse gastrointestinal effects, as compared with 71% of those who received 2 g of the drug. Of the 13 patients who discontinued treatment because of side effects, 11 were receiving the 2-g dose. This study indicates that the smaller 1-g dose of erythromycin is inadequate therapy for C. trachomatis infections and that the standard 2-g dose is frequently associated with adverse effects that require discontinuation of therapy.

Adult↗

[Hydrogen bond and acid-base interactions in erythromycin solutions].

The association and conformational structure of the molecule of erythromycin in solutions of CCl4, C2Cl4 and CHCl3 were studied by the IR spectra in the region of v OH and vC = O. The analysis of the concentration and temperature changes showed that the erythromycin association was accounted for by the hydrogen linkage of OH ... O = C to the ester group. In the monomer molecule of erythromycin, all hydroxyl groups participated in the intramolecular hydrogen linkage. Band 3513 cm-1 belonged to the OH group in the five-membered cycles of OH ... O. Components 3500, 3530 and 3560 cm-1 of the wide band vOH were assigned to the cycles with OH ... N and OH ... O linkages of a larger size. The association was due to a break in a part of the intramolecular hydrogen linkages. Addition of strong acceptors of proton-hexamethanol and trioctylphosphinoxide to the solution resulted in attenuation of these bands and appearance of a strong band vOH of the erythromycin-acceptor complexes. In the presence of monochloroacetic acid in the solution of CHCl3 stoichiometric protonization of erythromycin was observed. The total acid was in the form of anion (vaCO-2 1610 cm-1) up to a ratio of 1:1. The protonization proceeded according to the nitrogen atom since the antibiotic spectrum in the region of vC=O did not change. Propionic acid titrated erythromycin in methanol solution and in mixtures of water and methanol up to a ratio of 1:5 (v/v). However, in the solution of CHCl3 equilibrium between the neutral and ionized molecules of the acid was seen.

Acid-Base Equilibrium↗

Erythromycin--three decades later.

This article reviews some of the more recent developments relating to the clinical usage of erythromycin. The bactericidal and tissue-penetrating properties of this antibiotic are described and the suggestion that erythromycin has a very useful spectrum of activity in respiratory tract infections is supported by a variety of studies. We examine the increasing application of erythromycin in an extending number of problems such as sexually acquired disorders, a variety of diseases produced by infection with Legionella species and the enteritides associted with Campylobacter and Shigella species. The influence of erythromycin in particular, and of antimicrobial agents in general, on the immune system of the host is discussed. The immunomodulatory capacity of the antibiotics used deserves more attention. The interactions of erythromycin with theophylines and with carbamazepine are noted and amplified, and the consequences of the binding of erythromycin to plasma alpha 1-glycoprotein are examined. After some 3 decades of use, this remarkably safe antibiotic continues to display activities which deserve the attention of the clinician.

Adult↗

Reduction of the aerobic Gram negative bacterial flora of the gastro-intestinal tract and prevention of traveller's diarrhea using oral erythromycin.

Traveller's diarrhea is mostly due to aerobic Gram-negative bacterial species, especially enterotoxigenic Escherichia coli. Until today no fully satisfactory prophylactic regimen has been designed. We have previously reported that erythromycin can eliminate Enterbacteriaceae from the human faecal flora during several weeks without recolonization by highly resistant Gram-negative aerobic organisms. This effect has been reproduced in 17 out of 18 volunteers taking 1, 2 or 3 g per day of oral erythromycin base during 5 days. This effect is due to the very high faecal concentrations of the antibiotic (2,000-4,000 micrograms/g) compared to the MIC of erythromycin on aerobic Gram-negative species (10-500 micrograms/ml). MIC of erythromycin on bacterial species which cause traveller's diarrhea are within the same range. These considerations led us to perform a double-blind, randomized, placebo-controlled clinical trial of the efficacy of 1 g daily intake of erythromycin base in preventing traveller's diarrhea. Fourty-eight US citizens travelling to Acapulco (Mexico) were enrolled in the study. Mean duration stay was 5.87 days. Seven out of 24 subjects of the placbo group experienced diarrhea and non (p=0.0047) in the treated group. Study should be undertaken to evaluate the efficacy of oral erythromycin in preventing traveller's diarrhea in other parts of the world.

Adult↗

Failure of erythromycin in preventing bacterial endocarditis.

Use of oral erythromycin to prevent bacterial endocarditis has been accepted in the treatment of penicillin-allergic patients who required oral or sinusal surgery. A case of Streptococcus sanguis endocarditis, however, developed in a patient following intravenous erythromycin administration during surgery on the maxillary sinus. The organism isolated proved resistant to erythromycin. This isolation of an erythromycin-resistant organism, together with previous reports of the drug's failure in preventing endocarditis in animal models, and recognition of the bacteriostatic action of erythromycin, argue for caution in our current practice of using erythromycin as a single drug therapy to prevent endocarditis in the patient who is allergic to penicillin.

Adult↗

Effect of erythromycin on ethanol's pharmacokinetics and perception of intoxication.

STUDY OBJECTIVE: To determine the effect of erythromycin on ethanol's pharmacokinetics and perception of intoxication. DESIGN: Double-blind, randomized, placebo-controlled, crossover study. SETTING: A clinical research center. PARTICIPANTS: Ten healthy volunteers. INTERVENTIONS: Erythromycin base 500 mg or identical placebo was administered 3 times/day for 7 days. On day 8, ethanol 0.8 g/kg was administered by mouth concurrently with erythromycin or placebo. A 2-week washout period was allowed between each treatment arm. MEASUREMENTS AND MAIN RESULTS: Twelve blood samples were obtained over a 12-hour period to determine ethanol concentrations. Perception of intoxication was determined at each time point using a 10-cm visual analog scale. Ethanol concentrations were determined using a gas chromatographic method. Mean +/- SD ethanol pharmacokinetics for erythromycin versus placebo were time to peak ethanol plasma concentrations 1.1 +/- 0.4 hours versus 1.3 +/- 0.3 hours, peak ethanol concentrations 118 +/- 18 mg/dl versus 114 +/- 27 mg/dl, ethanol oral clearance (CL/F) 2.9 +/- 0.8 ml/min/kg versus 3.4 +/- 2.2 ml/min/kg, and area under the curve 481 +/- 104 mg.hour/dl versus 465 +/- 132 mg.hour/dl (p > 0.05). The blood ethanol concentrations and perception of intoxication scores on a visual analog scale were well correlated (r2 = 0.78, p < 0.01). Mean +/- SD areas under the effect versus time curve were 35.1 +/- 20.7 cm/hour and 31.5 +/- 18.2 cm/hour for erythromycin and placebo, respectively (p > 0.05). CONCLUSION: Oral erythromycin base 1500 mg/day compared with placebo does not alter ethanol's pharmacokinetics or perception of intoxication in healthy volunteers.

Administration, Oral↗

Effect of oral erythromycin on patients with diabetic gastroparesis.

BACKGROUND: Abnormal gastrointestinal motility is a well recognized complication of diabetes mellitus, and disordered gastric emptying may hamper glycemic control. The objects of this study were to investigate the effect of oral erythromycin on gastric emptying and to evaluate the effect of corrected gastric emptying on glycemic control in patients with diabetic gastroparesis. METHODS: Twenty patients of Type II (non-insulin-dependent) diabetes mellitus with typical symptoms of gastroparesis and delayed solid phase gastric emptying were studied. There were 18 males and 2 females, aged 49 to 72 years. Erythromycin (erythromycin estolate) was given orally at a dose of 250 mg, 3 times daily, 30 minutes before each meal. Radionuclide-labelled solid phase gastric emptying and fasting blood sugar (FBS) were studied after one day of erythromycin therapy, and again after 2 weeks of the therapy. The half time of gastric emptying (GETt1/2) represented the time needed for 50 percent of the initial radioactivity to leave the stomach, and was used to express the gastric emptying status. RESULTS: The GETt1/2 decreased from 198.0 +/- 58.9 minutes at baseline to 139.1 +/- 67.6 minutes following one day of erythromycin therapy (p < 0.01), and to 137.1 +/- 71.2 minutes after two weeks of treatment (vs. baseline p < 0.01). The FBS decreased from 159.0 +/- 40.2 mg/dl at baseline to 149.0 +/- 38.5 mg/dl following one day of therapy (p = 0.12, NS), and to 139.2 +/- 39.8 mg/dl after two weeks of treatment (vs. baseline p < 0.02). CONCLUSIONS: It was concluded that erythromycin is an effective prokinetic agent for diabetic gastroparesis, and that corrected gastric emptying may improve glycemic control.

Administration, Oral↗

Interferon suppresses erythromycin metabolism in rats and human subjects.

Interferon down-regulates expression of cytochrome P-450 3A in male rats. This study explored the hypothesis that interferon therefore decreases the metabolism of drugs catalyzed by cytochrome P-450 3A. Initial experiments in male rats used microsomal erythromycin N-demethylase activity as a probe for cytochrome P-450 3A catalytic activity. After administration of rat interferon-gamma, erythromycin metabolism was impaired (53% of control; p < 0.01). This change correlated with the decline in cytochrome P-450 3A-dependent androstenedione 6 beta-hydroxylase activity, indicating that the decrease in erythromycin N-demethylase activity could be attributed to interferon-mediated suppression of cytochrome P-450 3A. We then used the [14C]N-methyl erythromycin breath test to assess the activity of hepatic cytochrome P-450 3A in rats and human subjects before and after a single dose of interferon. In rats, rat interferon-gamma decreased erythromycin metabolism to 57% of control (p < 0.005). In the human study, six patients with chronic active hepatitis C and four healthy controls were examined 20 to 26 hr after receiving a subcutaneous injection of human interferon-alpha 2b. Interferon produced a small decrease (median = 15%; range = 3% to 35%) in erythromycin metabolism (p < 0.05), as determined by 2-hr excretion of 14CO2 in the breath. Thus interferon-mediated suppression of cytochrome P-450 3A is less strong in human subjects than in male rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Azithromycin and erythromycin in the treatment of cervical chlamydial infection during pregnancy.

OBJECTIVE: To compare azithromycin and erythromycin in regard to side effects, intolerance, and cure rate in a pregnant population with chlamydial cervicitis. METHODS: Thirty women were randomized to receive either erythromycin, 500 mg orally four times a day for 7 days, or azithromycin, 1 g orally as one dose. All subjects completed questionnaires identifying the incidence of nausea, vomiting, diarrhea, abdominal pain, and anorexia. Post-treatment cultures were taken from all subjects. RESULTS: All subjects receiving erythromycin reported two or more gastrointestinal side effects, versus none in the azithromycin group (P < .001). Five of 15 subjects in the erythromycin treatment arm were intolerant to the 500-mg dose given four times a day, compared to none in the azithromycin group (P < .025), so the dosage was lowered to 250 mg four times a day to complete the course. Repeat cervical testing demonstrated similar cure rates for both medications: 100 and 93% (14 of 15) for azithromycin and erythromycin, respectively. CONCLUSION: These data suggest that azithromycin is a valid treatment option in pregnant patients who cannot tolerate erythromycin because of side effects.

Administration, Oral↗

Proliferation of erythromycin-stimulated mouse peritoneal macrophages in the absence of exogenous growth factors.

Erythromycin (0.2-20 micrograms/ml) induced the proliferation of macrophages of mouse peritoneal exudate cells (PEC) in a liquid medium without exogenous growth factors. The proliferating macrophages formed giant colonies between days 22 and 26 of culture; these colonies continued to proliferate even after subculture. The erythromycin-induced cell proliferation was independent of fibroblasts, T cells, B cells, or endotoxins. This activity seemed to be specific to erythromycin since other antibiotics such as tetracycline, streptomycin, gentamicin, penicillin G, and josamycin did not induce the proliferation of macrophages. Any known cytokines, including IL-2, IL-3, IL-4, IL-6, and GM-CSF, were not detectable by ELISA tests in any of the culture supernatants sampled from day 7 through day 28. The culture supernatants, however, had the capability of inducing the growth of macrophages, only in the presence of bioactive erythromycin at concentrations higher than 1.6 micrograms/l. Moreover, the culture supernatants, sampled after giant colonies had been formed, were capable of inducing giant colonies in the culture of adherent PEC. Thus, the erythromycin-induced macrophage proliferation might be due to the direct effect of this antibiotic, whereas the formation of giant colonies might be due to the production of some unidentified soluble factor produced by the proliferating macrophages. These data indicate that mouse PEC contain a subset of peritoneal macrophages capable of responding to erythromycin by forming proliferating colonies without exogenous growth factors.

Animals↗