Erythromycin Base Research Articles

Effect of erythromycin base on theophylline kinetics.

Because of several recent reports describing altered theophylline elimination in the presence of salts of erythromycin, the effect of a 10-day course of erythromycin base on theophylline kinetics was studied in eight healthy adult men. Theophylline (4 mg/kg) was given on four separate study days: (1) prior to starting erythromycin, (2) on the third day of erythromycin administration, (3) on the tenth day of erythromycin administration, and (4) 2 weeks after the course of erythromycin was completed. Mean theophylline kinetic parameter values on each of the 4 study days were: apparent volume of distribution (Vd), 0.466, 0.466, 0.472, and 0.470 1/kg; elimination half-life (t1/2), 7.4, 7.8, 8.5, and 7.0 hr; and total body clearance (ClB), 0.747, 0.723, 0.683, and 0.821 ml/min/kg. A maximum decrease of 20.7% in theophylline ClB was noted by the third study day. Two weeks after erythromycin was discontinued, the greatest increase in ClB observed was 45.7%. Differences in t1/2 and ClB between the third and fourth study days were statistically significant (p less than 0.05).

Selection of an oral erythromycin product

The chemistry, bioavailability, and adverse effects of erythromycin base, stearate, estolate, and ethylsuccinate are reviewed. Criteria for the evaluation of erythromycin bioavailability studies include study design, patient population, meal composition and timing, and assay methodology. Based on these criteria, the bioavailability of individual erythromycin products are evaluated in this paper. Compared with other antibiotics, the erythromycins have a good safety record. However, both the estolate and ethylsuccinate forms of erythromycin may cause hepatotoxity. Considering bioavailability and adverse effect data, a specific brand of enteric-coated erythromycin base tablets is recommended for erythromycin-sensitive infections in adults. For pediatric patients, a liquid formulation of erythromycin estolate or erythromycin ethylsuccinate is recommended.

The influence of food on the bioavailability of new formulations of erythromycin stearate and base.

1. The effect of food on the bioavailability of two new formulations of erythromycin, 1) erythromycin stearate, 500 mg (Erythrocin, 250 mg capsule-shaped tablets) and 2) erythromycin base, 500 mg (Eryc, 250 mg capsules containing enteric-coated pellets) was studied in 16 healthy subjects. 2. The study was a balanced, randomized Latin square design and was conducted on 4 days. The four treatments were erythromycin stearate immediately before (EB) and after EA) breakfast and erythromycin base immediately before (eB) and after (eA) breakfast. 3. The mean +/- s.d. maximal plasma erythromycin concentrations were 2.09 +/- 1.06, 0.37 +/- 0.40, 1.8+ +/- 1.15 and 1.91 +/- 1.57 micrograms/ml and the mean +/- s.d. times at which these occurred were 1.3 +/- 0.7, 2.3 +/- 0.9, 4.4 +/- 1.9 and 4.3 +/- 1.1 h for EB, EA, eB and eA respectively. 4. The mean +/- s.d. areas under the curves (0 to 8 h) were 4.99 +/- 2.41, 1.04 +/- 1.57, 4.93 +/- 2.98 and 4.98 +/- 3.14 for EB, EA, eB and eA respectively. 5. The bioavailability of erythromycin stearate was significantly reduced by the prior administration of food, whereas the absorption of the base was not inhibited by food.

Use of Antibiotics in the Outpatient Setting

Antibiotics with small but definable mortality, such as chloramphenicol, should not be used when safer drugs will suffice. Antibiotics with a low (1 to 5 per cent) morbidity should not be used when safer drugs are available. Therefore, cleocin, minocycline, or oral erythromycin estolate should rarely be used and regular erythromycin base is almost always preferable. Fever should not be treated with antibiotics since they are not antipyretics. "Colds" should not be treated with antibiotics, but antibiotics should be administered to patients with a history of chronic bronchitis, sinusitis, and recurrent otitis as soon as any symptoms begin. Intramuscular antibiotics should not be given except for benzathine penicillin. Use placebos instead of antibiotics when the patient's psyche demands an intramuscular injection. Make certain that the needle, syringe, and solution are sterile. Agents other than penicillin or cephalosporins should be used in patients with a definite history of penicillin allergy. Combination antibiotics or broad spectrum antibiotics like cephelosporins or tetracyclines should not be used when narrow spectrum antibiotics of known efficacy are available for specific syndromes such as streptococcal pharyngitis.

Plasma Levels following Single and Repeated Doses of Erythromycin Estolate and Erythromycin Stearate

The pharmacokinetics of erythromycin and erythromycin 2′-propanoate were studied in healthy male volunteers following single and repeated doses of erythromycin stearate tablets, erythromycin estolate capsules, and a suspension. Estolate dosages gave rise to higher plasma levels of total drug than the stearate. However, the stearate yielded higher plasma levels of erythromycin base. Absorption of all dosage forms, except the suspension, was delayed, and pharmacokinetic interpretation of both single- and multiple-dose data required incorporation of an absorption lag time. The absorption of erythromycin stearate was inhibited by food and also by low fluid volumes in fasted subjects. Absorption of erythromycin estolate was increased in the presence of fixid and was not greatly affected by fluid volume. Although single-dose data poorly predicted circulating levels of erythromycin following repeated doses, trends observed after single doses were maintained during chronic treatment.

Effect of chlorpromazine and erythromycin on bile salt-induced cholestasis in the rat.

The effects of subacute administration of chlorpromazine HCI (CPZ), erythromycine base and erythromycin estolate on the cholestatic response to intravenous taurolithocholate (TLC) and taurochenodeoxycholate (TCDC) in the rat were investigated. All three enhanced the recovery of bile flow after TCDC but not after TLC. Erythromycin base and estolate enhanced bile flow recovery after TCDC and potentiated the increase of plasma 5'-nucleotidase, as did CPZ. Neither erythromycin estolate nor CPZ precipitated a cholestatic response in rat maintained for 9-13 days on a diet supplemented with 0.05% lithocholic acid. It is concluded that the interaction of CPZ and erythromycins with bile salts is not based on the cholestatic properties of the drugs, and hence is not a practical way of distinguishing cholestatic from non-cholestatic drugs.

Treatment of acne vulgaris with topically applied erythromycin and tretinoin

A twice daily application of 2% erythromycin base in hydroalcoholic solution accompanied by once daily use of 0.05% tretinoin (retinoic acid) solution was substantially more effective than tretinoin or erythromycin alone for treatment of inflammatory acne of moderate severity. Therapeutic enhancement by this combination can be attributed to the different modes of action, erythromycin acting chiefly by suppressing Propionibacterium acnes, while tretinoin is comedolytic. In addition, by altering the horny layer barrier, tretinoin doubtless increases the penetration of erythromycin.

Plasma concentration/time curve of erythromycin after a 12-hour intravenous infusion of erythromycin lactobionate in man

Summary As the pharmacokinetics after a slow infusion had not previously been evaluated in the doses used in this study, it was decided to measure the plasma concentration/time curve after a twelve-hour intravenous infusion of 2·0 g of erythromycin lactobionate in 2 litres of 0·9% normal saline. Six healthy medical students with no past history of cardiovascular, renal, hepatic, metabolic or gastrointestinal disease and no past drug allergy participated. The concentration of erythromycin base in venous blood was measured by small plate microbiological assay. Venous blood was taken at zero, 15, 30, 45, 60 min and at 2, 3, 4, 6, 8, 12, 16, 20 and 24 hr after starting the infusions. Duplicate assays were performed on all plasma samples at Guy's and at the manufacturer's laboratories. A full haematological and biochemical screening profile was performed before and after the study. The mean ± s.e. plasma erythromycin base concentration rose from 0·7 ± 0·2 μg/ml at 15 min to 6·06 ± 1·6 μg/ml at 1 hr. The peak plasma concentration was between 1·48 ± 0·25 μg/ml at 30 min and 7·21 ± 0·93 μg/ml at 4 hr. The plasma concentration at 12 hr was 6·17 ± 0·33 μg/ml, and fell to 0·37 ± 0·05 μg/ml at 24 hr. These findings suggest that therapeutically effective plasma concentrations follow a slow intravenous infusion of erythromycin lactobionate. There was no evidence of adverse haematological or biochemical function in the tests of blood, hepatic or renal function, apart from two volunteers who vomited after the infusions were discontinued.

Effectiveness of Topically Applied Antibiotics on Anaerobic Bacteria in the Pilo-Sebaceous Duct

An unspecific cream vehicle containing 1% erythromycin base was applied once a day for 10 days to one side of the forehead of 16 healthy subjects and the same vehicle without the active agent to the other side. Using the same procedure a solution containing 1.19% clindamycin phosphate (corresponding to 1% clindamycin base) and the corresponding unspecific vehicle was administered to another group of 17 healthy males. Prior to the treatment and after the end bacteria were obtained from the pilosebaceous ducts by means of a special sampling technique. Both ointments containing the antibiotics lead to a significant reduction of the bacterial growth in the pilosebaceous ducts regardless of whether evaluation is made of the total bacterial count or of Propionibacteria. Thus, it could be demonstrated that topical application enables some antibiotics to penetrate into the pilosebaceous duct in an adequate concentration to ensure antibacterial effectiveness if a suitable vehicle is used.

Hepatotoxic and cellular uptake interactions among surface active components of erythromycin preparations

Rat hepatoma cell cultures and Chang cell cultures derived from human liver were exposed to erythromycin estolate, erythromycin cetyl sulfate or to the individual components of these preparations, erythromycin propionate and sodium lauryl sulfate or erythromycin base and sodium cetyl sulfate respectively. Cytotoxicity was evaluated by leakage of cytoplasmic and lysosomal enzymes into the media. The uptake of the drugs by the cells was measured with radiolabeled compounds. The surface activity of the drugs was determined in vitro with a surface tension balance. Those drugs with the greatest surface activity were found to have the greatest cytotoxic effects on both cell culture lines. The cytotoxic effects of erythromycin cetyl sulfate were exclusively from the cetyl sulfate. With the erythromycin estolate combination, both lauryl sulfate and erythromycin propionate were cytotoxic. The presence of the latter increased the uptake of lauryl sulfate by the cells and resulted in a potentiation of the cytotoxic effect. Thus, the detergent ingredients used to enhance the gastrointestinal absorption of the drugs may also enhance their cell penetration and determine their hepatotoxicity in vitro; this form of cytotoxic drug interaction mechanism at the cellular level may explain the hepatotoxicity of some of these drugs in man.

THE EFFECT OF ANTIMICROBIAL AGENTS ON LEUKOCYTE CHEMOTAXIS

The effects of several chemotherapeutic agents on the chemotaxis of human leukocytes were studied in an in vitro system using a Sykes-Moore chamber and a double-filter technique. Chemotactic factor was generated by the interaction of normal human serum and zymosan. At concentrations comparable to and below therapeutic blood levels, tetracycline HCl, erythromycin base and clindamycin HCl were all inhibitory, causing marked suppression of leukocyte chemotaxis and slight reduction of random migration. Penicillin G-Na, dapsone, and sulfapyridine did not alter white cell motility at the concentrations of drug tested. It is postulated that the capacity of some of these agents to inhibit leukocyte chemotaxis may account, in part, for their efficacy in inflammatory skin diseases such as acne vulgaris.

Comparison of Erythromycin Base and Estolate in Gonococcal Urethritis

A randomized double-blind trial of 152 men with gonococcal urethritis compared the therapeutic efficacy of erythromycin estolate and erythromycin base. Twenty-one of 86 (24%) men treated with the estolate and 15 of 66 (23%) treated with the base had recurrent or persistent gonococcal infection when seen after a 9-g course of erythromycin. The serum erythromycin activity among estolate-treated patients (3.57 +/- 0.84 microgram/ml) was nearly twice that for base-treated patients (1.76 +/- 0.80 microgram/ml). Our findings do not support routine use of erythromycin for treatment of pregnant, penicillin-allergic patients.

Erythromycin Jaundice: Diagnosis by an In Vitro Challenge Test

A 53-year-old housewife who had developed severe cholestatic hepatitis following the administration of erythromycin estolate therapy two-and-a-half years previously, was studied by an in vitro "challenge" test in which peripheral venous lymphocytes were cultured in the presence of erythromycin estolate, erythromycin stearate and erythromycin base. Evidence of blastogenesis was observed in response to erythromycin estolate, but not to erythromycin stearate of erythromycin base. This test thus provided evidence that the patient was "sensitized" to erythromycin estolate without exposing her to the risk of in vivo challenge. Furthermore, in contrast to previous studies, the findings provide evidence that erythromycin estolate jaundice is mediated by immunological mechanisms.

A simple thin-layer chromatographic identification procedure for erythromycin base, stearate, estolate and ethylsuccinate

A simple thin-layer chromatographic identification procedure for erythromycin base, stearate, estolate and ethylsuccinate

Pharmacokinetics and biological availability of erythromycin

A pharmacokinetic model has been developed for erythromycin involving seven transfer or interaction steps. The major steps describing the role of erythromycin derivatives and dosage form design in the absorptive process, impact of protein binding on drug distribution, specificity of erythromycin for bacterial ribosomes, and the determination of serum half-life for various erythromycin salts and dosage forms, are discussed. Bioavailability data for several erythromycin products, including erythromycin stearate film-coated tablets (250 mg and 500 mg), erythromycin stearate oral suspension, erythromycin base enteric-coated and film-coated tablets, erythromycin ethyl succinate suspension and sachets, and erythromycin lactobionate i. v. are presented. Effects of clinical protocol and formulation differences on drug serum levels are briefly described. The authors express concern with the over-extrapolation of bioavailability results to clinical dosage regimens and use.

Topically Applied Erythromycin in Rosacea

To the Editor.— Intensive study has produced no important ideas concerning the causation or the nature of rosacea. The histopathology is not as distinctive as the clinical portrait. 1 It develops in adult life against a backdrop of intense and prolonged facial flushing from stimuli that cause mild erythema in ordinary persons. Though classified as an acneiform eruption, even being called acne rosacea, only rank beginners could mistake the two. Nonetheless, early onset rosacea can coexist with acne vulgaris. There is agreement that orally given antibiotics, notably tetracyclines, are the most effective means of controlling both the erythema and the follicular papulopustules. 2 Low doses are adequate. This is odd, because, unlike acne vulgaris, microorganisms have not been shown to participate in the disease process. 3,4 We recently found that a 2.0% solution of erythromycin base was at least as effective as orally given antibiotics in controlling moderately severe acne.

Erythromycin and clindamycin absorption and elimination in pregnant women.

Thirty-nine pregnant women admitted for therapeutic abortions during early or mid pregnancy were given erythromycin estolate, erythromycin base, or clindamycin hydrochloride orally in single or multiple doses. Peak serum levels of clindamycin were 3.4 to 9.0 mug/ml following a single dose of 450 mg, whereas peak serum levels of erythromycin were 0.29 to 7.2 mug/ml following 500 mg in a single dose. The individual variability of serum concentrations of erythromycin was greater than that reported in normal men and nonpregnant women, whereas the serum levels of clindamycin were rather uniform, and similar to what has been reported in nonpregnant individuals. Following multiple doses of each antibiotic, high serum levels were obtained in virtually all subjects, and urine levels were also higher. Following single doses the mean urinary recovery was 2% for erythromycin and 16.8% for clindamycin.

Liver cell culture toxicity and surfactant potency of erythromycin derivatives

When Chang liver cell cultures were exposed to a new erythromycin salt, erythromycin cetyl sulfate, and other marketed erythromycin derivatives (erythromycin base, stearate, and estolate) only the cetyl sulfate and estolate salts had cytotoxic effects. Both compounds were very active in lowering surface tension which suggests a possible relationship between this physiocochemical property and their cytotoxic potential in vitro. These in vitro results correlate with the known differences in clinical hepatotoxic potential of the marketed erythromycin derivatives and suggest the possible usefulness of this method for cytotoxicity screening of newly developed therapeutic drugs.

Drug-induced enteropathy characterized by lipid in macrophages

Groups of 10 male Upjohn Sprague-Dawley rats were treated po for 1 week with the synthetic 2′-dodecyl glutaramide ester of erythromycin. Rats given 1000 mg/kg daily ate about one-half of normal food consumption and showed essentially no growth. Weight gains of rats given 300 and 500 mg/kg were proportionally less affected. No gross lesions were observed. Lipid droplets accumulated in macrophages in the lamina propria of the small intestine and in the sinusoids of the mesenteric lymph nodes, in Kupffer cells in the liver and in fixed macrophages in the spleen. In fixed frozen sections these droplets stained well with Oil Red O. Toluidine blue stained epoxy sections were most useful in studying the distribution of the droplets. No evidence of acid-fastness or autofluorescence was observed in paraffin sections. The droplets resembled neutral lipid under electron microscopic examination. They appeared to undergo a gradual membranous degradation at their surface. At 3 weeks post-treatment most of the droplets had disappeared. Small aggregated myeloid figures were also present in the cells of the lamina propria of the small intestine and occasionally in the absorptive cells. Parallel studies with erythromycin base and the 2′-dodecyl glutaramide moiety, separately and simultaneously, did not produce the lipid accumulations in macrophages. From the latter results, it appeared that the ester was absorbed unhydrolyzed and converted rapidly to a chylomicron-like droplet. The reduction of orally administered d-xylose in the urine to about one-quarter of that in control rats was suggestive of malabsorption. Steatorrhea could not be confirmed by fecal lipid analyses because of the lipid structure of the ester.

Serum Protein Binding of Erythromycin, Lincomycin, and Clindamycin

Serum protein binding determination for erythromycin, lincomycin, and clindamycin utilizing ultrafiltration of serum containing antibiotic in a concentration of 5 mcg./ml. and tube dilution techniques revealed a high degree of binding: erythromycin base, 73%; erythromycin propionate, 93%; lincomycin, 72%; and clindamycin, 94%.