Impact of Long-Term Erythromycin Therapy on the Oropharyngeal Microbiome and Resistance Gene Reservoir in Non-Cystic Fibrosis Bronchiectasis.

Long-term macrolide therapy reduces rates of pulmonary exacerbation in bronchiectasis. However, little is known about the potential for macrolide therapy to alter the composition and function of the oropharyngeal commensal microbiota or to increase the carriage of transmissible antimicrobial resistance. We assessed the effect of long-term erythromycin on oropharyngeal microbiota composition and the carriage of transmissible macrolide resistance genes in 84 adults with bronchiectasis, enrolled in the Bronchiectasis and Low-dose Erythromycin Study (BLESS) 48-week placebo-controlled trial of twice-daily erythromycin ethylsuccinate (400 mg). Oropharyngeal microbiota composition and macrolide resistance gene carriage were determined by 16S rRNA gene amplicon sequencing and quantitative PCR, respectively. Long-term erythromycin treatment was associated with a significant increase in the relative abundance of oropharyngeal Haemophilus parainfluenzae (P = 0.041) and with significant decreases in the relative abundances of Streptococcus pseudopneumoniae (P = 0.024) and Actinomyces odontolyticus (P = 0.027). Validation of the sequencing results by quantitative PCR confirmed a significant decrease in the abundance of Actinomyces spp. (P = 0.046). Erythromycin treatment did not result in a significant increase in the number of subjects who carried erm(A), erm(B), erm(C), erm(F), mef(A/E), and msrA macrolide resistance genes. However, the abundance of erm(B) and mef(A/E) gene copies within carriers who had received erythromycin increased significantly (P < 0.05). Our findings indicate that changes in oropharyngeal microbiota composition resulting from long-term erythromycin treatment are modest and are limited to a discrete group of taxa. Associated increases in levels of transmissible antibiotic resistance genes within the oropharyngeal microbiota highlight the potential for this microbial system to act as a reservoir for resistance.IMPORTANCE Recent demonstrations that long-term macrolide therapy can prevent exacerbations in chronic airways diseases have led to a dramatic increase in their use. However, little is known about the wider, potentially adverse impacts of these treatments. Substantial disruption of the upper airway commensal microbiota might reduce its contribution to host defense and local immune regulation, while increases in macrolide resistance carriage would represent a serious public health concern. Using samples from a randomized controlled trial, we show that low-dose erythromycin given over 48 weeks influences the composition of the oropharyngeal commensal microbiota. We report that macrolide therapy is associated with significant changes in the relative abundances of members of the Actinomyces genus and with significant increases in the carriage of transmissible macrolide resistance. Determining the clinical significance of these changes, relative to treatment benefit, now represents a research priority.

Cholestasis and liver cell damage due to hypersensitivity to erythromycin stearate--recurrence following therapy with erythromycin succinate.

Erythromycin is a frequently used antibiotic in patients with atypical respiratory infection and/or an allergy to penicillin. We report the case of a young woman who developed severe cholestasis and jaundice following treatment with erythromycin stearate. Two years later her general practitioner prescribed erythromycin succinate for pharyngitis. She experienced a severe second episode of jaundice and malaise. Different esters of erythromycin have been introduced to reduce side effects such as allergic reactions to erythromycin. The findings in our patient underline the fact that hypersensitivity is caused by the erythromycin molecule, independent from the type of esterification. Because of these side effects newer makrolides should be given preference over erythromycin.

Effect of a single oral dose of two erythromycin ethylsuccinate formulations on gastric emptying in healthy volunteers: a scintigraphic study.

Macrolides are potential gastrokinetic agents. The purpose of this study was to assess the effect of a single oral dose of two erythromycin formulations on gastric emptying of the solid and liquid phases in twelve healthy volunteers and to seek a correlation between pharmacokinetic parameters and changes in gastric emptying. The gastric emptying times of liquids and solids were measured simultaneously by means of a scintigraphic technique after a single oral administration of amorphous erythromycin ethylsuccinate (500 mg), crystalline erythromycin ethylsuccinate (1000 mg) or a placebo, in a double-blind crossover study in three separate weeks. Blood samples were obtained for erythromycin assay. The two oral formulations induced a similar acceleration of gastric emptying. When compared to the placebo, both erythromycin preparations significantly shortened the gastric transit time of solids and liquids (respectively 30% and 20% on average, p < 0.01). The incidence of gastrointestinal side-effects was similar with the two erythromycin forms and the placebo. No correlation was found between the peak serum erythromycin concentrations and the solid or liquid gastric half-lives. With the amorphous formulation, the area under the plasma time-concentration curves was small and solid and liquid gastric emptying were strongly accelerated, pointing to a direct effect on the gastrointestinal smooth muscle.

The association of erythromycin ethylsuccinate with acute colitis in horses in Sweden.

In Sweden there are several reports of mares developing acute colitis while their foals were being treated orally for Rhodococcus equi pneumonia with the combination of erythromycin and rifampicin. In this study 6 adult horses were given low oral dosages of these antibiotics, singly or in combination. Within 3 days post administration of erythromycin, in one case in combination with rifampicin, 2 horses developed severe colitis (one fatal). Clostridium difficile was isolated from one of the horses, whereas no specific pathogens were isolated from the other. Both horses had typical changes in blood parameters seen in acute colitis. Clostridium difficile was also isolated from the faeces of a third horse given an even lower dosage of erythromycin in combination with rifampicin. This horse developed very mild clinical symptoms and recovered spontaneously. In the fourth horse given erythromycin only, very high numbers of Clostridium perfringens were isolated. The horses given rifampicin only did not develop any clinical symptoms and there were no major changes in their faecal flora. In conclusion, it has been demonstrated that low dosages of erythromycin ethylsuccinate can induce severe colitis in horses associated with major changes of the intestinal microflora. Clostridium difficile has been demonstrated as a potential aetiological agent in antibiotic-induced acute colitis.

Effects of two oral erythromycin ethylsuccinate formulations on the motility of the small intestine in human beings.

Fourteen-membered macrolides are known to produce alterations in digestive tract motor activity; these include the induction of strong gastric contractions and a decrease in the motility of the small intestine. The aim of the study was to compare the effects of two different formulations of erythromycin ethylsuccinate (EE) on duodenojejunal motility. Compared with the more commonly used crystalline formulation of EE (CEE), the amorphous formulation (AEE) has previously been described to have greater bioavailability and to induce significantly fewer gastrointestinal side effects when given at therapeutic and what have been considered to be equivalent oral doses (i.e., CEE, 1,000 mg every 12 h; AEE, 500 mg every 12 h). In a crossover double-blind study, duodenojejunal manometric recordings were performed for 10 volunteers treated with placebo, CEE at 1,000 mg, or AEE at 500 mg. Recordings for each volunteer were obtained for a fed period after a standard dinner and then for a nocturnal fasting period. When compared with the placebo, CEE significantly decreased the motility index of the duodenum during the 30 min after the peak serum erythromycin concentrations, shortened the duration of the fed state, and had no effect during the fasting state. In contrast, AEE did not significantly modify any motility parameter. Because AEE produced significantly lower concentrations in serum than CEE, these results do not necessarily imply that the two formulations of EE act differently on the motility of the small intestine.

Mycoplasma pneumoniae and Chlamydia pneumoniae in pediatric community-acquired pneumonia: comparative efficacy and safety of clarithromycin vs. erythromycin ethylsuccinate.

We evaluated 260 previously healthy children ages 3 through 12 years who had clinical signs and symptoms of pneumonia, radiographically confirmed. Patients were randomized 1:1 to a 10-day course of either clarithromycin suspension 15 mg/kg/day divided twice a day or erythromycin suspension 40 mg/kg/day divided twice a day or three times a day. Evidence of infection with Chlamydia pneumoniae was detected in 28% (74) of patients: 13% (34) by nasopharyngeal culture and 18% (48) by serology with the microimmunofluorescence assay. Evidence of infection with Mycoplasma pneumoniae was detected in 27% (69) of patients: 20% (53) by nasopharyngeal culture or polymerase chain reaction and 17% (44) by serology with the use of enzyme-linked immunosorbent assay. Serologic confirmation of infection was observed in 23% (8) and 53% (28) of patients with bacteriologically detected C. pneumoniae and M. pneumoniae, respectively. Treatment with clarithromycin vs. erythromycin, respectively, yielded the following outcomes: clinical success 98% (121 of 124) vs. 95% (105 of 110); radiologic success 98% (109 of 111) vs. 94% (92 of 110); and eradication by pathogen, C. pneumoniae 79% (15 of 19) vs. 86% (12 of 14) and M. pneumoniae 100% (9 of 9) vs. 100% (4 of 4). Adverse events were primarily gastrointestinal occurring in almost one-fourth of patients in both groups, and were mild to moderate in severity. Clarithromycin and erythromycin were similarly effective and safe for the treatment of radiographically proved, community-acquired pneumonia in children older than 2 years old.(ABSTRACT TRUNCATED AT 250 WORDS)

A comparison of the gastrointestinal side effects of two forms of erythromycin.

BACKGROUND: The gastrointestinal (GI) side effects of erythromycin frequently limit therapy and compliance. PCE Dispertab, a more expensive brand of erythromycin, has been promoted as a well-tolerated new dosage form; however, no studies compare its GI side effects with those of other forms of erythromycin. We compared erythromycin PCE (particles-in-tablet) with E.E.S. (erythromycin ethylsuccinate) to determine whether there is a difference in the incidence and severity of GI side effects. METHODS: This was a multicenter, prospective, single-blind, randomized trial. Observers, but not participants, were blinded to the brand of erythromycin taken until after data analysis. We enrolled ambulatory patients who were at least 18 years old and weighed at least 90 lb for whom erythromycin had been prescribed at a dosage of 1.0 g/d. Subjects were given either the particles-in-tablet form, 333 mg three times daily, or the ethylsuccinate form, 400 mg four times daily, for 10 days and asked to report efficacy, compliance, and the frequency and severity of four GI symptoms (abdominal pain, nausea, vomiting, and diarrhea) in a daily diary. RESULTS: There were no significant differences between the particles-in-tablet and ethylsuccinate forms in incidence of GI side effects (63% and 61%, respectively), average daily GI symptom severity score (0.62 and 0.68, respectively), and GI-related discontinuations (8.5% and 8.2%, respectively). The incidence of moderate or severe nausea was 5% for the particles-in-tablet form and 25% for the ethylsuccinate form (P < .001). CONCLUSIONS: Although ethylsuccinate caused a higher incidence of moderate to severe nausea, there were no differences in the three main outcome measures: incidence of GI side effects, average daily GI-symptom severity score, and GI-related discontinuations. Therefore, we support prescribing erythromycin ethylsuccinate as a first line of treatment because it costs less.

Multicenter double-blind study of the efficacy and tolerance of roxithromycin versus erythromycin ethylsuccinate in acute orodental infection in adults. Odontogenic Infections Study Group.

A total of 194 patients with orodental infection were randomized either to roxithromycin 150 mg twice daily plus placebo or to erythromycin 1 g twice daily plus placebo for a mean duration of 8 days. The infections consisted of cellulitis, pericoronitis, and adenopathy, or any two in combination. In the 176 cases in which efficacy was evaluable, outcome was satisfactory in 94% and 91% of cases treated with roxithromycin and erythromycin, respectively (p = 0.45). Patients were evenly distributed with respect to demographic characteristics, diagnosis, and concomitant treatment. Surgery was performed in 63%, primarily for abscess formation in cellulitis (p less than 0.001); 18% of patients with an abscess did not undergo surgery. The success rate was identical irrespective of whether surgery was performed, including in those with an abscess. Tolerance was evaluated in 1986 patients. Unwanted effects, elicited by direct questioning, were reported in approximately 20% of cases per group (19% for roxithromycin and 21% for erythromycin). They consisted of mild gastrointestinal upsets which caused treatment to be withdrawn in eight cases (four per group). Thus, roxithromycin and erythromycin twice daily for orodental infection are similar in both efficacy and tolerance.

Comparison of oral erythromycin ethylsuccinate and clavulanate-potentiated amoxicillin in the treatment of acute respiratory tract infections.

Seven hundred fifty patients with acute upper or lower respiratory tract infections were randomly assigned to receive 2 gm of erythromycin ethylsuccinate daily or 1.125 gm of clavulanate-potentiated amoxicillin daily in a single-blind, multicenter study. The efficacy of each formulation was similar, with close to 90% of patients in each treatment group being reported as either cured or improved. Gastrointestinal symptoms were the most commonly reported side effects, their overall incidence being similar in both treatment groups. However, diarrhea occurred more than twice as often in the amoxicillin group than the erythromycin group. In each group, the number of patients failing to complete treatment was similar; the main reasons cited for discontinuation were gastrointestinal symptoms. The results indicate that both erythromycin ethylsuccinate and clavulanate-potentiated amoxicillin are well tolerated and are equally effective for routine empirical treatment of acute respiratory tract infections.

Erythromycin ethylsuccinate, base and acistrate in the treatment of upper respiratory tract infection: two comparative studies of tolerability.

The efficacy and tolerability of erythromycin ethylsuccinate, erythromycin base and erythromycin acistrate were studied in two separate randomized studies in 80 and 82 primary health care patients with upper respiratory tract infections. In Study I, the patients were given either ethylsuccinate 666 mg tid or base 500 mg qid for ten days. Possible side-effects, abdominal pain, nausea, diarrhoea and vomiting, were recorded daily by the patient. Study II followed the same design as Study I with the exception of the side-effect evaluation method. Patients were given in a randomized fashion ethylsuccinate 666 mg tid, or acistrate 400 mg qid. Side-effect evaluation was based on a 10-cm analogue visual scale to record abdominal pain, while nausea, vomiting and diarrhoea were recorded as daily frequencies. These studies indicated that erythromycin ethylsuccinate caused significantly less abdominal pain than the base form (chi 2-test), but there were no significant differences in tolerance between the ethylsuccinate and acistrate forms. Other tolerance parameters revealed no real differences. The clinical response was good with all erythromycin preparations at the doses used in this study.

Erythromycin in acute pharyngitis: a comparison of efficacy and patient tolerance of two twice-daily preparations.

Two hundred sixty-five adult and adolescent patients with possible streptococcal pharyngitis were treated with either erythromycin ethylsuccinate or an enteric-coated erythromycin in a twice-daily dosage schedule. In patients with group A beta-hemolytic streptococcal infection, both preparations achieved a cure rate of 93%. Patients receiving the enteric-coated erythromycin reported significantly more gastrointestinal adverse effects than did the patients receiving erythromycin ethylsuccinate.