Gastrointestinal side effects after intravenous erythromycin

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1 Br. J. clin. Pharmac. (1986), 21, Gastrointestinal side effects after intravenous erythromycin lactobionate K. M. DOWNEY & D. M. CHAPUT DE SAINTONGE Department of Pharmacology and Therapeutics, The London Hospital Medical College, Turner Street, London El 2AD 1 Ten healthy normal volunteers received an intravenous infusion of erythromycin lactobionate over 60 min to a total dose of 800 mg (n = 9), and 524 mg (n = 1). 2 Blood samples were collected at 10 min intervals for 100 min and gastric contents aspirated, via a nasogastric tube, from pre-dose to 105 min after start of infusion. 3 Incidence and severity of three gastrointestinal symptoms (nausea, stomach discomfort and feelings of hunger), two CNS symptoms (dizziness and faintness) and a 'control' symptom (back pain) were measured using 100 mm visual analogue scales. 4 Rate of infusion and plasma erythromycin concentration correlated with nausea (P < 0.001) and stomach discomfort (P < 0.001); plasma erythromycin concentration was also correlated with dizziness (P < 0.05). 5 Concentrations of active erythromycin in the aspirate were ph dependent. In one subject the concentration of erythromycin in the aspirate exceeded that in the plasma by 100 fold. Bile staining of samples containing the highest levels of microbiologically active erythromycin makes the origin of the erythromycin in these samples uncertain. Keywords erythromycin side effects intravenous gastric aspirate Introduction Gastrointestinal disturbance after oral erythromycin is well known. Similar disturbance after intravenous erythromycin occurs in up to 95% of subjects (Putzi et al., 1983) and is sometimes serious enough to require cessation of therapy (Klika & Goodman, 1982). The reasons for the unwanted effects are not clear but may involve the development of high erythromycin concentrations in the gut (Marlin et al., 1983), possibly in the gastric secretions where basic drugs concentrate. The aim of this study was to measure erythromycin concentrations in plasma and in gastric secretions after an intravenous dose of erythromycin, to determine whether high concentrations do develop within the stomach and to relate these concentrations to gastrointestinal disturbance. 295 Methods Ten healthy male volunteers aged years (mean 32 years) and weighing kg (mean 75 kg) were studied. Informed written consent was obtained and the study had the approval of the local Ethics Committee. Subjects who had fasted overnight were intubated, via the nose, with a Portex Ryles tube (16 FG) which was screened into the most dependent part of the stomach. Each subject then received a control infusion of 0.9% w/v saline via an indwelling venous cannula, over 15 min. This was followed immediately by an intravenous infusion of erythromycin lactobionate (Erythrocin i.v. lactobionate, Abbott Laboratories) at a concentration of 4 g l-1 in 0.9% w/v saline, over 1 h, to a total dose of 800 mg. The initial rate of infusion was 3.6 mg min7l and this was approximately doubled every

2 296 K. M. Downey & D. M. Chaput de Saintonge 15 min to give rates of 7, 14.6 and 28.4 mg min-. All infusions were given with the subject in the supine position. Blood samples (5 ml) were collected prior to erythromycin infusion and every 10 min for 100 min from the start of infusion, via an indwelling venous cannula in the other arm. Overnight gastric contents were aspirated and discarded. Gastric contents were manually aspirated over 10 min sampling periods until 105 min after the start of erythromycin infusion. Aliquots of aspirate from each sampling period were adjusted to ph > 7 with sodium bicarbonate solution (2 ml of 8.4% w/v). Where possible aspirate ph was measured using ph indicator sticks (Spezialindikator, Merck). Side effects were measured using 100 mm visual analogue scales during the control infusion and every 10 min for 100 min from the start of erythromycin infusion. The scales recorded severity of the symptoms of nausea, stomach discomfort and feelings of hunger (Blenk et al., 1980), dizziness and faintness (Austin et al., 1980), and the 'control' symptom of back pain. The latter was chosen as it has not been reported as an erythromycin side effect and was not an obvious distractor. Subjects were observed for other side effects and the severity of these recorded. Erythromycin concentrations in both plasma and gastric aspirate were determined by microbiological assay using Micrococcus lutea NCTC 8340 as the test organism. Prior to assay all aspirate samples and standards were extracted into phosphate buffer (ph 7.3) using a modification of the extraction reported by Tserng & Wagner (1976). Where necessary samples were diluted to fall within the linear range of the assay ( mg 1-1). Coefficients of variation were less than 6% and less than 16% for plasma and aspirate samples respectively. Statistical analysis was carried out using Page's L test (1965), a significance test for linear ranks which makes no assumptions regarding distribution or interpersonal correspondence of symptom scores. The critical value for significance was taken as P < Results Back pain was felt by five out of ten subjects but this was unrelated to any other factor and was alleviated by subjects changing their position. Eight out of ten subjects experienced stomach discomfort. Six subjects felt nausea with two retching and one vomiting. Eight subjects felt some degree of faintness or dizziness. One subject became very faint and was unable to continue with the study, this subject consequently received only 524 mg of erythromycin. For those subjects who experienced a symptom the median score for the visual analogue scales together with the range of their individual scores is given in Figure 1, with the exception of the 'control' symptom. Rate of infusion correlated significantly with the severity of stomach discomfort (P < 0.001, n = 10) and nausea (P < 0.001, n = 10). Significant correlation was also found between plasma erythromycin concentration and stomach discomfort (P < 0.001, n = 9), nausea (P < 0.001, n = 9) and dizziness (P < 0.05, n = 9). The mean plasma erythromycin concentration and 95% confidence limits for each sampling time are shown in Figure 2. Maximum stomach discomfort occurred at the time of peak plasma erythromycin concentration in two subjects, 10 min before in four subjects, and 20 min before peak plasma erythromycin concentration in a further two. Maximum nausea occurred at the time of peak plasma erythromycin concentration in two subjects and 10 min before plasma erythromycin peak in three subjects. Concentrations of active erythromycin in the aspirate were generally below those in the plasma, but increased towards and sometimes exceeded the plasma erythromycin concentration as the aspirate ph tended towards neutrality (Table 1). Concentration of erythromycin in the plasma was exceeded by that in the aspirate on one occasion in one subject, on two in six subjects, and on three occasions in a further subject. The erythromycin aspirate/plasma concentration ratio was between 1.0 and 8.7 (mean 2.1) on 13 of these 16'occasions, but reached as high as 112 on one occasion. Of these 16 aspirate samples containing a higher active erythromycin concentration than the plasma, 15 were bile stained (Table 1), making the origin of the erythromycin in these samples uncertain. Maximum nausea was experienced by three subjects at a time of bile staining and by two subjects 5 min before bile staining. Maximum stomach discomfort, however, showed no clear relationship with the time of bile staining. Loss of erythromycin activity appears negligible over the ph range 5-8. Thus only where the aspirate sample ph was within this range, can the measured concentration be assumed to reflect total erythromycin. However, it was not possible to detect correlation between concentration of active unhydrolysed erythromycin and either nausea (n = 5) or stomach discomfort (n = 5) where aspirate ph was above 5.5.

3 GI side effects after i. v. erythromycin 297 a Start of infusion End of infusion 40r- b CD E c 0 Cu C._ C c c.)_ 4 E 0 w 0) 0 In Figure 1 Median score (O-*) and range of scores (v-m-) for visual analogue scales for the symptoms of dizziness (a), faintness (b), feelings of hunger (c), nausea (d), and stomach discomfort (e), for those subjects experiencing these symptoms following intravenous erythromycin lactobionate 800 mg (n 9), and 524 = mg (n 1). = Discussion I I I I Severity of stomach discomfort, nausea and dizziness were each found to correlate significantly with plasma erythromycin concentration, which l 40I 60I 80I Figure 2 Plasma erythromycin concentration (mean and 95% confidence limits) following intravenous erythromycin lactobionate 800 mg (n = 9), and 524 mg (n= 1). is contrary to the findings of Blenk et al. (1980) who were unable to detect any correlation between serum erythromycin levels and incidence or severity of abdominal symptoms. This discrepancy may be due in part to the differing methods of side-effect assessment, the current study using visual analogue scales as opposed to direct questioning by an observer. It may be argued that prior knowledge by the subjects of likely symptoms and even the method of recording, which itself suggests symptoms, may have led to an increase in symptom incidence. Prior knowledge of symptoms was unavoidable if true 'informed consent' was to be obtained. The method of recording may, if it is more sensitive than that used previously, lead to an apparent increase in symptom reporting. The aim of the study was to determine whether high erythromycin concentrations developed in gastric secretions after an intravenous dose. Lee et al. (1956) recovered erythromycin, after an intravenous dose, from the intestine of bile fistula rats suggesting entry via the intestine wall. Erythromycin found in the stomach of rats (Lee et al., 1956) was suggested to have entered through the stomach. Holland & Quay (1976) demonstrated secretion of erythromycin into the lumen of rabbit jejunal sections which proceeded against a concentration gradient. The present study shows that as suggested, erythromycin clearly enters the gastric contents.

4 298 K. M. Downey & D. M. Chaput de Saintonge Table 1 Individual values for plasma erythromycin concentration, aspirate erythromycin concentration and aspirate ph, following intravenous erythromycin lactobionate 800 mg (n = 9), and 524 mg (n = 1) Subject Plasma erythromycin concentration (mg L') ND ND ND ND ND Mean s.e. mean Subject Aspirate erythromycin concentration (mg L') ND ND ND 34.0 ND ND ND ND Aspirate ph 1 ND ND ND ND ND ND ND ND 3.6 ND ND ND **7.0 * ND 7.2 ND **7.3 **7.8 *7.3 *ND *2.0 *2.0 *2.2 *ND **ND ND *ND ND ND ND ND 6 ND ND ND ND ND ND ND ND ND **ND **ND *2.2 * *5.7 *3.9 ** ** * *7.6 **7.5 *7.6 * *1.6 * **7.4 **7.4 * **7.4 **ND ND = No data. * = Bile staining present. ** = Maximum bile staining for that subject. - = Not detectable or lower than lowest reliable determination. The inability of the assay method to detect micro- erythromycin in the aspirate samples was of biologically inactive hydrolysis products, means gastric or biliary origin. However, bile staining that total erythromycin present in a number of of 15 out of 16 aspirate samples having eryaspirate samples (where ph < 5.5) may have thromycin concentrations greater than in the been considerably higher than the observed plasma suggests that it is likely to be preery,3hromycin concentration. However, no cor- dominantly of biliary origin. The mean eryration could be detected between total erythro- thromycin aspirate/plasma concentration ratio ihycin in those samples with ph > 5.5 and either of 2.1 is lower than the mean erythromycin bile/ severity of stomach discomfort or nausea, but serum concentration ratio of 8.52, seen by sample size was small (n = 5). Chevlan et al. (1979), after intravenous ery- The reflux of bile during this study means that thromycin. The sample having an erythromycin it is not possible to say for certain whether the aspirate/plasma concentration ratio of 112 was

5 more 'bile stained' than the others, and this ratio is far greater than the largest erythromycin bile/ serum concentration ratio of 23.2 previously reported (Chevlan etal., 1979). The dosage, rate of infusion and plasma levels attained were all greater in the present study. The complexity of variables involved in the measurement of aspirate erythromycin concentrations; fluctuations in ph, the acid degradation of erythromycin and bile reflux, have served to cloud the interpretation of the amount of the total erythromycin entering the stomach from References GI side effects after i. v. erythromycin 299 the plasma. However, a number of subjects had observed erythromycin concentrations in their gastric aspirate many times greater than the corresponding plasma erythromycin concentration. We would like to thank Abbott Laboratories Limited who supplied the erythromycin and provided financial support for the studies, Sister G. Keenan of the Surgical Unit, The London Hospital for performing the intubations and gastric aspirations, Mr C. Glanville for technical assistance, and Miss W. Smith and Mrs C. Studd for secretarial assistance. Austin, K. L., Mather, L. E., Philpot, C. R. & McDonald, P. J. (1980). Intersubject and dose related variability after intravenous administration of erythromycin. Br. J. clin. Pharmac., 10, Blenk, H., Blenk, B., Jahneke, G., Simm, K., Lucke, B. V. & LaFranier, D. (1980). Erythromycin infusions for treatment of infections in the ear, nose and throat region. J. int. med. Res., 8, Suppl. 2, Chevlan, P., Hamilton-Miller, J. M. T. & Brumfitt, W. (1979). Biliary excretion of erythromycin after parenteral administration. Br. J. clin. Pharmac., 8, Holland, D. R. & Quay, J. F. (1976). Intestinal secretion of erythromycin base. J. pharm. Sci., 65, Klika, L. J. & Goodman, J. M. (1982). Gastrointestinal tract symptoms from intravenously administered erythromycin. J. Am. med. Ass., 248, Lee, Gheng-Chun., Anderson, R. C. & Chen, K. K. (1956). Distribution and excretion of radioactivity in rats receiving N-methyl-"4C-erythromycin. J. Pharmac. exp. Ther., 117, Marlin, G. E., Thompson, P. J., Jenkins, C. R., Burgess, K. R. & LaFranier, D. A. J. (1983). Study of serum levels, venous irritation and gastrointestinal side-effects with erythromycin lactobionate in patients which bronchopulmonary infection. Hum. Tox., 2, Page, E. B. (1965). Ordered hypothesis for multiple treatments: A significance test for linear ranks. J. Am. statistical Ass., March, Putzi, R., Blaser, J., Luthy, R., Wehrli, R. & Siegenthaler, W. (1983). Side effects due to the intravenous infusion of erythromycin lactobionate. Infection, 11, Simpson, J. S. (1963). Microbiological assay using large plate methods. In Analytical microbiology. Vol 1. ed. Kavanagh, F., pp London: Academic Press. Tserng, K. & Wagner, J. G. (1976). Fluorimetric determination of erythromycin and erythromycin propionate in whole blood or plasma and correlation of result with microbiological assay. Analyt. Chem., 48, (Received 17 October 1984, accepted 15 October 1985)