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Influence of Erdosteine, a Mucolytic Agent, on Amoxycillin Penetration Into Sputum in Patients with an Infective Exacerbation of Chronic Bronchitis

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Influence of Erdosteine, a Mucolytic Agent, on Amoxycillin Penetration Into Sputum in Patients with an Infective Exacerbation of Chronic Bronchitis Thorax: first published as 10.1136/thx.43.8.585 on 1 August 1988. Downloaded from Thorax 1988;43:585-590 Influence of erdosteine, a mucolytic agent, on amoxycillin penetration into sputum in patients with an infective exacerbation of chronic bronchitis GIOVANNI RICEVUTI, ANTONINO MAZZONE, ELVIRA UCCELLI, GABRIELLA GAZZANI, GIANCARLO B FREGNAN From the Section ofMedical Pathology I, Department ofInternal Medicine and Therapeutics, University of Pavia; the Department ofPharmaceutical Chemistry, University ofPavia; and the Research Center Laboratories, Ednond Pharma SRL, Milan, Italy ABSTRACT Twenty four patients with acute infective exacerbations of chronic bronchitis received amoxycillin alone or in combination with erdosteine (a mucolytic agent) for a week in a double blind, placebo controlled study. Clinical assessment scores, body temperature, serum and sputum amoxycillin concentrations, and sputum culture results were recorded in each group. Erdosteine significantly increased antibiotic concentrations in sputum but not in serum. The combined treatment also caused a more rapid decrease in sputum viscosity and in body temperature and faster sterilisation of the sputum. These results show that erdosteine increases amoxycillin concentration in sputum in patients with acute exacerbations ofchronic bronchitis. This effect may be due to a reduction in the viscosity of the bronchial secretions produced by erdosteine. copyright. Introduction Methods Although the exact role ofbacterial infections in acute PATIENTS exacerbations of chronic bronchitis is not clear, Twenty four patients (10 male and 14 female, aged 45- antibiotic treatment is widely used. In some patients, 71 years) with chronic bronchitis were studied during http://thorax.bmj.com/ however, the high viscosity ofthe bronchial secretions an acute, severe infective exacerbation. Thirteen may impair local antibiotic penetration. Previous patients also had asthma. All patients, formerly heavy studies'`5 have shown that administration of a smokers (> 20 cigarettes/day), smoked fewer than 15 mucolytic agent with an antibiotic can increase cigarettes a day at the time of the study. Pathogenic sputum concentrations of the latter. bacteria sensitive to amoxycillin were isolated from A new thiol derivative (erdosteine) with two blocked their sputum. None of the patients had received S-H radicals has recently been synthesised by Gobetti antibiotics, mucolytic drugs, or corticosteroids during et al.6 The drug has mucokinetic properties and the previous two weeks. The patients were allowed to on September 28, 2021 by guest. Protected is effective in reducing the viscosity of bronchial inhale 02 adrenergic bronchodilators during the trial secretions. Pharmacodynamic studies in animals and (three asthmatic patients in each group). No patients man indicate that the drug is well tolerated and devoid had liver or kidney disease, and all gave written of side effects. consent. The purpose of this study was to evaluate the penetration ofamoxycillin into the sputum after single STUDY DESIGN and multiple oral doses of the antibiotic given either The study was double blind. A doctor (not responsible alone or in combination with erdosteine. The concen- for disease follow up or data analysis) was assigned the trations achieved were compared with its in vitro task ofdividing the patients into two groups matched antibacterial activity and related to the subsequent for sex, sputum pathogen, and history ofconcomitant disappearance of clinical symptoms. asthma. Lung function (not determined) and degree of reversibility were not factors in the selection of these Address for reprint requests: Professor G B Fregnan, Edmond groups. The first group received amoxycillin 500 mg Pharma, via Gradisca 8, 20151 Milan, Italy. thrice daily and erdosteine 300 mg thrice daily and the Accepted 22 April 1988 second amoxycillin 500 mg and placebo, both thrice 585 Thorax: first published as 10.1136/thx.43.8.585 on 1 August 1988. Downloaded from 586 Ricevuti, Mazzone, Uccelli, Gazzani, Fregnan daily. The drugs were administered orally for seven from sputum (that is, Streptococcus pneumoniae, days. The staff who scored symptoms and undertook Haemophilus influenzae, and several staphylococci) by laboratory investigations were unaware of the the agar plate diffusion method. Erdosteine was also difference in the treatments. added in vitro to some sputum from patients receiving A positive clinical response was considered to have amoxycillin plus placebo and tested against the same occurred on the first day on which the patient became bacteria. Some samples were also analysed by high afebrile or the sputum was converted from pressure liquid chromatography according to the mucopurulent to mucoid. method described by Carlqvist and Westerlund.' The biological fluids, deproteinised with dichloroethane CLINICAL ASSESSMENT and perchloric acid, were then centrifuged and the Cough and dyspnoea intensity, sputum appearance aqueous phases injected into a high pressure liquid (viscosity and purulence), and body temperature were chromatography apparatus equipped with a determined daily and, except for the last, graded on a precolumn and a reverse phase column. The mobile scale from 0 to 3 according to the following scheme: phase consisted of phosphate buffer (pH 8)-methanol (92:8 v/v) at a flow rate of 1 ml/min. The postcolumn derivatisation was performed with an aqueous solu- Sputum tion of imidazole-mercuric chloride-Brij 35 (33%, Score Cough Dyspnoea Viscosity Purulence 0 I 1%, 0 12%), pH 7-2. Absorbance was measured at 310 nm. The sensitivity of the method was 0 1 g/ml 0 Absent Absent Normal Salivous I Minimal With moderate Slight Mucoid biological fluids. A fresh overnight culture of Sarcina exertion lutea was prepared and washed from an agar slope (climbing stairs) 2 Moderate With minimal Moderate Mucopurulent with sterile distilled water to give a suspension with a exertion (walking 50% transmission at 650 nm on a visible spectro- 200-300 m) photometer. The suspension was shaken for one hour Marked Purulent copyright. 3 Severe At rest to produce homogeneity and used as 1% inoculum. Assay plates were prepared with a layer ofseeded agar SPECIMEN COLLECTION BBL 10937 at pH 7 0. The assay method then followed Samples of sputum and serum were collected 0, 3, and the procedure described by Campbell.8 The lower limit 6 hours after the first and the 19th dose ofamoxycillin of antibiotic detectability in the biological specimens (performed on the seventh morning). Sputum was was 0 03 ig/ml and the variability of estimation washttp://thorax.bmj.com/ collected in plastic containers for 30 minutes before less than 5%. the appointed collection times and was immediately classified by its appearance on naked eye examination. SPUTUM CULTURE Sputum was collected for bacterial pathogen iden- ANTIBIOTIC ASSAY tification one to three days before treatment and on the Amoxycillin concentrations in sputum and serum second, fourth, sixth, seventh, and eight day of samples were measured microbiologically by the plate treatment just before the morning dose. Sputum was prepared as above, and cultures were set up on heated agar diffusion method, with a punch hole technique on September 28, 2021 by guest. Protected and Sarcina lutea ATCC 9341 as test organism. Before or unheated blood agar. assay the sputum was homogenised in equal quantities Properly identified strains were recultured on agar of sterile distilled water with glass beads. The samples BBL 10937 plates and their sensitivity to amoxycillin were further diluted when necessary. Twofold dilu- tested by disc agar diffusion bioassay. The minimum tions of amoxycillin in sterile distilled water at final inhibitory concentration of amoxycillin was deter- concentrations of 10, 0 5,0 25, 0-12, 0-06, and 0 03 ig/ mined on each strain isolated before the patients began ml were prepared immediately before use. A full set of antibiotic treatment. dilutions was included in each batch of assay for the preparation of the standard curves from which the STATISTICAL ANALYSIS drug concentrations in the specimens were calculated. The data were evaluated by analysis of variance of The specimens and standard dilutions were set up in the Mann-Whitney U test and a statistical difference duplicate. The plates were incubated for 24 hours and between the two treatment groups was taken as p . the mean diameters of the inhibition zones were used 0-05. for determining the drug concentrations. All assays were performed on the collection day. In a separate Results experiment the antibacterial activity of erdosteine alone or combined with amoxycillin was tested on CLINICAL SYMPTOMS Sarcina lutea and other specimens freshly isolated In both groups cough, dyspnoea, sputum viscosity and Thorax: first published as 10.1136/thx.43.8.585 on 1 August 1988. Downloaded from Influence oferdosteine on amoxycillin penetration into sputum in exacerbations ofchronic bronchitis 587 Table 1 Change in clinical symptoms over the seven days oftreatment Mean (SEM) scoret Period Mean (SEM) Treatment (days) Cough Dyspnoea SV SP BT (°C) Amoxycillin plus 0 2-4 (019) 2-6 (0-15) 30 (0-0) 28 (0-13) 390 (012) erdosteine 1 25 (0.15) 2-4 (0.22) 29 (008) 2-8 (0-13) 390(0-10) 2 2-3 (0-14) 1-9 (0-19) 2-3 (0-17) 2-3 (0-21) 38-7 (0.08)* 3 1 8 (0-21) 1-8 (0-17) 1-7 (0-14)* 2-0 (0 21) 38-3 (0.08)* 4 1-5 (0-19) 1 5 (0 19) 1-3 (0.14)* 1-8 (0-17) 37-6(0-18)* 5 1-3 (0-14) 1-3 (0-13) 1-1 (008)* 1-3 (0-14) 369 (005)* 6 0 92 (0 15) 1-0 (0-17) 0-66 (0-14)* 0 91 (0-14) 36 8 (0-03)* 7 0 67 (0 19) 0 58 (0 19) 0 41 (0-14) 0-58 (0-14) 36 8 (0 04) Amoxycillin plus 0 2 5 (0 15) 2-5 (0 15) 2-9 (0-08) 2-7 (0-14) 39 3 (0-14) placebo 1 2-6 (015) 2-4 (0-19) 2-9 (0-08) 2-7 (014) 39-2 (013) 2 2-3 (0-14) 2-1 (022) 2-8 (0-13) 25 (015) 390 (007) 3 2-2 (0 17) 1 9 (0 19) 2-7 (0-14) 2-3 (0-14) 38-7(009) 4 2-0 (0-17) 1-8 (0 17) 2-6 (0 14) 2-1 (0-14) 38-0(007) 5 1 8 (0 13) 1 5 (0 15) 1 8 (0-17) 1-4 (0-14) 37-1 (0 10) 6 1-4 (015) 1-3 (0-13) 1-4 (0-14) 1-2 (0 11) 37-0(006) 7 1 1 (019) 091(019) 091(0-14) 0-83(0-11) 36-9(004) p = 0 05 for amoxycillin plus erdosteine v amoxycillin plus placebo.
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