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Penetration of Amoxycillin/Clavulanic Acid Into Bronchial Mucosa with Different Dosing Thorax: First Published As 10.1136/Thx.49.10.999 on 1 October 1994

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Penetration of Amoxycillin/Clavulanic Acid Into Bronchial Mucosa with Different Dosing Thorax: First Published As 10.1136/Thx.49.10.999 on 1 October 1994 Thorax 1994;49:999-1001 999 Penetration of amoxycillin/clavulanic acid into bronchial mucosa with different dosing Thorax: first published as 10.1136/thx.49.10.999 on 1 October 1994. Downloaded from regimens I M Gould, G Harvey, D Golder, T M S Reid, S J Watt, J A R Friend, J S Legge, J G Douglas Abstract effect of lavage. Lung tissue obtained at tho- Background - The efficacy ofan antibiotic racotomy is non-homogenous and so represents is related to its concentration at the site of an average of concentrations found in different infection. Previous studies of the con- tissues. The concentration ofantibiotic in bron- centrations of amoxycillin and clavulanic chial mucosa provides a reliable guide to bron- acid (co-amoxiclav) in respiratory se- chial penetration9'0 and may be a better cretions or whole lung tissue have suffered predictor of clinical efficacy than the serum from methodological problems. The con- level" for treatment ofbronchitis and broncho- centration of amoxycillin and clavulanic pneumonia. Although one study has in- acid was determined in bronchial mucosal vestigated the concentration of amoxycillin in biopsy samples obtained at bronchoscopy bronchial mucosa,9 there have only been pro- following five different dosing regimens. visional reports on the bronchial mucosal levels Methods - Bronchial biopsy and serum ofclavulanic acid.'2'3 We have assessed levels of samples were obtained from 50 patients amoxycillin and clavulanic acid in the bronchial undergoing diagnostic bronchoscopy. Ten mucosa following the administration of co- patients each received 375 mg, 625 mg, amoxiclav by five different dosing regimens in 750 mg, and 3 25 g oral, and 1*2 g intra- patients undergoing diagnostic bronchoscopy. venous co-amoxiclav 1-3 hours before bronchoscopy. The concentrations of cla- vulanic acid and amoxycillin were de- Methods termined by high performance liquid The study was approved by the hospital ethical chromatography using a microbore col- committee and informed consent was obtained. http://thorax.bmj.com/ umn, solid phase extraction, and pre- Patients were excluded if they were pregnant, concentration to improve sensitivity suffering from severe cardiovascular or renal tenfold over previous methods. disease, hypersensitive to P-lactams, un- Results - Concentrations of both cla- dergoing bronchoscopy for diagnosis of in- vulanic acid and amoxycillin in bronchial fection, or had received systemic antibacterial mucosa were dose related and were well chemotherapy in the previous three days. Fifty above the MIC90 of co-amoxiclav for the patients, 10 for each dosing regimen, un- common bacterial respiratory pathogens dergoing diagnostic bronchoscopy were en- on September 27, 2021 by guest. Protected copyright. including Haemophilus influenzae, Mi- rolled. No patient had clinical signs ofbronchial crococcus catarrhalis and Streptococcus infection during the study. Patients received pneumoniae for all dosing regimens. Mean 375 mg, 625 mg, 750 mg, or 3-25 g oral co- mucosal levels were 200% and 118% of the amoxyiclav or 1 2 g intravenously 1-3 hours corresponding serum levels for amoxy- before bronchoscopy. cillin and clavulanic acid respectively. Fibreoptic bronchoscopy was performed un- Department of Conclusions - Amoxycillin and clavulanic der general anaesthetic and serum samples were Clinical Microbiology acid are concentrated in bronchial mucosa obtained prior to mucosal biopsy. Two biopsy I M Gould at the lowest dose of 375 mg specimens were taken from secondary carinae G Harvey and, even D Golder orally, are likely to produce tissue levels in both lungs. Grossly blood contaminated bi- T M S Reid in the lung sufficient to inhibit all the com- opsies were discarded. Specimens were trans- mon community acquired respiratory ported to the laboratory on ice, weighed and Department of Thoracic Medicine pathogens. buffered to pH 6 in 200 ,u1 NaH2PO4, and S J Watt stored at -70°C within 90 minutes of col- J AR Friend (Thorax 1994;49:999-1001) lection. Weighing the biopsy samples before J S Legge J G Douglas storage avoided any risk of artificial con- centration of the drug in the event of de- Aberdeen Royal Several studies have attempted to assess the siccation of the sample. Before assay mucosal Infirmary, Aberdeen AB9 2ZB, UK concentrations of amoxycillin and clavulanic samples were homogenised by ultrasonication acid in respiratory secretions'-' and whole lung on ice to prevent overheating during pro- Reprint requests to: Dr G Harvey. tissue.6 Antibiotic concentrations in sputum cessing. A tapered microtip attached to the horn Received 9 February 1993 and bronchial mucus vary greatly because of of an ultrasonicator (Branson Sonic Power, Returned to authors difficulty in sampling, drug instability, and con- Danbury, Connecticut, USA) was used and 6 April 1993 Revised version received tamination by blood and saliva.7'8 Bronchial each biopsy sample was subjected to 20-30 9 June 1994 washings also suffer from the same problems seconds of ultrasonication to give a uniform Accepted for publication 11 July 1994 and are further compounded by the dilutional suspension ready for high performance liquid 1000 Gould, Harvey, Golder, Reid, Watt, Fnend, Legge, Douglas Table 1 Mean (SD) and coefficient of vatiation (CV) in serum and bronchial mucosal levels of amoxycillin following administration of co-amoxiclav Dose of amoxycillin Serum levels Bronchial mucosa Thorax: first published as 10.1136/thx.49.10.999 on 1 October 1994. Downloaded from (co-amoxiclav) (mg/i) levels (mglkg) Mean (SD) CV Mean (SD) CV 250 mg (375 mg) 2-6 (1-37) 0-53 4-1 (1-58) 0-38 500mg (625mg) 5-6 (1-87) 0-33 10 1 (1-75) 0-17 500mg (750mg) 5-1 (1.59) 0-31 7-2 (2-58) 0-35 1 g (1-2g) 8-4 (2 34) 0-27 20-8 (5-71) 0-27 3g (3-25g) 10-9 (2 43) 0-22 23-1 (5-1) 0-22 Table 2 Mean (SD) and coefficient of variation (CV) in serum and bronchial mucosal levels of clavulanic acid Dose of clavulanic Serum levels Bronchial mucosa acid (co-amoxiclav) (mg/l) levels (mglkg) Mean (SD) CV Mean (SD) CV 125mg (375mg) 1-4 (0 82) 0-58 19 (0 72) 0-37 125 mg (625 mg) 2-3 (0-85) 0 37 2-4 (094) 0-38 250mg (750mg) 2-3 (1 15) 0-50 1-6 (047) 0 30 200mg (1-2g) 2-7 (0 77) 0-28 3-6 (1-35) 0-37 250 mg (3-25 g) 2-9 (1-4) 0-48 4-1 (1-65) 0-40 chromatography with a microbore column, proximate to peak levels.'7 Percentage pen- solid phase extraction, and preconcentration.'4 etration into the bronchial mucosa was 200% Spiked standards were prepared in water from for amoxycillin (range 158-248%) with con- pure powder. Fresh antibiotic free biopsy tissue centrations increasing with dose. Penetration was ultrasonicated with buffer to produce a for clavulanic acid was 118% (range 70-136%) control biopsy suspension. Standards and bi- and again concentrations increased with dose, opsy suspension or serum were mixed 1:1 to except for the 750 mg oral dose where levels give a range of known biopsy standards of 500, were lower than expected for no obvious reas- 250, 125, 64, 32, 16 and 8 jg/kg for clavulanic on. acid and 1000, 500, 250, 125, 64 and 32 jg/kg for amoxycillin. Blank standards were included. Serum standards were 4, 2, 1, 0 5 and 0 25 mg/ Discussion for clavulanic acid and 8, 4, 2, 1 and 0 5 mg/ The concentrations of amoxycillin and cla- for amoxycillin. The biopsy and serum stand- vulanic acid found in bronchial mucosa in this http://thorax.bmj.com/ ards were treated in the same way as the biopsy study are up to 20 times higher than in bron- and serum samples. For clavulanic acid internal chial mucus and sputum. 1-5 Higher con- standard (Salicylamide) was added, derivatised centrations of r-lactams occur in bronchial with imidazole, and concentrated using a C 18 mucosa than in mucus'8 and we have noticed Bond Elut cartridge as previously prescribed. a similar difference between bronchial mucus Amoxycillin was assayed by HPLC.'5 16. Plots and mucosal levels for aztreonam (un- of the standards were used to obtain the values published). The mucosal levels of amoxycillin of the samples after HPLC analysis. Lower are approximately double those where mean on September 27, 2021 by guest. Protected copyright. limits of the assay were 8 jg/l or gg/kg for mucosal concentrations of amoxycillin were clavulanic acid and 32 jg/l or gg/kg for amoxy- 75% ofsimultaneous serum levels.9 Preliminary cillin. Samples were assayed in batches of 6-10 results from a further study by the same group with standards stored under the same con- have shown similar levels to our own for both ditions. Within and between assay precision amoxycillin and clavulanic acid.'3 The differ- was 96-99%. ence in results might be due to the use of a bioassay,9 different times between drug dosing and biopsy sampling, and different biopsy Results weights, suggesting different tissue site Mean mucosal biopsy weights were 1 -69 mg, samples. 1-4 mg, 1-25 mg, 1-79 mg, and 1-34 mg for the The mucosal amoxycillin levels are well five dosage groups respectively. All samples had above the MIC90 of all common 1-lactamase detectable levels of amoxycillin and clavulanic negative respiratory pathogens, even at the acid in the mucosal biopsy and serum samples, 250 mg dose of amoxycillin. Similarly, the mu- with the exception of two patients on the cosal concentrations of clavulanic acid, even at 750 mg dose of co-amoxiclav who had un- the 125 mg dose, may be sufficient to maximally detectable levels of clavulanic acid (tables 1 inhibit the [-lactamases of all the common and 2).
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