The Distribution of Temafloxacin in Bronchial Epithelial Lining Fluid, Alveolar Macrophages and Bronchial Mucosa
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Eur Resplr J 1992,5,471-476 The distribution of temafloxacin in bronchial epithelial lining fluid, alveolar macrophages and bronchial mucosa D.R. Baldwin*, R. Wise**, J.M. Andrews**, J.P. Ashby**, D. Honeybourne* The distribution of temafloxacin in bronchial epithelial lining fluid, alveolar Dept of • Thoracic Medicine and macrophages and bronchial mucosa. D.R. Baldwin, R. Wise, J.M. Andrews, J.P. • • Microbiology Ashby, D. Honeybourne. Dudley Road Hospital ABSTRACT: The concentrations of temafloxacin, a new fluoroquinolone anti Birmingham, UK microbial, In the potential sites of pulmonary Infection were assessed by Correspondence: D. Honeybourne fibreoptic bronchoscopy with bronchoalveolar lavage. Dept of Thoracic Medicine Fourteen patients received a course of temafloxacin, 600 mg twice daily, for Dudley Road Hospital three days prior to sampling. The mean serum concentration was 9.6 (SEM 1.2) Birmingham, UK. 1 1 mg·t , compared with 14.9(sEM 1.8) mg·kg· for bronchial mucosa, 26.5 (sEM 3.6) 1 1 Keywords: Fluoroquinolones mg·l· for epithelial lining fluid and 83.0 (SEM 11.5) mg•l' for alveolar Pulmonary infection. macrophage. In the ten patients who completed the protocol, site concentra tions correlated well with serum concentrations. Received: July 5 1991 Accepted after revision December 3 Temafloxacin was concentrated in each of the potential sites of infection 1991. examined and is, therefore, a promising new agent for the treatment of respi ratory tract infection. Abbot! Laboratories provided financial Eur Respir J, 1992, 5, 471-476 support for this study. A recent approach to the assessment of antimicro Antibiotic concentrations measured in bron bials has been to investigate the pharmacokinetics of chial mucosa (BM) are not subject to the same new agents in potential sites of infection. This has difficulties with sampling as sputum and may afford been found to be necessary because of the great dis a more reliable prediction of clinical efficacy [16, 17] crepancy which may exist between serum concentra By means of bronchoalveolar lavage, we can now tions and those at other sites [1-4]. For some sites investigate two further sites, namely the alveolar there is a clear relationship between local concentra macrophage (AM) and epithelial lining fluid (ELF), tions and clinical efficacy. Antimicrobials which which represent pure intracellular and pure extracell concentrate in the urine are known to be effective even ular sites, respectively. Important methodological when serum concentrations would predict a clinical factors have made the interpretation of antimicrobial failure [5], this has also been noted for renal tissue concentrations in the AM and ELF difficult [18, 19], [6, 7]. For the respiratory tract the situation is more but with improved techniques this should become more complicated but evidence is accumulating that site meaningful [20-22]. concentrations are better predictors than serum Temafloxacin hydrochloride is a new fluoro concentrations. For example, some of the newer mac quinolone with antibacterial activity approximating rolide agents display in vivo activity which relates that of ciprofloxacin but with greater activity more closely to site concentrations than to their very against Streptococcus pneumoniae [23, 24]. It has low serum concentrations [8, 9]. recently been shown to be effective in acute purulent The tissues of the respiratory tract previously exacerbations of chronic bronchitis, except where studied include whole lung tissue, sputum and pleural Pseudomonas aeruginosa was isolated [25]. In this fluid [10-12] but, unfortunately, these sites may be study, we have investigated the concentrations of unrepresentative. Whole lung tissue consists of a temafloxacin achieved in serum, BM, AM and ELF in number of different tissue compartments and, therefore, patients taking a dose of 600 mg b. d. levels represent an average concentration. Sputum concentrations may be unreliable because of difficulties with sampling, contamination with blood and saliva, Patients and methods and sputum pooling over a number of hours thus producing antimicrobial instability and making con Fourteen patients ( 4 female) undergoing fibre clusions about pharmacokinetics difficult [13-15]. optic bronchoscopy for diagnostic purposes were in Finally, pleural fluid is only likely to be a useful cluded in the study. The final diagnoses were lung predictor of efficacy in empyema. cancer in five, haemoptysis alone in four, and focal 472 D.R. BALDWIN ET AL radiological abnormality alone in four. Their mean well with those of conventional bronchoalveolar lav age was 60 yrs (range 33-87 yrs) and weight 69.4 kg age (BAL). A median of 3.4 ml of lavage fluid was (range 52-83kg). Temafloxacin was administered in recovered. a dose of 600 mg b.d. for three days, with a final dose on the morning of bronchoscopy, making a total of seven doses. Exclusion criteria for the study were: 1) Calculation of epithelial lining fluid volume clinical or radiological evidence of cardiac failure; 2) disturbance of hepatic function (serum transaminase A urea dilution method was used as described by activity more than twice the upper limit of normal, RENNARD et al. [27]. This method was applied to the bilirubin above the normal range); 3) renal impairment microlavage specimen, where the lavage dwell time (blood urea greater than 9 mmol·[·1 or creatinine was short enough for the urea to represent accurately 1 greater than 140 IJ.mol·[· ); 4) a haemoglobin determi that contained in the epithelial lining fluid (ELF) [28]. nation of less than 10 g·d[·1; 5) a history of concomi The concentration of total protein in the ELF was then tant drug therapy, including any other investigational determined as follows: drug, antibiotics, antacids,. theophylline and drugs affecting the central nervous system other than seda Microlavage: tives 6) evidence of active lung infection; and 7) ELF volume [urea] lavage x volume lavage women with child-bearing potential. Subjects with = active lung infection were excluded to ensure a [urea] ELF"' homogeneous group. All patients provided fully informed written consent [protein] ELF = volume lavage x [protein] lavage and the study was approved by the Hospital Ethical ELF volume Committee. A blood biochemical profile (including urea, creati * (= [urea] blood) nine, calcium, bilirubin, aspartate transaminase, alka Therefore: line phosphatase and electrolyte determinations) and an [protein] ELF ::: [urea] ELF x [protein] lavage automated Coulter count were performed before and [urea] lavage after drug administration. Patients had a full physi cal examination before and after the study. The ELF protein concentration was then applied to the standard BAL to calculate the concentration of antibiotics in ELF recovered, since BAL protein var Sample collection ies far less with lavage dwell time [27]: Fibreoptic bronchost:opy was performed using a [antibiotic] ELF = [protein] ELF x [antibiotic] lavage premedication of 160 mg of nebulized 4% lignocaine [protein] lavage and 0.6 mg of intramuscular atropine, and sedation with 3-7 mg of intravenous midazolam. Mter care The median volume of ELF recovered by micro ful examination of the airways, "microlavage" (see lavage was 0.78% of the lavage aspirate, whereas for below) was performed in a distal lung subsegment conventional BAL the value was 1.5%. followed by a standard 200 ml bronchoalveolar lavage in a different lung segment (right middle lobe or lingula). Gentle aspiration was performed follow Sample processing ing each of the four 50 ml aliquots. The recovered fluid from the first 50 ml was discarded to avoid The microlavage and standard BAL specimens were contamination with proximal airway cells [26]. Bron centrifuged immediately in the bronchoscopy suite, at chial biopsies were then taken from macroscopically 400 x g for 5 min, after a small aliquot had been normal subcarinal mucosa (absence of erythema, removed for the total and differential cell counts. induration or nodularity) in all patients. Lastly, a se Total cell count preparations were again made imme rum sample was taken for temafloxacin concentration, diately, and to avoid cell loss due to adherence to total protein and urea concentration, and for a red cell surfaces, siliconized glassware and teflon containers count (RCC). were used at all times. The BAL supernatant was freeze dried and then resuspended in distilled water to yield a tenfold concentration. Bronchial biopsies were "Microlavage" collected into a humidity chamber and any blood stained samples were discarded. Following addition of This technique has been described previously [21, a known volume of cold phosphate buffer (pH 7.0), 22]. Briefly, a standard bronchial brush tube, 1.7 mm both the cell component and biopsies were ultrason in external diameter, is inserted under direct vision into icated on ice for 2 min at 50% duty cycle (Ultrasonic a distal subsegment and advanced until wedged. An Heat Systems W225). assistant then injects 20 ml of normal saline rapidly, The total white and red cell counts were performed and immediate gentle aspiration is performed. The using an Improved N eubauer haemocytometer. differential cell count obtained by microlavage agrees Samples were discarded if the red cell count was BRONCHOALVEOLAR DISTRIBUTION OF TEMAFLOXACIN 473 greater than 4 x 10S·ml·1• The differential count was last dose. Unfortunately, we were not able to sample performed on cellular monolayers prepared in trip bronchial mucosa and BAL in one patient due to licate by cytocentrifugation of 105 cells (100 J.ll of 106 technical difficulties and three patients did not com white cells·mt-1) at 450 rpm for 15 min (Shandon plete a full course of therapy because of nausea, nau cytospin 11). Slides were air-dried for 30 min prior sea and headache, and a skin rash resembling to staining with May-Griinwald-Giemsa stain. intertrigo. Two patients stopped 15 h before bron All samples were assayed for temafloxacin concen choscopy, but still had detectable ELF, serum and AM tration using a microbiological plate assay in which the levels. BM levels were detectable in only one of these indicator strain (E.