Journal of Antimicrobial Chemotherapy (1992) 30, 387-395

Pharmacokinetics of aztreonam in patients with liver cirrhosis and ascites M. E3 Touny", M. H Gtdnaidy*, M. Abdel Barry*, L. Osmanc and M. S. Sabbour'

The pharmacokinetics of aztreonam were studied in six healthy male subjects (group I) and 12 male patients with post-hepatitis liver cirrhosis and ascites. Patients were allocated into two groups according to serum creatinine; group II included nine patients with serum creatinine. < IS mg/L while group III included three patients with serum creatinine > IS mg/L. Aztreonam 1 g was given as iv bolus injection. Aztreonam reached a peak concentration in the astatic fluid (AF) of 6-2 ±2-3 mg/L at 4 h, and of 8-7 ±4-4 mg/L at 6 h in groups II and III respectively. The level of the drug in AF 24 h post-dosing was still higher than MIC*, for Enterobacteriaceae in most patients. The half-life of elimination from serum increased significantly (P > 0-001) from l-82±O14 h in group I to 6-6±21 h and to 8-87 ± 0 2 h in groups II and III, respectively. Both the central and the terminal volumes of distribution were higher in cirrhotic patients than in healthy volunteers. Liver cirrhosis and ascites resulted in a significant increase (P < 0-001) of the total body clearance (Cf) of aztreonam from 84 ±8 mL/h/kg in group I to 209 ±87 mL/h/kg in group II. However, the concomitant association of mild renal impairment in group III abolished this increase; Cl in group III was 122±50 mL/h/kg. The AUCo.., serum was 137-5±12-2, 78-5±24-9 and I51±42mg.h/L in groups I, II and II, respectively. The AUQ,.,,, ascites was 75 ±21 and 104 ±57-8 mg.h/L in groups II and III, respectively. The penetration ratio into AF expressed as AUCo.^ ascites/AUC,. „ scrum was 10 ±0-27 and 0-65 ±0-21 in groups II and III, respectively. Introduction Aztreonam inhibits most of the members of the family Enterobacteriaceae at concentrations < 1 mg/L. It also has significant activity against Pseudomona aeruginosa at concentrations of < 16 mg/L (Neu & Labthavikul, 1981), however, activity against aerobic Gram-positive and anaerobic bacteria is minimal. It is highly resistant to hydrolysis by most /Mactamases. Aztreonam is primarily excreted by the kidney (60-68%), has a serum protein binding of approximately 60%, and does not undergo extensive metabolism; the most prominent biotransformation product is SQ-26,992 which results from the hydrolytic opening of the /J-lactam ring (Swabb et al., 1983a; Swabb, Sugerman & Mckinstry, 1983ft). Patients with liver cirrhosis ( L Q and ascites are prone to develop various infections due to defects in host defence mechanisms. Spontaneous bacteria) peritonitis (SBP) is often a fatal complication in these patients (Rajkovic & Williams, 1986). Correspondence to: Professor M. S. Sabbour. 0305/7453/92/090387+09 $08.00/0

387 © 1992 The British Society for Antimicrobial Chemotherapy

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"Department of Internal Medicine, bDepartment of Pharmacology, 'Department of Clinical Pathology, Faculty of Medicine, Ain Shams University, Cairo, Egypt

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M. El. Touny et al

The aim of this work was to study the pharmacokinetics of aztreonam in the ascitic fluid and to assess if cirrhotic patients with ascites need dosage adjustment. Materials and methods Subjects

Administration of aztreonam AH subjects fasted overnight and for 2 h after the iv bolus injection of aztreonam (Squibb) 1 g. Blood and AF samples were withdrawn at 025, 0-5, 0-75, 1, 2, 4, 6, 8, 12 and 24 h post-dose. Separated serum and AF samples were stored undiluted at — 20°C pending assay within 48 h. Assay The concentrations of aztreonam in serum and AF samples were measured by a microbiological agar diffusion method using Escherichia coli SC 12155 (Squibb) as the indicator organism. Penassay seed agar (Difco) 30-5 g/L was the assay medium. Standards (2-6, 2-0, 1-4, 1-0, 06, 04 mg/L) were prepared in antibiotic-free pooled human serum. Both standards and samples were initially diluted 1/20 in 01 M phosphate buffer pH 6. Subsequent dilution to test level was made in a diluent composed of 5% serum and 95% buffer. The limit of quantitation was 04 mg/L. Pharmacokinetic and statistical analysis A computer was used to manipulate the data of every participant by pharmacokinetic programs. In group I the serum concentrations best fitted a two compartment open model: C, = /4e~" + 2te~* (1), while in both patients groups the serum concentrations of aztreonam fitted a three compartment open model: C, = Ae~*+Be'* + Ce~p (2). In equations (1) and (2) C, is the concentration of the drug at time t after iv injection. The

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Eighteen adult males participated in this study. None had a history of allergy to /Mactam antibiotics. Six were healthy individuals with normal renal and hepatic function (group I) and 12 were patients with LC and ascites. These patients were allocated into two groups according to serum crcatinine; group II included nine patients with serum creatinine < 15 mg/L (mean±s.D., 11 ±2 mg/L) and group III included three patients with serum creatinine > 15 mg/L (mean±s.D.,18±2 mg/L). All participants gave informed written consent and the study was approved by the Research Committee of the Faculty of Medicine, Ain Shams University. No subject received any antimicrobial drug for at least one week, or any diuretic for at least two days before the study. All participants received a clinical examination, electrocardiogram, urinalysis, liver and renal biochemical profile, prothrombin time and complete blood count. Ascitic fluid (AF) total proteins were measured in groups II and III. The diagnosis of LC was based on clinical and ultrasonographic findings. None of the patients had clinically evident hepatic encephalopathy and all were non-alcoholic. All patients except one had oedema of lower limbs. All patients in group III and six in group II showed bilharzial ova in their rectal snips. Four patients in group II and one in group III were HBsAg positive.

Aztreonam pharaucokinetks in drrfaosis

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Results The demographic characteristics and the blood physiological values of the subjects taking part in this study are shown in Table I. All patients had anaemia and hypoalbuminaemia. The serum and AF concentration of aztreonam are summarized in Table II and the mean serum concentration-time curves are shown in Figure 1. In the initial 6-h postdose period the serum concentrations were highest in group I. In contrast, after 8 h and 12 h the serum concentrations were greatest in group III (5-3 ± 1-8 and 4-5 ± 1-5 mg/L, respectively). The drug was still detectable in 5/6 group I subjects after 12 h, but was below the limit of detectability in all of them after 24 h. Mean concentrations of

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Flgnre 1. Maw icrum concentration versui time curves of aztreonam in groupi I ( • ) , II (A) and III (O)-

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method of residuals and least squares curve fitting was used to obtain the values of the time constants a, /? and y and the concentration intercepts A, B and C. The half-life (r 4 ) of each phase was calculated by logj/slope of the phase e.g. T^ = 0-693/a. The distribution rate constants K10, K12, K21, K13 and K31 were circulated according to Gibaldi & Perrier (1982). The apparent volume of the central compartment (KJ was calculated as Vc = Dose/A + B in group I and as Vt = Dose/A + B + C in groups II and III. The systemic clearance (C/) was calculated as C/= P^KIO. The apparent volume of the terminal distribution (V^ was calculated as Vp = C///J in group I and as Vp = Cl/y in the groups II and m . The area under the concentration-time curve (AUC

Pharmacokinetics of aztreonam in patients with liver cirrhosis and ascites.

The pharmacokinetics of aztreonam were studied in six healthy male subjects (group I) and 12 male patients with post-hepatitis liver cirrhosis and asc...
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