The dynamic observation of plasma concentration of antimicrobial agents during balanced ultrafiltration in vitro.

Routine perioperative intravenous antimicrobial agents are administered as surgical prophylaxis. However, whether balanced ultrafiltration during extracorporeal circulation has substantial effect on the concentration of antimicrobial agents remains unclear. The concentrations of antimicrobial agents in plasma and ultrafiltrate samples were measured in this pseudo-extracorporeal circulation model. Extracorporeal circulation consisted of cardiotomy reservoir, membrane oxygenator, and pediatric arterial line filter. A hemoconcentrator was placed between the arterial purge line and oxygenator venous reservoir. Fresh donor human whole blood was added into the circuit and mixed with Ringer's solution to obtain a final hematocrit of 24-28%. Two kinds of antimicrobial agents, cefotiam (320 mg) and cefmetazole (160 mg), were bolus added into the circuit. After 30 min of extracorporeal circulation, zero-balanced ultrafiltration was initiated and arterial line pressure was maintained at approximately 100 mm Hg with a Hoffman clamp. The rate of ultrafiltration (12 mL/min) was controlled by ultrafiltrate outlet pressure. An identical volume of Plasmalyte A was dripped into the circuit to maintain stable hematocrit during 45 min of experiment. Plasma and ultrafiltrate samples were drawn every 5 min, and concentrations of antimicrobial agents (including cefotiam and cefmetazole) were measured with high performance liquid chromatography. Both antimicrobial agents were detected in ultrafiltrate, demonstrating hemoconcentration may remove antimicrobial agents. The concentrations of plasma antimicrobial agents decreased linearly with the increase of ultrafiltrate volume. At end of balanced ultrafiltration, the concentration of plasma cefotiam was 104.96 ± 44.36 mg/L, which is about 44.38% ± 7.42% of the initial concentration (238.95 ± 101.12 mg/L) (P < 0.001); the concentration of plasma cefmetazole decreased linearly to 25.76 ± 14.78 mg/L, which is about 49.69% ± 10.49% of the initial concentration (51.49 ± 28.03 mg/L) (P < 0.001). The total amount of cefotiam in ultrafiltrate is 27.16% ± 12.17% of the total dose administered, whereas cefmetazole in ultrafiltrate is 7.74% ± 4.17%. Balanced ultrafiltration may remove antimicrobial agents from plasma and has a prominent influence on plasma concentration of antimicrobial agent. The strategy of surgical prophylaxis should consider this unique technique during extracorporeal circulation.

Automated high-performance liquid chromatographic method for the simultaneous determination of cefotiam and delta 3-cefotiam in human plasma using column switching.

An automated high-performance liquid chromatographic method using column switching was established for the simultaneous determination of cefotiam (I) and delta 3-cefotiam (II) in human plasma after oral administration of cefotiam hexetil dihydrochloride. The method allowed the determination of analytes in plasma by the direct injection of diluted specimen with phosphate buffer. The analytes were enriched onto the C18 short pretreatment column by 0.05 M phosphate buffer (pH 7.7), while proteins and endogenous hydrophilic substances in plasma were washed off to waste. The enriched analytes were then back-flushed onto the analytical C18 column, separated by a mixture of 0.05 M phosphate buffer (pH 7.7)-acetonitrile (88:12, v/v) and detected by the ultraviolet absorbance at 254 nm. Recoveries from spiked plasma were quantitative, and the coefficients of variation were below 4%. The lower detection limits in plasma were 10 ng/ml for both I and II. Concentrations of I and II in plasma determined by the present method were in good agreement with those obtained by the conventional deproteinization method.

The blood binding of cefotiam and cyclohexanol, metabolites of the prodrug cefotiam hexetil, in-vitro.

The binding of cefotiam and cyclohexanol to human serum, isolated proteins and erythrocytes has been studied in-vitro by equilibrium dialysis. The two molecules are 50% bound to serum proteins and the free fraction for both compounds remained constant within the therapeutic concentration range. Human serum albumin (HSA) was exclusively responsible for the cefotiam binding (48%) with a saturable process characterized by one binding site (n = 1.00 +/- 0.14) with a very weak affinity (Ka = 1457 +/- 352 M-1). Like other cephalosporins, cefotiam showed no binding to alpha 1-acid glycoprotein, lipoproteins or gamma-globulins. Cyclohexanol is mainly bound to HSA with a weak affinity (Ka approximately 1,800 M-1) but lipoproteins and alpha 1-acid glycoprotein bind about 30% of bound cyclohexanol in serum. Interactions with free fatty acids (FFA) or bilirubin were studied at physiopathological concentrations. HSA-bound cefotiam was displaced by FFA (1260 microM) and bilirubin (330 microM), whereas the cyclohexanol binding was inhibited only by FFA. The cefotiam binding site seems to be close to the warfarin site (site I) whereas cyclohexanol probably shares the diazepam site (site II) on HSA. There is no mutual inhibition of binding between cefotiam and cyclohexanol at therapeutic levels. The binding of both compounds to erythrocytes is low and restricted when measured in the presence of plasma.

Pharmacokinetics of cefotiam in plasma, parotid saliva and mixed saliva in healthy adults.

Cefotiam (Spizef; CAS 61622-34-2) at a dose of 2 g was administered intravenously to 10 young, healthy, male volunteers. Multiple simultaneous blood, parotid saliva, and mixed saliva samples were collected for 7 h. The antibiotic assay was carried out by high-pressure liquid chromatography. Significant salivary cefotiam concentrations were found for 2 to 4 h, potentially inhibitory to a wide array of pathogens commonly isolated from the upper aerodigestive tract. Salivary cefotiam concentrations were correlated to plasma levels (p less than 0.01), but saliva/plasma ratios varied considerably. It is unlikely that passive diffusion is the applicable transfer mechanism for cefotiam secretion into saliva.

[Time-course of the concentration of cefotiam in human extra-vascular pulmonary tissue].

The concentration of cefotiam in the blood and in blood-free, extra-vascular pulmonary tissue (lung tissue) was determined and its transition into the lung tissue was observed. One gram of cefotiam was injected intravenously into 27 lobectomized cases of bronchogenic carcinoma at 30 (n = 8), 60 (n = 6), 120 (n = 7) and 180 minutes (n = 6) before thoracotomy. Informed consent was obtained from these patients before the study. Lung samples were collected from the resected lobe immediately after thoracotomy, and the blood samples were also collected. Drug concentrations of the lung and blood specimens were determined. The blood volume of the lung sample was determined according to the gravimetric method with hemoglobin as an index. The drug concentration in the lung tissue was determined by the difference of the concentration between blood and lung. The time-courses of lung tissue drug concentration and blood drug concentration were compared. The lung tissue drug concentration reached a peak at 30 minutes after intravenous injection and thereafter decreased gradually, reaching equilibrium at about 50% of the blood concentration. Thirty minutes after intravenous injection, the lung tissue drug concentration was higher than the blood concentration, suggesting a higher rate of transition of the drug from the blood to the lung tissue than vice versa.

[Comparison of intraocular penetration level of cefuzonam sodium and cefotiam after intravenous and subconjunctival injection].

We investigated the intraocular penetration of a new Cephem type antibiotic: Cefuzonam sodium (CZON) following intravenous and subconjunctival injection. CZON was administered to 28 eyes in 26 patients by 1 g intravenous injection (IV) and to 11 eyes in 10 patients by 20 mg/0.2 ml subconjunctival injection (SCI). The penetration level of CZON by the IV method was from less than 0.0025-3.35 micrograms/ml into aqueous humor, from less than 0.0025-0.315 microgram/mg into iris tissue and 2.7-157.5 micrograms/ml into serum. The penetration level of CZON by the SCI method was from less than 0.0025-12.8 micrograms/ml into aqueous humor, from less than 0.0025-0.0426 microgram/mg into iris tissue and 1.03-18.5 micrograms/ml into serum. The penetration level of CZON into aqueous humor by SCI was higher than by IV administration. In comparison with the penetration level of CZON and Cefotiam (CTM), both aqueous humor and serum levels of CTM were higher than those of CZON. These results suggested that therapeutic levels in aqueous humor effective against gram-positive and gram-negative pathogens were achieved with the 1 g IV and 20 mg SCI of CZON. However levels effective against Staphylococcus epidermidis were only erratically attained.

[Bone diffusion of cefotiam in men]. / Etude de la diffusion osseuse du céfotiam chez l'homme.

A 2g single dose of cefotiam was given by rapid intravenous injection to 17 patients undergoing total hip replacement as a prophylaxis. The concentrations of the antibiotic in plasma and femoral head (cancellous bone, cortical bone and capsule) were measured at different time (40 to 250 minutes) following the injection of the drug. Evaluation was done by liquid chromatography. Mean antibiotic concentrations were 70.5 micrograms/ml, 41.4 micrograms/g, 16.9 micrograms/g and 8.1 micrograms/g respectively in plasma, capsule, cancellous and cortical bones. 240 minutes following the injection, mean concentrations of cefotiam were higher than 2.3 micrograms/ml in plasma and 1.8 micrograms/g in bone. Diffusion in cancellous bone is twofold high as in cortical bone and elimination half lif is higher in bone than in plasma (248.8 minutes versus 59.6 minutes in plasma). These results suggest that a 2g intravenous bolus injection of cefotiam given at the induction of anaesthesia should provide an effective prophylaxis during total hip replacement.