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.

Serum concentrations of antibiotics during severe invasive surgery such as esophagectomy for esophageal cancer.

This study was performed to confirm the antibiotic regimen during a severe invasive surgery, such as esophagectomy, with a long procedure and a large amount of normal volumes of infusion. Ten patients with esophageal cancer were enrolled in this study, and cefmetazole sodium concentrations in serum were measured during esophagectomy. The ranges of minimum inhibitory concentrations for 90% of isolates of cefmetazole sodium for microorganisms in our institutions for 8 years were investigated. The maximum concentration was 83.9 µg/mL just after the completion of infusion, and its half-life was 1.5 hours. Serum concentration of cefmetazole sodium was kept above 16 µg/mL for 4 hours during esophagectomy. It was kept above 32 µg/mL for 2.5 hours after injection. There are almost no differences in the pharmacokinetics of cefmetazole sodium between common use and during esophagectomy. In addition, additive infusion of antibiotics 4 hours after the first infusion was recommended during esophagectomy.

Effects of air tourniquet on the antibiotics concentration, in bone marrow, injected just before the start of operation.

Infection is one of the most serious complications after artificial arthroplasty. In order to establish the effective prevention for after operative infection, we measured the serum and bone marrow blood cefmetazole (CMZ) concentration time dependently (1 g CMZ, one shot). Furthermore, we studied the effect of air tourniquet on CMZ transmit into bone marrow blood. Thirteen knees with total knee arthroplasty (TKA) were included in the study. As a control group, 11 hips with total hip arthroplasty (THA) were also included. In TKA, air tourniquet was used during operation in all cases. Just before the start of the operation, 1 g CMZ was injected intravenously (one shot). Subsequently we sampled peripheral blood and bone marrow blood time dependently. Cefmetazole concentration was measured with HPLC. In the THA group, serum and bone marrow blood CMZ concentration showed almost the same time-dependent change. On the other hand, in the TKA group we could not detect CMZ in bone marrow blood in cases where CMZ was injected within 8 min before starting use of an air tourniquet. If CMZ was injected more than 10 min before starting use of the air tourniquet, CMZ concentration in bone marrow blood was much lower than minimum inhibitory concentration (MIC) for Staphylococcus aureus; but after releasing the air tourniquet, CMZ concentration in bone marrow blood was higher than MIC for S. aureus. These data suggested that our injection method is effective for prevention of infection both during and just after operation in the THA but in the TKA, CMZ should be injected more than 10 min before starting to use the air tourniquet.

Determination of unbound cefmetazole in rat blood by on-line microdialysis and microbore liquid chromatography: a pharmacokinetic study.

A specific and sensitive microbore liquid chromatographic method for the determination of unbound cefmetazole in rat blood was developed. A microdialysis probe was inserted into the jugular vein/right atrium of a Sprague-Dawley rat. Cefmetazole (10 mg/kg, i.v.) was then administered via the femoral vein. Dialysates were automatically injected into a liquid chromatographic system via an on-line injector. Isocratic elution of cefmetazole was achieved by LC-UV within 10 min. Intra- and inter-assay accuracy and precision of the assay were < or = 10%. The detection limit of cefmetazole was 20 ng/ml. Pharmacokinetic analysis of results indicated that unbound cefmetazole levels in rats best fit a biexponential decay model.

Influence of timing of antibiotic administration on tissue concentrations during surgery.

BACKGROUND: Prophylactic antibiotics must be administered so as to achieve adequate tissue levels before the initial surgical incision. We characterized antimicrobial tissue concentrations following intravenous administration at various times prior to surgical incision. PATIENTS AND METHODS: Twelve patients scheduled for elective colorectal surgery were randomized to receive cefmetazole 2 g by intravenous push either immediately prior to incision or 15 to 60 minutes prior. Blood and wound-muscle samples were obtained at predetermined intervals and assayed by high-performance liquid chromatography. RESULTS: Tissue distribution of the study drug was extremely rapid. All patients had theoretically adequate tissue levels at the time of incision. Levels above MIC90 of the common pathogens were sustained throughout the surgical procedure regardless of the timing of administration. CONCLUSIONS: Administration of cefmetazole immediately prior to surgical incision should be effective prophylaxis for surgical wound infections.

Pharmacokinetic parameters from data relating to the plasma and biliary excretion kinetics of cefmetazole in rats.

The plasma disposition kinetics and the biliary excretion kinetics of cefmetazole after i.v. administration to rats anaesthetized with pentobarbital sodium were studied. Parametric estimation was carried out using non-linear regression methods with uni- and bivariate analyses. On the basis of statistical criteria a two-compartment model was chosen as the most appropriate for fitting the plasma concentration data, establishing a mean half-life value of the slow disposition phase at around 13 min. Analysis of the plasma and biliary data revealed a mean value for the biliary excretion constant of 0.049 l/min and 0.113 l/min for the urinary excretion constant. The cumulative biliary excretion data showed a mean value of 36.25% of the dose administered. The relationship between the biliary excretion rates and plasma concentrations seems to point to a saturable mechanism of excretion.

Pharmacokinetics and dose proportionality of cefmetazole in healthy young and elderly volunteers.

The pharmacokinetics and dose proportionality of cefmetazole were studied in 24 healthy volunteers (12 young and 12 elderly). Each volunteer received single 0.5-, 1-, and 2-g doses of cefmetazole administered intravenously over 5 min according to a three-way crossover design. Serial plasma and urine samples were collected over a 24-h period following dosing and assayed for cefmetazole by a high-performance liquid chromatography method. Results of the dose proportionality portion of the study indicated that cefmetazole pharmacokinetics are linear and proportional with dose in both age groups. Comparisons of pharmacokinetic parameters between the young and elderly groups indicated that the systemic clearance was significantly lower in elderly than in young volunteers (92.4 versus 112 ml/min). Additionally, creatinine clearance was significantly lower in elderly (74.1 ml/min) than in young (92.9 ml/min) subjects. No significant differences between age groups were observed for volume of distribution, urinary recovery, terminal half-life, nonrenal clearance, or renal clearance, although half-life was slightly prolonged in elderly volunteers relative to that in young volunteers (1.54 versus 1.34 h), and renal clearance was slightly lower in elderly than in young volunteers (83.7 versus 96.1 ml/min). Both systemic and renal clearance were significantly correlated with creatinine clearance. These results indicate that the observed age-related differences in the pharmacokinetics of cefmetazole are most likely due to differences in renal function between the two age groups. The small reduction in cefmetazole elimination in the elderly would not warrant dose adjustment in this population.

Disposition of cefmetazole in healthy volunteers and patients with impaired renal function.

The disposition of cefmetazole was studied in 25 subjects with various degrees of renal function after a 1,000-mg, constant-rate, 30-min intravenous infusion of cefmetazole sodium. In six subjects with creatinine clearance (CLCR) of greater than 90 ml/min per 1.73 m2 (group 1), the terminal elimination half-life (t1/2 beta) was 1.31 +/- 0.54 h (mean +/- standard deviation), cefmetazole total body clearance (CLP) was 132.8 +/- 25.1 ml/min per 1.73 m2, and volume of distribution at steady state was 0.165 +/- 0.025 liter/kg. The fraction of dose excreted unchanged in the urine was 84.0% +/- 26.1%. Subjects with CLCRS of 40 to 69 (group 2, n = 6) and 10 to 39 (group 3, n = 6) ml/min per 1.73 m2 demonstrated prolongation of the t1/2 beta (3.62 +/- 1.06 and 5.93 +/- 1.81 h, respectively) and significant reductions in cefmetazole CLP (52.8 +/- 14.3 and 30.2 +/- 10.2 ml/min per 1.73 m2, respectively), compared with group 1. In seven subjects on chronic hemodialysis (group 4) studied during an interdialytic period, the cefmetazole t1/2 beta was increased to 24.10 +/- 8.12 h and the CLP was reduced to 6.8 +/- 2.1 ml/min per 1.73 m2. Cefmetazole CLP correlated positively with CLCR (r = 0.951, P less than 0.001): CLP = (1.181 . CLCR) -- 0.287. The disposition of cefmetazole was also assessed in six group 4 subjects during an intradialytic period. The t1/2 beta during hemodialysis (2.09 +/- 0.69 h) was significantly shorter than that observed during the interdialytic period. The hemodialysis clearance of cefmetazole was 86.1 +/- 20.1 ml/min, and the fraction of cefmetazole removed during hemodialysis was 59.8% +/- 5.9%. It is recommended that patients with renal insufficiency received standard doses of cefmetazole at extended intervals and patients on maintenance hemodialysis received standard doses after hemodialysis.

[A study of tissue transfer of cefmetazole in the blood and uterus in pregnant rabbits].

Analysis was made to determine concentrations of cefmetazole (CMZ) in maternal serum, and intrauterine tissues of myometrium, placenta, fetal membrane, amniotic fluid and fetal lung after one shot intravenous infusion of 100 mg of CMZ to rabbits with 25th day-pregnancy, and the following results were obtained. 1. Concentrations of CMZ in maternal serum, myometrium and placenta reached their maximum levels in 30 minutes after administration, then decreased rapidly. 2. The concentration of CMZ in the fetal membrane reached its maximum level in 30 to 60 minutes after the administration, then it decreased to a nearly constant level. 3. The concentration of CMZ in the amniotic fluid showed its maximum level in 30 minutes after administration, then decreased, but somewhat increased again thereafter. 4. The concentration of CMZ in the fetal lung was elevated gradually after administration, then decreased after reaching its maximum level at 90 minutes, after administration to a nearly constant level. It was deemed, however, that higher concentrations would be necessary to achieve therapeutic effects because attained concentrations were lower than those in other tissues.

Pharmacokinetics of intravenous cefmetazole with emphasis on comparison between predicted theoretical levels in tissue and actual skin window fluid levels.

Cefmetazole is a cephamycin antibiotic which is resistant to hydrolysis by various beta-lactamases. This study evaluated the pharmacokinetics of cefmetazole, including its intravascular and interstitial fluid distribution, by using the skin window (SW) technique. A 2-g dose of cefmetazole was given intravenously over 30 min to each of 12 healthy adult male volunteers every 6 h for nine doses. Plasma levels were assayed at predetermined intervals after doses 1, 5, and 9. Interstitial fluid levels were determined by the SW technique. Antibiotic levels were assayed by the agar well bioassay technique. A concentration-versus-time plot indicates that cefmetazole is rapidly distributed, with mean peak levels in plasma equal to 126 micrograms/ml at the end of the half-hour infusion. The mean plasma half-life was 1.1 h. Plasma and tissue distribution constants permitted calculation of theoretical levels in tissue. Parallel elimination slopes for SW and theoretical tissue level showed that the SW model distribution kinetics are closely related. The area under the curve for the SW was 73.9 mg.h/liter. This was comparable to the theoretical level in tissue, which was 96 mg.h/liter. Furthermore, the area under the curve of theoretical tissue level/plasma was 0.6 and that of SW/plasma was 0.47. These results demonstrate that the SW technique yielded a result quite close to the theoretical tissue level. Ultrafiltration analysis indicated that as cefmetazole levels in plasma increased from 10 to 250 micrograms/ml, plasma protein binding of the antibiotic dropped from 85 to 65%. Finally, 60 to 70% of the drug was recovered from the urine as biologically active drug over 6 h postinfusion.

Comparative intraoperative concentrations of two cephalosporins with activity against anaerobic bacteria.

We determined the intraoperative concentrations of cefmetazole and cefoxitin in serum and muscle from the wound of 30 patients who were undergoing cholecystectomies. The study employed an open-label design in which all patients randomly received cefoxitin sodium (30 mg/kg) or cefmetazole sodium (15 or 30 mg/kg) intravenously with the induction of anesthesia. Total serum and wound-muscle concentrations achieved with cefmetazole 30 mg/kg were significantly greater than those achieved with a similar dose of cefoxitin. Cefmetazole in a 15 mg/kg dose was comparable with cefoxitin 30 mg/kg in achieved concentrations. The elimination half-life for cefoxitin was much shorter than that for cefmetazole (41 min v. 64-68 min, respectively) and this relates to a shorter duration of action for the former. The choice of agent for surgical prophylaxis should incorporate factors relating to drug pharmacokinetic properties as well as microbiological factors.

Enhancement of colonic drug absorption by the paracellular permeation route.

Colonic absorption of poorly absorbable cefmetazole was shown to increase considerably by the addition of 1% sodium caprate, sodium laurate, and mixed micelles composed of sodium oleate and sodium taurocholate. At 0.25%, their effects were weaker but still significant. Colonic absorption of inulin was also increased by the promoters at a concentration of 0.25%. These results suggest that there is a common route between inulin and cefmetazole absorption, i.e., the paracellular route. Sodium taurocholate, sodium caprylate, and EDTA disodium salts (EDTA-2Na) at 1% enhanced cefmetazole absorption less than caprate, laurate, or mixed micelles, but no such effect was found at 0.25%. The colonic pore radius was determined from the equivalent pore theory using an everted sac procedure. Caprate, laurate, and mixed micelles at 0.25% caused this radius to increase significantly, thus making it possible for inulin to permeate the everted sac from the mucosal to the serosal side. The effects of taurocholate, caprylate, and EDTA-2Na for increasing colonic pore sizes and the degree of inulin permeation were less than those of caprate, laurate, or mixed micelles. The change in the paracellular route is thus considered to result from the increase in pore size.

[Penetration of cefmetazole and netilmicin into the cerebrospinal fluid].

1. Cefmetazole (CMZ) and netilmicin (NTL) were administered by one-shot intravenous and intramuscular injection, respectively, and measurements were made on their concentrations in the serum as well in the cerebrospinal fluid (CSF) which was collected using a drainage tube inserted into the cisterna basalis after the operation of ruptured cerebral aneurysm. 2. Concentrations of CMZ and NTL in the CSF changed nearly in parallel to those in the serum. 3. A one-shot intravenous injection of these drugs seemed to achieve their high concentrations in the CSF, though high concentrations may not last very long.