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A microdialysis method followed by a microbore liquid chromatographic ultraviolet detection procedure has been performed for the assay of unbound cefsulodin in rat blood. A microdialysis probe was inserted into the jugular vein for blood sampling. This method involves an on-line design for submitting dialysate into the liquid chromatographic system. The chromatographic conditions consisted of a mobile phase of methanol-100 mM monosodium phosphoric acid (10:90, v/v, pH 5.0) pumped through a microbore reversed-phase column at a flow-rate of 0.05 ml/min. Detection wavelength was set at 265 nm. Microdialysis probes, being laboratory-made, were screened for acceptable in vivo recovery while chromatographic resolution and detection were validated for response linearity as well as intra- and inter-day variabilities. The method was then applied to pharmacokinetics profiling of cefsulodin in the blood following intravenous administration of cefsulodin (20 mg/kg) in rats. Pharmacokinetics were calculated from the corrected data for dialysate concentrations of cefsulodin versus time. Based on pharmacokinetic calculation, cefsulodin best fitted to a two-exponential disposition. This study provided specific pharmacokinetic information for protein-unbound cefsulodin and demonstrated the applicability of this continuous sampling method for pharmacokinetic study.

The aim of this quantitative structure-activity relationship (QSAR) study was to investigate the influence of lipophilicity on the diffusion of cephalosporins into the cerebrospinal fluid (CSF). The lipophilicity was expressed as the chromatographic capacity factor (log k'w) determined by high-performance liquid chromatography in a reversed-phase system. The penetration of eight cephalosporins into CSF was studied in male Wistar rats receiving the drugs intramuscularly (1.5 mg/kg). One hour after administration, CSF and blood samples were collected, and concentrations of free drug were measured in CSF (CCSF) and in plasma (CP). A significant parabolic relationship was sought between lipophilicity (log k'w) and the capacity of diffusion across the blood-brain barrier expressed as log (CCSF/CP). The cephalosporins exhibiting a moderate lipophilicity diffused well into CSF. A pharmacokinetic study was performed at 1, 2 and 4 h after administration of three cephalosporins: cefazolin, ceftriaxone and cefsulodin. These compounds were choosen according to their lipophilicities (low, moderate and high values, respectively). The AUC0-4h for both free plasma (AUCP) and cerebrospinal fluid (AUCCSF) concentrations were determined. The AUCCSF/AUCP ratio presented a maximum value for a strongly albumin bound cephalosporin, ceftriaxone. In our experimental conditions, the ideal lipophilicity (log k'w) range for diffusion of cephalosporins from plasma into CSF was between 1.6 and 1.8.

The steady-state renal clearance of cefsulodin was studied in 6 patients with cystic fibrosis and 8 healthy controls. The drug was administered by constant rate infusion to obtain 2 values of plasma concentration, 2 and 30 mg/L. As an estimate of the glomerular filtration rate, the renal clearance of inulin was measured simultaneously. The results showed the figures for inulin clearance to be approximately 30% higher in cystic fibrosis patients than in healthy controls at both concentrations, and a corresponding increase in the renal clearance of cefsulodin was seen in patients over controls. The ratio between the renal clearances of the 2 substances was on average 0.9 in both groups. The correlation found between the 2 renal clearances (r = 0.75; p less than 0.001) indicates that glomerular filtration rate has considerable influence on the renal elimination of cefsulodin. This finding emphasises the importance of glomerular filtration rate for the renal clearance of drugs in cystic fibrosis.

Pharmacokinetics and clinical studies on cefsulodin (CFS) were conducted in neonates. 1. MIC's of CFS, sulbenicillin and gentamicin (GM) were determined using 7 strains of Pseudomonas aeruginosa clinically isolated from neonates and maintained as stock cultures. CFS was found to be nearly as active as GM. 2. When CFS 20 mg/kg was administered to a 12-day-old neonate by intravenous bolus injection, serum concentrations were 8.7 micrograms/ml before administration and 51.7 micrograms/ml at 30 minutes, 44.4 micrograms/ml at 1 hour, 38.6 micrograms/ml at 2 hours and 11.1 micrograms/ml at 6 hours after administration. The half-life was 2.5 hours. 3. CFS was administered alone or combination with other drugs to 3 neonates. The drug was clinically effective in 2 cases and slightly effective in another. Bacteriologically, one case was rated as decreased, another as replaced, and the remaining one as unchanged. 4. Neither side effects nor abnormal laboratory values attributable to CFS were found.

The kinetics of cefotiam and cefsulodin were studied in plasma and dialysate after intravenous and intraperitoneal administration of 1 g to patients undergoing continuous ambulatory peritoneal dialysis. Instillation of autologous hemoglobin as a marker permitted calculation of the cavity volume and, hence, the rate of transfer to and from the peritoneal cavity with time. The patients were divided into 4 groups. Groups 1 and 2 were intravenously given cefotiam (5 patients) and cefsulodin (4 patients), respectively. Groups 3 and 4 (5 patients each) were given cefsulodin intraperitoneally. Group 3 did not have peritonitis, while the patients in Group 4 were studied during peritonitis. Blood and dialysate samples were obtained at selected times during the 5-hour dwell and, for plasma, until 24 hours after drug administration. Pharmacokinetic analysis of the data showed that only 6.0 and 8.7% of the intravenous doses of cefotiam and cefsulodin, respectively, were recovered in the dialysate at the end of the dwell. The net amounts of cefsulodin lost from the dialysate after intraperitoneal administration were 81 and 84%, in Groups 3 and 4 respectively. The peritoneal transfer clearances (using a unidirectional clearance model), calculated after intravenous (17 +/- 10 ml/min, Group 2) and intraperitoneal (17 +/- 5 ml/min, Group 3) administrations were the same. Mass balance of cefsulodin in the body and in the dialysate after intraperitoneal administration indicated that a significant amount (40%, Group 3) of the dose is unaccounted for. One explanation for this imbalance is retention of the drug in the peritoneal lining. This hypothesis is supported by the retention being lower in the peritonitis patients (less than 20%, Group 4), for whom the linings are expected to be partially eroded.

Fourteen neonates and premature infants with ages ranging 1 to 28 days were intravenously given one shot injection of 20 mg/kg of cefsulodin (CFS). Plasma and urine levels and recovery rates of CFS were determined in the first 6 hours after administration. For prophylaxis of infection, a daily average dose of 52.8 mg/kg of CFS was injected intravenously to 3 neonates with ages ranging 2 to 16 days in 2 to 3 divided doses during an average period of 7 days. Along with observations of prophylactic effects on infection, side effects and abnormalities in laboratory test values were examined. The results obtained are summarized below: 1. Of the 9 patients with birth weight of 2,500 g or above, the plasma levels peaked in 6 patients at 5 minutes, in 2 patients at 15 minutes and in the other at 1 hour after administration, with peak levels ranging between 35.8 and 60.6 micrograms/ml. Subsequently, gradual decreases or bimodal tapering changes were noted in the plasma levels. The cause of the delay in the occurrence of maximum peak observed in the 3 patients at 15 minutes or 1 hour after administration and the cause of the appearance of bimodal tapering changes in 3 subjects are not known. A tendency was observed that the younger the age of subject was, the larger the AUC and the longer the half-life became. Half-lives in all 9 neonates were longer than those in average infants who were given intravenous injection at the same dose. 2. Of 5 patients with birth weight of less than 2,500 g, the determination of peak plasma levels was not performed in those within 7 days after birth. Plasma levels, however, were observed to reach their peaks in 4 patients at 5 minutes and in another at 15 minutes after administration, the levels ranging between 41.5 and 56.0 micrograms/ml. Subsequently to this, gradual decreases and bimodal tapering changes of plasma levels were noted. The cause of the delay in plasma levels to reach their maximum peaks values in the 1 patient to 15 minutes after administration and the cause of occurrence of bimodal tapering changes in the 2 patients are not known. A tendency was observed that the younger the age of subjects was, the larger the AUC and the longer the half-life became. This tendency was similar to that observed in the group with birth weight of 2,500 g or above.(ABSTRACT TRUNCATED AT 400 WORDS)

Pharmacokinetic studies on cefsulodin (CFS) were carried out in perinatal mothers and infants. The results obtained are summarized as follows. 1. CFS was promptly absorbed upon intravenous drip infusion in pregnant women, producing dose-related peak serum levels. Placental transference to the fetus occurred quickly and at high levels. Upon intravenous drip infusion of 1-2 g of CFS, drug concentration of the cord blood and amniotic fluid exceeded MICs of clinically isolated strains of Pseudomonas aeruginosa. These levels in cord blood ranged 3.3-16.9 micrograms/ml upon 1 g intravenous drip infusion and 0.8-21.6 micrograms/ml upon 2 g intravenous drip infusion, and in amniotic fluid they were 1.3-15.6 micrograms/ml upon 1 g administration and 5.5-17.9 micrograms/ml upon 2 g administration. The drug was transferred into newborn infant through placenta, showing no tendency to accumulate. According to the above results, it appears possible to successfully prevent or treat perinatal infections through administration of the dose of 1-2 g twice daily. 2. Moreover, newborn infants delivered from mothers receiving CFS administration showed no laboratory test abnormalities. 3. The penetration of CFS into mother's milk occurred at low levels, and the transference from milk to newborn infants appeared to occur at even low levels. The above results have demonstrated that CFS is a clinically useful antibiotic for prophylaxis and treatment of perinatal Pseudomonas infections.

Seventeen patients with various grades of kidney function were injected each with cefsulodin (CFS) 1 g dissolved in 20 ml of saline. Serum and urine concentrations of CFS were determined using high performance liquid chromatography up to 24 hours after administration. Pharmacokinetic analysis was done using a two-compartment model. The results were discussed by comparing creatinine clearance (Ccr) values divided into 4 groups: greater than or equal to 70 ml/min (group I), 50-less than 70 ml/min (group II), 30-less than 50 ml/min (group III), and less than 30 ml/min (group IV). A delay in the disappearance of CFS from the blood was observed with a decrease in Ccr. Half-lives of CFS in blood (T 1/2 beta) were 1.03 hours (group I), 2.09 hours (group II), 3.44 hours (group III), and 4.52 hours (group IV). Serum clearance (Cls) and Ccr were found to be related with an equation: Cls = 1.60 x Ccr + 7.70. The correlation coefficient (r) was 0.881. Ccr and T 1/2 beta were found to be related with an equation: T 1/2 beta = 31.27 x Ccr-0.688, and the area under the curve (AUC) was found to be related to Ccr with AUC = 4,226 x Ccr-0.81. Urinary excretion rates up to 24 hours after administration were 84.4% (group I), 69.1% (group II), 67.5% (group III), and 56.5% (group IV). This means that CFS is excreted in urine with a relatively high recovery even in the case of low Ccr less than 30 ml/min.

Four neonates and young infants were treated with cefsulodin (CFS) at doses ranging from 20-25 mg/kg every 6 hours for 6.25 to 17 days, and clinical efficacy and side effects were evaluated. Among the 4 infants with bacterial infections including meningitis, bronchitis and pneumonia, the results were good in 2 patients with meningitis, but unknown in 2 patients because of additional use of gentamicin. One of the 4 patients had eosinophilia. Minimal inhibitory concentrations of CFS against 4 isolates of Pseudomonas aeruginosa were 1.56 against one and 12.5 micrograms/ml against other 3 strains with an inoculum size of 10(3) CFU. Serum concentrations of CFS were measured in one- and four-month-old infants upon 25.3 and 20.9 mg/kg bolus intravenous injection of the antibiotic, respectively. The values were 36.4 and 33.4 at 30 minutes, and 5.1 and 3.2 micrograms/ml at 6 hours after injection, respectively. Serum half-lives were 1.89 and 1.69 hours, respectively. Total body clearances and volume distributions were 3.16 and 3.76 ml/min/kg, and 519.0 and 551.2 ml/kg, respectively.

The efficacy of cefsulodin against infections caused by Pseudomonas aeruginosa was investigated first in an open trial and then in a controlled comparative study in which ticarcillin was used. The first trial consisted of 16 patients with proven Pseudomonas aeruginosa infections, 9 of whom also received an aminoglycoside. In the second trial 28 such patients were evaluated (14 on cefsulodin 1 g 4 times daily and 14 on ticarcillin 5 g 4 times daily); all patients also received an aminoglycoside. The results of the two trials were similar in that 75% of the patients of the first trial and 86% of the second group exhibited an excellent or good response to cefsulodin. For the ticarcillin group a similar response was noted. In the first trial the sensitivity of P. aeruginosa did not change markedly, whereas one strain of the cefsulodin group became resistant in the second trial. Pharmacokinetic data were in agreement with those reported in the literature. Side effects were rare.

The rat granuloma pouch model was used to study the penetration of imipenem into inflammatory exudate and its efficacy in an experimental local infection. Rats were given a single intravenous injection of drug via the tail vein at a dose of 40 mg/kg. The peak concentrations of imipenem, ceftizoxime, cefazolin, and cefsulodin in exudates ranged from 10.1 to 12.3 mg/l, except that ampicillin achieved only 5.4 mg/l. Imipenem rapidly reached peak concentration after injection, but the half life for elimination of imipenem from exudate was 77.7 min, which was shorter than that of other beta-lactam antibiotics. Imipenem exhibited more rapid reduction in bacterial growth than cefsulodin in an experimental local infection with Pseudomonas aeruginosa in the pouch model. The results suggested that imipenem was an effective agent in treating the local infection.

A pair of strains of Pseudomonas aeruginosa (3-Pre: cefsulodin-sensitive, inducible beta-lactamase; and 3-Post: cefsulodin-resistant, elevated beta-lactamase, derived from 3-Pre by subculture in the presence of cefsulodin) were taken as representative of the class of bacteria resistant to third-generation cephalosporins due to elevated synthesis of the normally inducible, chromosomally encoded beta-lactamase. These two strains were used to differentiate between 'trapping' and 'hydrolytic' mechanisms of cefsulodin resistance by (a) measuring the outer-membrane permeabilities to cefsulodin, (b) measuring the kinetics of cefsulodin hydrolysis and the stoichiometry of cefsulodin trapping by the periplasmic beta-lactamase, and (c) comparing the predictions of the trapping and hydrolysis hypotheses with the minimum inhibitory concentrations (MIC) of cefsulodin. The MIC of cefsulodin for strains 3-Pre and 3-Post were 2.35 microM (1.25 micrograms ml-1) and 37.6 microM (20.0 micrograms ml-1) respectively. The permeability parameter for cefsulodin of the outer membrane of the resistant strain was 0.0034 cm3 min-1 mg dry mass-1, so the flux of cefsulodin across its outer membrane at the MIC was calculated to be 0.120 nmol min-1 mg dry mass-1. Hydrolysis of cefsulodin by the beta-lactamase in the periplasm occurred at a rate of 0.118 nmol min-1 mg dry mass-1 which can thus account for resistance by matching the above rate of inflow. Trapping by the beta-lactamase, even with a 1:1 stoichiometry, would require the enzyme to be synthesized at 5.0 micrograms protein min-1 mg dry mass-1 or about 40% of the dry mass/generation. We conclude that hydrolysis, but not trapping, adequately explains the resistance to cefsulodin in P. aeruginosa 3-Post. A similar calculation for latamoxef resistance, using data taken from the literature, led to the same conclusion.