Penetration and exposure of cefotiam into the peritoneal fluid of abdominal surgery patients after intravenous administration.

The present study aimed to examine the peritoneal pharmacokinetics and pharmacodynamic exposure of intravenous cefotiam. One gram of cefotiam was administered to eight patients before abdominal surgery. Venous blood and peritoneal fluid (PF) samples were obtained at the end of infusion (0.5 h) and 1, 2, 3, 4, 5, and 6 h afterwards. The drug concentrations in the plasma and PF were determined, analyzed pharmacokinetically, and used for a stochastic simulation with minimum inhibitory concentration (MIC) data. Cefotiam penetrated well into the PF with the area under the drug concentration-time curve ratio of 0.88 +/- 0.18 (mean +/- SD, n = 8). Regarding the pharmacodynamic exposures against Escherichia coli and Klebsiella species, the probabilities of attaining the bacteriostatic target (40% of the time above MIC) in the PF using 0.5 g every 12 h, 1 g every 12 h, and 2 g every 12 h were 88.3-93.6%. However, 1 g every 8 h was needed for 89.7 and 91.6% probabilities of attaining the bactericidal target (70% of the time above MIC). These results should help us to understand better the peritoneal pharmacokinetics of cefotiam while also helping us to choose the appropriate dosage for intra-abdominal infections.

Development of breakpoints of cephems for intraabdominal infections based on pharmacokinetics and pharmacodynamics in the peritoneal fluid of patients.

We developed breakpoints for cephem antibacterial agents for intraabdominal infections based on pharmacokinetics (PK) and pharmacodynamics (PD) at the target site. Cefepime (CFPM), cefotiam (CTM), cefozopran (CZOP), and flomoxef (FMOX) were each administered to 8-10 patients before abdominal surgery, and venous blood and peritoneal fluid (PF) samples were obtained. The drug concentrations in plasma and PF were determined and analyzed using population pharmacokinetic modeling. Using the pharmacokinetic model parameters, a Monte Carlo simulation was conducted to estimate the probabilities of attaining the bacteriostatic and bactericidal targets (40% and 70% of the time above the minimum inhibitory concentration (T > MIC), respectively) in PF. The bacteriostatic and bactericidal breakpoints were determined as the highest MIC values at which the bacteriostatic and bactericidal probabilities in PF were > or =80%, which values varied with drug and dosing regimen. Site-specific PK-PD-based breakpoints for CFPM, CTM, CZOP, and FMOX are proposed, and should help us to select appropriate cephems and design their dosing regimens for intraabdominal infections.

Adaptive responses of renal organic anion transporter 3 (OAT3) during cholestasis.

During cholestasis, bile acids are mainly excreted into the urine, but adaptive renal responses to cholestasis, especially molecular mechanisms for renal secretion of bile acids, have not been well understood. Organic anion transporters (OAT1 and OAT3) are responsible for membrane transport of anionic compounds at the renal basolateral membranes. In the present study, we investigated the pathophysiological roles of OAT1 and OAT3 in terms of renal handling of bile acids. The Eisai hyperbilirubinemic rats (EHBR), mutant rats without multidrug resistance-associated protein 2, showed higher serum and urinary concentrations of bile acids, compared with Sprague-Dawley (SD) rats (wild type). The protein expression level of rat OAT3 was significantly increased in EHBR compared with SD rats, whereas the expression of rat OAT1 was unchanged. The transport activities of rat and human OAT3, but not OAT1, were markedly inhibited by various bile acids such as chenodeoxycholic acid and cholic acid. Cholic acid, glycocholic acid, and taurocholic acid, which mainly increased during cholestasis, are transported by OAT3. The plasma concentration of beta-lactam antibiotic cefotiam, a specific substrate for OAT3, was more increased in EHBR than in SD rats despite upregulation of OAT3 protein. This may be due to the competitive inhibition of cefotiam transport by bile acids via OAT3. In conclusion, the present study clearly demonstrated that OAT3 is responsible for renal secretion of bile acids during cholestasis and that the pharmacokinetic profile of OAT3 substrates may be affected by cholestasis.

Quantitative prediction of oral absorption of PEPT1 substrates based on in vitro uptake into Caco-2 cells.

The method for predicting the fraction absorbed (Fa) of the PEPT1 substrates was established based on the in vitro uptake into Caco-2 cells. Uptake of a drug into Caco-2 cells was measured, and the carrier-mediated initial uptake clearance (DeltaCL uptake) was calculated as the difference between the uptake clearance in the absence of glycyl-sarcosine (Gly-Sar) and that in the presence of 30 mM Gly-Sar. The DeltaCL uptake of each drug was then divided by that of cephradine to obtain DeltaCL*uptake, which was a normalized parameter to correct for inter-day and/or inter-cell variability. Then, cephradine (CED), cefixime (CFIX), and cefotiam (CTM) were selected as marker compounds having excellent, medium and poor absorption, respectively. The DeltaCL*uptake and Fa values for CED, CFIX and CTM were fitted to the equation derived from the complete radial mixing (CRM) model, and the scaling factor (A') was obtained. Using the A' value, Fa was predicted from the DeltaCL*uptake value of each drug. Good correlation was observed between the predicted and reported Fa values, which demonstrated that Fa of PEPT1 substrates can be predicted based on the in vitro uptake in Caco-2 cells.

[Intraocular penetration of cefotiam hydrochloride, a kind of cephalosporin after filtration surgery in rabbit eyes].

PURPOSE: In this study, we measured the cefotiam dihydrochloride (CTM) concentration in ocular tissue after filtration surgery in rabbit eyes. METHODS: CTM (20 mg/kg body weight) was administered intravenously 30 min before filtration surgery which was performed by double flap procedure on the right eyes of white rabbits. The aqueous humor and serum were extracted at 10 min after surgery and at 30 min, 60 min, and 120 min. Drug concentration in all of the specimens was measured by high performance liquid chromatography (HP-LC). RESULT: The CTM concentrations of aqueous humor in the nonoperated eyes were 0.44 +/- 0.16(mean +/- standard deviation) microg/ml (n = 4) (40 min after intravenous dosage), 0.36 +/- 0.17microg/ml (n = 4) (60 min after intravenous dosage), 0.38 +/- 0.34, microg/ml(n = 3) (90min after intravenous dosage) and 0.27 +/- 0.10 microg/ml (n = 5) (150 min after intravenous dosage). In contrast, CTM concentration in the aqueous humor of the operated eyes was 2.4 +/- 0.95 microg/ml (n = 4) at 10 min after surgery (40 min after intravenous dosage), 2.11 +/- 1.10 microg/ml (n = 4) at 30 min after surgery (60 min after intravenous dosage), 1.18 +/- 0.78 microg/ml (n = 4) at 60 min after surgery (90 min after intravenous dosage) and 0.47 +/- 0.1 microg/ml (n = 5) at 120 min after surgery (150 min after intravenous dosage). The intraocular penetration of CTM at 10 min and at 120 min after filtration surgery was significantly higher in comparison with the drug concentration in the nonoperated eyes (p < 0.05). CONCLUSION: The intraocular penetration of CTM after filtration surgery was much higher in comparison with the drug concentration in the nonoperated eyes. These results may be useful to predict the intraocular penetration of CTM in human eyes after filtration surgery.

Inhibitory effect of zinc on PEPT1-mediated transport of glycylsarcosine and beta-lactam antibiotics in human intestinal cell line Caco-2.

PURPOSE: The aim of this study was to examine the effects of zinc on the intestinal peptide transporters (PEPT1 and basolateral peptide transporter) and to elucidate the mechanism of the interactions. METHODS: Caco-2 cells were pretreated with zinc, and the uptake studies were carried out. RESULTS: Zinc treatment resulted in the inhibition of [14C]glycylsarcosine (Gly-Sar) uptake via PEPT1 in a concentration-dependent manner, whereas it showed moderate inhibitory effect on the basolateral peptide transporter. Zinc also inhibited the uptake of oral beta-lactam antibiotics such as ceftibuten and cephradine by PEPT1. Kinetic analysis showed that zinc treatment increased Km values without affecting Vmax values of the [14C]Gly-Sar uptake. The inhibition of [14C]Gly-Sar uptake induced by zinc was observed in the presence of an H+ gradient but not in the absence of an H+ gradient. CONCLUSIONS: These results indicate that zinc is a competitive inhibitor of PEPT1. Zinc inhibited the PEPT1 function, possibly by interacting with histidine residues of PEPT1 that are part of an H+-binding site. These findings would provide important information for clinical, physiologic, and biochemical aspects of peptide transporters.

Suitability of cefotiam and cefuroxime axetil for the perioperative short-term prophylaxis in tonsillectomy patients.

The efficacy of the perioperative short-term prophylaxis with cefotiam (CAS 66309-69-1) and cefuroxime axetil (CAS 64544-07-6) was analysed by the assessment of the pharmacological kinetics in the serum and the tonsil tissue in 50 patients with recurrent tonsillitis. Twenty-four patients received 1 g cefotiam by the intravenous route 30 min to 4 h before the tonsillectomy, and 26 patients received 250 mg cefuroxime axetil orally 1 to 6 h before the tonsillectomy. Bactericidal serum levels were reached for cefotiam up to 4 h after intravenous application and for cefuroxime axetil up to 3 h after oral application. In the tissue of the tonsil there were proved levels which were definitely above the MIC 90 (MIC = minimum inhibitory concentration) known for the clinically relevant germs for cefotiam after 30 min up to 2 h, for cefuroxime axetil after only 2 h. Considering the distribution areas, the capacity of the protein binding and the microbiological measuring methods, one can expect an efficient antibiotic coverage after an intravenous one-shot bolus injection of 1 g cefotiam from 30 min to 4 h and after oral application of 250 mg cefuroxime axetil on an empty stomach from 1 to 6 h. Because of the short duration of a tonsillectomy and the serum and tonsil tissue kinetics cefotiam and cefuroxime axetil are suitable for the perioperative antibiotic prophylaxis of high-risk patients.

Pharmacokinetics of antibiotic prophylaxis in major orthopedic surgery and blood-saving techniques.

The pharmacokinetics of cefuroxime, cefotiam, cefamandole, and ampicillin/sulbactam were randomly measured in 40 patients undergoing major orthopedic surgery associated with high blood and volume turnover and intraoperative blood salvage. Serum and bone concentrations and the pharmacokinetics occurring in the context of these procedures were measured. No changes in elimination half-life relative to a normal population occurred with cefuroxime, cefotiam, and ampicillin. Serum and tissue concentrations were slightly lower with cefamandole and sulbactam, but reapplication of the initial dose was required with all antibiotics 4 hours after the first application.

Effect of side chains including the N-methyl-tetrazole-thiol group of beta-lactam antibiotics on transport in cultured kidney epithelial cells LLC-PK1.

In this study, the transcellular transport characteristics of four beta-lactam antibiotics (cefotaxime, cefmenoxime, cefmetazole, and cefotiam) were investigated in a kidney epithelial cell line LLC-PK1, especially focusing on the effect of the N-methyl-tetrazole-thiol (NMTT) group attached to 7-amino-cephalosporanic acid. There were no directional differences between the apical-to-basolateral and basolateral-to-apical transport of cefotaxime, cefmenoxime, and cefmetazole, suggesting that the NMTT group does not influence the transcellular transport behaviors of beta-lactam antibiotics. In contrast, cefotiam transport across LLC-PK1 cell monolayers was 1.3-fold greater in the basolateral-to-apical direction than in the apical-to-basolateral direction. It is considered that the ionization of nitrogen in the N-dimethylaminoethyl group attached to NMTT is a factor in the secretory-oriented movement of cefotiam. The transcellular transport of cefotiam in both directions was significantly depressed at a low temperature (4 degrees C) and by 2,4-dinitrophenol. The basolateral-to-apical transport of cefotiam was also shown to be concentration-dependent. These results suggest that a specialized transport process might participate in the transcellular transport of cefotiam. The lipophilicities of these beta-lactam antibiotics were not correlated to the degree of transcellular transport, directly.

Antibacterial activity of peritoneal exudate in patients treated with 2 g cefotiam for surgical anti-microbial prophylaxis.

The objective of this study was to investigate the presence of antibacterial activity in peritoneal exudate (PE) of patients treated with cefotiam (CFT). CFT (2 g) was administered as a 'single-shot' antimicrobial prophylaxis to 6 patients at the beginning of colorectal resection. Samples of PE were collected from each patient on days 1, 2 and 3 after surgery. CFT was detectable in the samples of day 1 for 5 of the 6 patients. The influence of PE on antibacterial activity of the antimicrobial drug was evaluated carrying out the MICs of CFT against Escherichia coli K-12, E. coli (ATCC 10798), Klebsiella pneumoniae (ATCC 1003), Proteus rettgeri (Sanelli) and Staphylococcus aureus (ATCC 29213) with and without the addition of PE. The presence of PE enhanced the antimicrobial activity of CFT against gram-negative strains, but not against S. aureus (ATCC 29213). These results suggest the presence of substances in PE that possess endogenous antibacterial activity. Thus, antimicrobial activity in PE cannot be predicted by evaluating pathogen sensitivity in vitro only.

Pharmacokinetics of ampicillin, sulbactam and cefotiam in patients undergoing orthopedic surgery.

As perioperative prophylaxis for major orthopedic operations 81 patients were given the fixed combination of ampicillin (1 g)/sulbactam (0.5 g) or cefotiam (2 g) as short infusions. The three beta-lactams were rapidly distributed into the different tissues and their pharmacokinetic profiles were found to be very similar. It was noteworthy that ampicillin, sulbactam and cefotiam penetrated within minutes, not only into skin, fat and muscles, but also into bone. Thus 0.25 h after starting the infusion the following mean concentrations were measured in bone: 21.8 +/- 10.5 mg/kg ampicillin, 4.9 +/- 2.2 mg/kg sulbactam and 19.4 +/- 10.6 mg/kg cefotiam. For a period of at least 2 h the concentrations measured in serum and in the different tissues affected by the operation (skin, fat, muscle, bone) were above the MICs for pathogens which are involved in postoperative wound infections. On the basis of pharmacokinetic data, ampicillin/sulbactam and cefotiam seem about equally suitable for perioperative prophylaxis in major orthopedic operations.

Low-dose, single-shot perioperative antibiotic prophylaxis in colorectal surgery.

Reductions of frequency of administration and dosage of antibiotic agents used in colorectal surgery may lower costs and the occurrence of adverse side effects. In a prospective randomized trial we evaluated two single-short regimens, a low dose of 1 g cefotiam against a standard dose of 2 g cefotiam, both in combination with 500 mg metronidazole. The low-dose group had twice the number of patients with wound sepsis (4 of 30) than the group receiving the standard antibiotic regimen (2 of 30). Two hours after infusion, the antibiotic concentrations in samples of serum, subcutaneous fatty tissue, and colonic wall of those patients receiving 1 g cefotiam were < 1 mg/l. The concentrations after administration of 2 g cefotiam were higher, as expected, and without any adverse side effects. In conclusion, we prefer infection prophylaxis by the standard dose of 2 g cefotiam plus 500 mg metronidazole in colorectal surgery.

Concentration of cephalosporins in tissues of the head and neck after parenteral infusion.

Cephalosporins are successfully used in the therapy of acute sinusitis, purulent parotitis, and lymphadenitis. Anti-infectious prophylaxis in major head and neck surgery may be performed with cephalosporins as first choice. For sufficient prophylaxis or therapy, an effective level of the antibiotic drug in the serum and tissue of the target organs is necessary. In a comparative investigation, we measured serum and tissue levels of three regions of the head and neck (parotid glands, paranasal sinuses, soft tissue of the neck) of the second-generation cephalosporins, cefuroxime and cefotiam, after a single parenteral infusion. Both antibiotics reach levels which are effective against bacteria typically causing spontaneous or postoperative infection of head and neck tissue. Effective levels of cefuroxime both at the investigated tissue sites and in serum are greater than those of cefotiam, and cefuroxime is eliminated from serum less rapidly. The pharmacologic data show that both drugs are suitable for therapy and perioperative prophylaxis of purulent head and neck infections, but various data indicate that there is an advantage in favor of cefuroxime.

[Transperitoneal resorption of cefotiam in CAPD patients with and without peritonitis]. / Transperitoneale Resorption von Cefotiam bei CAPD-Patienten mit und ohne Peritonitis.

BACKGROUND: Cephalosporins of the second generation have been repeatedly recommended for the treatment of peritonitis associated with continuous ambulatory peritoneal dialysis (CAPD), because they are effective against most of the clinically relevant bacteria. In this study, we tested cefotiam, a member of this group of antibiotics, for its suitability in this indication, and determined the intraperitoneal dosage needed to achieve effective serum levels. PATIENTS AND METHODS: IN 10 CAPD-patients with and 10 without peritonitis, cefotiam was added to the dialysis bags (2 l) over a period of seven days. Prior to initiating antibiotic treatment, a sample of dialysis fluid was submitted to bacteriological and cytological examination. During the treatment period, the bags were changed four times a day. In the first three patients 0.5 g cefotiam/bag was administered. Two to four days after initiating treatment, these patients developed nausea and occasional vomiting. Thereupon, all the other patients were given a dose of 0.5 cefotiam/bag only on the first day--a loading dose--followed by 0.25 g/bag for the next six days. Samples of blood and dialysate were obtained after 24, 48, 72, 96, 120, 144 and 168 hours. The cefotiam concentration was determined by the agar diffusion technique. Side effects were checked by clinical observation and measurement of GOT, GOP, alkaline phosphatase, gamma GT, Na, K, and creatinine together with a blood count at the beginning and end of the trial. RESULTS: Among the peritonitis patients, Staphylococcus epidermidis and Staphylococcus pyogenes aureus were each found in four, and Pseudomonas aeruginosa in two patients. In all patients effective serum levels were reached after one day of treatment. In the following period, these levels were maintained. Serum concentrations were higher in patients with than in those without peritonitis (18 to 21 micrograms/ml and 11 to 16 micrograms/ml, respectively). The first three patients had toxic cefotiam levels of about 30 micrograms/ml. All the cases of staphylococcus-induced peritonitis were cured with this therapeutic regimen, while those with Pseudomonas aeruginosa peritonitis required additional treatment with tobramycin. Neither clinical nor chemical side effects were observed. CONCLUSION: Using the regimen described, cefotiam is an effective and safe first-line antibiotic for the treatment of CAPD-related peritonitis.

Synergic activity of imipenem/cilastatin combined with cefotiam against methicillin-resistant Staphylococcus aureus.

The synergic activity of imipenem/cilastatin combined with cefotiam was studied in a mouse bacteraemia model. Combinations of imipenem plus cefotiam in ratios from 1:5 to 1:160 were more effective than either imipenem alone or cefotiam alone (P < 0.05). Synergy was observed against both beta-lactamase producing and beta-lactamase non-producing MRSA. Staggered combinations of imipenem with cefotiam (each drug was administered at a different time) were studied in an in-vitro pharmacokinetic system to clarify relationships between killing kinetics and pharmacodynamics of the combinations. In the in-vitro system, cefotiam (1 g over 30 min) administered 2 h after imipenem administration (250 mg over 30 min) reduced viable cell counts to an undetectable level and maintained this for 4 h, while the simultaneous administration of imipenem and cefotiam maintained an undetectable cell count for only 2 h. Furthermore, imipenem administered after cefotiam showed no synergy. These results indicate that the timing of dosing of each antibiotic influences synergy, and administration of cefotiam 2 h after imipenem is more effective than the other regimens.

Cefotiam concentrations in the sinus fluid of patients with chronic sinusitis after administration of cefotiam hexetil.

Cefotiam hexetil is a prodrug of cefotiam. The concentrations of cefotiam in plasma and sinus secretions were determined in 18 patients (10 males, 8 females, aged 39.3 +/- 13.0 years) with chronic sinusitis. All patients received two 200 mg oral doses of cefotiam hexetil 12 h apart and were divided into four groups according to the time which elapsed between the last dose and collection of secretion samples. The last dose was given 2 h (group I), 3 h (group II), 4 h (group III) or 6 h (group IV) before sinus puncture. Cefotiam concentrations were measured by high-pressure liquid chromatography and microbiological assay, results being very similar with both methods. Mean concentrations of cefotiam with the standard deviation in sinus exudates were 1.04 +/- 0.60 mg/l at 2 h (n = 6), 1.04 +/- 0.33 mg/l at 3 h (n = 4), 0.75 +/- 0.74 mg/l at 4 h (n = 4) and < 0.10 mg/l at 6 h (n = 4). Mean sinus fluid concentrations were higher than mean plasma concentrations in all groups. These results suggest that cefotiam concentrations higher than the MICs for common pathogens are found in sinus secretions up to 4 h after oral administration of cefotiam hexetil.

[Antimicrobial activity of cefetamet against fresh clinical isolates of Branhamella catarrhalis].

Against strains of Branhamella catarrhalis which were separated from various RTIs (respiratory tract infections) in 1991 antimicrobial activities (MICs) of cefetamet (CFMT) were determined, and the following conclusions were obtained. 1. The MIC80 of CFMT against B. catarrhalis was 0.39 microgram/ml, which was higher than that of cefixime (CFIX) by one dilution or twofold, but was lower than that of cefpodoxime (CPDX) by two dilutions or fourfold and that of cefotiam (CTM) by three dilutions or eightfold. 2. The fact that all of the 50 strains tested were beta-lactamase producers appeared to indicate that CFMT was stable against BRO-1 and BRO-2 beta-lactamases produced by B. catarrhalis. 3. Blood concentrations of the test drug, CFMT, and control drugs upon normal single doses were calculated using pharmacokinetic parameters. Lengths of time periods during which drug concentrations stayed above their MICs against B. catarrhalis obtained in this study were determined for CFMT, CFIX, CPDX and CTM. They were, respectively, 12 hours, 12 hours, 6 hours, and 2 hours, thus CFMT appeared to remain above MIC for sufficiently long time for the treatment of RTIs which are affected by B. catarrhalis directly or indirectly.