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We determine the association constants for ligand-protein complex formation using the flow injection method. We carry out the measurements at high flow rates (F=1 mL min(-1)) of a carrier phase. Therefore, determination of the association constant takes only a few minutes. Injection of 1 nM of the ligand (10 μL of 1 μM concentration of the ligand solution) is sufficient for a single measurement. This method is tested and verified for a number of complexes of selected drugs (cefaclor, etodolac, sulindac) with albumin (BSA). We obtain K=4.45×10(3) M(-1) for cefaclor, K=1.00×10(5) M(-1) for etodolac and K=1.03×10(5) M(-1) for sulindac in agreement with the literature data. We also determine the association constants of 20 newly synthesized 3β- and 3α-aminotropane derivatives with potential antipsychotic activity--ligands of 5-HT1A, 5-HT2A and D2 receptors with the albumin. Results of the studies reported here indicate that potential antipsychotic drugs bind weakly to the transporter protein (BSA) with K≈10(2)-10(3) M(-1). Our method allows measuring K in a wide range of values (10(2)-10(9) M(-1)). This range depends only on the solubility of the ligand and sensitivity of the detector., (Copyright © 2014 Elsevier B.V. All rights reserved.)

α-Amino acid ester hydrolases (AEHs) are enzymes of interest to the semi-synthesis of β-lactam antibiotics with α-amino, such as cephalexin and cefaclor. An undesired side reaction, the hydrolysis of α-amino acid ester, had hindered applications in antibiotics synthesis. Although the enzymes' S/H ratio can be increased by protein engineering, such approaches require a suitable screening assay. Such a screening assay has not yet been described for AEHs. In this paper, we report a 96-well plate format screening procedure for AEHs based on two spectrophotometric assays. To reduce the hydrolysis reaction while maintaining synthesis activity, and to evaluate the effectiveness of the screening strategy, we introduced random mutations in part of the aeh gene from Xanthomonas rubrillineans by error-prone PCR. By a parallel plate-based screening strategy, three mutants with improved S/H ratio, R87L, T132N and N219I, were obtained., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Amoxicillin and cefaclor are two of the widely used beta-lactam antibiotics in the treatment of urinary tract infections. Both drugs are eliminated mainly by the kidney and rely on renal excretion to exert their antibacterial activities in the urinary tract. Previous studies have suggested the involvement of organic anion and oligopeptide transporters in membrane transport of beta-lactams. The objective of the current study was to examine the kinetics of amoxicillin and cefaclor interactions with human renal transporters human organic anion transporter 1 (hOAT1), human peptide transporter 1 (hPepT1), and human peptide transporter 2 (hPepT2) in detail, both as substrates and as inhibitors. Using fluorescence protein tagging and cell sorting, we established Madin-Darby canine kidney cell lines stably expressing highly functional hOAT1, hPepT1, and hPepT2. Amoxicillin and cefaclor inhibited hOAT1-mediated [(3)H]para-aminohippuric acid uptake (K(i) = 11.0 and 1.15 mM, respectively). However, our uptake study revealed that neither drug was transported by hOAT1. Amoxicillin and cefaclor competitively inhibited hPepT2-mediated [(3)H]glycylsarcosine uptake (K(i) = 733 and 65 muM, respectively), whereas much lower affinity for hPepT1 was observed with both antibiotics. Direct uptake studies demonstrated that amoxicillin and cefaclor were transported by hPepT1 and hPepT2. Kinetic analysis showed that hPepT2-mediated uptake of both drugs was saturable with K(m) of 1.04 mM for amoxicillin and 70.2 muM for cefaclor. hPepT2, and to a lesser extent hPepT1, may play an important role in apical transport of amoxicillin and cefaclor in the renal tubule. hOAT1, in contrast, is not involved in basolateral uptake of these antibiotics.

Stopped-flow tryptophan fluorescence under single turnover and pseudo-first-order conditions has been used to investigate the kinetic mechanism of beta-lactam hydrolysis by the Stenotrophomonas maltophilia L1 metallo-beta-lactamase. For the cephalosporin substrates nitrocefin and cefaclor and the carbapenem meropenem, a substantial quench of fluorescence is observed on association of substrate with enzyme. We have assigned this to a rearrangement event subsequent to formation of an initial collision complex. For the colorimetric compound nitrocefin, decay of this dark inter- mediate represents the overall rate-determining step for the reaction and is equivalent to decay of a previously observed state in which the beta-lactam amide bond has already been cleaved. For both cefaclor and meropenem, the rate-determining step for hydrolysis is loss of a second, less quenched state, in which, however, the beta-lactam amide bond remains intact. We suggest, therefore, that the mechanism of hydrolysis of nitrocefin by binuclear metallo-beta-lactamases may be atypical and that cleavage of the beta-lactam amide bond is the rate-determining step for breakdown of the majority of beta-lactam substrates by the L1 enzyme.

Cefaclor is not reducible at a mercury electrode, but it can be determined polarographically and by cathodic stripping voltammetry as its initial alkaline degradation product which is obtained in high yield by hydrolysis of cefaclor in Britton-Robinson (B-R) buffer pH 10 at 50 degrees C for 30 min (reduction peak at pH 10, -0.70 V). Differential pulse polarographic calibration graphs are linear up to at least 1 x 10(-4) mol/l(-1). Recoveries of 93% of the cefaclor (n = 3) were obtained from urine spiked with 38.6 microg/ml(-1) using this polarographic method with 1 ml urine made up to 10 ml with pH 10 buffer. Using cathodic stripping voltammetry and accumulating at a hanging mercury drop electrode at - 0.2 V for 30 s, linear calibration graphs were obtained from 0.35 to 40 microg/ml(-1) cefaclor in B-R buffer pH 10. A relative standard deviation of 4.2% (eta = 5) was obtained, and the limit of detection was calculated to be 2.9 ng/ml(-1). Direct determination of cefaclor in human urine (1 ml of urine was made up to 10 ml with pH 10 buffer) spiked to 0.39 microg/ml(-1) was made (recovery 98.6%).

Cefaclor is a well-absorbed oral cephalosporin antibiotic. Peak concentrations in serum are attained within 30-60 minutes. Food intake reduces the rate, but not the extent of absorption. Cefaclor is not metabolized to a significant degree, but it degrades chemically in the body with an approximate half-life of 2 hours. Most of the drug is excreted unchanged in the urine, the serum half-life after oral administration is 0.5-0.7 hours. Due to the chemical degradation, cefaclor does not accumulate to the same degree as other cephalosporins in case of renal impairment.

The human Caco-2 cell line spontaneously differentiates in culture to epithelial cells possessing intestinal enterocytic-like properties. These cells possess a proton-dependent dipeptide transport carrier that mediates the uptake of the cephalosporin antibiotic cephalexin (Dantzig, A.H. and Bergin, L. (1990) Biochim. Biophys. Acta 1027, 211-217). In the present study, the uptake of cefaclor was examined and found to be sodium-independent, proton-dependent, and energy-dependent. The initial rate of D-[3-phenyl-3H]cefaclor uptake was measured over a wide concentration range; uptake was mediated by a single saturable transport carrier with a Km of 7.6 mM and a Vmax of 7.6 nmol/min per mg protein and by a non-saturable component. Uptake was inhibited by dipeptides but not amino acids. The carrier showed a preference for the L-isomer. The effect of the presence of a 5-fold excess of other beta-lactam antibiotics was examined on the initial rates of 1 mM cefaclor and 1 mM cephalexin uptake. Uptake rates were inhibited by the orally absorbed antibiotics, cefadroxil, cefaclor, loracarbef, and cephradine and less so by the parenteral agents tested. The initial uptake rates of both D-[9-14C]cephalexin and D-[3-phenyl-3H]cefaclor were competitively inhibited by cephalexin, cefaclor, and loracarbef with Ki values of 9.2-13.2, 10.7-6.2, and 7.7-6.4 mM, respectively. Taken together, these data suggest that a single proton-dependent dipeptide transport carrier mediates the uptake of these orally absorbed antibiotics into Caco-2 cells, and provide further support for the use of Caco-2 cells as a cellular model for the study of the intestinal proton-dependent dipeptide transporter.

Cefaclor sustained its inhibitory activity against a beta-lactamase-producing strain of Haemophilus influenzae. Although a relatively high permeability coefficient was calculated for ampicillin compared with that calculated for cefaclor, the resulting periplasmic concentration of cefaclor was 5.7 times that of ampicillin. The efficacy of cefaclor may be due to its higher beta-lactamase resistance, which allows it to achieve a greater periplasmic concentration and adequate binding to crucial penicillin-binding proteins.

Penicillin-binding protein (PBP) 2 is the major PBP of five that have been identified in susceptible strains of Staphylococcus aureus. Beta-lactam antibiotic binding to PBP 2 is important for the antibacterial effect. Antibiotic binding to PBP 2 in strain 209P was examined with sodium dodecyl sulfate-polyacrylamide gel electrophoresis in competition assays using [3H]penicillin as the radiolabel. Clavulanic acid, which is specifically bound by PBP 2, and cefaclor, which is specific for PBP 3, were studied. Cefaclor, which alone appeared not to bind PBP 2, in combination inhibited PBP 2 binding of clavulanic acid. By varying the temperature during radiolabeling with [3H]penicillin in cefaclor competition assays and in direct radiolabeling assays with [3H]cefaclor, it was shown that cefaclor was bound by PBP 2 with high affinity (50% inhibitory concentration, less than or equal to 0.1 microgram/ml) and that the apparent low-affinity binding (50% inhibitory concentration, greater than 10 micrograms/ml) in competition assays performed at 37 degrees C was due to rapid deacylation. Two penicillin-binding peptides of PBP 2 also were identified in fluorographs of PBPs separated by nonequilibrium pH gradient gel and two-dimensional electrophoresis. Rapid deacylation for some antibiotics and the presence of two penicillin-binding peptides are two properties of PBP 2 that should be considered when correlating results of binding assays with effects of beta-lactam antibiotics on S. aureus.

Cefaclor is an oral cephalosporin antibiotic which has a broad antibacterial spectrum. The purpose of this study was to investigate the effect of food on the absorption of cefaclor and to analyze kinetically the absorption process of this drug. Cefaclor was given to eight volunteers at five test times: after overnight fasting, after two rice meals (350 and 700 cal [1 cal = 4.184 J]), and after two bread meals (500 and 1,000 cal). Urinary recoveries of cefaclor and concentrations of the drug in plasma were determined for each administration. Areas under the concentration-time curves and urinary recoveries were not affected by food intake, but the maximum concentration of drug in serum was reduced and the time to maximum concentration of drug in serum was prolonged depending on the type and the quantity of the meal. The larger the quantity of the meal, the more the maximum concentration of drug in serum and the time to maximum concentration of drug in serum were affected. The rice meals affected the absorption process of cefaclor more than the bread meals. The concentrations of cefaclor in plasma following administration after overnight fasting were well fitted to a conventional one-compartment model with a first-order absorption process, but those after the other administrations were not fitted to the model. For the pharmacokinetic analysis of those data, it was necessary to introduce a transfer process from administration site to absorption site to the conventional model. The concentrations in plasma after rice and bread meals were best fitted to the model with a zero-order transfer process than to that with a first-order process. The velocity of the transfer process depended on the type and volume of the meal.

A high-performance liquid chromatographic (HPLC) method is reported for the determination of a new carbacephem antibiotic, loracarbef, a hydroxylated analogue, and two cephalosporins, cefaclor and cephalexin, in plasma, serum, and urine. The antibiotics are extracted from plasma by means of C18 solid-phase cartridges. Urine samples are diluted with water and directly injected on the HPLC system. The HPLC system utilizes a Supelcosil LC-18-DB (250 mm x 4.6 mm I.D.) reversed-phase column and ultraviolet detection at 265 nm. The limit of quantitation is 0.5 micrograms/ml for each compound. Excellent correlation of plasma concentrations is shown between results determined by HPLC and those obtained by microbiological agar-well diffusion assays. Stability studies of loracarbef in human plasma show the antibiotic to be stable for at least 24 h at room temperature and for at least twelve months at -20 degrees C.

Concentration of cefaclor, a new oral cephalosporin, was measured in prostatic tissue of ten patients undergoing suprapubic prostatectomy. The average prostatic tissue concentrations were 0.51 +/- 0.22 microgram and 0.74 +/- 0.67 microgram per gram of tissue following the oral administration of 250-milligram and 500-milligram doses, respectively. The prostate/plasma ratios of cefaclor were approximately 0.7 indicating no evidence of accumulation of the drug in prostatic tissue. Levels of cefaclor achieved in human prostatic disease are equal to or less than the minimum inhibitory concentration of strains of known facultative bacterial pathogens associated with prostatitis.

Sixty-two patients with bronchopneumonia or bronchitis were treated with cefaclor. In 42 patients (= 68%), the therapy was clinically successful. Of the patients who did not respond to therapy, cefaclor-resistant bacteria were found in the sputum culture of seven. Of the remaining 13 patients, ten suffered a secondary infection with cefaclor-resistant bacteria, and in three patients the pathogen found before therapy persisted, although sensitive to cefaclor on testing. In seven patients therapy was clinically successful although cefaclor-resistant pathogens were present before the start of therapy. In the entire group of patients investigated no increase of SGOT, SGPT, alkaline phosphatase, bilirubin, urea or creatinine was observed. In two patients alkaline phosphatase and SGOT increased slightly; in three patients SGPT increased slightly. On the other hand, in several patients initially elevated SGOT, SGPT and alkaline phosphatase activity decreased during therapy. Clinical side-effects were seen in two patients. In one patient with known penicillin allergy a pruritic exanthema developed; in the other patient, who had dermatitis herpetiformis, exacerbation of skin efflorescences occurred.

Twelve normal volunteers in the fasting state were given 1000 mg cefaclor, and the serum and urine concentrations over 8 h and 24 h respectively were measured. The average peak serum concentration was 34.6 +/- 7.8 mg/l, this value being reached after 65.2 +/- 11.1 min; the half-life was 42.5 +/- 8.3 min. In another six volunteers the absorption of 500 mg of 'cefaclor following administration in the fasting state and after a test breakfast was studied. The peak serum concentrations after administration in the fasting state were 16.1 +/- 3.2 mg/l, and after a meal 12.5 +/- 1.9 mg/l; the areas under the curve did not differ. The low recovery rate of cefaclor in urine observed in this series of investigations could be partly explained by the inactivation of the substance in urine. Cefaclor was administered therapeutically to 23 patients, most of whom were suffering from bronchopulmonary infections and chronic pyelonephritis. The results of therapy were good in four patients, satisfactory in 13 patients and unsatisfactory in three patients. Intolerance was rare.

In a randomized crossover study, the pharmacokinetics of two new cephalosporin antibiotics, cefaclor (CCL), and cefadroxil (CDX), were determined after oral administration of 1000 mg (capsules) on an empty stomach in 12 normal subjects in comparison to cephalexin (CEX). Serum concentrations were measured during a period of 8 h and urine recovery during 24 h. The significant parameters of bioavailability of an orally administered substance were determined. The maximum serum concentrations (ymax) were 38.8 +/- 8.1 mg/l (CEX), 34.6 +/0 7.8 mg/l (CCL), 33.0 +/- 5.4 mg/l (CDX); the areas under the curve were 93.0 +/- 14.8 h . mg/l (CEX), 74.5 +/- 9.9 h . mg/l (CCL), and 108.5 +/- 18.4 h . mg/l (CDX). In a further crossover study with 6 subjects, 1000 mg CEX and CDX were given during a standard breakfast. The ymax of CEX decreased to 23.1 +/- 6.6 mg/l in contrast to CDX with an unchanged ymax of 32.7 +/- 3.4 mg/l.

Current (regular) preparation of cefaclor (CCL) require the 3-time-a-day administration. S6472 (sustained release preparation) which can be used with the twice-a-day administration in the morning and the evening is capsule and granule preparations consisting of 40% of nonenteric and 60% of enteric coated granules of CCL. Phase I clinical studies of S6472 were conducted in 12 nonfasted healthy adult male volunteers with cross over method using a single dose of 375 mg in capsule and granule forms of S6472, and 250 mg in capsule form of regular CCL as a control drug. The volunteers received the 3 preparations at 1-week interval. The summary of the results from the above studies is as follows: Grouping of the volunteers. The 12 volunteers were divided into 3 groups (each group consists of 4 volunteers) and there were no significant differences between each group regarding background factors of the volunteers. Tolerance. None of the volunteers who received the 3 preparations at 1-week interval complained of subjective abnormalities. No abnormalities which are considered to be due to S6472 and regular CCL were found in the clinical laboratory tests carried out before the administration and 1 week after the completion of the studies. Plasma level. There were no significant differences between capsule and granule forms of S6472 regarding Cmax and AUC, and it was confirmed that bioavailability of both preparations was the same. It was also confirmed that plasma levels of the 2 preparations of S6472 were maintained for longer period of time than those of regular CCL. Urinary excretion. Mean urine levels of the 2 preparations of S6472 every 2 hours after the administration were confirmed to be maintained for longer period of time than those of regular CCL. There were no significant differences between the 2 preparations of S6472 regarding urinary recovery rate. However, the significant differences between the 2 preparations of S6472 and regular CCL were observed. Urinary recovery rate of the 2 preparations of S6472 was 87 approximately 88% of that of regular CCL.

A novel 1-carbacephem, LY163892, was determined to be more stable to plasmid-mediated beta-lactamases than cefaclor. Chromosomal-mediated Type Ia and IVc enzymes destroyed LY163892 at rates ranging from 16 to 93% that of nitrocefin. LY163892 showed minimal ability to inhibit beta-lactamases other than Type Ia (P99).

Either 500 mg cefaclor or amoxycillin was administered at random thrice daily to 50 adult outpatients with acute or acute-to-chronic bronchitis. A total of 31 pathogens were isolated from sputum, mostly Streptococcus pneumoniae [17] or Haemophilus influenzae [3], or both [2]. All pathogens but one were susceptible to cefaclor; all but six were susceptible to amoxycillin. Satisfactory clinical results were obtained in 62.5% of the patients treated with cefaclor and 66% of the patients treated with amoxycillin.

Cefaclor given per os 20 mg/kg body weight was readily absorbed and distributed to adenoid tissue and to middle ear effusion in children with chronic OME. The levels obtained were above the MIC values of most strains of respiratory pathogens. The penetration characteristics were the same after the first and the 20th dose in a b.i.d. regimen. Elimination was completed within about 12 h. The double dose, 40 mg/kg body weight, did not give higher levels but a longer duration.

The concentration of cefaclor in serum and bile was determined for up to 360 minutes after a single oral dose of 1 g cefaclor in 18 patients with continuous T-drainage of the bile duct. The rate of absorption varied, there being marked differences in the time. The peak bile concentration of 12.1 mcg/ml was reached after 120 min; the peak serum concentration of 12.3 mcg/ml, on the other hand, was reached after only 90 min. There was no accumulation of cefaclor in the bile.

The pharmacokinetics of the oral cephalosporins cefaclor, cephradine, and cephalexin were examined following single 500 mg oral doses to fasted, healthy volunteers. Absorption of the three compounds was rapid following a brief lag period and peak serum levels were obtained in 1-1.5 hours. Serum levels of cefaclor tended to be lower than those of cephradine and cephalexin during the 2-5 hour postdosing period and cefaclor was eliminated more rapidly than other cephalosporins from serum. No difference was observed in the overall bioavailability of the three antibiotics based on comparable FD/V values. Urine levels of the three cephalosporins greatly exceeded the minimum inhibitory concentrations of susceptible organisms during 0-6 hours postdosing, but were considerably reduced during the 6-12 hour collection period. Total urinary recovery of antibiotic activity accounted for almost 90 percent of dosed cephradine and cephalexin compared to 55 percent of dosed cefaclor. Lower serum levels and reduced urinary recovery of intact cefaclor are probably due primarily to its chemical instability. The reduced levels of cefaclor may be compensated for therapeutically by its greater in vitro antibacterial activity.

Sultamicillin, an antibiotic combining ampicillin and the beta-lactamase inhibitor sulbactam, was administered to 13 patients diagnosed as having acute sinusitis. Specimens from sinus were obtained for all 13 patients by transantral puncture. Pharmacokinetics, bacteriology, and therapeutic efficacy were assessed. Eighty-five percent (11 of 13) were cured; two treatment failures were subsequently shown to have chronic (rather than acute) sinusitis during surgical exploration. Diarrhea was frequently encountered, and Clostridium difficile-associated enteritis was documented for one patient. Beta-lactamase-producing organisms were not encountered in this study; however, this study provides impetus for further controlled clinical trials.

The chemistry, pharmacology, pharmacokinetics, bacterial spectrum, clinical use, dosage, adverse reactions, and dosage forms and cost of cefaclor are reviewed. Cefaclor, a congener of cephalexin monohydrate, is a new semisynthetic cephalosporin antibiotic. It is well absorbed when given orally on an empty stomach; absorption is delayed by the presence of food. Although metabolism may play a role in the disposition of cefaclor, elimination is primarily renal. Cefaclor's spectrum of activity is similar to that of cefalexin, including a wide range of gram-negative and gram-positive bacteria; in particular, Escherichia coli, Klebsiella spp., Proteus mirabilis, Salmonella spp., and Haemophilus influenzae are more susceptible to clinically achievable concentrations of cefaclor than cephalexin. Cefaclor has been demonstrated to be effective against beta-lactamase-producing H. influenzae resistant to ampicillin, but further studies are needed to establish the clinical significance of this activity. Efficacy of cefaclor has been demonstrated in urinary tract, upper and lower respiratory tract, and skin and soft tissue infections in adults and children as well as in pediatric otitis media. Adverse reactions, mostly gastrointestinal, are generally mild and occur in few patients. Usual doses are 250-500 mg every eight hours in adults and 20--40 mg/kg/day in children, although this pediatric dose may be two low for otitis media. Clinical superiority of cefaclor over less expensive antibiotics has not been demonstrated.

Bronchial mucosal biopsy specimens were obtained during fibreoptic bronchoscopy in 30 patients receiving a new oral cephalosporin antibiotic, cefaclor (10 had 250 mg, 10 had 500 mg, and 10 had 1000 mg every eight hours). In 10 patients (from all dosage groups) cefaclor was undetectable in the bronchial mucosa but in every case the serum concentration was low, suggesting incomplete absorption. The mean (SD) bronchial mucosal concentration after 250 mg was 3.78 (1.77) micrograms/g (range 2.1-5.8 micrograms/g, n = 4), after 500 mg 4.43 (2.04) micrograms/g (range 2.0-7.1 micrograms/g, n = 8), and after 1000 mg 7.73 (2.76) micrograms/g (range 5.0-12.7 micrograms/g, n = 6). A significantly higher concentration in the bronchial mucosa was achieved with 1000 mg than with 250 mg (p less than 0.05) or 500 mg (p less than 0.025). These concentrations should be effective against Streptococcus pneumoniae, most strains being inhibited below 1.0 microgram/ml. The concentrations were within one dilution of the minimal inhibitory concentration for Haemophilus influenzae, most strains being inhibited below 4.0 micrograms/ml. Some strains of H influenzae will not be inhibited by the concentrations of cefaclor found in the bronchial mucosa, particularly those that are ampicillin resistant.

In the present study 21 patients undergoing retrograde cholangio-pancreatography (ERCP) were given cefamandole, cefazolin or cefaclor, and plasma and bile concentrations were measured. The cannulation of the common bile duct was possible in most of the patients investigated, but no bile could be obtained in 7 of them. In the patients in whom bile was obtained, concentrations comparable to other studies were estimated, despite a wide variation in the individual patients. In addition, cefaclor, which is not known to be excreted in the bile, showed sufficiently high inhibitory bile concentrations. Using ERCP for the estimation of bile concentrations of different drugs useful information can be obtained about the excretion of certain substances. However, for sophisticated pharmacokinetic studies, the method has certain limitations as compared with classical T-tube sampling.

The clinical effectiveness of cefaclor 500 mg three times daily in the treatment of acute infective exacerbations of chronic bronchitis has been investigated by a double-blind comparison with amoxycillin in the same dose in 30 in-patients and 50 out-patients. The two antibiotics were equally effective, in terms of resolution of presenting symptoms, sputum conversion and fall in 24 h sputum weight. Side effects were infrequent. Serum and sputum concentrations of antibiotics and 24 h urinary recovery were measured in 27 patients. Concentration of both cefaclor and amoxycillin was found to be significantly lower in mucoid sputum than in purulent sputum, in contrast to earlier reports in the case of amoxycillin. No clinical advantage was apparent for patients achieving higher sputum concentration of either antibiotic.

The absorption and excretion of cefaclor were studied in 10 newborn infants. A mean peak serum concentration of 7.7 microgram/ml was achieved at 1 hour after an oral dose of 7.5 mg/kg. It is concluded that cefaclor is a well absorbed and tolerated cephalosporin for use in newborn infants.

Seventy-nine patients that had persistent or recurrent secretory otitis media for over 3 months and were scheduled for myringotomy and/or adenoidectomy received a single dose of cefaclor (20 or 40 mg/kg) orally 0.5-4 hours before surgery. Cefaclor concentrations were determined in serum, middle ear fluid and/or blood-free adenoid tissue homogenate using microbiological methods. Concentrations in adenoid homogenate ran parallel to those in serum, indicating a rapid penetration to adenoid tissue. Penetration to middle ear fluid was delayed in comparison. In the 51 patients receiving 20 mg/kg, peak levels occurred after 0.5 hour in serum as well as in adenoid homogenate and middle ear fluid with mean values of 29, 7.5 and 5.1 mg/l, respectively. Concentrations in the middle ear fluid were greater than 2.0 mg/l from 0.5 to 3 hours after this dose. In the 28 patients receiving 40 mg/kg, concentrations levelled after 0.5 hour in serum and in adenoid homogenate, with mean values of 21-33 mg/l and 6.3-12 mg/l, respectively. Concentrations in the middle ear fluid reached 7.8 mg/l 2 hours after this dose. A dose of 20 mg/kg appears to be suitable for treatment of respiratory tract infections on a b.i.d. basis.

In order to see absorption and excretion of S6472 (sustained release preparations of cefaclor (CCL], 3 studies regarding, 1) influence of meals (single dose of 375 mg in capsule form), 2) dose response (single dose of 375 mg vs. 750 mg in granule form) and 3) continuous administration (twice-a-day administration of 750 mg in granule form for 8 days) were conducted in 15 healthy adult male volunteers using capsule and granule forms of S6472. The following is the summary of the results from the above studies: Tolerance. In the above 3 studies, none of the 15 volunteers complained of subjective abnormalities. In the clinical laboratory tests performed before the administration of S6472 and at the next day of the completion of the studies, the values from the laboratory tests were within normal range. Influence of meals. The average time for peak plasma level of CCL and decrease in the plasma level following the administration of S6472 were the fastest in the fasted volunteers, followed by the volunteers with light meals and usual meals. From this, it was confirmed that plasma levels of CCL were maintained for longer period of time in the non-fasted volunteers than in the fasted volunteers. In the volunteers who had light and usual meals, the peak plasma levels, AUC of the plasma levels and urinary recovery rate were almost the same. Influence by amount of meals was scarcely observed. Dose response. Mean serum levels and their AUC in the volunteers receiving 750 mg of S6472 were approximately twice as much as those in the volunteers receiving 375 mg of S6472, and dose response between the 2 doses was confirmed. Continuous administration. Mean serum levels and their AUC at the first dose and the 15th dose (final dose) were almost the same. In the continuous administration of S6472 for 8 days (15 doses), no accumulation of CCL in the body was observed.

Fundamental and clinical studies on S6472, a new prolonged acting preparation of cefaclor, were performed and the following results were obtained. Serum level and urinary excretion. 750 mg of S6472, 500 mg of cefaclor (CCL) and 500 mg of cephalexin (CEX) were orally administered in 6 healthy adult volunteers by the cross over method to measure serum level and urinary excretion. The serum level-time curve of S6472 showed 2 peaks at 1 and 6 hours after administration. The peak serum level of S6472 was 4.2 micrograms/ml and 2.9 micrograms/ml, respectively, 1 and 6 hours after administration. The peak serum level of CCL and CEX was 5.8 micrograms/ml and 12.1 micrograms/ml, respectively, 2 hours after administration. The urine level-time curve of S6472 also showed 2 peaks at 0-2 and 4-6 hours after administration and the peak urine level was 1,320 micrograms/ml and 994 micrograms/ml, respectively, 0-2 and 4-6 hours after administration. The peak urine level of CCL was 1,337 micrograms/ml, 0-2 hours after administration and that of CEX was 2,079 micrograms/ml, 2-4 hours. The mean urinary excretion of S6472, CCL and CEX was 56%, 69% and 94% of dose at 12 hours after administration. Clinical evaluation. S6472 was tried in 200 cases of various urinary tract infections. For one group of 85 cases with acute uncomplicated cystitis, clinical effects were evaluated as excellent in 40 cases, moderate in 42 cases and poor in 3 cases, and the overall clinical effectiveness rate was 96.5%. For another group of 68 cases with complicated urinary tract infection, clinical effects were evaluated as excellent in 9 cases, moderate in 27 cases and poor in 32 cases, and the overall clinical effectiveness rate was 52.9%. Side effects. Side effects were observed in 7 cases with diarrhea, epigastralgia, stomatitis, eruption and facial swelling. Administration of S6472 was discontinued in 2 cases, but in 7 cases all symptoms were transient.

Fourty patients undergoing tonsillectomy for recurrent tonsillitis were administered penicillin V, amoxicillin, cefaclor or josamycin. Antibiotic concentrations in serum and tonsillar tissues were determined by microbiological assay. Cefaclor demonstrated a superior diffusion than penicillin V and amoxicillin, but nevertheless inferior to that of josamycin.

Penetration into the middle ear of four antibiotics commonly used in treatment of otitis media was studied by administering a single oral dose of amoxicillin, cefaclor, erythromycin-sulfisoxazole, or trimethoprim-sulfamethoxazole to 83 children with chronic serous otitis media. The antibiotic was given 15-240 min before the removal of middle ear fluid (MEF) by ventilation tubes inserted through the tympanic membrane. At the time MEF was obtained, a sample of blood was drawn from the patient, and concentrations of antibiotic in both specimens were assayed either microbiologically by a disk diffusion method or by high-pressure liquid chromatography. Amoxicillin had the highest ratio of mean peak concentration in MEF to minimal inhibitory concentration (MIC) for the three most common pathogens of otitis media (Streptococcus pneumoniae, ampicillin-sensitive Haemophilus influenzae, and Streptococcus pyogenes), whereas trimethoprim-sulfamethoxazole had the highest ratio of mean peak concentration in MEF to MIC for ampicillin-resistant Haemophilus influenzae.

This study was conducted to develop a prolonged action preparation of cefaclor (CCL) which can offer, with the twice-a-day administration, as much effectiveness as its conventional preparation (Kefral capsule) with the 3 times-a-day administration. Absorption site of CCL in gastrointestinal tract, preparation form (enteric coated granules) which slowly release CCL, dissolution property of the form, and mixed ratio of the form and rapid release form (nonenteric coated granules) were studied and complex granules consisting of 40% of nonenteric coated granules and 60% of enteric coated granules which dissolve at pH 6 were chosen as a prolonged action preparation of CCL. Bactericidal activity of the prolonged action preparation (S6472) was confirmed to be the same as that of the conventional preparation by comparative viable cell count study in which concentrations of CCL simulated to plasma concentrations following the administration of S6472 at the dosage of 375 mg b.i.d. and the conventional preparation at the dosage of 250 mg t.i.d. were used. From the above, S6472 is considered to be a prolonged action preparation of CCL which serve our purpose. Since S6472 can be given with the twice-a-day administration, its daytime administration is not necessary. Therefore, S6472 is considered to be much useful preparation for the patients.

The concentrations of cefadroxil and cefaclor in serum were studied in eight healthy volunteers receiving 1,000 mg of both substances three times per day for 8 days. Intraindividual comparisons showed an increase in peak serum levels of cefadroxil from days 1 to 8 in seven of eight volunteers. Cefaclor peak concentrations did not rise during the 8 days.

Haemodialysis is utilised therapeutically as supportive treatment for end-stage renal disease (ESRD). In conjunction with haemodialysis therapy, ESRD patients frequently receive a large number of drugs to treat a multitude of intercurrent conditions. Because of the impaired renal function in ESRD patients, dosage reduction is often recommended to avoid adverse drug reactions, particularly for drugs and active metabolites with extensive renal excretion. On the other hand, if the removal of a drug by haemodialysis during concomitant drug therapy is significant, a dosage supplement would be required to ensure adequate therapeutic efficacy. Knowledge of the impact of haemodialysis on the elimination of specific drugs is therefore essential to the rational design of the dosage regimen in patients undergoing haemodialysis. This review addresses the clinical pharmacokinetic aspects of drug therapy in haemodialysis patients and considers: (a) the effects of ESRD on the general pharmacokinetics of drugs; (b) dialysis clearance and its impact on drug and metabolite elimination; (c) the definition of dialysability and the criteria for evaluation of drug dialysability; (d) pharmacokinetic parameters which are useful in the prediction of drug dialysability; and (e) the application of pharmacokinetic principles to the adjustment of dosage regimens in haemodialysis patients. Finally, drugs commonly associated with haemodialysis therapy are tabulated with updated pharmacokinetics and dialysability information.

A 500 mg dose of cefaclor (CCL) was administered orally before surgery to each of patients with respiratory diseases and in fasting. Average concentrations of CCL in sera were 4.04 micrograms/ml at 1.5 hours, 3.03 micrograms/ml at 2 hours, 1.68 microgram/ml at 3 hours and 0.45 microgram/ml at 5 hours after administration. Average concentrations in lung tissues during operation were 0.120 microgram/g at 3 hours, 0.272 microgram/g at 4 hours and 0.297 microgram/g at 5 hours after administration. Ratios of concentrations of CCL in lung tissues to that in sera were from 7.1 to 66.0 percent. The CCL was considered to be a useful antibiotic for the treatment of patients with respiratory diseases.

Biliary excretion of cefaclor, a new orally active cephalosporin, was studied in vitro using an isolated rabbit liver preparation perfused for 3 h (n = 5). Under these conditions, bile recovery amounted to 2.3% of the cefaclor dose added to the circulating blood (10 mg). In humans, after oral administration of a 1-gram dose of cefaclor to cholecystectomized patients provided with a T tube (n = 10), a mean biliary peak concentration of 7.6 +/- 2.4 microgram/ml was observed at the 3rd hour. Cumulative biliary excretion amounted to 0.05% of the administered dose. Assays performed on samples collected during cholecystectomy in 10 patients 1 h after intake of a 1-gram dose of cefaclor showed mean concentrations of 13.7 +- 1.2 micrograms/ml in serum, 8.1 +/- 1.3 micrograms/ml in common duct bile and 5.9 +/- 1.4 micrograms/ml in gallbladder bile. These results were compared with the data obtained after administration of seven other cephalosporins studied under identical conditions.

Fundamental and clinical studies on S 6472 were carried out and following results were obtained. Serum concentrations after single oral administration showed 2 peaks at 1 or 2 hours and 5 or 6 hours in the cases with normal meal. Namely this drug has much more maintenance of serum concentration than normal cefaclor. In maintenance of serum concentrations after the administration, there were no obviously difference between normal and heavy meal. S 6472 was administered twice a day to 7 patients with various infections (bronchopneumonia 2 cases, acute bronchitis 1 case, purulent tonsillitis 4 cases) and clinical responses were all effective results. Pathogenic bacteria of S. aureus, S. pneumoniae, S. pyogenes and H. influenzae were completely eliminated in all cases. No significant side effects were observed. On the above results, this administration method of S 6472 twice a day was considered to be good response against mild or moderate bacterial infections in children.

A study in which 375 mg of S6472 was orally given to 3 healthy adult volunteers before a meal, after a light meal, and after a usual meal in the cross-over method revealed the highest levels, both in serum and urine, in cases treated before a meal. In cases administered after a light or square meal, the serum level was less, but approximately 2 micrograms/ml over 6 hours after administration. No difference was seen in the AUC. The effective rate of S6472 when given at 750 approximately 1,500 mg/day was 74.6% in 62 patients with skin or soft tissue infectious diseases. Neither subjective or objective adverse reactions were seen in any case. Clinical laboratory testing revealed 1 case each of anemia and increased BUN, for which S6472 was not responsible.

Serum and/or urine levels of cefaclor (CCL) were studied in 4 patients during the therapy with CCL. In patients with severely impaired renal function, moderately higher serum and urine levels of CCL persisted, serum half-lives of CCL were moderately prolonged and urinary excretion of CCL slightly decreased. Although dosage modification of CCL is necessary in patients with renal dysfunction, multiple doses of 250 mg every 8 hours may be safe and effective even in patients with impaired renal function.

Ro 15-8074, a new cephalosporin the pivaloyloxymethylester of which (Ro 15-8075) is orally absorbable, showed greater in vitro activity than cefaclor against 48 Neisseria gonorrhoeae strains, including 25 penicillinase-producing strains. Unlike cefaclor, Ro 15-8074 was unaffected by increase in inoculum size, and it exhibited a remarkable stability against gonococcal beta-lactamase hydrolysis.

Oral cefaclor is rapidly absorbed in patients with a shortened gastrointestinal tract (23 cm). A case is reported of a 27-month-old female child who had received oral cefaclor for five days in treatment of otitis media. The child had had a bowel resection at birth. She did not respond to oral therapy with cefaclor and was admitted to the hospital, where she received cefamandole intramuscularly. The patient recovered in five days. Further investigation using cefaclor with this patient demonstrated serum concentrations below the minimum inhibitory concentration of Hemophilus influenzae, pneumococcus, and many other organisms. When oral antibiotics are prescribed, it is necessary to monitor serum concentrations to ensure absorption.