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A specific and rapid high performance liquid chromatographic (HPLC) method with UV detection (254 nm) was developed for the determination of cefroxadine in human plasma. The sample extraction was performed by a simple procedure, vortexing and centrifugation of sample following addition of 60% trichloroacetic acid. Cephalexin was used as an internal standard (I.S.). The HPLC analysis was carried out on a Capcell Pak C18 analytical column with a mobile phase of 50 mM ammonium formate buffer/pH 3.5 and acetonitrile (90:10, v/v). No interference was observed near the peaks of cefroxadine and I.S. The calibration curve was linear over the range of 0.5-40 microg/mL and the lower limit of quantification (LLOQ) was 0.5 microg/mL. The method was validated with excellent sensitivity, accuracy, precision and stability. This assay was successfully applied to determine the pharmacokinetic parameters of cefroxadine in Korean healthy volunteers after an oral administration of two 250 mg cefroxadine capsules. As a result, the plasma half-life was 1.00+/-0.26 h and the mean AUC(0-6 h) was 46.25+/-6.41microgh/mL. The maximum plasma concentration (C(max)) of 17.62+/-4.87 microg/mL reached 1.44+/-0.39 h after administration.

Cephradine, the first generation cephalosporin, is active against a wide range of Gram-positive and Gram-negative bacteria including penicillinase-producing Staphylococci. Since the presence of complexing ligand may affect the bioavailability of a metal in the blood or tissues, therefore, in order to study the probable interaction of cephradine with essential and trace elements present in human body, cephradine has been reacted with cobalt, copper, zinc and cadmium metal halides in L:M ratio of 2:1 in methanol and the products recrystallized from suitable solvents to pure crystals of consistent melting points. Infrared and ultraviolet studies of these complexes were carried out and compared with ligand. Magnetic susceptibility studies of these complexes were also carried out showing their paramagnetic behavior. From the infra red studies and elemental analysis of the complexes, it has been shown that the drug molecule serves as a bidentate ligand coordinating through both its carboxylate at C-3 and beta-lactam nitrogen and the metal having a square planar or octahedral geometry. To evaluate the changes in microbiological activity of cephradine after complexation, antibacterial studies were carried out by observing the changes in MIC (minimum inhibitory concentration) of the complexes and compared with the parent drug by measuring the zone of inhibition of complexes and compared with the parent cephalosporin against both Gram-positive and Gram-negative organisms. For MIC observation, serial dilution method was employed and zone series were determined by disk diffusion method. Our investigations reveal that formation of complexes results in decrease in antibacterial activity of cephradine and MIC values are increased.

The inhibitory effects of five angiotensin-converting enzyme (ACE) inhibitors on the uptake of an aminocephalosporin antibiotic, cefroxadine, by rabbit small intestinal brush-border membrane vesicles were examined in the presence of an inward H+ gradient. Dixon plot analysis showed that all these ACE inhibitors inhibited the uptake of cefroxadine, which is transported by a H+/oligopeptide transporter in the membrane, in the order of enalapril

Effects of angiotensin-converting enzyme (ACE) inhibitors, captopril, enalapril maleate and quinapril, on the uptake of aminocephalosporin antibiotic, cefroxadine, by rabbit small intestinal brush border membrane vesicles were examined. These ACE inhibitors significantly inhibited the uptake of cefroxadine, which is transported by H+/dipeptide transporter in the membrane, in the order of captopril < enalapril < quinapril in the presence of an inward H+ gradient. Inhibitory effect of quinapril was more marked than that of aminocephalosporin cephradine, while in the absence of an inward H+ gradient inhibition by these ACE inhibitors was much less. Dixon plot analysis showed that the inhibition by enalapril and quinapril in the presence of an inward H+ gradient occurred in a competitive manner and estimated inhibition constants of these two drugs to be 5.3 mM and 0.46 mM, respectively. These results suggested the strong affinity of these ACE inhibitors, especially quinapril, on the H+/dipeptide transporter.

Characteristics of transport of an oral aminocephalosporin, cefroxadine, in rabbit small intestinal brush border membrane vesicles were examined. Uptake rate of cefroxadine was saturable in the presence of an inward H+ gradient, and kinetic parameters were similar to those of cephradine. However, the uptake rate was almost linear with the concentration in the absence of an inward H+ gradient up to 5 mM. Overshoot phenomenon was observed in the presence of an inward H+ gradient at 37 degrees C, but it disappeared with decrease of temperature. The Arrhenius plot of uptake rate constant showed a break point at approximately 30 degrees C. Cefroxadine uptake was optimum in the vicinity of pH 5.5 at 37 degrees C, but the dependence on extravesicular pH disappeared at 15 degrees C. The uptake of cefroxadine in the presence of an inward H+ gradient was markedly inhibited by other aminocephalosporins such as cephalexin, but the inhibition was only slight in the absence of an inward H+ gradient. Alkyl alcohols such as n-hexyl alcohol also inhibited H(+)-coupled uptake of cefroxadine at the concentration range at which the alcohols increased the membrane fluidity, and overshoot phenomenon diminished, suggesting that H(+)-coupled transport of cefroxadine is sensitive to the alcohol-induced increase in membrane fluidity. On the other hand, the alcohols rather stimulated its uptake in the absence of an H+ gradient.

An impurity of unknown identity was isolated from commercial cefradine by liquid chromatography on poly (styrene-divinylbenzene) with HOAc (0.01 M)-CH3CN (94:6, v/v) as the mobile phase. The structure was elucidated as 4',5'-dihydrocefradine using nuclear magnetic resonance spectroscopy (NMR) and mass spectrometry (MS). The structure was confirmed by comparison with the chromatographic retention characteristics and photodiode-array detected ultraviolet spectrum of the synthetic compound and with its infrared, NMR and MS spectra. The presence of 4',5'-dihydrocefradine in cefradine has not been described previously.

Stabilized, bedridden, inactive trauma patients on enteral nutrition via continuous, constant rate tube feeding (2 different formulas) were given a single dose of cefroxadine p.o. There were no differences in the pharmacokinetic parameters between the groups on different enteral nutrition. These patients were compared to cefroxadine absorption in ambulatory healthy subjects after a standardized meal (bolus-fed). The mean residence time was significantly longer in the patients, and the extent of absorption was slightly reduced with one enteral nutrition formulation and significantly reduced with the other. The other pharmacokinetic parameters were not significantly different. The difference is believed to be caused by reduction in splanchnic blood flow in the immobilized patients, weakening of migrating motor complex due to tube feeding and the lower temperature (4 degrees C) of enteral nutrition.

Peroral absorption of cefroxadine given to 7 24-h fasted trauma patients by nasogastric tube within the first day of admission was compared to that obtained in fasted healthy volunteers. The trauma patients exhibited significantly lower Cmax and reduced AUC. Even though rate and extent of bioavailability cannot be determined from these two different population groups since the total clearance must be assumed to be different in patients and healthy subjects, a reduced bioavailability is assumed based on pathophysiologic reflections.

The effect of cefroxadine, an aminocephalosporin (beta lactam antibiotic) on rat intestinal L-leucine transport has been studied. Cefroxadine inhibited the L-leucine uptake by the intestinal mucosa in a dose-dependent fashion. In vivo studies showed that cefroxadine reduced L-leucine absorption. This effect was irreversible. Only the active transport component of the absorption was inhibited. Oxygen consumption of the mucosa was reduced by cefroxadine which inhibited the activity of the basolateral (Na(+)-K+) ATPase also.

The pharmacokinetics of cefroxadine in healthy human volunteers was studied in plasma and urine, after an infusion administration of 1 g of this drug for 0.5 h. Blood and urine samples were microbiologically quantified by diffusion on solid gelose using Bacillus Subtilis ATCC 6633 as the test organism. Plasma and urine profiles were fitted to a reduced two-compartment model not having inactivating biotransformation as a route of elimination. The parameters of distribution for this model show a rapid disposition (t1/2 alpha = 0.28 h) and an average volume of the central compartment of 0.15 +/- 0.04 l/kg (range 0.20-0.09). The dominant terminal half-life (beta-phase) was 1.17 +/- 0.26 h (range 0.90-1.67). The total body volume 0.41 +/- 0.09 l/kg (range 0.30-0.52) indicates that there is no diffusion of the antibiotic into intracellular fluids of poorly perfused tissues due to its high elimination rate.

The in vitro activity of cefroxadine was studied and found to be at least comparable to that previously reported for cefalexin and cefradine. The activity of cefroxadine was superior to that of amoxicillin against tested isolates. Time-killing studies showed that the addition of 4 X minimum inhibitory concentration (MIC) of cefroxadine to growing cultures reduced viable counts by 4 log units within a 3 h incubation. A diffusion test with a 30 microgram cefroxadine disk produced acceptable interpretive results with tentative zone size breakpoints of less than or equal to 14 mm for resistance and greater than or equal to 17 mm for susceptibility.

Cefroxadine (CXD) is an orally administered synthesized cephalosporin antibiotic developed by Ciba-Geigy Limited (Switzerland) in 1972. We have studied the clinical effectiveness of this drug in a total of 45 cases of various types of infections in the dentistry and the oral surgery. The studies resulted in showing 18 markedly effective cases, 19 effective cases, 5 slightly effective cases, 1 ineffective case, and 2 unknown cases showing an effective rate of 82.2%. Side effects manifested in 2 cases, of which 1 case was considered to be attributable to CXD, and the occurrence frequency of side effects was as low as 2.2%. In bacteriological test, there were many cases of mixed infections by Gram-positive and Gram-negative bacteria, and these infections were those which are observed in high frequency in dentistry and oral surgery infections. As a result of an overall evaluation of CXD clinical effects, the drug considered to be an antibiotic which is highly useful in dentistry and oral surgery.

The penetration of four cephalosporins into tissue fluid obtained with a skinabrasion technique was studied. Two oral antibiotics, cephalexin and CGP 9000, had similar pharmacology and penetrated the fluid in equivalent amounts. Cefuroxime (33% protein-bound) and cefoxitin (65-79% proteinbound) attained levels in tissue fluid which were very similar to their blood levels. The level of antibiotic in the tissues seems to be closely related to the blood level and is not adversely affected by protein binding.

A double-blind controlled trial of cefroxadine (CXD) 250 mg t.i.d. was undertaken to objectively evaluate its safety and effectiveness in the treatment of acute suppurative otitis media and acute exacerbation of chronic suppurative otitis media, using cephalexin (CEX) 250 mg q.i.d. as a control drug, and the following results were obtained. In the treatment of acute suppurative otitis media, the 2 drugs produced almost equal outcomes, showing no significant difference in assessments of both overall effects and usefulness. In the treatment of acute exacerbation of chronic suppurative otitis media, the 2 drugs exhibited no significant difference as well in overall effects by Wilcoxon's two-sample test. However, the CEX group had significantly more nonresponsive patients, i.e. 35.5% as compared with 9.7% of the CXD group (chi 2-test, P less than 0.05). In the assessment of clinical usefulness as well, no significant difference was observed between the 2 groups. In the assessment of overall effects based on the patients whose isolated organisms were sensitive to the drugs, CEX group had more patients not responding to the treatment of acute exacerbation of chronic suppurative otitis media (chi 2-test, P less than 0.05). Bacteriological effects were not significantly different between the 2 drugs in both acute suppurative otitis media and acute exacerbation of chronic suppurative otitis media. Overall safety rating was not significantly different between the 2 drugs. Side effects occurred as the symptoms of digestive organ in 2 patients each in both groups (equally an incidence of 2.6%). As for the improvement of each symptom after treatment (assessed on day 3), CXD was superior in the improvement rate of otorrhea volume as the main symptom of acute exacerbation of chronic suppurative otitis media, while CEX was superior in that of otoobstruction feeling. From the above findings, it is presumed that CXD is a safe drug which can exhibit equal or superior therapeutic effects to CEX in the treatment of acute suppurative otitis media and acute exacerbation of chronic suppurative otitis media, at 3/4 of the CEX dose level.

Basic and clinical evaluations of a new oral cephalosporin cefroxadine (CXD) in pediatric fields were investigated, and the following results were obtained. 1. MICs of CXD against various bacteria were compared with those of cephalexin (CEX). MIC peaks of CXD against clinically isolated S. aureus (22 strains), S. pyogenes (25), S. pneumoniae (8), H. influenzae (23), and E. coli (23) in pediatric fields, were 1.56, 0.2, 1.56, 25 approximately 50 and 6 .25 microgram/ml, respectively in the inoculum size of 10(8) cells/ml, and they were 1.56, less than 0.1, 0.78, 25 and 6.25 microgram/ml respectively in the inoculum size of 10(6) cells/ml. In comparison with CEX, MIC peaks of CXD against S. aureus, S. pyogenes, H. influenzae and E. coli were almost the same with those of the former, it was, however, better by 1 approximately 2 tubes than that of CEX against S. pneumoniae. 2. CXD in the form of dry syrup was administered orally at a dose of either 10 mg/kg or 20 mg/kg to 5 children, and the serum levels and the urinary excretion were evaluated. In the case of 3 children who were administered a dose of 10 mg/kg the mean serum levels were 11.9 microgram/ml after 30 minutes, 13.7 microgram/ml after 1 hour, 4.7 microgram/ml after 2 hours, 0.7 microgram/ml after 4 hours, and 0.3 microgram/ml after 6 hours, while those 2 children who were administered a dose of 20 mg/kg, they were 15.1, 28.5, 12.5, 2.0 and 0.9 microgram/ml respectively. The mean periods of half-life in serum were 0.87 hour in the case of 10 mg/kg and 0.94 hour in the case of 20 mg/kg. The mean excretion rates were 83.8% in the case of 10 mg/kg and 59.8% in the case 20 mg/kg. 3. CXD dry syrup was administered to 31 children with various bacterial infections i.e. acute pharyngitis (15 cases), acute purulent tonsillitis (10 cases), acute bronchitis (4 cases) and 1 case each of acute pyelonephritis and acute purulent cervical lymphadenitis, and the clinical and bacteriological responses and side effect were investigated. The clinical response was either excellent or good in all of the cases. Out of the S. pyogenes (20 strains), S. aureus (1), S. pneumoniae (2), E. coli (1) and H. influenzae (1), bacteriological eradication was observed in all strains with the exception of 1 strain each in S. pyogenes and H. influenzae in which reduction was observed. No side effects and abnormal laboratory findings were observed.

Cefroxadine (CXD) was studied in the field of obstetrics and gynecology and the following results were obtained. MIC values of CXD against 55 clinical isolates were investigated, from 6.25 to 12.5 micrograms/ml for 8 strains of E. coli, 6.25 micrograms/ml for 3 strains of K. pneumoniae and from 0.39 to 3.13 micrograms/ml for 9 strains of anaerobes such as Peptostreptococcus and Peptococcus in 10(6) cells/ml. Transfer of CXD into intrapelvic organ such as uterus, uterine tube and ovary after the oral administration of 500 mg was investigated. The concentrations in the tissues of genitalia ranged from 5.84 to 7.44 micrograms/g about 2 hours later after the administration. CXD was orally given to 18 patients with infections of genital organs at daily dose of 1,500 mg (500 mg 3 times a day). The clinical response was good, and efficacy rate was 88.9%. No remarkable side effects were observed.

The antibacterial effects of subminimal inhibitory concentrations (sub-MICs) of antibiotics were studied in two animal models. In mice, the oral cephalosporin CGP 9000 was effective in 11 of 20 different gram-negative infections and cephalexin was effective in one of these infections, both at 50% effective doses (ED(50)) that produced peak concentrations of drug in plasms equal to one-half to one-sixteenth the minimal inhibitory concentration (MIC) for the infecting organism. In gram-positive infections, both antibiotics were effective only at concentrations above the MIC. In rabbits, sub-MICs of cephaloridine, ampicillin, and gantamicin were maintained for 6-10 hr by intravenous infusion. At steady-state concentrations equal to one half to one-eighth the MIC, the beta-lactam antibiotics caused elongation and filamentation, and gentamicin caused enlargement, of Proteus mirabilis, Escherichia coli, and Salmonella typhimurium in peritoneal exudate; the number of viable cells of each of these bacteria was temporarily reduced. In infections with E. coli and P. mirabilis, sub-MIC's of beta-lactam antibiotics and of gentamicin prolonged the survival rates for infected animals beyond those for control animals. Rabbits infected with S. typhimurium and treated with ampicillin at a concentration of one-third the MIC Tended to die sooner than did control animals.

Basic and clinical evaluations of cefroxadine were carried out in children, and the following results were obtained. 1. Cefroxadine 20 mg/kg was administered to 9 children with heart disease for the prophylaxis against infections before undergoing cardiocatheterization and cardioangiography, and serum levels were determined. Peak levels reached after 30 minutes in 4 of the 9 cases, with a mean peak level of 22.5 mcg/ml and after 1 hour in 5 cases, with a mean peak level of 16.2 mcg/ml. Half life was 3.1 hours in the former group in a 6-hour blood sampling (1.04 hours in a 2-hour sampling) while in the latter group it was 1.37 hours. 2. Clinical responses were evaluated in 56 children comprising 23 cases of pharyngitis, 8 of tonsillitis, 13 of scarlet fever, 10 of urinary tract infections and 2 of impetigo. Fifty of these cases had excellent and good responses showing a efficacy rate of 89.3%. 3. From 42 of the cases, 43 strains were isolated as causative organisms. Major organisms included 27 strains of S. pyogenes, 9 of E. coli and 3 of S. aureus. As for bacteriological responses, all strains were eradicated. 4. No severe side effects were observed except for diarrhea of 1 cases and eosinophilia of 2 cases. Furthermore, no children refused to take cefroxadine dry syrup.

Fundamental and clinical studies on cefroxadine (CXD) were carried out, and we have obtained the following results. (1) Sensitivity distribution: As for the sensitivity distribution in S. aureus, the peak was within the ranges from 3.13 to 6.25 microgram/ml in the inoculum size of 10(9) CFU/ml, the distribution was less than or equal to 0.1 to 50 microgram/ml in the inoculum size of 10(6) CFU/ml, with the peak at 1.56 to 6.25 microgram/ml. In S. pyogenes, the sensitivity distribution ranged between less than 0.1 and 1.56 microgram/ml, with the peak at 0.1 microgram/ml in the inoculum size of 10(9) CFU/ml. In the inoculum size of 10(6) CFU/ml, however, the all strains were distributed within the ranges of 0.1 to 0.78 microgram/ml, and the growth of 49 out of 54 strains (91%) was inhibited at less than or equal to 0.1 microgram/ml. In E. coli, the sensitivity peak was at 25 to 50 microgram/ml in the inoculum size of 10(8) CFU/ml, and 5 strains (9.3%) were detected with greater than 100 microgram/ml. Of the 5 strains, 1 strain showed cross tolerance with CEX, the remaining 4 strains was at 50 microgram/ml and at 25 microgram/ml in 2 strains each. In the case of inoculum size of 10(6) CFU/ml, the sensitivity distribution was all within the ranges from 0.78 to 12.5 microgram/ml, except for 1 strain at 100 microgram/ml, with the peak being within the ranges from 3.13 to 12.5 microgram/ml. As for the above 100 microgram/ml-strain, it was showing cross tolerance with CEX. (2) Serum concentration: CXD was administered at a dose level of 10 mg/kg and 20 mg/kg between meals to 5 children, and CXD concentration in their serum was measured. In the group of the 10 mg/kg administration: average 30 minutes value; 8.7 microgram/ml, 1 hour value; 9.15 microgram/ml, 2 hours value; 7.4 microgram/ml, 3 hours value; 2.85 microgram/ml, 4 hours value; 1.0 microgram/ml and 6 hours value; 0.32 microgram/ml, with half-life of 0.88 hours. In the group of the 20 mg/kg administration: average 30 minutes value; 11.7 microgram/ml, 1 hour value; 16.8 microgram/ml, 2 hours value; 10.7 microgram/ml, 3 hours value; 8.15 microgram/ml, 4 hours value; 3.33 microgram/ml, 6 hours value; 1.22 microgram/ml, with half-life of 1.03 hours. A significant interrelation in dose response was observed between the 2 groups. (3) CLINICAL RESULTS: Clinical investigation were held in 29 cases (47 boys and 32 girls). Their diseases comprised of 2 acute pharyngitis, 28 acute purulent tonsillitis, 11 scarlet fever, 3 cervical purulent lymphadenitis, 14 acute bronchitis, 7 acute pneumonia, 11 urinary tract infection and 3 skin soft tissue infection. The drug was effective in 74 out of the 79 cases (93.7%). Causative organism was proved in 60 out of the 79 cases. Fifty-five cases (91.7%) were observed bacterial disappearance or reduction in the 60 cases. Side effects were observed in a total of 3 cases (3.8%), i.e. 2 cases of abnormal values in the laboratory findings (an eosinophilia and/or an elevation of the GPT readings) and 1 case of manifestation of exanthema.

A method employing high pressure liquid chromatography has been developed for the new cephalosporin cefroxadine (CGP 9000). This uses Lichrosorb RP-8 5 micron as the stationary phase and 2 mM phosphoric acid mixed with methanol in the ratio 72:28 for the mobile phase. The retention time is 6.5 minutes. The procedure has a correlation with microbiological assay of r = 0.968 for sera after oral dosage and r = 0.944 after intravenous doses. Correlations in sera from each individual has ranged from 0.957 to 0.998. A protein binding of 5 per cent was found for a concentration of 10 microgram/ml and of 7.5 per cent at 2 microgram/ml. The HPLC method had a recovery of 92.5 at a low level of 2 microgram/ml and 95 per cent at 10 microgram/ml.

Clinical effect and excretion into wound exudate of a new semisynthetic cephalosporin cefroxadine (CXD), were studied. CXD was given in 25 cases of surgical infections; 6 cases of wound infection, 9 cases of abscess, 9 cases of infected atheroma and 1 case of furuncle. CXD was orally administered in daily dose of 750 to 1,500 mg. Clinical results were excellent in 1 case, good in 18 cases, fair in 3 cases and poor in 3 cases. The overall clinical efficacy rate was 76.0%. Clinical efficacy classified by diagnosis was 66.7% in wound infection, 66.7% in abscess, 88.9% in infected atheroma, and 100% in furuncle. Side effects were not observed in all cases among 25 patients in CXD trials. Studies of excretion into wound exudate of CXD were performed in 1 postoperative case of mamma carcinoma after oral administration of 500 mg of CXD. The concentration of CXD in exudate was 1.12 micrograms/ml in 2 hours, 3.48 micrograms/ml in 3 hours, 4.13 micrograms/ml in 4 hours, 5.56 micrograms/ml in 5 hours and 4.41 micrograms/ml in 6 hours after administration, which was observed that CXD was excreted in wound exudate in high concentration.

Serum and tonsillary tissue levels of cefroxadine, a new broad-spectrum cephalosporin, proving to be effective in several infections, particularly in the ENT ones, were measured in patients scheduled for tonsillectomy. Twenty patients (12 males, 8 females) aged between 11 and 25 years (mean 18.0 years) were given cefroxadine for 2 days (500 mg every 12 h), and on the 3rd day 500 mg of the drug was given before surgical operation. Tonsillar tissues were taken 2 h after dosing and blood samples before, 1, 2, 4 and 6 h after the drug administration in 8 out of 20 enrolled patients. Cefroxadine concentrations were measured according to microbiological methods. Cefroxadine tonsillary levels were 1.13 +/- 1.73 micrograms/g, approaching the MIC for sensitive bacteria. The time course of plasma levels is superimposable to previous studies. These findings suggest a rapid penetration of cefroxadine in tonsillar tissue and seem to confirm the clinical efficacy of the drug in ENT infections.

In this multicentre trial, 1072 hospitalized children, 573 boys and 499 girls (847 of whom were aged less than 6 years), affected by respiratory tract (376 patients) or ENT (696 patients) infections were treated for 10 days with cefroxadine per os, at an average dose of 650 mg/day (325 mg every 12 h corresponding to 25 mg/kg b.w.). Most patients (1047; 97.7%) completed the trial, while 25 patients were withdrawn from the study (20 patients for viral diseases and 5 for side-effects). Of the patients affected by respiratory tract infections, 361 completed the trial and 342 of them (94.7%) were cured in 6.0 days on average. Of the patients affected by ENT infections, 686 completed the trial and 649 of them (94.6%) were also cured in an average of 6.0 days. In the two groups the signs and symptoms of the disease significantly (p less than 0.001) decreased by the end of the study. Some patients (80; 7.6%) complained of side-effects, mainly gastric discomfort (4.9%), skin rash (2.2%) and glossitis (0.5%). In conclusion, cefroxadine exerts a satisfactory antibacterial action with only a few days of treatment, and it appears to be very well tolerated.

Two new penicillins and a new cephalosporin have been synthesized by condensing 2-hydroxy-1-naphthaldehyde with epicillin, 6-aminopenicillanic acid and cephradine, and subsequently reducing the SCHIFF bases with NaBH4. The antimicrobial activities of these compounds are also described.

Clinical efficacy of cefroxadine dry syrup, a new oral cephalosporin antibiotic, was evaluated in children, and the following results were obtained. 1. Three children were given a single oral dose of about 10 mg/kg of the drug when fasting, and its blood concentrations were determined. Blood concentrations were maximum at 30 approximately 60 minutes, i.e., 16.9 approximately 18.2 microgram/ml, and markedly low at 4 hours. 2. Thirty-six patients with the following diseases were tested with 23.1 approximately 44.4 mg/kg/day of the drug in 3 to 4 divided doses; 21 patients with lacunar tonsillitis, 2 with tonsillitis, 1 with scarlet fever, 4 with bronchitis and tonsillitis, 2 with cystitis, 4 with pyelonephritis, 1 with impetigo and 1 with probable Mycoplasma pneumonia. An overall efficacy rate in 35 patients excluding the last mentioned case was 91.4%, i.e., excellent in 20, good in 12 and poor in 3, and an eradication rate of the causative organisms was 88.9%. 3. Adverse reactions noted were diarrhea in 1 patient, eruption and diarrhea in 1 transient neutropenia in 1, eosinophilia in 3 and an elevation of GOT and GPT in 1. None were significant. 4. Taste and flavor of the drug was considered to be well palatable to children. 5. Taking into consideration of the results of fundamental evaluation of the drug, cefroxadine dry syrup is considered to be a potent new antibiotic in children, and the recommended dose will be 10 mg/kg 3 to 4 times a day.

The pharmacokinetic parameters of cefroxadin and cephalexin were compared after simultaneous oral administration of the two cephalosporins to 21 subjects. The influence of the dose, the formulation, and food intake on these parameters was investigated. Both drugs were equally well absorbed from all of the tested formulations; identical percentages of the dose were recovered in the urine in all cases. The elimination half-life of cefroxadin and, consequently, the area under the plasma concentration-time curve were about 10% less than those of cephalexin. Plasma concentrations and cumulative excretion curves of the two drugs were almost superimposable. Food intake had the same effect on both drugs; absorption was slowed, but the amounts absorbed were almost the same as those in fasted subjects.

The application of microbore systems (15 cm X 1 mm I.D. columns filled with Nucleosil C18, 5 microns particle size) to the determination of cephalexin and cadralazine in plasma was investigated. Factors such as mobile phase flow-rate, detector flow-cell volume and injection volume were examined with regard to the needs of routine drug analysis. Mobile phase flow-rates of 50-60 microliters/min were used. A flow cell with an optical path length of 6 mm and an intermediary volume (2.4 microliters) was selected for UV detection in order to obtain sufficient sensitivity. Large volumes of non-eluting solvent containing the drug were injected on the column. The addition of an ion-pairing reagent to samples containing cephalexin and cefroxadin prior to the injection was found to improve the chromatographic performance. The blood sample size required for analysis with microbore columns was smaller than that with conventional columns. The analysis time was similar and the limit of quantitation was also similar, provided that large sample volumes were injected on the microbore column.

Cefroxadine (CXD), an oral cephalosporin antibiotic was studied in the field of obstetrics and gynecology and the following results were obtained. CXD was orally given to 22 cases at daily dose of 1,500 mg 3 times a day. CXD administration was given to 22 cases in all; 4 with cervicitis, 6 with endometritis, 2 with puerperal fever, 4 with bartholinitis, 5 with adnexitis and 1 with vulvitis, respectively. Overall efficacy rate was 77.3% (17/22) (excellent 4, good 13, fair 5). As for side effects, a slight diarrhea was observed. CXD was considered to be a useful antibiotic in the field of obstetrics and gynecology by above the results.

Cefroxadine and cephalexin were compared in a double-blind study in patients with complicated urinary tract infections. Patients were treated orally with 1 g t.i.d. for five days. Bacterial counts in the urine were determined 1, 3 and 8 hours after the first dose and on the second, third and fifth day of treatment. A decrease in the bacterial population below 10(4) organisms/ml of urine was taken as being indicative of chemotherapeutic effect. Urine specimens were inactivated enzymatically before culture to eliminate any residual cephalosporin. A significant reduction in the bacterial count was seen one and three hours after the first dose, and, to a much greater extent, after eight hours. Reduction in the bacterial count was more frequent in the group treated with cefroxadine. The results during the first eight hours indicate that cefroxadine kills more rapidly than cephalexin, which is in agreement with the experimental findings. Whether the transient differences observed in the rates of inhibition are of clinical relevance remains uncertain.

Cefroxadine dry syrup was administered to 57 children with acute febrile respiratory tract infections and 2 children with scarlet fever in the dose of 40 mg/kg/day q.i.d. for 2 approximately 7 days. 65 strains of organism were isolated as pathogen from the 59 patients, and 50 of the 65 strains (76.9%) showed bacteriologically good responses. Clinically, 55 children (93.2%) had good response. Out of 63 strains isolated from the 57 cases with respiratory infections, 48 strains (76.2%) showed good bacteriological response. As for the type of pathogen, all strains of Staphylococcus aureus, 86.4% of Streptococcus haemolyticus and 90.0% of Streptococcus pneumoniae had good response, but as for Haemophilus influenzae it was only 47.6%. In one child, Streptococcus pneumoniae appeared during cefroxadine treatment in addition to the preexisting Haemophilus influenza. From the 4 children having no response for their respiratory infections, H. influenzae were isolated in 3 cases and Streptococcus haemolyticus was isolated in 1 case, before starting the treatment. As for side effects, mild diarrhea developed in only 3 children.

A study was made with the newly developed cefroxadine (CXD) dry syrup by measuring the serum level, urine excretion and recovery rate in 10 children who were orally administered 5, 10 and 20 mg/kg at 1 hour after meals and the following results were gained. Also, its clinical efficacies and side effects were investigated in the following cases who were treated with a mean dose of 33 mg/day divided into 3 to 4 portions for a period of 9 days on the average; viz. a total of 151 cases consisting of 9 cases of pharyngitis, 39 of tonsillitis, 11 of streptococcal infection, i.e. scarlet fever, 7 of bronchitis, 6 of pneumonia, 1 of otitis media, 6 of purulent lymphadenitis, 1 of purulent parotitis, 1 of subcutaneous abscess and 3 of impetigo. 1. The serum level tends to reach its maximum level within 1 hour after administration. The mean concentrations of 5, 10 and 20 mg/kg dose in the foregoing time were 6.35, 9.12 and 21.62 mcg/ml respectively and dose response was observed. CXD showed higher concentration than CEX, CED and CFT. The mean half-life periods of the 3 dose were 72, 84 and 66 minutes respectively and variations were observed, but the drugs maintains a satisfactory serum level. 2. The time which showed highest urine excretion was mainly in the 0 to 2 hours bracket and the average concentrations of 5 , 10 and 20 mg/kg dose in the foregoing time were 381.2, 771.7 and 1,577.7 mcg/ml respectively. The dose response was more evident than in the serum concentrations. The average recovery rates within 6 hours were 93.6, 88.3 and 94.3% respectively and they were similar to those of CEX, CED and CFT. 3. The clinical effects were evaluated were in 148 cases out of the total of 151 and 136 cases, or 91.9% showed good or excellent efficacy response. 4. The daily dose groups of less than 30 mg/kg and 31 to 40 mg/kg formed the majority and there was no difference in the comparison of the clinical effectiveness in these 2 groups. Administration of a daily dose of 20 to 40 mg/kg is sufficient for the treatment of the aforementioned mild diseases except for pneumonia. 5. The clinical effects were compared between the 3 and 4 times a day treatment groups, but there was no difference between these two groups with regard to the foregoing daily dose. The 3 times a day treatment is acceptable, but the 4 times a day treatment is preferable when pharmacokinetics if taken into account. 6. The bacteriological effects in 41 cases, or 97.6% out of the 42 cases were above the efficacy base line and a high efficacy rate was achieved. 7. With regard to side effects, diarrhea developed in 4 cases and eosinophilia in 6 cases, abnormal simultaneous increases in GOT and GPT in 1 case and 1 case each for abnormal values in LDH and BUN were seen in the clinical test values. The foregoing results show that CXD has high efficacy and safety and it can be said that it is a drug required in the pediatric field.

CXD was administered orally at an average dose of 28.6 mg/kg (18.3 approximately 42.3 mg/kg) for an average 6 days (3 approximately 12 days) to a total of 99 pediatric cases with skin and soft tissue infections (impetigo 89, abscess 7 and furuncle 3) ranging from 3 months to 9 years old. The drug was given twice to 4 times per day after meals. The clinical and bacteriological effects and adverse reactions of CXD as well as the susceptibility of the causative organisms against CXD and CEX were studied, and the results obtained are as described below: 1. According to judgement of the attending doctors, CXD had a high global efficacy rate of 90.9%. 2. Analysis of the attending physicians' evaluations of the clinical effects on impetigo revealed that a dose of CXD 20.5 approximately 30.4 mg/kg t.i.d. can produce satisfactory responses. 3. According to the assessments by Evaluation Committee, the global clinical effects after 3, 5 and 7 days were 81.4, 91.2 and 94.6%, respectively. This indicates that clinical responses increased with prolongation of the treatment period, viz. better responses obtained after 5 and 7 days. This suggests that a minimum of 5 days administration is required for treating these infections. 4. As for impetigo having the largest number of patients in this study, a dose of CXD 20.5 approximately 30.4 mg/kg per day seemed to produce satisfactory clinical effects. 5. As for dose per day, the t.i.d. regimen of CXD 20.5 approximately 30.4 mg/kg seemed to exhibit satisfactory clinical responses, as already mentioned. Because of quite a small number of patients on the q.i.d. regimen of higher doses, however, the question of whether the t.i.d. treatment with 20.5 approximately 30.4 mg is adequate or not should be determined by a comparative study between the q.i.d. and t.i.d. treatments. 6. As for bacteriological responses, a high global effect of 87.1% was obtained with CXD against S. aureus and S. pyogenes isolated from 74 and 1 cases, respectively. 7. As for impetigo with predominant number of cases, CXD was highly effective bacteriologically at a daily dose of 20.5 approximately 30.4 mg/kg t.i.d. As an appropriate comparative evidence with the q.i.d. treatment was lacking, however, therapeutic validity of the t.i.d. treatment could not be determined definitely. 8. Utility was evaluated by the attending physicians on the total 99 cases, and CXD showed as high as 88.9%. 9. There were neither non-compliances nor adverse reactions to this treatment. 10. CXD showed a distribution of antimicrobial activity similar to that of CEX, against 74 isolates of S. aureus with the MICs of CXD ranging from 1.56 to 25 mcg/ml and those of CEX ranging from 0.78 to 25 mcg/ml, with peak MIC being 3.13 mcg/ml for both drugs. As for S. pyogenes, only one isolate from the same species, CXD was antimicrobial activity at 0.2 mcg/ml and CEX was antimicrobial at 0.39 mcg/ml. The above findings suggest that CXD is highly effective against acute skin and soft tissue infections in pediatrics.

Clinical studies of cefroxadine (CXD), a new orally active of cephalosporin, in obstetrical and gynecological field were performed, and the results were summarized as follows. CXD was orally administered to 16 cases of obstetrical and gynecological infections in daily dose 750 approximately 1,500 mg. Clinical efficacy was 88.9% in endometritis (9 cases), 100% in cervicitis (2 cases), 75% in adnexitis (4 cases) and 100% in suppurative haematoma vulva (1 case), respectively. Overall efficacy was 87.5% (14/16). Clinical efficacy classified by caused organisms was 83.3% (10/12) overall, and bacteriological effect was 91.7% (11/12). Neither side effects nor abnormalities in laboratory findings caused by this drug were observed. Based on these results, CXD should be considered a very safe and useful drug for treating obstetrical and gynecological infections.

The clinical efficacy and safety of cefixime (CFIX), a new oral cephalosporin, were compared with those of cefroxadine (CXD) in patients suffering from acute lacunar tonsillitis in a double blind study. Two hundred and fifty two patients were given each orally 100 mg of CFIX b.i.d. or 250 mg of CXD t.i.d. for, in principle, 7 days. Number of patients evaluated for clinical efficacy was 202 (103 treated with CFIX and 99 treated with CXD). As for the backgrounds of patients, more severe cases were found in the CFIX group than in the CXD group (P less than 0.01). Efficacy rates evaluated by individual doctors were 88.3% in the CFIX group and 91.9% in the CXD group. There was no significant difference between the 2 groups. Efficacy rates on the third day after the initiation of treatment evaluated by the committee were 40.8% in the CFIX group and 47.9% in the CXD group with no significant difference. Efficacy rate on the 7th day, however, was 79.8% in the CFIX group and 93.4% in the CXD group, showing a significant difference (P less than 0.05). Bacteriological effectiveness were satisfactory for both groups with eradication rates of 93.4% for the CFIX and 96.9% for the CXD group. Number of patients evaluated for safety was 226 (110 treated with CFIX and 116 treated with CXD). No significant difference was observed between the 2 drug groups in incidences of side effects; gastrointestinal disturbances or rashes were noted in 6 patients (5.5%) of the CFIX group and in 5 patients (4.3%) of the CXD group. As for the abnormal laboratory findings, elevation of GOT & GPT was observed in 1 patients of the CFIX group. From these results, it was concluded that 100 mg b.i.d. of CFIX was as useful as 250 mg t.i.d. of CXD in the treatment of acute lacunar tonsillitis.

The pharmacokinetics of cefroxadin have been studied after the administration of single oral and intravenous doses to healthy volunteers. Cefroxadin was assayed by HPLC. The kinetics in plasma following i.v. administration were described by using a three-compartment model. An additional disposition phase was observed following oral administration that could not be detected after the low i.v. dose. The terminal half-life was 1.03 h. The apparent volume of distribution at the steady state was consistent with a diffusion of the antibiotic in all extracellular fluids. The AUC after oral administration was linearly related to the dose. The urinary excretion amounted to 95% of the dose with virtually complete absorption of orally administered drug.

A total of 64 out-patients with significant urinary tract infection were randomly allocated to treatment with cefroxadine 250 mg q.i.d. or cephalexin 500 mg q.i.d. for ten days. Urine cultures were performed before allocation to the treatment groups and on Days 0, 1, 3, 7 and 21. Twenty patients discontinued treatment prematurely because of insignificant bacteriuria on Day 0. Both drug regimes--the cefroxadine dose was half that of cephalexin--showed good activity during treatment, and no statistically significant differences were found between the two drugs. At follow-up, several relapses were found in both treatment groups. Adverse drug reactions were only reported by three patients in the cefroxadine group, and by none in the cephalexin group.

The pharmacokinetics of cefroxadine, a new orally active broad-spectrum cephalosporin, was studied in healthy volunteers and patients with impaired renal function after a single oral dose of 500 mg. The pharmacokinetic parameters of cefroxadine were obtained by analysing the serum level data of the drug based on a one-compartment open model. The mean serum half-life of cefroxadine was 0.97 h in healthy subjects, and was prolonged to 41.7 h in patients with a creatinine clearance of less than 5 ml/min. There was a significant linear correlation (p less than 0.001) between the elimination rate constant of the drug and the creatinine clearance. In healthy subjects, 71% of the administered dose was excreted in the urine collected over the first 6 h.

CGP 9000 (cefroxadine), a new cephalosporine derived from N-acyl-3-alkoxy-7-amino-3-cefem-4-carboxylic acid for exclusively oral use, has been experimented on 67 patients, 41 adults and 20 children. CGP 9000 appeared to possess good therapeutic activity, even in low doses: its rapid absorption and moderate sero-protein bond are a guarantee of an immediate and almost total bioavailability.

The new semi-synthetic oral cephalosporin, CGP 9,000, has been evaluated in a large number of hospitalized patients with urinary infections. A total of 57 of these patients suffering from concomitant diabetes was matched with an equal number of non-diabetic patients. Patients were treated for 10 days with either 500 mg or 1.0 g CGP, or 1.0 g cephalexin. The predominant pathogens isolated were E. coli, Strep. faecalis, Proteus mirabilis and Klebsiella spp. Comparison of the results showed that the eradication rate was similar in diabetic and non-diabetic patients and there were no significant differences between the three treatment groups. There was a similar improvement in pyuria, and therapeutic response was equally as good in diabetic patients on 500 mg CGP 9,000 per day as in non-diabetic patients and in the other treatment groups. No unwanted effects on renal function were observed in the high-risk diabetic group.

To evaluate the efficacy, safety, and utility of cefroxadine (CXD) for the treatment of complicated urinary tract infections, a double blind study comparing CXD with cephalexin (CEX) was carried out. Patient received either 1,500 mg/day of CXD 3 times a day, or 2,000 mg/day of CEX 4 times a day for 5 days by oral route, and the following results were obtained. Of the 305 patients, clinical efficacies were evaluated in 220 cases (CXD 105 cases, CEX 115 cases) except that excluded or dropped out. Side effect was evaluated in 301 cases (CXD 150 cases, CEX 151 cases). There was no statistically significant difference in the back ground characteristics between the 2 groups. Overall clinical assessment by the committee according to the "Criteria for Evaluation of Clinical Efficacy of Antimicrobial Agents on Urinary Tract Infection" patients evaluated as better than "good" were 64 of 105 (61.0%) for CXD and 75 of 115 (65.2%) for CEX. The difference between the 2 groups was not statistically significant. In effect on pyuria, patients evaluated as better than "decreased" were 58 of 105 (55.2%) for CXD and 69 of 115 (60.0%) for CEX. The difference between the 2 groups was not statistically significant. In effect of bacteriuria, patients evaluated as better than "decreased" were 57 of 105 (54.3%) for CXD and 69 of 115 (60.0%) for CEX. The difference between the 2 groups was not statistically significant. Analyses were stratified according to classification by the type of infection, diagnosis, degree of pyuria before treatment, and bacterial count before treatment. There were no statistically significant differences between the 2 treatment groups as to any item. In evaluation by attending physician, patients evaluated as better than "good" were 81 of 140 (57.9%) for CXD, and 85 of 141 (60.3%) for CEX. Statistically significant difference was not observed between the 2 groups. In drug usefulness by attending physician, patients evaluated as better than "usefulness" were 106 of 140 (75.7%) for CXD, and 109 of 141 (77.3%) for CEX. The difference between the 2 groups was not statistically significant. In evaluation of the infections with sensitive species to both CXD and CEX by the committee according to "Criteria for Evaluation of Clinical Efficacy of Antimicrobial Agents on Urinary Tract Infections, overall clinical efficacies were evaluated in 102 (CXD 48 cases, CEX 54 cases) which were infected with sensitive species. There was no statistically significant difference in the back ground characteristics between the 2 treatment groups.(ABSTRACT TRUNCATED AT 400 WORDS)

Cefroxadine (CXD), a new cephalosporin, was orally administered to 22 cases in total; 5 with wound infection, 4 with felon, 3 with acute pyelonephritis, 2 with furuncle, 2 with infected atheroma, 2 with phlegmone, 2 with abscess, 1 with acute mastitis, and 1 with lymphadenitis. The daily dose was 500 to 1,000 mg, and maximal total dose and duration was 5 g and 5 days, respectively. Therapeutic results were good in 20 cases (effectiveness rate: 91%), fair in 1 and poor in 1. No side effect was observed in all cases among 22 patients with CXD.

Urinary enzyme excretion was studied in 56 patients treated with cephalosporins in order to evaluate their potential nephrotoxicity. Only in 4 out of 56 patients (7%) was increased NAG, gamma-GT, AlP excretion seen. A rapid return to normal values was observed just after the end of the therapy.