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Currently, beta-lactamase-negative (BLN) ampicillin-resistant (AR) strains of Haemophilus influenzae are prevalent in Japan. BLNAR strains are defined by the presence of specific mutation(s) in the ftsI gene but are not phenotypically distinguishable by ampicillin (ABPC) susceptibility. In the present study, we showed that cephalexin (CEX), cefsulodin (CFS), and cefaclor (CCL) disk diffusion tests can be effectively used to identify BLNAR strains. A total of 169 clinical isolates of BLN H. influenzae, consisting of 113 of BLNAR and 56 of BLN, ampicillin-susceptible (AS), were included. All the isolates were genetically defined by detection of the TEM gene and partial sequencing of the ftsI gene. The Clinical and Laboratory Standards Institute (CLSI) standard broth microdilution and disk diffusion tests for ABPC provided 20% and 19% false susceptible rates, respectively. Alternatively, 34 cephem agents were tested using disk diffusion. Of the agents tested, CEX, CFS, and CCL disks could effectively discriminate between BLNAR and BLNAS isolates. All the BLNAS isolates showed visible growth inhibitory zones around CEX and CFS disks, but 108 (95.6%) and 106 (93.8%) BLNAR isolates did not. The results indicated 100% predictive values (PVs) for BLNAR and PVs for BLNAS were 91.8% for CEX and 88.9% for CFS. The CLSI-based interpretations for CCL (> or =20 mm) also highly correlated with BLNAR and BLNAS, PVs for BLNAR and for BLNAS being 100% and 93.3%, respectively. With simplicity and discriminability of the test method, we recommend a CEX disk diffusion test in combination with a rapid beta-lactamase test to identify BLNAR isolates in clinical laboratories.

Consensus has been achieved supporting the efficacy of antimicrobials in the management of acute otitis media with effusion (OME). No such agreement has been reached into medical management of the patient in whom middle ear effusion (MEE) persists beyond the conventional 10- to 14-day treatment cycle. This study is designed to demonstrate the efficacy of antibiotics administered in a single daily dose in the management of persistent otitis media with effusion (POME). Seventy-nine subjects who had MEE in 116 ears after conventional therapy were randomized into medication and placebo groups and followed by the authors on a blinded basis. The results demonstrate the efficacy of pulse-dosed antibiotics in the management of POME. Prevention of relapses during therapy was responsible for the superior outcome for children in the treatment group.

Effects of cefaclor (3-chloro-7-D-(2-phenyl-glycinamido)-3-cephem-4-carboxylic acid) on PAF, ADP, collagen, endotoxin, and thrombin-induced platelet aggregation were examined in vitro with the use of guinea pig platelet-rich plasma and washed platelets. PAF, even at concentrations lower than its minimum effective concentration, enhanced ADP- or endotoxin-induced platelet aggregation and prolonged the time to attain the maximum aggregation. PAF also enhanced collagen-induced platelet aggregation and shortened the lag time. Cefaclor (CCL) inhibited the PAF, ADP or thrombin induced platelet aggregation and shortened their maximum aggregation times at higher concentrations such as 300 micrograms/ml or more. CCL also inhibited the collagen-induced platelet aggregation and prolonged the lag time, but showed no effect on endotoxin-induced platelet aggregation. The effect of CCL was almost the same as that of latamoxef (LMOX). CCL and LMOX, however, showed no effect on cellular Ca2+ increase produced by PAF, ADP, or thrombin, suggesting that the inhibitory effect of CCL and LMOX on platelet aggregation is caused by the inhibition of fibrinogen binding to the glycoprotein IIb/IIIa complex.

The in vitro activity of a new cephalosporin (CPX) was assessed against 260 strains of anaerobic bacteria. A comparison was done with two other oral cephalosporins cefaclor (CFA) and cefuroxime (CXM). MICs were determined by an agar-dilution method on wilkins chalgren agar. The three antibiotics had little activity against Bacteroïdes fragilis group. Cefpodoxime was more active than the two other cephalosporins against Fusobacterium and Bacteroïdes spp. At 4 mg/l concentration the percentages of susceptibility were respectively CFA 8% CXM 11% for all the Gram negative bacilli. Inversely, a better activity was detected against Gram positive anaerobes; the three cephalosporins inhibiting respectively CFA 65% CXM 75% CFX 46% of 94 tested strains. All Veillonella spp. and Propionibacteria were inhibited by cefpodoxime 4 mg/l. The activity of the three cephalosporins were similar weak against Gram negative anaerobes but greater against Gram positive strict anaerobes.

Fifty-four children with acute diarrhoea were treated orally with 50 mg/kg/day of either ampicillin in 4 divided doses, or with cefaclor in 3 divided doses for 5 days. Shigella was isolated from the stool of 28 patients, 6 of whom were hospitalized. All isolates, including ampicillin-resistant strains, were susceptible in vitro to cefaclor. For ampicillin-sensitive infections, the clinical response and clearing of Shigella from stools appeared to occur more rapidly in patients treated with ampicillin than in those treated with cefaclor. In areas where ampicillin resistance is a problem, cefaclor appears not to be a drug of choice for the treatment of Shigella.

Clinical efficacy and safety of S6472 (long active cefaclor (CCL)) and CCL were compared by a double-blind study using 248 patients with bacterial bronchitis. Patients were orally administered with either 375 mg of S6472 2 times or 250 mg of CCL 3 times daily for 7 days, and the following results were obtained. Clinical efficacy judged by a committee: The efficacy rates on acute bronchitis were 87.2% for S6472 and 82.6% for CCL, and the efficacy rates on chronic bronchitis were 70.3% for S 6472 and 64.7% for CCL. There was no significant difference between the 2 drugs in clinical efficacy. Clinical efficacy judged by doctors in charge: Results of the clinical efficacy judged by doctors in charge were similar to the efficacy judged by the committee. Bacteriological efficacy judged by the committee: Eradication rate for the S6472 group was 71.1% (32 of 45 patients) and that for the CCL group was 67.4% (29 of 43 patients). There was no significant difference between the 2 drugs in the bacteriological efficacy. Side effects and abnormal laboratory findings: Side effects were observed in 5 cases (4.2%) in the S6472 group and in 5 cases (4.0%) in the CCL group. These side effects, however, were not serious, and no remarkable abnormal laboratory values were observed. There was no significant difference between the 2 drugs in the incidence of side effects or abnormal laboratory findings. Clinical utility: When the clinical utility was expressed by the utility rate (very useful and useful), it was 79.5% in the S6472 group (117 patients) and 76.2% in the CCL group (122 patients) (judged by the committee). When the utility was judged by doctors in charge, it was 73.3% in S6472 group (120 patients) and 71.4% in CCL group (126 patients). From the above results, it has been concluded that S6472 taken twice daily is equivalent to CCL in effectiveness on bacterial bronchitis.

A randomized, double-blind, controlled trial was carried out to compare amoxycillin and cefaclor in the treatment of respiratory tract infections in general practice. Their effect on the microflora of the oropharynx, their clinical effectiveness, side-effects and the incidence of superinfections were monitored. Amoxycillin and cefaclor were given three times daily in a dosage of 375 and 250 mg, respectively, for 7 days. In 72 patients treated with amoxycillin, the oropharynx became colonized with resistant Gram-negative rods in 24, with Pseudomonas in 1, with Staphylococcus aureus in 3 and with yeasts in 2 patients. In 67 patients treated with cefaclor only 2 patients became colonized with Gram-negative rods. In the amoxycillin group, 5 superinfections developed within 4 weeks after treatment. No superinfection occurred after treatment with cefaclor. Clinically, cefaclor was more effective than amoxycillin and showed fewer side-effects.

In an attempt to investigate penetration of cefaclor into human aqueous humor, we administered 500-mg and 1-g doses of cefaclor to 39 patients about to undergo cataract extraction. Average aqueous humor levels of 0.27, 0.27, and 0.17 microgram/mL were achieved at 1, 2, and 4 hours, respectively, after the 500-mg oral dose. After 1 g orally, we found average aqueous humor levels of 0.61, 0.64, 0.72, 0.4, and 0.31 microgram/mL at 1, 2, 3, 4, and 5 hours, respectively. Therapeutic levels in primary aqueous humor were consistently achieved against Streptococcus pneumoniae and St pyogenes, group A.

A comparison of the minimal inhibitory concentrations (MIC) of cefaclor and cephalexin shows that cefaclor is noticeably superior against Citrobacter. Enterobacter and Proteus mirabilis. Only slight differences are seen against other enterobacteria and Staphylococcus aureus. Both cefaclor and cephalexin are completely ineffective against enterococci and Pseudomonas aeruginosa. Regression analysis to correlate the inhibition zone diameter and MIC of cefaclor produced a very good correlation (r = -0.9741). Using 30 mcg discs on DST agar, inhibition zones of more than 20 mm are to be interpreted as "sensitivity" and zones of less than 13 mm as "resistance".

This report deals with studies of the effectiveness, tolerance and toxicity of cefaclor in the treatment of 45 patients with urinary tract infections (40 cases) and pneumonia (5 cases) caused by susceptible pathogens. Cefaclor was administered orally in a dosage of 1 to 3 g per day for 7 to 11 days. Clinical and laboratory examinations were performed before, during, at the end of treatment, and 4 weeks later in cases of urinary infection. All 5 patients with pneumonia and bronchopneumonia were cured. Clinical and bacteriological cures were obtained in 28 (70%) of the 40 cases of urinary tract infections. Identification and typing of microorganisms, disk sensitivity tests, minimal inhibitory concentrations and cefaclor blood levels also were determined.

In both Mueller-Hinton agar (MHA) and antibiotic medium no. 1 (AB1) cefaclor was more active than cephalothin or cephalexin against Enterobacteriaceae. Its activity was equivalent to cephalexin against S. aureus in MHA. Cefaclor was particularly active against P. mirabilis. The activity of this antibiotic was greated in AB1 than in MHA. The inoculum effect was pronounced for cefaclor when compared with cephalothin, but cefaclor retained greater activity even against the higher inoculum. In volunteers with normal renal function, cefaclor produced slightly lower blood levels than those reported for cephalexin. Absorption after eating was decreased and delayed. Despite severe renal failure, substantial urine levels of antibiotic were still achieved. In contrast to cephalexin, plasma half-life for cefaclor was only moderately prolonged by renal failure (two-to-threefold) and only minimally shortened by haemodialysis. Adequate concentrations of cefaclor in sputum, active against common respiratory pathogens, could not be consistently demonstrated after the oral administration of a 1 gram dose of cefaclor.

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.

Cefaclor appeared to be an effective antibiotic against both beta-lactamase-positive and beta-lactamase-negative strains of Haemophilus influenzae type b when tested with 10(5) colony-forming units per ml. With inocula in excess of 10(6) colony-forming units per ml, these organisms were neither inhibited nor killed at concentrations of 400 micrograms/ml. This inoculum effect was also demonstrated in time-kill curve studies.

The antibacterial activity of the new oral cephalosporin cefaclor was investigated using 623 freshly isolated bacterial strains. A high degree of efficacy of cefaclor was noticed against Escherichia coli, Proteus mirabilis and Klebsiella. Nearly all strains which were sensitive to ampicillin, tetracycline and co-trimoxazole were also inhibited by cefaclor. Some of the strains resistant to the three above-mentioned antibiotics were also sensitive to cefaclor as follows: all of ten P. mirabilis strains resistant to co-trimoxazole, 54% of the E. coli strains resistant to ampicillin, tetracycline and co-trimoxazole, and 18% of the Klebsiella strains resistant to tetracycline and co-trimoxazole.

S6472 is a mixture of cefaclor (CCL) granules with gastric-soluble coating and those with enteric-soluble coating at the ratio (in potency) of 4 to 6. With administration of this formulation, a prolonged blood level of CCL is obtained. S6472 and CCL were administered orally to 19 healthy male volunteers between 20 and 27 years of age (mean: 23 years) weighing between 51 and 80 kg (mean: 64.7 kg). Four subjects were given 2 capsules and 5 subjects were given 4 capsules each containing 187.5 mg of S6472, 30 minutes after breakfast and supper for 5 days. Five subjects were given 1 capsule and 5 subjects were given 2 capsules each containing 250 mg of CCL 30 minutes after breakfast, lunch and supper for 5 days. The number of fecal bacteria was examined 5 days before the start of administration, the day of the start of administration, 3 and 5 days after the start of administration, and 3, 5 and 10 days after the end of administration. Concentration of CCL in feces and susceptibility of isolated fecal bacteria (at the inoculum size of 10(6) cells/ml) to CCL were examined. Adverse reactions and the effects on laboratory test values were also checked. In 4 subjects receiving 375 mg of S6472 twice a day, the mean population of E. coli was 10(7)-10(9) cells/g feces on all days of observation. There was no effect on the population of Klebsiella sp., Citrobacter sp. Enterobacter sp. and other Enterobacteriaceae. The mean population of all Enterobacteriaceae was 10(8)-10(9) cells/g feces on all days of observation. The population of other Gram-negative bacilli did not show a consistent change, either. There was no effect on the population of Gram-positive bacteria such as Staphylococcus sp., Enterococcus, sp., Micrococcus sp., and of Candida sp. Among anaerobic bacteria, Bacteroides sp. showed the mean population of 10(10) cells/g feces on all days of examination. C. difficile was isolated from 2 subjects out of 4 at the level of 10(2)-10(3) cells/g feces 5 days after the start of administration and 3 days after the end of administration. However, there was no production of toxin in either of the 2 subjects. In another subject, C. difficile was isolated at 10(2)-10(4) cells/g feces with a toxin titre of 10(-3)-10(-4) 3 and 5 days after the start of administration and 10 days after the end of administration. The total population of anaerobic bacteria was 10(10)-10(11) cells/g feces on all days of examination.(ABSTRACT TRUNCATED AT 400 WORDS)

The bactericidal activity against Staphylococcus aureus 290-P, Escherichia coli NIHJ-JC2 and Klebsiella pneumoniae ATCC-10031 (10(6)/ml) was studied during 24 h, using an in vitro kinetic model which simulates the drug concentrations occurring in human serum after oral doses of amoxicillin (0.5 g or 1 g) or cefaclor (0.25 g or 0.50 g), 2 or 3 times a day. After the first antibiotic exposure, a high level of bactericidal activity (99-99.9%) was observed. Complete bactericidal activity was observed in all cases against S. aureus, but only after 3 times per day exposures in the case of E. coli and K. pneumoniae. Twice per day exposures of amoxicillin or cefaclor were invariably ineffective for these two species of Enterobacteriaceae (10(9) bacterial survivors/ml). These findings were related to subinhibitory concentrations which were or not able to prevent or reduce the bacterial regrowth after the first exposure of the antibiotics.

Susceptibilities of 169 strains of 30 bacterial species to cefaclor (CCL) were determined by the 2-fold agar dilution method in parallel with the diameter of inhibition zones by the single-disc method, under the experimental condition established by Kanazawa. The experiments demonstrated significant correlation between MIC by the dilution method and diameter of inhibition zone in each of conventional assay of the over-night (about 16 hours) incubation, delayed assay (about 24 hours incubation), and rapid assay (after 3-4 or 5-6 hours incubation), thus confirming applicability of the single-disc assay for CCL. Analysis of the data obtained by using CCL disc containing 30 micrograms revealed the primary regression equation to be: D (diameter, mm) = 28.2--10.2 log MIC (micrograms/ml) in conventional assay, D = 33.8--13.0 log MIC (micrograms/ml) in delayed assay, D = 17.9--5.1 log MIC (micrograms/ml) in 3-4 hours rapid assay and D = 22.6--7.4 log MIC (micrograms/ml) in 5-6 hours rapid assay, respectively. The range of variations in MICs estimated from the diameter of inhibition zone by the disc test was then calculated in comparison with that in MIC determined by the 2-fold agar dilution assays, as reference for the experimental errors which may be involved in the estimation of MIC of CCL by the single-disc assay.

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.

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.

Cefaclor (CCL) is a cephem antibiotic for oral use. Thirty cases of infection of oral regions, in the First Department of Oral and Maxillofacial Surgery, School of Dentistry, the University of Tokushima, were treated with CCL at 750 mg/day. The results were as follows: The efficacy rate for all kinds of diseases was 80.0% in 3 days and 96.7% in 5 days and 86.7% as an overall assessment by the patients' doctors. With regard to the degree of symptoms, the efficacy rate for cases with moderate symptoms was less than that for mild cases in 3 days and according to the assessment by the patients' doctors. Some moderate cases required increased medication because no beneficial effect was observed. In sensitivity tests, CCL was shown to be effective on all 27 isolated clones of bacteria tested. CCL caused no detectable changes in laboratory data. No side effects were observed in any case. From these results, it is concluded that CCL is a highly effective antibiotic for use on infections of the oral regions.

Cefaclor, a new orally administered cephalosporin, was evaluated by a randomized trial for effectiveness in the treatment of uncomplicated urethritis due to Neisseria gonorrhoeae in men. Regimens included 2,3, and 4 g of cefaclor, with or without 1 g of orally administered probenecid, as single daily doses for three days. The diagnoses were confirmed by isolation of N. gonorrhoeae; cures or therapeutic failures were determined by follow-up cultures on day 7 after completion of therapy. Sixty-six (73%) of 90 treated patients were evaluable for efficacy. The bacteriologic cure rate was 98% (65/66); one patient treated with 2 g of cefaclor plus probenecid had a positive culture for N. gonorrhoeae on follow-up examination. Adverse reactions consisted of mild nausea in five patients (7%) and vomiting in one patient (1%) who received 3- or 4-g doses. No treatment was discontinued, and no abnormality of screening hematologic tests or enzymes was observed. Thus, cefaclor, given in multiple doses, was highly efficacious for treatment of uncomplicated gonococcal urethritis in men.

The dependence of the antibacterial activity of the two oral cephalosporins cefixime and cefaclor on pharmacokinetic properties was investigated in an in vitro model using strains of enterobacteria and a streptococcal strain. In the cultures the course of serum concentrations of the respective antibiotic was simulated. The more rapidly attained (1 h) high peak levels (17.5 micrograms/ml) of cefaclor (500 mg dose) in no case showed an advantage over the more slowly reached (3 h) low peak levels (2.5 micrograms/ml) of cefixime (200 mg dose). Cefixime was comparable to cefaclor with respect to its initial killing velocity, whereas it was generally superior with respect to maximum values for reduction of bacterial counts. Due to its long elimination half-life (2.5 h) cefixime prevented regrowth for at least twice as long as cefaclor, which has a short half-life (0.7 h). As a result of its antibacterial activity and pharmacokinetic properties cefixime can be administered less frequently than cefaclor.

The in vitro activity of cefaclor, cephalothin and cefadroxil to 50 Escherichia coli, 23 Klebsiella pneumoniae and 20 Proteus mirabilis strains was tested with the disc diffusion and microdilution plate techniques. Cefaclor was more active than cefadroxil, while cephalothin was intermediate. The differences seriously affected the classification into the routine SIR system. For susceptibility testing we question the use of cephalothin as a class representative of oral cephalosporins.

Twenty-eight patients with acute otitis media were treated in a random double blind manner with either amoxycillin or cefaclor. The predominant organisms isolated were H. influenzae and S. pneumoniae. All patients responded satisfactorily except one, treated with cefaclor, whose compliance with the regimen was very doubtful. One instance of mild elevation of SGOT and one case of mild erythematous rash occurred in each treatment group. In this limited study, cefaclor appeared comparable to amoxycillin in the treatment of acute otitis media.

A prospective double blind trial compared the fixed combination of erythromycin-sulfisoxazole (E/S) with cefaclor in the treatment of acute otitis media. One hundred nineteen children in six centers across Canada were studied. Diagnostic tympanocentesis of 134 ears yielded 135 bacterial isolates: Streptococcus pneumoniae (42%); Haemophilus influenzae (21%); Branhamella catarrhalis (10%); Streptococcus pyogenes (5%); and other bacteria (22%). Seventy-seven percent of strains of B. catarrhalis and 14% of strains of H. influenzae were beta-lactamase producers. E/S exhibited greater in vitro activity against H. influenzae and B. catarrhalis. Twenty-three patients had bacteriologically sterile middle ear fluid. The overall clinical outcome at Days 10 and 31 was identical in both treatment groups. Otoscopic findings improved more rapidly in the E/S group than in the cefaclor group at 10 and 31 days (P less than or equal to 0.04). In cases where pre-treatment middle ear fluid was negative on routine bacterial culture, complete cure at 10 days was observed in 75% of patients treated with E/S but only in 14% of those treated with cefaclor (P = 0.02). Side effects were infrequent and comparable between the test drugs. E/S is at least as effective as cefaclor in the management of acute otitis media and may be superior, particularly for cases not yielding bacteria on routine culture.

Laboratory aspects of cefaclor, a new orally-effective cephalosporin antibiotic, are summarized. On the basis of data from a variety of studies, the useful antibacterial spectrum of cefaclor is shown to include all classes of bacteria that are generally susceptible to cephalothin and cephalexin. Against many Enterobacteriaceae, Haemophilus sp. and Streptococcus pneumoniae, cefaclor has a significant potency advantage over cephalexin. Bacteria that are susceptible to cefaclor are killed by concentrations at or near the inhibitory concentration. In vitro enzymatic hydrolysis experiments have shown that cefaclor is a relatively good substrate for several beta-lactamases. Orally administered cefaclor is effective in protection of mice from the lethal effects of intraperitoneal challenges with cefaclor-susceptible bacteria. The chemical instability of cefaclor, test medium composition and inoculum density influence the results of in vitro susceptibility tests with cefaclor. Methods for routine susceptibility testing are described.

805 clinical isolates were investigated for their in vitro sensitivity against Ro 15-8074 and Ro 19-5247 in comparison to cefaclor and cefalexin in a serial dilution test on solid medium. Ro 19-5247 had the strongest activity of all drugs tested against streptococci (except Streptococcus faecalis) and was as active as cefaclor and cefalexin against most strains of Staphylococcus aureus. Ro 19-5247 was the only oral cephalosporin active against Bordetella pertussis. It was on average 160 times more active than cefaclor against Haemophilus influenzae. In its activity against enterobacteria Ro 19-5247 was always superior to cefaclor and cefalexin. Only a few strains of Enterobacter aerogenes, Enterobacter cloacae, Klebsiella pneumoniae, Proteus vulgaris and Serratia marcescens were resistant to Ro 19-5247 as were all strains of Enterobacter agglomerans and Klebsiella ozaenae. Ro 15-8074 was inactive against staphylococci but ten times more active than cefaclor and cefalexin against Streptococcus pyogenes. There was no difference in the activity against Streptococcus pneumoniae and Streptococcus agalactiae. Against Haemophilus influenzae Ro 15-8074 acted 12 times stronger than cefaclor and 100 times stronger than cefalexin. The activity against enterobacteria corresponded to that of Ro 19-5247. Ro 15-8074 was also active against most strains of Enterobacter cloacae and Proteus vulgaris which were resistant to cefaclor and cefalexin.

The in vitro activity of cefaclor was compared with that of cephalexin and cephradine. This new antibiotic was the most active of the oral agents against Haemophilus influenzae (especially non-beta-lactamase producing strains). It was also significantly more active against N. gonorrhoeae and the Enterobacteriaceae. The instability in agar raises some issues that need further study.

The effect of cefaclor on the steady state pharmacokinetics of theophylline was investigated in healthy young adults by comparing the pharmacokinetic parameters as found during a nine days course of theophylline alone and as obtained during co-medication with the antibiotic cefaclor. The pharmacokinetic parameters obtained on Day 9 during the two periods of drug treatment accounted for the following figures respectively: minimum plasma concentration 5.0 +/- 1.7 mg X 1(-1) (mean +/- SD) and 6.0 +/- 2.0 mg X 1(-1); maximum plasma concentration 9.7 +/- 2.6 mg X 1(-1) and 9.0 +/- 2.6 mg X 1(-1); time to peak 3.2 +/- 0.4 h and 3.9 +/- 0.8 h; AUC 132.54 +/- 41.73 mg X 1(-1) X h and 126.90 +/- 40.45 mg X 1(-1) X h; half-life of elimination 6.6 +/- 1.6 h and 7.1 +/- 1.2 h; clearance 0.059 +/- 0.011 1 X h-1 X kg-1 and 0.063 +/- 0.014 1 X h-1 X kg-1; volume of distribution 0.54 +/- 0.09 1 X kg-1 and 0.64 +/- 0.17 1 X kg-1. Only the values for cmax and tmax after cefaclor co-treatment were slightly, but significantly (p less than 0.05) different from the values found after administration of theophylline alone. As the volume of distribution and the clearance were not affected by cefaclor, it is concluded that both drugs can be given concomitantly without any dosage adjustment of theophylline.

The effect of cefaclor (CCl) and other orally applied antibiotics were examined on different parameters of the immune response. It could be shown that CCl enhances specific IgM response in a dose dependent profile. This is dependent on the application time relative to immunization because it reduces the reaction if given thereafter. IgG response is inhibited in low but not in higher doses. Cellular immune reaction in CCl treated animals evaluated with the footpad swelling test shows also a dose dependent profile but it is always enhanced compared with controls. The cortisone or cyclophosphamide induced immunosuppression is largely abrogated. Prostaglandin E2 (PGE2) production by macrophages and PGE2-sensitivity of lymphocytes are rather reduced if cell donors were treated with CCl. Interleukin 1 production is clearly stimulated. The enhanced survival rate of CCl treated animals observed in experimental infections with the primary resistant Candida species is explained by the concomitant inhibition of PGE2-production as an inhibitor of immune reactions and reduction of PGE2-sensitivity together with a stimulation of cellular immunity.

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 influence of Cefaclor and of Tobramycin on phagocytosis of sheep erythrocytes by murine peritoneal macrophages was investigated. The antibiotics in various concentrations were either added to the cells directly during the phagocytosis period or injected i.v. into cell donor mice at different times before cell harvest and the cells subsequently assayed for phagocytic activity in vitro. When antibiotic was added during the phagocytosis a dose-dependent inhibition of phagocytosis was observed which, however, became significant only at extremely high concentrations of the antibiotic. In all other experimental set-ups, phagocytosis was not influenced by antibiotics. Restrictive usage of either antibiotic in clinical situation does not appear mandatory on the basis of the reported observations.

The zone sizes and MICs of ampicillin, cefaclor and cephalexin were determined for 2458 clinical isolates of Haemophilus influenzae collected in 1986 during a national survey of the prevalence of resistance in this species. Cefaclor showed greater in-vitro activity than cephalexin against all isolates, with a modal MIC of 4 mg/l compared with 8 mg/l. MIC50 values for the 2201 ampicillin-sensitive and 157 beta-lactamase-positive resistant strains were similar for both cephalosporins (4 mg/l for cefaclor, and 8 mg/l for cephalexin). A further 100 strains with a reduced zone (less than 20 mm) to a 2 micrograms ampicillin disc showed a definite (MIC greater than or equal to 4 mg/l) or intermediate (MIC 1 or 2 mg/l) degree of intrinsic resistance to ampicillin. Both cephalosporins showed a marked and significant rise in MIC values for this group. Cefaclor is the more active agent against ampicillin-sensitive and beta-lactamase-positive H. influenzae but strains with an intrinsic mechanism of resistance to ampicillin are markedly less sensitive to both cefaclor and cephalexin.

A comparative study was conducted on the in vitro activity of cefaclor and other oral cephalosporins against a large number of freshly isolated clinical strains of gram-negative and gram-positive bacteria. The activity of cefaclor against gram-positive pathogens is very similar to that of cephalexin. The action of cefaclor against Streptococcus pneumoniae is superior. Cefaclor is the most active antibiotic against strains of Haemophilus influenzae, and is also more active than cephalexin and cephradine against non-beta-lactamase producing strains of Escherichia coli, Klebsiella species and Proteus mirabilis.

Clinically relevant, recent isolates of common Gram-positive pathogens were examined for their in vitro susceptibility to cefaclor. Group A streptococci and pneumococci were uniformly sensitive (MICs 0.06--0.12 micrograms/ml) to both cefaclor and cephalothin. Cefaclor was 5--10-fold less active than cephalothin against group B streptococci. S. aureus strains were uniformly more susceptible to cephalothin than to cefaclor, but among isolates from children, almost all were sensitive to the latter drug. In clinical studies of patients with skin and soft tissue infections, cefaclor proved effective. Over 90% of patients with staphylococcal bullous impetigo, streptococcal and mixed streptococcal-staphylococcal forms of pyoderma were cleared after 7--10 day courses of treatment. In addition, twice-daily therapy, examined more recently, proved as effective in these forms of infection as did the conventional dose schedule. No significant adverse reactions were noted. Cefaclor appears to be an effective orally absorbed cephalosporin for common skin and soft tissue infections.

The agar diffusion method was used to test the antibacterial efficacy of cefaclor against bacterial strains isolated routinely from patients in two hospitals in Berlin. A comparison was made with the efficacy of oxacillin, azlocillin, amikacin, gentamicin, ampicillin, co-trimoxazole, tetracycline, penicillin, cefazolin, nalidixic acid and nitrofurantoin. A total of 1235 strains of Staphylococcus aureus, enterococci, Escherichia coli, Klebsiella, Enterobacter, Proteus species, Citrobacter and Pseudomonas aeruginosa were tested. Cefaclor was superior to the other substances in its activity against E. coli, Klebsiellae, and Proteus mirabilis. Co-trimoxazole and tetracycline, on the other hand, proved more effective against indole-positive Proteus species and Citrobacter. Tetracycline was also more effective against Enterobacter. Ampicillin was the most effective agent against enterococci, and oxacillin the most effective against S. aureus. Cefaclor showed good antibacterial activity against strains which were resistant to the orally administrable agents ampicillin, tetracycline and co-trimoxazole.

A double-blind comparative study of S6472 and cefaclor (CCL) was conducted to evaluate the therapeutic efficacy, safety and usefulness in the treatment of skin and soft tissue infections. Either 750 mg b.i.d. of S6472 or 750 mg t.i.d. of CCL was administered orally to patients for a period of 7 consecutive days. Of the 250 cases (123 cases of S6472 group and 127 cases of CCL group) recruited in this trial, 228 cases (114 cases of S6472 and 114 cases of CCL) were adopted by the committee members for the evaluation of therapeutic efficacy, 238 cases (118 cases of S6472 group and 120 cases of CCL group) for usefulness, and 245 cases (121 cases of S6472 group and 124 cases of CCL group) were adopted for the evaluation of side effects. The backgrounds of both patients group were almost similar. The results obtained were as follows: Overall clinical effectiveness Of the 114 patients treated with S6472, excellent clinical responses were obtained in 11 patients, good in 79, fair in 19, poor in 5 (efficacy rate 78.9%), and of the 114 patients treated with CCL, excellent were in 16, good in 78, fair in 13, poor in 7 (efficacy rate 82.5%). There was no statistically significant difference between the 2 groups. Clinical effectiveness classified by initial severity and bacteriological efficacy There was no significant difference between the 2 groups in the clinical effectiveness classified by initial severity and in the bacteriological efficacy. Side effects were noticed in 5 patients of 121 treated with S6472 (4.1%) and in 2 patients of 124 treated with CCL (1.6%), and other 13 patients developed some abnormal laboratory findings. But these undesirable reactions were mild, and developed no significant difference between the 2 groups in the incidence of side effects. There was no significant difference between the 2 groups in the usefulness of the drugs. Conclusively, 750 mg b.i.d. of S6472 is anticipative of the same clinical efficacy, safety and usefulness as compared with that of 750 mg t.i.d. of CCL in the treatment of skin and soft tissue infections.

Cefaclor was given orally in doses of 250 mg every 8 h for 7 days to 10 volunteers. Saliva and faecal specimens were taken up to 16 days for cultivation of aerobic and anaerobic microorganisms and for assay of cefaclor. Cefaclor was not detected in saliva or faeces. In the oropharynx only minor changes in the anaerobic part of the microflora were observed. The microflora was normalized within 1 week after the administration of cefaclor had stopped. The aerobic intestinal microflora was unchanged during and after cefaclor administration while a minor impact on the anaerobic intestinal microflora was observed. The anaerobic intestinal flora returned to its normal state within 1 week. No new colonization with cefaclor resistant microorganisms were observed and no side effects were registered during the investigation period.

The influence of cefaclor taken for 8 days (250 mg every 8 h) on the pharmacokinetics of a single intravenous dose of theophylline (2 mg/kg administered on the 8th cefaclor day) was studied in a crossover fashion among 11 healthy adults (10 men and one woman). Theophylline concentrations were measured serially for 12 h by an immunofluorescence polarization technique. No influence of cefaclor was detectable on theophylline clearance, half-life, or volume of distribution. It is concluded that cefaclor and theophylline can be administered together safely.

A single oral dose of 3 g cefaclor was effective in the treatment of uncomplicated gonococcal infection in women due to penicillinase-producing strains of Neisseria gonorrhoeae (PPNG). Cefaclor was equally active in vitro against both PPNG (MIC range, 0.01-1.0 microgram/ml) and non-PPNG strains (MIC range, 0.005-2.0 micrograms/ml). As empirical treatment cefaclor was effective in 53 of 57 (93%) patients compared with ampicillin, to which only 37 of 53 (69.8%) patients responded. This difference was attributed to the 40% incidence of PPNG in the patients studied; as expected, such patients responded poorly to ampicillin.

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.

Five hundred and eighty-six strains of eight species of Enterobacteriaceae were tested for their resistance against cefaclor, cefamandole, cephalothin, ampicillin, mezocillin, tetracycline and co-trimoxazole. Cefaclor showed a low rate of resistance against Escherichia coli (1.2%), Klebsiella (2%) and Proteus mirabilis (3.1%), but a high rate of resistance against indole-positive Proteus species (60%) and Serratia (80%). Cefamandole was also effective against cefaclor and ampicillin resistant strains. Multiresistant strains were predominant especially amongst Enterobacter, Serratia and indole-positive Proteus species. Of 266 ampicillin resistant strains, 198 strains (74.4%) proved to be sensitive to cefaclor. Among the orally administered antibiotics cefaclor exhibited the best result with 12.1% resistant strains compared to 14.8% strains resistant to co-trimoxazole and 45.4% resistant to ampicillin.

Interpretive zone-size standards currently used for cephalothin and cefamandole disk tests also may be applied to tests with disks containing 30 micrograms of cefaclor or cefazolin. Against 627 representative isolates, susceptibility to cefaclor and cefazolin could be predicted by testing cephalothin. However, cefazolin is more active than cephalothin against isolates of Escherichia coli with a TEM beta-lactamase plasmid. The expanded spectrum of cefamandole continues to necessitate separate testing. Against methicillin-resistant staphylococci, cefaclor disks were more reliable than cephalothin or cefamandole, but false-susceptible results were seen with all four disks. For testing Haemophilus influenzae, the cefazolin disks were not reliable; cephalothin or cefaclor disks could predict susceptibility to either drug.

Serum and tissue concentrations of cefaclor were determined a total of 155 and 96 times respectively in 16 volunteers after a single dose of 1 g. At this dosage peak concentrations of 13.5, 14.5 and 13.4 mcg/ml were measured after 60, 90 and 120 minutes respectively. Tissues in which concentrations were measured included cortical bone, spongy bone, muscle, fascia, cutis and subcutis. By measuring blood concentrations of the tissue samples, a division could be made for purposes of calculation into intravascular and extravascular active components. Low amounts of extravascular cefaclor could be established merely in the fascia and in the cutis. The cefaclor concentrations found in spongy bone, muscles and subcutis proved to be determined to a large extent by the intravascular antibiotic. No cefaclor could be detected in cortical bone at the given dosage.

The antibacterial activity of cefaclor against 100 non-beta-lactamase producing and 11 beta-lactamase producing isolates of Haemophilus influenzae was compared with that of cephalexin, ampicillin, chloramphenicol, tetracycline and co-trimoxazole. A new standardized microtiter dilution technique was used. Cefaclor showed greater activity than did cephalexin and inhibited beta-lactamase producing H. influenzae isolates. Ampicillin was the most active compound against non-beta-lactamase producing isolates. One of our strains was resistant to chloramphenicol and one resistant to tetracycline.

The effect of the antibiotic drug cefaclor on steady state pharmacokinetics of theophylline was studied in healthy adults by comparing the pharmacokinetic parameters as found during a 9 days course of theophylline alone and as obtained during comedication with cefaclor. Theophylline plasma concentrations were measured by means of HPLC analysis. On the ninth day of each of the 2 periods of drug administration, a concentration-time curve was evaluated. It showed no influence of cefaclor on volume of distribution and clearance of theophylline and only a slight, but significant (p less than 0.05) influence on the values for Cmax and tmax after cefaclor co-treatment. It is concluded that both drugs can be given concomitantly without any dosage adjustment of theophylline.

Twelve healthy young male subjects received either cefixime, a new oral cephalosporin (CL 284,635), or cefaclor (six subjects on each drug) orally for 2 weeks. In the case of cefixime, single daily doses of 400 mg were taken; with cefaclor, the dosage was 250 mg three times daily. Modest changes in the fecal flora were noted in both drug groups, but the changes were of different types. In the case of cefixime, there was more of an impact on the indigenous flora, and in the case of cefaclor, there was more ingrowth of new flora. With cefixime, Enterobacteriaceae were usually decreased (the decrease in Escherichia coli count was statistically significant), as were counts of clostridia and sometimes Bifidobacterium spp.; the Bacteroides fragilis group was eliminated in one subject. Coincident with these decreases, four subjects had increases in counts of group D streptococci of 3 logs or more. There was new appearance of Clostridium difficile in four subjects and of Staphylococcus aureus in one; four new strains of Enterobacteriaceae appeared. With cefaclor, there was no decrease of E. coli counts; two subjects had elimination of Bifidobacterium spp. There was little change in counts of group D streptococci. On the other hand, there were 13 new strains of Enterobacteriaceae, two of S. aureus, and three of C. difficile.

The third part of our 3-years' continuous investigation on the clinical effect of cefaclor (CCL) against urinary tract infections was reported herein. CCL, a daily dose of 0.75 g t.i.d., has been applied for the treatment of (I) 69 cases with the uncomplicated acute cystitis in the women, and (II) 44 cases with the complicated. Rates of effectiveness obtained were 94.2% in (I), which was a little lower than the first or the second part of our report, and 70.5% in (II), which equaled the mean value of our first and second reports. Any definite difference was not obtained between the effectiveness rates in those who had ever been treated with CCL and those who not, in both (I) and (II) groups.