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Summary of laboratory studies on the antibacterial activity of cefaclor.

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. Cefaclor has a significant potency advantage over cephalexin against many Enterobacteriaceae, Haemophilus sp. and Streptococcus pneumoniae. 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.

Animals

Summary of laboratory studies on the antibacterial activity of cefaclor.

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.

Animals

[Subinhibitory activity of cefaclor and cephalexin (author's transl)].

The determination of the minimal inhibitory concentration (MIC), which is usually performed after 18 to 24 hours of incubation, results in the case of cefaclor in a false picture of the actual activity. Cefaclor is chemically so unstable that after 24 hours only 2-5% of the substance is microbiologically active. In order to compare the activity of cefaclor and cephalexin, the effect of subinhibitory concentrations of both antibiotics against Escherichia coli and Klebsiella pneumoniae strains was studied by means of turbidimetry. After eight hours the absolute inhibitory concentration of cefaclor was lower than that of cephalexin with both methods. At the same time the effect of subinhibitory concentrations of both antibiotics was equal. Automatic measurement over 20 hours showed at the end of the experiment a higher MIC, and also a higher subinhibitory range, for cefaclor than for cephalexin. In our opinion the absolute inhibitory concentration after eight hours should be the criterion used to evaluate the effectiveness of cefaclor and cephalexin, and not the MIC which is usually used. The eight-hour criterion should also be applied in clinical use.

Cefaclor

[Thin layer and high pressure liquid chromatography investigations with cefaclor in urine and serum (author's transl)].

After oral administration of 500 mg cefaclor, antibacterially active metabolites could not be detected in human urine using thin layer chromatography followed by bioautography. Degradation products of cefaclor could also not be detected in the serum of human volunteers (n = 10) using high pressure liquid chromatography with a reversed phase system. Cefaclor was eluated as a single and homogenous peak with a retention period of 2.9 min. High pressure liquid chromatography for the measurement of cefaclor serum levels and a technique for preparation of serum samples are described. After administration of 500 mg cefaclor to volunteers (n = 10), the average peak serum concentration of 9.8 mg/l, determined by high pressure liquid chromatography, was observed after one hour. Four hours later the serum level was 0.3 mg/l. Using microbiological methods no statistically significant difference was obtained in comparison with the chromatography results. Some of the sera stored at -75 degrees C for four weeks showed a substantial loss of activity of cefaclor.

Administration, Oral

Comparative study of cefaclor and amoxicillin in treatment of urinary tract infection.

Cefaclor or amoxicillin was given to 51 randomly assigned patients with urinary tract infections. Inclusion in the study required two pretreatment urine cultures yielding the same organism (susceptible to both antibiotics) in concentrations greater than or equal to 10(5)/ml. Both drugs were administered as 250 mg. orally every eight hours for ten days. Cefaclor was given to 27 patients and amoxicillin to 24. Most patients in both groups had negative urine cultures at five to nine days and four to six weeks following therapy. One patient in each group was unsuccessfully treated. Relapse or reinfection occurred with similar frequency in both treatment groups. Both antibiotics were well tolerated. minimal inhibiting concentrations (MICS) of cefaclor, amoxicillin, cephradine, and cephalexin were determined by an agar dilution technique for the 44 available pretreatment isolates (41 Escherichia coli and 3 Proteus mirabilis). Mean MICs (micrograms./ml., +/- SD) were 2.2 +/- 1.4 for cefaclor, 4.4 +/- 2.0 with amoxicillin, 8.1 +/- 4.2 for cephradine, and 5.7 +/- 3.0 with cephalexin. Cefaclor is highly active in vitro against those gram-negative bacteria which are commonly isolated from urine. Cefaclor is as effective as amoxicillin when administered three times daily for the treatment of urinary tract infection.

Amoxicillin

An evaluation of the toxicity of cefaclor in laboratory animals.

The toxicity of cefaclor, a new orally-administered cephalosporin, was evaluated in laboratory animals given single or multiple doses of the antibiotic. The acute toxicity data for cefaclor in mice, rats, dogs and monkeys were comparable to that previously reported for cephalexin. Rats were maintained on dietary mixtures of cefaclor which provided average daily doses of approximately 230 to 950 mg/kg for 28 days in subacute toxicity tests, and 160 to 675 mg/kg for 1 year in chronic toxicity tests. Treatment-related effects in the above studies were limited to soft stool excretion and caecal dilatation in the subacute test. Effects in dogs given daily oral doses of 50 to 200 mg/kg for 30 days were limited to a transient moderate fall in haemoglobin concentration in the two males at the highest dose. Soft stool excretion and occasional episodes of emesis were observed in dogs given cefaclor for 1 year at oral doses of 100 to 400 mg/kg/day. A reversible thrombocytopenia occurred in one animal at the highest dose. Analysis of various tissue fluids taken 2 hours after the last dose revealed that the concentration of cefaclor in the synovial fluid was approximatley one-half of that in serum. The results of these studies indicate that cefaclor has a low toxic potential in the species tested.

Animals

In vitro susceptibility of Haemophilus influenzae to sulfamethoxazole-trimethoprim and cefaclor, cephalexin, and cephradine.

Sulfamethoxazole-trimethoprim and three oral cephalosporins, cefaclor, cephalexin, and cephradine, were evaluated in vitro as possible alternatives to chloramphenicol in the treatment of non-central nervous system infections due to ampicillin-resistant Haemophilus influenzae. Sixty-four isolates of H. influenzae, including 31 beta-lactamase-positive strains, were tested by the agar dilution method. All strains were inhibited by 0.78/0.039 mug sulfamethoxazole-trimethoprim per ml and by 0.78 mug of chloramphenicol per ml. At 6.25 mug/ml, 100, 11, and 3% of all strains were inhibited by cefaclor, cephalexin, and cephradine, respectively. Thus, on the basis of drug concentrations presumably achievable in serum, 100% of strains were susceptible to sulfamethoxazole-trimethoprim, chloramphenicol, and cefaclor. However, a considerable inoculum effect was noted with both beta-lactamase-positive and -negative strains, when tested with sulfamethoxazole-trimethoprim; the minimal inhibitory concentrations of cefaclor were only slightly affected. Also, synergistic effects of sulfamethoxazole-trimethoprim, sulfamethoxazole-erythromycin, and sulfamethoxazole-cefaclor were seen when combinations were tested against both beta-lactamase-positive and -negative strains, as determined by minimal inhibitory concentrations measured by the broth dilution method and by killing curve analyses. These results support further evaluation of these combinations and of cefaclor alone for the treatment of non-central nervous system infections due to H. influenzae.

Cephalosporins

[Resistance of gram-negative bacteria against cefaclor and other antibiotics (author's transl)].

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.

Cefaclor

Treatment of acute otitis media of infancy with cefaclor.

The emergence of ampicillin-resistant Haemophilus as a clinical problem in otitis media necessitates a search for alternative, effective therapy. An orally absorbable cephalosporin derivative, cefaclor, is equally effective in vitro against ampicillin-susceptible and -resistant Haemophilus and against other bacteria that cause acute otitis media. Two dosage schedules of cefaclor (40 and 60 mg/kg/day) were evaluated in 95 infants with acute otitis media. Bacterial origin was determined by a culture of tympanocentesis fluid. Success rates using the smaller dosage were inferior to those using the larger dosage. Results of therapy for pneumococcal and Haemophilus infection with 60 mg/kg/day were comparable to those previously found with amoxicillin trihydrate or with combinations of trisulfapyrimadines with erythromycin or penicillin V. One patient with an ampicillin-resistant Haemophilus infection responded well to cefaclor and did not have a relapse. Cefaclor was well tolerated and caused an acceptably low incidence of minor, adverse effects. Cefaclor deserves further testing as a candidate for preferred status as a single-drug treatment of acute otitis media.

Acute Disease

[In vitro activity of cefaclor (author's transl)].

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.

Bacteria

[The antibacterial efficacy of cefaclor against bacteria resistant to ampicillin, tetracycline and co-trimoxazole (author's transl)].

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.

Cefaclor

[Bacteriological in vitro investigations with cefaclor. Correlation of inhibition zone diameter and minimal inhibitory concentration (author's transl)].

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".

Bacteria

Cefaclor in the treatment of susceptible infections in infants and children.

Fifjty-two outpatients, aged from six months to 17 years, and suffering from Group A streptococcal pharyngitis, skin and soft tissue infection, urinary tract infection, or otitis media were enrolled in the study. The dosage of cefaclor was 20 to 40 mg/kg/day in three or four divided doses for ten days. In 43 children given either cefaclor suspension or capsules, plasma level estimations were performed. Cefaclor readily produces therapeutic plasma levels in children. Cefaclor appears to be a safe, well tolerated and effective antimicrobial agent in children. It has a distinct advantage over other antibiotics in children with Haemophilus influenzae otitis media and should be considered as a primary drug in treatment of otitis media.

Adolescent

Successful treatment with cefaclor of gonococcal urethritis in men.

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.

Cefaclor

Cefaclor in the treatment of uncomplicated gonococcal urethritis.

Cefaclor is a cephalosporin antibiotic whose chemical structure is similar to that of cephalexin. The substitution of a chloro group for the methyl group of cephalexin has produced a compound with markedly improved antibacterial activity, while retaining the property of gastrointestinal absorption. Cefaclor has shown good in vitro activity against Neisseria gonorrhoeae. In a controlled clinical trial, 40 men with uncomplicated gonococcal urethritis received cefaclor given as a one gram loading dose, followed by 500 mg 4 times daily for 3 days, for a total dose of 7 g. All patients were re-evaluated at 3 to 7 days following completion of therapy. Two patients did not complete the entire course of therapy and were eventually treated with another regimen. Of 38 men who took the full course of therapy, 35 were clinically and bacteriologically cured. Two men were clinically infected but had negative pretreatment cultures. Of 19 men with beta-lactamase-positive gonococcal urethritis, 18 were cured, whereas among 17 men with penicillin-sensitive strains, all were cured. There were no adverse reactions to the drug, and all patients expressed a preference for the oral regimen. The success of cefaclor in this pilot study suggests that additional clinical trials should be performed.

Adult

Comparison of cefaclor and ampicillin in the treatment of shigellosis.

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.

Ampicillin

[Treatment of bronchitis with cefaclor (Panoral) (author's transl)].

14 patients from the Allergy Unit of an outpatient clinic suffering from acute exacerbation of chronic bronchitis and 13 outpatients with acute bronchitis were treated with 250 mg cefaclor (Panoral) 3 times daily per os for 5 days. 59% of the organisms isolated from cefaclor-sensitive sputum at the time of prominent clinical symptoms were resistent to tetracycline, 53% of them were resistant to penicillin, and 37% were resistant to ampicillin. 12 out of the 14 patients with acute exacerbation of chronic bronchitis became asymptomatic, and no organisms could be detected in the sputum of 13 out of the same 14 patients two days after cessation of cefaclor treatment. In 12 out of the 13 patients with acute bronchitis, the acute clinical symptoms disappeared and in 11 out of the 13 patients the initial sputum organisms were two days after stopping cefaclor treatment.

Bronchitis

[The antibacterial efficacy of cefaclor in routine testing of clinical material from two Berlin hospitals (author's transl)].

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.

Bacteria