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Pharmacokinetics of cefaclor in chronic middle ear effusions.

Fifty children aged 1 to 13 years with chronic or recurrent otitis media with effusion received a single dose of cefaclor (15 mg/kg body weight) by the oral route 30 minutes to seven hours before the removal of middle ear effusion and insertion of tympanostomy tubes. Serum and middle ear aspirate concentrations of the antibiotic were determined employing a microbiological assay technique by a disk diffusion method. Middle ear specimens were also cultured for aerobic bacteria. The mean peak serum concentration level (8.49 +/- 7.89 micrograms/ml) was observed after 30 minutes, whereas the middle ear peak level (0.47 +/- 0.78 micrograms/ml) occurred after one hour. Of the 87 middle ear specimens, 37 had cefaclor concentrations which were detectable within the resolution of the bioassay method (greater than 0.16 micrograms/ml). There was no correlation between the type of middle ear effusion (mucoid or serous) and the concentration of cefaclor in the middle ear. Only 18% of the middle ear cultures were positive for aerobic bacteria; Hemophilus influenzae was the most common organism.

Adolescent↗

Evaluation of cefaclor in acute otitis media caused by ampicillin-resistant H. influenzae.

Cefaclor was used to treat 13 children with acute otitis media caused by ampicillin-resistant strains of Hemophilus influenzae. The children were re-examined on days 4, 10, and 28. Pharmacologic compliance was assessed by means of a bioinhibition assay on a urine specimen obtained on days 4, 7, and 10. Nine of the 13 children had evidence by tympanogram of residual otitis media with effusion (secretory otitis media). Of these, three were noted to have a bulging, yellow or grey eardrum, which suggested an ongoing acute process. A second middle ear culture was obtained from two of the 3 children, but no pathogens were recovered. Two others had recurrence of otitis shortly after cessation of therapy. Cefaclor is an acceptable antibiotic for the treatment of ampicillin-resistant acute otitis media; but, after cefaclor therapy, some children continued to have a bulging eardrum and sterile pus in the middle ear or had recurrences of otitis soon after cessation of therapy.

Acute Disease↗

Onset of Hemophilus influenzae type-b meningitis during cefaclor therapy for preseptal cellulitis.

Second generation cephalosporins are frequently used for the treatment of bacteremic Hemophilus influenzae type b infections. "Breakthrough" meningitis during cefamandole therapy has documented the need for adequate cerebrospinal fluid penetration by these antibiotics if they are to be used in the therapy of Hemophilus infections. A child with H. influenzae type b preseptal cellulitis is reported who initially responded to treatment with intravenous cefuroxime and oral cefaclor. However, while still receiving cefaclor, the child was readmitted with H. influenzae meningitis. Microtiter broth dilution susceptibility testing performed during the second admission showed the isolate to be relatively resistant to cefuroxime (minimum bactericidal concentration [MBC] = 4 micrograms/ml) and resistant to cefaclor (MBC greater than 16 micrograms/ml). This experience documents the need to monitor the clinical response closely during therapy of H. influenzae bacteremic infections with these second generation cephalosporin treatment regimens. In addition, attention should be paid to minimum inhibitory concentrations of these cephalosporins, since variations in H. influenzae type b susceptibility to these agents may limit their efficacy.

Cefaclor↗

Single-dose ceftriaxone versus 10 days of cefaclor for otitis media.

We conducted a controlled clinical trial to determine the efficacy of single-dose intramuscular ceftriaxone for the treatment of acute otitis media. Fifty-four children aged 18 months to 6 years with clinical and tympanometric evidence of otitis media were randomized to receive either 50 mg/kg ceftriaxone or 10 days of oral cefaclor 40 mg/kg/day. Resolution of symptoms and clinical and tympanometric appearance of the tympanic membrane at follow-up visits were used to determine outcome. Thirty-one children received ceftriaxone and 23 received oral cefaclor. There were no treatment failures. There were no significant differences between groups in persistence of effusion or recurrence of acute otitis media. We conclude that a single intramuscular dose of ceftriaxone compares favorably with 10 days of oral cefaclor for the treatment of acute otitis media.

Acute Disease↗

Comparative target site pharmacokinetics of immediate- and modified-release formulations of cefaclor in humans.

Optimal dosing of beta-lactam antibiotics aims at maximizing the time at which drug levels in the interstitial space fluid (ISF)--the fluid that surrounds the causative microorganisms at the target site--exceed the minimal inhibitory concentration (MIC). One potentially attractive strategy to achieve this goal is to administer antibiotics as oral sustained-release formulations. The present study was designed to test the hypothesis that sustained-release formulations could lead to a more suitable pharmacokinetic profile in the ISF at the relevant target site. For this purpose, time versus cefaclor concentration profiles attained in the ISF were measured following administration of two formulations, an immediate- (500 mg IR) and a modified-release formulation in two different doses (500 mg MR and 750 mgMR) in a three-way crossover study of healthy male volunteers (n = 12). For the measurement of unbound cefaclor concentrations in the ISF of human skeletal muscle, the in vivo microdialysis technique was employed. For all three formulations, unbound cefaclor concentration in the ISF closely followed individual plasma concentration profiles in a dose-dependent pattern, with ISF to unbound plasma ratios ranging from 0.67 to 0.73. The mean residence time was found to be significantly longer for the MR formulations versus the IR formulation. The data of the present study indicate that time above MIC values at the target site can be substantially prolonged if an antibiotic is administered as a sustained-release product.

Adult↗

Comparative study of cefaclor and amoxycillin in the treatment of respiratory tract infections in general practice.

A single-blind, randomized study was carried out in 101 general practice patients with respiratory infection to compare the effectiveness of 250 mg cefaclor 3-times daily with that of 250 mg amoxycillin 3-times daily. Assessment of 5 specific symptoms was carried out by the doctor before treatment and again 1 week later, and patients recorded their own opinion of any change in their condition. The results suggest that cefaclor was at least as effective as amoxycillin in producing resolution or improvement in symptoms and the median time to maximum response was somewhat shorter. Only 1 patient (on cefaclor) had a side-effect sufficiently severe to warrant cessation of therapy.

Adolescent↗

Anaphylactic reaction to oral cefaclor in a child.

Adverse drug reactions are a common clinical problem. It has been estimated that 6% to 15% of hospitalized patients experience some sort of adverse drug reaction. Clinical manifestations of adverse drug reactions include skin rash; a serum sickness-like reaction; drug fever; pulmonary, hepatic, and renal involvement; and systemic anaphylaxis. Many of these adverse events are not immunologically mediated. Actual allergic or immunologic drug reactions probably account for <25% of adverse drug reactions overall. Antibiotics are one of the major contributors to drug hypersensitivity. Cefaclor, an oral second-generation cephalosporin with a beta-lactam ring, is used against various infectious diseases of the respiratory tract, especially in children. Several cases of cefaclor hypersensitivity have been reported. The most common presentations are either erythematous or papular eruptions, although serum sickness-like reactions have also been described. Anaphylactic reactions, although rare, have been observed in adults. Here we report a case of anaphylactic reaction to cefaclor in a 21/2-year-old patient.

Administration, Oral↗

Accelerated conditions for stability assessment of bulk and formulated cefaclor monohydrate.

The stability of cefaclor monohydrate drug substance and formulated products was studied under accelerated conditions in order to provide a rapid indication of differences that might result from a change in manufacturing process or source of the sample. The USP stability-indicating related substances assay was used to assess the extent of sample degradation. An Arrhenius study of drug substance stability from 45 to 70 degrees C predicted a degradation rate consistent with that observed in room-temperature studies. Qualitative degradation profiles of samples held at 65 degrees C for 2 weeks were also very similar to those of samples held at room temperature for 2 years. Based on these results, additional studies were conducted at 65 degrees C for 2 weeks on drug substance and formulated product samples. Stability differences were observed among some capsule formulations that had also exhibited real time differences. In some studies, rapid degradation after 5 days was observed at 65 degrees C followed by a slower rate from 5 to 15 days. Similar behavior was observed for cefaclor monohydrate containing high amounts of amorphous cefaclor, suggesting that differences in amorphous content could be an explanation for stability differences observed in various samples. The accelerated conditions were shown to differentiate samples and can provide a rapid indication of relative stability.

Administration, Oral↗

An evaluation of cefaclor in Pakistani children with pharyngotonsillitis.

OBJECTIVE: To assess the efficacy, safety of cefaclor for the treatment of pharyngotonsillitis in Pakistani children. METHOD: Pakistani children between the ages of two to twelve years and diagnosed with pharyngotonsillitis were eligible to participate in the study. Cefaclor was administered three times daily for a total dose of 20-40 mg/kg/day, depending on the severity of the infection, for 7 days. Patients were evaluated on the basis of symptomatic response and antibiotic susceptibility pattern as a result of bacteriological examination. RESULTS: Based on observed pre-therapy signs/symptoms of infection with pharyngotonsillitis, 99% of patients (95% CI=94.9% to 100.0%) were reported as having a symptomatic response of Cure or Improvement by end of study. Group A b-haemolytic Streptococci was the most prevalent pathogen isolated pre-therapy (occurring in 45% of patients). Of all patients for whom this pathogen was isolated, 64% had complete eradication by end of therapy, while there was persistence or superinfection in 36% of patients. Only 9 occurrences of non-serious adverse events were observed among 7 of the 107 patients, including diarrhea (5), nausea (1), vomiting (1), rash (1) and stomatitis (1). CONCLUSION: Based on the high symptomatic response rate of 99% and the positive safety data, cefaclor was found to be effective and safe in treating Pakistani children with pharyngotonsillitis.

Anti-Bacterial Agents↗

[Clinical efficacy and tolerability of short course therapy with cefaclor compared with long-term therapy for treatment of acute otitis media in children].

Clinical efficacy and tolerability of two different regimens of cefaclor were studied in 410 paediatric patients affected by non-recurrent acute otitis media (AOM). 204 patients were randomly treated with cefaclor given at the dosage of 50 mg/kg/die in two doses for 5 days; 206 patients with 40 mg/kg/die in two doses for 10 days. Diagnosis of acute otitis media was based on the following signs and symptoms: otalgia, fever, possible otorrhea, alterations of tympanic membrane under otoscopic examination. At the end of the treatment 95.5% of patients were cured after short-term therapy and 94.8% after long-term therapy. At the follow-up (two months after the interruption of treatment) 19 and 17 patients respectively had a recurrence. Side effects were observed in 6.9% and 8.7% of patients respectively (not statistically significant); they were mild, never requiring interruption of the treatment. Cefaclor therapy is very effective for treating children aged 2-6 years affected by acute otitis media, with no significant difference related to treatment duration. Short-course treatments appear better in terms of compliance and tolerability.

Acute Disease↗

[Cefaclor versus penicillin V in staphylococcal infections in children].

Although rheumatic fever virtually no longer occurs in France, pharyngitis due to group A beta-hemolytic streptococci (ABHS) remains a common pediatric problem. American studies have underscored the high rate of bacteriologic treatment failures and recurrences of ABHS pharyngitis. Furthermore, several comparative studies have demonstrated that cephalosporins provide better results on these two parameters. This prospective randomized study compared the effectiveness of penicillin V (50,000 to 100,000 IU/kg/day in three divided doses) and Cefaclor (20 to 40 mg/kg/day in three divided doses), each given for ten consecutive days. From September 1989 through October 1990, 117 children (mean age 5.7 years) were entered into the study. All study subjects were seen as outpatients and found to have ABHS pharyngitis on the basis of a rapid screening test and confirmatory bacteriologic studies. Cefaclor was given to 56 patients and penicillin V to 61. Reevaluation with a repeat bacteriologic study was performed in all patients at the end of the treatment period, or earlier in the event of new clinical manifestations, and towards D40. Among patients given penicillin V, bacteriologic failure rate at completion of therapy was 19.6%, clinical failure rate on D10 was 8%, and recurrence rate on D40 was 16.5%. Cefaclor exhibited greater bacteriologic and clinical effectiveness, with 3.4% bacteriologic failures on D10 (p less than 0.01), 1.7% clinical failures on D10, 8.9% clinical recurrences between D10 and D40, and an overall 10.6% rate of failure or recurrence (p = 0.05).

Adolescent↗

Treatment of beta-hemolytic streptococcal pharyngitis with cefaclor or penicillin. Efficacy and interaction with beta-lactamase-producing organisms in the pharynx.

The recommended treatment for group A beta-hemolytic streptococcal pharyngitis has continued to be penicillin given in parenteral or oral form. Treatment failures, as determined by the continued presence of the streptococcal organism in the pharynx, however, do occur in 6% to 25% of patients treated with penicillin. Furthermore, beta-lactamase produced by other bacteria in the pharynx could potentially inactivate the penicillin, resulting in increased treatment failures or infection relapses. A study was undertaken to compare the efficacy of cefaclor, which is relatively resistant to inactivation by beta-lactamase, with penicillin for eradicating the group A beta-hemolytic streptococcal organism from the throats of 93 patients with pharyngitis. Additionally, extensive cultures for potential beta-lactamase-producing organisms were conducted on 37 patients; 27% of these had one or more pharyngeal organisms that were producing beta-lactamase. No statistically significant difference was found between the clinical responses or the bacteriological cure rates of those treated with cefaclor and those treated with penicillin when stratified by the presence or absence of beta-lactamase-producing organisms. The prevalence of beta-lactamase-producing organisms in the pharynx, however, was increased after treatment with penicillin, whereas no change was noted following treatment with cefaclor.

Adolescent↗

[An open randomized trial, Pediazole versus cefaclor in the treatment of acute otitis media in children].

The combination of erythromycin ethylsuccinate and acetyl sulfafuroxazole (Pediazole = ES) is effective against Hemophilus influenzae, including beta-lactamase-producing strains, and against Streptococcus pneumoniae, including macrolide-resistant strains. In this study, mean daily dosage was 40-50 mg/kg for cefaclor and 50 mg/kg ES + 150 mg/kg sulfamide for Pediazole. Both products were given in three divided doses per day for ten days. Tolerance was evaluable in 106 children and effectiveness in 103 children including 52 in the ES group and 51 in the cefaclor group. Mean age was 23.5 months and both groups were comparable as concerns age, weight, previous ENT disease, and severity of the otitis media. Tolerance was satisfactory in both groups. Clinical results were as follows: failures before or at completion of the course, 5/52 in the ES group versus 13/51 in the cefaclor for the treatment of children with acute otitis media.

Acute Disease↗

In vivo efficacy of cefcanel daloxate in comparison with cefaclor.

Cefcanel daloxate is a new prodrug cephalosporin for oral use, with cefcanel as the antibacterially active principle. The in vivo efficacy of this prodrug in comparison with cefaclor was assessed in a localized thigh infection model in mice. Mice were infected intramuscularly in the thigh and treated orally with cefcanel daloxate or cefaclor with three doses given 70 min apart. One strain each of S. aureus, Escherichia coli and Klebsiella pneumoniae was used as test organism. The first dose was given 60 min after staphylococcal infection or 15 min after infection with the Gram-negative strains. The doses given were 0.1 or 0.5 mmol/kg body weight, respectively. The animals were killed at predetermined times, the thigh was excised and homogenized and a count of viable bacteria was made. Decrease in bacterial numbers was used as a measure of the efficacy. The plasma and muscle concentrations of the two investigated drugs were also determined. Both drugs caused a reduction in viable count by approx. 90% for all test organisms, while in the untreated animals the number of bacteria increased 4 to 10 times within 6 hours after challenge. The plasma and tissue peak levels of cefcanel following administration of the daloxate were lower than those for cefaclor but cefcanel displayed a longer half-life.

Absorption↗

[Comparison of 3 antibiotics, cefaclor, josamycin and penicillin V in the treatment of acute throat infections. A multicenter study: 581 cases].

Five hundred and eighty one patients, both adults and children, of either sex, with acute throat infections, with or without associated pharyngitis, were randomized into three groups comparable as to age, general condition and temperature before treatment, previous infectious episodes, history of allergy and underlying conditions. Cefaclor was administered to the first group (C), josamycin to the second group (J) and penicillin V to the third group (V); duration of therapy was practically the same, respectively 8.41, 8.20 and 8.14 days. Concurrent administration of paracetamol was allowed and was comparable for all three groups. Response was assessed on the basis of clinical criteria only, including onset of apyrexia in particular. In group C apyrexia was obtained within 48 hours or less in 54.4% of the patients versus 35.7% only in Group J (p less than 0.001) and 41.5% in group V (p less than 0.02). Onset of overall clinical improvement was 3 days or less in 69.5% of the patients receiving C versus 50.3% for those receiving J (p less than 0.001) and 57.2% for those receiving V (p less than 0.02). Adverse reactions were significantly more frequent in the josamycin group (p less than 0.001) and penicillin group (p less than 0.05) than in the cefaclor group. The most common type of adverse reactions was gastrointestinal upsets in the josamycin (43/49) and the cefaclor group (9/10) and skin reactions in the penicillin group (9/20).

Acute Disease↗

[Growth curves and killing rate of Haemophilus influenzae exposed to amoxicillin, cefaclor and cefotaxime].

The antibacterial activity of beta-lactams against H. influenzae is difficult to evaluate as a result of the osmotic-pressure-dependent formation of filaments and spheroplasts whose viability is still under debate. We compared growth curves obtained by optic density measurements and by UFC/ml counts for H. influenzae in the presence of amoxicillin, cefaclor and cefotaxime in various concentrations. Only the early response to antibiotics, observed during the first six hours of antibiotic-culture contact, was considered. Results showed, for each of the three antibiotics: an increase in optic density with formation of abnormal organisms that correlated poorly with antibiotic concentrations; a stable number of UFC/ml for more than 90 mn, followed by a slow fall reaching at the most 1.5 Log 10 UFC/ml at the sixth hour. We conclude that amoxicillin, cefaclor and cefotaxime in active concentrations rapidly produce the formation of abnormal organisms with an increase in biomass as a result. These abnormal organisms lose their viability slowly, even with concentrations greater than 50 time the MIC. Cefaclor's MIC and MBC are underestimated when results are read only after 24 hours.

Amoxicillin↗

[The effect of subinhibitory concentrations of cefaclor, erythromycin and doxycycline on phagocytosis and intracellular killing of E. coli by human neutrophil granulocytes].

After determination of granulocyte basic parameters of polymorphonuclear neutrophilic leukocytes obtained from 5 unselected intensive care unit patients and 5 healthy volunteers phagocytosis of an E. coli strain isolated from clinically proven infection (urinary tract infection) was investigated with and without preincubation of the strain with subinhibitory concentrations (1/4 and 1/2 minimum inhibitory concentration; incubation time: 30 min) of cefaclor, erythromycin and doxycycline. The results show that it is very difficult to compare granulocyte functions because they differ widely in individual ranges among both groups. Nevertheless in comparison to the untreated strain a higher amount of ingestion by the granulocytes of both collectives could be obtained after preincubation with cefaclor or erythromycin; thereby cefaclor seemed to be the most effective drug.

Anti-Bacterial Agents↗

Cefaclor compared with amoxycillin acute otitis media with effusion: a preliminary report.

A double-blind, randomized clinical trial comparing cefaclor with amoxycillin in the treatment of acute otitis media with effusion (OME) in infants and children is being conducted at Children's Hospital of Pittsburgh. Although the randomization code has not yet been broken, the results of treating the first 55 children are reported, since they appear to be of interest. Of the 62 ears with acute OME on which an initial tympanocentesis was performed, 41 positive cultures were isolated from the middle ear aspirates. Of the 10 ears from which Haemophilus influenzae was isolated, one had a type b strain, and of the remaining unencapsulated strains, one was resistant to both penicillin G and ampicillin. In the one ear from which Staphylococcus aureus was isolated, the organism was found to be resistant to ampicillin. However, all of the organisms were sensitive in vitro to cefaclor. In 88% of all subjects observed for the first 2 weeks, the initial symptomatic response was excellent. Six children had persistent signs and symptoms of acute OME and received a second tympanocentesis; however, none of the effusions from the repeat aspiration revealed an organism. An effusion was still present in 97% of the ears after 3 days, in 69% after 2 weeks, and in 48% 6 weeks after initiation of the study. Tympanocentesis did not appear to affect either the initial clinical response or the persistence of effusion. There were no adverse reactions to either drug in this study. Because an apparent increase in the incidence of ampicillin-resistant strains of H. influenzae is being reported, and because of the presence of ampicillin-resistant S. aureus in some ears with acute OME, a new antimicrobial effective against all the common pathogens causing acute middle ear disease would be desirable. In this respect, the preliminary findings of treatment with cefaclor from this study appear promising.

Acoustic Impedance Tests↗