Pre-formulation Study of Salicylidine-cephalexin-Zn(II) dihydrate, a New Derivative of Cefalexin.

BACKGROUND: Salicylidine-cefalexin-Zn(II)·2H2O, a new derivative of cefalexin, has been reported to possess enhanced anti-microbial activity and lower toxicity than cefalexin. It is, therefore, desirable to carry out a pre-formulation study to determine its pharmaceutical properties which will be useful in conversion of the new molecule into various dosage forms. METHODS: The compound was synthesized by the previously reported method and characterized by elemental, Fourier-transform infrared and electronic spectral analyses. Crystallinity was determined by powder x-ray diffraction. Particle size distribution was determined by a laser-based sizer. Other properties including flow, density and compaction strength were determined by use of appropriate standard methods. The compound was also evaluated as a prodrug through dissolution study by the USP method. RESULTS: It was found that the new derivative is an amorphous powder with different bulk density, porosity, compressibility, plasticity and flow properties as compared to cefalexin. The amorphous character of the new compound suggests that it will have better bioavailability. The dissolution study indicated that this compound is hydrolyzed to produce cefalexin in water in a sustained manner, thus it will act as a prodrug in vivo. The release data fitted well into Highuchi model. CONCLUSION: Various pharmaceutical properties essentially required for formulation of salicylidine-cefalexin-Zn(II)·2H2O into dosage forms were determined. This study has shown that the new drug would behave as a prodrug for cefalexin with better bioavailability.

Functional expression of stereoselective metabolism of cephalexin by exogenous transfection of oligopeptide transporter PEPT1.

Gastrointestinal absorption of the beta-lactam antibiotic cephalexin (CEX) is highly stereoselective: l- and d-CEX are both taken up by intestinal epithelial cells through the brush-border membrane, most likely via oligopeptide transporter PEPT1, but l-CEX is not found in serum or urine after administration p.o. because of its rapid intestinal metabolism, whereas d-CEX is well absorbed in the unchanged form. We examined the contribution of PEPT1 to the stereoselective uptake and metabolism of CEX. We observed stereoselective metabolism of CEX after exogenous transfection of PEPT1 alone into mammalian cell lines: l-CEX, but not d-CEX, was metabolized to 7-aminodesacetoxycephalosporanic acid (7-ADCA) in HeLa and human embryonic kidney 293 cells stably and transiently expressing human PEPT1, respectively, whereas such metabolism was minor in cells expressing the vector alone. The formation rate of 7-ADCA depended on the amount of PEPT1 cDNA transfected. l-CEX metabolism was rapid because only 7-ADCA was found inside and outside the cells during incubation with l-CEX. The characteristics of PEPT1-mediated metabolism of l-CEX were similar, but not identical, to those of PEPT1-mediated transport. PEPT1-mediated metabolism was also observed in permeabilized cells expressing PEPT1, in which PEPT1-mediated intracellular substrate accumulation was negligible, suggesting that the increase in l-CEX metabolism by PEPT1 transfection cannot be fully explained by an increase in uptake and subsequent exposure to intracellular hydrolases. The present findings show that stereoselectivity in CEX absorption can be fully explained in terms of PEPT1, implying that the l-CEX hydrolase is PEPT1 itself or is induced by PEPT1.

Beta-lactam antibiotics functionalized with gem-bisphosphonates.

Acylation of amoxycillin and cephalexin with acids III, V and VII, and with isocyanate VIII furnished the corresponding beta-lactam antibiotics (X and XIII-XV, respectively). The antibacterial activity of these new antibiotic analogues against Helicobacter pylori was found to be identical with those of amoxycillin, Augmentin, erythromycin and ciprofloxacin.

Micellar electrokinetic capillary chromatography for the separation of cefalexin and its related substances.

Micellar electrokinetic capillary chromatography (MEKC) was examined for analysis of cefalexin and its related substances. Good selectivity was obtained with two different buffer solutions: a sodium acetate buffer (50 mM, pH 5.25) containing sodium dodecyl sulfate (50 mM SDS) or sodium phosphate buffer (40 mM, pH 7.0) containing 100 mM SDS. Both methods permit cefalexin to be completely separated from its ten related substances within 20 min. The robustness of the method, using pH 5.25 acetate buffer, was examined by means of a full-fraction factorial design to test the influence of buffer pH, concentration of SDS and buffer concentration. The parameters for validation such as linearity, precision, limit of detection and limit of quantitation are also reported. The results show that method 1 is suitable for the analysis of cefalexin.

Isolation and structural elucidation of an impurity of cefradine.

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

Clinical evaluation of drug efficacy in UTI in men: the significance of bacterial elimination on day one.

With the purpose of assessing whether the effect of a drug at an early stage of administration could serve to predict efficacy at the end of drug treatment, a cephem antibiotic was administered for 5 days (days 0-4) by injection in males with complicated UTI. Results showed that the bacteriological effect on day 1 was reflected in the overall clinical efficacy on day 5. The activity of an antibacterial agent appeared to be reflected in the ability to eliminate bacteria 1 to 2 days after the start of drug administration.

Comparison of complicated urinary tract infections in men and women.

Whether or not the efficacy of antimicrobial agents in complicated urinary tract infection (UTI) in men and women can be evaluated with the same protocol was studied in a total of 416 male and 387 female patients. Clinical and bacteriological efficacies achieved in male patients were significantly lower than those achieved in female patients. The most important reason for the difference in clinical and bacteriological efficacies was due to the difference of infecting organisms between male and female patients. It was concluded that complicated UTI in men and women can alternatively be studied with the same protocol in so far as the results were stratified according to sex and infecting organism.

Synthesis and biological activity of novel 3-(2-propenyl)-cephalosporins. I.

The synthesis, antibacterial activity and oral absorption of novel cephalosporins (3a-3d) having a 2-propenyl group at the C-3 position are described. Diphenylmethyl 7-amino-3-(2-propenyl)-3-cephem-4-carboxylate HCl (4) prepared from 7-aminocephalosporanic acid in 12 steps was acylated with various acid moieties to give cephems 3a-3d. The cephems 3a-3c showed similar antibacterial activities as cefixime. However, these cephems were not well absorbed orally.

Synthesis and antimicrobial activities of some new tetrahydro-2H-1,3,5-thiadiazine-2-thione derivatives of cephalexin.

In this study, compounds with a 7-[2-(dihydro-5-substituted 6-thioxo-2H-1,3,5-thiadiazine-3[4H]-yl)-2-phenyl]acetamido-3 -methyl-3- cephem-4-carboxylic acid structure were synthesized by reacting cephalexin monohydrate with formaldehyde and dithiocarbamic acid salts prepared from some primary amines. The structure of the compounds was confirmed by spectral data and elementary analysis. The antimicrobial activities of the compounds were investigated against some bacteria (Staphylococcus aureus, Streptococcus faecalis, Escherichia coli and Pseudomonas aeruginosa) and some Candida sp. (C. albicans, C. parapsilosis, C. stellatoidea and C. pseudotropicalis) by using tube dilution method. In microbiological studies, cephalexin monohydrate was used as reference standard. Both compounds were synthesized and cephalexin monohydrate was found ineffective against S. faecalis and P. aeruginosa in the concentrations studied. While most of the compounds showed bacteriostatic activity against S. aureus, compounds 1, 3 and 7 showed the same activity against E. coli. On the other hand, compound 3, 5, 6, 7 and 10 showed anticandidal activity, whereas cephalexin monohydrate was not active against any Candida sp. Compound 11 was found effective against C. stellatoidea and C. pseudotropicalis.

Serum sickness in children after antibiotic exposure: estimates of occurrence and morbidity in a health maintenance organization population.

The computerized outpatient records of the Harvard Community Health Plan, a 230,000-member health maintenance organization, were used to determine the frequency with which serum sickness is recognized in the practice setting after exposure to antibiotics. The medical records of 3,487 children who had been prescribed cefaclor or amoxicillin were searched in December 1986 for coded diagnoses of serum sickness and related conditions. Diagnoses were validated by blinded review of dictated and written office notes. There were 12 cases of serum sickness in 11,523 child-years. During this time, these children were prescribed 13,487 courses of amoxicillin, 5,597 courses of trimethoprim-sulfamethoxazole (TMP-SMZ), 3,553 courses of cefaclor, and 2,325 courses of penicillin V. Serum sickness was considered to be antibiotic-related if it occurred within 20 days of initiation of antibiotic therapy. Five cases were temporally associated with cefaclor, one with both amoxicillin and TMP-SMZ, four with TMP-SMZ alone, and one with penicillin V alone. One case was not associated with any antibiotic exposure. All antibiotic-related cases occurred in children under age 6 years who were treated for otitis media or streptococcal pharyngitis, and most cases began 7-11 days after initiation of antibiotic. All but one of the antibiotic-related cases occurred in children who had relatively heavy lifetime antibiotic exposure. The risk of serum sickness was significantly elevated after cefaclor compared with amoxicillin, even among the most heavily exposed children (relative risk = 14.8, p = 0.01, 95% confidence interval 2.0-352.0). Most cases prompted several physician visits, but none required hospitalization.

Treatment of sinus empyema in adults. A coordinated Nordic multicenter trial of cefixime vs. cefaclor.

In sinus empyema, H. influenzae is the most prevalent pathogen in some subpopulations and in case of therapeutic failure. Cefixime, the first oral cephalosporin of the 3rd generation, is highly potent in vitro against H. influenzae. To study the efficacy and safety of cefixime in adults with acute sinusitis, a coordinated, double-blind multicenter trial was designed for purulent cases, as confirmed by antral aspiration. A total of 364 patients were enrolled in the study with 125 cases randomized to the reference group, assigned to treatment with cefaclor. Evaluation was based on clinical outcome and on antral reaspiration (86% of the cases). No significant differences between the treatment groups were found, as regards short-term or long-term clinical outcome. However, the clinical examination overestimated the therapeutic results. Only 4% of the patients were considered as failures, but the re-aspiration demonstrated remaining suppuration in 14% of all cases (p less than 0.001). Based on re-aspiration, the failure rate among patients with initial growth of pathogens was lower for cefixime (8%) than for cefaclor (20%) (p less than 0.05). Such a difference was not found among patients with growth of H. influenzae. No serious adverse reactions were recorded, but loose stools and diarrhoea were significantly more frequent in the cefixime treatment group. Five patients (2%) in the cefixime treatment group discontinued their treatment due to adverse events.

[Randomized study of cefatrizine versus cefaclor in conjunctivitis otitis syndrome]. / Etude randomisée céfatrizine versus céfaclor dans le syndrome otite-conjonctivite.

The association conjunctivitis-otitis is highly suggestive of Haemophilus influenzae infection. This conjunctivitis otitis syndrome could be a good model to assess the efficacy of different antibiotic regimen in the treatment of acute otitis media due to HI without tympanocentesis. This prospective randomized trial compared the efficacy of two orally cephalosporins which demonstrate in vitro an activity against HI. This study was conducted from 4.20.1988 to 3.15.1989 and involved 73 children with COS examined in an outpatient clinic. The mean age was 17.7 months. Before treatment culture were taken from the lower palpebral conjunctivae. 81 strains was found: HI 61 (beta-lactamase-producing 15), Streptococcus pneumoniae 16, Branhamella Catarrhalis 4. The 73 patients were treated with 40 to 50 mg/kg/day of the test drug for ten days, 25 with Cefaclor in 3 divided dose (group 1), 24 with Cefatrizine in 3 divided dose (group 2), 24 with Cefatrizine in 2 divided dose (group 3). The recoveries was obtained in 17/25 in the group 1, 18/24 in the group 2, 15/24 in the group 3. There was no significant difference between the 3 groups.

The efficacy of pulse-dosed antibiotic therapy in the management of persistent otitis media with effusion.

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.

[Effect of cefaclor on guinea pig platelet aggregation in vitro].

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.

Phase I study of multiple-dose cefprozil and comparison with cefaclor.

The objectives of this study were to assess the safety and tolerance of cefprozil, to characterize the pharmacokinetics of cefprozil after administration of multiple doses of the drug, and to compare these pharmacokinetic parameters with those obtained with cefaclor. The volunteers received 28 doses of 250, 500, or 1,000 mg of cefprozil or 500 mg of cefaclor every 8 h for 10 days. Serial blood samples and the total volume of urine voided by each individual were collected for pharmacokinetic evaluation on days 1, 5, and 10. Both cephalosporins were well tolerated after multiple oral dosing. The peak levels in plasma (Cmax) of cefprozil ranged from 5.7 to 18.3 micrograms/ml after oral administration of 250- to 1,000-mg doses. The regression analysis of Cmax on cefprozil dose showed a dose-linear response. The mean Cmax of cefaclor ranged from 15.2 to 16.7 micrograms/ml and did not change significantly on multiple dosing. The overall mean terminal half-life of cefprozil was 1.2 h and was invariant with respect to dose or duration of dosing. The area under the plasma-concentration-versus-time curve from 0 h to infinity (AUC0-infinity) of cefprozil increased in a dose-proportional manner with an increase in dose. The overall urinary recovery (61% of dose) and renal clearance values of cefprozil were generally invariant with respect to dose and duration of dosing. While cefprozil was apparently absorbed less rapidly and achieved lower Cmax values than cefaclor, the AUC0-infinity of cefprozil was nearly twofold greater than that of cefaclor. The half-life of cefprozil was also twofold longer than that observed for cefaclor. Although the urinary recovery of cefaclor (75% of dose) was significantly higher than that of cefprozil (61% of dose), the concentrations of cefprozil in urine remained significantly higher than those of cefaclor from 2 to 8 h postdosing. If the therapeutic concept is maintained that levels of beta-lactam antibiotics in plasma should exceed the MIC for the offending organisms over a period that approximates the dosing interval, then cefprozil would appear to be suitable for twice-daily administration, whereas cefaclor should probably be administered three or even four times a day.

Comparison of cefprozil and cefaclor pharmacokinetics and tissue penetration.

The pharmacokinetics and tissue penetration, as judged by skin blister fluid, of cefprozil and cefaclor were examined in 12 healthy male volunteers. Doses of 250 and 500 mg of each drug were given to fasting subjects in a crossover fashion. Serially obtained plasma, skin blister fluid, and urine samples were analyzed for cefprozil or cefaclor by validated high-pressure liquid chromatographic methods. After oral administration of 250 and 500 mg of cefprozil, mean concentrations in plasma rose to peak levels (Cmax) of 6.1 and 11.2 micrograms/ml, respectively, and those of cefaclor were 10.6 and 17.3 micrograms/ml, respectively. The elimination half-life of cefprozil (1.3 h) was significantly longer than that of cefaclor (0.6 h), and as a result, the area under the curve for cefprozil was about two times greater than that for cefaclor. Both cephalosporins were primarily excreted unchanged in urine. The mean skin blister Cmax values were 3.0 and 5.8 micrograms/ml for cefprozil and 3.6 and 6.5 micrograms/ml for cefaclor after the 250- and 500-mg oral doses, respectively. The mean Cmax values in skin blister fluid for both cephalosporins were comparable and were significantly lower than the corresponding Cmax values in plasma. However, the levels of cefprozil and cefaclor in skin blister fluid declined more slowly than they did in plasma. The skin blister fluid half-life estimates for cefprozil were significantly longer than they were for cefaclor. Parallel to the observation in plasma, the mean skin blister fluid areas under the curve for cefprozil were significantly higher than they were for cefaclor. The plasma and skin blister fluid pharmacokinetic analyses suggest that the exposure of humans to cefprozil is significantly greater than that to cefaclor at the same dose.

Comparison of the effects of food on the pharmacokinetics of cefprozil and cefaclor.

The objective of this study was to assess the effects of food on the pharmacokinetics of cefprozil and cefaclor. A group of 12 healthy male volunteers received a single 250-mg dose of cefprozil or cefaclor under fasting conditions as well as after the intake of food. There was a 1-week washout period between each treatment. Serial blood samples were collected and assayed for cefprozil or cefaclor by specific high-pressure liquid chromatographic methods. The mean +/- standard deviation peak concentration (Cmax) of cefprozil in plasma was 6.13 +/- 1.22 micrograms/ml under the fasting condition and 5.27 +/- 1.06 micrograms/ml after breakfast, and these values were not significantly different from each other. The corresponding median time to reach Cmax was prolonged after food intake, but this difference was not significant. The mean Cmax values of cefaclor decreased significantly from 8.70 +/- 2.72 micrograms/ml under the fasting condition to 4.29 +/- 1.52 micrograms/ml after breakfast, and the corresponding median times to reach Cmax were significantly prolonged. The mean half-lives of cefprozil and cefaclor were nearly identical for the two treatments, suggesting that the elimination kinetics of these cephalosporins remained unaltered when the drugs were administered with food. The area under the plasma-concentration-versus-time curves for fasted and fed conditions were not significantly different for both drugs. The results of this study indicate that the extent of absorption and rate of elimination of both cephalosporins remain unaltered in the presence of food. However, the absorption rate of cefaclor is significantly reduced in the presence of food, while that of cefprozil remains unaltered. As a result, the Cmax of cefaclor is significantly reduced in the presence of food, whereas that of cefprozil is not significantly affected. Cefprozil can be administered with a meal without markedly affecting levels in blood.

The efficacy of cefaclor vs amoxicillin on recovery after tonsillectomy in children.

Tonsillectomy and adenoidectomy continues to be one of the most commonly performed operations in the pediatric age group. The morbidity from tonsillectomy can be severe and includes throat and ear pain, fever, lethargy, and poor oral intake. A previous study at the Children's Hospital of Philadelphia (Pa) demonstrated the efficacy of amoxicillin therapy in minimizing some of these postoperative symptoms. However, some children continue to have a prolonged recovery even while receiving this antibiotic regimen. Because of these children and the high incidence of Staphylococcus found in tonsillar core tissue, a randomized, prospective study was undertaken at the Children's Hospital of Philadelphia to evaluate the efficacy of cefaclor vs amoxicillin in patients recovering from tonsillectomy. The patients received either ampicillin or cefazolin intravenously at the time of surgery and for 12 to 24 hours postoperatively. When oral intake was adequate, they received either amoxicillin or cefaclor orally for 7 additional postoperative days. Intraoperative cultures of the oropharynx and tonsillar tissue were obtained, as well as cultures of the tonsillar fossa 7 to 14 days postoperatively. The patients were evaluated for severity and duration of postoperative symptoms as well as complications. The results of this study showed no difference between the two groups of patients. We conclude that there is no justification for routine use of cefaclor over amoxicillin in the posttonsillectomy patient.

[Comparative antibacterial activity of cefpodoxime, cefuroxime and cefaclor against strict anaerobic bacteria]. / Activité antibactérienne comparée du cefpodoxime, du cefuroxime et du céfaclor envers les anaérobies stricts.

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.