Comparative Pharmacology of Cefaclor and Cephalexin

Two cephalosporin antibiotics, cefaclor and cephalexin, were administered orally to healthy, adult male volunteers for comparison of their pharmacological properties. In doses of 250 mg orally, cefaclor produced a peak serum concentration of 6.01 ± 0.55 (standard deviation [SD]) μg/ml compared with 9.43 ± 2.36 μg/ml for cephalexin (P < 0.01). The half-lives were 0.58 ± 0.07 (SD) h and 0.80 ± 0.12 (SD) h, and elimination constants were 1.22 ± 0.15 and 0.88 ± 0.13 h−1 for cefaclor and cephalexin, respectively (P < 0.001). Neither drug showed accumulation over the dosing period, and both were well tolerated.

MATERIALS AND METHODS Antibiotics. Cefaclor and cephalexin were supplied by Eli Lilly and Co., Indianapolis, Ind.
Human volunteers. Twenty healthy men with no known allergies to cephalosporin antibiotics participated in the studies after informed written consent was obtained. None were taking any other antimicrobial agents during the investigational period. Their ages ranged between 21 and 32 years of age and their weights ranged between 145 and 220 pounds (ca. 72 to 110 kg). Prestudy physical examinations and laboratory parameters were normal.
Procedure. The subjects were randomly divided into two groups of 10 individuals each. They were assigned to a crossover sequence of the two antibiotic regimens to be taken during two separate dosing periods. Each dosing period was 4 days in duration and separated by 1 week. Group I received 250 mg of cefaclor in capsules orally every 6 h (q6h) during the first period, followed by 250 mg of cephalexin in capsule form orally q6h during the second dosing period. Group II followed a reverse order. All subjects complied with the dosage time schedule.
All subjects fasted for 8 h before each dosing period. After the first dose, a fast of 2 h was maintained before and after each subsequent dose. A control venous blood sample was drawn before the first dose and showed no detectable antibiotic activity in either of the two dosing periods. Venous blood samples for assay of plasma antibiotic concentration were obtained at 0.5, 0.75, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 24.0, 36.0, 48.0, 60.0, 72.0, 72.5, 72.75, 73.0, 73.5, 74.0, 75.0, 76.0, 78.0, and 90.0 h after the initial dose. Urine samples were collected in 2-h intervals from time 0 to 6 h and from 72 to 78 h. There was a loss of up to 50% activity of cefaclor in serum samples that were left at room temperatures for 3 to 8 h. Therefore, all blood samples were immediately iced, and the serum was separated in a refrigerated centrifuge and either immediately placed in a -70°C freezer or assayed. Using these precautions, a 14.17 + 1.47 (standard deviation [SD])% loss of activity was found in 16 samples evaluated.
The following tests were performed before and after each dosing period: hemoglobin, hematocrit, leukocyte count and differential, platelet estimation, urinalysis, blood urea nitrogen, glucose, sodium, potassium, chloride, bicarbonate, calcium, phosphorus, alkaline phophatase, lactic dehydrogenase, serum glutamic oxalacetic transaminase, serum glutamic pyruvic transaminase, cholesterol, total bilirubin, total protein, albumin, uric acid, and creatinine. Creatinine clearances were performed before and after the first dosing period. Blood pressures and pulses were taken before and after the dosing periods. All subjects were questioned daily during the test periods for possible adverse effects.
Antibiotic assays. The concentrations of cephalexin and cefaclor were determined by an agar well diffusion technique (1). Cephalexin assays were performed with antibiotic medium no. 1 using Sarcina lutea 9341 as the test organism for serum assays and Bacillus subtilis for urine assays. All cefaclor assays were performed withB. subtilis as the test organism on antibiotic medium no. 1. Reference standards were diluted in pooled normal human serum for serum assays. Urine samples were diluted in potassium phosphate buffer with the pH adjusted to 6.0 for cephalexin and to 4.5 for cefaclor. All samples and standards were tested in triplicate.
The plates were incubated at 37°C for 18 h. Zones of inhibition were measured by a Fisher-Lilly zone reader, and antibiotic concentrations were computed by comparing the mean zone of inhibition of each sample with the curve constructed from the zone sizes of the standard dilutions.
Calculated plasma half-life. Plasma concentrations obtained between 0 and 6 h were plotted on semilog graph paper versus time. The half-life was determined from the best-fit line through the points of decline of blood levels (0.75 to 4 h) by using the method of least squares. The elimination constant (Kd) was determined from the formula: Kd = 0.693/ ti,2.

RESULTS
Cefaclor plasma concentrations usually peaked within 1 h after dosing and steadily declined over the next 4 h, with no cefaclor detectable in the serum at 6 h ( Table 1). At 1 h, the mean concentration was 4.98 + 2.01 (SD) ,ug/ml (range, 0 to 10 pg/ml) and was comparable to levels achieved on day 4 of therapy: 3.57 + 1.52 (SD) ,g/ml (range, 0 to 6.1 p.g/ml).
Plasma concentrations of cephalexin were maximal between 0.75 and 1 h ( Serum half-life was determined for each antibiotic during the 0.75to 4-h interval, when a linear decline in antibiotic serum concentrations occurred. The mean serum half-life for cefaclor was 0.578 ± 0.074 h, and for cephalexin it was 0.802 ± 0.115 h (P < 0.001, Student's t test). The elimination constant for the same interval was 1.217 + 0.146 h-' for cefaclor and 0.881 ± 0.129 h-1 for cephalexin (P < 0.001, Student's t test).
Cefaclor and cephalexin concentrations in urine were determined on 2-h fractions collected during days 1 and 4 of therapy (Table 3). A total of 44.2% of the ingested dose of cefaclor was excreted within 2 h after administration of the drug; 23.6% was excreted from 2 to 4 h, and 2.3% was found in the urine between 4 and 6 h. Over the total 6-h interval, 70.1% of the total oral dose was detected in the urine.
Comparable values for cephalexin were 57.8% excreted from 0 to 2 h, 29.5% excreted from 2 to 4 h, and 8.9%o from 4 to 6 h after ingestion ofthe drug. During the 0to 6-h interval, 96.3% of the total dose was excreted.
Adverse reactions. No changes in pulse or blood pressure were noted during the course of treatment with either drug. All hematological and biochemical tests remained within normal limits except for one transient rise in serum glutamic oxalacetic transaminase while the subject was taking cefaclor. No drug sensitization could be detected. All urinalyses remained normal. Creatinine clearances were within normal limits, except for one determination of 14.8 ml/min obtained on subject no. 20 while he was taking cefaclor. Since simultaneous serum creatinine and blood urea nitrogen were normal and preceding and subsequent (2 weeks later) creatinine clearances were normal, this was believed to be due to laboratory error in the determination of urinary creatinine excretion.
Gastrointestinal tolerance of both antibiotics was, in general, good, with only 6 subjects complaining of transient mild gastrointestinal disturbance: subject 10, 1 liquid stool (cephalexin); subject 4, two episodes of mild nausea 30 min after ingestion of di-ug (cephalexin); subject 6, transient abdominal discomfort and diaphoresis after the morning dose on day 1 (cefaclor); subject 8, "indigestion" after the morning dose on 2 days (cefaclor); subject 17, mild diarrhea on days 3 and 4 (cefaclor); and subject 20, mild nausea and diarrhea on day 1 (cefaclor). No   subject withdrew from the study because of these side effects. One subject (no. 1) was withdrawn from the study on the last day of ingestion of cefaclor because he developed aseptic meningitis. He was the index case of a small epidemic of aseptic meningitis involving four related individuals from whom an enterovirus was cultured, all of whom had been in contact with children manifesting an acute upper respiratory infection and skin rash. Recovery was uneventful. The prior ingestion of cefaclor was not believed to have contributed to his illness.

DISCUSSION
Cefaclor, a new oral cephalosporin, has been compared favorably in vitro with other cephalosporins. This drug is 2 to 16 times more active against Streptococcus pneumoniae, staphylococcus, and various species of gram-negative bacilli than cephalexin (N. J. Bill and J. A. Washington, Prog. Abstr. Intersci. Conf. Antimicrob. Agents Chemother. 16th, Chicago, Ill., Abstr. no. 356, 1976). It has demonstrated activity against a number of Escherichia coli, klebsiella, and proteus strains that were resistant to cephalexin (W. M. Scheld, 0. M. Korzeniowski, and M. A. Sande, submitted for publication). Preliminary data suggests an enhanced activity against H. influenzae in contrast to other cephalosporin antibiotics (5). Preston (Prog. Abstr. Intersci. Conf. Antimicrob. Agents Chemother. 16th, Chicago, Ill., Abstr. no. 352, 1976) suggested that cefaclor may be more effective than ampicillin in the treatment of (3-lactamase-producing H. influenzae in mice. Pharmacodynamic studies of cefaclor in laboratory animals have shown rapid gastrointestinal absorption after oral administration and a relative resistance to metabolic degradation or alteration (2,3). Studies with [14C]cefaclor showed resistance to metabolism and un-changed elimination of the biologically active form in rats and mice, comparable to data obtained with cephalexin (4). In dogs, however, cefaclor is labile to metabolism, with only a 60% bioavailability of intact antibiotic after an oral dose, and only 21.5% urinary excretion of the active fraction in 24 h.
In this study, cefaclor was compared with cephalexin. Both drugs were rapidly absorbed, showing mean maximal serum levels 0.75 to 1.0 h after ingestion of a 250-mg oral dose. Peak serum concentrations (on days 1 and 4) of cefaclor were lower than those obtained with cephalexin (6.01 and 4.58 ,g/ml versus 9.34 and 8.50 jig/ml) (P < 0.001), as were the mean 4-h levels plained of mild gastrointestinal disturbancetwo were receiving cephalexin and four were receiving cefaclor. No allergic side effects were noted, and all physical and laboratory parameters remained normal.
In conclusion, when compared with its parent compound cephalexin, cefaclor, a new oral cephalosporin, produced one-third lower peak serum levels and was more rapidly excreted.
However, a 2 to 16 times greater activity by weight in vitro against many gram-negative organisms, including strains of E. coli, klebsiella, and proteus resistant to cephalexin, suggests its potential usefulness as an alternative to cephalexin in selected bacterial infections.