ANTINICUOBIAL AGENTS AND CMEMOTHI1EAPY, May 1976, p. 800-803
Copyright © 1976 American Society for Microbiology
Vol. 9, No. 5 Printed in U.S.A.
Cefatrizine (SK&F 60771), a New Oral Cephalosporin: Serum Levels and Urinary Recovery in Humans After Oral or Intramuscular Administration -Comparative Study with Cephalexin and Cefazolin PAUL ACTOR,* DONALD H. PITKIN, GEORGE LUCYSZYN, JERRY A. WEISBACH, AND JOSE L. BRAN
Smith Kline & French Laboratories, Philadelphia, Pennsylvania 19101,* and Hospital General San Juan de Dios, Guatemala City, Guatemala
Received for publication 8 December 1975
Cefatrizine (SK&F 60771), a new broad-spectrum cephalosporin, was administered in a 0. 5-g dose either orally or intramuscularly to volunteers in a crossover study. After oral administration, the average peak serum levels were 5.6 and 22.1 ,Ag/ml for cefatrizine and cephalexin, respectively. The serum half-life of cefatrizine appeared to be more extended than that of cephalexin. Urinary recovery of cefatrizine (35%) was approximately half that of cephalexin (68%) after oral administration. After intramuscular injection of 0.5 g, the average peak serum level of cefatrizine (12.0 ,ug/ml) was approximately one-fourth that of cefazolin (44.0 ,ug/ml). The serum half-life after intramuscular injection was 86 min for cefatrizine and 118 min for cefazolin. Urinary recovery was 45% of the intramuscularly administered dose, as compared with cefazolin, which was 74%.
Cefatrizine (SK&F 60771) is a new orally active semisynthetic cephalosporin with broadspectrum antibacterial activity (1, 5, 7-9). Chemically, cefatrizine is 7-[R-( -)-2-amino-2-
was administered orally after reconstitution in 15 ml of 0.1 N HCl and 45 ml of parenteral water. These formulations showed no loss in potency when kept at 4 C for up to 3 h. Cefatrizine for intramuscular (0.5 g) was reconstituted using 2.8 ml of a (p-hydroxyphenyl)acetamido-]-3-[lH-1,2,3-tria- injection an equimolar concentration of solution containing zole - 4(5) - ylthiomethyll3 - cephem - 4 - carboxylic sodium carbonate. This was used immediately beacid. Laboratory studies employing rodents cause of the alkali lability of this antibiotic (92% of show this antibiotic produces high and sus- initial activity was recovered 30 min after reconstitained serum levels after oral or parenteral tution). Cefazolin was reconstituted in 2.0 ml of administration (1, 6). It has outstanding protec- parenteral water. Experimental protocols. A total of 32 male subtive activity in mice infected with a variety of gram-positive or gram-negative bacterial path- jects were employed in the two studies. All subjects penicilogens, reflecting its excellent pharmacokinetic had no history of hypersensitivityof towards or other asthma or or history lins cephalosporins profile in this animal species. We have found a allergies. None of the subjects received any antimivariable pharmacokinetic response among ani- crobials or probenecid for 1 week prior to these studmal species when cefatrizine was administered ies (1 month in the case of parenteral bezathine either orally or parenterally to mice, dogs, penicillin G). In addition, no other medication was squirrel monkeys, or rabbits (1). The purpose of administered for 48 h before or during the studies. A this study was to determine the serum levels complete medical history was taken and a physical and urinary excretion of cefatrizine in compari- examination and laboratory tests were performed on son with those of cephalexin and cefazolin after each subject prior to the start of the study and again oral or parenteral administration to human vol- after 24 h following cephalosporin administration. In the oral and the intramuscular studies, 16 unteers. subjects were randomized into two equal groups and given either cefatrizine or the corresponding control MATERIALS AND METHODS cephalosporin. The subjects were fasted for 8 h preAntibiotics. Cefatrizine (SK&F 60771) was syn- ceding and 3 h after administration of a 0.5-g dose, thesized in the Smith Kline & French Laboratories. but water was permitted ad lib. Blood and urine Cefazolin and cephalexin were obtained as commer- samples were obtained prior to and at selected time cial preparations from Smith Kline & French Labo- intervals after dosing. One week later, the two ratories and Eli Lilly & Co., respectively. A formu- groups were crossed over and the opposite cephalolation containing 0.5 g of cefatrizine or cephalexin sporin was administered to each group. Blood and 800
VOL. 9, 1976
CEFATRIZINE, A NEW ORAL CEPHALOSPORIN
urine samples were collected in the same way as in the first phase of the study. Assay. All blood samples obtained were allowed
50
to clot in the cold, and the separated sera were stored at -20 C for no longer than 3 weeks prior to
Total urine voided for each subject over the designated time period was collected, and an aliquot was stored at -20 C for assay. A disk agar diffusion assay employing buffered (pH 6.0) Pen-Assay Seed Agar seeded with Bacillus subtilis ATCC 6633 as the indicator organism was used to determine the antibiotic content of each sample (3). Since extensive examination of blood and urine have revealed no biologically active metabolites, the assay system is assumed to measure only cefatrizine.
801
30
assay.
RESULTS AND DISCUSSION Oral doses of 0.5 g of cefatrizine or cephalexin were well tolerated by all recipients. A plot of the serum concentrations versus time for the 16 subjects receiving the -two antibiotics is shown in Fig. 1. It can be seen from this figure that the peak serum concentration for cefatrizine occurs later than that observed for cephalexin and that cefatrizine serum levels tend to decline at a slower rate. The average serum concentration of cefatrizine was significantly lower than that observed with cephalexin at all tested intervals up to 2 h after administration (Table 1). At 4 h, the cefatrizine serum concentrations were approximately twice that of cephalexin, suggesting a longer half-life for cefatrizine. At 8 h after dosing, 2 of 16 subjects showed trace amounts of cefatrizine in their sera, whereas none of the subjects had measurable levels of cephalexin at this sampling time. The average peak serum concentration obtained for cefatrizine (5.6 ,ug/ ml) was significantly lower than that of cephalexin (22.1 jig/ml). The serum concentrations obtained with cefatrizine are similar to those recently reported by Del Busto et al. (Prog. Abstr. Intersci. Conf. Antimicrob. Agents Chemother., 15th, Washington, D. C., Abstr. 325, 1975), who showed a peak serum value of 6.2 ,ug/ml after a 0.5-g oral dose. Table 2 shows the urinary recovery and urinary concentrations at various sample intervals after oral dosing. The urinary recovery for cefatrizine (35%) over the 12 h postadministration was approximately half that of cephalexin (68%). This poorer recovery primarily reflects a difference in the 0- to 2-h sampling period. The urinary concentrations obtained with cefatrizine are far in excess of the minimum inhibitory concentrations needed to inhibit susceptible urinary tract pathogens (1, 5). Intramuscular injections of 0.5 g of cefatrizine or cefatrizine or cefazolin were well tolerated in all recipients. There was no local reaction at the injection site, and fleeting pain was
20 a
E
Cephalexin ot
1-
W P.
5
Cefatrizie
2
1
2 3 TIME (HOURS)
4
5
FIG. 1. Average serum levels in 16 subjects after oral administration of 0.5 g of cefatrizine or cephalexin.
the only side effect observed with both cephalosporins. A plot of the serum concentrations obtained after a 0.5-g intramuscular dose versus time is shown in Fig. 2. The average serum concentrations obtained with cefazolin at every sample time were significantly higher than those of cefatrizine (Table 3). The average peak serum level for cefazolin (44.0 ,ug/ml) was approximately four times higher than that of cefatrizine (12.0 ,g/ml). The estimated half-life of cefatrizine was 86 min and that of cefazolin was 118 min. The values obtained for cefazolin are similar to those reported in previous studies (2, 4). The peak serum concentration of cefatrizine after intramuscular administration is approximately twice that obtained after oral administration, suggesting incomplete gastrointestinal absorption. Urinary recovery of cefatrizine over the 12-h period after injection was significantly lower than that of cefazolin (Table 4). The total amount recovered was 45%, as compared with that of cefazolin, which was 74%. Urine concentrations of cefatrizine over the 12-h period were well above the minimum inhibitory concentra-
802
ANTIMICROB. AGENTS CHZMOTHZR.
ACTOR ET AL.
TABLz 1. Average serum concentration and range in 16 subjects after oral administration of 0.5 g of cefatrizine or cephalexin-crossover study Serum concn (yg/ml) Cefatrizine Cephalexin Time sampled (h) Avg
10 (min) 0.5 1.0 1.5 2.0 4.0 8.0
SEP
Avg 3.6 ± 19.2 ± 17.4 ± 10.3 ± 6.1 ± 1.1 ± 0
Range
2.4 + 0.6 4.4 + 0.5 4.7 ± 0.3 4.6 ± 0.4 2.7 ± 0.3 0.11
0-11.0 0.9-10.0 2.2-7.4 2.3-7.0 0-4.9 0-1.0
Range 1.2-7.2b
SE 0.9 2.5 1.6 0.8 0.5 0.2
2.3-32.3 10.4-33.8 5.7-17.0 3.7-9.7 0.4-2.4 0
22.1
5.6 ±0.5 Avg peak SE, Standard error. b Data for seven subjects at 10 min.
2.1
a
50
TABLE 2. Urinary recovery of cefatrizine and cephalexin after 0.5-g oral dose-crossover study Cefatrizine
40
Cephalexin
0
30 time (h)
Aevgl
(j.g/ml) 0-2 2-4 4-6 6-12 a
% Re-
Avg level
% Re-
covered
(yg/ml)
covered
409 838 294 54
18 6 3
Statistically significant: P
39a 21 5 3
2081
8a
=
1058 262 52
Copyright © 1976 American Society for Microbiology
Vol. 9, No. 5 Printed in U.S.A.
Cefatrizine (SK&F 60771), a New Oral Cephalosporin: Serum Levels and Urinary Recovery in Humans After Oral or Intramuscular Administration -Comparative Study with Cephalexin and Cefazolin PAUL ACTOR,* DONALD H. PITKIN, GEORGE LUCYSZYN, JERRY A. WEISBACH, AND JOSE L. BRAN
Smith Kline & French Laboratories, Philadelphia, Pennsylvania 19101,* and Hospital General San Juan de Dios, Guatemala City, Guatemala
Received for publication 8 December 1975
Cefatrizine (SK&F 60771), a new broad-spectrum cephalosporin, was administered in a 0. 5-g dose either orally or intramuscularly to volunteers in a crossover study. After oral administration, the average peak serum levels were 5.6 and 22.1 ,Ag/ml for cefatrizine and cephalexin, respectively. The serum half-life of cefatrizine appeared to be more extended than that of cephalexin. Urinary recovery of cefatrizine (35%) was approximately half that of cephalexin (68%) after oral administration. After intramuscular injection of 0.5 g, the average peak serum level of cefatrizine (12.0 ,ug/ml) was approximately one-fourth that of cefazolin (44.0 ,ug/ml). The serum half-life after intramuscular injection was 86 min for cefatrizine and 118 min for cefazolin. Urinary recovery was 45% of the intramuscularly administered dose, as compared with cefazolin, which was 74%.
Cefatrizine (SK&F 60771) is a new orally active semisynthetic cephalosporin with broadspectrum antibacterial activity (1, 5, 7-9). Chemically, cefatrizine is 7-[R-( -)-2-amino-2-
was administered orally after reconstitution in 15 ml of 0.1 N HCl and 45 ml of parenteral water. These formulations showed no loss in potency when kept at 4 C for up to 3 h. Cefatrizine for intramuscular (0.5 g) was reconstituted using 2.8 ml of a (p-hydroxyphenyl)acetamido-]-3-[lH-1,2,3-tria- injection an equimolar concentration of solution containing zole - 4(5) - ylthiomethyll3 - cephem - 4 - carboxylic sodium carbonate. This was used immediately beacid. Laboratory studies employing rodents cause of the alkali lability of this antibiotic (92% of show this antibiotic produces high and sus- initial activity was recovered 30 min after reconstitained serum levels after oral or parenteral tution). Cefazolin was reconstituted in 2.0 ml of administration (1, 6). It has outstanding protec- parenteral water. Experimental protocols. A total of 32 male subtive activity in mice infected with a variety of gram-positive or gram-negative bacterial path- jects were employed in the two studies. All subjects penicilogens, reflecting its excellent pharmacokinetic had no history of hypersensitivityof towards or other asthma or or history lins cephalosporins profile in this animal species. We have found a allergies. None of the subjects received any antimivariable pharmacokinetic response among ani- crobials or probenecid for 1 week prior to these studmal species when cefatrizine was administered ies (1 month in the case of parenteral bezathine either orally or parenterally to mice, dogs, penicillin G). In addition, no other medication was squirrel monkeys, or rabbits (1). The purpose of administered for 48 h before or during the studies. A this study was to determine the serum levels complete medical history was taken and a physical and urinary excretion of cefatrizine in compari- examination and laboratory tests were performed on son with those of cephalexin and cefazolin after each subject prior to the start of the study and again oral or parenteral administration to human vol- after 24 h following cephalosporin administration. In the oral and the intramuscular studies, 16 unteers. subjects were randomized into two equal groups and given either cefatrizine or the corresponding control MATERIALS AND METHODS cephalosporin. The subjects were fasted for 8 h preAntibiotics. Cefatrizine (SK&F 60771) was syn- ceding and 3 h after administration of a 0.5-g dose, thesized in the Smith Kline & French Laboratories. but water was permitted ad lib. Blood and urine Cefazolin and cephalexin were obtained as commer- samples were obtained prior to and at selected time cial preparations from Smith Kline & French Labo- intervals after dosing. One week later, the two ratories and Eli Lilly & Co., respectively. A formu- groups were crossed over and the opposite cephalolation containing 0.5 g of cefatrizine or cephalexin sporin was administered to each group. Blood and 800
VOL. 9, 1976
CEFATRIZINE, A NEW ORAL CEPHALOSPORIN
urine samples were collected in the same way as in the first phase of the study. Assay. All blood samples obtained were allowed
50
to clot in the cold, and the separated sera were stored at -20 C for no longer than 3 weeks prior to
Total urine voided for each subject over the designated time period was collected, and an aliquot was stored at -20 C for assay. A disk agar diffusion assay employing buffered (pH 6.0) Pen-Assay Seed Agar seeded with Bacillus subtilis ATCC 6633 as the indicator organism was used to determine the antibiotic content of each sample (3). Since extensive examination of blood and urine have revealed no biologically active metabolites, the assay system is assumed to measure only cefatrizine.
801
30
assay.
RESULTS AND DISCUSSION Oral doses of 0.5 g of cefatrizine or cephalexin were well tolerated by all recipients. A plot of the serum concentrations versus time for the 16 subjects receiving the -two antibiotics is shown in Fig. 1. It can be seen from this figure that the peak serum concentration for cefatrizine occurs later than that observed for cephalexin and that cefatrizine serum levels tend to decline at a slower rate. The average serum concentration of cefatrizine was significantly lower than that observed with cephalexin at all tested intervals up to 2 h after administration (Table 1). At 4 h, the cefatrizine serum concentrations were approximately twice that of cephalexin, suggesting a longer half-life for cefatrizine. At 8 h after dosing, 2 of 16 subjects showed trace amounts of cefatrizine in their sera, whereas none of the subjects had measurable levels of cephalexin at this sampling time. The average peak serum concentration obtained for cefatrizine (5.6 ,ug/ ml) was significantly lower than that of cephalexin (22.1 jig/ml). The serum concentrations obtained with cefatrizine are similar to those recently reported by Del Busto et al. (Prog. Abstr. Intersci. Conf. Antimicrob. Agents Chemother., 15th, Washington, D. C., Abstr. 325, 1975), who showed a peak serum value of 6.2 ,ug/ml after a 0.5-g oral dose. Table 2 shows the urinary recovery and urinary concentrations at various sample intervals after oral dosing. The urinary recovery for cefatrizine (35%) over the 12 h postadministration was approximately half that of cephalexin (68%). This poorer recovery primarily reflects a difference in the 0- to 2-h sampling period. The urinary concentrations obtained with cefatrizine are far in excess of the minimum inhibitory concentrations needed to inhibit susceptible urinary tract pathogens (1, 5). Intramuscular injections of 0.5 g of cefatrizine or cefatrizine or cefazolin were well tolerated in all recipients. There was no local reaction at the injection site, and fleeting pain was
20 a
E
Cephalexin ot
1-
W P.
5
Cefatrizie
2
1
2 3 TIME (HOURS)
4
5
FIG. 1. Average serum levels in 16 subjects after oral administration of 0.5 g of cefatrizine or cephalexin.
the only side effect observed with both cephalosporins. A plot of the serum concentrations obtained after a 0.5-g intramuscular dose versus time is shown in Fig. 2. The average serum concentrations obtained with cefazolin at every sample time were significantly higher than those of cefatrizine (Table 3). The average peak serum level for cefazolin (44.0 ,ug/ml) was approximately four times higher than that of cefatrizine (12.0 ,g/ml). The estimated half-life of cefatrizine was 86 min and that of cefazolin was 118 min. The values obtained for cefazolin are similar to those reported in previous studies (2, 4). The peak serum concentration of cefatrizine after intramuscular administration is approximately twice that obtained after oral administration, suggesting incomplete gastrointestinal absorption. Urinary recovery of cefatrizine over the 12-h period after injection was significantly lower than that of cefazolin (Table 4). The total amount recovered was 45%, as compared with that of cefazolin, which was 74%. Urine concentrations of cefatrizine over the 12-h period were well above the minimum inhibitory concentra-
802
ANTIMICROB. AGENTS CHZMOTHZR.
ACTOR ET AL.
TABLz 1. Average serum concentration and range in 16 subjects after oral administration of 0.5 g of cefatrizine or cephalexin-crossover study Serum concn (yg/ml) Cefatrizine Cephalexin Time sampled (h) Avg
10 (min) 0.5 1.0 1.5 2.0 4.0 8.0
SEP
Avg 3.6 ± 19.2 ± 17.4 ± 10.3 ± 6.1 ± 1.1 ± 0
Range
2.4 + 0.6 4.4 + 0.5 4.7 ± 0.3 4.6 ± 0.4 2.7 ± 0.3 0.11
0-11.0 0.9-10.0 2.2-7.4 2.3-7.0 0-4.9 0-1.0
Range 1.2-7.2b
SE 0.9 2.5 1.6 0.8 0.5 0.2
2.3-32.3 10.4-33.8 5.7-17.0 3.7-9.7 0.4-2.4 0
22.1
5.6 ±0.5 Avg peak SE, Standard error. b Data for seven subjects at 10 min.
2.1
a
50
TABLE 2. Urinary recovery of cefatrizine and cephalexin after 0.5-g oral dose-crossover study Cefatrizine
40
Cephalexin
0
30 time (h)
Aevgl
(j.g/ml) 0-2 2-4 4-6 6-12 a
% Re-
Avg level
% Re-
covered
(yg/ml)
covered
409 838 294 54
18 6 3
Statistically significant: P
39a 21 5 3
2081
8a
=
1058 262 52
