ANTiMICROBIAL AGENTS AND CHEMOTHERAPY, Dec. 1978, P. 838-841
Vol. 14, No. 6
0066-4804/78/0014-0838$02.00/0 Copyright i) 1978 American Society for Microbiology
Printed in U.S.A.
Pharmacokinetics and Safety of Cefamandole in Infants and Children CHIA T. CHANG, ABDUL J. KHAN,* MELANIE M. AGBAYANI, RAMESH JHAVERI, IRFAN AMIN, AND HUGH E. EVANS Department of Pediatrics, Jewish Hospital and Medical Center of Brooklyn, Brooklyn, New
York 11238
Received for publication 5 July 1978
Cefamandole, a new cephalosporin antibiotic, has greater activity against common pathogens, including Escherichia coli, Haemophilus influenzae, and Proteus (including indole-positive strains), than available cephalosporin drugs. We have evaluated the safety and pharmacokinetics of this drug in 30 infants and children. Blood levels and urinary excretion of the drug were similar to those previously found in adults. The only side effects were mild and transient elevation of serum glutamic oxalacetic transaminase in 12 patients and of blood urea nitrogen in 1 patient in whom serum creatinine remained normal and unchanged.
Cefamandole (CM), a new semisynthetic broad-spectrum cephalosporin (CSP) antibiotic, has greater in vitro activity against all Enterobacteriaceae than other CSP antibiotics (4, 10, 11, 13). Its spectrum includes such gram-negative organisms as indole-producing Proteus, Ser-
None of the patients had a history of hypersensitivity to CSPs or penicillins, or any evidence of renal or liver impairment. An average daily dose of 75 mg/kg (range, 50 to 100 mg/kg) in three divided doses was given parenterally every 8 h to those weighing less than 25 kg. Patients weighing 25 kg or more were given 500 mg intramuscularly (i.m.) every 8 h. The ratia marcescens, and Enterobacter spp., which average duration of treatment was 8.2 and 8.5 days for are resistant to other available CSP drugs (4, pneumonia and UTI cases, respectively. 11). Against Haemophilus influenzae, a comThe diagnosis of clinical pneumonia in each case mon pathogen in the pediatric age group, CM was confirmed by roentgenograms, which were rehas been found to be one of the most active of peated during and after therapy. Blood cultures in all the CSP antibiotics (4). CM, active against am- were sterile. Lung aspiration and/or tracheal aspirawas not performed. picillin-resistant strains of H. influenzae and tionThe diagnosis of UTI was based on at least two Salmonella and methicillin-resistant strains of consecutively urine cultures and defined as Staphylococcus aureus (10), has somewhat lim- growth of overpositive 105 single organisms per ml in pure ited activity against Listeria monocytogenes and culture from midstream, clean catch urine or any enterococci (7, 10). The drug has been found to growth on suprapubic bladder aspiration. All of the be effective and safe in a limited number of primary pathogens were susceptible to a 30,ug disk of pediatric patients treated for various bacterial CM (2). All patients were kept under close observation infections, including pneumonia (1, 14). Phar- during the entire treatment period. Liver function macokinetic data, including half-life (tl/2) and studies (serum glutamic oxalacetic transaminase volume distribution of this drug in infants and [SGOT], bilirubin, alkaline phosphatase), renal function studies (blood urea nitrogen, serum creatinine, children, have not been reported as yet. We have urinalysis), complete blood count, and Coombs' test studied the pharmacokinetics of CM in a group obtained before treatment were repeated during therof infants and children treated for clinical pneu- apy (between days 3 and 5) and 1 to 2 days after monia and urinary tract infection (UTI). treatment to monitor possible drug toxicity. (This work was presented in part at the 16th Pharmacokinetic studies. Blood specimens for Interscience Conference on Antimicrobial the antibiotic levels after one single dose (i.m. in 13, Agents and Chemotherapy, Chicago, Ill., Octo- intravenous [i.v.] in 14) of CM were collected once during the treatment period (usually between days 3 ber 1976.) and 5). The i.v. dose was diluted to a concentration of SUBJECTS AND METHODS 25 mg/ml and infused over a period of exactly 5 min. Thirty infants and children (15 males and 15 fe- Serum specimens at 0.25, 0.5, 1, 2, and 4 h after the males) ranging in age from 3 months to 13 years (mean end of i.v. infusion and at 0.5, 1, 2, and 4 h after i.m. age, 4 years), including 8 infants younger than 1 year, doses were collected and kept frozen at -40°C. In 22 with pneumonia and 8 with UTI, were included. three cases an additional specimen at 7.5 h was also Written informed consent was obtained from each collected. In 19 patients, after the dose urine was parent. pooled for approximately 4 h, and the volume was 838
VOL. 14, 1978
CEFAMANDOLE IN PEDIATRIC PATIENTS
recorded. A 10-ml amount from this pool was frozen (-40°C) for bioassay. Blood specimens belonging to three subjects thawed out and were discarded. Antibiotic levels in the sera and urine were performed at Eli Lilly Laboratories, Indianapolis, Ind., by an agar diffusion plate assay method (3). This method utilized agar medium no. 1 (Difco Laboratories, Detroit, Mich.) and Bacillus subtilis (ATCC 6633) as the test organism. Pharmacokinetic calculation. Serum antibiotic concentrations were plotted against time, using a semilogarithmic graph. The serum half-life was calculated when the blood levels were declining exponentially during the elimination phase. The formula utilized for half-life (t1/2) calculation was In 2/K, where K is the elimination rate constant represented by the slope of the regression line determined by the method of least squares (6). The volume distributions (Vd) were determined by the formula: Vd = dose (milligrams x 1,000)/[Ec (milligrams per milliliter) x weight (kilograms)]. Ec is the estimated serum concentration at the onset of the elimination phase obtained by extrapolating the serum concentration time curve back to the Y intercept. For statistical evaluation Student's t test and regression analysis were utilized. RESULTS
Blood and urinary concentrations and pharmacokinetics are presented in Table 1. The blood levels after the end of a 5-min i.v. infusion peaked at 0.25 h and with i.m. routes they peaked at 0.5 h. The average 0.5-h level (26.2 ,tg/ml) after 16.5 mg/kg i.v. was not significantly different from 19.4 ,ug/ml obtained after a comparable i.m. dose (P > 0.1). Blood levels, however, were similar at 1-, 2-, and 4-h intervals whether the drug was given i.v. or i.m. Average
839
concentrations after a smaller i.m. dose (13.3 mg/kg) were in general lower throughout, as compared to the 16.4-mg/kg i.m. dose; the differences, however, were significant only at 0.5 (P < 0.05) and 1 (P < 0.05) h. The blood levels at 0.25 h after a higher i.v. dose (32.5 mg/kg) and at 0.5 h after a comparable i.m. dose (32.3 mg/kg) of CM were higher than after previous doses. The number of cases in these dose groups was small for any statistical evaluation. Peak blood levels at 0.25 h and 0.5 h obtained with 16.4-mg/kg i.m. and 16.5-mg/kg i.v. doses when analyzed by regression analysis in relation to age and weight of the subjects did not reveal any significant correlation; values of T were 0.1 in each analysis. Blood levels determined at 7.5 h after i.m. doses in three cases were less than 0.25,ug/ml. The mean concentration in the urine was 1,726 ,ug/ml, with a range of 330 to 3,500 ,g/ml, and an average of 60% of the dose was excreted within 4 h after administration. The tl/2 and volume distribution (Vd) values are presented in Table 1. The mean tl/2 of 56 (+3.7) min with average i.m. doses of 16.4 mg was significantly longer (P < 0.05) than the 47 (±2.0) min obtained with a comparable dose given i.v. The average Vd of the i.m. group, 615 (+71) ml/kg, was significantly larger (P < 0.005) than that of the i.v. group (375 ± 14). No differences in tl/2 values were found by increasing or decreasing the dose with either route. When analyzed for body weight the tl/2 and Vd values of those weighing 10 kg were comparable in the groups given the test doses of 16.4 mg/kg i.m. and 16.5 mg/kg i.v. (P > 0.1 in each serum
TABLE 1. Blood levels and pharmacokinetics of CM Avg (±1 SD) blood levels (ug/ml) at: Avg dose
N
and route
cases
Urine 4-h ex-
Mean tl,2 Mean Vd
f oh
0.25 h
0.5 h
1h
2h
4 (h SD
S
(gf/ml, ±1 mean ±1 SD)
(% of dose,
mean ± 1
SD)
16.5 i.v.
13
16.4 i.m. 13.3 i.m. 32.3 i.m.
32.5 i.v.
7 3 3 1
12.0
4.6
1.4
47**a
375**a
(8.4)
(3.8)
(2.9)
(2.0)
0.0
19.4
12.6
3.9
1.1
(7.6)
(2.9) 2.5 (0.2)
(1.0)
0.0
(11.0) 12.1 (7.5)
(1,344) 615** 1,363c (71) (1,076)
53.3 (23)
0.16 1.0
34.3 (7.6) 90
Average Compare * P < 0.005, ** P < 0.005. b Mean of ten cases. 'Mean of five cases. a
1,462b
26.9
(14.6)
0.06
(0.01)
4.7
(1.8) 17.0 22
56*
(3.7)
(14)
62.4
(22.4) 62.5
(15.8)
1.03 (0.2)
54
518
(14)
(162)
1.5 (0.9) 0.6
69 (23) 47
532 (265)
(1,036)
514
1,600
53
1,726
60
2,193
47.5
(4.9)
840
ANTIMICROB. AGENTS CHEMOTHER.
CHANG ET AL.
analysis). When analyzed for age (Table 2), the t1/2 values of infants
Vol. 14, No. 6
0066-4804/78/0014-0838$02.00/0 Copyright i) 1978 American Society for Microbiology
Printed in U.S.A.
Pharmacokinetics and Safety of Cefamandole in Infants and Children CHIA T. CHANG, ABDUL J. KHAN,* MELANIE M. AGBAYANI, RAMESH JHAVERI, IRFAN AMIN, AND HUGH E. EVANS Department of Pediatrics, Jewish Hospital and Medical Center of Brooklyn, Brooklyn, New
York 11238
Received for publication 5 July 1978
Cefamandole, a new cephalosporin antibiotic, has greater activity against common pathogens, including Escherichia coli, Haemophilus influenzae, and Proteus (including indole-positive strains), than available cephalosporin drugs. We have evaluated the safety and pharmacokinetics of this drug in 30 infants and children. Blood levels and urinary excretion of the drug were similar to those previously found in adults. The only side effects were mild and transient elevation of serum glutamic oxalacetic transaminase in 12 patients and of blood urea nitrogen in 1 patient in whom serum creatinine remained normal and unchanged.
Cefamandole (CM), a new semisynthetic broad-spectrum cephalosporin (CSP) antibiotic, has greater in vitro activity against all Enterobacteriaceae than other CSP antibiotics (4, 10, 11, 13). Its spectrum includes such gram-negative organisms as indole-producing Proteus, Ser-
None of the patients had a history of hypersensitivity to CSPs or penicillins, or any evidence of renal or liver impairment. An average daily dose of 75 mg/kg (range, 50 to 100 mg/kg) in three divided doses was given parenterally every 8 h to those weighing less than 25 kg. Patients weighing 25 kg or more were given 500 mg intramuscularly (i.m.) every 8 h. The ratia marcescens, and Enterobacter spp., which average duration of treatment was 8.2 and 8.5 days for are resistant to other available CSP drugs (4, pneumonia and UTI cases, respectively. 11). Against Haemophilus influenzae, a comThe diagnosis of clinical pneumonia in each case mon pathogen in the pediatric age group, CM was confirmed by roentgenograms, which were rehas been found to be one of the most active of peated during and after therapy. Blood cultures in all the CSP antibiotics (4). CM, active against am- were sterile. Lung aspiration and/or tracheal aspirawas not performed. picillin-resistant strains of H. influenzae and tionThe diagnosis of UTI was based on at least two Salmonella and methicillin-resistant strains of consecutively urine cultures and defined as Staphylococcus aureus (10), has somewhat lim- growth of overpositive 105 single organisms per ml in pure ited activity against Listeria monocytogenes and culture from midstream, clean catch urine or any enterococci (7, 10). The drug has been found to growth on suprapubic bladder aspiration. All of the be effective and safe in a limited number of primary pathogens were susceptible to a 30,ug disk of pediatric patients treated for various bacterial CM (2). All patients were kept under close observation infections, including pneumonia (1, 14). Phar- during the entire treatment period. Liver function macokinetic data, including half-life (tl/2) and studies (serum glutamic oxalacetic transaminase volume distribution of this drug in infants and [SGOT], bilirubin, alkaline phosphatase), renal function studies (blood urea nitrogen, serum creatinine, children, have not been reported as yet. We have urinalysis), complete blood count, and Coombs' test studied the pharmacokinetics of CM in a group obtained before treatment were repeated during therof infants and children treated for clinical pneu- apy (between days 3 and 5) and 1 to 2 days after monia and urinary tract infection (UTI). treatment to monitor possible drug toxicity. (This work was presented in part at the 16th Pharmacokinetic studies. Blood specimens for Interscience Conference on Antimicrobial the antibiotic levels after one single dose (i.m. in 13, Agents and Chemotherapy, Chicago, Ill., Octo- intravenous [i.v.] in 14) of CM were collected once during the treatment period (usually between days 3 ber 1976.) and 5). The i.v. dose was diluted to a concentration of SUBJECTS AND METHODS 25 mg/ml and infused over a period of exactly 5 min. Thirty infants and children (15 males and 15 fe- Serum specimens at 0.25, 0.5, 1, 2, and 4 h after the males) ranging in age from 3 months to 13 years (mean end of i.v. infusion and at 0.5, 1, 2, and 4 h after i.m. age, 4 years), including 8 infants younger than 1 year, doses were collected and kept frozen at -40°C. In 22 with pneumonia and 8 with UTI, were included. three cases an additional specimen at 7.5 h was also Written informed consent was obtained from each collected. In 19 patients, after the dose urine was parent. pooled for approximately 4 h, and the volume was 838
VOL. 14, 1978
CEFAMANDOLE IN PEDIATRIC PATIENTS
recorded. A 10-ml amount from this pool was frozen (-40°C) for bioassay. Blood specimens belonging to three subjects thawed out and were discarded. Antibiotic levels in the sera and urine were performed at Eli Lilly Laboratories, Indianapolis, Ind., by an agar diffusion plate assay method (3). This method utilized agar medium no. 1 (Difco Laboratories, Detroit, Mich.) and Bacillus subtilis (ATCC 6633) as the test organism. Pharmacokinetic calculation. Serum antibiotic concentrations were plotted against time, using a semilogarithmic graph. The serum half-life was calculated when the blood levels were declining exponentially during the elimination phase. The formula utilized for half-life (t1/2) calculation was In 2/K, where K is the elimination rate constant represented by the slope of the regression line determined by the method of least squares (6). The volume distributions (Vd) were determined by the formula: Vd = dose (milligrams x 1,000)/[Ec (milligrams per milliliter) x weight (kilograms)]. Ec is the estimated serum concentration at the onset of the elimination phase obtained by extrapolating the serum concentration time curve back to the Y intercept. For statistical evaluation Student's t test and regression analysis were utilized. RESULTS
Blood and urinary concentrations and pharmacokinetics are presented in Table 1. The blood levels after the end of a 5-min i.v. infusion peaked at 0.25 h and with i.m. routes they peaked at 0.5 h. The average 0.5-h level (26.2 ,tg/ml) after 16.5 mg/kg i.v. was not significantly different from 19.4 ,ug/ml obtained after a comparable i.m. dose (P > 0.1). Blood levels, however, were similar at 1-, 2-, and 4-h intervals whether the drug was given i.v. or i.m. Average
839
concentrations after a smaller i.m. dose (13.3 mg/kg) were in general lower throughout, as compared to the 16.4-mg/kg i.m. dose; the differences, however, were significant only at 0.5 (P < 0.05) and 1 (P < 0.05) h. The blood levels at 0.25 h after a higher i.v. dose (32.5 mg/kg) and at 0.5 h after a comparable i.m. dose (32.3 mg/kg) of CM were higher than after previous doses. The number of cases in these dose groups was small for any statistical evaluation. Peak blood levels at 0.25 h and 0.5 h obtained with 16.4-mg/kg i.m. and 16.5-mg/kg i.v. doses when analyzed by regression analysis in relation to age and weight of the subjects did not reveal any significant correlation; values of T were 0.1 in each analysis. Blood levels determined at 7.5 h after i.m. doses in three cases were less than 0.25,ug/ml. The mean concentration in the urine was 1,726 ,ug/ml, with a range of 330 to 3,500 ,g/ml, and an average of 60% of the dose was excreted within 4 h after administration. The tl/2 and volume distribution (Vd) values are presented in Table 1. The mean tl/2 of 56 (+3.7) min with average i.m. doses of 16.4 mg was significantly longer (P < 0.05) than the 47 (±2.0) min obtained with a comparable dose given i.v. The average Vd of the i.m. group, 615 (+71) ml/kg, was significantly larger (P < 0.005) than that of the i.v. group (375 ± 14). No differences in tl/2 values were found by increasing or decreasing the dose with either route. When analyzed for body weight the tl/2 and Vd values of those weighing 10 kg were comparable in the groups given the test doses of 16.4 mg/kg i.m. and 16.5 mg/kg i.v. (P > 0.1 in each serum
TABLE 1. Blood levels and pharmacokinetics of CM Avg (±1 SD) blood levels (ug/ml) at: Avg dose
N
and route
cases
Urine 4-h ex-
Mean tl,2 Mean Vd
f oh
0.25 h
0.5 h
1h
2h
4 (h SD
S
(gf/ml, ±1 mean ±1 SD)
(% of dose,
mean ± 1
SD)
16.5 i.v.
13
16.4 i.m. 13.3 i.m. 32.3 i.m.
32.5 i.v.
7 3 3 1
12.0
4.6
1.4
47**a
375**a
(8.4)
(3.8)
(2.9)
(2.0)
0.0
19.4
12.6
3.9
1.1
(7.6)
(2.9) 2.5 (0.2)
(1.0)
0.0
(11.0) 12.1 (7.5)
(1,344) 615** 1,363c (71) (1,076)
53.3 (23)
0.16 1.0
34.3 (7.6) 90
Average Compare * P < 0.005, ** P < 0.005. b Mean of ten cases. 'Mean of five cases. a
1,462b
26.9
(14.6)
0.06
(0.01)
4.7
(1.8) 17.0 22
56*
(3.7)
(14)
62.4
(22.4) 62.5
(15.8)
1.03 (0.2)
54
518
(14)
(162)
1.5 (0.9) 0.6
69 (23) 47
532 (265)
(1,036)
514
1,600
53
1,726
60
2,193
47.5
(4.9)
840
ANTIMICROB. AGENTS CHEMOTHER.
CHANG ET AL.
analysis). When analyzed for age (Table 2), the t1/2 values of infants
