Drugs 42 (Suppl. 3): 57-60, 1991 0012-6667/91/0300-0057/$2.00/0 © Adis International Limited. All rights reserved. DRSUP3227
Clinical Trials of Cefpodoxime Proxetil Suspension in Paediatrics Ryochi Fujii Research Institute of Chemotherapy for Mother and Child, Department of Pediatrics, School of Medicine, Teikyo University, Tokyo, Japan
Summary
The pharmacokinetics, bacteriological and clinical efficacy, and safety of the suspension formulation of cefpodoxime pTOxetil, an oral cephalosporin antibacterial, were evaluated in paediatric patients with various infections. With single doses of 3 and 6 mgJkg (cefpodoxime equivalent) a dose response was evident in the serum concentration values. Absorption, as evidenced by serum concentrations and areas under the concentration-time curve, was enhanced when the suspension was administered before a meal. The overall clinical efficacy (defined as an excellent or good response) in evaluable patients (those from whom a pathogen was isolated) was 94,7% (451 of 476). Bacteriological eradication rates were as follows: Gram-positive bacteria 91.3%; Gram-negative bacteria 88,6%, and 90.0% overall. Side effects occurred in 17 (2.29%) patients, and transient and reversible abnormal laboratory values were found in a few patients.
Cefpodoxime proxetil is a new cephalosporin prodrug, which is de-esterified in the body to the active moiety cefpodoxime. Cefpodoxime is resistant to various ~-lactamases, and so its effectiveness against prevalent ~-lactamase-producing strains is expected. Cefpodoxime is a broad spectrum antibacterial agent with MICso values of < 3.13 mg/L for the following species: Staphylococcus aureus (methicillin-susceptible strains), Streptococcus pyogenes, S. pneumoniae, Escherichia coli, Klebsiella pneumoniae, Citrobacter spp., Enterobacter spp., Proteus mirabilis, P. rettgeri, P. vulgaris, P. inconstans, Haemophilus injluenzae, and Moraxella (Branhamella) catarrhalis (Tajima et al. 1988). The compound is inactive against Enterococcus faecalis and Pseudomonas aeruginosa. In Japan, cefpodoxime proxetil has been widely studied in the clinical setting in adults. Its features and utility have been evaluated at both the 35th
General Meeting of the Japanese Society of Chemotherapy and the 27th Interscience Conference on Antimicrobial Agents and Chemotherapy. The formulation of cefpodoxime proxetil in a suspension, and the completion of bioequivalency testing comparing the suspension and tablet formulations enabled study in paediatric patients to begin in 1986. The following is a report of pharmacokinetic and clinical studies of cefpodoxime proxetil in paediatric patients, conducted with the cooperation of 17 institutes throughout Japan.
1. Pharmacokinetic Study A pharmacokinetic study was conducted in 60 paediatric patients aged 7.0 ± 0.4 years with normal renal function. A single oral dose of cefpodoxime proxetil suspension was administered (3 or 6 mg/kg of cefpodoxime equivalent). Blood and urinary concentrations of cefpodoxime were deter-
Drugs 42 (Suppl. 3) 1991
58
2. Clinical Study
mined by high performance liquid chromatography. The respective mean values for area under the concentration-time curve (AUC), half-life, and peak serum concentration (C max ) [fasting/nonfasting] were 9.93 ± 0.78/8.73 ± 0.43 mg/L· h, 2.43 ± 0.33/2.28 ± 0.16 hours, and 2.24 ± 0.21/1.65 ± 0.07 mg/L for a 3 mg/kg dose, and 20.20 ± 1.93/ 18.54 ± 1.85 mg/L· h, 2.43 ± 0.39/3.25 ± 0.79 hours, and 4.68 ± 0.54/3.71 ± 0.41 mg/L for a 6 mg/kg dose. Thus, AUC and C max demonstrated a dose response that was slightly higher at both dosages when administered Defore meals. However, the half-life was unaffected by food and showed no apparent dose dependency. Respective mean urinary concentrations at 0 to 2, 2 to 4, and 4 to 6 hours (fasting/nonfasting) were 103.3 ± 36.6/62.8 ± 12.1, 145.0 ± 30.9;128.6 ± 18.0, and 88.0 ± 11.4/72.5 ± 12.6 mg/L for a 3 mg/kg dose, and 108.0 ± 23.2/71.9 ± 11.4, 410.7 ± 122.7/222.3 ± 44.6, and 344.7 ± 128.8/145.0 ± 28.5 mg/L for a 6 mg/kg dose. Thus, the peak urinary concentration occurred 2 to 4 hours after administration. On average, 30% of an administered dose was recovered during the first 8 hours after administration.
A clinical study was carried out in 742 paediatric patients with various infections. Informed consent was obtained from the parents of all children examined in these studies. A pathogen was isolated from 476, who were included in the efficacy analysis. Patients were approximately evenly distributed with regard to sex, and 170 (35.8%) were aged < 3 years (a quarter of these being infants aged < I year), 188 (39.5%) were 3 to 6 years of age, 115 (24.2%) were 6 to 12 years of age and 3 (0.6%) were 12 to 16 years of age. Primary diseases treated included tonsillitis/pharyngitis and laryngitis (32.1 %), acute bronchitis and pneumonia (19.1 %), urinary tract infections (20.5%), scarlet fever and otitis media (8.2%), and others. Infections were of moderate severity in 53.9% of the children, severe in 1.4%, and mild in the remainder. 2.1 Clinical Efficacy A good or excellent clinical response was obtained in 94.7% of children overall. Efficacy rates per indication were as follows: tonsillitis, 112 of 115 (97.4%); pharyngitis and laryngitis, 36 of 38 (94.7%); acute bronchitis, 29 of 29 (100%); pneu-
Table I. Clinical effectiveness classified by diagnosis in 476 evaluable Japanese paediatric patients treated with cefpodoxime proxetil suspension
Diagnosis
No. of patients
Clinical response excellent
good
fair 1 2
Pharyngitis and laryngitis Tonsillitis Acute bronchitis Pneumonia Scarlet fever Impetigo SSSS Other SST I UTI Otitis media Other
38 115 29 62 30 66 6 17 97 9 7
25 71 15 39 27 37 1 6 63 2
11 41 14 19 3 24 4 10 30 4 4
Total
476
287
164
a Defined as an excellent or good response. Abbreviations: SSSS = staphylococcal scaled skin syndrome; SSTI
= skin and
poor
3 3
2
1 3
3
16
9
soft tissue infection; UTI
Efficacy rate (%)8 94.7 97.4 100.0 93.5 100.0 92.4 83.3 94.1 95.9 66.7 71.4 94.7
= urinary tract infection.
Clinical Trials of Cefpodoxime Proxetil
59
Table II. Bacteriological efficacy of cefpodoxime proxetil in 476 evaluable Japanese paediatric patients treated with cefpodoxime
proxetil suspension Organism
No. of strains
Eradicated
Decreased
Unchanged
Eradication rate (%)
Staphylococcus aureus S. epidermidis Streptococcus pyogenes S. pneumoniae Enterococcus spp. Other Gram·positive bacteria
117 5 87 28 4 10
102 5 85 25 2 10
2
13
2
2 1 2
Subtotal
251
229
4
18
91.2
Haemophilus influenzae H. parainfluenzae Escherichia coli Klebsiella spp. Proteus spp. Enterobacter spp. Citrobacter freundii Pseudomonas aeruginosa Moraxella catarrhalis Other Gram-negative bacteria
101 15 80 3 4
86 14 80 3 4
12
3
14 7
11 4
3 38
85.1 93.3 100.0 100.0 100.0 0.0 100.0 0.0 78.6 57.1
Subtotal
227
203
16
8
89.4
Total
478
432
20
26
90.4
a
87.2 100.0 97.7 89.3 50.0 100.0
Morganella morganii, 1 strain; Shigella sonnei, 2 strains.
monia, 58 of 62 (93.5%); scarlet fever, 30 of 30 (100%); urinary tract infections, 93 of 97 (95.9%); and otitis media, 6 of 9 (66.7%) [table I]. Examination of the clinical effect in relation to the daily dose revealed that cefpodoxime proxetil resulted in a good or excellent response in 33 of 36 (9\.6%) patients administered a daily dose < 4.5 mg/kg, in 27 of 27 (100%) administered 4.5 to 7.5 mg/kg, in 225 of 267 (95.5%) administered 7.5 to 10.5 mg/kg, in 77 of 83 (92.8%) administered 10.5 to 13.5 mg/kg, in 35 of 37 (94.6%) administered 13.5 to 16.5 mg/kg, and in 24 of 26 (92.3%) administered more than 16.5 mg/kg, showing a high rate of effectiveness for each dose. Analysis according to dose frequency revealed the following good or excellent response rates: twice daily, 28 of 28 (100%); 3 times daily, 415 of 440 (94.3%); and 4 times daily, 8 of 8 (100%).
38 children in this study were administered cefpodoxime proxetil after failing to respond to more than 3 days' therapy with another antimicrobial. Cefpodoxime proxetil was clinically effective in 35 of these patients, approximately half of whom achieved an excellent clinical response, with the remainder achieving a good response. Clinical response to cefpodoxime proxetil was observed in 91.7% of children previously treated unsuccessfully with a penicillin, 93.8% of children previously treated with a cephalosporin, and 92.1 % of children previously treated with another or unknown drug. For reference, results were also analysed in the 235 patients from whom no pathogen was isolated. A clinical efficacy rate (good or excellent response) of 93.6% was reported in this group of patients.
60
Drugs 42 (Suppl. 3) /99/
2.2 Bacteriological Efficacy A total of 478 pathogens were isolated from the 476 evaluable patients. The bacteriological efficacy rates by pathogen (defined as eradication of the pathogen) were as follows: S. allrells. 102 of 117 (87.2%): s. pyogenes. 85 of 87(97.7%): S. pneumoniae. 25 of 28 (89.3%): Gram-positive bacteria overall. 229 of 251 (91.2%): H. inflllen=ae, 86 of 101 (85.1%): E. coli. 80 of 80 (100%): M. catarrhalis, II of 14 (78.6%): and Gram-negative bacteria overall. 203 of 227 (89.4%) [table II). 37 of these pathogens had been isolated from patients previously treated unsuccessfully for more than 3 days with a different antibacterial. 28 of these pathogens, including S. aureus. S. pyogenes. H. influen=ae. E. coli. Klebsiella spp. and M. catarrhalis, were completely eradicated, and 5 were decreased in number. Effective clinical courses were observed in many patients whose causative organisms could not be completely eradicated. 2.3 Adverse Events Adverse events and laboratory findings were investigated in all 742 paediatric patients. Adverse events were reported in 17 (2.3%) patients and included rash (n = 2), vomiting (n == 2), diarrhoea or loose stools (n = 12), and diarrhoea and candidiasis (n = I). All adverse events were mild and
transient, even with continuation of cefpodoxime proxetil in some instances. Abnormal laboratory findings included eosinophilia in 14 patients, an increased platelet count in 4, increased prothrombin time in I. and increased hepatic transaminases in 14. These abnormalities were all minor and reversible. Only II (1.4%) of the 742 children included in this study complained of bitterness in the taste of the cefpodoxime proxetil suspension. Only I patient refused to take the suspension, which was replaced by another antibacterial after 3 days.
3. Conclusion Cefpodoxime proxetil suspension was easily administered and well tolerated in paediatric patients. As a standard daily dose for Japan, 3 mg/kg 3 times daily is recommended for community-acquired infections caused by susceptible organisms.
Reference Tajima M. Ohya S. Utsui Y. Domon H. Sakao K. et aJ. Ant ibacterial activity of CS-807. a new orally active cephalosporin . I. Comparison of ill f ilm activity of CS-807. Chemotherapy (Tokyo) 36 (SuppJ. I): 104-145. 1988 Correspondence and reprints: Prof. R. Fujii. Research Institute of Chemotherapy for Mother and Child. Department of Pediatrics. School of Medicine. Teik yo Uni versit y. 2-55-12 Ikebukuro. Toshima-ku Tokyo 171. Japan .
Clinical Trials of Cefpodoxime Proxetil Suspension in Paediatrics Ryochi Fujii Research Institute of Chemotherapy for Mother and Child, Department of Pediatrics, School of Medicine, Teikyo University, Tokyo, Japan
Summary
The pharmacokinetics, bacteriological and clinical efficacy, and safety of the suspension formulation of cefpodoxime pTOxetil, an oral cephalosporin antibacterial, were evaluated in paediatric patients with various infections. With single doses of 3 and 6 mgJkg (cefpodoxime equivalent) a dose response was evident in the serum concentration values. Absorption, as evidenced by serum concentrations and areas under the concentration-time curve, was enhanced when the suspension was administered before a meal. The overall clinical efficacy (defined as an excellent or good response) in evaluable patients (those from whom a pathogen was isolated) was 94,7% (451 of 476). Bacteriological eradication rates were as follows: Gram-positive bacteria 91.3%; Gram-negative bacteria 88,6%, and 90.0% overall. Side effects occurred in 17 (2.29%) patients, and transient and reversible abnormal laboratory values were found in a few patients.
Cefpodoxime proxetil is a new cephalosporin prodrug, which is de-esterified in the body to the active moiety cefpodoxime. Cefpodoxime is resistant to various ~-lactamases, and so its effectiveness against prevalent ~-lactamase-producing strains is expected. Cefpodoxime is a broad spectrum antibacterial agent with MICso values of < 3.13 mg/L for the following species: Staphylococcus aureus (methicillin-susceptible strains), Streptococcus pyogenes, S. pneumoniae, Escherichia coli, Klebsiella pneumoniae, Citrobacter spp., Enterobacter spp., Proteus mirabilis, P. rettgeri, P. vulgaris, P. inconstans, Haemophilus injluenzae, and Moraxella (Branhamella) catarrhalis (Tajima et al. 1988). The compound is inactive against Enterococcus faecalis and Pseudomonas aeruginosa. In Japan, cefpodoxime proxetil has been widely studied in the clinical setting in adults. Its features and utility have been evaluated at both the 35th
General Meeting of the Japanese Society of Chemotherapy and the 27th Interscience Conference on Antimicrobial Agents and Chemotherapy. The formulation of cefpodoxime proxetil in a suspension, and the completion of bioequivalency testing comparing the suspension and tablet formulations enabled study in paediatric patients to begin in 1986. The following is a report of pharmacokinetic and clinical studies of cefpodoxime proxetil in paediatric patients, conducted with the cooperation of 17 institutes throughout Japan.
1. Pharmacokinetic Study A pharmacokinetic study was conducted in 60 paediatric patients aged 7.0 ± 0.4 years with normal renal function. A single oral dose of cefpodoxime proxetil suspension was administered (3 or 6 mg/kg of cefpodoxime equivalent). Blood and urinary concentrations of cefpodoxime were deter-
Drugs 42 (Suppl. 3) 1991
58
2. Clinical Study
mined by high performance liquid chromatography. The respective mean values for area under the concentration-time curve (AUC), half-life, and peak serum concentration (C max ) [fasting/nonfasting] were 9.93 ± 0.78/8.73 ± 0.43 mg/L· h, 2.43 ± 0.33/2.28 ± 0.16 hours, and 2.24 ± 0.21/1.65 ± 0.07 mg/L for a 3 mg/kg dose, and 20.20 ± 1.93/ 18.54 ± 1.85 mg/L· h, 2.43 ± 0.39/3.25 ± 0.79 hours, and 4.68 ± 0.54/3.71 ± 0.41 mg/L for a 6 mg/kg dose. Thus, AUC and C max demonstrated a dose response that was slightly higher at both dosages when administered Defore meals. However, the half-life was unaffected by food and showed no apparent dose dependency. Respective mean urinary concentrations at 0 to 2, 2 to 4, and 4 to 6 hours (fasting/nonfasting) were 103.3 ± 36.6/62.8 ± 12.1, 145.0 ± 30.9;128.6 ± 18.0, and 88.0 ± 11.4/72.5 ± 12.6 mg/L for a 3 mg/kg dose, and 108.0 ± 23.2/71.9 ± 11.4, 410.7 ± 122.7/222.3 ± 44.6, and 344.7 ± 128.8/145.0 ± 28.5 mg/L for a 6 mg/kg dose. Thus, the peak urinary concentration occurred 2 to 4 hours after administration. On average, 30% of an administered dose was recovered during the first 8 hours after administration.
A clinical study was carried out in 742 paediatric patients with various infections. Informed consent was obtained from the parents of all children examined in these studies. A pathogen was isolated from 476, who were included in the efficacy analysis. Patients were approximately evenly distributed with regard to sex, and 170 (35.8%) were aged < 3 years (a quarter of these being infants aged < I year), 188 (39.5%) were 3 to 6 years of age, 115 (24.2%) were 6 to 12 years of age and 3 (0.6%) were 12 to 16 years of age. Primary diseases treated included tonsillitis/pharyngitis and laryngitis (32.1 %), acute bronchitis and pneumonia (19.1 %), urinary tract infections (20.5%), scarlet fever and otitis media (8.2%), and others. Infections were of moderate severity in 53.9% of the children, severe in 1.4%, and mild in the remainder. 2.1 Clinical Efficacy A good or excellent clinical response was obtained in 94.7% of children overall. Efficacy rates per indication were as follows: tonsillitis, 112 of 115 (97.4%); pharyngitis and laryngitis, 36 of 38 (94.7%); acute bronchitis, 29 of 29 (100%); pneu-
Table I. Clinical effectiveness classified by diagnosis in 476 evaluable Japanese paediatric patients treated with cefpodoxime proxetil suspension
Diagnosis
No. of patients
Clinical response excellent
good
fair 1 2
Pharyngitis and laryngitis Tonsillitis Acute bronchitis Pneumonia Scarlet fever Impetigo SSSS Other SST I UTI Otitis media Other
38 115 29 62 30 66 6 17 97 9 7
25 71 15 39 27 37 1 6 63 2
11 41 14 19 3 24 4 10 30 4 4
Total
476
287
164
a Defined as an excellent or good response. Abbreviations: SSSS = staphylococcal scaled skin syndrome; SSTI
= skin and
poor
3 3
2
1 3
3
16
9
soft tissue infection; UTI
Efficacy rate (%)8 94.7 97.4 100.0 93.5 100.0 92.4 83.3 94.1 95.9 66.7 71.4 94.7
= urinary tract infection.
Clinical Trials of Cefpodoxime Proxetil
59
Table II. Bacteriological efficacy of cefpodoxime proxetil in 476 evaluable Japanese paediatric patients treated with cefpodoxime
proxetil suspension Organism
No. of strains
Eradicated
Decreased
Unchanged
Eradication rate (%)
Staphylococcus aureus S. epidermidis Streptococcus pyogenes S. pneumoniae Enterococcus spp. Other Gram·positive bacteria
117 5 87 28 4 10
102 5 85 25 2 10
2
13
2
2 1 2
Subtotal
251
229
4
18
91.2
Haemophilus influenzae H. parainfluenzae Escherichia coli Klebsiella spp. Proteus spp. Enterobacter spp. Citrobacter freundii Pseudomonas aeruginosa Moraxella catarrhalis Other Gram-negative bacteria
101 15 80 3 4
86 14 80 3 4
12
3
14 7
11 4
3 38
85.1 93.3 100.0 100.0 100.0 0.0 100.0 0.0 78.6 57.1
Subtotal
227
203
16
8
89.4
Total
478
432
20
26
90.4
a
87.2 100.0 97.7 89.3 50.0 100.0
Morganella morganii, 1 strain; Shigella sonnei, 2 strains.
monia, 58 of 62 (93.5%); scarlet fever, 30 of 30 (100%); urinary tract infections, 93 of 97 (95.9%); and otitis media, 6 of 9 (66.7%) [table I]. Examination of the clinical effect in relation to the daily dose revealed that cefpodoxime proxetil resulted in a good or excellent response in 33 of 36 (9\.6%) patients administered a daily dose < 4.5 mg/kg, in 27 of 27 (100%) administered 4.5 to 7.5 mg/kg, in 225 of 267 (95.5%) administered 7.5 to 10.5 mg/kg, in 77 of 83 (92.8%) administered 10.5 to 13.5 mg/kg, in 35 of 37 (94.6%) administered 13.5 to 16.5 mg/kg, and in 24 of 26 (92.3%) administered more than 16.5 mg/kg, showing a high rate of effectiveness for each dose. Analysis according to dose frequency revealed the following good or excellent response rates: twice daily, 28 of 28 (100%); 3 times daily, 415 of 440 (94.3%); and 4 times daily, 8 of 8 (100%).
38 children in this study were administered cefpodoxime proxetil after failing to respond to more than 3 days' therapy with another antimicrobial. Cefpodoxime proxetil was clinically effective in 35 of these patients, approximately half of whom achieved an excellent clinical response, with the remainder achieving a good response. Clinical response to cefpodoxime proxetil was observed in 91.7% of children previously treated unsuccessfully with a penicillin, 93.8% of children previously treated with a cephalosporin, and 92.1 % of children previously treated with another or unknown drug. For reference, results were also analysed in the 235 patients from whom no pathogen was isolated. A clinical efficacy rate (good or excellent response) of 93.6% was reported in this group of patients.
60
Drugs 42 (Suppl. 3) /99/
2.2 Bacteriological Efficacy A total of 478 pathogens were isolated from the 476 evaluable patients. The bacteriological efficacy rates by pathogen (defined as eradication of the pathogen) were as follows: S. allrells. 102 of 117 (87.2%): s. pyogenes. 85 of 87(97.7%): S. pneumoniae. 25 of 28 (89.3%): Gram-positive bacteria overall. 229 of 251 (91.2%): H. inflllen=ae, 86 of 101 (85.1%): E. coli. 80 of 80 (100%): M. catarrhalis, II of 14 (78.6%): and Gram-negative bacteria overall. 203 of 227 (89.4%) [table II). 37 of these pathogens had been isolated from patients previously treated unsuccessfully for more than 3 days with a different antibacterial. 28 of these pathogens, including S. aureus. S. pyogenes. H. influen=ae. E. coli. Klebsiella spp. and M. catarrhalis, were completely eradicated, and 5 were decreased in number. Effective clinical courses were observed in many patients whose causative organisms could not be completely eradicated. 2.3 Adverse Events Adverse events and laboratory findings were investigated in all 742 paediatric patients. Adverse events were reported in 17 (2.3%) patients and included rash (n = 2), vomiting (n == 2), diarrhoea or loose stools (n = 12), and diarrhoea and candidiasis (n = I). All adverse events were mild and
transient, even with continuation of cefpodoxime proxetil in some instances. Abnormal laboratory findings included eosinophilia in 14 patients, an increased platelet count in 4, increased prothrombin time in I. and increased hepatic transaminases in 14. These abnormalities were all minor and reversible. Only II (1.4%) of the 742 children included in this study complained of bitterness in the taste of the cefpodoxime proxetil suspension. Only I patient refused to take the suspension, which was replaced by another antibacterial after 3 days.
3. Conclusion Cefpodoxime proxetil suspension was easily administered and well tolerated in paediatric patients. As a standard daily dose for Japan, 3 mg/kg 3 times daily is recommended for community-acquired infections caused by susceptible organisms.
Reference Tajima M. Ohya S. Utsui Y. Domon H. Sakao K. et aJ. Ant ibacterial activity of CS-807. a new orally active cephalosporin . I. Comparison of ill f ilm activity of CS-807. Chemotherapy (Tokyo) 36 (SuppJ. I): 104-145. 1988 Correspondence and reprints: Prof. R. Fujii. Research Institute of Chemotherapy for Mother and Child. Department of Pediatrics. School of Medicine. Teik yo Uni versit y. 2-55-12 Ikebukuro. Toshima-ku Tokyo 171. Japan .
