Drugs 42 (Suppl. 3): 1-5. 1991 00 12-6667/91 / 0300-000 I/$2.50/0 © Adis International Limited. All rights reserved. DRSUP3231
Summary of Clinical Experience with Cefpodoxime Proxetil in Adults in Japan Joichi Kumazawa Department of Urology, Faculty of Medicine, Kyushu University, Fukuoka, Japan
Summary
Cefpodoxime proxetil is an oral cephem antibiotic of a new ester type, developed by Sankyo Co., Ltd in Japan. It has a broad antibacterial spectrum, which includes Staphylococcus. and a long half-life, allowing twice-daily administration. In Japan, clinical studies on this drug were performed in various fields, including internal medicine, surgery, urology, otorhinolaryngology, and obstetrics and gynaecology. Good or excellent clinical responses were observed in 2275 of 2902 patients analysed, giving a 78.4% efficacy rate overall. Side effects occurred in 98 patients (2.7%); these were mainly gastrointestinal and included diarrhoea, nausea, and vomiting. Abnormal laboratory test results observed included increased AST in 2.8% (55 of 1973), increased ALT in 3.2% (63 of 1965), and eosinophilia in 2.4% (36 of 1521).
Cefpodoxime proxetil is an oral cephem antibiotic of a new ester type, developed by Sankyo Co. Ltd in Japan. It has an aminothiazolyl radical with a methoxyimino substitution at position 7 of the cephem skeleton, a methoxymethyl group at position 3, and a proxetil radical (ester) in carboxylic acid at position 4 (fig. 1). This drug is absorbed from the intestinal tract after oral administration and hydrolysed to cefpodoxime (which has antibacterial activity) by nonspecific esterases in the intestinal wall. The antibacterial activity of cefpodoxime against major pathogens is very good. M1C80 (MIC in mgJ L inhibiting 80% of tested strains) values against Gram-positive spp. were 6.25 mgJL against> 2000 strains of Staphylococcus spp., 12.5 mg/L against 495 strains of S. aureus (including methicillin-resistant strains), 0.5 mg/L against> 800 strains of streptococci, and 0.5 mgJL against> 250 strains of Streptococcus pneumoniae(data on me, Sankyo Co.,
Cefpodoxime: R = H Cefpodoxime proxetil: R
= CHOCOOCH I
CH " "-
3
CH3
CH3
Fig. 1. Chemical structures of cefpodoxime and cefpodoxime proxetil.
Ltd). MIC80 values against aerobic Gram-negative spp., including Neisseria gonorrhoeae (0.05 mg/L, n = 88), Moraxella (Branhamella) catarrhalis (3 .13 mgJL, n = 134), Escherichia coli (0.39 mg/L, n =
Drugs 42 (Suppl. 3) /99/
2
1077), Klebsiella spp. (0.2 mg/L, n = 818), Proteus spp. (~ 0.78 mg/L, n => 700), and Haemophilus influenzae (0.1 mg/L, n = 274), were also found to be sufficiently low (data on file, Sankyo Co., Ltd). Absorption is higher when cefpodoxime proxetil is administered after meals, relative to fasting values. Administration of single doses of cefpodoxime proxetil (equivalent to 100mg or 200mg cefpodoxime) to Japanese adults after a meal resulted in mean peak cefpodoxime concentrations in blood of 1.7 mg/L and 3.1 mg/L, respectively, disclosing dose dependency; AVCs were 8.3 mgt L • hand 16.4 mg/L' h, respectively, also disclosing dose dependency (data on file, Sankyo Co., Ltd) [table I]. The half-life was l.9 hours with both doses, and urinary recovery rates were 4l.8% (Ioomg dose) and 45.3% (200mg dose). The usefulness of cefpodoxime proxetil has been confirmed by preclinical and clinical studies in Japan; phase I studies were initiated in 1984 after preclinical studies, and general clinical studies were performed from 1985 to 1987.
Nakajima et al. 1988; Nakamuta et al. 1988; Odagiri et al. 1988). 1.1 Clinical and Bacteriological Efficacy Of 3509 patients enrolled in general studies, 2980 were analysed for clinical efficacy. Good or excellent responses were observed in 2340 patients, giving an overall efficacy rate of 78.5%. Clinical efficacy rates were 70 to 95% in most of the diseases (table II). Exceptions were complicated pyelonephritis (56.6%) and gonococcal urethritis (97.7%). Efficacy rates in patients in whom causative organisms were identified (2570 of a total of 3509) were slightly lower (83.0%). The overall bacterial eradication rate was 90% (2931 of 3261 cases), reflecting sufficient activity against a broad spectrum of clinically important pathogens. Eradication rates for the individual species are given in table III. 1.2 Adverse Events
1. Clinical Studies in Japan Clinical studies were performed at 322 institutes in Japan in various medical disciplines, including internal medicine, surgery, urology, otorhinolaryngology, and obstetrics and gynaecology, and the results cumulated by infectious disease. Most of these studies were published in Chemotherapy (Tokyo) 36 (Suppl. I) 1988 (see also Fujii et al. 1988;
Among 3650 patients administered cefpodoxime proxetil in general clinical studies, 116 episodes of adverse events occurred in 98 patients (2.7%). Gastrointestinal symptoms, mainly diarrhoea, nausea and vomiting, were observed most frequently (85 episodes); there were 15 episodes of allergic symptoms and 16 of other symptoms. All adverse events were mild to moderate in severity,
Table I. Effects of single doses of cefpodoxime proxetil (equivalent to 100mg or 200mg cefpodoxime) administered to Japanese adults after a meal (data on file, Sankyo Co., Ltd) Dose
No. of patients
(mg)
tt;.
Cmax
tmax
AUC
Urinary recovery
(h)
(mg/L)
(h)
(mg/L' h)
(%)
100
16
1.9
1.7
2.8
8.3
41.8
200
45
1.9
3.1
2.9
16.4
45.3
Abbreviations:
tv.
= half-life; Cmax = peak plasma concentration; tmax = time to reach Cmax ; AUC = area under the plasma
concentration-time curve.
Clinical Experience in Adults in Japan
3
Table II. Assessment of clinical efficacy of cefpodoxime proxetil in Japanese adults by disease
Disease
Responsive/evaluated
Effectiveness (%)
83.3
Respiratory tract infections (total)
676/812
Pneumonia
160/183
87.4
70/82
85.4
Chronic bronchitis
149/187
79.7
Tonsillitis
175/194
90.2
Pharyngolaryngitis
15/17
88.2
Bronchiectasis (by infection)
63/86 44/63
73.3
851/1155
73.7
94/166
56.6
Acute bronchitis
Secondary infection of chronic respiratory tract diseases Urinary tract infections (total)
Complicated pyelonephritis
69.8
Simple cystitis
362/394
91.9
Complicated cystitis
352/551
63.9
Gonorrhoeal urethritis
43/44
97.7
Infections associated with surgery (total)
20/23
87.0
Mastitis
20/23
87.0
422/494
85.4
52/55 34/41
94.5
Cellulitis Lymphangitis
15/18
83.3
Felon
55/63
87.3
Subcutaneous abscess
60/76
78.9
Infectious atheroma
103/122
84.4
Periproctal abscess
38/41
92.7
Others
65/78
83.3
Gynaecological infections (total)
79/88
89.8
Bartholinitis
79/88
89.8
Otorhinolaryngological infections (total)
227/330
68.8
Otitis media
169/247
68.4
58/83
69.9
2340/2980
78.5
Superficial suppurative disease (total)
Furuncle
Sinusitis Grand total
82.9
4
Drugs 42 (Suppl. 3) 1991
Table III. Bacteriological eradication by cefpodoxime proxetil in Japanese adults Bacterium
Eradicated/
Bacteriological
evaluated
eradication (%)
Gram-positive bacteria
674/774
87.1
S. aureus
339/398
85.2
S. epidermidis
186/215
86.5
Genus Staphylococcus
Genus Streptococcus
368/377
S. pyogenes
68/68
S. pneumoniae
90/92
97.7 100 97.8
Gram-negative bacteria Neisseria gonorrhoeae
50/55
90.9
30/36
83.3
Escherichia coli
560/600
93.3
Genus Klebsiella
113/126
89.7
82/93
88.2
80/91
87.9
P. mirabilis
59/65
90.8
P. vulgaris
8/9
P. rettgeri
11/11
Moraxella catarrhalis
K. pneumoniae
Genus Proteus and Providencia
P. stuartii
Genus Citrobacter Genus Enterobacter Haemophilus influenzae
and disappeared with discontinuation of cefpodoxime proxetil or with some treatment. Abnormal laboratory test results were observed in 150 patients, and included increased AST in 2.8% (55 of 1973), increased ALT in 3.2% (63 of 1965), and eosinophilia in 2.4% (36 of 1521). These changes are commonly observed with existing (3lactam antibacterials.
2. Discussion and Conclusions Cefpodoxime proxetil is rapidly absorbed after oral administration, and then hydrolysed to the active compound cefpodoxime. This drug adequately
88.9 100
2/6
33.3
37/47
78.7
48/62
77.4
126/136
92.6
penetrates various tissues, including tonsillar and dermal tissue, as well as sputum [see Chemotherapy (Tokyo) 36 (Suppl. I) 1988]. Higher blood concentrations are attained with administration of cefpodoxime proxetil after meals than during fasting, but about 40% is excreted into urine in both cases. Cefpodoxime has a broad antibacterial spectrum and antibacterial activity against Gram-positive organisms, such as Staphylococcus, as well as excellent potency against Gram-negative organisms. This drug is also stable in the presence of (3lactamases. Thus, cefpodoxime proxetil is expected to be useful for treating infections associated with
Clinical Experience in Adults in Japan
general and orthopaedic surgery, the respiratory and urinary tracts, obstetrics and gynaecology, and otorhinolaryngology. Since cefpodoxime proxetil is administered twice daily, patient compliance may be better than with existing drugs requiring administration 3 to 4 times daily. Furthermore, the results of preclinical and clinical studies have revealed high levels of clinical efficacy and no particular problems with safety. Thus, cefpodoxime proxetil is a new highly useful cephem antibacterial, having both strong antibacterial activity and pharmacokinetics that promise to widen the applicability of oral treatment.
References Fujii A, Maeda H, Arakawa S, Matsumoto 0, Kamidono S. Clinical and fundamental studies on CS-807 for male gonococcal urethritis. Nishi Nippon Hinyokika 50: 2113-2122,1988
5
Nakajima K, Oshinoya Y, Uchibayashi T, Ohkawa M, Hisazumi H. A clinical evaluation of CS-807 in patients with urinary tract infections. Acta Urologica Japonica 34: 1515-1518, 1988 Nakamuta S, Masaki Z, Matsumoto T, Kumazawa J, Kushimoto T. Clinical study on CS-807 at a daily dose of200mg and 400mg for complicated urinary tract infections. Nishi Nippon Hinyokika 50: 2099-2111, 1988 Odagiri S, Matsunaga K, Suzuki K, Murohashi K, Takahashi H, et al. Clinical studies of cefpodoxime proxetil in respiratory tract infections. Japanese Journal of Antibiotics 41: 1538-1544, 1988
Correspondence and reprints: Prof. J. Kumazawa. Department of Urology, Faculty of Medicine, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka City, Fukuoka 812, Japan.
Summary of Clinical Experience with Cefpodoxime Proxetil in Adults in Japan Joichi Kumazawa Department of Urology, Faculty of Medicine, Kyushu University, Fukuoka, Japan
Summary
Cefpodoxime proxetil is an oral cephem antibiotic of a new ester type, developed by Sankyo Co., Ltd in Japan. It has a broad antibacterial spectrum, which includes Staphylococcus. and a long half-life, allowing twice-daily administration. In Japan, clinical studies on this drug were performed in various fields, including internal medicine, surgery, urology, otorhinolaryngology, and obstetrics and gynaecology. Good or excellent clinical responses were observed in 2275 of 2902 patients analysed, giving a 78.4% efficacy rate overall. Side effects occurred in 98 patients (2.7%); these were mainly gastrointestinal and included diarrhoea, nausea, and vomiting. Abnormal laboratory test results observed included increased AST in 2.8% (55 of 1973), increased ALT in 3.2% (63 of 1965), and eosinophilia in 2.4% (36 of 1521).
Cefpodoxime proxetil is an oral cephem antibiotic of a new ester type, developed by Sankyo Co. Ltd in Japan. It has an aminothiazolyl radical with a methoxyimino substitution at position 7 of the cephem skeleton, a methoxymethyl group at position 3, and a proxetil radical (ester) in carboxylic acid at position 4 (fig. 1). This drug is absorbed from the intestinal tract after oral administration and hydrolysed to cefpodoxime (which has antibacterial activity) by nonspecific esterases in the intestinal wall. The antibacterial activity of cefpodoxime against major pathogens is very good. M1C80 (MIC in mgJ L inhibiting 80% of tested strains) values against Gram-positive spp. were 6.25 mgJL against> 2000 strains of Staphylococcus spp., 12.5 mg/L against 495 strains of S. aureus (including methicillin-resistant strains), 0.5 mg/L against> 800 strains of streptococci, and 0.5 mgJL against> 250 strains of Streptococcus pneumoniae(data on me, Sankyo Co.,
Cefpodoxime: R = H Cefpodoxime proxetil: R
= CHOCOOCH I
CH " "-
3
CH3
CH3
Fig. 1. Chemical structures of cefpodoxime and cefpodoxime proxetil.
Ltd). MIC80 values against aerobic Gram-negative spp., including Neisseria gonorrhoeae (0.05 mg/L, n = 88), Moraxella (Branhamella) catarrhalis (3 .13 mgJL, n = 134), Escherichia coli (0.39 mg/L, n =
Drugs 42 (Suppl. 3) /99/
2
1077), Klebsiella spp. (0.2 mg/L, n = 818), Proteus spp. (~ 0.78 mg/L, n => 700), and Haemophilus influenzae (0.1 mg/L, n = 274), were also found to be sufficiently low (data on file, Sankyo Co., Ltd). Absorption is higher when cefpodoxime proxetil is administered after meals, relative to fasting values. Administration of single doses of cefpodoxime proxetil (equivalent to 100mg or 200mg cefpodoxime) to Japanese adults after a meal resulted in mean peak cefpodoxime concentrations in blood of 1.7 mg/L and 3.1 mg/L, respectively, disclosing dose dependency; AVCs were 8.3 mgt L • hand 16.4 mg/L' h, respectively, also disclosing dose dependency (data on file, Sankyo Co., Ltd) [table I]. The half-life was l.9 hours with both doses, and urinary recovery rates were 4l.8% (Ioomg dose) and 45.3% (200mg dose). The usefulness of cefpodoxime proxetil has been confirmed by preclinical and clinical studies in Japan; phase I studies were initiated in 1984 after preclinical studies, and general clinical studies were performed from 1985 to 1987.
Nakajima et al. 1988; Nakamuta et al. 1988; Odagiri et al. 1988). 1.1 Clinical and Bacteriological Efficacy Of 3509 patients enrolled in general studies, 2980 were analysed for clinical efficacy. Good or excellent responses were observed in 2340 patients, giving an overall efficacy rate of 78.5%. Clinical efficacy rates were 70 to 95% in most of the diseases (table II). Exceptions were complicated pyelonephritis (56.6%) and gonococcal urethritis (97.7%). Efficacy rates in patients in whom causative organisms were identified (2570 of a total of 3509) were slightly lower (83.0%). The overall bacterial eradication rate was 90% (2931 of 3261 cases), reflecting sufficient activity against a broad spectrum of clinically important pathogens. Eradication rates for the individual species are given in table III. 1.2 Adverse Events
1. Clinical Studies in Japan Clinical studies were performed at 322 institutes in Japan in various medical disciplines, including internal medicine, surgery, urology, otorhinolaryngology, and obstetrics and gynaecology, and the results cumulated by infectious disease. Most of these studies were published in Chemotherapy (Tokyo) 36 (Suppl. I) 1988 (see also Fujii et al. 1988;
Among 3650 patients administered cefpodoxime proxetil in general clinical studies, 116 episodes of adverse events occurred in 98 patients (2.7%). Gastrointestinal symptoms, mainly diarrhoea, nausea and vomiting, were observed most frequently (85 episodes); there were 15 episodes of allergic symptoms and 16 of other symptoms. All adverse events were mild to moderate in severity,
Table I. Effects of single doses of cefpodoxime proxetil (equivalent to 100mg or 200mg cefpodoxime) administered to Japanese adults after a meal (data on file, Sankyo Co., Ltd) Dose
No. of patients
(mg)
tt;.
Cmax
tmax
AUC
Urinary recovery
(h)
(mg/L)
(h)
(mg/L' h)
(%)
100
16
1.9
1.7
2.8
8.3
41.8
200
45
1.9
3.1
2.9
16.4
45.3
Abbreviations:
tv.
= half-life; Cmax = peak plasma concentration; tmax = time to reach Cmax ; AUC = area under the plasma
concentration-time curve.
Clinical Experience in Adults in Japan
3
Table II. Assessment of clinical efficacy of cefpodoxime proxetil in Japanese adults by disease
Disease
Responsive/evaluated
Effectiveness (%)
83.3
Respiratory tract infections (total)
676/812
Pneumonia
160/183
87.4
70/82
85.4
Chronic bronchitis
149/187
79.7
Tonsillitis
175/194
90.2
Pharyngolaryngitis
15/17
88.2
Bronchiectasis (by infection)
63/86 44/63
73.3
851/1155
73.7
94/166
56.6
Acute bronchitis
Secondary infection of chronic respiratory tract diseases Urinary tract infections (total)
Complicated pyelonephritis
69.8
Simple cystitis
362/394
91.9
Complicated cystitis
352/551
63.9
Gonorrhoeal urethritis
43/44
97.7
Infections associated with surgery (total)
20/23
87.0
Mastitis
20/23
87.0
422/494
85.4
52/55 34/41
94.5
Cellulitis Lymphangitis
15/18
83.3
Felon
55/63
87.3
Subcutaneous abscess
60/76
78.9
Infectious atheroma
103/122
84.4
Periproctal abscess
38/41
92.7
Others
65/78
83.3
Gynaecological infections (total)
79/88
89.8
Bartholinitis
79/88
89.8
Otorhinolaryngological infections (total)
227/330
68.8
Otitis media
169/247
68.4
58/83
69.9
2340/2980
78.5
Superficial suppurative disease (total)
Furuncle
Sinusitis Grand total
82.9
4
Drugs 42 (Suppl. 3) 1991
Table III. Bacteriological eradication by cefpodoxime proxetil in Japanese adults Bacterium
Eradicated/
Bacteriological
evaluated
eradication (%)
Gram-positive bacteria
674/774
87.1
S. aureus
339/398
85.2
S. epidermidis
186/215
86.5
Genus Staphylococcus
Genus Streptococcus
368/377
S. pyogenes
68/68
S. pneumoniae
90/92
97.7 100 97.8
Gram-negative bacteria Neisseria gonorrhoeae
50/55
90.9
30/36
83.3
Escherichia coli
560/600
93.3
Genus Klebsiella
113/126
89.7
82/93
88.2
80/91
87.9
P. mirabilis
59/65
90.8
P. vulgaris
8/9
P. rettgeri
11/11
Moraxella catarrhalis
K. pneumoniae
Genus Proteus and Providencia
P. stuartii
Genus Citrobacter Genus Enterobacter Haemophilus influenzae
and disappeared with discontinuation of cefpodoxime proxetil or with some treatment. Abnormal laboratory test results were observed in 150 patients, and included increased AST in 2.8% (55 of 1973), increased ALT in 3.2% (63 of 1965), and eosinophilia in 2.4% (36 of 1521). These changes are commonly observed with existing (3lactam antibacterials.
2. Discussion and Conclusions Cefpodoxime proxetil is rapidly absorbed after oral administration, and then hydrolysed to the active compound cefpodoxime. This drug adequately
88.9 100
2/6
33.3
37/47
78.7
48/62
77.4
126/136
92.6
penetrates various tissues, including tonsillar and dermal tissue, as well as sputum [see Chemotherapy (Tokyo) 36 (Suppl. I) 1988]. Higher blood concentrations are attained with administration of cefpodoxime proxetil after meals than during fasting, but about 40% is excreted into urine in both cases. Cefpodoxime has a broad antibacterial spectrum and antibacterial activity against Gram-positive organisms, such as Staphylococcus, as well as excellent potency against Gram-negative organisms. This drug is also stable in the presence of (3lactamases. Thus, cefpodoxime proxetil is expected to be useful for treating infections associated with
Clinical Experience in Adults in Japan
general and orthopaedic surgery, the respiratory and urinary tracts, obstetrics and gynaecology, and otorhinolaryngology. Since cefpodoxime proxetil is administered twice daily, patient compliance may be better than with existing drugs requiring administration 3 to 4 times daily. Furthermore, the results of preclinical and clinical studies have revealed high levels of clinical efficacy and no particular problems with safety. Thus, cefpodoxime proxetil is a new highly useful cephem antibacterial, having both strong antibacterial activity and pharmacokinetics that promise to widen the applicability of oral treatment.
References Fujii A, Maeda H, Arakawa S, Matsumoto 0, Kamidono S. Clinical and fundamental studies on CS-807 for male gonococcal urethritis. Nishi Nippon Hinyokika 50: 2113-2122,1988
5
Nakajima K, Oshinoya Y, Uchibayashi T, Ohkawa M, Hisazumi H. A clinical evaluation of CS-807 in patients with urinary tract infections. Acta Urologica Japonica 34: 1515-1518, 1988 Nakamuta S, Masaki Z, Matsumoto T, Kumazawa J, Kushimoto T. Clinical study on CS-807 at a daily dose of200mg and 400mg for complicated urinary tract infections. Nishi Nippon Hinyokika 50: 2099-2111, 1988 Odagiri S, Matsunaga K, Suzuki K, Murohashi K, Takahashi H, et al. Clinical studies of cefpodoxime proxetil in respiratory tract infections. Japanese Journal of Antibiotics 41: 1538-1544, 1988
Correspondence and reprints: Prof. J. Kumazawa. Department of Urology, Faculty of Medicine, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka City, Fukuoka 812, Japan.
