K. M a t s u m o t o
Cefodizime: The Japanese Clinical Experience Summary: In a clinical trial conducted in Japan from 1985-1988, the efficacy of cefodizime was studied in 2,227 adult and 449 pediatric patients. Of these, 1,366 adult and 203 pediatric patients had pathogens isolated and were evaluable. Cefodizime was effective in 78.8% of the adult patients, and adverse reactions occurred in 2.3%. In pediatric patients cefodizime was effective in 91.1% of the cases, and adverse reactions developed in 5.1%. A very high concentration of cefodizime is achieved in blood soon after administration and its penetration into tissues is also high. Moreover, cefodizime exhibits phagocytosis enhancement activity. The above-mentioned excellent efficacy rates, low rates of side effects and enhancement of phagocytic activity make cefodizime an antibiotic of choice in adult and pediatric patients. Zusammenfassung: Cefodizim: Erfahrungen in Japan. In einer klinischen Studie, die in Japan zwischen 1985 und 1988 durchgeffihrt wurde, erhielten 2.227 Erwachsene bzw. 449 p/idiatrische Patienten eine Therapie mit Cefodizim, deren Wirksamkeit bei 1.366 Erwachsenen bzw. 203 Kindern analysiert wurde, bei denen pathogene Erreger nachgewiesen werden konnten. Bei Erwachsenen lag die Ansprechrate bei 78.8%; in 2,3% der F~ille traten Nebenwirkungen auf. P~idiatrische Patienten hatten eine Ansprechrate von 91,1% mit 5,1% Nebenwirkungen. Cefodizim erreicht bald nach der Applikation sehr hohe Blutspiegel und besitzt hohe Gewebe-Penetrationsf~ihigkeit. Dar~ber hinaus hat Cefodizim die Eigenschaft, die Phagozytose zu steigern. Hohe klinische Wirksamkeit, niedrige Nebenwirkungsraten und Phagozytosef6rderung qualifizieren Cefodizim zum Antibiotikum der Wahl bei erwachsenen und p~idiatrischen Patienten.
Introduction Along with the recent progress of medical science, the number of compromised hosts has increased, as has the incidence of infections in these patients. In treating these infections successfully, one of the most important considerations is how to enhance the host defense mechanism of the immunocompromised patient. Granulocyte-colony stimulating factor (G-CSF), with gamma globulins working as auxiliaries, is a promising enhancer for the host defense mechanisms. The most desirable antibiotics for treatment are those which not only control or destroy bacteria directly but also work in concert with the host defense mechanisms.
Various studies on cefodizime have demonstrated it to eradicate bacteria directly and in cooperation with host defense mechanisms, particularly the phagocytes [1-3]. Cefpimizole has also been shown to exhibit the same action [4]. However, cefodizime has been established as a third-generation cephem antibiotic with a broad antibacterial spectrum, good pharmacokinetics [1, 5], and bactericidal activity that works in cooperation with the host defense mechanisms [6]. Materials and Methods Clinical trials with cefodizime were conducted in several hospitals in Japan from 1985 to 1988. Pathogens were identified in 1,366 of 2,227 adults and 203 of 449 pediatric patients treated with cefodizime. Strains included in the study were restricted to those sensitive to cefodizime. The main dose was 1 g twice daily administered for four to 14 days in the adults, and 60 to 80 mg/kg/daygiven for four to seven days in children. The efficacy was evaluated on a four-grade scale: excellent, for improvement achieved within three days; good, for improvement within seven days; fair, for improvement within 14 days, and poor, for improvement later than 14 days or no improvement. The indicators of efficacy were fever, leukocyte count, inflammatory markers including C-reactive protein, clinical symptoms and percent of bacteria eradicated. The success rate of cefodizime (responder rate) was expressed as the rate of patients receiving cefodizime treatment who were classified as "good" and "excellent" responders.
Results
Adult Cases In total, cefodizime was effective in 78.8% of the adult patients. Classified by diagnosis, the responder rate was five of eight patients with septicemia, 83.9% in 118 patients with pneumonia, 69.2% in 26 patients with cholecystitis and cholangitis, 79% in 162 patients with pyelonephritis, 70.3% in 367 patients with cystitis, and 83.6% in 53 patients with peritonitis including pelvic peritonitis and Douglas abscess (Figure 1). Moreover, to clarify effectiveness in elderly patients, clinical efficacy was investigated in patients classified according to diagnosis and age. In cases with pneumonia, efficacy rates in the patients aged 50 to 70 years were almost the same as those in patients more than 70 years. The same results were obtained in pyelonephritis and cystitis cases (Figure 2). Prof. K. Matsumoto, M.D., Department of Internal Medicine, Institute of Tropical Medicine, Nagasaki University, 12-4 Sakamoto-Machi, Nagasaki 852, Japan.
Infection 20 (1992) Suppl. 1 © MMV Medizin Verlag GmbH Mtinchen, Mtinchen 1992
S 31
IC Matsuraoto:
Cefodizime in Japan
Diagnosis
No. of patients
Septicemia
8
Pneumonia
118
Cholecystitis and cholangitis
26
Pyelonephritis
162
Cystitis
367
Peritonitis (incl. pelvic peritonitis & Douglas abscess)
Response rate (%) *
53 0
I
I
I
I
I
I
I
I
I
10
20
30
40
50
60
70
80
90
100
* : Excellent & Good/Total x 100 Figure 1: Clinical efficacy of cefodizime in adult patients.
Diagnosis Septicemia Pneumonia Cholecystitis and cholangitis Pyelonephritis Cystitis Peritionitis ncl. pelvic peritonitis Douglas abscess)
Age 16 - 50 50 - 70 />70 16 - 50 50 - 70 I>70 16 - 50 50 - 70 ~>70 16 - 50 50 - 70 >~70 16 - 50 50 - 70 ~>70 16 - 50 50 - 70 >I 70
* : Excellent & Good/Total x 100
No. of patients 2 4 2 24 60 34 5 10 11 53 63 46 26 108 233 25 23 5
Response rate (%) * ~+M"
I
I
i0.
II
I
I
I
I'|+~' I
l:~- ,
II
Iq0~ ¢'n
;1'11 |,tlI
II
r#J~
I III
+ 0
I 10
II
I . 20
I 30
I 40
I 50
'~'/~ III 60
I'tl I'n
1
I
I
70
80
90
100
Figure 2: Clinical efficacy of cefodizime in adult patients in different age distributions.
Adverse reactions occurred in 2.3% of the 2,227 adult patients studied, including dropout cases. They were not severe, nor were they characteristic of cefodizime (Figure
3). Pediatric Cases The total responder rate in pediatric cases was 91.1%. On the basis of diagnosis, the responder rate was 97.8% in patients with pneumonia and three of three in meningitis patients (Figure 4). Adverse reactions developed in 5.1% of the 449 children studied. The most common adverse reaction was diarrhea ( F i g u r e 5).
Case 1; A 63-year-old male patient presented with multiple myeloma and pneumonia. Cefodizime treatment was started at a dosage of 1 g twice daily. Fever subsided S 32
in two days, the pathogen Streptococcus pneumoniae was eradicated in three days, and chest X-ray also showed improvement. This patient was classified as an excellent responder. Quantitative culture and Gram staining were performed on all good quality sputum specimens from all patients with respiratory tract infections. Gram-stained smears of good quality sputum from this patient taken before treatment and 3 h after the first administration of cefodizime showed a number of S. pneumoniae had been destroyed or changed into filamentous form.
Case 2: A 69-year-old severely leukopenic male patient presented with septicemia. The pathogen Klebsiella pneurnoniae was eradicated after four days of treatment, and complete improvement was obtained in ten days. An abrupt high fever that developed on day 7 may be attributed to a blood transfusion reaction.
Infection 20 (1992) Suppl. 1 © MMV Medizin Verlag GrnbH MOnchen,Miinchen 1992
K. Matsumoto: Cefodizime in Japan
-
1.08%
Allergic reactions -
Fever Eruption Drug e r u p t i o n Wheal - Urticaria - Pruritus - Other
2,227 p a t i e n t s
~rse ~
Gastrointestinal - Diarrhea
-
cases cases cases cases cases cases cases
19 3 3 2 2 1
cases cases cases cases cases case
1.35%
disorders
- Lienteric s t o o l s - Vomiting - A b d o m i n a l pain Anorexia - Other
(2.29%)
7 5 3 2 2 2 3
(24 c a s e s )
0.36%
Other reactions
(30 c a s e s )
(8 c a s e s )
2 cases 6 cases
- Vertigo - Other
Figure 3: The incidence of adverse reactions of cefodizime in adult patients.
Diagnosis
Response rate (%)*
No. of patients
Septicemia
2
Pneumonia
90
Pyelonephritis
2
Meningitis
3
Acute bronchitis
17
Tonsillitis
20
I
t
1
I
1
t
I
I
I
10
20
30
40
50
60
70
80
90
100
* : Excellent & Good/-rotal x 100 Figure 4: Clinical efficacy of cefodizime in pediatric patients.
Bacteriological Results
found against Haemophilus species: all 208 strains were eradicated (Table 1).
Of a total of 2,090 strains, 1,763 strains were eradicated. This result was superior to the results obtained with other cephem antibiotics. Of the gram-negative cocci, all strains of Moraxella catarrhalis and Neisseria gonorrhoeae were eradicated. Among gram-negative bacilli, cefodizime eradicated the major strains. Particularly good activity was
Abnormal Laboratory Findings Abnormalities with an incidence of 0.5% or more are presented in Table 2. Most abnormalities in both adults and children were increases in GOT or GPT. These results were comparable to the results of Japanese studies on other cephem antibiotics.
Infection 20 (1992) Suppl. 1 © MMV Medizin Verlag GmbH Mfinchen, M/Jnchen 1992
S 33
IC Matsumoto: Cefodizime in Japan
449 patients
0 . 6 7 % (3 c a s e ~
- - Allergic reactions
2 cases 1 case
- Eruption - Pruritus
Gastrointestinal disorders - Diarrhea - Lienteric s t o o l s - Angular stomatitis (5.12%)
4 . 4 5 % (20 cases) 14 c a s e s 5 cases 1 case
-- Other
0 . 2 2 % (1 case)
Angialgia
1 case
Figure 5: The incidence of adverse reactions of cefodizime in pediatric patients.
3. Cooperative activity with host defence mechanisms
2. Pharmacokinetics
1. Antibacterial activity
- High concentration in blood - High penetration into tissues
- Cooperative activity with phagocytes and complement
Treatment of infection Antibiotic concentration in tissues
MIC
Time
Figure 6: The possible factors involved in the in vivo efficacy of cefodizime.
Discussion
Cefpimizole was first produced in Japan by Ajinomoto in 1986 and has some characteristic antibiotic properties. However, it has a narrow antibiotic spectrum and its pharmacokinetic properties are not entirely satisfactory. Interestingly, cefodizime induces a phagocytic enhancement action against pathogens treated with this drug [1, 6, 7]. Figure 6 shows the relationstiip between time and the concentration of cefodizime in tissue, indicating in vivo activity. Soon after administration the concentration of cefodizime is very high due to high concentrations in blood as well ashigh penetration into tissues. Antibacterial activity is therefore high, but there is relatively less cooperation with S 34
the host defense mechanisms when concentrations are above the MIC. Even when levels of cefodizime in blood and tissues are lower, the drug is still potent because cooperation with the host defense mechanisms is relatively higher at sub-MIC levels. Oishi et al. [2] showed that when macrophages are treated with cefodizime, the phagocytic function is enhanced. In Japan the investigations on cefodizime were started in 1981. After recognition of the above-mentioned characteristics of this antibiotic, clinical trials were begun in 1985 for bacterial infections in adults. After the recognition of the safety and efficacy of this drug, a clinical trial was started in pediatric patients. In order to avoid confusion in evaluating the effectiveness
Infection 20 (1992) Suppl. 1 © MMV Medizin Verlag GmbH Mtinchen, Mtinchen 1992
K. Matsumoto: Cefodizime in Japan Table 1: Bacteriological efficacy of cefodizime against 2,090 trains isolated from adult and pediatric patients.
Staphylococcus spp. Streptococcus spp. Peptostreptococcus spp. Moraxella catarrhalis Neisseria gonorrhoeae Haemophilus spp. Escherichia coil Citrobacter spp. Klebsiella spp. Enterobacter spp. Serratia spp. Proteus spp. Providencia spp. Morganella morganii Bacteroides spp,
318 226 48 40 60 208 221 47 142 75 99 53 15 20 67
76.1 98.7 97.9 100 100 100 94.6 85.1 95.1 78.7 71.7 90,6 93.3 100 91.0
of this drug, the cases presented here are those in which pathogenic bacteria were identified; in general, these pathogens were sensitive to cefodizime. Moreover, data on efficacy was investigated in patients who were classified according to diagnosis and age. The total efficacy rates for adult and pediatric cases were 78.8% and 91.1%, respectively. These excellent efficacy rates, as well as the low rate of side effects and the enhanced activity of phagocytes, has made cefodizime an antibiotic of choice in both adult and pediatric patients.
References 1. Oishi, K., Matsumoto, K., Yoshida, T., Morito, T., Shishido, H., Yamamoto, M., Watanabe, K.: Cefodizime (THR-221) in respiratory tract infections - synergistic effect on human alveolar macrophages in vitro. Chemotherapy 36 (Suppl. 5) (1988) 545-563.
2. Oishi, IC, Matsumoto, K., Yamamoto, M., Morito, T., Yoshida, T.:
Table 2: Abnormal findings (abnormalities with an incidence of >- 0.5%) in laboratory parameters of adult and pediatric )atients treated with cefodizime.
Hematological tests Leukocytes Eosinophits (%) t t Platelets Biochemical tests 1" GOT t GPT Alkaline phosphatase t Direct bilirubin t y-GT t LDH LAP t Others t Coombs' test
2,490 1,619
0.6 2.4
2,0t4 2,016
4.2 5.7
1,931
1.5
1,236 1,388 883
1.6 0.7 1.0
169
0.6
435 415
6.0 2.7
419 419
6,2 6.2
175
0.6
Stimulatory effect of cefodizime on macrophage-mediated phagocytosis. J. Antibiot. 42 (1989) 989-992,
3. Limbert, M., Bartlett, R. R., Diekneite, G., Klesel, N., Schorlemmer, It. U., Seibert, G,, WinNer, I., Schrinner, E.: Cefodizime, an aminothiazolyl cephalosporin. IV. Influence on the immune system. J, Antibiot. 37 (1984) 1719-1726.
4. Ohnishi, H., Kosuzume, H., Inaba, H., Okura, M., Moehizuki, H., Suzuki, Y., Fujii, R.: Effects of AC-1370, a new semisynthetic cephalosporin, on phagocytic functions. Antimicrob. Agents Chemother. 25 (1983) 874-880. 5. Jones, R. N., Barry, A. L., Thornsberry, C., Wilson, H. W.: In vitro antimicrobial activity evaluation of cefodizime (HR-221), a new semisynthetic cephalosporin. Antimicrob. Agents Chemother. 20 (1981) 760-768. 6. Nomura, S., Tabuchi, H., Nagayama, A.: In vitro activity of cefodizime (THR-221) against clinical isolates and stimulation of phagocyte activity. Chemotherapy 36 (Suppl. 5) (1988) 117-127. 7. Ono, Y., Ueda, Y., Baba, M., Nishiya, H., Kunii, O.: Influence of a sub-inhibitory concentration of antibiotics on opsonophagocytic function of Klebsiella pneumoniae by human phagocytes. Chemotherapy 37 (1989) 1487-1491.
Infection 20 (1992) Suppl. 1 © MMV Medizin Verlag GmbH Mfinchen, Mfinchen 1992
S 35
Cefodizime: The Japanese Clinical Experience Summary: In a clinical trial conducted in Japan from 1985-1988, the efficacy of cefodizime was studied in 2,227 adult and 449 pediatric patients. Of these, 1,366 adult and 203 pediatric patients had pathogens isolated and were evaluable. Cefodizime was effective in 78.8% of the adult patients, and adverse reactions occurred in 2.3%. In pediatric patients cefodizime was effective in 91.1% of the cases, and adverse reactions developed in 5.1%. A very high concentration of cefodizime is achieved in blood soon after administration and its penetration into tissues is also high. Moreover, cefodizime exhibits phagocytosis enhancement activity. The above-mentioned excellent efficacy rates, low rates of side effects and enhancement of phagocytic activity make cefodizime an antibiotic of choice in adult and pediatric patients. Zusammenfassung: Cefodizim: Erfahrungen in Japan. In einer klinischen Studie, die in Japan zwischen 1985 und 1988 durchgeffihrt wurde, erhielten 2.227 Erwachsene bzw. 449 p/idiatrische Patienten eine Therapie mit Cefodizim, deren Wirksamkeit bei 1.366 Erwachsenen bzw. 203 Kindern analysiert wurde, bei denen pathogene Erreger nachgewiesen werden konnten. Bei Erwachsenen lag die Ansprechrate bei 78.8%; in 2,3% der F~ille traten Nebenwirkungen auf. P~idiatrische Patienten hatten eine Ansprechrate von 91,1% mit 5,1% Nebenwirkungen. Cefodizim erreicht bald nach der Applikation sehr hohe Blutspiegel und besitzt hohe Gewebe-Penetrationsf~ihigkeit. Dar~ber hinaus hat Cefodizim die Eigenschaft, die Phagozytose zu steigern. Hohe klinische Wirksamkeit, niedrige Nebenwirkungsraten und Phagozytosef6rderung qualifizieren Cefodizim zum Antibiotikum der Wahl bei erwachsenen und p~idiatrischen Patienten.
Introduction Along with the recent progress of medical science, the number of compromised hosts has increased, as has the incidence of infections in these patients. In treating these infections successfully, one of the most important considerations is how to enhance the host defense mechanism of the immunocompromised patient. Granulocyte-colony stimulating factor (G-CSF), with gamma globulins working as auxiliaries, is a promising enhancer for the host defense mechanisms. The most desirable antibiotics for treatment are those which not only control or destroy bacteria directly but also work in concert with the host defense mechanisms.
Various studies on cefodizime have demonstrated it to eradicate bacteria directly and in cooperation with host defense mechanisms, particularly the phagocytes [1-3]. Cefpimizole has also been shown to exhibit the same action [4]. However, cefodizime has been established as a third-generation cephem antibiotic with a broad antibacterial spectrum, good pharmacokinetics [1, 5], and bactericidal activity that works in cooperation with the host defense mechanisms [6]. Materials and Methods Clinical trials with cefodizime were conducted in several hospitals in Japan from 1985 to 1988. Pathogens were identified in 1,366 of 2,227 adults and 203 of 449 pediatric patients treated with cefodizime. Strains included in the study were restricted to those sensitive to cefodizime. The main dose was 1 g twice daily administered for four to 14 days in the adults, and 60 to 80 mg/kg/daygiven for four to seven days in children. The efficacy was evaluated on a four-grade scale: excellent, for improvement achieved within three days; good, for improvement within seven days; fair, for improvement within 14 days, and poor, for improvement later than 14 days or no improvement. The indicators of efficacy were fever, leukocyte count, inflammatory markers including C-reactive protein, clinical symptoms and percent of bacteria eradicated. The success rate of cefodizime (responder rate) was expressed as the rate of patients receiving cefodizime treatment who were classified as "good" and "excellent" responders.
Results
Adult Cases In total, cefodizime was effective in 78.8% of the adult patients. Classified by diagnosis, the responder rate was five of eight patients with septicemia, 83.9% in 118 patients with pneumonia, 69.2% in 26 patients with cholecystitis and cholangitis, 79% in 162 patients with pyelonephritis, 70.3% in 367 patients with cystitis, and 83.6% in 53 patients with peritonitis including pelvic peritonitis and Douglas abscess (Figure 1). Moreover, to clarify effectiveness in elderly patients, clinical efficacy was investigated in patients classified according to diagnosis and age. In cases with pneumonia, efficacy rates in the patients aged 50 to 70 years were almost the same as those in patients more than 70 years. The same results were obtained in pyelonephritis and cystitis cases (Figure 2). Prof. K. Matsumoto, M.D., Department of Internal Medicine, Institute of Tropical Medicine, Nagasaki University, 12-4 Sakamoto-Machi, Nagasaki 852, Japan.
Infection 20 (1992) Suppl. 1 © MMV Medizin Verlag GmbH Mtinchen, Mtinchen 1992
S 31
IC Matsuraoto:
Cefodizime in Japan
Diagnosis
No. of patients
Septicemia
8
Pneumonia
118
Cholecystitis and cholangitis
26
Pyelonephritis
162
Cystitis
367
Peritonitis (incl. pelvic peritonitis & Douglas abscess)
Response rate (%) *
53 0
I
I
I
I
I
I
I
I
I
10
20
30
40
50
60
70
80
90
100
* : Excellent & Good/Total x 100 Figure 1: Clinical efficacy of cefodizime in adult patients.
Diagnosis Septicemia Pneumonia Cholecystitis and cholangitis Pyelonephritis Cystitis Peritionitis ncl. pelvic peritonitis Douglas abscess)
Age 16 - 50 50 - 70 />70 16 - 50 50 - 70 I>70 16 - 50 50 - 70 ~>70 16 - 50 50 - 70 >~70 16 - 50 50 - 70 ~>70 16 - 50 50 - 70 >I 70
* : Excellent & Good/Total x 100
No. of patients 2 4 2 24 60 34 5 10 11 53 63 46 26 108 233 25 23 5
Response rate (%) * ~+M"
I
I
i0.
II
I
I
I
I'|+~' I
l:~- ,
II
Iq0~ ¢'n
;1'11 |,tlI
II
r#J~
I III
+ 0
I 10
II
I . 20
I 30
I 40
I 50
'~'/~ III 60
I'tl I'n
1
I
I
70
80
90
100
Figure 2: Clinical efficacy of cefodizime in adult patients in different age distributions.
Adverse reactions occurred in 2.3% of the 2,227 adult patients studied, including dropout cases. They were not severe, nor were they characteristic of cefodizime (Figure
3). Pediatric Cases The total responder rate in pediatric cases was 91.1%. On the basis of diagnosis, the responder rate was 97.8% in patients with pneumonia and three of three in meningitis patients (Figure 4). Adverse reactions developed in 5.1% of the 449 children studied. The most common adverse reaction was diarrhea ( F i g u r e 5).
Case 1; A 63-year-old male patient presented with multiple myeloma and pneumonia. Cefodizime treatment was started at a dosage of 1 g twice daily. Fever subsided S 32
in two days, the pathogen Streptococcus pneumoniae was eradicated in three days, and chest X-ray also showed improvement. This patient was classified as an excellent responder. Quantitative culture and Gram staining were performed on all good quality sputum specimens from all patients with respiratory tract infections. Gram-stained smears of good quality sputum from this patient taken before treatment and 3 h after the first administration of cefodizime showed a number of S. pneumoniae had been destroyed or changed into filamentous form.
Case 2: A 69-year-old severely leukopenic male patient presented with septicemia. The pathogen Klebsiella pneurnoniae was eradicated after four days of treatment, and complete improvement was obtained in ten days. An abrupt high fever that developed on day 7 may be attributed to a blood transfusion reaction.
Infection 20 (1992) Suppl. 1 © MMV Medizin Verlag GrnbH MOnchen,Miinchen 1992
K. Matsumoto: Cefodizime in Japan
-
1.08%
Allergic reactions -
Fever Eruption Drug e r u p t i o n Wheal - Urticaria - Pruritus - Other
2,227 p a t i e n t s
~rse ~
Gastrointestinal - Diarrhea
-
cases cases cases cases cases cases cases
19 3 3 2 2 1
cases cases cases cases cases case
1.35%
disorders
- Lienteric s t o o l s - Vomiting - A b d o m i n a l pain Anorexia - Other
(2.29%)
7 5 3 2 2 2 3
(24 c a s e s )
0.36%
Other reactions
(30 c a s e s )
(8 c a s e s )
2 cases 6 cases
- Vertigo - Other
Figure 3: The incidence of adverse reactions of cefodizime in adult patients.
Diagnosis
Response rate (%)*
No. of patients
Septicemia
2
Pneumonia
90
Pyelonephritis
2
Meningitis
3
Acute bronchitis
17
Tonsillitis
20
I
t
1
I
1
t
I
I
I
10
20
30
40
50
60
70
80
90
100
* : Excellent & Good/-rotal x 100 Figure 4: Clinical efficacy of cefodizime in pediatric patients.
Bacteriological Results
found against Haemophilus species: all 208 strains were eradicated (Table 1).
Of a total of 2,090 strains, 1,763 strains were eradicated. This result was superior to the results obtained with other cephem antibiotics. Of the gram-negative cocci, all strains of Moraxella catarrhalis and Neisseria gonorrhoeae were eradicated. Among gram-negative bacilli, cefodizime eradicated the major strains. Particularly good activity was
Abnormal Laboratory Findings Abnormalities with an incidence of 0.5% or more are presented in Table 2. Most abnormalities in both adults and children were increases in GOT or GPT. These results were comparable to the results of Japanese studies on other cephem antibiotics.
Infection 20 (1992) Suppl. 1 © MMV Medizin Verlag GmbH Mfinchen, M/Jnchen 1992
S 33
IC Matsumoto: Cefodizime in Japan
449 patients
0 . 6 7 % (3 c a s e ~
- - Allergic reactions
2 cases 1 case
- Eruption - Pruritus
Gastrointestinal disorders - Diarrhea - Lienteric s t o o l s - Angular stomatitis (5.12%)
4 . 4 5 % (20 cases) 14 c a s e s 5 cases 1 case
-- Other
0 . 2 2 % (1 case)
Angialgia
1 case
Figure 5: The incidence of adverse reactions of cefodizime in pediatric patients.
3. Cooperative activity with host defence mechanisms
2. Pharmacokinetics
1. Antibacterial activity
- High concentration in blood - High penetration into tissues
- Cooperative activity with phagocytes and complement
Treatment of infection Antibiotic concentration in tissues
MIC
Time
Figure 6: The possible factors involved in the in vivo efficacy of cefodizime.
Discussion
Cefpimizole was first produced in Japan by Ajinomoto in 1986 and has some characteristic antibiotic properties. However, it has a narrow antibiotic spectrum and its pharmacokinetic properties are not entirely satisfactory. Interestingly, cefodizime induces a phagocytic enhancement action against pathogens treated with this drug [1, 6, 7]. Figure 6 shows the relationstiip between time and the concentration of cefodizime in tissue, indicating in vivo activity. Soon after administration the concentration of cefodizime is very high due to high concentrations in blood as well ashigh penetration into tissues. Antibacterial activity is therefore high, but there is relatively less cooperation with S 34
the host defense mechanisms when concentrations are above the MIC. Even when levels of cefodizime in blood and tissues are lower, the drug is still potent because cooperation with the host defense mechanisms is relatively higher at sub-MIC levels. Oishi et al. [2] showed that when macrophages are treated with cefodizime, the phagocytic function is enhanced. In Japan the investigations on cefodizime were started in 1981. After recognition of the above-mentioned characteristics of this antibiotic, clinical trials were begun in 1985 for bacterial infections in adults. After the recognition of the safety and efficacy of this drug, a clinical trial was started in pediatric patients. In order to avoid confusion in evaluating the effectiveness
Infection 20 (1992) Suppl. 1 © MMV Medizin Verlag GmbH Mtinchen, Mtinchen 1992
K. Matsumoto: Cefodizime in Japan Table 1: Bacteriological efficacy of cefodizime against 2,090 trains isolated from adult and pediatric patients.
Staphylococcus spp. Streptococcus spp. Peptostreptococcus spp. Moraxella catarrhalis Neisseria gonorrhoeae Haemophilus spp. Escherichia coil Citrobacter spp. Klebsiella spp. Enterobacter spp. Serratia spp. Proteus spp. Providencia spp. Morganella morganii Bacteroides spp,
318 226 48 40 60 208 221 47 142 75 99 53 15 20 67
76.1 98.7 97.9 100 100 100 94.6 85.1 95.1 78.7 71.7 90,6 93.3 100 91.0
of this drug, the cases presented here are those in which pathogenic bacteria were identified; in general, these pathogens were sensitive to cefodizime. Moreover, data on efficacy was investigated in patients who were classified according to diagnosis and age. The total efficacy rates for adult and pediatric cases were 78.8% and 91.1%, respectively. These excellent efficacy rates, as well as the low rate of side effects and the enhanced activity of phagocytes, has made cefodizime an antibiotic of choice in both adult and pediatric patients.
References 1. Oishi, K., Matsumoto, K., Yoshida, T., Morito, T., Shishido, H., Yamamoto, M., Watanabe, K.: Cefodizime (THR-221) in respiratory tract infections - synergistic effect on human alveolar macrophages in vitro. Chemotherapy 36 (Suppl. 5) (1988) 545-563.
2. Oishi, IC, Matsumoto, K., Yamamoto, M., Morito, T., Yoshida, T.:
Table 2: Abnormal findings (abnormalities with an incidence of >- 0.5%) in laboratory parameters of adult and pediatric )atients treated with cefodizime.
Hematological tests Leukocytes Eosinophits (%) t t Platelets Biochemical tests 1" GOT t GPT Alkaline phosphatase t Direct bilirubin t y-GT t LDH LAP t Others t Coombs' test
2,490 1,619
0.6 2.4
2,0t4 2,016
4.2 5.7
1,931
1.5
1,236 1,388 883
1.6 0.7 1.0
169
0.6
435 415
6.0 2.7
419 419
6,2 6.2
175
0.6
Stimulatory effect of cefodizime on macrophage-mediated phagocytosis. J. Antibiot. 42 (1989) 989-992,
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