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cefoperazone for the treatment of infections in patients with hematologic diseases
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DIAGN MICROBIOLINFECTDIS 1989;12:215S-219S
Efficacy of Sulbactam/Cefoperazone for the Treatment of Infections in Patients with Hematologic Diseases Atsushi Horiuchi, Hirofumi Hasegawa, Takashi Kageyama, Tsuyoshi Yonezawa, Teruo Kitani, Tohru Masaoka, Kojiro Yasunaga, Hiroya Kawagoe, and Kiyoyasu Nagai
The efficacy and safety of sulbactam/cefoperazone (SBT/CPZ) was studied in 94 patients with severe infections and concomitant hematologic diseases. All of the study patients were included in the evaluation for safety, and 76 cases were evaluable for efficacy. Clinical efficacy was excellent in 13 cases (17.1%), good in 27 cases (35.5%), fair in seven cases (9.2%), and poor in 29 cases (38.2%). The bacteriologic eradication was 66.7% for Gram-negative bacilli and 50.0% for Gram-positive bacteria. The efficacy rate for neutropenic pa-
tients with counts less than 50 m m 3 and 100 m m 3 w e r e 47.5 and 42.9%, respectively. Efficacy in patients for whom other antibiotic therapy before treatment with SBT/CPZ had been ineffective was 46.2%. Side effects were reported in one case (1.1%), and abnormal serum liver tests in five cases (5.3%); both returned to normal after discontinuation of the study medication. SBT/CPZ was an effective antibiotic for the treatment of severe infections in the presence of concurrent hematologic diseases.
INTRODUCTION
tibacterial spectrum of activity could be obtained. In this study, investigators from the Hanshin Study Group of Hematopoietic Disorders and Infections evaluated the efficacy and safety of SBT/CPZ (1:1, w/w) for the treatment of severe infections in patients with concomitant hematologic diseases.
Although a variety of antibiotics have been developed in recent years, the number of pathogens resistant to these drugs have also increased. The mechanism of resistance to beta-lactam antibiotics is primarily due to inactivation by beta-lactamases. To counteract this effect, cephalosporin antibiotics that are not hydrolyzed by these enzymes have been synthesized. Sulbactam (SBT) is a beta-lactamase inhibitor that was first introduced by Pfizer in the United States in 1977. The other drug, cefoperazone (CPZ), is a cephem antibiotic with potent antibacterial activity. These two drugs were combined to produce sulbactam/cefoperazone (SBT/CPZ) so that a broader anFrom the Hanshin Study Group of HematopoieticDisorders and Infections,Japan. Address reprint requests to: Dr. Atsushi Horiuchi, Department of Internal Medicine, KinkiUniversitySchool of Medicine, 377 Ohnohigashi, Osaka-sayama,589 Japan. Received May 17, 1989; revised and accepted May 27, 1989. Published 1989 Elsevier Science PublishingCo., Inc. 655 Avenue of the Americas, New York, NY 10010
SUBJECTS A N D METHODS Table 1 lists the institutional affiliations of the Hanshin Study Group of Hematopoietic Disorders and Infections. The study included a total of 94 patients who were treated with SBT/CPZ. The primary hematological diagnosis for 75% of these patients was acute leukemia. The classification of patients by their underlying hematologic diseases is given in Table 2. Eighteen of the 94 patients were excluded from the study because of concurrent use of other antibiotics, tumor fever, or for other reasons. Seventy-six patients were evaluated for efficacy of the drug. Safety of SBT/CPZ was determined for all 94 patients. The 76 patients who were evaluated for efficacy included
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A. Horiuchi et al.
TABLE 1.
Hanshin Study Group of Hematopoietic Disorders and Infections, Departments of Internal Medicine, Japan
Kinki University School of Medicine Osaka Medical College Osaka University Medical School Research Institute for Microbial Diseases, Osaka University Center for Adult Diseases, Osaka Kansai Medical University Osaka National Hospital Hyogo College of Medicine
48.2 g. Of the 76 efficacy evaluable patients, 26 were given 4 g daily and 50 were given 6 g a day. Clinical response to treatment with SBT/CPZ was evaluated as follows: excellent--the principal signs and symptoms of infectious disease disappeared or improved within 3 days after onset of treatment with the drug; good--the primary signs and symptoms of infectious disease disappeared within 7 days after onset of treatment; fair--the principal signs and symptoms disappeared after more than 7 days following the onset of therapy; and poor--No improvement seen.
RESULTS
43 men and 33 women, with a mean age of 43.2 years and a range of 10 to 80 + years. The types of infections that were treated are given in Table 3. Sepsis was suspected in 80.3% of the 76 evaluable patients. Sepsis was defined as any case in which the focus of infection could not be identified in spite of inflammatory signs such as a continuous high fever, a positive C-reactive protein test, an elevated erythrocyte sedimentation rate, or other findings which improved following administration of the antibiotic. Sulbactam/cefoperazone was infused intravenously over a period of I hr or more at a daily maximum dosage of 4 to 6 g in two or three divided doses. The duration of treatment ranged from 3 to 32 days, with a mean of 9.5 days. Total drug administered ranged from 10 to 192 g, with a mean of
TABLE 2.
Table 4 shows the rate of clinical efficacy by daily dose. The clinical response of the patients treated with a SBT/CPZ regimen of 4 g daily was excellent in five and good in eight cases, with an efficacy rate of 50%. Clinical response of the 50 patients treated with a regimen of 6 g daily was excellent in eight and good in 19 patients with an efficacy rate of 54.0%. The overall rate of efficacy for the 76 evaluable patients was 52.6%. Table 5 gives the clinical effectiveness of SBT/CPZ by type of infection. The overall efficacy rates were 33.3% for sepsis, 50.8% for suspected sepsis, 40% for pneumonia, and 86% for all other types of infections. Table 6 shows the efficacy rate by neutrophil counts before and after treatment with SBT/CPZ. The efficacy rate for those patients in whom neutrophil counts
Underlying Diseases and Number of Patients
Underlying Diseases
No. of Evaluable Patients (%)
Acute myeloblastic leukemia Acute promyelocytic leukemia Acute myelomonocytic leukemia Acute monocytic leukemia Erythroleukemia Acute lymphocytic leukemia Adult T cell leukemia Atypical leukemia Myelodysplastic syndrome Chronic myelocytic leukemia (b.c.) Hodgkin's disease Non-Hodgkin's lymphoma Multiple myeloma Immunoblastic lymphadenopathy Aplastic anemia Idiopathic thrombocytopenic purpura Common variable immunodeficiency Total
27 (35.5%) 7 (9.2%) 6 (7.9%) 5 (6.6%) 2 (2.6%) 4 (5.3%) 2 (2.6%) 1 (1.4%) 2 (2.6%) 3 (3.9%) 2 (2.6%) 6 (7.9%) 4 (5.3%) 1 (1.4%) 3 (3.9%) 1 (1.4%) 0( ) 76 (100.0%)
No. of Safety Evaluable Patients (%) 32 (34.0%) 8 (8.5%) 7 (7.4%) 5 (5.3%) 2 (2.1%o) 7 (7.4%) 2 (2.1%) 1 (1.1%) 3 (3.2%) 3 (3.2%) 2 (2.1%) 10 (10.6%) 5 (5.3%) 1 (1.1%) 4 (4.3%) 1 (1.1%) 1 (1.1%) 94 (100.0%)
Sulbactam/Cefoperazone and Hematologic Diseases
Infections Treated With Sulbactam/ Cefoperazone
TABLE 3.
Infections
No. of Patients (%)
Sepsis Suspected sepsis Pneumonia Urinary tract infection Cellulitis Oral infection Decubitus infection Total
3 (3.9%) 61 (80.3%) 5 (6.6%) 3 (3.9%) 2 (2.7%) 1 (1.3%) 1 (1.3%) 76 (100%)
were below 100 mm 3 prior to treatment was 43.8%. In this group, although neutrophil counts rose during SBT/CPZ treatment, the efficacy rate did not increase. Conversely, in those patients in whom neutrophil counts were 101 mm 3 or higher, the efficacy rate increased when neutrophil counts rose during treatment with SBT/CPZ. Table 7 shows the efficacy rate of SBT/CPZ for the 26 study patients who were treated with other antibiotics before SBT/CPZ therapy, as well as for the 50 patients who were not previously treated with any antibiotics. The efficacy rates for these two groups were 46.2 and 56.0%, respectively, with a difference in efficacy observed between these two patient groups. In those patients who were treated with prior antibiotic therapy, efficacy rates were 57.1% for patients treated with a single drug and 33.1% for patients previously treated with two other antibiotics. In this clinical trial, 16 causative organisms were identified in 11 patients; the number of Gram-negative and Gram-positive bacteria identified were 6 and 10, respectively. Table 8 shows the organism eradication by SBT/CPZ of these causative organisms. The eradication rate of SBT/CPZ was 66.7% for Gram-negative bacteria and 50.0% for Gram-positive bacteria. The clinical effectiveness of SBT/CPZ in those patients in whom the causative organisms were identifiable was 63.6%, and 50.8% in the group in which these organisms were not identified.
TABLE 4.
Clinical Effectiveness by Daily Dose
Daily Excellent Good Dose 4.0 g 6.0 g Total
5 8 13
8 19 27
aEfficacyrate (E.R.) =
Fair Poor 2 5 7
11 18 29
Total
E.R. (%)a
26 50 76
50.0 54.0 52.6
Excellent + Good Total x 100.
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Of the 94 patients treated with SBT/CPZ, skin rash developed in one patient. Abnormalities in laboratory findings were reported in five patients, four of whom demonstrated transient elevations in SGOT or SGPT liver enzymes. In the fifth patient, increases in BUN and serum creatinine were noted. None of these abnormalities were severe, and improvement was seen as soon as SBT/CPZ treatment was discontinued.
DISCUSSION Many penicillin or cephalosporin antibiotics are unstable in the presence of beta-lactamase. Sulbactam/ cefoperazone combined in a ratio of 1:1 (w/w) is a parenteral agent with broad-spectrum antibacterial activity. Cefoperazone is a third-generation cephalosporin, and sulbactam is an irreversible inhibitor of selected beta-lactamase. Although SBT exhibits weak antibacterial activity when used alone, it strongly inactivates beta-lactamase of the penicillinase type and inactivates some cephalosporinases. It has been reported that the use of SBT combined with a betalactam antibiotic successfully prevents inactivation by beta-lactmase, which increases the drug's antibacterial activity against resistant organisms (English et al., 1978). Cefoperazone is stable in the presence of cephalosporinase type beta-lactamase, which is produced by bacteria such as Escherichia coli, Pseudomonas aeruginosa, Enterobacter cloacae, and Citrobacter freundii (Mitsuhashi et al., 1980), but is partially hydrolyzed by the pencillinase type beta-lactamase that certain organisms produce (Yu, 1981). Thus, SBT/CPZ is a combination antibiotic with a broad-spectrum antibactericidal activity and safety profile. In particular, SBT/CPZ demonstrates remarkably strong antibactericidal activity when tested against CPZ-resistant strains (Lynch et al., 1981). Infections associated with aplastic anemia and hematopoietic malignancies such as acute leukemia and malignant lymphoma are apt to become life-threatening as a result of neutropenia and depressed immunity due either to the antitumor agents used to treat the underlying disease or to the tumor. In many of these patients the only symptom of infection is fever with no identifiable foci or pathogens. Thus, treatment with broad-spectrum antibiotics must be instituted early on when any infection is suspected in patients with underlying hematopoietic disorders. The efficacy of SBT/CPZ infections associated with hematologic diseases was 52.6%, similar to the efficacy of 50 to 60% that has been achieved in other studies by our group. In hematopoietic diseases in which the neutro-
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A. H o r i u c h i et al.
T A B L E 5.
Clinical E f f e c t i v e n e s s of S u l b a c t a m / C e f o p e r a z o n e b y Specific Infection Type
Infections
Excellent
Sepsis Suspected sepsis Pneumonia Urinary tract infection Cellulitis Oral infection Decubitus infection Total ~Efficacy rate (E.R.) =
T A B L E 6.
Good
Poor
Total
E.R. (%)a
7
2 23 3
3 61 5 3 2 1 1 76
33.3 50.8 40.0 100.0 100.0 100.0 0 52.6
1 20 2 3 1
11
1 1 13
27
7
1 29
Excellent + Good x 100. Total
Clinical E f f e c t i v e n e s s C l a s s i f i e d b y Change in Neutrophil Count
Before/Change in Count <100 m m 3 No change or decrease Increase 101-500 m m 3 No change or decrease Increase />501 m m 3 ~Efficacy rate (E.R.) =
T A B L E 7.
Fair
E.R. (%)4
7/16 5/15
43.8 33.3
3/8 7/7 18/30
37.5 100.0 60.0
Excellent + Good x 100. Total
C o m p a r i s o n of Efficacy Rates B e t w e e n G r o u p s W i t h a n d W i t h o u t Prior T r e a t m e n t With Antibiotics
CEPs + AGs CEPs + PCs CEPs + SBT PCs + AGs CEPs + Other
Prior Antibiotics
Excellent
Good
Fair
Poor
Total
E.R. (%)4
No Yes Sulbactam Cephalosporins Penicillins Aminoglycosides Other Total
11 2
6 1
1
17 10 4 1 1
16 13 1 3 1 1
56.0 46.2 80.0 25.0 66.7
1
1 7
50 26 5 4 3 1 1 14 4 3 2 1 2 12
50.0 33.3 50.0
Cephalosporins + aminoglycosides Cephalosporins + penicillins Cephalosporins + sulbactam Penicillins + aminoglycosides Cephalosporins + other Total
aEfficacy rate (E.R.) =
Excellent + Good Total x 100.
6
2
2 2
1 1
1
3
1
1
1 2 7
57.1
33.3
Sulbactam/Cefoperazone and Hematologic Diseases
TABLE 8.
Eradication Rate of Causative Organisms
Gram Stain/Causative Organism
Eradicated/ Isolated
Eradicated/ Isolated (%)
Negative
Echerichia coli Pseudomonas aeruginosa Pseudomonas cepacia Pseudomonas spp. Neisseria spp. Bacteroides spp. Positive Staphylococcus aureus Staphylococcus epidermidis Staphylococcus spp. Streptococcus pneumoniae Streptococcus spp. Enterococcus faecalis
0/1 1/1 1/1 1/1 0/1 1/1 0/1 1/1 0/1 0/1 0/1
66.7%
50.0%
219S
phils are decreased, the effectiveness of antibiotic t h e r a p y often d e p e n d s on the change in peripheral neutrophil counts d u r i n g treatment. In the patients with n e u t r o p h i l counts of ~<100 m m 3 before administration of SBT/CPZ, the efficacy rate was 43.8% w h e n the counts did not increase. The efficacy rate rose to 66.7% w h e n neutrophil counts increased during SBT/CPZ treatment for patients. Sulbactam/cefoperazone was a d m i n i s t e r e d to 26 patients in w h o m t h e r a p y with other antibiotics had resulted in ineffective t r e a t m e n t with an efficacy of 46.2%. H o w e v e r , the efficacy for the 50 patients not previously treated with other antibiotics was 56.0%. The side effects observed in this s t u d y w e r e minimal. We conclude that SBT/CPZ is an efficacious a n d well-tolerated antibiotic for the t r e a t m e n t of severe infections associated with hematologic diseases.
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REFERENCES English AR, Retsema JA, Girard AR, et al. (1978) CP45,899, a beta-lactamase inhibitor that extends the antibacterial spectrum of beta-lactam. Initial bacteriological characterization. Antimicrob Agents Chemother 14:414. Lynch JE, Retsema JA, Pitts NE, et al. (1981) Influence of sulbactam (CP-45,899) on the activity of cefoperazone under conditions simulating human pharmacokinetics. Presented to the 21st Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, IL, November 4-6.
Mitsuhashi S, Minami S, Matsubara A, et al. (1980) In vitro and in vivo antibacterial activity of cefoperazone. Clin Ther 3:1. Yu PKW, Washington II JA (1981) Bactericidal activity of cefoperazone with CP-45,899 against large inocula of beta-lactamase producing Haemophilus influenzae. Antimicrob Agents Chemother 20:63.
DIAGN MICROBIOLINFECTDIS 1989;12:215S-219S
Efficacy of Sulbactam/Cefoperazone for the Treatment of Infections in Patients with Hematologic Diseases Atsushi Horiuchi, Hirofumi Hasegawa, Takashi Kageyama, Tsuyoshi Yonezawa, Teruo Kitani, Tohru Masaoka, Kojiro Yasunaga, Hiroya Kawagoe, and Kiyoyasu Nagai
The efficacy and safety of sulbactam/cefoperazone (SBT/CPZ) was studied in 94 patients with severe infections and concomitant hematologic diseases. All of the study patients were included in the evaluation for safety, and 76 cases were evaluable for efficacy. Clinical efficacy was excellent in 13 cases (17.1%), good in 27 cases (35.5%), fair in seven cases (9.2%), and poor in 29 cases (38.2%). The bacteriologic eradication was 66.7% for Gram-negative bacilli and 50.0% for Gram-positive bacteria. The efficacy rate for neutropenic pa-
tients with counts less than 50 m m 3 and 100 m m 3 w e r e 47.5 and 42.9%, respectively. Efficacy in patients for whom other antibiotic therapy before treatment with SBT/CPZ had been ineffective was 46.2%. Side effects were reported in one case (1.1%), and abnormal serum liver tests in five cases (5.3%); both returned to normal after discontinuation of the study medication. SBT/CPZ was an effective antibiotic for the treatment of severe infections in the presence of concurrent hematologic diseases.
INTRODUCTION
tibacterial spectrum of activity could be obtained. In this study, investigators from the Hanshin Study Group of Hematopoietic Disorders and Infections evaluated the efficacy and safety of SBT/CPZ (1:1, w/w) for the treatment of severe infections in patients with concomitant hematologic diseases.
Although a variety of antibiotics have been developed in recent years, the number of pathogens resistant to these drugs have also increased. The mechanism of resistance to beta-lactam antibiotics is primarily due to inactivation by beta-lactamases. To counteract this effect, cephalosporin antibiotics that are not hydrolyzed by these enzymes have been synthesized. Sulbactam (SBT) is a beta-lactamase inhibitor that was first introduced by Pfizer in the United States in 1977. The other drug, cefoperazone (CPZ), is a cephem antibiotic with potent antibacterial activity. These two drugs were combined to produce sulbactam/cefoperazone (SBT/CPZ) so that a broader anFrom the Hanshin Study Group of HematopoieticDisorders and Infections,Japan. Address reprint requests to: Dr. Atsushi Horiuchi, Department of Internal Medicine, KinkiUniversitySchool of Medicine, 377 Ohnohigashi, Osaka-sayama,589 Japan. Received May 17, 1989; revised and accepted May 27, 1989. Published 1989 Elsevier Science PublishingCo., Inc. 655 Avenue of the Americas, New York, NY 10010
SUBJECTS A N D METHODS Table 1 lists the institutional affiliations of the Hanshin Study Group of Hematopoietic Disorders and Infections. The study included a total of 94 patients who were treated with SBT/CPZ. The primary hematological diagnosis for 75% of these patients was acute leukemia. The classification of patients by their underlying hematologic diseases is given in Table 2. Eighteen of the 94 patients were excluded from the study because of concurrent use of other antibiotics, tumor fever, or for other reasons. Seventy-six patients were evaluated for efficacy of the drug. Safety of SBT/CPZ was determined for all 94 patients. The 76 patients who were evaluated for efficacy included
216S
A. Horiuchi et al.
TABLE 1.
Hanshin Study Group of Hematopoietic Disorders and Infections, Departments of Internal Medicine, Japan
Kinki University School of Medicine Osaka Medical College Osaka University Medical School Research Institute for Microbial Diseases, Osaka University Center for Adult Diseases, Osaka Kansai Medical University Osaka National Hospital Hyogo College of Medicine
48.2 g. Of the 76 efficacy evaluable patients, 26 were given 4 g daily and 50 were given 6 g a day. Clinical response to treatment with SBT/CPZ was evaluated as follows: excellent--the principal signs and symptoms of infectious disease disappeared or improved within 3 days after onset of treatment with the drug; good--the primary signs and symptoms of infectious disease disappeared within 7 days after onset of treatment; fair--the principal signs and symptoms disappeared after more than 7 days following the onset of therapy; and poor--No improvement seen.
RESULTS
43 men and 33 women, with a mean age of 43.2 years and a range of 10 to 80 + years. The types of infections that were treated are given in Table 3. Sepsis was suspected in 80.3% of the 76 evaluable patients. Sepsis was defined as any case in which the focus of infection could not be identified in spite of inflammatory signs such as a continuous high fever, a positive C-reactive protein test, an elevated erythrocyte sedimentation rate, or other findings which improved following administration of the antibiotic. Sulbactam/cefoperazone was infused intravenously over a period of I hr or more at a daily maximum dosage of 4 to 6 g in two or three divided doses. The duration of treatment ranged from 3 to 32 days, with a mean of 9.5 days. Total drug administered ranged from 10 to 192 g, with a mean of
TABLE 2.
Table 4 shows the rate of clinical efficacy by daily dose. The clinical response of the patients treated with a SBT/CPZ regimen of 4 g daily was excellent in five and good in eight cases, with an efficacy rate of 50%. Clinical response of the 50 patients treated with a regimen of 6 g daily was excellent in eight and good in 19 patients with an efficacy rate of 54.0%. The overall rate of efficacy for the 76 evaluable patients was 52.6%. Table 5 gives the clinical effectiveness of SBT/CPZ by type of infection. The overall efficacy rates were 33.3% for sepsis, 50.8% for suspected sepsis, 40% for pneumonia, and 86% for all other types of infections. Table 6 shows the efficacy rate by neutrophil counts before and after treatment with SBT/CPZ. The efficacy rate for those patients in whom neutrophil counts
Underlying Diseases and Number of Patients
Underlying Diseases
No. of Evaluable Patients (%)
Acute myeloblastic leukemia Acute promyelocytic leukemia Acute myelomonocytic leukemia Acute monocytic leukemia Erythroleukemia Acute lymphocytic leukemia Adult T cell leukemia Atypical leukemia Myelodysplastic syndrome Chronic myelocytic leukemia (b.c.) Hodgkin's disease Non-Hodgkin's lymphoma Multiple myeloma Immunoblastic lymphadenopathy Aplastic anemia Idiopathic thrombocytopenic purpura Common variable immunodeficiency Total
27 (35.5%) 7 (9.2%) 6 (7.9%) 5 (6.6%) 2 (2.6%) 4 (5.3%) 2 (2.6%) 1 (1.4%) 2 (2.6%) 3 (3.9%) 2 (2.6%) 6 (7.9%) 4 (5.3%) 1 (1.4%) 3 (3.9%) 1 (1.4%) 0( ) 76 (100.0%)
No. of Safety Evaluable Patients (%) 32 (34.0%) 8 (8.5%) 7 (7.4%) 5 (5.3%) 2 (2.1%o) 7 (7.4%) 2 (2.1%) 1 (1.1%) 3 (3.2%) 3 (3.2%) 2 (2.1%) 10 (10.6%) 5 (5.3%) 1 (1.1%) 4 (4.3%) 1 (1.1%) 1 (1.1%) 94 (100.0%)
Sulbactam/Cefoperazone and Hematologic Diseases
Infections Treated With Sulbactam/ Cefoperazone
TABLE 3.
Infections
No. of Patients (%)
Sepsis Suspected sepsis Pneumonia Urinary tract infection Cellulitis Oral infection Decubitus infection Total
3 (3.9%) 61 (80.3%) 5 (6.6%) 3 (3.9%) 2 (2.7%) 1 (1.3%) 1 (1.3%) 76 (100%)
were below 100 mm 3 prior to treatment was 43.8%. In this group, although neutrophil counts rose during SBT/CPZ treatment, the efficacy rate did not increase. Conversely, in those patients in whom neutrophil counts were 101 mm 3 or higher, the efficacy rate increased when neutrophil counts rose during treatment with SBT/CPZ. Table 7 shows the efficacy rate of SBT/CPZ for the 26 study patients who were treated with other antibiotics before SBT/CPZ therapy, as well as for the 50 patients who were not previously treated with any antibiotics. The efficacy rates for these two groups were 46.2 and 56.0%, respectively, with a difference in efficacy observed between these two patient groups. In those patients who were treated with prior antibiotic therapy, efficacy rates were 57.1% for patients treated with a single drug and 33.1% for patients previously treated with two other antibiotics. In this clinical trial, 16 causative organisms were identified in 11 patients; the number of Gram-negative and Gram-positive bacteria identified were 6 and 10, respectively. Table 8 shows the organism eradication by SBT/CPZ of these causative organisms. The eradication rate of SBT/CPZ was 66.7% for Gram-negative bacteria and 50.0% for Gram-positive bacteria. The clinical effectiveness of SBT/CPZ in those patients in whom the causative organisms were identifiable was 63.6%, and 50.8% in the group in which these organisms were not identified.
TABLE 4.
Clinical Effectiveness by Daily Dose
Daily Excellent Good Dose 4.0 g 6.0 g Total
5 8 13
8 19 27
aEfficacyrate (E.R.) =
Fair Poor 2 5 7
11 18 29
Total
E.R. (%)a
26 50 76
50.0 54.0 52.6
Excellent + Good Total x 100.
217S
Of the 94 patients treated with SBT/CPZ, skin rash developed in one patient. Abnormalities in laboratory findings were reported in five patients, four of whom demonstrated transient elevations in SGOT or SGPT liver enzymes. In the fifth patient, increases in BUN and serum creatinine were noted. None of these abnormalities were severe, and improvement was seen as soon as SBT/CPZ treatment was discontinued.
DISCUSSION Many penicillin or cephalosporin antibiotics are unstable in the presence of beta-lactamase. Sulbactam/ cefoperazone combined in a ratio of 1:1 (w/w) is a parenteral agent with broad-spectrum antibacterial activity. Cefoperazone is a third-generation cephalosporin, and sulbactam is an irreversible inhibitor of selected beta-lactamase. Although SBT exhibits weak antibacterial activity when used alone, it strongly inactivates beta-lactamase of the penicillinase type and inactivates some cephalosporinases. It has been reported that the use of SBT combined with a betalactam antibiotic successfully prevents inactivation by beta-lactmase, which increases the drug's antibacterial activity against resistant organisms (English et al., 1978). Cefoperazone is stable in the presence of cephalosporinase type beta-lactamase, which is produced by bacteria such as Escherichia coli, Pseudomonas aeruginosa, Enterobacter cloacae, and Citrobacter freundii (Mitsuhashi et al., 1980), but is partially hydrolyzed by the pencillinase type beta-lactamase that certain organisms produce (Yu, 1981). Thus, SBT/CPZ is a combination antibiotic with a broad-spectrum antibactericidal activity and safety profile. In particular, SBT/CPZ demonstrates remarkably strong antibactericidal activity when tested against CPZ-resistant strains (Lynch et al., 1981). Infections associated with aplastic anemia and hematopoietic malignancies such as acute leukemia and malignant lymphoma are apt to become life-threatening as a result of neutropenia and depressed immunity due either to the antitumor agents used to treat the underlying disease or to the tumor. In many of these patients the only symptom of infection is fever with no identifiable foci or pathogens. Thus, treatment with broad-spectrum antibiotics must be instituted early on when any infection is suspected in patients with underlying hematopoietic disorders. The efficacy of SBT/CPZ infections associated with hematologic diseases was 52.6%, similar to the efficacy of 50 to 60% that has been achieved in other studies by our group. In hematopoietic diseases in which the neutro-
218S
A. H o r i u c h i et al.
T A B L E 5.
Clinical E f f e c t i v e n e s s of S u l b a c t a m / C e f o p e r a z o n e b y Specific Infection Type
Infections
Excellent
Sepsis Suspected sepsis Pneumonia Urinary tract infection Cellulitis Oral infection Decubitus infection Total ~Efficacy rate (E.R.) =
T A B L E 6.
Good
Poor
Total
E.R. (%)a
7
2 23 3
3 61 5 3 2 1 1 76
33.3 50.8 40.0 100.0 100.0 100.0 0 52.6
1 20 2 3 1
11
1 1 13
27
7
1 29
Excellent + Good x 100. Total
Clinical E f f e c t i v e n e s s C l a s s i f i e d b y Change in Neutrophil Count
Before/Change in Count <100 m m 3 No change or decrease Increase 101-500 m m 3 No change or decrease Increase />501 m m 3 ~Efficacy rate (E.R.) =
T A B L E 7.
Fair
E.R. (%)4
7/16 5/15
43.8 33.3
3/8 7/7 18/30
37.5 100.0 60.0
Excellent + Good x 100. Total
C o m p a r i s o n of Efficacy Rates B e t w e e n G r o u p s W i t h a n d W i t h o u t Prior T r e a t m e n t With Antibiotics
CEPs + AGs CEPs + PCs CEPs + SBT PCs + AGs CEPs + Other
Prior Antibiotics
Excellent
Good
Fair
Poor
Total
E.R. (%)4
No Yes Sulbactam Cephalosporins Penicillins Aminoglycosides Other Total
11 2
6 1
1
17 10 4 1 1
16 13 1 3 1 1
56.0 46.2 80.0 25.0 66.7
1
1 7
50 26 5 4 3 1 1 14 4 3 2 1 2 12
50.0 33.3 50.0
Cephalosporins + aminoglycosides Cephalosporins + penicillins Cephalosporins + sulbactam Penicillins + aminoglycosides Cephalosporins + other Total
aEfficacy rate (E.R.) =
Excellent + Good Total x 100.
6
2
2 2
1 1
1
3
1
1
1 2 7
57.1
33.3
Sulbactam/Cefoperazone and Hematologic Diseases
TABLE 8.
Eradication Rate of Causative Organisms
Gram Stain/Causative Organism
Eradicated/ Isolated
Eradicated/ Isolated (%)
Negative
Echerichia coli Pseudomonas aeruginosa Pseudomonas cepacia Pseudomonas spp. Neisseria spp. Bacteroides spp. Positive Staphylococcus aureus Staphylococcus epidermidis Staphylococcus spp. Streptococcus pneumoniae Streptococcus spp. Enterococcus faecalis
0/1 1/1 1/1 1/1 0/1 1/1 0/1 1/1 0/1 0/1 0/1
66.7%
50.0%
219S
phils are decreased, the effectiveness of antibiotic t h e r a p y often d e p e n d s on the change in peripheral neutrophil counts d u r i n g treatment. In the patients with n e u t r o p h i l counts of ~<100 m m 3 before administration of SBT/CPZ, the efficacy rate was 43.8% w h e n the counts did not increase. The efficacy rate rose to 66.7% w h e n neutrophil counts increased during SBT/CPZ treatment for patients. Sulbactam/cefoperazone was a d m i n i s t e r e d to 26 patients in w h o m t h e r a p y with other antibiotics had resulted in ineffective t r e a t m e n t with an efficacy of 46.2%. H o w e v e r , the efficacy for the 50 patients not previously treated with other antibiotics was 56.0%. The side effects observed in this s t u d y w e r e minimal. We conclude that SBT/CPZ is an efficacious a n d well-tolerated antibiotic for the t r e a t m e n t of severe infections associated with hematologic diseases.
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Mitsuhashi S, Minami S, Matsubara A, et al. (1980) In vitro and in vivo antibacterial activity of cefoperazone. Clin Ther 3:1. Yu PKW, Washington II JA (1981) Bactericidal activity of cefoperazone with CP-45,899 against large inocula of beta-lactamase producing Haemophilus influenzae. Antimicrob Agents Chemother 20:63.