THE JOURNAL OF INFECTIOUS DISEASES • VOL. 134, SUPPLEMENT © 1976 by the University of Chicago. All rights reserved.
• AUGUST 1976
Clinical Use of Tobramycin in Patients with Surgical Infections Due to Gram-Negative Bacilli From the Department of Surgery, Nihon University School of Medicine, Tokyo, Japan
S. Ishiyama, I. Nakayama, H. Iwamoto, S. Iwai,
I. Murata, and M. Ohashi
Chemotherapeutic regimens presently available in Japan for the treatment of pseudomonas infections are: (1) administration of a large dose of carbenicillin, sulbenicillin (disodium u-sulfobenzylpenicillin), or amikacin; (2) administration of a single dose of gentamicin, tobramycin, dibecacin (3',4'-diamino-3',4'-dideoxykanamycin B), or sisomicin; (3) administration of carbenicillin or sulbenicillin for maintenance therapy after shortterm treatment with one of the aminoglycosides mentioned above (occasionally, oral carfecillin [a-phenoxycarbonyl-benzylpenicillin] or indanylcarbenicillin can be substituted for maintenance therapy); and (4) concomitant chemotherapy with an aminoglycoside and one of the synthetic penicillins mentioned. In addition, use of antiOEP (original endotoxin protein) globulin or pipemidic acid in combination with these antibiotics is now being investigated. Tobramycin is a new aminoglycoside antibiotic which is highly active against both aerobic gramnegative and gram-positive bacteria. The shortcoming of this group of drugs is the possibility of side effects, namely, ototoxicity or nephrotoxicity. For this reason, serious investigation is needed to find a dosage regimen that will result in clinical efficacy with minimal side effects. Therefore, we investigated the clinical use of tobramycin in patients with severe surgical infections due to gramPlease address requests for reprints to Dr. S. ·Ishiyama, Department of Surgery, Nihon University School of Medicine, 8, l-chome, Kandasurugadai, Chiyodaku, Tokyo, Japan.
negative bacilli, particularly Pseudomonas aeruginasa. Materials and Methods
Twenty-three patients with various infections including acute peritonitis, intraabdominal abscess, wound infections (including infections of serious burns), sepsis accompanying renal transplantation, and urinary tract infections associated with cancer were treated with various doses of tobramycin. Their clinical responses are summarized in table 1. Clinical signs and symptoms such as temperature, leukocytosis, and purulent discharge and results of tests of clinical chemistry were checked as criteria of success of the treatment. The underlying diseases were considered as factors that influenced the results. Table 1. Clinical responses to tobramycin of 23 patients with severe infections due to gram-negative bacilli.
Type of infection Postoperative peritonitis Intraabdominal abscess Wound infection Sepsis (with renal transplantation or necrotizing pharyngeal sarcoma) Complicated urinary tract infection (with recurrent rectal cancer) Total
S178
No. of therapeutic successes/no. of cases (%) 6/9 (66.7) 1/4 (25.0) 4/5 (80.0)
0/2
2/3 (66.7)
13/23 (56.5)
Downloaded from http://jid.oxfordjournals.org/ at University of Iowa Libraries/Serials Acquisitions on July 13, 2015
Twenty-three patients with acute peritonitis, intraabdominal abscess, wound infections (including infection of serious bums), sepsis accompanying renal transplantation, or urinary tract infection associated with cancer were treated with various dosage regimens of tobramycin, and their clinical responses were analyzed. For the conditions studied, the optimal regimen was 3 mg/kg per day in three divided doses. No clinical effectiveness was noted in this study for doses of ;;:::4 mg/kg per day.
Clinical Use of Tobramycin
S179
Results and Comments
Table 2. Bacteriological response to tobramycin of pathogens isolated from 23 patients with severe surgical infections.
Date
tobramycin Organism
(ug/rnl)
(%)
Pseudomonas aeruginosa Escherichia coli Enterobacter cloacae Klebsiella Citrobacter Proteus rettgeri
0.4-1.56
9/14 (64.3) 2/4(50.0) 2/3 (66.7) 2/2 (100) 2/2 (100) 0/1
8/X
Figure 1. Course of infection in a 58-year-old man (weight, 60 kg) with diffuse peritonitis after cholecystoduodenostomy for malignancy in the head of the pancreas. CBPC = carbenicillin-penicillin; CEZ = cefazolin; TOB = tobramycin; WBC white blood cells; Kleb. Klebsiella; Citro. Citrobacter; Ps. Pseudomonas; and Ent. cloacae Enterobacter cloacae.
= = = =
CEZ
9
11
10
12
13
1 gX 2
16
17
18
19
38
37
~
pus
~ Kleb., Citro. ,Ps.
Date
Ent . cI oacae
6600
W.B.C.
11/X
12
13
14
TOB
c
=
15
40 mg X 3
39
Kleb ., Citro.
=
14
TOB
=
Figure 2. Course of infection in a 63-year-old man (weight, 36 kg) with pyelonephritis complicated by recurrent rectal cancer. Escherichia coli was isolated from his urine. tobramycin; WBC white TOB blood cells.
0.8 1.56
Some patients failed to improve on a twice daily regimen of tobramycin but responded to three times daily administration. For example, in a 63-year-old man with pyelonephritis complicated by recurrent rectal cancer, 40 mg twice a day was not successful, but an increase in dosage to 40 mg three times a day resulted in prompt improvement (figure 2).
CB-PC5g X 2
C
No. susceptible/no. of isolates
MICof
6300
15
16
40 mg X 2
17
18
TOB
19
20
21
22
23
40 mg X 3
39
38
37 urine ( pyuria)
urine ( pyuria)
~
~ E. coli (-+*-) W.B.C.
5300
E. coli (+) 4400
urine ( clear)
20
Downloaded from http://jid.oxfordjournals.org/ at University of Iowa Libraries/Serials Acquisitions on July 13, 2015
The therapeutic outcome was successful in 13 (56.5%) of the 23 patients. The patients had serious infections that would have resulted in death had they not been treated. Fourteen strains of Pseudomonas were isolated as single organisms or in mixed cultures with other pathogens, and nine of the strains were eliminated after treatment. The rate of elimination was 64.3% (table 2). Forty milligrams of tobramycin three times daily was successful in some patients who had not responded to previous antibiotic therapy. The patient whose course is shown in figure 1 had diffuse peritonitis after cholecystoduodenostomy for malignancy in the head of the pancreas. Sulbenicillin, cefazolin, and 80 mg of tobramycin daily were all ineffective, whereas 120 mg of tobramycin daily was successful. The microorganisms isolated were Klebsiella, Citrobacter, and Pseudomonas.
Ishiyama et al.
8180
Date
6/1
C
CET
10
11
12
13
14
15
TOB
TOB 40 mg X 3
11
18
19
TOB
40 mg X3
39
16
38
pus
Diet (soup) -+
Drain
~
Kleb.
SOOT
~
E. coli
Staph . epid .
W.B.C. 10800 SGPT
~
drawn off
E. coli, Ps.
pus
urine
10800 79 70
75 53
33 24
Figure 3. Course of infection in a 67-year-old man (weight, 52 kg) with diffuse peritonitis due to leakage after gastrectomy for cancer. Escherichia coli and Pseudomonas (Ps.) were cultured from the abdominal discharge. CET = cephalothin; TOB = tobramycin; Kleb. = Klebsiella; Staph. epid. = Staphylococcus epidermidis; WBC white blood cells; SGOT aspartate aminotransferase; and SGPT alanine aminotransferase.
=
=
=
In some patients a reduction of the dosage resulted in therapeutic failure. Figure 3 shows the course in a 67-year-old man with diffuse peritonitis due to leakage after gastrectomy for cancer. Escherichia coli and Pseudomonas were cultured from the abdominal discharge. Administration of tobramycin three times a day succeeded at first, but when the number of injections was reduced to two a day, the patient's temperature rose again and Klebsiella and Staphylococcus epidermidis were cultured from his urine (figure 3). It is to be expected that patients will respond
differently to tobramycin depending on both the severity of the infections and the underlying disease. However, the dose and frequency of administration of the drug certainly affect the efficacy. The clinical response of 23 patients was
analyzed in terms of the total daily dose and the number of administrations per day (table 3). All of the patients who received the drug twice a day failed to show successful results, irrespective of whether 2 or 3 rug/kg was given per day. No clinical effectiveness was noted with ~4 mg/ kg per day in this study. Our findings suggest that im injection of 3 mg of tobramycin/kg in three divided doses per day is the optimal regimen for treatment of severe infections. We observed no remarkable side effects during the administration of tobramycin in doses of
• AUGUST 1976
Clinical Use of Tobramycin in Patients with Surgical Infections Due to Gram-Negative Bacilli From the Department of Surgery, Nihon University School of Medicine, Tokyo, Japan
S. Ishiyama, I. Nakayama, H. Iwamoto, S. Iwai,
I. Murata, and M. Ohashi
Chemotherapeutic regimens presently available in Japan for the treatment of pseudomonas infections are: (1) administration of a large dose of carbenicillin, sulbenicillin (disodium u-sulfobenzylpenicillin), or amikacin; (2) administration of a single dose of gentamicin, tobramycin, dibecacin (3',4'-diamino-3',4'-dideoxykanamycin B), or sisomicin; (3) administration of carbenicillin or sulbenicillin for maintenance therapy after shortterm treatment with one of the aminoglycosides mentioned above (occasionally, oral carfecillin [a-phenoxycarbonyl-benzylpenicillin] or indanylcarbenicillin can be substituted for maintenance therapy); and (4) concomitant chemotherapy with an aminoglycoside and one of the synthetic penicillins mentioned. In addition, use of antiOEP (original endotoxin protein) globulin or pipemidic acid in combination with these antibiotics is now being investigated. Tobramycin is a new aminoglycoside antibiotic which is highly active against both aerobic gramnegative and gram-positive bacteria. The shortcoming of this group of drugs is the possibility of side effects, namely, ototoxicity or nephrotoxicity. For this reason, serious investigation is needed to find a dosage regimen that will result in clinical efficacy with minimal side effects. Therefore, we investigated the clinical use of tobramycin in patients with severe surgical infections due to gramPlease address requests for reprints to Dr. S. ·Ishiyama, Department of Surgery, Nihon University School of Medicine, 8, l-chome, Kandasurugadai, Chiyodaku, Tokyo, Japan.
negative bacilli, particularly Pseudomonas aeruginasa. Materials and Methods
Twenty-three patients with various infections including acute peritonitis, intraabdominal abscess, wound infections (including infections of serious burns), sepsis accompanying renal transplantation, and urinary tract infections associated with cancer were treated with various doses of tobramycin. Their clinical responses are summarized in table 1. Clinical signs and symptoms such as temperature, leukocytosis, and purulent discharge and results of tests of clinical chemistry were checked as criteria of success of the treatment. The underlying diseases were considered as factors that influenced the results. Table 1. Clinical responses to tobramycin of 23 patients with severe infections due to gram-negative bacilli.
Type of infection Postoperative peritonitis Intraabdominal abscess Wound infection Sepsis (with renal transplantation or necrotizing pharyngeal sarcoma) Complicated urinary tract infection (with recurrent rectal cancer) Total
S178
No. of therapeutic successes/no. of cases (%) 6/9 (66.7) 1/4 (25.0) 4/5 (80.0)
0/2
2/3 (66.7)
13/23 (56.5)
Downloaded from http://jid.oxfordjournals.org/ at University of Iowa Libraries/Serials Acquisitions on July 13, 2015
Twenty-three patients with acute peritonitis, intraabdominal abscess, wound infections (including infection of serious bums), sepsis accompanying renal transplantation, or urinary tract infection associated with cancer were treated with various dosage regimens of tobramycin, and their clinical responses were analyzed. For the conditions studied, the optimal regimen was 3 mg/kg per day in three divided doses. No clinical effectiveness was noted in this study for doses of ;;:::4 mg/kg per day.
Clinical Use of Tobramycin
S179
Results and Comments
Table 2. Bacteriological response to tobramycin of pathogens isolated from 23 patients with severe surgical infections.
Date
tobramycin Organism
(ug/rnl)
(%)
Pseudomonas aeruginosa Escherichia coli Enterobacter cloacae Klebsiella Citrobacter Proteus rettgeri
0.4-1.56
9/14 (64.3) 2/4(50.0) 2/3 (66.7) 2/2 (100) 2/2 (100) 0/1
8/X
Figure 1. Course of infection in a 58-year-old man (weight, 60 kg) with diffuse peritonitis after cholecystoduodenostomy for malignancy in the head of the pancreas. CBPC = carbenicillin-penicillin; CEZ = cefazolin; TOB = tobramycin; WBC white blood cells; Kleb. Klebsiella; Citro. Citrobacter; Ps. Pseudomonas; and Ent. cloacae Enterobacter cloacae.
= = = =
CEZ
9
11
10
12
13
1 gX 2
16
17
18
19
38
37
~
pus
~ Kleb., Citro. ,Ps.
Date
Ent . cI oacae
6600
W.B.C.
11/X
12
13
14
TOB
c
=
15
40 mg X 3
39
Kleb ., Citro.
=
14
TOB
=
Figure 2. Course of infection in a 63-year-old man (weight, 36 kg) with pyelonephritis complicated by recurrent rectal cancer. Escherichia coli was isolated from his urine. tobramycin; WBC white TOB blood cells.
0.8 1.56
Some patients failed to improve on a twice daily regimen of tobramycin but responded to three times daily administration. For example, in a 63-year-old man with pyelonephritis complicated by recurrent rectal cancer, 40 mg twice a day was not successful, but an increase in dosage to 40 mg three times a day resulted in prompt improvement (figure 2).
CB-PC5g X 2
C
No. susceptible/no. of isolates
MICof
6300
15
16
40 mg X 2
17
18
TOB
19
20
21
22
23
40 mg X 3
39
38
37 urine ( pyuria)
urine ( pyuria)
~
~ E. coli (-+*-) W.B.C.
5300
E. coli (+) 4400
urine ( clear)
20
Downloaded from http://jid.oxfordjournals.org/ at University of Iowa Libraries/Serials Acquisitions on July 13, 2015
The therapeutic outcome was successful in 13 (56.5%) of the 23 patients. The patients had serious infections that would have resulted in death had they not been treated. Fourteen strains of Pseudomonas were isolated as single organisms or in mixed cultures with other pathogens, and nine of the strains were eliminated after treatment. The rate of elimination was 64.3% (table 2). Forty milligrams of tobramycin three times daily was successful in some patients who had not responded to previous antibiotic therapy. The patient whose course is shown in figure 1 had diffuse peritonitis after cholecystoduodenostomy for malignancy in the head of the pancreas. Sulbenicillin, cefazolin, and 80 mg of tobramycin daily were all ineffective, whereas 120 mg of tobramycin daily was successful. The microorganisms isolated were Klebsiella, Citrobacter, and Pseudomonas.
Ishiyama et al.
8180
Date
6/1
C
CET
10
11
12
13
14
15
TOB
TOB 40 mg X 3
11
18
19
TOB
40 mg X3
39
16
38
pus
Diet (soup) -+
Drain
~
Kleb.
SOOT
~
E. coli
Staph . epid .
W.B.C. 10800 SGPT
~
drawn off
E. coli, Ps.
pus
urine
10800 79 70
75 53
33 24
Figure 3. Course of infection in a 67-year-old man (weight, 52 kg) with diffuse peritonitis due to leakage after gastrectomy for cancer. Escherichia coli and Pseudomonas (Ps.) were cultured from the abdominal discharge. CET = cephalothin; TOB = tobramycin; Kleb. = Klebsiella; Staph. epid. = Staphylococcus epidermidis; WBC white blood cells; SGOT aspartate aminotransferase; and SGPT alanine aminotransferase.
=
=
=
In some patients a reduction of the dosage resulted in therapeutic failure. Figure 3 shows the course in a 67-year-old man with diffuse peritonitis due to leakage after gastrectomy for cancer. Escherichia coli and Pseudomonas were cultured from the abdominal discharge. Administration of tobramycin three times a day succeeded at first, but when the number of injections was reduced to two a day, the patient's temperature rose again and Klebsiella and Staphylococcus epidermidis were cultured from his urine (figure 3). It is to be expected that patients will respond
differently to tobramycin depending on both the severity of the infections and the underlying disease. However, the dose and frequency of administration of the drug certainly affect the efficacy. The clinical response of 23 patients was
analyzed in terms of the total daily dose and the number of administrations per day (table 3). All of the patients who received the drug twice a day failed to show successful results, irrespective of whether 2 or 3 rug/kg was given per day. No clinical effectiveness was noted with ~4 mg/ kg per day in this study. Our findings suggest that im injection of 3 mg of tobramycin/kg in three divided doses per day is the optimal regimen for treatment of severe infections. We observed no remarkable side effects during the administration of tobramycin in doses of
