Chemotherapy 1990;36:251-253
© 1990 S. Karger AG, Basel 0009-3157/90/0364-0251 $ 2.75/0
Penetration of Aminoglycosides into Human Peritoneal Tissue Francis Serourd, Michael Danb, Alfred Goreac, Adi Gilad\ Maier Krispina , Stephen A. Bergerc “Department of Surgery A and b Infectious Diseases Unit, The E. Wolfson Medical Center, Holon; c Department of Microbiology, Tel Aviv Medical Center, Tel Aviv, Israel
Key Words. Aminoglycoside metabolism • Peritoneum • Peritonitis Abstract. Each of 30 patients underwent elective laparotomy following administra tion of a single intravenous dose of amikacin, netilmicin or tobramycin. Therapeutic concentrations of amikacin were achieved in peritoneal tissue in 10/10 patients. Only 13/20 samples from patients receiving the other two antibiotics showed antibacterial ac tivity. Our data suggest that the penetrability of tobramycin (53%) and amikacin (39%) into the uninflamed peritoneal tissue is superior to that of netilmicin (16%).
Despite the development of new anti microbial agents, aminoglycosides contin ue to play a major role in the treatment of gram-negative bacillary infections, includ ing those localized in the abdomen. Be cause of their narrow therapeutic ratio, it is important to document the penetrability of aminoglycosides into sites of infection such as the peritoneum. While the penetration of antibiotics into the peritoneal fluid has been exten sively studied [1], no data are available concerning the concentrations in the peri toneal tissue. This has prompted us to in vestigate the penetration of amikacin, net ilmicin and tobramycin into the peritoneal tissue of patients undergoing elective lapa rotomy.
Material and Methods Thirty adult patients ( 13 females, 17 males) sched uled for elective laparotomy were studied. Serum creatinine concentrations were normal in all in stances, and none had received antimicrobial agents in the preceding 72 h. None of the patients had a clin ical or operative evidence of peritoneal infection. On the morning of surgery, each subject randomizedly received a single dose of either amikacin (7.5 mg/kg), netilmicin (2.0 mg/kg) or tobramycin (1.0 mg/kg) by intravenous infusion over 30 min. Upon entering the abdominal cavity, tissue was ex cised from the noninflamed peritoneum and rinsed in nonbacteriostatic saline. A concomitant blood sample was obtained, and the elapsed time since drug administration was noted. Serum was separated from blood by centrifugation. All the specimens were frozen and stored at -70°C until the time of the bio assay. Tissue samples were homogenized in a microhomogenizer with antibiotic-free pooled human serum. All the specimens were assayed for amikacin, netilmicin and tobramycin activity by a standard bio-
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Introduction
252
Serour/Dan/Gorea/Gilad/Krispin/Berger Table 1. Patient characteristics (mean ± SE)
Amikacin Netilmicin Tobramycin
Age years
Sex m /f
Weight kg
Time of tissue sample, min
51.6 ±6.8 53.4 ±7.3 60.8 ±3.6
6/4 4/6 7/3
66 ±5.8 79 ±3.9 72 ± 2.9
260 ±28 300 ±28 270 ± 15
Table 2. Penetration of amikacin, netilmicin and tobramycin into human peritoneal tissue
Amikacin Netilmicin Tobramycin '
Number of samples with antibiotic activity
Tissue concentration1 mg/ml
Percent of concurrent serum level
10/10 5/10 7/10
2.49 ± 0.43 1.03 ±0.21 0.5 ±0.2
39 16.5 53
Samples with measurable antibiotic activity (means ± SE).
assay with 6-mm paper disks (Difco Laboratories, Detroit, Mich., USA) and Iso-Sensitest agar (pH 7.1-7.2; Oxoid, London, UK), using Proteus mirabilis as the test organism. A single individual performed all laboratory studies using identical technique and reagents. Plates were examined after overnight incu bation at 36 °C. Standard curves for serum and peri toneal tissue assays were prepared in quadruplicate, each with five antibiotic concentrations. In all in stances, control curves were identical and exhibited coefficients of variation of ¿5.0% at minimal and maximal concentration.
tibiotics were detected in 13 of 20 spe cimens. When detectable tissue levels were documented, the penetrability (peri toneal tissue concentration/concomitant serum concentration x 100) of tobramy cin exceeded that of the other drugs. No relationship was noted between tissue concentration and time after drug admin istration.
Discussion
Demographic data are summarized in table 1. Cholecystectomy, colectomy and gastrectomy accounted for the majority of operative procedures in each group. Con centrations in peritoneal tissue are shown in table 2. Whereas therapeutic concentra tions of amikacin were present in all 10 specimens submitted, the remaining an
Although Shear et al. [2] investigated the peritoneal transport of antibiotics in man over 20 years ago, subsequent investi gations deal primarily with the concentra tion of these drugs in peritoneal fluid only [1]. Data on the peritoneal fluid penetra tion of antibiotics in the absence of in flammation or hepatorenal disease are sparse; indeed, the relevant literature is
Downloaded by: Kings's College London 137.73.144.138 - 10/21/2017 12:37:22 PM
Results
Penetration of Aminoglycosides into Human Peritoneal Tissue
References 1 Wittman DH, Schassan HH: Penetration of eight ß-lactam antibiotics in the peritoneal fluid. A pharmacokinetic investigation. Arch Surg 1983; 118:205-213. 2 Shear L, Shinsberger JH, Barry KG: Peritoneal transport of antibiotics in man. N Engl J Med 1965;272:666-669. 3 Wittman DH, Schassan HH: Distribution of moxaiactam in serum bone tissue fluid and peri toneal fluid. Rev Infect Dis 1982;4(suppl):610616. 4 Wittman DH, Schassan HH, Kohler F, et al: Pharmacokinetics studies of ceftazidime in serum bone bile tissue fluid and peritoneal fluid. J Antimicrob Chemother 1981 ;8(suppl B):293-297. 5 Berger SA, Dan M, Serour F, Gorea A, Levenberg A, Krispin M: Penetration of third-genera tion cephalosporins into human peritoneal tissue. Chemotherapy 1989;35:326-329. 6 Moore RD, Smith CR, Lietmen PS: Association of aminoglycosides plasma levels with therapeut ic outcome in gram-negative pneumonia. Am J Med 1984;77:660-662. 7 Kaiser AB: Antimicrobial prophylaxis in surgery. N Engl J Med 1986;315:1129-1138.
Dr. M. Dan The E. Wolfson Medical Center Holon 58100 (Israel)
Downloaded by: Kings's College London 137.73.144.138 - 10/21/2017 12:37:22 PM
limited to the analysis of postoperative peritoneal fluid drainage following admin istration of a number of (3-lactam agents [1, 3, 4], Recently, we have studied the penetration of third-generation cephalo sporins into the uninflamed peritoneal tis sue and found that ceftriaxone achieved the highest tissue concentrations [5], Although aminoglycosides continue to be extensively used in the prevention and treatment of intra-abdominal infections, their concentration in the peritoneal fluid has not been adequately studied. More over, no data have been available on their penetrability into the peritoneal tissue. The clinical relevance of pharmacokinetic data, especially with compounds such as aminoglycosides, has been recently reem phasized [6]. The prophylactic use of antibiotics in elective laparotomy is controversial [7], If adequate local tissue levels are, in fact, relevant in abdominal surgery, our data suggest that tobramycin and amikacin may be superior to netilmicin for the pro phylaxis and treatment of peritonitis due to sensitive microorganisms.
253
© 1990 S. Karger AG, Basel 0009-3157/90/0364-0251 $ 2.75/0
Penetration of Aminoglycosides into Human Peritoneal Tissue Francis Serourd, Michael Danb, Alfred Goreac, Adi Gilad\ Maier Krispina , Stephen A. Bergerc “Department of Surgery A and b Infectious Diseases Unit, The E. Wolfson Medical Center, Holon; c Department of Microbiology, Tel Aviv Medical Center, Tel Aviv, Israel
Key Words. Aminoglycoside metabolism • Peritoneum • Peritonitis Abstract. Each of 30 patients underwent elective laparotomy following administra tion of a single intravenous dose of amikacin, netilmicin or tobramycin. Therapeutic concentrations of amikacin were achieved in peritoneal tissue in 10/10 patients. Only 13/20 samples from patients receiving the other two antibiotics showed antibacterial ac tivity. Our data suggest that the penetrability of tobramycin (53%) and amikacin (39%) into the uninflamed peritoneal tissue is superior to that of netilmicin (16%).
Despite the development of new anti microbial agents, aminoglycosides contin ue to play a major role in the treatment of gram-negative bacillary infections, includ ing those localized in the abdomen. Be cause of their narrow therapeutic ratio, it is important to document the penetrability of aminoglycosides into sites of infection such as the peritoneum. While the penetration of antibiotics into the peritoneal fluid has been exten sively studied [1], no data are available concerning the concentrations in the peri toneal tissue. This has prompted us to in vestigate the penetration of amikacin, net ilmicin and tobramycin into the peritoneal tissue of patients undergoing elective lapa rotomy.
Material and Methods Thirty adult patients ( 13 females, 17 males) sched uled for elective laparotomy were studied. Serum creatinine concentrations were normal in all in stances, and none had received antimicrobial agents in the preceding 72 h. None of the patients had a clin ical or operative evidence of peritoneal infection. On the morning of surgery, each subject randomizedly received a single dose of either amikacin (7.5 mg/kg), netilmicin (2.0 mg/kg) or tobramycin (1.0 mg/kg) by intravenous infusion over 30 min. Upon entering the abdominal cavity, tissue was ex cised from the noninflamed peritoneum and rinsed in nonbacteriostatic saline. A concomitant blood sample was obtained, and the elapsed time since drug administration was noted. Serum was separated from blood by centrifugation. All the specimens were frozen and stored at -70°C until the time of the bio assay. Tissue samples were homogenized in a microhomogenizer with antibiotic-free pooled human serum. All the specimens were assayed for amikacin, netilmicin and tobramycin activity by a standard bio-
Downloaded by: Kings's College London 137.73.144.138 - 10/21/2017 12:37:22 PM
Introduction
252
Serour/Dan/Gorea/Gilad/Krispin/Berger Table 1. Patient characteristics (mean ± SE)
Amikacin Netilmicin Tobramycin
Age years
Sex m /f
Weight kg
Time of tissue sample, min
51.6 ±6.8 53.4 ±7.3 60.8 ±3.6
6/4 4/6 7/3
66 ±5.8 79 ±3.9 72 ± 2.9
260 ±28 300 ±28 270 ± 15
Table 2. Penetration of amikacin, netilmicin and tobramycin into human peritoneal tissue
Amikacin Netilmicin Tobramycin '
Number of samples with antibiotic activity
Tissue concentration1 mg/ml
Percent of concurrent serum level
10/10 5/10 7/10
2.49 ± 0.43 1.03 ±0.21 0.5 ±0.2
39 16.5 53
Samples with measurable antibiotic activity (means ± SE).
assay with 6-mm paper disks (Difco Laboratories, Detroit, Mich., USA) and Iso-Sensitest agar (pH 7.1-7.2; Oxoid, London, UK), using Proteus mirabilis as the test organism. A single individual performed all laboratory studies using identical technique and reagents. Plates were examined after overnight incu bation at 36 °C. Standard curves for serum and peri toneal tissue assays were prepared in quadruplicate, each with five antibiotic concentrations. In all in stances, control curves were identical and exhibited coefficients of variation of ¿5.0% at minimal and maximal concentration.
tibiotics were detected in 13 of 20 spe cimens. When detectable tissue levels were documented, the penetrability (peri toneal tissue concentration/concomitant serum concentration x 100) of tobramy cin exceeded that of the other drugs. No relationship was noted between tissue concentration and time after drug admin istration.
Discussion
Demographic data are summarized in table 1. Cholecystectomy, colectomy and gastrectomy accounted for the majority of operative procedures in each group. Con centrations in peritoneal tissue are shown in table 2. Whereas therapeutic concentra tions of amikacin were present in all 10 specimens submitted, the remaining an
Although Shear et al. [2] investigated the peritoneal transport of antibiotics in man over 20 years ago, subsequent investi gations deal primarily with the concentra tion of these drugs in peritoneal fluid only [1]. Data on the peritoneal fluid penetra tion of antibiotics in the absence of in flammation or hepatorenal disease are sparse; indeed, the relevant literature is
Downloaded by: Kings's College London 137.73.144.138 - 10/21/2017 12:37:22 PM
Results
Penetration of Aminoglycosides into Human Peritoneal Tissue
References 1 Wittman DH, Schassan HH: Penetration of eight ß-lactam antibiotics in the peritoneal fluid. A pharmacokinetic investigation. Arch Surg 1983; 118:205-213. 2 Shear L, Shinsberger JH, Barry KG: Peritoneal transport of antibiotics in man. N Engl J Med 1965;272:666-669. 3 Wittman DH, Schassan HH: Distribution of moxaiactam in serum bone tissue fluid and peri toneal fluid. Rev Infect Dis 1982;4(suppl):610616. 4 Wittman DH, Schassan HH, Kohler F, et al: Pharmacokinetics studies of ceftazidime in serum bone bile tissue fluid and peritoneal fluid. J Antimicrob Chemother 1981 ;8(suppl B):293-297. 5 Berger SA, Dan M, Serour F, Gorea A, Levenberg A, Krispin M: Penetration of third-genera tion cephalosporins into human peritoneal tissue. Chemotherapy 1989;35:326-329. 6 Moore RD, Smith CR, Lietmen PS: Association of aminoglycosides plasma levels with therapeut ic outcome in gram-negative pneumonia. Am J Med 1984;77:660-662. 7 Kaiser AB: Antimicrobial prophylaxis in surgery. N Engl J Med 1986;315:1129-1138.
Dr. M. Dan The E. Wolfson Medical Center Holon 58100 (Israel)
Downloaded by: Kings's College London 137.73.144.138 - 10/21/2017 12:37:22 PM
limited to the analysis of postoperative peritoneal fluid drainage following admin istration of a number of (3-lactam agents [1, 3, 4], Recently, we have studied the penetration of third-generation cephalo sporins into the uninflamed peritoneal tis sue and found that ceftriaxone achieved the highest tissue concentrations [5], Although aminoglycosides continue to be extensively used in the prevention and treatment of intra-abdominal infections, their concentration in the peritoneal fluid has not been adequately studied. More over, no data have been available on their penetrability into the peritoneal tissue. The clinical relevance of pharmacokinetic data, especially with compounds such as aminoglycosides, has been recently reem phasized [6]. The prophylactic use of antibiotics in elective laparotomy is controversial [7], If adequate local tissue levels are, in fact, relevant in abdominal surgery, our data suggest that tobramycin and amikacin may be superior to netilmicin for the pro phylaxis and treatment of peritonitis due to sensitive microorganisms.
253
