THE JOURNAL OF INFECTIOUS DISEASES • VOL. 134, SUPPLEMENT © 1976 by the University of Chicago. All rights reserved.
•
AUGUST 1976
PHARMACOLOGY AND TOXICITY Aspects of the Pharmacology and Toxicology of Tobramycin in Animals and Humans K. S. Israel, J. S. Welles, and H. R. Black
From the Division of Infectious Diseases, Department of Medicine, Indiana University School of Medicine; and the Lilly Laboratory for Clinical Research, Wishard Memorial Hospital, Indianapolis, Indiana
Tobramycin, a new, stable, water-soluble aminoglycoside antibiotic, is derived from nebramycin, an antibiotic complex of eight chemically related compounds produced by Streptomyces tenebrarius. Tobramycin (factor 6) demonstrated a greater in vitro antibacterial activity, particularly with respect to Pseudomonas, than did any of the other factors [1, 2]. Generally, the clinical pharmacology of tobramycin is similar to that of gentamicin when the drugs are given im or iv [3-5]. Both aminoglycosides are excreted primarily by the kidney and undergo no detectable metabolic change. Both are excreted to a minimal extent in bile and are retained in patients with renal failure. In some studies with animals, tobramycin exhibited a lesser nephrotoxic potential than did gentamicin. Tobramycin also appears to be less toxic than gentamicin to the function of the eighth cranial nerve of guinea pigs and cats.
The pharmacokinetics of tobramycin in normal human volunteers and in adult and pediatric patients with normal or abnormal renal function has been studied by many clinical investigators. In addition, a number of studies with various animal models have described the toxicologic and pharmacologic effects of tobramycin on the eighthcranial-nerve function, the eye, kidney, and central nervous system. This paper reviews published literature and presents some unpublished data from studies at the Lilly Research Laboratories (Indianapolis, Ind.). Studies in Animals
Toxicology. The toxicologic characteristics of tobramycin were found to be similar to those reported for the other aminoglycosides. In comparative toxicology studies in animals, tobramycin demonstrated a subtle but consistent advantage over gentamicin [6]. Reparable nephrosis indicative of renal injury was observed in rats given daily sc doses of 15 mg/kg for 30 days. Fourteen of 20 rats given
Please address requests for reprints to Dr. H. R. Black, Lilly Laboratory for Clinical Research, Wishard Memorial Hospital, Indianapolis, Indiana 46202.
597
Downloaded from http://jid.oxfordjournals.org/ at Cambridge University on August 10, 2015
The pharmacology and toxicology of tobramycin in animals and humans are reviewed. After intramuscular and intravenous administration, tobramycin diffuses throughout most body tissues and tissue fluids. Therapeutic concentrations can be obtained by intravitreal or intradural injections. Dogs tolerate intracisternal doses of 0.2 mg/kg without adverse reaction. The half-life of tobramycin in cochlear fluid of guinea pigs and in renal tissues of rats is significantly longer than the serum half-life in these species and is reflected in the ototoxic and nephrotoxic potential of tobramycin and other aminoglycosides. In man, the serum half-life of tobramycin is 2 hr; renal clearance, apparent volume of distribution, and recovery from urine are similar to those parameters for gentamicin. The serum halflife in neonates is prolonged (4.5-8.7 hr). Concentrations of tobramycin in serum are effectively reduced by hemodialysis, but peritoneal dialysis is less efficient in elimination of the antibiotic. Tobramycin crosses the placenta and is concentrated in the kidney and urine of the fetus.
S98
Table 1.
Concentrations of 14C-tobramycin in rat tissues after sc doses of 100 mg of tobramycin/kg. Concentration at indicated hr after dose Body site
0.5
1
2
4
8
Whole blood Serum Pancreas Adrenals Ovaries Thymus Kidneys Liver Spleen Lungs Gluteal fat Stomach Small intestine Diaphragm Heart Gluteal muscle Brain Bone without marrow Urine (accumulation)
75* 136 33 83 158 18 486 25 23 71 50 43 33 58 47 27 3
55 128 18 36 50 14 466 19 21 52 46 40 31 33 36
23 40
4
0.4 0.8
5
7 2
9 4 9 8 3 242 7 6 9 5 6 5 5 5 1 1
78
105
42
12
965
2,136
6,970
11
21 36 8
271 9 10 26 17 16 13
18 13
11
0
0 0 0
257 6 7 6 0
0 0 0 0
0 0 6
5,646 10,799
* Concentrations in tissues and in blood and blood serum are expressed as equivalent /-tg/g and ug/rnl, respectively. Values represent the mean of three determinations. tobramycin in the cochlear lymph of guinea pigs 2 hr after single sc doses of 50, 100, and 150 mg/kg were 7, 19, and 68 ug/ml, respectively. After a single sc dose of 250 rug/kg, the level was constant throughout the first 6-hr period. A slow decline occurred over the next 6 hr, and relatively constant levels were noted from 12 to 24 hr (table 2). The t 1h of tobramycin in the inner ear fluid was 14.7 ± 2.4 hr and that in the blood was 1.4 ± 0.1 hr. Although there was no evidence of antibiotic accumulation in the blood during the 10-day study, the concentrations in the cochlear Table 2.
Concentrations of tobramycin in serum and cochlear lymph of guinea pigs after 250-mg dose given sc. Concentrations (ug/rnl) at indicated hr after dose Fluid
Serum Cochlear lymph
1
2
587 286 34
33
6
12
18
24
48
57
1
2
1
0.2
33
11
11
9
4
Downloaded from http://jid.oxfordjournals.org/ at Cambridge University on August 10, 2015
tobramycin and 18 of 20 rats given gentamicin were found to have regenerating epithelium. Such changes were not observed in any of 20 rats given 7.5 mg of tobramycin/kg daily for 30 days, whereas two of 20 rats given a similar dose of gentamicin showed reparable nephrosis. A similar relation of the nephrotoxic potential of the two antibiotics in rats was noted by Patel et al. [7], who used urinary excretion of certain enzymes as a measure of renal injury. Differences in renal tissue tyz for tobramycin (74 hr) and gentamicin (109 hr) noted by Luft and Kleit [8] may account for the small but consistent differences in toxicologic effects of these two similar compounds in rats. The toxicity of tobramycin to the central nervous system was studied in mice, rats, and dogs. The intracerebral LD50 for mice was 29.4 ± 1.6 rug/kg, and the intracisternal LD50 for rats was 17.7 ± 6.6 mg/kg. An intracisternal dose of 5 mg of tobramycin/kg was lethal to one of three dogs and caused paralysis in another; however, an intracisternal dose of 0.2 mg/kg caused no adverse effect. These data reflect species differences. However, as is the case with other antibiotics, such as penicillin, the data indicate a smaller margin of safety in the direct administration of tobramycin into the central nervous system than by other routes. Distribution in body fluids and tissues. Tissue levels of 14e-Iabeled tobramycin in rats are shown in table 1. The drug penetrated into all tissues examined, but levels in brain tissue were of little significance. Pennington and Reynolds [9] studied the penetration of tobramycin into bronchial secretions of dogs after iv doses of 1.7 mg/kg. The antibiotic was detected as early as 5 min after administration and at 2 hr it reached a peak that was approximately 10% of that observed in serum. Tissue fluid concentrations have been measured with a dog model [10]. In this study, tobramycin appeared in tissue fluid at a slower rate than in serum and disappeared slowly over a 24-hr period. Peak concentration in the tissue fluid was about 10% of that observed in serum. When tobramycin was administered every 12 hr, trough levels in tissue fluid exceeded those in serum. In a study at the Lilly toxicology laboratories (Indianapolis, Indiana) , the concentrations of
Israel, Welles, and Black
599
Pharmacology and Toxicology of Tobramycin
Studies in Humans
Serum concentrations. After single im doses of tobramycin, concentrations in serum peaked at 0.5-1 hr in adult patients or normal volunteers with normal renal function [16-18]. In a study by Black and Griffith [16], single im doses of 1 mg/ kg in five male volunteers produced a peak mean concentration of 4.86 ug/ml in serum 0.5-1 hr after administration. Mean serum concentrations of ~ 1 ug/rnl were observed at 8 hr. In early studies reported by Black and Griffith [3] and by Meyers et al. [19], slightly higher concentrations of gentamicin than of tobramycin were noted in serum after single im injections of 50 and 75 mg. In a study by Regamey et al. [4], comparable concentrations in blood were obtained when dosages of both antibiotics were equivalent. To assess further the disparity between serum concentrations of tobramycin and gentamicin reported by other investigators, a cooperative study was conducted by Drs. George Arcieri, Allan Waitz, and Marvin Weinstein of Schering Corp. (Bloomfield, N.J.) and by Dr. H. R. Black of the Lilly Research Laboratories. Each of ten healthy male volunteers were given 1 mg of gentamicin and 1 mg of tobramycin/kg im in a cross-over study conducted separately by each company. Sera from all 20 subjects were assayed for gentamicin and tobramycin by both laboratories. A minimal variance in the serum concentrations of the antibiotics, thought to be caused by variability in the assay, was observed. It was concluded that there was no statistically significant difference between the mean serum concentrations obtained after equivalent doses of the two antibiotics (figure 1). Studies by Black and Griffith (unpublished data) showed that multiple doses of tobramycin administered im every 8 hr for four days (~6.3 rug/kg per day) or for 10 days (~4.2 mg/kg per day) were tolerated well, without accumulation in serum, by healthy male volunteers. Mean peak concentrations in serum after multiple im doses given at 8-hr intervals were comparable to those obtained after a single dose in subjects with normal renal function. Doses of 2 mg of tobramyciri/kg given im to neonates every 12 hr (total, 16 doses) produced satisfactory levels in serum without accumulation
Downloaded from http://jid.oxfordjournals.org/ at Cambridge University on August 10, 2015
fluid after five daily doses were greater than those found after a single dose. The ototoxic potential of tobramycin in experimental animals was expected and observed by Welles et al. [6] and was further defined by Brummett et al. [11, 12] and Federspil [13]. In all of these studies, tobramycin was found less ototoxic than gentamicin. Experimental routes of administration. Several studies in animals on the penetration of tobramycin into ocular fluids and the irritative potential to eye tissues have been published. At concentrations of 3 %, topically applied ophthalmic solutions of tobramycin were not irritating to eyes of rabbits; however, there was no apparent penetration into ocular fluids [14]. Bennett and Peyman [15] demonstrated therapeutic concentrations without histologic evidence of ocular damage after intravitreal injections of 500 ~g (0.5% solution, O.I-ml dose) into the eyes of rabbits. These workers treated experimental pseudomonas endophthalmitis in rabbits and reported excellent results if therapy was initiated 7 hr after infection, but less satisfactory results when therapy was delayed for 10 hr. They found intravitreal administration, but not systemic and subconjunctival injections, to be adequate therapy for this type of experimental infection. Tobramycin was also introduced directly, by aerosolization, into the tracheobronchial tree of seven-day-old Harlan rats. The animals were exposed to an aqueous mist of a 5 % solution of tobramycin for 1 hr daily, five days per week for three weeks. The mist was generated by a DeVilbiss nebulizer (DeVilbiss, Somerset, Pa.) and contained particles ranging from 3 to 10 urn in diameter. The tobramycin solution gave an atmospheric concentration of 2.5 mg of the drug/liter. Necropsy revealed no evidence of tissue injury. In another experiment concentrations of tobramycin in blood were determined in rats (125150 g) after exposure for 1 hr to a 5 % tobramycin aerosol as described above. A mean peak concentration of 2.3 ug/rnl occurred in serum 2 hr after exposure. At 9 hr, the concentration of antibiotic in serum had diminished to 0.05 ug/ml. No tobramycin was detected at 14 hr. Serum concentrations (ug/rnl) of drug at other intervals tested were as follows: 30 min, 1.6; 1 hr, 2.1; 4 hr, 1.5; and 6 hr, 0.12.
S100
Israel, Welles, and Black
5.50 .......... Lilly Assay - Gentamicin
5.00
... ~
~...._
4.50
- - - Schering Assay - Tabramycin
•
AUGUST 1976
PHARMACOLOGY AND TOXICITY Aspects of the Pharmacology and Toxicology of Tobramycin in Animals and Humans K. S. Israel, J. S. Welles, and H. R. Black
From the Division of Infectious Diseases, Department of Medicine, Indiana University School of Medicine; and the Lilly Laboratory for Clinical Research, Wishard Memorial Hospital, Indianapolis, Indiana
Tobramycin, a new, stable, water-soluble aminoglycoside antibiotic, is derived from nebramycin, an antibiotic complex of eight chemically related compounds produced by Streptomyces tenebrarius. Tobramycin (factor 6) demonstrated a greater in vitro antibacterial activity, particularly with respect to Pseudomonas, than did any of the other factors [1, 2]. Generally, the clinical pharmacology of tobramycin is similar to that of gentamicin when the drugs are given im or iv [3-5]. Both aminoglycosides are excreted primarily by the kidney and undergo no detectable metabolic change. Both are excreted to a minimal extent in bile and are retained in patients with renal failure. In some studies with animals, tobramycin exhibited a lesser nephrotoxic potential than did gentamicin. Tobramycin also appears to be less toxic than gentamicin to the function of the eighth cranial nerve of guinea pigs and cats.
The pharmacokinetics of tobramycin in normal human volunteers and in adult and pediatric patients with normal or abnormal renal function has been studied by many clinical investigators. In addition, a number of studies with various animal models have described the toxicologic and pharmacologic effects of tobramycin on the eighthcranial-nerve function, the eye, kidney, and central nervous system. This paper reviews published literature and presents some unpublished data from studies at the Lilly Research Laboratories (Indianapolis, Ind.). Studies in Animals
Toxicology. The toxicologic characteristics of tobramycin were found to be similar to those reported for the other aminoglycosides. In comparative toxicology studies in animals, tobramycin demonstrated a subtle but consistent advantage over gentamicin [6]. Reparable nephrosis indicative of renal injury was observed in rats given daily sc doses of 15 mg/kg for 30 days. Fourteen of 20 rats given
Please address requests for reprints to Dr. H. R. Black, Lilly Laboratory for Clinical Research, Wishard Memorial Hospital, Indianapolis, Indiana 46202.
597
Downloaded from http://jid.oxfordjournals.org/ at Cambridge University on August 10, 2015
The pharmacology and toxicology of tobramycin in animals and humans are reviewed. After intramuscular and intravenous administration, tobramycin diffuses throughout most body tissues and tissue fluids. Therapeutic concentrations can be obtained by intravitreal or intradural injections. Dogs tolerate intracisternal doses of 0.2 mg/kg without adverse reaction. The half-life of tobramycin in cochlear fluid of guinea pigs and in renal tissues of rats is significantly longer than the serum half-life in these species and is reflected in the ototoxic and nephrotoxic potential of tobramycin and other aminoglycosides. In man, the serum half-life of tobramycin is 2 hr; renal clearance, apparent volume of distribution, and recovery from urine are similar to those parameters for gentamicin. The serum halflife in neonates is prolonged (4.5-8.7 hr). Concentrations of tobramycin in serum are effectively reduced by hemodialysis, but peritoneal dialysis is less efficient in elimination of the antibiotic. Tobramycin crosses the placenta and is concentrated in the kidney and urine of the fetus.
S98
Table 1.
Concentrations of 14C-tobramycin in rat tissues after sc doses of 100 mg of tobramycin/kg. Concentration at indicated hr after dose Body site
0.5
1
2
4
8
Whole blood Serum Pancreas Adrenals Ovaries Thymus Kidneys Liver Spleen Lungs Gluteal fat Stomach Small intestine Diaphragm Heart Gluteal muscle Brain Bone without marrow Urine (accumulation)
75* 136 33 83 158 18 486 25 23 71 50 43 33 58 47 27 3
55 128 18 36 50 14 466 19 21 52 46 40 31 33 36
23 40
4
0.4 0.8
5
7 2
9 4 9 8 3 242 7 6 9 5 6 5 5 5 1 1
78
105
42
12
965
2,136
6,970
11
21 36 8
271 9 10 26 17 16 13
18 13
11
0
0 0 0
257 6 7 6 0
0 0 0 0
0 0 6
5,646 10,799
* Concentrations in tissues and in blood and blood serum are expressed as equivalent /-tg/g and ug/rnl, respectively. Values represent the mean of three determinations. tobramycin in the cochlear lymph of guinea pigs 2 hr after single sc doses of 50, 100, and 150 mg/kg were 7, 19, and 68 ug/ml, respectively. After a single sc dose of 250 rug/kg, the level was constant throughout the first 6-hr period. A slow decline occurred over the next 6 hr, and relatively constant levels were noted from 12 to 24 hr (table 2). The t 1h of tobramycin in the inner ear fluid was 14.7 ± 2.4 hr and that in the blood was 1.4 ± 0.1 hr. Although there was no evidence of antibiotic accumulation in the blood during the 10-day study, the concentrations in the cochlear Table 2.
Concentrations of tobramycin in serum and cochlear lymph of guinea pigs after 250-mg dose given sc. Concentrations (ug/rnl) at indicated hr after dose Fluid
Serum Cochlear lymph
1
2
587 286 34
33
6
12
18
24
48
57
1
2
1
0.2
33
11
11
9
4
Downloaded from http://jid.oxfordjournals.org/ at Cambridge University on August 10, 2015
tobramycin and 18 of 20 rats given gentamicin were found to have regenerating epithelium. Such changes were not observed in any of 20 rats given 7.5 mg of tobramycin/kg daily for 30 days, whereas two of 20 rats given a similar dose of gentamicin showed reparable nephrosis. A similar relation of the nephrotoxic potential of the two antibiotics in rats was noted by Patel et al. [7], who used urinary excretion of certain enzymes as a measure of renal injury. Differences in renal tissue tyz for tobramycin (74 hr) and gentamicin (109 hr) noted by Luft and Kleit [8] may account for the small but consistent differences in toxicologic effects of these two similar compounds in rats. The toxicity of tobramycin to the central nervous system was studied in mice, rats, and dogs. The intracerebral LD50 for mice was 29.4 ± 1.6 rug/kg, and the intracisternal LD50 for rats was 17.7 ± 6.6 mg/kg. An intracisternal dose of 5 mg of tobramycin/kg was lethal to one of three dogs and caused paralysis in another; however, an intracisternal dose of 0.2 mg/kg caused no adverse effect. These data reflect species differences. However, as is the case with other antibiotics, such as penicillin, the data indicate a smaller margin of safety in the direct administration of tobramycin into the central nervous system than by other routes. Distribution in body fluids and tissues. Tissue levels of 14e-Iabeled tobramycin in rats are shown in table 1. The drug penetrated into all tissues examined, but levels in brain tissue were of little significance. Pennington and Reynolds [9] studied the penetration of tobramycin into bronchial secretions of dogs after iv doses of 1.7 mg/kg. The antibiotic was detected as early as 5 min after administration and at 2 hr it reached a peak that was approximately 10% of that observed in serum. Tissue fluid concentrations have been measured with a dog model [10]. In this study, tobramycin appeared in tissue fluid at a slower rate than in serum and disappeared slowly over a 24-hr period. Peak concentration in the tissue fluid was about 10% of that observed in serum. When tobramycin was administered every 12 hr, trough levels in tissue fluid exceeded those in serum. In a study at the Lilly toxicology laboratories (Indianapolis, Indiana) , the concentrations of
Israel, Welles, and Black
599
Pharmacology and Toxicology of Tobramycin
Studies in Humans
Serum concentrations. After single im doses of tobramycin, concentrations in serum peaked at 0.5-1 hr in adult patients or normal volunteers with normal renal function [16-18]. In a study by Black and Griffith [16], single im doses of 1 mg/ kg in five male volunteers produced a peak mean concentration of 4.86 ug/ml in serum 0.5-1 hr after administration. Mean serum concentrations of ~ 1 ug/rnl were observed at 8 hr. In early studies reported by Black and Griffith [3] and by Meyers et al. [19], slightly higher concentrations of gentamicin than of tobramycin were noted in serum after single im injections of 50 and 75 mg. In a study by Regamey et al. [4], comparable concentrations in blood were obtained when dosages of both antibiotics were equivalent. To assess further the disparity between serum concentrations of tobramycin and gentamicin reported by other investigators, a cooperative study was conducted by Drs. George Arcieri, Allan Waitz, and Marvin Weinstein of Schering Corp. (Bloomfield, N.J.) and by Dr. H. R. Black of the Lilly Research Laboratories. Each of ten healthy male volunteers were given 1 mg of gentamicin and 1 mg of tobramycin/kg im in a cross-over study conducted separately by each company. Sera from all 20 subjects were assayed for gentamicin and tobramycin by both laboratories. A minimal variance in the serum concentrations of the antibiotics, thought to be caused by variability in the assay, was observed. It was concluded that there was no statistically significant difference between the mean serum concentrations obtained after equivalent doses of the two antibiotics (figure 1). Studies by Black and Griffith (unpublished data) showed that multiple doses of tobramycin administered im every 8 hr for four days (~6.3 rug/kg per day) or for 10 days (~4.2 mg/kg per day) were tolerated well, without accumulation in serum, by healthy male volunteers. Mean peak concentrations in serum after multiple im doses given at 8-hr intervals were comparable to those obtained after a single dose in subjects with normal renal function. Doses of 2 mg of tobramyciri/kg given im to neonates every 12 hr (total, 16 doses) produced satisfactory levels in serum without accumulation
Downloaded from http://jid.oxfordjournals.org/ at Cambridge University on August 10, 2015
fluid after five daily doses were greater than those found after a single dose. The ototoxic potential of tobramycin in experimental animals was expected and observed by Welles et al. [6] and was further defined by Brummett et al. [11, 12] and Federspil [13]. In all of these studies, tobramycin was found less ototoxic than gentamicin. Experimental routes of administration. Several studies in animals on the penetration of tobramycin into ocular fluids and the irritative potential to eye tissues have been published. At concentrations of 3 %, topically applied ophthalmic solutions of tobramycin were not irritating to eyes of rabbits; however, there was no apparent penetration into ocular fluids [14]. Bennett and Peyman [15] demonstrated therapeutic concentrations without histologic evidence of ocular damage after intravitreal injections of 500 ~g (0.5% solution, O.I-ml dose) into the eyes of rabbits. These workers treated experimental pseudomonas endophthalmitis in rabbits and reported excellent results if therapy was initiated 7 hr after infection, but less satisfactory results when therapy was delayed for 10 hr. They found intravitreal administration, but not systemic and subconjunctival injections, to be adequate therapy for this type of experimental infection. Tobramycin was also introduced directly, by aerosolization, into the tracheobronchial tree of seven-day-old Harlan rats. The animals were exposed to an aqueous mist of a 5 % solution of tobramycin for 1 hr daily, five days per week for three weeks. The mist was generated by a DeVilbiss nebulizer (DeVilbiss, Somerset, Pa.) and contained particles ranging from 3 to 10 urn in diameter. The tobramycin solution gave an atmospheric concentration of 2.5 mg of the drug/liter. Necropsy revealed no evidence of tissue injury. In another experiment concentrations of tobramycin in blood were determined in rats (125150 g) after exposure for 1 hr to a 5 % tobramycin aerosol as described above. A mean peak concentration of 2.3 ug/rnl occurred in serum 2 hr after exposure. At 9 hr, the concentration of antibiotic in serum had diminished to 0.05 ug/ml. No tobramycin was detected at 14 hr. Serum concentrations (ug/rnl) of drug at other intervals tested were as follows: 30 min, 1.6; 1 hr, 2.1; 4 hr, 1.5; and 6 hr, 0.12.
S100
Israel, Welles, and Black
5.50 .......... Lilly Assay - Gentamicin
5.00
... ~
~...._
4.50
- - - Schering Assay - Tabramycin
