SCIENTIFIC
COMPARISON
OF SERUM AND PROSTATIC
ARTICLES
LEVELS
OF TOBRAMYCIN*
CHARLES AUSTIN
B. WILLIAMS, S. LITVAK,
J. WILLIAM
M.D.
M.D.
McROBERTS,
M.D.
From the Department of Surgery, Division of Urology, University of Kentucky Medical Center, Lexington, Kentucky
- Tobramycin sulfate, an aminoglycoside antibiotic, has been shown to be effective in the treatment of complicated urinary tract infections. Because of this, a study was undertaken to determine the penetrance of tobramycin into the prostate gland. It was found that the drug is concentrated at inhibitory levels in the prostate gland after the routinely recommended administration and should be useful in the treatment of bacterial prostatic infection.
ABSTRACT
Tobramycin sulfate is an aminoglycoside antibiotic discovered by Stark, Hoehn, and Knox in 1967.l Clinical trials have shown the drug to be effective for the treatment of complicated urinary tract infections. 2,3 The drug has broadspectrum antibacterial activity, being especially effective against the gram-negative bacilli. Its recognized spectrum includes Staphylococcus aureus, Escherichia coli, Citrobacter, Klebsiella, Enterobacter, Proteus (indole-positive and -negative), Providencia, and Pseudomonas aeruginosa. 4-8 Since this group includes virtually all the recognized causative organisms of bacterial prostatitis,g as well as the preponderance of organisms currently accounting for nosocomial infections,” a study was undertaken to determine the penetrance of tobramycin into the prostate gland. Pharmacology Tobramycin is derived from complex “nebramycin,” produced Of the eight myces tenebrarius. in the complex, tobramycin is the It is administered parenterally
the antibiotic by S treptoknown factors most active.l’ and achieves
*Supported by a grant from Eli Lilly and Co., Indianapolis, Indiana.
UROLOGY
/ JUNE 1979 / VOLUME
XIII,
NUMBER
6
blood levels similar to those of gentamicin.4-6 The half-life in patients with normal renal function averages two to three hours, with 60 per cent of the administered dose excreted within six hours. Tobramycin is distributed throughout many areas of the body, but its peak concentrations are in the urine. It is eliminated almost exclusively by glomerular filtration, the half-life varying inversely with the creatinine clearance. Practically no serum protein binding occurs, and the renal and ototoxicity is similar to that of gentamicin. ‘l-l3 Methods Twenty-two male volunteers who were hospitalized to undergo transurethral resection of the prostate were utilized in this study. The clinical diagnosis was benign prostatic hyperplasia in all patients. There was no demonstrable urinary tract infection at the time of the resection, and renal function was believed to be normal, based on serum creatinine levels of 1.5 mg./lOO ml. or less. No patient received antibiotics within one week of surgery. Nineteen patients were given 80 mg. of tobramycin sulfate intramuscularly from forty-five to one hundred twenty minutes prior to the transurethral resection. Because of clinical indications or scheduling arrangements, 2 patients
Findings Serum levels of tobramycin varied from 1.5 to 4.4 pg./ml. Prostatic tissue levels of the drug
PFOSTATE ,&.lGm.
1.0
1.5
2.0
2.5
3.0 s_
*Except
Proteus
FIGURE 1.
(see
‘rable
3.5
4.0
4.5
5.0
p.lGm.
I).
Prostate
and serum
concentration
of
tobramycin.
received three doses eight hours apart, and 1 patient received thirteen doses eight hours apart, the final dose for each occurring within the aforementioned time period. Simultaneous specimens of venous blood and prostate were taken during the first part of the resection. The prostatic specimens were washed thoroughly with saline to prevent contamination with blood. Both specimens were placed on ice; within one hour the serum was separated from the blood sample by centrifugation, and the prostatic tissue and sera were frozen. Microbiologic assay of the activity of the tobramycin was carried out utilizing the agar diffusion plate method with Bacillus subtilis as the test organism.14 TABLE I.
Comment The in vitro efficacy of tobramycin has been well documented. However, the achievable levels of tobramycin in the prostate have not been reported previously. Its effectiveness and toxicity is similar to that of gentamicin, except that tobramycin has been found consistently to be two to four times as potent as gentamicin against Ps. aeruginosa.4,5,7 The minimum inhibitory concentration (MIC) of tobramycin is not significantly different from its minimum bactericidal concentration.6 The MIC against Pseudomonas rarely exceeds 1.5 pg./ml., and in greater than 90 per cent of strains it is 1.0 Levels of 1.6 pg./ml Fg./ml. or less. 6~11~12~15 inhibit
Inhibition of gram-negative
virtually
all other
prostatic
pathogens,
bacteria by tobramycin4~6*11’12*15
Pseudomonas aeruginosa (%)
Proteus mirabilis (W
Proteus morganii (%)
Indole (+) Proteus (%)
Other
Other* Gram-negative Bacilli @I
1.0 1.6 2.0
90 98 98
90
89
79
‘98’
‘48’
‘87’
85 95 98
*Includes
E. coli, Citrobacter,
Klebsiella,
Enterobacter,
Value (/&ml.)
590
ranged from 0.9 to 6.0 pg./Gm. There was no direct correlation between the serum and prostate concentrations. Two patients received no drug and had no detectable levels of tobramycin in either the serum or the prostate; these patients were used as controls. Ninetyfive per cent of the patients achieved serum levels of 2.0 pg./ml. or greater. Sixty-five per cent achieved prostatic levels of 2.0 pg./Gm., and 15 per cent had tissue levels from 1.6 to 1.9 pg./Gm. (Fig. 1). The mean serum concentration (2.8) was almost identical to the mean prostatic concentration (2.7), and there was no significant difference between the patients who received multiple drug doses and those who received one dose. The highest levels in both the serum and the prostate were obtained by patients who received a single administration of tobramycin. No level approached the recognized toxic value of 12 pg./ml.13 The pathologic diagnosis in all cases was benign prostatic hyperplasia, some with elements of chronic prostatitis.
Providencia.
UROLOGY
!
JUNE 1979
/
VOLUME
XIII,
NUMBER
6
the notable exception being indole-positive Proteus organisms. 4 However, a large study has shown that a level of 2.0 pg./ml. inhibits 87 per cent of these troublesome strains (Table I).5 Levels higher than this add essentially nothing to the drug’s effectiveness, since resistant Proteus organisms remain resistant at most safe, attainable levels.’ With an intramuscular loading-dose of 1 mg./Kg. (regardless of renal function), maximum serum levels averaging 4 ,ug./ml. can be expected thirty to ninety minutes after administration.‘lJ3 In this study, a standard dose was used, approximating 1 mg./Kg. in most patients, as might be a common and convenient approach There were no complicain clinical practice. tions attributable to the drug. Prostatic levels sufficient to inhibit virtually all common prostatic pathogens were achieved in 65 per cent of the patients; and if certain indole-positive Proteus strains are eliminated, this figure rises to 80 per cent. All patients achieved prostatic levels sufficient to inhibit greater than 90 per cent of Ps. aeruginosa strains.6 There are no reliable data available which show conclusively that tissue concentrations of tobramycin in the prostate can be compared directly with serum concentrations, since the former is calculated using weight of the tissue, while the latter calculation uses volume of serum. However, in vitro tests suggest that the comparison is valid. l4 The comparison of prostatic interstitial levels with prostatic fluid levels is beyond the scope of this study. Summary Tobramycin sulfate is an aminoglycoside antibiotic with proved in vitro and in vivo inhibitory activity against most urinary tract pathogens. This study shows that the drug is concentrated at inhibitory levels in the prostate gland after routine recommended administration. Using
UROLOGY
/
JUNE
1979
/
VOLUME
XIII,
NUMBER
6
the usual precaution for aminoglycoside toxicity, the drug should be useful in the treatment of acute bacterial prostatic infection, particularly when caused by Ps. aeruginosa. 800 Rose Street Lexington,
Kentucky 40506 (DR. LITVAK)
References 1. Stark W, Hoehn M, and Knox N: Nebramycin, a new broad-spectrum antibiotic complex, Antimicrob. Agents Chemother. 7: 314 (1968). 2. Tobramycin sulfate (Nebcin), Med. Lett. Drugs Ther. 17: 85 (1975). 3. Westenfelder S, Welling G, and Madsen P: Efficacy and pharmacokinetics of tobramycin in patients with chronic urinary tract infections and various degrees of renal impairment, J. Clin. Study Treat. Inf. 2: 76 (1974). 4. Briedis D, and Robson H: Comparative ability of netilmicin, gentamicin, amikacin, and tobramycin against Pseudomonas aeruginosa and Enterobacteriaceae, Antimicrob. Agents Chemother. 10: 592 (1976). 5. Duncan I, and Penner J: Comparative ability of tobramycin and gentamicin against Pseudomonas, Proteus, and Providencia species, Can. Med. Assoc. J. 113: 29 (1975). 6. Eickhoff T, and Ehret J: In vitro activity of netilmicin compared with gentamicin, tobramycin, amikacin, and kanamycin, Antimicrob. Agents Chemother. 11: 791 (1977). 7. Rahal JJ: How to choose the newest aminoglycosides, Curr. Prescrib. Au-gust, 1977, p. 30. 8. Ries K. Levison M. and Kave D: In vitro evaluation of a new aminoglycoside derivative of ‘kanamycin, a comparison with tobramycin and gentamicin, Antimicroh. Agents Chemother. 3: 532 (1973). 9. Meares EM: Prostatitis, a review, Urol. Clin. North Am. 2: 3 (1975). 10. Eickhoff TC: New antibacterial treatment of nosocomial infections, Bull. N.Y. Acad. Med. 51: 1056 (1975). 11. Naber K, Westenfelder S, and Madsen P: Pharmacokinetics of the aminoglycoside antibiotic tobramycin in humans, Antimicrob. Agents Chemother. 3: 469 (1973). 12. Brewer NS: The aminoglycosides: streptomycin, kanamycin, gentamicin, tobramycin, amikacin, neomycin, Mayo Clin. Proc. 52: 675 (1977). 13. Eli Lilly and Company: Nebcin (tobramycin sulfate). In: Physicians’ Desk Reference, Oradell, N. J., Medical Economics Co., 1978, pp. 1033-1035. 14. Simmons RJ, bead of microbiological assay development, Eli Lilly and Company, personal communication, 1978. 15. Blair D, et al: Therapy of Pseudomonas aeruginosa infections with tobramycin, Antimicroh. Agents Cbemotber. 8: 22 (1975).
591
COMPARISON
OF SERUM AND PROSTATIC
ARTICLES
LEVELS
OF TOBRAMYCIN*
CHARLES AUSTIN
B. WILLIAMS, S. LITVAK,
J. WILLIAM
M.D.
M.D.
McROBERTS,
M.D.
From the Department of Surgery, Division of Urology, University of Kentucky Medical Center, Lexington, Kentucky
- Tobramycin sulfate, an aminoglycoside antibiotic, has been shown to be effective in the treatment of complicated urinary tract infections. Because of this, a study was undertaken to determine the penetrance of tobramycin into the prostate gland. It was found that the drug is concentrated at inhibitory levels in the prostate gland after the routinely recommended administration and should be useful in the treatment of bacterial prostatic infection.
ABSTRACT
Tobramycin sulfate is an aminoglycoside antibiotic discovered by Stark, Hoehn, and Knox in 1967.l Clinical trials have shown the drug to be effective for the treatment of complicated urinary tract infections. 2,3 The drug has broadspectrum antibacterial activity, being especially effective against the gram-negative bacilli. Its recognized spectrum includes Staphylococcus aureus, Escherichia coli, Citrobacter, Klebsiella, Enterobacter, Proteus (indole-positive and -negative), Providencia, and Pseudomonas aeruginosa. 4-8 Since this group includes virtually all the recognized causative organisms of bacterial prostatitis,g as well as the preponderance of organisms currently accounting for nosocomial infections,” a study was undertaken to determine the penetrance of tobramycin into the prostate gland. Pharmacology Tobramycin is derived from complex “nebramycin,” produced Of the eight myces tenebrarius. in the complex, tobramycin is the It is administered parenterally
the antibiotic by S treptoknown factors most active.l’ and achieves
*Supported by a grant from Eli Lilly and Co., Indianapolis, Indiana.
UROLOGY
/ JUNE 1979 / VOLUME
XIII,
NUMBER
6
blood levels similar to those of gentamicin.4-6 The half-life in patients with normal renal function averages two to three hours, with 60 per cent of the administered dose excreted within six hours. Tobramycin is distributed throughout many areas of the body, but its peak concentrations are in the urine. It is eliminated almost exclusively by glomerular filtration, the half-life varying inversely with the creatinine clearance. Practically no serum protein binding occurs, and the renal and ototoxicity is similar to that of gentamicin. ‘l-l3 Methods Twenty-two male volunteers who were hospitalized to undergo transurethral resection of the prostate were utilized in this study. The clinical diagnosis was benign prostatic hyperplasia in all patients. There was no demonstrable urinary tract infection at the time of the resection, and renal function was believed to be normal, based on serum creatinine levels of 1.5 mg./lOO ml. or less. No patient received antibiotics within one week of surgery. Nineteen patients were given 80 mg. of tobramycin sulfate intramuscularly from forty-five to one hundred twenty minutes prior to the transurethral resection. Because of clinical indications or scheduling arrangements, 2 patients
Findings Serum levels of tobramycin varied from 1.5 to 4.4 pg./ml. Prostatic tissue levels of the drug
PFOSTATE ,&.lGm.
1.0
1.5
2.0
2.5
3.0 s_
*Except
Proteus
FIGURE 1.
(see
‘rable
3.5
4.0
4.5
5.0
p.lGm.
I).
Prostate
and serum
concentration
of
tobramycin.
received three doses eight hours apart, and 1 patient received thirteen doses eight hours apart, the final dose for each occurring within the aforementioned time period. Simultaneous specimens of venous blood and prostate were taken during the first part of the resection. The prostatic specimens were washed thoroughly with saline to prevent contamination with blood. Both specimens were placed on ice; within one hour the serum was separated from the blood sample by centrifugation, and the prostatic tissue and sera were frozen. Microbiologic assay of the activity of the tobramycin was carried out utilizing the agar diffusion plate method with Bacillus subtilis as the test organism.14 TABLE I.
Comment The in vitro efficacy of tobramycin has been well documented. However, the achievable levels of tobramycin in the prostate have not been reported previously. Its effectiveness and toxicity is similar to that of gentamicin, except that tobramycin has been found consistently to be two to four times as potent as gentamicin against Ps. aeruginosa.4,5,7 The minimum inhibitory concentration (MIC) of tobramycin is not significantly different from its minimum bactericidal concentration.6 The MIC against Pseudomonas rarely exceeds 1.5 pg./ml., and in greater than 90 per cent of strains it is 1.0 Levels of 1.6 pg./ml Fg./ml. or less. 6~11~12~15 inhibit
Inhibition of gram-negative
virtually
all other
prostatic
pathogens,
bacteria by tobramycin4~6*11’12*15
Pseudomonas aeruginosa (%)
Proteus mirabilis (W
Proteus morganii (%)
Indole (+) Proteus (%)
Other
Other* Gram-negative Bacilli @I
1.0 1.6 2.0
90 98 98
90
89
79
‘98’
‘48’
‘87’
85 95 98
*Includes
E. coli, Citrobacter,
Klebsiella,
Enterobacter,
Value (/&ml.)
590
ranged from 0.9 to 6.0 pg./Gm. There was no direct correlation between the serum and prostate concentrations. Two patients received no drug and had no detectable levels of tobramycin in either the serum or the prostate; these patients were used as controls. Ninetyfive per cent of the patients achieved serum levels of 2.0 pg./ml. or greater. Sixty-five per cent achieved prostatic levels of 2.0 pg./Gm., and 15 per cent had tissue levels from 1.6 to 1.9 pg./Gm. (Fig. 1). The mean serum concentration (2.8) was almost identical to the mean prostatic concentration (2.7), and there was no significant difference between the patients who received multiple drug doses and those who received one dose. The highest levels in both the serum and the prostate were obtained by patients who received a single administration of tobramycin. No level approached the recognized toxic value of 12 pg./ml.13 The pathologic diagnosis in all cases was benign prostatic hyperplasia, some with elements of chronic prostatitis.
Providencia.
UROLOGY
!
JUNE 1979
/
VOLUME
XIII,
NUMBER
6
the notable exception being indole-positive Proteus organisms. 4 However, a large study has shown that a level of 2.0 pg./ml. inhibits 87 per cent of these troublesome strains (Table I).5 Levels higher than this add essentially nothing to the drug’s effectiveness, since resistant Proteus organisms remain resistant at most safe, attainable levels.’ With an intramuscular loading-dose of 1 mg./Kg. (regardless of renal function), maximum serum levels averaging 4 ,ug./ml. can be expected thirty to ninety minutes after administration.‘lJ3 In this study, a standard dose was used, approximating 1 mg./Kg. in most patients, as might be a common and convenient approach There were no complicain clinical practice. tions attributable to the drug. Prostatic levels sufficient to inhibit virtually all common prostatic pathogens were achieved in 65 per cent of the patients; and if certain indole-positive Proteus strains are eliminated, this figure rises to 80 per cent. All patients achieved prostatic levels sufficient to inhibit greater than 90 per cent of Ps. aeruginosa strains.6 There are no reliable data available which show conclusively that tissue concentrations of tobramycin in the prostate can be compared directly with serum concentrations, since the former is calculated using weight of the tissue, while the latter calculation uses volume of serum. However, in vitro tests suggest that the comparison is valid. l4 The comparison of prostatic interstitial levels with prostatic fluid levels is beyond the scope of this study. Summary Tobramycin sulfate is an aminoglycoside antibiotic with proved in vitro and in vivo inhibitory activity against most urinary tract pathogens. This study shows that the drug is concentrated at inhibitory levels in the prostate gland after routine recommended administration. Using
UROLOGY
/
JUNE
1979
/
VOLUME
XIII,
NUMBER
6
the usual precaution for aminoglycoside toxicity, the drug should be useful in the treatment of acute bacterial prostatic infection, particularly when caused by Ps. aeruginosa. 800 Rose Street Lexington,
Kentucky 40506 (DR. LITVAK)
References 1. Stark W, Hoehn M, and Knox N: Nebramycin, a new broad-spectrum antibiotic complex, Antimicrob. Agents Chemother. 7: 314 (1968). 2. Tobramycin sulfate (Nebcin), Med. Lett. Drugs Ther. 17: 85 (1975). 3. Westenfelder S, Welling G, and Madsen P: Efficacy and pharmacokinetics of tobramycin in patients with chronic urinary tract infections and various degrees of renal impairment, J. Clin. Study Treat. Inf. 2: 76 (1974). 4. Briedis D, and Robson H: Comparative ability of netilmicin, gentamicin, amikacin, and tobramycin against Pseudomonas aeruginosa and Enterobacteriaceae, Antimicrob. Agents Chemother. 10: 592 (1976). 5. Duncan I, and Penner J: Comparative ability of tobramycin and gentamicin against Pseudomonas, Proteus, and Providencia species, Can. Med. Assoc. J. 113: 29 (1975). 6. Eickhoff T, and Ehret J: In vitro activity of netilmicin compared with gentamicin, tobramycin, amikacin, and kanamycin, Antimicrob. Agents Chemother. 11: 791 (1977). 7. Rahal JJ: How to choose the newest aminoglycosides, Curr. Prescrib. Au-gust, 1977, p. 30. 8. Ries K. Levison M. and Kave D: In vitro evaluation of a new aminoglycoside derivative of ‘kanamycin, a comparison with tobramycin and gentamicin, Antimicroh. Agents Chemother. 3: 532 (1973). 9. Meares EM: Prostatitis, a review, Urol. Clin. North Am. 2: 3 (1975). 10. Eickhoff TC: New antibacterial treatment of nosocomial infections, Bull. N.Y. Acad. Med. 51: 1056 (1975). 11. Naber K, Westenfelder S, and Madsen P: Pharmacokinetics of the aminoglycoside antibiotic tobramycin in humans, Antimicrob. Agents Chemother. 3: 469 (1973). 12. Brewer NS: The aminoglycosides: streptomycin, kanamycin, gentamicin, tobramycin, amikacin, neomycin, Mayo Clin. Proc. 52: 675 (1977). 13. Eli Lilly and Company: Nebcin (tobramycin sulfate). In: Physicians’ Desk Reference, Oradell, N. J., Medical Economics Co., 1978, pp. 1033-1035. 14. Simmons RJ, bead of microbiological assay development, Eli Lilly and Company, personal communication, 1978. 15. Blair D, et al: Therapy of Pseudomonas aeruginosa infections with tobramycin, Antimicroh. Agents Cbemotber. 8: 22 (1975).
591
