THE JOURNAL OF INFECTIOUS DISEASES • VOL. 134, SUPPLEMENT © 1976 by the University of Chicago. All rights reserved.
•
AUGUST 1976
Bacteriological, Clinical, and Pharmacological Investigations with Tobramycin in Patients with Serious Urinary Tract Infection Eva Ivan, A. E. Nagy, and Klara N. Csatary
From Szonyi Tibor Hospital, Vac, Hungary
Aminoglycoside antibiotics have played a significant role in the combat of infections due to gramnegative bacteria. In Hungary tobramycin therapy had not been used until recently. During in vitro studies of tobramycin, we observed excellent effects against many bacterial strains (mainly of Pseudomonas, Staphylococcus, and A cinetobacter) derived from clinical sources. Tobramycin was especially active against Pseudomonas aeruginosa, polyresistant Staphylococcus aureus, indole-positive Proteus, Acinetobacter anitratum, and Acinetobacter lwoffi (table 1). From comparisons of the antibacterial spectrum of tobramycin with the spectra of other aminoglycoside antibiotics, it was obvious that tobramycin was the most effective antibiotic of the aminoglycoside group. The drug had a broad antibacterial spectrum similar to that of gentamicin, with the same low (and sometimes lower) level of toxicity. The antibacterial spectrum was determined by the standardized Bauer-Kirby disk sensitivity method [1] on Mueller-Hinton agar. Disks containing ·10 !lg of tobramycinwere supplied for susceptibility tests by Lilly Research We thank Eli Lilly GmbH (Budapest, Hungary) for supplying the tobramycin for injections. Please address requests for reprints to Dr. A. E. Nagy, Szonyi Tibor Hospital, H-2061 Vac, Hungary.
S153
Laboratories (Bad Homburg, West Germany). Bacteria giving zone diameters of ~ 14 mm were regarded as susceptible, and those giving zone diameters of < 14 mm were regarded as resistant. Clinical Studies
Fifty hospitalized patients (aged 17-70 years) who were suffering from serious urinary tract infections were treated with tobramycin. Most of these patients had chronic infections and had previously received several courses of therapy with antibiotics other than tobramycin. Patients received a total of 2-2.5 mg of tobramycin/kg per day in two im injections (12 hr apart) for seven days. For infections due to P. aeruginosa, therapy was given for 10 days. We regarded the total abolition of bacteria immediately, three months, and six months after therapy as the main parameter of recovery (figure 1). However, we also took into account changes in clinical course, renal function, and roentgenographic findings. Therapy. with this regimen gave good clinical results, with no (or only slight) adverse reactions. We observed no ototoxicity or nephrotoxicity. Comparing the parameters of recovery with those in another group of patients who were suffering from the same disease and were treated
Downloaded from http://jid.oxfordjournals.org/ at University of Illinois at Urbana-Champaign on September 7, 2015
In studies of tobramycin an excellent effect was noted against many strains of bacteria of the family Enterobacteriaceae and of Pseudomonas aeruginosa and Staphylococcus derived from clinical sources. When the susceptibility of the strains to tobramycin was compared with susceptibility to other aminoglycoside antibiotics, tobramycin was clearly the most effective antibiotic of this group. Therapy of chronic urinary tract infection with tobramycin resulted in good clinical effects with no (or only slight) adverse reactions. When the parameters of recovery in patients treated with tobramycin were compared with those in other patients who had the same diseases but were treated with gentamicin, tobramycin yielded clinical results that were as good as (and occasionally better than) those produced by gentamicin. Studies of the pharmacokinetics of tobramycin showed a high rate of absorption from the muscles, a high rate of renal excretion, and effective therapeutic concentrations (higher than the minimal inhibitory concentration for the infecting strains) in renal tissue homogenates.
S154
[win, Nagy, and Csatdry
Table 1.
Resistance of various bacteria to aminoglycoside antibiotics.
Organism Escherichia coli Klebsiella Enterobacter Proteus
indole-negative indole-positive
Total * Sm mycin.
= streptomycin;
Km
Sm
Km
Pm
Nm
Gm
Tm
568 88 94
26 34 58
6 14 11
6 14 9
5 5 9
0.4 2.3 9
4.2 4.5 15
116 20 30 118 228 1,262
35 60 10 70 16
16 40 3 75 0
12 40 0 92 0
2 30 0 9 0
3.5 0 0 5 0
56.5 0 0 8.5 0
= kanamycin;
Pm
= paromomycin;
with gentamicin, we found that results with tobramycin were as good as (and occasionally better than) those with gentamicin, especially in cases of infection caused by P. aeruginosa. Pharmacological studies were performed for patients who had end-stage renal disease and were being nephrectomized. These patients received 150 mg of tobramycin in 2 hr before surgery. A fine tissue homogenate was prepared from the kidney with a Biomix homogenator (Labor MIM, Budapest, Hungary) and aseptic technique. Serial dilutions were made from the renal homogenates and from the 2-hr blood and urine samples, and bioassays were carried out by the agar diffusion method on Grove-Randall no. 5 medium (pH 8) with S. aureus strain ATCC 6538P as the test organism. Figure 2 shows the mean level of tobramycin in five renal tissue homogenates and in serum samples obtained at the time of nephrectomy.
.,.
o
100
Kl- Enteroboctl!r
1IO
~ Ps
60
~Proteus
40
= neomycin;
Gm
= gentamicin;
Tm
= tobra-
mcg/ml
10
9
6
Serum
KidMy
Figure 2. Average concentrations of tobramycin obtained at the same time in the serum and the kidney of five patients given 150 mg im 2 hr before nephrectomy.
Conclusion
Cl!fUQlflOSO
•
E CoIl
•
Sterll
20
1lIIIaN therapy aftIIr ltw'apy
Nm
J monthaftIIr 6 month clter therapr therapy
Figure 1. Change in level of bacteriuria after administration of tobramycin to 50 patients with serious urinary tract infections.
These data indicate that tobramycin reaches the renal parenchyma in sufficient quantity; the average MIC of the organisms causing urinary tract infection is well below the average level of tobramycin that we found in renal tissue. In other words, we can obtain therapeutic concentrations of tobramycin in the kidney. Tobramycin is obviously the antibiotic of choice when P. aeruginosa is present in the
Downloaded from http://jid.oxfordjournals.org/ at University of Illinois at Urbana-Champaign on September 7, 2015
Acinetobacter Pseudomonas Staphylococcus aureus
Percentage resistant to*
No. of strains
Tobramycin Therapy for Urinary Infection
urinary tract. When other polyresistant bacterial strains are the infecting agents, two effective aminoglycoside antibiotics (tobramycin and gentamicin) with similar antibacterial spectra and with the same low toxicity are thus available.
5155
Reference 1. Bauer, A. W., Kirby, W. M. M., Sherris, J. C., Turck,
M. Antibiotic susceptibility testing by a standardized single disc method. Am. J. Clin. Pathol. 45:493-496, 1966.
Downloaded from http://jid.oxfordjournals.org/ at University of Illinois at Urbana-Champaign on September 7, 2015
•
AUGUST 1976
Bacteriological, Clinical, and Pharmacological Investigations with Tobramycin in Patients with Serious Urinary Tract Infection Eva Ivan, A. E. Nagy, and Klara N. Csatary
From Szonyi Tibor Hospital, Vac, Hungary
Aminoglycoside antibiotics have played a significant role in the combat of infections due to gramnegative bacteria. In Hungary tobramycin therapy had not been used until recently. During in vitro studies of tobramycin, we observed excellent effects against many bacterial strains (mainly of Pseudomonas, Staphylococcus, and A cinetobacter) derived from clinical sources. Tobramycin was especially active against Pseudomonas aeruginosa, polyresistant Staphylococcus aureus, indole-positive Proteus, Acinetobacter anitratum, and Acinetobacter lwoffi (table 1). From comparisons of the antibacterial spectrum of tobramycin with the spectra of other aminoglycoside antibiotics, it was obvious that tobramycin was the most effective antibiotic of the aminoglycoside group. The drug had a broad antibacterial spectrum similar to that of gentamicin, with the same low (and sometimes lower) level of toxicity. The antibacterial spectrum was determined by the standardized Bauer-Kirby disk sensitivity method [1] on Mueller-Hinton agar. Disks containing ·10 !lg of tobramycinwere supplied for susceptibility tests by Lilly Research We thank Eli Lilly GmbH (Budapest, Hungary) for supplying the tobramycin for injections. Please address requests for reprints to Dr. A. E. Nagy, Szonyi Tibor Hospital, H-2061 Vac, Hungary.
S153
Laboratories (Bad Homburg, West Germany). Bacteria giving zone diameters of ~ 14 mm were regarded as susceptible, and those giving zone diameters of < 14 mm were regarded as resistant. Clinical Studies
Fifty hospitalized patients (aged 17-70 years) who were suffering from serious urinary tract infections were treated with tobramycin. Most of these patients had chronic infections and had previously received several courses of therapy with antibiotics other than tobramycin. Patients received a total of 2-2.5 mg of tobramycin/kg per day in two im injections (12 hr apart) for seven days. For infections due to P. aeruginosa, therapy was given for 10 days. We regarded the total abolition of bacteria immediately, three months, and six months after therapy as the main parameter of recovery (figure 1). However, we also took into account changes in clinical course, renal function, and roentgenographic findings. Therapy. with this regimen gave good clinical results, with no (or only slight) adverse reactions. We observed no ototoxicity or nephrotoxicity. Comparing the parameters of recovery with those in another group of patients who were suffering from the same disease and were treated
Downloaded from http://jid.oxfordjournals.org/ at University of Illinois at Urbana-Champaign on September 7, 2015
In studies of tobramycin an excellent effect was noted against many strains of bacteria of the family Enterobacteriaceae and of Pseudomonas aeruginosa and Staphylococcus derived from clinical sources. When the susceptibility of the strains to tobramycin was compared with susceptibility to other aminoglycoside antibiotics, tobramycin was clearly the most effective antibiotic of this group. Therapy of chronic urinary tract infection with tobramycin resulted in good clinical effects with no (or only slight) adverse reactions. When the parameters of recovery in patients treated with tobramycin were compared with those in other patients who had the same diseases but were treated with gentamicin, tobramycin yielded clinical results that were as good as (and occasionally better than) those produced by gentamicin. Studies of the pharmacokinetics of tobramycin showed a high rate of absorption from the muscles, a high rate of renal excretion, and effective therapeutic concentrations (higher than the minimal inhibitory concentration for the infecting strains) in renal tissue homogenates.
S154
[win, Nagy, and Csatdry
Table 1.
Resistance of various bacteria to aminoglycoside antibiotics.
Organism Escherichia coli Klebsiella Enterobacter Proteus
indole-negative indole-positive
Total * Sm mycin.
= streptomycin;
Km
Sm
Km
Pm
Nm
Gm
Tm
568 88 94
26 34 58
6 14 11
6 14 9
5 5 9
0.4 2.3 9
4.2 4.5 15
116 20 30 118 228 1,262
35 60 10 70 16
16 40 3 75 0
12 40 0 92 0
2 30 0 9 0
3.5 0 0 5 0
56.5 0 0 8.5 0
= kanamycin;
Pm
= paromomycin;
with gentamicin, we found that results with tobramycin were as good as (and occasionally better than) those with gentamicin, especially in cases of infection caused by P. aeruginosa. Pharmacological studies were performed for patients who had end-stage renal disease and were being nephrectomized. These patients received 150 mg of tobramycin in 2 hr before surgery. A fine tissue homogenate was prepared from the kidney with a Biomix homogenator (Labor MIM, Budapest, Hungary) and aseptic technique. Serial dilutions were made from the renal homogenates and from the 2-hr blood and urine samples, and bioassays were carried out by the agar diffusion method on Grove-Randall no. 5 medium (pH 8) with S. aureus strain ATCC 6538P as the test organism. Figure 2 shows the mean level of tobramycin in five renal tissue homogenates and in serum samples obtained at the time of nephrectomy.
.,.
o
100
Kl- Enteroboctl!r
1IO
~ Ps
60
~Proteus
40
= neomycin;
Gm
= gentamicin;
Tm
= tobra-
mcg/ml
10
9
6
Serum
KidMy
Figure 2. Average concentrations of tobramycin obtained at the same time in the serum and the kidney of five patients given 150 mg im 2 hr before nephrectomy.
Conclusion
Cl!fUQlflOSO
•
E CoIl
•
Sterll
20
1lIIIaN therapy aftIIr ltw'apy
Nm
J monthaftIIr 6 month clter therapr therapy
Figure 1. Change in level of bacteriuria after administration of tobramycin to 50 patients with serious urinary tract infections.
These data indicate that tobramycin reaches the renal parenchyma in sufficient quantity; the average MIC of the organisms causing urinary tract infection is well below the average level of tobramycin that we found in renal tissue. In other words, we can obtain therapeutic concentrations of tobramycin in the kidney. Tobramycin is obviously the antibiotic of choice when P. aeruginosa is present in the
Downloaded from http://jid.oxfordjournals.org/ at University of Illinois at Urbana-Champaign on September 7, 2015
Acinetobacter Pseudomonas Staphylococcus aureus
Percentage resistant to*
No. of strains
Tobramycin Therapy for Urinary Infection
urinary tract. When other polyresistant bacterial strains are the infecting agents, two effective aminoglycoside antibiotics (tobramycin and gentamicin) with similar antibacterial spectra and with the same low toxicity are thus available.
5155
Reference 1. Bauer, A. W., Kirby, W. M. M., Sherris, J. C., Turck,
M. Antibiotic susceptibility testing by a standardized single disc method. Am. J. Clin. Pathol. 45:493-496, 1966.
Downloaded from http://jid.oxfordjournals.org/ at University of Illinois at Urbana-Champaign on September 7, 2015
