Scot. moo. J., 1976,21: 75
TOBRAMYCIN IN URINARY TRACT INFECTION Andrew G. Graham Departments of Urology, Western Infirmary and Royal Hospital for Sick Children, Glasgow
IN 1971 Black and Griffith gave a clear indication of the potential value of tobramycin in the treatment of urinary infection, favourable comparisons with gentamicin being made. On this basis, a clinical trial of tobramycin was carried out in the Urological Department of the Western Infirmary over a 2-year period 1972-1974. The trial was designed (1) to assess the effectiveness of the drug, (2) to record any adverse effects, and (3) to provide information regarding serum and urine levels in clinical use under average conditions. Patients studied Details of the 50 patients studied are summarised briefly in Table I. All had significant urinary infections requiring treatment; many had already had courses of other antibiotics without benefit. All the prostate cases had been catheterised for urinary retention and were infected prior to surgery. Of the bladder carcinoma group, 9 were undergoing a course of radiotherapy. The 6 'catheter' cases had a variety of lower urinary tract conditions in which an indwelling catheter was a common factor at the time of treatment. In 10 patients the infection was known to be chronic. It was realised that the underlying conditions militated against ready eradication of the superimposed infection (necrotic tumour, stones, high residual urine volumes, foreign material) and offered a real challenge to treatment. In the interests of safety, no patient whose blood urea exceeded 8 mmol. per 1. was included in the trial. Organisms treated Cultures were obtained by dipslide inoculum of mid-stream or catheter collections of urine. The usual diagnostic criterion of > 100,000 organisms per ml. was applied. In cases of mixed growth, the major colonies only were recorded, to avoid confusion. The organisms and their sensitivity to some of the common antibacterials are summarised in Table II. All organisms were found to be
sensitive to both tobramycin and gentamicin. The minimum inhibitory concentrations (MICs) oftobramycin lay within the range 1.0 to 5.0 mg. per 1. Mode of treatment It was arbitrarily decided to use a 5-day
course based on a daily dosage of 3 mg. per kg. body weight. This was achieved most conveniently by giving 100 mg. twice daily intramuscularly. The studies of Black and Griffith (1971) showed that effective urinary levels of tobramycin could be anticipated even 12 hours after injection, and a treatment regime involving only 2 injections daily seemed desirable, provided it proved adequate. Results Efficacy. In 46 patients the urine was sterile on the 3rd day of treatment, and in all 50 patients the post-treatment urine, on the 6th or 7th day, was sterile. Although short-term assessment was the only object of the trial, 44 patients had routine urine cultures in the following weeks, and in the absence of further instrumentation, only 1 case suffered a recurrence of infection. Adverse reactions. None was recorded. Routine full haematological and biochemical studies were performed before, during, and after treatment in order to assess any upset of renal, hepatic, or haemopoietic function. No significant variations occurred. Pharmacological studies. In the first 20 patients, on one or more days during treatment, serum levels of tobramycin at 1 and 4 hours after injection were measured by a plate-diffusion method (McAllister & Tait, 1976). The patients voided urine just before the injection, and again at 2 hours when the level was assayed. No restrictions on fluid intake were imposed, and the urine tobramycin level obtained therefore represents the average excretion in the first 2 hours after injection, not a peak level. In 2 co-operative
Graham
patients, hourly urine levels up to 10 hours after injections were obtained. The serum and urine levels are shown in Figure 1. The l-hour serum levels ranged from 2.5 to 12.0 mg. per 1. (mean 5.0), and the 4-hour from 1.4 to 4.7 mg. per 1. (mean 2.5).
Table I. Patients studied. Sex:
Male-35.
Age:
37 to 81 years
Conditions:
Female-IS. -_._--._-
18 11
Prostatectomy Bladder carcinoma Urethral stricture 'Catheters' Bladder stones Renal stones
7 6
5 3
50
Total patients Serum Levels
Urine
mg'I 12
The 2-hour urine levels were 30 to 470 mg. per 1. (mean 180) and, at 10 hours, levels of 30 and 10 mg. per 1. were recorded (Fig. 2), still well above the MICs of the causal organisms in this series.
11
10 8 7
4
500
• •• h •
9
~
3 2
I
I'· II
300
•
••
Iii. u· -
1
4
1
·• ··•• •
400
200
2.5
••
Conclusion 180
•
•• •• ••
100
0
I
0
2 hours
Fig. 1. Serum and urine levels of tobramycin in 20 patients. Serum Levels mg/l 400
300
In the series of patients studied, tobramycin proved remarkably successful in eliminating infection from the urinary tract in a wide variety of formidable conditions. A dosage of 100 mg. twice daily intramuscularly for 5 days proved adequate. The high urinary levels of tobramycin, well above the MICs against the causal organisms, would appear to explain the drug's effectiveness in urinary tract infections. No adverse reactions were noted in the patients studied, and routine serum assays appear necessary only if renal function is significantly impaired.
200
REFERENCES
Black, H. R., Griffith, R. S. (1971). Preliminary studies with Nebrarnycin factor 6. Antimicrobial Agents and Chemotherapy, 314
100
o 5 10 hours Fig. 2. Hourly urine excretion levels of tobramycin in 2 patients.
McAllister, T. A., Tait, S. C. (1976). Tobramycin: laboratory aspects. Journal of Infectious Diseases. In press
Table n. Causal organisms and their sensitivities in 50 patients. Organisms
T
Escherichia coli 'coliforms' Proteus mirabilis Pseudomonas aeruginosa Klebsiella aerogenes Providencia stuartii Acinetobacter anitratus
30 4 6 4
Total Abbreviations:
76
G
K
2
30 4 6 4 2 2
2
2
2 2
50
50
43
l
25
4 6 4 2
Col 30 4 4 4 1 1
Cep 30 4 5
2
46
39
A
Co
26 3 6
30 4 6 1 1
2
2
37
44
T'-Tobramycin G-Gentamicin Col-Colistin K-Kanamycin A-Ampicillin Co-Cotrimoxazole Nf-Nitrofurantoin,
Nf
Total
27 3 3
30 4 6 4 2 2 2
33
50
Cep-Cephaloridine
TOBRAMYCIN IN URINARY TRACT INFECTION Andrew G. Graham Departments of Urology, Western Infirmary and Royal Hospital for Sick Children, Glasgow
IN 1971 Black and Griffith gave a clear indication of the potential value of tobramycin in the treatment of urinary infection, favourable comparisons with gentamicin being made. On this basis, a clinical trial of tobramycin was carried out in the Urological Department of the Western Infirmary over a 2-year period 1972-1974. The trial was designed (1) to assess the effectiveness of the drug, (2) to record any adverse effects, and (3) to provide information regarding serum and urine levels in clinical use under average conditions. Patients studied Details of the 50 patients studied are summarised briefly in Table I. All had significant urinary infections requiring treatment; many had already had courses of other antibiotics without benefit. All the prostate cases had been catheterised for urinary retention and were infected prior to surgery. Of the bladder carcinoma group, 9 were undergoing a course of radiotherapy. The 6 'catheter' cases had a variety of lower urinary tract conditions in which an indwelling catheter was a common factor at the time of treatment. In 10 patients the infection was known to be chronic. It was realised that the underlying conditions militated against ready eradication of the superimposed infection (necrotic tumour, stones, high residual urine volumes, foreign material) and offered a real challenge to treatment. In the interests of safety, no patient whose blood urea exceeded 8 mmol. per 1. was included in the trial. Organisms treated Cultures were obtained by dipslide inoculum of mid-stream or catheter collections of urine. The usual diagnostic criterion of > 100,000 organisms per ml. was applied. In cases of mixed growth, the major colonies only were recorded, to avoid confusion. The organisms and their sensitivity to some of the common antibacterials are summarised in Table II. All organisms were found to be
sensitive to both tobramycin and gentamicin. The minimum inhibitory concentrations (MICs) oftobramycin lay within the range 1.0 to 5.0 mg. per 1. Mode of treatment It was arbitrarily decided to use a 5-day
course based on a daily dosage of 3 mg. per kg. body weight. This was achieved most conveniently by giving 100 mg. twice daily intramuscularly. The studies of Black and Griffith (1971) showed that effective urinary levels of tobramycin could be anticipated even 12 hours after injection, and a treatment regime involving only 2 injections daily seemed desirable, provided it proved adequate. Results Efficacy. In 46 patients the urine was sterile on the 3rd day of treatment, and in all 50 patients the post-treatment urine, on the 6th or 7th day, was sterile. Although short-term assessment was the only object of the trial, 44 patients had routine urine cultures in the following weeks, and in the absence of further instrumentation, only 1 case suffered a recurrence of infection. Adverse reactions. None was recorded. Routine full haematological and biochemical studies were performed before, during, and after treatment in order to assess any upset of renal, hepatic, or haemopoietic function. No significant variations occurred. Pharmacological studies. In the first 20 patients, on one or more days during treatment, serum levels of tobramycin at 1 and 4 hours after injection were measured by a plate-diffusion method (McAllister & Tait, 1976). The patients voided urine just before the injection, and again at 2 hours when the level was assayed. No restrictions on fluid intake were imposed, and the urine tobramycin level obtained therefore represents the average excretion in the first 2 hours after injection, not a peak level. In 2 co-operative
Graham
patients, hourly urine levels up to 10 hours after injections were obtained. The serum and urine levels are shown in Figure 1. The l-hour serum levels ranged from 2.5 to 12.0 mg. per 1. (mean 5.0), and the 4-hour from 1.4 to 4.7 mg. per 1. (mean 2.5).
Table I. Patients studied. Sex:
Male-35.
Age:
37 to 81 years
Conditions:
Female-IS. -_._--._-
18 11
Prostatectomy Bladder carcinoma Urethral stricture 'Catheters' Bladder stones Renal stones
7 6
5 3
50
Total patients Serum Levels
Urine
mg'I 12
The 2-hour urine levels were 30 to 470 mg. per 1. (mean 180) and, at 10 hours, levels of 30 and 10 mg. per 1. were recorded (Fig. 2), still well above the MICs of the causal organisms in this series.
11
10 8 7
4
500
• •• h •
9
~
3 2
I
I'· II
300
•
••
Iii. u· -
1
4
1
·• ··•• •
400
200
2.5
••
Conclusion 180
•
•• •• ••
100
0
I
0
2 hours
Fig. 1. Serum and urine levels of tobramycin in 20 patients. Serum Levels mg/l 400
300
In the series of patients studied, tobramycin proved remarkably successful in eliminating infection from the urinary tract in a wide variety of formidable conditions. A dosage of 100 mg. twice daily intramuscularly for 5 days proved adequate. The high urinary levels of tobramycin, well above the MICs against the causal organisms, would appear to explain the drug's effectiveness in urinary tract infections. No adverse reactions were noted in the patients studied, and routine serum assays appear necessary only if renal function is significantly impaired.
200
REFERENCES
Black, H. R., Griffith, R. S. (1971). Preliminary studies with Nebrarnycin factor 6. Antimicrobial Agents and Chemotherapy, 314
100
o 5 10 hours Fig. 2. Hourly urine excretion levels of tobramycin in 2 patients.
McAllister, T. A., Tait, S. C. (1976). Tobramycin: laboratory aspects. Journal of Infectious Diseases. In press
Table n. Causal organisms and their sensitivities in 50 patients. Organisms
T
Escherichia coli 'coliforms' Proteus mirabilis Pseudomonas aeruginosa Klebsiella aerogenes Providencia stuartii Acinetobacter anitratus
30 4 6 4
Total Abbreviations:
76
G
K
2
30 4 6 4 2 2
2
2
2 2
50
50
43
l
25
4 6 4 2
Col 30 4 4 4 1 1
Cep 30 4 5
2
46
39
A
Co
26 3 6
30 4 6 1 1
2
2
37
44
T'-Tobramycin G-Gentamicin Col-Colistin K-Kanamycin A-Ampicillin Co-Cotrimoxazole Nf-Nitrofurantoin,
Nf
Total
27 3 3
30 4 6 4 2 2 2
33
50
Cep-Cephaloridine
