THE JOURNAL OF INFECTIOUS DISEASES • VOL. 134, SUPPLEMENT © 1976 by the University of Chicago. All rights reserved.
• AUGUST 1976
A Randomized, Comparative Study of Tobramycin and Gentamicin in Treatment of Acute Urinary Tract Infections From the Department of Internal Medicine, Baylor College of Medicine, Houston, Texas
Brian D. Walker and Layne O. Gentry
The ever-increasing number of cases of opportunistic infections with gram-negative bacteria has been associated with emergence of resistance to the commonly used antimicrobial agents. The frequent use of gentamicin in the therapy of gramnegative bacterial infections has resulted in the development of gentamicin-resistant organisms. Because these commonly encountered, resistant organisms are causing increased morbidity and mortality rates, there is a need for more effective agents. Tobramycin is a new aminoglycoside that has an in vitro antibacterial spectrum similar to that of gentamicin [1, 2]. However, the in vitro activity of tobramycin against strains of Pseudomonas is two- to fourfold greater than that of gentamicin [3]. Tobramycin thus adds to the antibacterial spectrum of the aminoglycosides. Tobramycin is a derivative of the actinomycete Streptomyces tenebrarius, and its active component is factor 6 of the nebramycin complex. Since gentamicin and tobramycin have been independently compared as to their clinical phar-
This study was supported by Eli Lilly and Company, Indianapolis, Indiana, and by the Clinical Research Center of Baylor College of Medicine. Please address requests for reprints to Dr. L. O. Gentry, Department of Internal Medicine, Baylor College of Medicine, Houston, Texas 77025.
8146
macology [4] and in vitro bacteriology [1], we elected to compare these two drugs in the therapy of acute urinary tract infections. Materials and Methods
Patients in this study were referred from the Emergency Center or Inpatient Medical or Surgical Services, Harris County Hospital District, Houston, Texas. Informed consent was obtained from all patients according to the guidelines of the Human Experimentation Committee, Baylor College of Medicine. Patients adrriitted with urinary tract infections had clinical .symptoms of frequency, dysuria, and urgency, and infections in all patients were confirmed bacteriologically (> 105 colonies of bacterialml of urine). Urinary tract infection was further delineated into pyelonephritis and cystitis. The diagnostic criteria for pyelonephritis were symptoms of urgency, frequency, dysuria, and flank pain associated with fever of > 101 F and laboratory findings of leukocytosis C> 13,000 white blood cells [WBCl/ rnm"), pyuria (> 10 WBC per high-power field), and WBC or granular casts on urinalysis. Those patients with urinary tract infection who did not meet the diagnostic criteria for pyelonephritis were considered to have cystitis. All patients were randomly assigned to treatment with either tobramycin or gentamicin by a
Downloaded from http://jid.oxfordjournals.org/ at East Carolina University on September 11, 2015
Eighty patients with urinary tract infections were randomly divided into two equal groups; one group received tobramycin, and the other received gentamicin. The daily dose of antibiotic for each group was 3 mg/kg. Mean levels in serum were 4.5 and 4.7 ug/rnl, respectively, 1 hr after an intramuscular injection, and the mean duration of therapy was 6.5 days. Mean ages and sex ratios were similar in the two groups. Essentially equal numbers of patients with pyelonephritis and cystitis were assigned randomly to each group. Eradication of infection was similar in patients in the two treatment groups, and there was not a significant number of relapses or reinfections in either group. Renal function was abnormal in seven patients treated with gentamicin and in two patients treated with tobramycin. One patient in the gentamicin group developed a skin eruption. Our data suggest that tobramycin is as effective as gentamicin in the treatment of acute urinary tract infection and may be less nephrotoxic at similar doses.
Comparison of Tobramycin and Gentamicin
8147
Results
Eleven males and 29 females were treated with tobramycin; six males and 34 females were treated with gentamicin. The mean age was similar in the two treatment groups (males, 60 years; females, 36 years). The original urinary pathogens isolated at the time of diagnosis are shown in table 1; all the usual gram-negative pathogens are included. Escherichia coli was the most prevalent organism in both treatment groups, and the other gram-negative bacteria represent organisms commonly encountered in the hospital environment. The one patient infected with Staphylococcus epidermidis is the exception; this organism is an unusual pathogen in our experience. This patient had recurrent cystitis with persistently positive results of cultures of bladder urine. Evaluation revealed no underlying cause or precipitating factor. The two-week assessment of tobramycin and Table 1. Bacterial etiology of urinary tract infections in two groups of patients treated with tobramycin or gentamicin. Treatment Organisms cultured
Escherichia coli Klebsiella pneumoniae Enterobacter aerogenes Proteus mirabilis Pseudomonas aeruginosa Providencia stuartii Serratia marcescens Staphylococcus epidermidis Total
Tobramycin
Gentamicin
25 7 3 3 1 0 0 1 40
28 7 2 0 1 1 1 0 40
NOTE. Data are given as the number of patients with infection due to the given organism.
gentamicin therapy in patients with normal and abnormal urinary tract anatomy is shown in table 2. Twenty-three patients with no detectable complicating factors were treated with tobramycin. Infections were eliminated in 19 of these patients, and relapse with the same sensitive pathogen occurred in four patients; however, a second course of antibiotic therapy eradicated the infections. Similarly, 12 patients with uncomplicated infections received gentamicin; of these patients four had a relapse with the same pathogen and required a second course of antibiotic therapy for eradication of the organism during the relapse. Twelve patients in the group treated with tobramycin had urinary tract obstruction, and infections were eliminated in nine. Of the remaining three patients, one had a relapse with the same pathogen, and two other patients became reinfected with a different pathogen during or after therapy. These three patients did not become cured until the obstruction had been removed. Similarly, nine patients treated with gentamicin had underlying urinary tract obstruction; seven of these patients were cured, and the other two had relapses with the same pathogen, with the infections resolving only after the obstruction had been removed. When an indwelling urethral catheter was used to relieve obstruction, reinfection frequently occurred despite antibiotic therapy. Anatomic abnormality of the urinary tract without obstruction was demonstrated by iv • pyelography in five patients who were treated with tobramycin; the infection was eliminated in four patients, and one patient relapsed with the same pathogen after tobramycin therapy and required further treatment. Two of six patients with anatomic abnormalities of the urinary tract who were treated with gentamicin had a similar relapse and required additional therapy. Intections were eliminated in the other four patients. One patient with urinary tract obstruction caused by ureteral stones who was treated with tobramycin developed a persistent infection with a strain of Providencia stuartii that was resistant to all antibiotics tested. Infection could not be eradicated until the stone was removed. Serum for assay of levels of antibiotics were obtained 1 hr after an im injection; the mean levels of tobramycin and gentamicin were 4.5 ug/ ml and 4.7 ug/rnl, respectively. The mean dura-
Downloaded from http://jid.oxfordjournals.org/ at East Carolina University on September 11, 2015
computer list; each patient received 1 mg of antibiotic/kg of body weight every 8 hr by im injection. A laboratory profile consisting of routine urinalysis and determinations of WBC and differential counts, hematocrit, and levels of hemoglobin, blood urea nitrogen, serum creatinine, electrolytes, aspartate aminotransferase, and alkaline phosphatase was done before, during, and after antibiotic therapy. Urine cultures were obtained at similar intervals. Further diagnostic studies were performed as indicated by the clinical condition.
Walker and Gentry
S148
Table 2. Comparison of results of treatment of urinary tract infections two weeks after therapy.
WIith
t 0 bramycm . or gentamicin
Treatment Tobramycin Complicating factor (s)
No. treated 23
Urinary tract obstruction
12
Anatomical abnormality
5
Total
Four relapses, same pathogen; 19 cures One relapse, same pathogen; two reinfections, different pathogen; nine cures One relapse, same pathogen; four cures
40
Table 3. Adverse side effects related to antibiotic therapy of urinary tract infection. Treatment Abnormal renal function * Ototoxicity . Hepatic dysfunction t Skin eruption
25 9
6
Results Four relapses, same pathogen; 21 cures Two relapses, same pathogen; seven cures Two relapses, same pathogen; four cures
40
tion of therapy was the same (6.5 days) in both groups. Associated side effects of tobramycin and gentamicin therapy are listed in table 3. Abnormal renal function as manifested by an increase in level of serum creatinine and a decrease in rate of creatinine clearance was observed in patients in both groups. Seven patients treated with gentamicin-had decreased renal function, whereas only two patients treated with tobramycin had similar decreased renal function. Ototoxicity was not detected in either group of patients. However, hepatic dysfunction manifested by a mildly elevated level of alkaline phosphatase without other laboratory abnormalities was seen in both groups. These elevated levels returned to normal after therapy had been completed. Without any prior history of allergy, one patient developed an erythematous maculopapular eruption and peripheral blood eosinophilia during therapy with gentamicin. No other medication was being administered during this time, and these
Adverse side effect
No. treated
Results
Tobramycin
Gentamicin
2 0 2 0
7 0 3
1
NOTE. Data are given as the number of patients with the indicated side effect. Forty patients received tobramycin, and 40 received gentamicin. * Increased level of serum creatinine. t Increased level of alkaline phosphatase.
manifestations cleared after discontinuation of therapy.
Discussion
The randomly selected populations in this study were appropriately matched with respect to age and sex and were similarly treated with equal doses of either gentamicin or tobramycin. The distribution of bacterial pathogens was similar for both treatment groups, and the effectiveness of tobramycin in the treatment of infections with gram-negative bacteria was demonstrated. We were unable to observe any significant differences between tobramycin and gentamicin in antibacterial activity or in effectiveness in the .eradication of urinary tract infection. Because only two pseudomonas infections were encountered, we were unable to demonstrate the increased effectiveness of tobramycin against Pseudomonas. Decreases in renal function observed in this study occurred most frequently in older patients. Underlying renal disease is more common in the elderly population and may account for some of these changes; however, because the populations were well matched, antibiotic therapy undoubtedly contributed in part to the nephrotoxicity observed [5, 6]. It would follow that gentamicin was responsible for more nephrotoxicity than tobramycin. The lack of signs of ototoxicity in this study probably reflects the dose of drug used. Although hepatic dysfunction occurred, as manifested by an elevated level of alkaline phosphatase, we were unable to attribute this clearly to antibiotic therapy.
Downloaded from http://jid.oxfordjournals.org/ at East Carolina University on September 11, 2015
None
Gentamicin
Comparison of Tobramycin and Gentamicin
References 1. Burger, L. M., Sanford, J. P., Zweighaft, T. Tobra-
mycin: bacteriological evaluation. Am. J. Med. Sci. 265: 135-142, 1973. 2. Britt, M. R., Garibaldi, R. A., Wilfert,' J.N.,· Smith, C. B. In vitro activity of tobramycin and gentamicin. Antimicrob. Agents Chemother. 2:236241, 1972. 3. Malavi, A., Barza, M., Cole, W., Berman, H., Weinstein L. In vitro assessment of tobramycin, a new aminoglycoside with anti-pseudomonas activity. Chemotherapy 18:7-16, 1973.
S149
4. Meyers, B. R., Hirschman, S. Z. Pharmacologic studies on tobramycin and comparison with gentamicin. J. Clin. Pharmacol. 12:321-324, 1972. 5. Benner, E. J., Kranhold, J., Bush, W. Tobramycin: in vitro activity, dosage nomogram derived from renal handling and clinical efficacy. In Tobramycin, selected proceedings from the Eighth International Congress of Chemotherapy, Athens, September 8-15, 1973. Excerpta Medica, Amsterdam, 1974, p. 16-23. 6. Gingell, J. C., Waterworth, P. M. Dose of gentamicin in patients with normal renal function and renal impairment. Br. Med. J. 2: 19-23, 1968. Downloaded from http://jid.oxfordjournals.org/ at East Carolina University on September 11, 2015
• AUGUST 1976
A Randomized, Comparative Study of Tobramycin and Gentamicin in Treatment of Acute Urinary Tract Infections From the Department of Internal Medicine, Baylor College of Medicine, Houston, Texas
Brian D. Walker and Layne O. Gentry
The ever-increasing number of cases of opportunistic infections with gram-negative bacteria has been associated with emergence of resistance to the commonly used antimicrobial agents. The frequent use of gentamicin in the therapy of gramnegative bacterial infections has resulted in the development of gentamicin-resistant organisms. Because these commonly encountered, resistant organisms are causing increased morbidity and mortality rates, there is a need for more effective agents. Tobramycin is a new aminoglycoside that has an in vitro antibacterial spectrum similar to that of gentamicin [1, 2]. However, the in vitro activity of tobramycin against strains of Pseudomonas is two- to fourfold greater than that of gentamicin [3]. Tobramycin thus adds to the antibacterial spectrum of the aminoglycosides. Tobramycin is a derivative of the actinomycete Streptomyces tenebrarius, and its active component is factor 6 of the nebramycin complex. Since gentamicin and tobramycin have been independently compared as to their clinical phar-
This study was supported by Eli Lilly and Company, Indianapolis, Indiana, and by the Clinical Research Center of Baylor College of Medicine. Please address requests for reprints to Dr. L. O. Gentry, Department of Internal Medicine, Baylor College of Medicine, Houston, Texas 77025.
8146
macology [4] and in vitro bacteriology [1], we elected to compare these two drugs in the therapy of acute urinary tract infections. Materials and Methods
Patients in this study were referred from the Emergency Center or Inpatient Medical or Surgical Services, Harris County Hospital District, Houston, Texas. Informed consent was obtained from all patients according to the guidelines of the Human Experimentation Committee, Baylor College of Medicine. Patients adrriitted with urinary tract infections had clinical .symptoms of frequency, dysuria, and urgency, and infections in all patients were confirmed bacteriologically (> 105 colonies of bacterialml of urine). Urinary tract infection was further delineated into pyelonephritis and cystitis. The diagnostic criteria for pyelonephritis were symptoms of urgency, frequency, dysuria, and flank pain associated with fever of > 101 F and laboratory findings of leukocytosis C> 13,000 white blood cells [WBCl/ rnm"), pyuria (> 10 WBC per high-power field), and WBC or granular casts on urinalysis. Those patients with urinary tract infection who did not meet the diagnostic criteria for pyelonephritis were considered to have cystitis. All patients were randomly assigned to treatment with either tobramycin or gentamicin by a
Downloaded from http://jid.oxfordjournals.org/ at East Carolina University on September 11, 2015
Eighty patients with urinary tract infections were randomly divided into two equal groups; one group received tobramycin, and the other received gentamicin. The daily dose of antibiotic for each group was 3 mg/kg. Mean levels in serum were 4.5 and 4.7 ug/rnl, respectively, 1 hr after an intramuscular injection, and the mean duration of therapy was 6.5 days. Mean ages and sex ratios were similar in the two groups. Essentially equal numbers of patients with pyelonephritis and cystitis were assigned randomly to each group. Eradication of infection was similar in patients in the two treatment groups, and there was not a significant number of relapses or reinfections in either group. Renal function was abnormal in seven patients treated with gentamicin and in two patients treated with tobramycin. One patient in the gentamicin group developed a skin eruption. Our data suggest that tobramycin is as effective as gentamicin in the treatment of acute urinary tract infection and may be less nephrotoxic at similar doses.
Comparison of Tobramycin and Gentamicin
8147
Results
Eleven males and 29 females were treated with tobramycin; six males and 34 females were treated with gentamicin. The mean age was similar in the two treatment groups (males, 60 years; females, 36 years). The original urinary pathogens isolated at the time of diagnosis are shown in table 1; all the usual gram-negative pathogens are included. Escherichia coli was the most prevalent organism in both treatment groups, and the other gram-negative bacteria represent organisms commonly encountered in the hospital environment. The one patient infected with Staphylococcus epidermidis is the exception; this organism is an unusual pathogen in our experience. This patient had recurrent cystitis with persistently positive results of cultures of bladder urine. Evaluation revealed no underlying cause or precipitating factor. The two-week assessment of tobramycin and Table 1. Bacterial etiology of urinary tract infections in two groups of patients treated with tobramycin or gentamicin. Treatment Organisms cultured
Escherichia coli Klebsiella pneumoniae Enterobacter aerogenes Proteus mirabilis Pseudomonas aeruginosa Providencia stuartii Serratia marcescens Staphylococcus epidermidis Total
Tobramycin
Gentamicin
25 7 3 3 1 0 0 1 40
28 7 2 0 1 1 1 0 40
NOTE. Data are given as the number of patients with infection due to the given organism.
gentamicin therapy in patients with normal and abnormal urinary tract anatomy is shown in table 2. Twenty-three patients with no detectable complicating factors were treated with tobramycin. Infections were eliminated in 19 of these patients, and relapse with the same sensitive pathogen occurred in four patients; however, a second course of antibiotic therapy eradicated the infections. Similarly, 12 patients with uncomplicated infections received gentamicin; of these patients four had a relapse with the same pathogen and required a second course of antibiotic therapy for eradication of the organism during the relapse. Twelve patients in the group treated with tobramycin had urinary tract obstruction, and infections were eliminated in nine. Of the remaining three patients, one had a relapse with the same pathogen, and two other patients became reinfected with a different pathogen during or after therapy. These three patients did not become cured until the obstruction had been removed. Similarly, nine patients treated with gentamicin had underlying urinary tract obstruction; seven of these patients were cured, and the other two had relapses with the same pathogen, with the infections resolving only after the obstruction had been removed. When an indwelling urethral catheter was used to relieve obstruction, reinfection frequently occurred despite antibiotic therapy. Anatomic abnormality of the urinary tract without obstruction was demonstrated by iv • pyelography in five patients who were treated with tobramycin; the infection was eliminated in four patients, and one patient relapsed with the same pathogen after tobramycin therapy and required further treatment. Two of six patients with anatomic abnormalities of the urinary tract who were treated with gentamicin had a similar relapse and required additional therapy. Intections were eliminated in the other four patients. One patient with urinary tract obstruction caused by ureteral stones who was treated with tobramycin developed a persistent infection with a strain of Providencia stuartii that was resistant to all antibiotics tested. Infection could not be eradicated until the stone was removed. Serum for assay of levels of antibiotics were obtained 1 hr after an im injection; the mean levels of tobramycin and gentamicin were 4.5 ug/ ml and 4.7 ug/rnl, respectively. The mean dura-
Downloaded from http://jid.oxfordjournals.org/ at East Carolina University on September 11, 2015
computer list; each patient received 1 mg of antibiotic/kg of body weight every 8 hr by im injection. A laboratory profile consisting of routine urinalysis and determinations of WBC and differential counts, hematocrit, and levels of hemoglobin, blood urea nitrogen, serum creatinine, electrolytes, aspartate aminotransferase, and alkaline phosphatase was done before, during, and after antibiotic therapy. Urine cultures were obtained at similar intervals. Further diagnostic studies were performed as indicated by the clinical condition.
Walker and Gentry
S148
Table 2. Comparison of results of treatment of urinary tract infections two weeks after therapy.
WIith
t 0 bramycm . or gentamicin
Treatment Tobramycin Complicating factor (s)
No. treated 23
Urinary tract obstruction
12
Anatomical abnormality
5
Total
Four relapses, same pathogen; 19 cures One relapse, same pathogen; two reinfections, different pathogen; nine cures One relapse, same pathogen; four cures
40
Table 3. Adverse side effects related to antibiotic therapy of urinary tract infection. Treatment Abnormal renal function * Ototoxicity . Hepatic dysfunction t Skin eruption
25 9
6
Results Four relapses, same pathogen; 21 cures Two relapses, same pathogen; seven cures Two relapses, same pathogen; four cures
40
tion of therapy was the same (6.5 days) in both groups. Associated side effects of tobramycin and gentamicin therapy are listed in table 3. Abnormal renal function as manifested by an increase in level of serum creatinine and a decrease in rate of creatinine clearance was observed in patients in both groups. Seven patients treated with gentamicin-had decreased renal function, whereas only two patients treated with tobramycin had similar decreased renal function. Ototoxicity was not detected in either group of patients. However, hepatic dysfunction manifested by a mildly elevated level of alkaline phosphatase without other laboratory abnormalities was seen in both groups. These elevated levels returned to normal after therapy had been completed. Without any prior history of allergy, one patient developed an erythematous maculopapular eruption and peripheral blood eosinophilia during therapy with gentamicin. No other medication was being administered during this time, and these
Adverse side effect
No. treated
Results
Tobramycin
Gentamicin
2 0 2 0
7 0 3
1
NOTE. Data are given as the number of patients with the indicated side effect. Forty patients received tobramycin, and 40 received gentamicin. * Increased level of serum creatinine. t Increased level of alkaline phosphatase.
manifestations cleared after discontinuation of therapy.
Discussion
The randomly selected populations in this study were appropriately matched with respect to age and sex and were similarly treated with equal doses of either gentamicin or tobramycin. The distribution of bacterial pathogens was similar for both treatment groups, and the effectiveness of tobramycin in the treatment of infections with gram-negative bacteria was demonstrated. We were unable to observe any significant differences between tobramycin and gentamicin in antibacterial activity or in effectiveness in the .eradication of urinary tract infection. Because only two pseudomonas infections were encountered, we were unable to demonstrate the increased effectiveness of tobramycin against Pseudomonas. Decreases in renal function observed in this study occurred most frequently in older patients. Underlying renal disease is more common in the elderly population and may account for some of these changes; however, because the populations were well matched, antibiotic therapy undoubtedly contributed in part to the nephrotoxicity observed [5, 6]. It would follow that gentamicin was responsible for more nephrotoxicity than tobramycin. The lack of signs of ototoxicity in this study probably reflects the dose of drug used. Although hepatic dysfunction occurred, as manifested by an elevated level of alkaline phosphatase, we were unable to attribute this clearly to antibiotic therapy.
Downloaded from http://jid.oxfordjournals.org/ at East Carolina University on September 11, 2015
None
Gentamicin
Comparison of Tobramycin and Gentamicin
References 1. Burger, L. M., Sanford, J. P., Zweighaft, T. Tobra-
mycin: bacteriological evaluation. Am. J. Med. Sci. 265: 135-142, 1973. 2. Britt, M. R., Garibaldi, R. A., Wilfert,' J.N.,· Smith, C. B. In vitro activity of tobramycin and gentamicin. Antimicrob. Agents Chemother. 2:236241, 1972. 3. Malavi, A., Barza, M., Cole, W., Berman, H., Weinstein L. In vitro assessment of tobramycin, a new aminoglycoside with anti-pseudomonas activity. Chemotherapy 18:7-16, 1973.
S149
4. Meyers, B. R., Hirschman, S. Z. Pharmacologic studies on tobramycin and comparison with gentamicin. J. Clin. Pharmacol. 12:321-324, 1972. 5. Benner, E. J., Kranhold, J., Bush, W. Tobramycin: in vitro activity, dosage nomogram derived from renal handling and clinical efficacy. In Tobramycin, selected proceedings from the Eighth International Congress of Chemotherapy, Athens, September 8-15, 1973. Excerpta Medica, Amsterdam, 1974, p. 16-23. 6. Gingell, J. C., Waterworth, P. M. Dose of gentamicin in patients with normal renal function and renal impairment. Br. Med. J. 2: 19-23, 1968. Downloaded from http://jid.oxfordjournals.org/ at East Carolina University on September 11, 2015
