Comparison of Amikacin and Gentamicin in the Treatment of Urinary Tract Infections
The use of standard doses of gentamicin and small doses of amikacin was compared in the treatment of urinary tract infections in 30 adults. Patients were prospectively randomized to treatment with 3 to 4 mg/kg/day of gentamicin (group 1) or 9 mg/kg/day of amikacin (group 2). The age and sex of the patient, and the duration of the treatment were sfmilar in the two groups. Eleven of the 15 patients in each group were diagnosed clinically as having pyelonephritis. The majority of patients in both groups either required a permanent Foley catheter or had associated diseases predisposing to urinary tract infections. In nine of 15 patients in each group, the bacterial etiology was Pseudomonas aeruginosa. Bacteriologic cures were achieved in nine of 15 patients treated with gentamicin (group 1) and in 10 of 15 patients treated with amikacin (group 2). The mean peak concentration of gentamicin was 5.4 pg/ml (range: 2 to 13 pg/ml), and the mean peak concentration of amikacin was 11.2 pg/ml (range: 8.2 to 19.6 pg/ml). In the patients treated with gentamicin, there was no correlation between the peak serum concentration of gentamictn, the in vitro minimum inhibitory concentration and the bacteriologic response to treatment. No direct evidence of antibiotic-induced toxtcity was detected. These results suggest that a reduced amikacin dosage schedule gave results essentially equivalent to standard doses of gentamicin in adults with urinary tract infections.
D. N. GILBERT, M.D. N. EUBANKS,
M.D.*
J. JACKSON,
M.D.
Portland, Oregon
From the Leslie Gilbert Infectious Diseases Laboratory, Providence Medical Center and the Department of Medicine, University of Oregon !-k&h Sciences Center, Portland, Oregon. This study was presented at the U.S. Amikacin Symposium, University of California Medical School, Los Angeles, California, November 9-10, 1976. It was supported in part by a grant from Bristol Laboratories. Requests for reprints should be addressed to Dr. David N. Gilbert, Providence Medical Center, 700 N. E. 47th Avenue, Portland, Oregon 97213. *Present address: Tieton R.S. Box 189. Naches. Washington 98937.
924
June 1977
This study explores the potential of small doses of amikacin in the treatment of urinary tract infections in adults: The investigation was motivated by two major factors. First, the in vitro antimicrobial spectrum of amikacin is similar to gentamicin and, hence, includes the majority of organisms that cause urinary tract infections [l-7]. Secondly, accumulated data with amikacin suggest a more favorable therapeutic ratio (mean peak serum concentration to minimum inhibitory concentration) for amikacin as compared to other aminoglycoside antibiotics [ 1,3,4]. Published pharmacokinetic studies demonstrate that 7.5 mg/kg of intramuscular amikacin results in average peak serum concentrations between 17 and 23 pg/ml [ 81. Thus, it was hypothesized that for urinary tract infections the dosage of amikacin, and hence the peak serum concentration of amikacin, could be reduced and that serum and urine concentrations inhibitory for those organisms which commonly produce infection could still be achieved. It was hoped that the lower dosage would lessen the risk of amikatin-induced toxicity.
The American Journal of Medlclne
Volume 62
COMPARISON 0~ AMIKACIN AND GENTAMICINAXBERT
A prospective randomized study was designed. Instead of the maximum recommended dosage of amikacin, 15 mg/kg/day, the dosage of amikacin employed was 9 mg/kg/day. The gentamicin dosage was 3 to 4 mg/kg/day. The results indicate that both amikacin and gentamicin, in the dosages employed, are clinically and bacteriologically effective in the treatment of urinary tract infections in adults. No obvious difference in the occurrence of toxic reactions was observed.
ET AL.
(2) Cure with reinfection, when urine cultures were negative during therapy but more than IO5 new organisms/ml of urine appeared within 10 days after therapy was discontinued. (3) Persistence, when more than lo5 organisms/ml of the original infecting organism were present in the urine during and after therapy. (4) Superinfection, therapy.
when reinfection
developed
during
MATERIALS AND METHODS Patients studied were hospitalized in an acute care community hospital. They were required to be over the age of 15 years and to have a culture of mid-stream, clean-catch urine with more than lo5 organisms/ml, susceptible to gentamicin by the Kirby-Bauer disc diffusion method. Patients were excluded from the study if they had a history of allergy to aminoglycoside antibiotics, recent antimicrobial therapy, evidence of auditory or vestibular disease and laboratory evidence of impaired renal function. The patients were examined and, based on the criteria of Kunin, the urinary tract infection was classified as cystitis, pyelonephritis, prostatitis/epididymitis or asymptomatic bacteriuria [9]. After obtaining informed consent, the patient was assigned at random to either gentamicin or amikacin treatment according to a standard table of random numbers. Patients given gentamicin received a loading dose of 1.5 mg/kg followed by a maintenance dosage of 3 to 4 mg/ kg/day given in three divided doses. Amikacin was administered in a dosage of 9 mg/kg/day in three divided doses. Patients were treated for seven to 14 days. Drugs were administered either intramuscularly or intravenously. Intravenous amikacin and gentamicin were infused over a 30 minute period. Serum for determining antibiotic concentration was obtained 1 hour after the initiation of the intravenous infusion. If the antibiotic was given intramuscularly, serum was obtained 1 hour later. These 1 hour determinations are referred to as “peak” serum concentrations of gentamicin and amikacin. Peak and nadir serum aminoglycoside concentrations were determined after the first 72 hours of therapy. The gentamicin concentration was determined by adenylating enzyme method and the amikacin concentration was determined by the acetylating enzyme method [ 10.111. Concentrations of antibiotic in urine were not determined. The dosage of amikacin was not altered to obtain any specific peak serum concentration. Gentamicin dosage was adjusted to maintain a peak concentration between 4 and 8 pg/ml. During therapy, patients were examined frequently for evidence of drug-related toxicity and to evaluate their clinical response to treatment. A repeat urine specimen for culture was obtained during therapy. Two to 10 days after completion of treatment, urine for culture was obtained. Bacteriologic results of therapy were classified as follows [9] :
(1) Cure, when urine cultures were negative (less than lo4 organisms/ml) during therapy and on follow-up urine culture.
(5) Relapse, when more than 105/ml of the original infecting organism were present in the post-treatment urine specimen after the demonstration of less than lo4 organisms/ml during therapy. When urine isolates were of the same -genus and species as the initial isolate, differentiation between relapse and reinfection was based upon pyocine typing for Pseudomonas isolates and serotyping for other aerobic gramnegative bacilli. No specific studies were made to localize infection to the upper and/or lower urinary tract. Agar-plate dilution susceptibility testing was performed by standard methods utilizing a Steer’s replicator device [ 121. The calcium and magnesium concentration of the agar was approximated to concentrations normally found in serum by a previously-published method [ 131. Disc-diffusion susceptibility testing was carried out by standard methods for both gentamicin and amikacin [ 141. Using the 10 pg amikacin disc, a zone diameter of equal to or more than 14 mm was considered sensitive and a zone size of equal to or less than 12 mm was interpreted as resistant. A zone diameter of 13 mm was interpreted as intermediate. With agar-plate dilution a minimum inhibitory concentration (MC) of amikacin equal to or less than 16 fig/ml was considered sensitive and more than 32 pg/ml was considered resistant. For gentamicin, an agar-plate dilution MIC more than 6.3 pg/ml was considered resistant and equal to or less than 6.3 pg/ml was interpreted as sensitive. In the patient group treated with amikacin, audiograms were obtained before and after treatment when it was thought that the patient’s mental status allowed valid testing. Patients were questioned daily regarding tinnitus, decreased hearing, sensation of fullness in the ears and possible vestibular symptoms. Renal impairment was defined as a twofold or greater increase in the serum creatinine concentration with a resulting maximum concentration of equal to or more than 1.5 mg/ 100 ml, or a decrease in the endogenous creatinine clearance of at least 50 per cent from base line values. RESULTS A total of 15 patients were treated with gentamicin (group l), and 15 patients were treated with amikacin (group 2). The patients treated with gentamicin ranged in age from 20 to 82 years and the patients treated with amikacin from 16 to 86 years. The male:female ratio was nearly equivalent (8:7 in group 1 and 7:8 in group 2). Patients in group 1 were treated for a mean of 11
June 1977 The Amerlcen Journalof Medicine Volume 62
925
COMPARISON
TABLE
I
OF AMIKACIN
Bacterial
Etiology
Organism Pseudomonas aeruginosa Escherichia coli Klebsiella species Serratia marcescens Proteus mirabilis Proteus rettgeri Total l
AND GENTAMICIN-GILBERT
by Treatment
ET AL.
Group
Group 1
Group 2
9” 4” 1 1 1 I*
9 5 1
17
Two mixed
. . . .
.. 15
infections.
days (seven to 22 day range). The patients in group 2 were treated for a mean of 10 days (seven to 14 day range). Classification of Urinary Tract Infection. Pyelonephritis was diagnosed in 11 patients in group 1 and in 11 patients in group 2. One patient in group 1 and two patients in group 2 had positive blood cultures. The diagnosis of cystitis was made in one patient in group 1 and no patients in group 2. ProstatitisIepididymitis was diagnosed in three patients in group 1 and in one patient in group 2. Asymptomatic bacteriuria was the diagnosis in three patients in group 2. There were no patients with asymptomatic bacteriuria in group 1. It is pertinent that 10 of the 15 patients in group 2 and 11 of the 15 patients in group 1 had Foley catheters in place at the time a urinary tract infection was diagnosed. Of the five patients in group 2 without an indwelling catheter, three patients had significant underlying disease (lymphoma, multiple myeloma, phenacetin nephritis) which may have contributed to their urinary tract infection. Of the four patients without an indwelling Foley catheter in group 1, three had a significant underlying disease (nephrolithiasis, phenacetin nephritis, chronic prostatitis) which may have contributed to their urinary tract infection. Bacterial Etiology. The infecting organisms in the two groups were similar. Ps. aeruginosa was the most common isolated pathogen in both groups (Table I). The second most common isolate was Escherichia coli followed by single isolations of Klebsiella species, Serratia marcescens, Proteus mirabilis and Proteus rettgeri. By Kirby-Bauer disc-diffusion susceptibility testing, all bacterial isolates in both patient groups were susceptible to gentamicin and amikacin. With the exception of one Ps. aeruginosa (MIC 25 Fg/ml), all bacterial strains in group 2 met the agar-plate dilution criteria (equal to or less than 16 pg/ml) for sensitivity. In group 1, three Ps. aeruginosa isolates and one Pr. rettgeri isolate had an MIC of 12.5 pg/ml and were categorized as resistant. Clinical and Bacteriologic Response to Treatment. In symptomatic patients, the signs and symptoms of urinary tract infection disappeared rapidly in all patients
926
June 1977
The American Journal of Medicine
Volume 62
in both groups. There was no evident difference in the rapidity with which symptoms resolved. All patients randomized completed the study. The bacteriologic response to treatment is shown in Table II. Using the criteria described, nine of 15 patients in group 2 were considered cured. In one patient treated with gentamicin, the infecting organism persisted. This occurred in a patient with papillary necrosis due to analgesic abuse and Ps. aeruginosa pyelonephritis. After the phenacetin ingestion was discontinued, the patient was cured with a course of amikacin treatment. One patient in group 1 and two patients in group 2 were classified as having a superinfection. In two instances the superinfecting organism was a group D Streptococcus (group 2) and in one instance Candida albicans (group 1). All three patients had underlying diseases which required the presence of an indwelling Foley catheter during treatment. Two patients in group 1 and two patients in group 2 were classified as having a cure with reinfection. Three of the four patients either had had an indwelling Foley catheter for a long time or had undergone a surgical procedure which diverted the urinary stream, e.g., ureterosigmoidostomy. Two patients in group 1 and one patient in group 2 were classified as having a bacteriologic relapse due to Ps. aeruginosa. Because of the number of patients requiring permanent indwelling Foley catheters, long-term bacteriologic evaluation did not seem pertinent to the in vivo antimicrobial effectiveness of the drugs under study. Therefore, no long-term bacteriologic studies were performed. In group 2, urine for post-treatment bacteriologic study was collected within two or 10 days (mean four days) of the end of treatment. In group 1 the posttreatment urine was collected between two and 16 days after the completion of treatment (mean five days). Aminoglytoside Serum Concentrations. Peak serum concentrations of gentamicin were obtained for all 15 patients. Peak concentrations of amikacin were available for 14 of the 15 patients. As shown in Figure 1, the gentamicin concentrations ranged from 2 to 13 kg/ml, with a geometric mean value O? 5.4 pg/ml. The amikacin concentrations ranged from 8.2 to 19.6 pg/ml, with a geometric mean of 11.2 pug/ml. TA.BLE II
Bacteriologic
Classification Cure Persistence Superinfection Cure with reinfection Relapse Total
Response
to Treatment
Group 1
Group 2
(no.)
(no.)
9 1 1 2 2
10
15
15
2 2 1
COMPARISON OF AMIKACIN AND GENTAMICIN-GILBERT
18
16
A
(I?
A A
;
A
i
8 0
A
6
( I = Number of Patients 0
-
L
Gentamicin Figure 1. Peak serum concentrations, treated with gentamicin or amikacin.
= Geometric Mean Value
L
Amikacin pg/ml,
ET AL.
peak antibiotic concentration in vivo in six of the 11 patients in group 1 as compared to only one of the 15 patients in group 2. Despite the unfavorable ratio between the MIC and the peak gentamicin concentration, five of the six patients treated with gentamicin had a bacteriologic cure. Persistence occurred in one patient whose Ps. aeruginosa remained sensitive to gentamicin in vitro. In one patient treated with amikacin, despite an MIC higher than the serum concentration, bacteriologic cure was achieved. There was no clinical eviAminoglycoside Toxicity. dence of vestibular or auditory toxicity in either group. No audiograms were obtained in group 1. In group 2, audiograms were obtained in four patients during the first 48 hours of treatment with follow-up audiograms obtained 10 to 14 days later. Three of the four patients had mild perceptive hearing loss on their base line examinations. The post-treatment audiograms were unchanged in all four instances. Two patients in each group met the criteria for nephrotoxicity. In three of the four patients, the diagnosis was Ps. aeruginosa pyelonephritis; in the fourth patient, the diagnosis was asymptomatic bacteriuria due to Ps. aeruginosa. In three of the four patients there were underlying dieases involving the kidneys. Three of the four had received a cephalosporin antibiotic prior to the initiation of aminoglycoside therapy. At the time renal impairment was observed, the peak amikacin concentrations were 19.5 and 10.1 gglml, and the peak gentamicin concentrations were 11 and 4 pg/ml. In one of the two patients treated with amikacin, endogenous creatinine clearance returned to base line values; in the other, creatinine clearance decreased from 155 to 56 cc/min and remained at the lower level for the duration of the three month follow-up period. Of the two patients who were treated with gentamicin, renal function returned to normal in one; in the other azotemia persisted and the patient subsequently died due to pulmonary emboli.
of patients
TABLE III It was of interest to attempt a correlation between the “peak” serum antibiotic concentration, the in vitro MIC determined by the agar-plate dilution technic and the bacteriologic results of treatment. It was possible to complete this analysis for all 15 patients in group 2 and for 11 of 15 patients in group 1. As shown in Table Ill, the peak serum antibiotic concentration in vivo was greater than the MIC in five of 11 patients in group 1 and in 14 of 15 patients in group 2. A bacteriologic cure resulted in all five patients in group 1 and in 13 of the 14 patients in group 2, with one instance of bacteriologic relapse. In contrast, the MIC was greater than the
Correlation of “Peak” Serum Antibiotic Concentration (PAC), Minimum Inhibitory Concentration (MIC) and Bacteriologic Results of Therapy -___ PAC> MIC
MIC > PAC -_____ Group 1 Group 2 Group 1 Group 2 NO. of patients/ total patients studied* Bacteriologic result curet Persistence/relapse
5111 515 0
14115 13114 1114
6111 516 116
l/15 l/l 0
* Data available for all 15 patients in group 2 and 11 of 15 patients in group 1. t Includes cure with superinfection and cure with reinfection.
June 1977
The American Journal of Medicine
Volume 62
927
COMPARISON OF AMIKACIN AND GENTAMICIN-GILBERT
ET AL.
COMMENTS
This study demonstrates many of the weaknesses and frustrations of therapeutic trials for urinary tract infections. There is no comparison with an untreated control group. Localization by clinical criteria of the site of infection within the urinary tract is imprecise [ 151. At the time this study was conducted, noninvasive localizing procedures were not readily available and invasive procedures were not considered to be justified [ 161. It is difficult to quantify the influence of necessary foreign bodies, e.g., catheters and underlying urologic disease, on the course of the infection‘and the patient’s treatment. Even if these variables were subject to control and true double-blind prospective protocols employed, it is anticipated that very large numbers of patients would be necessary to demonstrate statistically significant differences, The results of this small prospective randomized study of urinary tract infections in adults suggest that the bacteriologic cure rates are similar after treatment with small doses of amikacin and standard doses of gentamicin. It is emphasized that our definition of bacteriologic cure was based upon the results of the urine culture obtained between two and 10 days after completion of therapy. This is discrepant with the Food and Drug Administration protocol for urinary tract infections which implies that follow-up urine cultures must be negative at one and four to six weeks after the termination of therapy to define a cure [ 171. As demonstrated in our study population, many of the patients in whom aminoglycoside therapy is indicated, have underlying diseases involving the urinary tract or neurologic system and frequently require a permanent indwelling Foley catheter. As a result, the urine becomes colonized frequently during or after a course of antimicrobial therapy. An antibacterial effect is demonstrated by the eradication of the initial infecting organism, even ifthe eradication lasts for only a short period of time. Similarly, the occurrence of a superinfection during treatment or reinfection with a different organism does not detract from the antimicrobial efficacy demonstrated by eradication of the initial infecting organism. In such a small group of patients, it is difficult to make definitive statements regarding the efficacy of the reduced amikacin dosage. However, in patients with pyelonephritis, there is a precedent for utilization of doses of antimicrobial agents that produce high urine concentrations but serum concentrations that predictably would be lower than the MIC for the offending organism [ 181. In patients with bacteremia complicating their pyelonephritis, it might be desirable to have serum concentrations which exceed the MIC of the infecting bacteria. In the 30 patients which constitute the present study, three patients had pyelonephritis complicated by
928
June 1977
The American Journal of Medicine
Volume 82
bacteremia: the infecting organism was Esch. coli in two patients and Ps. aeruginosa in the third. In all three patients, the measured peak serum concentration of aminoglycoside antibiotic exceeded the MIC. Since the peak serum concentration achieved with therapeutic doses of amikacin are so much higher than the corresponding levels for gentamicin, it is not surprising that, even with the smaller dosage of amikacin used in this study, the peak serum level frequently exceeded the in vitro MIC of organisms isolated from amikacin-treated patients. It was of interest that the peak gentamicin concentration and the in vitro MIC did not correlate with the bacteriologic cure rate (Table Ill). Despite the small numbers of patients, six gentamitin-treated patients (group 1) had a bacterial isolate with an MIC greater than the measured peak serum aminoglycoside concentration, and yet bacteriologic cure was achieved in five of these six. These results support the importance of urine, rather than serum, concentrations. A review of the recent literature indicates a high bacteriologic cure rate with amikacin in urinary tract infections. Meyer and associates [ 191 described 36 patients with a variety of infections treated with amikacin. Among these were six febrile patients with urinary tract infections. Of these six patients, five had bacteriologic cures and one initially showed improvement but suffered a late relapse. Tally et al. [20] reported the clinical and bacteriologic response to amikacin therapy in 12 patients with serious infections with gentamicin-resistant gram-negative bacilli. In four of these 12, the urinary tract was involved. There was a good clinical response in all four patients. Because there was no follow-up urine cultures until 30 days after the end of treatment, it is difficult to judge the bacteriologic response to treatment. Lastly, Sharp et al. [ 2 1] described 11 patients with 12 episodes of urinary tract infection due to drug-resistant Pr. rettgeri. All patients were infected either after a urologic procedure or after the utilization of an indwelling urethral catheter. The Proteus were all resistant to more than 125 pg/ml of gentamicin. Bacteriologic cures were obtained in 11 of the 12 episodes of infection. In conclusion, this prospective randomized study of urinary tract infections in adults treated with either standard doses of gentamicin or lower than standard doses of amikacin resulted in similar bacteriologic and clinical responses. If confirmed in a larger group of patients, the use of a smaller dosage of amikacin may lower the potential of drug-related toxicity. ACKNOWLEDGMENT
We wish to express our thanks to Dr. Harold Rose for Ps. aeruginosa pyocine typing.
COMPARISON OF AMIKACIN
AND GENTAMICIN-GILBERT
ET AL.
REFERENCES
2.
3.
4.
5.
6.
7.
a. 9.
10.
Weinstein RJ, Young LS, Hewitt WL: Activity of three aminoglycosides and two penicillins against four species of gram-negative bacilli. Antimicrob Agents Chemother 7: 172,1975. Price KE, Pursiano TA, DeFuria MD, et al.: Activity of B&K6 (amikacin) against clinical isolates resistant to one or more aminoglycoside antibiotics. Antimicrob Agents &smother 5: 143, 1974. Rahal JJ Jr, Simberkoff MS, Kagan K, et al.: Bactericidal efficacy of Sch. 20569 and amikacin against gentamicinsensitive and gentamicin-resistant organisms. Antimicrob Agents Chemother 9: 595, 1976. Kelly MT, Matsen JM: In vitro activity, synergism, and testing parameters of amikacin with comparisons to other aminoglycoside antibiotics. Antimicrob Agents Chemother 9: 440, 1976. Yu PKW, Washington JA II: Comparative in vitro activity of three aminoglycoside antibiotics. BB-K6, kanamycin and gentamicin. Antimicrob Agents Chemother 4: 133, 1973. Young LS, Hewitt WL: Activity of five aminoglycoside antibiotics in vitro against gram-negative bacilli and Staphylococcus aureus. Antimicrob Agents Chemother 4: 617, 1973. Braude Al: Current concepts of pyelonephritis. Medicine (Baltimore) 52: 257, 1973. Clarke JT, Libke RD. Fiegamey C, et al.: Comparaive pharmacokinetics of amikacin and kanamycin. Clin Pharmacol Therap 15: 610, 1974. Kunin CM: Detection, Prevention and Management of Urinary Tract Infections, 2nd ed, Philadelphia, Lea & Febiger. 1974, P 7. Smith AL, Smith DH: Gentamicin: adenine mononucleotide transferase. Partial purification, characterization and use in the clinical quantitation of gentamicin. J Infect Dis 129:
11.
12.
13.
14.
15. 16.
17.
ia. 19.
20.
21.
June 1977
391.1974. Stevens P, Young LS, Hewitt WL: Radioimmunoassay acetylating radioenzymatic assay and microbioassay of gentamicin. A comparative study. J Lab Clin Med 66: 349, 1975. Edcsson HM, Sherris JC: Antibiotic sensitivity testing. Report of an international collaborative study. Acta Pathol Microbial Stand [B] 217: 65, 1971. Gilbert DN. Kutscher E, Ireland P, et al.: Effect of the concentrations of magnesium and calcium on the in vitro susceptibility of Pseudomonas aeruginosa to gentamicin. J Infect Dis 124(S): 37. 1971. Bauer AW, Kirby WMM, Sherris JC, et al.: Antibiotic susceptibility testing by a standardized single disc method. Am J Clin Pathol 45: 493, 1966. Sanford JP: Urinary tract infections and symptoms. Ann Rev Med 26: 465, 1975. Jones SR, Smith JW, Sanford JP: Localization of urinary tract infections by detection of antibody-coated bacteria in urine sediment. N Engl J Med 290: 591, 1974. Guidelines for Protocols of New Antimicrobial Efficacy in Urinary Tract Infections. Food and Drug Administration, 1975. Stamey TA, Fair WR, Timothy MM, et al.: Serum versus urinary antimicrobial concentrations in cure of urinary tract infections. N Engl J Med 291: 1159. 1974. Meyer RD, Lewis RP, Carmalt ED, et al.: Amikacin therapy for serious gram-negative bacillary infections. Ann Intern Med 83: 790, 1975. Tally FP, Louie TJ, Weinstein WM, et al.: Amikacin therapy for severe gram-negative sepsis. Ann Intern Med 83: 484, 1975. Sharp PM, Saenz CA, Martin RR: Amikacin (BEK6) treatment of multiple-drug-resistant Proteus infections. Antimicrob Agents Chemother 5: 435, 1974.
The American Journal of Medklne
Volume 62
929
The use of standard doses of gentamicin and small doses of amikacin was compared in the treatment of urinary tract infections in 30 adults. Patients were prospectively randomized to treatment with 3 to 4 mg/kg/day of gentamicin (group 1) or 9 mg/kg/day of amikacin (group 2). The age and sex of the patient, and the duration of the treatment were sfmilar in the two groups. Eleven of the 15 patients in each group were diagnosed clinically as having pyelonephritis. The majority of patients in both groups either required a permanent Foley catheter or had associated diseases predisposing to urinary tract infections. In nine of 15 patients in each group, the bacterial etiology was Pseudomonas aeruginosa. Bacteriologic cures were achieved in nine of 15 patients treated with gentamicin (group 1) and in 10 of 15 patients treated with amikacin (group 2). The mean peak concentration of gentamicin was 5.4 pg/ml (range: 2 to 13 pg/ml), and the mean peak concentration of amikacin was 11.2 pg/ml (range: 8.2 to 19.6 pg/ml). In the patients treated with gentamicin, there was no correlation between the peak serum concentration of gentamictn, the in vitro minimum inhibitory concentration and the bacteriologic response to treatment. No direct evidence of antibiotic-induced toxtcity was detected. These results suggest that a reduced amikacin dosage schedule gave results essentially equivalent to standard doses of gentamicin in adults with urinary tract infections.
D. N. GILBERT, M.D. N. EUBANKS,
M.D.*
J. JACKSON,
M.D.
Portland, Oregon
From the Leslie Gilbert Infectious Diseases Laboratory, Providence Medical Center and the Department of Medicine, University of Oregon !-k&h Sciences Center, Portland, Oregon. This study was presented at the U.S. Amikacin Symposium, University of California Medical School, Los Angeles, California, November 9-10, 1976. It was supported in part by a grant from Bristol Laboratories. Requests for reprints should be addressed to Dr. David N. Gilbert, Providence Medical Center, 700 N. E. 47th Avenue, Portland, Oregon 97213. *Present address: Tieton R.S. Box 189. Naches. Washington 98937.
924
June 1977
This study explores the potential of small doses of amikacin in the treatment of urinary tract infections in adults: The investigation was motivated by two major factors. First, the in vitro antimicrobial spectrum of amikacin is similar to gentamicin and, hence, includes the majority of organisms that cause urinary tract infections [l-7]. Secondly, accumulated data with amikacin suggest a more favorable therapeutic ratio (mean peak serum concentration to minimum inhibitory concentration) for amikacin as compared to other aminoglycoside antibiotics [ 1,3,4]. Published pharmacokinetic studies demonstrate that 7.5 mg/kg of intramuscular amikacin results in average peak serum concentrations between 17 and 23 pg/ml [ 81. Thus, it was hypothesized that for urinary tract infections the dosage of amikacin, and hence the peak serum concentration of amikacin, could be reduced and that serum and urine concentrations inhibitory for those organisms which commonly produce infection could still be achieved. It was hoped that the lower dosage would lessen the risk of amikatin-induced toxicity.
The American Journal of Medlclne
Volume 62
COMPARISON 0~ AMIKACIN AND GENTAMICINAXBERT
A prospective randomized study was designed. Instead of the maximum recommended dosage of amikacin, 15 mg/kg/day, the dosage of amikacin employed was 9 mg/kg/day. The gentamicin dosage was 3 to 4 mg/kg/day. The results indicate that both amikacin and gentamicin, in the dosages employed, are clinically and bacteriologically effective in the treatment of urinary tract infections in adults. No obvious difference in the occurrence of toxic reactions was observed.
ET AL.
(2) Cure with reinfection, when urine cultures were negative during therapy but more than IO5 new organisms/ml of urine appeared within 10 days after therapy was discontinued. (3) Persistence, when more than lo5 organisms/ml of the original infecting organism were present in the urine during and after therapy. (4) Superinfection, therapy.
when reinfection
developed
during
MATERIALS AND METHODS Patients studied were hospitalized in an acute care community hospital. They were required to be over the age of 15 years and to have a culture of mid-stream, clean-catch urine with more than lo5 organisms/ml, susceptible to gentamicin by the Kirby-Bauer disc diffusion method. Patients were excluded from the study if they had a history of allergy to aminoglycoside antibiotics, recent antimicrobial therapy, evidence of auditory or vestibular disease and laboratory evidence of impaired renal function. The patients were examined and, based on the criteria of Kunin, the urinary tract infection was classified as cystitis, pyelonephritis, prostatitis/epididymitis or asymptomatic bacteriuria [9]. After obtaining informed consent, the patient was assigned at random to either gentamicin or amikacin treatment according to a standard table of random numbers. Patients given gentamicin received a loading dose of 1.5 mg/kg followed by a maintenance dosage of 3 to 4 mg/ kg/day given in three divided doses. Amikacin was administered in a dosage of 9 mg/kg/day in three divided doses. Patients were treated for seven to 14 days. Drugs were administered either intramuscularly or intravenously. Intravenous amikacin and gentamicin were infused over a 30 minute period. Serum for determining antibiotic concentration was obtained 1 hour after the initiation of the intravenous infusion. If the antibiotic was given intramuscularly, serum was obtained 1 hour later. These 1 hour determinations are referred to as “peak” serum concentrations of gentamicin and amikacin. Peak and nadir serum aminoglycoside concentrations were determined after the first 72 hours of therapy. The gentamicin concentration was determined by adenylating enzyme method and the amikacin concentration was determined by the acetylating enzyme method [ 10.111. Concentrations of antibiotic in urine were not determined. The dosage of amikacin was not altered to obtain any specific peak serum concentration. Gentamicin dosage was adjusted to maintain a peak concentration between 4 and 8 pg/ml. During therapy, patients were examined frequently for evidence of drug-related toxicity and to evaluate their clinical response to treatment. A repeat urine specimen for culture was obtained during therapy. Two to 10 days after completion of treatment, urine for culture was obtained. Bacteriologic results of therapy were classified as follows [9] :
(1) Cure, when urine cultures were negative (less than lo4 organisms/ml) during therapy and on follow-up urine culture.
(5) Relapse, when more than 105/ml of the original infecting organism were present in the post-treatment urine specimen after the demonstration of less than lo4 organisms/ml during therapy. When urine isolates were of the same -genus and species as the initial isolate, differentiation between relapse and reinfection was based upon pyocine typing for Pseudomonas isolates and serotyping for other aerobic gramnegative bacilli. No specific studies were made to localize infection to the upper and/or lower urinary tract. Agar-plate dilution susceptibility testing was performed by standard methods utilizing a Steer’s replicator device [ 121. The calcium and magnesium concentration of the agar was approximated to concentrations normally found in serum by a previously-published method [ 131. Disc-diffusion susceptibility testing was carried out by standard methods for both gentamicin and amikacin [ 141. Using the 10 pg amikacin disc, a zone diameter of equal to or more than 14 mm was considered sensitive and a zone size of equal to or less than 12 mm was interpreted as resistant. A zone diameter of 13 mm was interpreted as intermediate. With agar-plate dilution a minimum inhibitory concentration (MC) of amikacin equal to or less than 16 fig/ml was considered sensitive and more than 32 pg/ml was considered resistant. For gentamicin, an agar-plate dilution MIC more than 6.3 pg/ml was considered resistant and equal to or less than 6.3 pg/ml was interpreted as sensitive. In the patient group treated with amikacin, audiograms were obtained before and after treatment when it was thought that the patient’s mental status allowed valid testing. Patients were questioned daily regarding tinnitus, decreased hearing, sensation of fullness in the ears and possible vestibular symptoms. Renal impairment was defined as a twofold or greater increase in the serum creatinine concentration with a resulting maximum concentration of equal to or more than 1.5 mg/ 100 ml, or a decrease in the endogenous creatinine clearance of at least 50 per cent from base line values. RESULTS A total of 15 patients were treated with gentamicin (group l), and 15 patients were treated with amikacin (group 2). The patients treated with gentamicin ranged in age from 20 to 82 years and the patients treated with amikacin from 16 to 86 years. The male:female ratio was nearly equivalent (8:7 in group 1 and 7:8 in group 2). Patients in group 1 were treated for a mean of 11
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COMPARISON
TABLE
I
OF AMIKACIN
Bacterial
Etiology
Organism Pseudomonas aeruginosa Escherichia coli Klebsiella species Serratia marcescens Proteus mirabilis Proteus rettgeri Total l
AND GENTAMICIN-GILBERT
by Treatment
ET AL.
Group
Group 1
Group 2
9” 4” 1 1 1 I*
9 5 1
17
Two mixed
. . . .
.. 15
infections.
days (seven to 22 day range). The patients in group 2 were treated for a mean of 10 days (seven to 14 day range). Classification of Urinary Tract Infection. Pyelonephritis was diagnosed in 11 patients in group 1 and in 11 patients in group 2. One patient in group 1 and two patients in group 2 had positive blood cultures. The diagnosis of cystitis was made in one patient in group 1 and no patients in group 2. ProstatitisIepididymitis was diagnosed in three patients in group 1 and in one patient in group 2. Asymptomatic bacteriuria was the diagnosis in three patients in group 2. There were no patients with asymptomatic bacteriuria in group 1. It is pertinent that 10 of the 15 patients in group 2 and 11 of the 15 patients in group 1 had Foley catheters in place at the time a urinary tract infection was diagnosed. Of the five patients in group 2 without an indwelling catheter, three patients had significant underlying disease (lymphoma, multiple myeloma, phenacetin nephritis) which may have contributed to their urinary tract infection. Of the four patients without an indwelling Foley catheter in group 1, three had a significant underlying disease (nephrolithiasis, phenacetin nephritis, chronic prostatitis) which may have contributed to their urinary tract infection. Bacterial Etiology. The infecting organisms in the two groups were similar. Ps. aeruginosa was the most common isolated pathogen in both groups (Table I). The second most common isolate was Escherichia coli followed by single isolations of Klebsiella species, Serratia marcescens, Proteus mirabilis and Proteus rettgeri. By Kirby-Bauer disc-diffusion susceptibility testing, all bacterial isolates in both patient groups were susceptible to gentamicin and amikacin. With the exception of one Ps. aeruginosa (MIC 25 Fg/ml), all bacterial strains in group 2 met the agar-plate dilution criteria (equal to or less than 16 pg/ml) for sensitivity. In group 1, three Ps. aeruginosa isolates and one Pr. rettgeri isolate had an MIC of 12.5 pg/ml and were categorized as resistant. Clinical and Bacteriologic Response to Treatment. In symptomatic patients, the signs and symptoms of urinary tract infection disappeared rapidly in all patients
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in both groups. There was no evident difference in the rapidity with which symptoms resolved. All patients randomized completed the study. The bacteriologic response to treatment is shown in Table II. Using the criteria described, nine of 15 patients in group 2 were considered cured. In one patient treated with gentamicin, the infecting organism persisted. This occurred in a patient with papillary necrosis due to analgesic abuse and Ps. aeruginosa pyelonephritis. After the phenacetin ingestion was discontinued, the patient was cured with a course of amikacin treatment. One patient in group 1 and two patients in group 2 were classified as having a superinfection. In two instances the superinfecting organism was a group D Streptococcus (group 2) and in one instance Candida albicans (group 1). All three patients had underlying diseases which required the presence of an indwelling Foley catheter during treatment. Two patients in group 1 and two patients in group 2 were classified as having a cure with reinfection. Three of the four patients either had had an indwelling Foley catheter for a long time or had undergone a surgical procedure which diverted the urinary stream, e.g., ureterosigmoidostomy. Two patients in group 1 and one patient in group 2 were classified as having a bacteriologic relapse due to Ps. aeruginosa. Because of the number of patients requiring permanent indwelling Foley catheters, long-term bacteriologic evaluation did not seem pertinent to the in vivo antimicrobial effectiveness of the drugs under study. Therefore, no long-term bacteriologic studies were performed. In group 2, urine for post-treatment bacteriologic study was collected within two or 10 days (mean four days) of the end of treatment. In group 1 the posttreatment urine was collected between two and 16 days after the completion of treatment (mean five days). Aminoglytoside Serum Concentrations. Peak serum concentrations of gentamicin were obtained for all 15 patients. Peak concentrations of amikacin were available for 14 of the 15 patients. As shown in Figure 1, the gentamicin concentrations ranged from 2 to 13 kg/ml, with a geometric mean value O? 5.4 pg/ml. The amikacin concentrations ranged from 8.2 to 19.6 pg/ml, with a geometric mean of 11.2 pug/ml. TA.BLE II
Bacteriologic
Classification Cure Persistence Superinfection Cure with reinfection Relapse Total
Response
to Treatment
Group 1
Group 2
(no.)
(no.)
9 1 1 2 2
10
15
15
2 2 1
COMPARISON OF AMIKACIN AND GENTAMICIN-GILBERT
18
16
A
(I?
A A
;
A
i
8 0
A
6
( I = Number of Patients 0
-
L
Gentamicin Figure 1. Peak serum concentrations, treated with gentamicin or amikacin.
= Geometric Mean Value
L
Amikacin pg/ml,
ET AL.
peak antibiotic concentration in vivo in six of the 11 patients in group 1 as compared to only one of the 15 patients in group 2. Despite the unfavorable ratio between the MIC and the peak gentamicin concentration, five of the six patients treated with gentamicin had a bacteriologic cure. Persistence occurred in one patient whose Ps. aeruginosa remained sensitive to gentamicin in vitro. In one patient treated with amikacin, despite an MIC higher than the serum concentration, bacteriologic cure was achieved. There was no clinical eviAminoglycoside Toxicity. dence of vestibular or auditory toxicity in either group. No audiograms were obtained in group 1. In group 2, audiograms were obtained in four patients during the first 48 hours of treatment with follow-up audiograms obtained 10 to 14 days later. Three of the four patients had mild perceptive hearing loss on their base line examinations. The post-treatment audiograms were unchanged in all four instances. Two patients in each group met the criteria for nephrotoxicity. In three of the four patients, the diagnosis was Ps. aeruginosa pyelonephritis; in the fourth patient, the diagnosis was asymptomatic bacteriuria due to Ps. aeruginosa. In three of the four patients there were underlying dieases involving the kidneys. Three of the four had received a cephalosporin antibiotic prior to the initiation of aminoglycoside therapy. At the time renal impairment was observed, the peak amikacin concentrations were 19.5 and 10.1 gglml, and the peak gentamicin concentrations were 11 and 4 pg/ml. In one of the two patients treated with amikacin, endogenous creatinine clearance returned to base line values; in the other, creatinine clearance decreased from 155 to 56 cc/min and remained at the lower level for the duration of the three month follow-up period. Of the two patients who were treated with gentamicin, renal function returned to normal in one; in the other azotemia persisted and the patient subsequently died due to pulmonary emboli.
of patients
TABLE III It was of interest to attempt a correlation between the “peak” serum antibiotic concentration, the in vitro MIC determined by the agar-plate dilution technic and the bacteriologic results of treatment. It was possible to complete this analysis for all 15 patients in group 2 and for 11 of 15 patients in group 1. As shown in Table Ill, the peak serum antibiotic concentration in vivo was greater than the MIC in five of 11 patients in group 1 and in 14 of 15 patients in group 2. A bacteriologic cure resulted in all five patients in group 1 and in 13 of the 14 patients in group 2, with one instance of bacteriologic relapse. In contrast, the MIC was greater than the
Correlation of “Peak” Serum Antibiotic Concentration (PAC), Minimum Inhibitory Concentration (MIC) and Bacteriologic Results of Therapy -___ PAC> MIC
MIC > PAC -_____ Group 1 Group 2 Group 1 Group 2 NO. of patients/ total patients studied* Bacteriologic result curet Persistence/relapse
5111 515 0
14115 13114 1114
6111 516 116
l/15 l/l 0
* Data available for all 15 patients in group 2 and 11 of 15 patients in group 1. t Includes cure with superinfection and cure with reinfection.
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COMPARISON OF AMIKACIN AND GENTAMICIN-GILBERT
ET AL.
COMMENTS
This study demonstrates many of the weaknesses and frustrations of therapeutic trials for urinary tract infections. There is no comparison with an untreated control group. Localization by clinical criteria of the site of infection within the urinary tract is imprecise [ 151. At the time this study was conducted, noninvasive localizing procedures were not readily available and invasive procedures were not considered to be justified [ 161. It is difficult to quantify the influence of necessary foreign bodies, e.g., catheters and underlying urologic disease, on the course of the infection‘and the patient’s treatment. Even if these variables were subject to control and true double-blind prospective protocols employed, it is anticipated that very large numbers of patients would be necessary to demonstrate statistically significant differences, The results of this small prospective randomized study of urinary tract infections in adults suggest that the bacteriologic cure rates are similar after treatment with small doses of amikacin and standard doses of gentamicin. It is emphasized that our definition of bacteriologic cure was based upon the results of the urine culture obtained between two and 10 days after completion of therapy. This is discrepant with the Food and Drug Administration protocol for urinary tract infections which implies that follow-up urine cultures must be negative at one and four to six weeks after the termination of therapy to define a cure [ 171. As demonstrated in our study population, many of the patients in whom aminoglycoside therapy is indicated, have underlying diseases involving the urinary tract or neurologic system and frequently require a permanent indwelling Foley catheter. As a result, the urine becomes colonized frequently during or after a course of antimicrobial therapy. An antibacterial effect is demonstrated by the eradication of the initial infecting organism, even ifthe eradication lasts for only a short period of time. Similarly, the occurrence of a superinfection during treatment or reinfection with a different organism does not detract from the antimicrobial efficacy demonstrated by eradication of the initial infecting organism. In such a small group of patients, it is difficult to make definitive statements regarding the efficacy of the reduced amikacin dosage. However, in patients with pyelonephritis, there is a precedent for utilization of doses of antimicrobial agents that produce high urine concentrations but serum concentrations that predictably would be lower than the MIC for the offending organism [ 181. In patients with bacteremia complicating their pyelonephritis, it might be desirable to have serum concentrations which exceed the MIC of the infecting bacteria. In the 30 patients which constitute the present study, three patients had pyelonephritis complicated by
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bacteremia: the infecting organism was Esch. coli in two patients and Ps. aeruginosa in the third. In all three patients, the measured peak serum concentration of aminoglycoside antibiotic exceeded the MIC. Since the peak serum concentration achieved with therapeutic doses of amikacin are so much higher than the corresponding levels for gentamicin, it is not surprising that, even with the smaller dosage of amikacin used in this study, the peak serum level frequently exceeded the in vitro MIC of organisms isolated from amikacin-treated patients. It was of interest that the peak gentamicin concentration and the in vitro MIC did not correlate with the bacteriologic cure rate (Table Ill). Despite the small numbers of patients, six gentamitin-treated patients (group 1) had a bacterial isolate with an MIC greater than the measured peak serum aminoglycoside concentration, and yet bacteriologic cure was achieved in five of these six. These results support the importance of urine, rather than serum, concentrations. A review of the recent literature indicates a high bacteriologic cure rate with amikacin in urinary tract infections. Meyer and associates [ 191 described 36 patients with a variety of infections treated with amikacin. Among these were six febrile patients with urinary tract infections. Of these six patients, five had bacteriologic cures and one initially showed improvement but suffered a late relapse. Tally et al. [20] reported the clinical and bacteriologic response to amikacin therapy in 12 patients with serious infections with gentamicin-resistant gram-negative bacilli. In four of these 12, the urinary tract was involved. There was a good clinical response in all four patients. Because there was no follow-up urine cultures until 30 days after the end of treatment, it is difficult to judge the bacteriologic response to treatment. Lastly, Sharp et al. [ 2 1] described 11 patients with 12 episodes of urinary tract infection due to drug-resistant Pr. rettgeri. All patients were infected either after a urologic procedure or after the utilization of an indwelling urethral catheter. The Proteus were all resistant to more than 125 pg/ml of gentamicin. Bacteriologic cures were obtained in 11 of the 12 episodes of infection. In conclusion, this prospective randomized study of urinary tract infections in adults treated with either standard doses of gentamicin or lower than standard doses of amikacin resulted in similar bacteriologic and clinical responses. If confirmed in a larger group of patients, the use of a smaller dosage of amikacin may lower the potential of drug-related toxicity. ACKNOWLEDGMENT
We wish to express our thanks to Dr. Harold Rose for Ps. aeruginosa pyocine typing.
COMPARISON OF AMIKACIN
AND GENTAMICIN-GILBERT
ET AL.
REFERENCES
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391.1974. Stevens P, Young LS, Hewitt WL: Radioimmunoassay acetylating radioenzymatic assay and microbioassay of gentamicin. A comparative study. J Lab Clin Med 66: 349, 1975. Edcsson HM, Sherris JC: Antibiotic sensitivity testing. Report of an international collaborative study. Acta Pathol Microbial Stand [B] 217: 65, 1971. Gilbert DN. Kutscher E, Ireland P, et al.: Effect of the concentrations of magnesium and calcium on the in vitro susceptibility of Pseudomonas aeruginosa to gentamicin. J Infect Dis 124(S): 37. 1971. Bauer AW, Kirby WMM, Sherris JC, et al.: Antibiotic susceptibility testing by a standardized single disc method. Am J Clin Pathol 45: 493, 1966. Sanford JP: Urinary tract infections and symptoms. Ann Rev Med 26: 465, 1975. Jones SR, Smith JW, Sanford JP: Localization of urinary tract infections by detection of antibody-coated bacteria in urine sediment. N Engl J Med 290: 591, 1974. Guidelines for Protocols of New Antimicrobial Efficacy in Urinary Tract Infections. Food and Drug Administration, 1975. Stamey TA, Fair WR, Timothy MM, et al.: Serum versus urinary antimicrobial concentrations in cure of urinary tract infections. N Engl J Med 291: 1159. 1974. Meyer RD, Lewis RP, Carmalt ED, et al.: Amikacin therapy for serious gram-negative bacillary infections. Ann Intern Med 83: 790, 1975. Tally FP, Louie TJ, Weinstein WM, et al.: Amikacin therapy for severe gram-negative sepsis. Ann Intern Med 83: 484, 1975. Sharp PM, Saenz CA, Martin RR: Amikacin (BEK6) treatment of multiple-drug-resistant Proteus infections. Antimicrob Agents Chemother 5: 435, 1974.
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