International Urology and Nephrology 24 (3), pp. 221-- 227 (1992)

A Comparative Trial of Aztreonam versus Gentamicin in the Treatment of Urinary Tract Infections D . A . WALLER, S. W . H . KENDALL, P. WHELAN

Department of Urology, St. James's University Hospital, Leeds, UK (Accepted August 2, 1991)

A prospective, randomized trial was conducted to compare the efficacy of aztreonam, a m o n o b a c t a m antibiotic, and gentamicin in the treatment of serious urinary tract infections. Fifty-five patients with a suspected or confirmed infection were randomized, 28 received aztreonam and 27 received gentamicin. Both antibiotics had a high clinical response rate (aztreonam 92%, gentamicin 85%). However, the duration of treatment was significantly shorter (p = 0.037, Wilcoxon R a n k Sum Test) when aztreonam was used. There were no cases of toxicity with either antibiotic but 5 patients who received gentamicin required dose alteration. Aztreonam is well tolerated and is no less effective than gentamicin in the treatment of urinary tract infections and has advantages in convenience of use and duration of treatment.

Introduction

Aztreonam is the first member of a new class of beta lactam antibiotics called monobactams (monocyclic bacterially produced beta lactam antibiotics). It has been shown to have potent, specific in vitro activity against a wide spectrum of gram negative aerobic organisms including Pseudomonas aeruginosa [1 ]. While its in vitro bactericidal activity against these organisms is similar to some third generation cephalosporins, its unique chemical structure confers upon it several advantages. It is active against organisms which are resistant to many other antibiotics by virtue of its capacity to withstand hydrolysis by beta lactamase enzymes [2]. Unlike most other beta lactam antibiotics (e.g. cephalosporins and penicillin) it does not increase the production of chromosomally mediated beta lactamase by gram negative organisms [3, 4]. Finally, because of its specific activity against gram negative aerobes it causes little alteration of gut flora, and thus should reduce the incidence of gastrointestinal disturbances [5]. The efficacy of aztreonam in the treatment of urinary tract infections has been shown in large multi centre trials [6]. There was a favourable clinical response in 99% of patients and a microbiological cure in 83%. These results compare favourably with similar cure rates reported with tobramycin in similar serious VSP, Utrecht Akad~miai Kiad6, Budapest

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vs. genlarazicin

urinary tract infections [7]. The overall incidence of adverse side effects following treatment with aztreonam has been shown to be no higher than in a control group [6]. However, the incidence of proven toxicity with aminoglycosides, specifically nephrotoxicity and ototoxicity, has been well established [8]. The purpose of this study was to directly compare the efficacy and toxicity of aztreonam and the aminoglycosides gentamicin in the treatment of serious urinary tract infections.

Patients and methods

A prospective comparative trial of aztreonam versus gentamicin in the treatment of urinary tract infections was undertaken. Fifty-five patients, who were either admitted with or who acquired a urinary tract infection during hospitalization, were randomly assigned to treatment with either aztreonam (1 g 12 hourly) or gentamicin (initial dose 80 mg 8 hourly monitored by regular measurement of serum levels). Males or females over eighteen years of age with suspected or confirmed severe urinary tract infection (more than 10 organisms per ml) were included. Patients who were symptomatic of urinary sepsis and who had heavy pyuria (more than 10 pus cells per high power field) but less than 10 organisms per ml of urine were also included. On randomization a complete physical examination was performed. Urine culture, blood count, serum urea and electrolytes and, where indicated, blood cultures were taken. The patients received regular clinical assessment and were withdrawn from the study if their condition did not respond to treatment. Urine cultures were taken at regular intervals during treatment, at the end of treatment and at subsequent outpatient reviews at four to six weeks post discharge when the patients' symptomatic progress was assessed. Clinical response to therapy was defined as resolution of symptoms and physical signs. Microbiological response was defined as total clearance of bacteriuria during the course of treatment. In the abacteriuric, symptomatic patients response to treatment was determined by clearance of pyuria together with symptoms. Results

Twenty-eight patients (16 females, 12 males) were randomized to treatment with aztreonam and 27 patients (18 females, 9 males) received gentamicin (Table 1). The patient characteristics were similar for both groups. Almost half of each group had urinary tract infection complicated by a specific contributory urological problem; the commonest of these was a postinstrumentation infection. The patients were withdrawn in the aztreonam group due to non-compliance with study protocol (Table 2). Most patients presented with a combination of urinary symptoms of infection, loin pain and pyrexia (Table 3). International Urology and Nephrology 24, 1992

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Table 1 Patient characteristics

No. of patients Male : female M e a n age (years) No. of patients withdrawn due to non-compliance Patients remaining Uncomplicated infection Underlying urological complications Postinstrumentation Calculus Urinary conduit Miscellaneous

Aztreonam

Gentamicin

28 12 : 16 56 : 31

27 9 : 18 72 : 37

3 25 12

0 27 15

6 2 2 3

6 4 0 2

Table 2 Patients withdrawn (Aztreonam group) Patient

Reason for withdrawal

1. Male, 74 years old 2. Female, 26 years old 3. Female, 22 years old

9. Allergic reaction: rash, diarrhoea and vomiting Patient incooperative a n d non-compliant Patient took self discharge

Table 3 Presenting clinical features Aztreonam (n = 25)

Dysuria/frequency; loin pain, pyrexia Dysuria/frequency; loin pain Dysuria/frequency Loin pain, pyrexia Pyrexia alone Asymptomatic bacteriuria Total

Gentamicin (n = 27)

9 5 3 6 1 1

12 6 2 3 3

25

27

1

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Table 4 Clinical response to treatment Aztreonam (n = 25)

Gentamicin (n = 27)

23 2

23 4

Clinical cure Treatment failure Response rate

(23/25)

92 70

(23/27)

85%

Table 5 Treatment failures Patient

Reason of failure

Aztreonam group 1. Male, 78 years old 2. Female, 44 years old

No response of symptoms to treatment within 48 hours, no organisms isolated. No clearance of persistent Pseudomonas infection. Indwelling catheter.

Gentamicin group 1. Female, 27 years old 2. Female, 49 years old 3. Female, 23 years old 4. Female, 66 years old

Pain and pyrexia unchanged. Diagnosis: pyelonephrosis secondary to ureteric stone. N o organisms isolated. Pyrexia unchanged after 72 hours. E. coli isolated. Responded to subsequent aztreonam. No clearance of persistent E. coli infection due to persistent vesico-enteric fistula secondary to Crohn's disease. Symptoms unchanged. Proteus isolated. Responded to subsequent aztreonam.

Table 6 Characteristics of patients with negative urine culture

No. of patients Male 9 female Mean age (years) Uncomplicated infection Complicated infection Cure (pyuria cleared) Initial response rate International Urology and Nephrolopy 24, 1992

Aztreonam

Gentamicin

15 5 : 10 53 : 33 9 6 14

12 2 : 10 62 : 35 10 2 11

(14/15)

9370

(11/12)

92

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Table 7 Microbiological response to treatment Organism

No.

Initial cure

Treatment failure

Reinfection at 4 t o 6 w e e k s

Aztreonam E. coli Pseudomonas aeruginosa

5 2

5 1

0 1

I 1

Proteus

2

2

0

0

Strept. faecalis

1

1

0

0

9

1

2

10 Overall initial response rate (9110) 90~ Gentamiein E. coli Pseudomonas aeru#inosa

9 2

7 2

2 0

2 2

Proteus Klebsiella Mixed growth

1 1 2

0 1 2

1 0 0

0 0 0

12

3

4

15 Overall initial response rate (12/15) 80 Table 8

Comparative duration of treatment and time period to resolution of symptoms

Aztreonam Gentamicin

Course o f treatment m e a n (days)

Resolution of symptoms m e a n (days)

4.70 5.78

2.50 2.87

There was a high positive clinical response rate in each group (Table 4), 92 ~ to aztreonam and 85 ~ to gentamicin with only six treatment failures (Table 5). O f these six patients two had underlying anatomical abnormalities, i.e. a ureteric calculus causing obstructed kidney and a vesico-enteric fistula secondary to Crohn's disease. A high proportion of patients in both groups (60 ~ in the aztreonam group and 4 4 ~ in the gentamicin group) had negative pretreatment urine cultures (Table 6), however, all the patients were symptomatic (Table 3) and had significant pyuria (more than 10 W B C per high power field). In the group of patients in whom a positive urine culture (more than 10 organisms per ml) was obtained there was a high cure rate with both antibiotics International U'roloyy and Nephrology 24, 1992

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Waller et al. : A z t r e o n a m vs. ge nt am i e i n

(Table 7). Two patients who had an initial response to aztreonam were found to have evidence of reinfection on review at 4 to 6 weeks, and four patients who initially were cured by gentamiein developed reinfection. Escherichia coli was the most commonly isolated organism. There were no cases of either nephrotoxicity or ototoxicity with either antibiotic, but in 5 out o f 24 patients who received gentamicin the dose had to be modified on the basis o f abnornaal serum levels. The duration of required treatment was significantly less (p = 0.037) with aztreonam (4.7 _ 0.28 days) than gentamicin (5.8 ___ 0.27 days) (Table 8). Since the data in the sample were not normally distributed, an appropriate distribution-free significance test was used (Wilcoxon Rank Sum Test).

Discussion

This study confirmed the efficacy o f aztreonam in the treatment o f gram negative urinary tract infections. Aztreonam was shown to be no less effective than gentamicin in the treatment of these infections. However, aztreonam was found to have definite advantages over gentamicin with regard to convenience o f use. The mean duration was found to be significantly shorter when aztreonam was used (Table 8) indicating the potential clinical benefits of this drug. No patient showed any evidence of nephrotoxicity or ototoxicity. However, in 5 of the 27 patients who received gentamicin a change of dosage during treatment was necessary due to abnormal serum levels. Gentamicin was commonly given in eight hourly doses, whereas aztreonam in twelve hourly doses. Aztreonam therefore proved to be a more convenient drug to use and more popular with junior doctors as frequent monitoring of serum levels and dosage changes were not necessary and less frequent administration was required. An unexpected result was the large proportion (56 %) o f patients with negative urine cultures despite the presence of infective symptoms (Table 6) and significant pyuria (more than 10 WBC per high power field). We believe that these patients did have serious urinary tract infections and have included their data. We attribute the lack of microbiological confirmation to the diagnostic criteria used, i.e. more than l0 organisms per ml o f urine which has been shown to have an unacceptably low sensitivity in certain groups of patients [9]. Evidence from a further study of women presenting with urinary frequency and dysuria revealed that 52% had less than 10 organisms per ml midstream urine and subsequent bacteriuria on suprapubic aspiration [10]. This bacteriuria was taken to be significant as 90 % of the isolates were known urinary pathogens; all patients had persistent pyuria and all showed a symptomatic response to antibiotics. The explanation for this low density bacteriuria was thought to be the frequency o f voiding associated with the condition and diuresis caused by an associated increased fluid intake. The conclusion of this study was that for the study population International Urology and Nephrology 24, 1992

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of symptomatic women the diagnostic criteria for infection should be the presence of more than 10 organisms per ml urine. We feel justified in extrapolating these findings to our data and including these symptomatic abacteriuric patients since the majority of this group were women. In addition, all these patients had heavy pyuria which is closely identified with symptomatic infection [11] and whose absence provides strong evidence against infection [12]. In conclusion, this trial has shown that aztreonam is a well tolerated alternative to gentamicin and is at least as effective in the treatment of serious urinary tract infections. Furthermore, aztreonam has definite advantages over gentamicin in terms of convenience of use and duration of treatment.

Acknowledgement We would like to acknowledge the following for their help in this study: Dr Ghonhein, Consultant Microbiologist; Mr M. Alen, Ms J. Robinson and Ms L. Sartori from E. R. Squibb and Sons, Ltd. and Mrs Louise Stockdale.

References 1. Lindsay, G., Woods, P. B. : Susceptibility of 90,000 Gram negative isolates to Aztreonam and other antibiotics. 5th Mediterranean Congress of Chemotherapy 1986, Book of Abstracts, pp. 98-321. 2. Bush, K., Sykes, R. B. : Interaction of beta-lactam antibiotics with beta-laetamases as a cause for resistance. In: Bryan, L. E. (ed.): Antimierobial Drug Resistance. Academic Press, New York 1984, pp. 1-31. 3. Farmer, T. H., Reading, C. : Induction of the beta-lactamases of a strain of Pseudomonas aeruginosa, Morganella morganii and Enterobacter cloacae, d. Antimierob. Chemother., I9, 401 (1987). 4. Wiser, R., Ashby, J. P., Piddock, L. J. V. : Induction of beta-Iactamases in Gram negative bacilli. J. Antimicrob. Chemother., 20, 767 (1987). 5. Borriello, S. P. : Effects of antimicrobials on normal gut flora and function. In : Howard, A. J. (ed.): Royal Society of Medicine International Congress Symposium Series 1988, 139, pp. 55-59. 6. Henry, S. A., Bendush, C. B.: Aztreonam: Worldwide overview of the treatment of patients with Gram negative infections. Am. J. Med., 78 (Suppl. 2A), 57 (1985). 7. Bendush, C. B., Weber, R.: Tobramycin sulphate: A summary of worldwide experience from clinical trials. J. Infect. Dis., 134 (Suppl.), 30 (1976). 8. Averiei, G. M., Falco, F. G., Smith, H. M. : Clinical research experience with gentamicin: incidence of adverse reactions. Med. d. Aust., 1 (Suppl.), 30 (1970). 9. Platt, R. : Quantitative definition of bacteriuria (Infectious Diseases Symposium). Am. J. Med., 75, 44 (1983). 10. Stamm, W. E., Counts, G. W., Running, K. R., Finn, S., Turck, M., Holmes, K. K.: Diagnosis of coliform infection in acutely dysuric women. N. EngL J. Med., 307, 463 (1982). 11. Stamm, W. E. : Measurement of pyuria and its relation to bacteriuria (Infectious Diseases Symposium). Am. J. Med. 75, 53 (1983). 12. Musher, D. M., Thoransteinsson, S- B., Airola, V. M. : Quantitative urinanalysis. J A M A , 236, 2069 (1979). 2

International Urology and Nephrology 24, 1992