Originalia H. W. Asbach
A Randomized, Dose Comparison Study of Cefodizime in the Treatment of Lower Urinary Tract Infections in Women Summary: In a prospective randomized study, the efficacy and safety of I and 2 g of cefodizime administered as single intramuscular injections were compared in a total of 50 women having either complicated or uncomplicated lower urinary tract infections (LUTI). Bacteriological culture of urine and safety laboratory tests were performed before and after treatment. 18/25 patients in the 1 g cefodizime group and 22/25 in the 2 g cefodizime group showed satisfactory clinical and bacteriological response to treatment. The inadequately treated patients all had complicating factors on entry to the study (residual urine in six cases, a bladder malignancy in two, neurogenic bladder and diabetes mellitus with glucosuria in one case each). Cefodizime proved efficacious in female patients with uncomplicated LUTI, as well as in those aged over 65 years, patients having mild renal insufficiency, mild glucosuria, unsuccessful oral antibiotic pretreatment or recurrent and postoperative infections. In no case were there any systemic adverse reactions to cefodizime or clinically significant changes in laboratory tests. Zusammenfassung: Randomisierte Dosisfindungsstudie fiir Cefodizim bei Frauen mit Infektionen des unteren Harntraktes. In dieser prospektiven randomisierten Studie wurden die Wirksamkeit und Vertrfiglichkeit einer Einmaldosis von 1 oder 2 g Cefodizim i.m. bei 50 Frauen mit Infektionen der unteren Harnwege untersucht. Vor und nach Behandlung wurden ein Harnstatus mit Urinbakteriologie sowie Laboruntersuchungen durchgeffihrt. In der Dosisgruppe 1 g wurden 18 von 25 Patienten geheilt, in der Dosisgruppe 2 g 22 von 25. Bei allen unzureichend behandelten Patientinnen war vor Therapiebeginn ein komplizierter Harnweginfekt festgestellt worden (sechsmal Restharn, zweimal ein Blasentumor und je einmal eine neurogene Blasenentleerungsst6rung und eine Glukosurie bei Diabetes mellitus). Cefodizim war bei unkomplizierten Harnwegsinfektionen, aber auch bei Patientinnen fiber 65 Jahre, bei gering eingeschrfinkter Nierenfunktion, bei antibiotischer Vorbehandlung und bei rezidivierenden oder postoperativen Infektionen wirksam. Systemische Nebenwirkungen oder klinisch relevante Laborver~inderungen wurden nicht beobachtet.
subsequently confirmed that single-dose regimens do not predispose to earlier or more frequent recurrence of infection [2]. Claims of fewer side effects, less likelihood of selecting resistant bacteria, better compliance and lower costs have all been put forward as advantages of singledose treatment [3,4]. Although early original experience with single-dose cephaloridine was disappointing, probably due to the high incidence of upper urinary tract involvement [5], broader spectrum parenteral cephalosporins such as cefotaxime have since been used for single-dose treatment of LUTI with good results [6]. Cefodizime is a new third generation cephalosporin characterized by an antimicrobial spectrum similar to that of cefotaxime [7,8]. Cefodizime has been shown to exhibit high in vitro therapeutic activity in experimental infections [9]. This activity of cefodizime extended to pathogens against which cefodizime was less active in vitro than the comparative agents used. The in vivo superiority of cefodizime was particularly marked in immunocompromised animals. Immunomodulating effects were also demonstrated in patients [10]. Pharmacokinetic investigation of cefodizime in man has shown the elimination half-life to be 4 h [11]. 80% of the administered drug was recovered as unchanged compound from urine within 48 h of a single dose [12]. In phase I studies cefodizime was well tolerated [12]. Cefodizime was found efficacious in the treatment of lower respiratory tract infections [11,13] at a dose of 1 g b.i.d. The aim of this study was to explore the efficacy and safety of two different doses of cefodizime administered as a single i.m. injection in women having lower urinary tract infections [14].
Patients and Methods Written informed consent was obtained prior to the patient's inclusion in the study. Adult, female patients attending the outpatient clinics of Kreiskrankenhaus, Liibbecke and patients who acquired LUTI during hospital stay were allocated at random to one of the two treatment groups. Excluded from the study were patients aged under 18 years, patients with a history of hypersensitivity to 13-1actam antibiotics or receiving concomitant antibiotics, those with renal impairment (serum creatinine above 2.4 mg/dl), serious hepatic disease and pregnant women or nursing mothers. Women of childbearing age were admitted to the study only when using effective contraceptive measures. Received: 4 September 1990/Revisionaccepted: 31 October 1990
Introduction In 1967 Graneberg und Brumfitt [1] reported on single-dose antibiotic therapy in the treatment of acute lower urinary tract infections (LUTI) in females. Numerous studies have
Prof. Dr. med. H. W. Asbach, Kreiskrankenhaus, Urologische Klinik, W-4490 Liibbecke, Germany. Reprint requests to: Dr. med. H. W. Asbach, Theodor-Heuss-Platz 8, W-5630 Remscheid, Germany.
Infection 19 (1991) No. 2 © MMV Medizin Verlag GmbH Mfinchen, Miinchen 1991
85 / 31
H. W. Asbach: Cefodizime in Lower Urinary Tract Infections Patients received a single intramuscular injection of either 1 g cefodizime (group 1) or 2 g cefodizime (group 2). The antibiotic was supplied by Hoechst AG. Cefodizime was reconstituted in a 1% lignocaine hydrochloride solution immediately prior to injection. 5 ml or 10 ml respectively of the solution were administered to the patients as a slow intramuscular injection over a 3-min period. Bacteriological culture of catheter urine and the laboratory investigations listed below were performed within 48 h prior to the administration of cefodizime and five to seven days thereafter. To be admitted to the trial, at least one single pathogen at a concentration of --> 105 cfu/ml, sensitive to cefodizime in vitro, had to be isolated from urine. Susceptibility of the organisms to cefodizime was determined by disc sensitivity testing using a 30 ~tg cefodizime disc (produced by Oxoid). Organisms were regarded as sensitive to cefodizime if the inhibition zone was -> 22 mm, an inhibition zone of -< 15 mm indicated resistance to cefodizime. Urinalysis was performed to screen for proteinuria, gluc0suria, hematuria, pyuria and nitrite. In addition to a complete blood count, serum creafinine, urea and total bilirubin were determined. Body temperature and symptoms of the infection as well as antibiotic tolerance were followed up daily. Results
Abdominal surgery Age over 65 years Creatinine > 1.5 mg/dl Glucosuria Recurrent/chronic LUTI Oral antibiotic pretreatment Cystoscopy Sphincterotomy TUR of bladder tumor Bladder neck suspension Urethral stenosis (no OP) Residual urine Bladder tumor Neurogenic bladder
1 6 2 1" 10 2 2 1 0 3 1 4 1 1
0 8 5 3# 10 2 0 1 2 1 1 2 2 0
Number of aggravating factors Number of patients Patients with uncomplicated LUTI
35 17 8
37 17 8
Patient had diabetes mellitus. 4~ Mild glucosuria - no diabetes mellitus. Table 2: Causative organisms isolated at baseline.
Patient Population
A total of 50 Caucasian women with L U T I entered the study, 25 being randomly allocated to each of the two treatment groups. No major differences between groups were present on entry to the study in terms of age, weight or height. Three patients in group 1 and six in group 2 had congestive heart failure. In group 1 one patient presented with oedema, in group 2 three patients were reported to have arterial hypertension and one had cerebrovascular insufficiency. Concomitant medication comprised oral contraceptives in 14 patients, digitalis in nine, heparin in three, furosemide in two and antihypertensives in three. General medical condition on entry to the study was assessed as "good" in 39 patients (22 in group 1 and 17 in group 2) and as " p o o r " in 11 (three in group 1 and eight in group 2). None of the patients was critically ill, The history of L U T I was an acute episode in 15 patients in both groups and recurrent or chronic in the remainder. The eight outpatients in each group had acute uncomplicated LUTI. Table 1 depicts the aggravating factors and complications found in the other patients on entry into the study (35 complications among 17 patients in group 1 and 37 complications among 17 patients in group 2). The causative organisms isolated from the four patients who had received unsuccessful antimicrobial pretreatment were resistant to the antibiotics given. No evidence of upper urinary tract infection was demonstrable. On admission to the study almost all the patients reported frequency, urgency and dysuria. T h r e e patients in group 1 and four patients in group 2 complained additionally of suprapubic pain and in seven and six patients, respectively, macrohaematuria was present. Pyuria and microhaematuria as well as urinary nitrite were present in virtually all pa32 / 86
Table 1: Complicating factors of lower urinary tract infection present on entry into the study.
Escherichia coli Citrobacterfreundii Proteus mirabilis Proteus vulgaris Klebsiella pneumoniae Staphylococcus aureus Enterococcus faecalis*
17
10
0 6 1 2 1 1
1 8 0 6 0 1
No. of organisms No. of patients
28 25
26 25
Resistant to cefodizime (CDZ). tients at baseline. One patient in group 1 and four patients in group 2 had a body temperature above 37.5°C. Leucocytosis (total W B C > 11.2 x 109/1) was found in four patients in group 1 and in 11 patients in group 2. One patient in group 1 had asymptomatic bacteriuria. Clinical and Bacteriological Response
The causative organisms are shown in Table 2.95% of the pathogens were enterobacteriaceae, all of which were sensitive to cefodizime in vitro. Eighteen patients in group 1 and 22 patients in group 2 showed satisfactory clinical and bacteriological response [14]. At the follow-up visit five to seven days after therapy these patients reported remission of all clinical symptoms. Urinalysis had considerably improved or become normal. Eradication of the causative pathogens was demonstrated in every case. Seven patients in group 1 were bacteriological "non-responders". In two cases with residual urine Proteus mirabi-
Infection 19 (1991) No. 2 © MMV Medizin Verlag GmbH Miinchen, Mfinchen 1991
H. W. Asbach: Cefodizime in Lower Urinary Tract Infections l/s and a resistant Enterococcus faecalis persisted, in two other cases with residual urine the original infecting organism was replaced by a resistant E. faecalis. In one patient having a neurogenic bladder Escherichia coli was eradicated but P. mirabilis developed resistance to cefodizime and a resistant E. faecalis was found at follow-up. In one patient with diabetes mellitus and moderate glucosuria E. coli persisted. In another case E. coli persisted in a patient who developed LUTI after a cystoscopy, where a bladder tumor was found. Three patients in group 2 were bacteriological "non-responders". In one patient with urethral stenosis and residual urine a resistant E. faecalis persisted. One patient with residual urine showed complete relief of symptoms and initial eradication of P. mirabilis but had a relapse two weeks later. In one patient who had undergone transurethral resection of a bladder malignancy Klebsiella pneumoniae was only reduced from 106 to 103 cfu/ml, with persisting pyuria four days after the administration of 2 g cefodizime.
Antibiotic Tolerance All 50 patients were evaluable for tolerance of cefodizime. Several patients in both groups complained of mild pain at the injection site. No systemic adverse reactions were documented. Laboratory data showed no clinically significant changes in haematological and biochemical parameters when initial and follow-up results were compared. Discussion
This open, randomized, dose comparison study showed
similar efficacy of 1 g and 2 g cefodizime given as single intramuscular doses in the treatment of uncomplicated lower urinary tract infections. Moreover cefodizime proved effective in recurrent and in postoperative LI_YI'I,in the elderly, in patients with mild renal impairment and in patients with mild glucosuria. However, a single shot of cefodizime does not appear to be an adequate treatment when residual urine is present or in patients with underlying urinary tract pathology, such as urethral stenosis or a bladder malignancy. The findings of this study are in accordance with the results published for cefotaxime [6] and ceftriaxone [15,16]. The "non-responders" proved to require further urological care [4]. The relatively small numbers of patients studied precludes any conclusions being drawn as to which dose regimen is most efficacious; indeed, both regimens showed similar clinical and microbiological efficacy against infections caused by cefodizime-sensitive pathogens. No systemic adverse reactions were observed in either group. Localized adverse reactions, notably pain at the injection site were probably related to injection of the full dose within less than the 3-min period laid down in the study protocol for the intramuscular injection. In summary, we conclude that cefodizime was effective in all patients treated for uncomplicated LUTI when administered as a single 1 g or 2 g intramuscular dose. Cefodizime was also effective in patients suffering recurrent or postoperative LUTI and in the elderly, even with mild renal impairment or mild glucosuria. Tolerance of cefodizime was good.
References 1. Griineberg, R. N., Brumfltt, W.: Single-dose treatment of acute urinary tract infection: A controlled trial. Br. Med. J. 3 (1967) 649-651. 2. Philbrick, J. T., Bracikowskl, J. P.: Single-dose treatment for uncomplicated urinary tract infections. Arch. Intern. Med. 145 (1985) 1672-1678. 3. Gleckman, R. A.: Treatment duration for urinary tract infections in adults. Antimicrob. Agents Chemother. 31 (1987) 1-5. 4. Naber, K. G.: Single-dose therapy of uncomplicated urinary tract infections in females - treatment of choice? Infection 17 (1989) 119-120. 5. Porpaczy, P.: Cefotaxime in the treatment of urinary tract infections. J. Antimicrob. Chemother. 18 (1984) 311-315. 6. Brumfitt, W., Faiers, M. C., Franklin, I. N. S.: The treatment of urinary infection by means of a single dose of cephaloridine. Postgrad. Med. J. 46 (1970) 65-69. 7. Limbert, M., Klesel, N., Seeger, K., Seibert, G., Winkler, I., Schrinner, E.: Cefodizime, an aminothiazolyl-cephalosporine, I. In vitro activity. J. Antibiotics 37 (1984) 1719-1726. 8. Kasai, K., Tsuji, A., Miyazakl, S., Goto, S., Fujimoto, K., Masuyoshi, S., Arai, S.: In vitro antibacterial activity and [3-1actamase stability of cefodizime, a new cephalosporine antibiotic. Jap. J. Antibiotics 37 (1984) 1294-1305. 9. Limbert, M., Bartlett, 1L, Dickniete, G., Klesel, M., Schnorlemmer, H. U., Seibert, G., Winkler, I., Schrinner, E.: Cefodizime, an amino-
Infection 19 (1991) No. 2
10.
11.
12.
13.
14. 15.
16.
thiazolyl-cephalosporin, IV. Influence on the immune system. J. Antibiotics 37 (1984) 1719-1726. Vanholder, R., Van Landschoot, N., Dagrosa, E. E., Ringoir, S.: Cefodizime: a new cephalosporin with apparent immune-stimulating properties in chronic renal failure. Nephrol. Dial. Transplant. 2 (1988) 221-224. Maesen, F. P. V., Davies, B. I., Baur, C., Sumajow, C. A.: Cefodizime in acute purulent exacerbations of chronic respiratory disease. J. Antimicrob. Chemother. 22 (1988) 229-235. Dagrosa, E. E., Hajdu, P., Malerczyk, V., de I_ooze, S., Seeger, K., Gr6tsch, H.: Dose linearity and other pharmacokinetics of cefodizime after single dose intravenous administration. Clinical Therapeutics 10 (1987) No. 1 (Abstract). Boelaert, J., Lambrecht, E., Van Couter, A., Temmeran, B., Dagrosa, E., Gordts, G., Van Landut, H. W.: Cefodizime versus cefuroxime for acute lower respiratory tract infections in geriatric patients. 15th ICC, (1987) Abstract No. 1333. Simon, C., Stille, W.: Antibiotika-Therapie in Klinik und Praxis. Schattauer, Stuttgart - New York 1985, p. 378. Rosenberg, J. M., Levy, R. C., Cicmanec, J. F., Hedges, J. R., Burke, B. M.: Single-dose ceftriaxone treatment of urinary tract infections. Ann. Emerg. Med. 14 (1985) 970-972. Iravani, A., Richart, G. A.: Single-dose ceftriaxone versus multipledose trimethoprim-sulfamethoxazole in the treatment of acute urinary tract infections. Antimicrob. Agents Chemother. 27 (1985) 158-161.
© MMV Medizin Verlag GmbH Miinchen, Miinchen 1991
87 / 33
A Randomized, Dose Comparison Study of Cefodizime in the Treatment of Lower Urinary Tract Infections in Women Summary: In a prospective randomized study, the efficacy and safety of I and 2 g of cefodizime administered as single intramuscular injections were compared in a total of 50 women having either complicated or uncomplicated lower urinary tract infections (LUTI). Bacteriological culture of urine and safety laboratory tests were performed before and after treatment. 18/25 patients in the 1 g cefodizime group and 22/25 in the 2 g cefodizime group showed satisfactory clinical and bacteriological response to treatment. The inadequately treated patients all had complicating factors on entry to the study (residual urine in six cases, a bladder malignancy in two, neurogenic bladder and diabetes mellitus with glucosuria in one case each). Cefodizime proved efficacious in female patients with uncomplicated LUTI, as well as in those aged over 65 years, patients having mild renal insufficiency, mild glucosuria, unsuccessful oral antibiotic pretreatment or recurrent and postoperative infections. In no case were there any systemic adverse reactions to cefodizime or clinically significant changes in laboratory tests. Zusammenfassung: Randomisierte Dosisfindungsstudie fiir Cefodizim bei Frauen mit Infektionen des unteren Harntraktes. In dieser prospektiven randomisierten Studie wurden die Wirksamkeit und Vertrfiglichkeit einer Einmaldosis von 1 oder 2 g Cefodizim i.m. bei 50 Frauen mit Infektionen der unteren Harnwege untersucht. Vor und nach Behandlung wurden ein Harnstatus mit Urinbakteriologie sowie Laboruntersuchungen durchgeffihrt. In der Dosisgruppe 1 g wurden 18 von 25 Patienten geheilt, in der Dosisgruppe 2 g 22 von 25. Bei allen unzureichend behandelten Patientinnen war vor Therapiebeginn ein komplizierter Harnweginfekt festgestellt worden (sechsmal Restharn, zweimal ein Blasentumor und je einmal eine neurogene Blasenentleerungsst6rung und eine Glukosurie bei Diabetes mellitus). Cefodizim war bei unkomplizierten Harnwegsinfektionen, aber auch bei Patientinnen fiber 65 Jahre, bei gering eingeschrfinkter Nierenfunktion, bei antibiotischer Vorbehandlung und bei rezidivierenden oder postoperativen Infektionen wirksam. Systemische Nebenwirkungen oder klinisch relevante Laborver~inderungen wurden nicht beobachtet.
subsequently confirmed that single-dose regimens do not predispose to earlier or more frequent recurrence of infection [2]. Claims of fewer side effects, less likelihood of selecting resistant bacteria, better compliance and lower costs have all been put forward as advantages of singledose treatment [3,4]. Although early original experience with single-dose cephaloridine was disappointing, probably due to the high incidence of upper urinary tract involvement [5], broader spectrum parenteral cephalosporins such as cefotaxime have since been used for single-dose treatment of LUTI with good results [6]. Cefodizime is a new third generation cephalosporin characterized by an antimicrobial spectrum similar to that of cefotaxime [7,8]. Cefodizime has been shown to exhibit high in vitro therapeutic activity in experimental infections [9]. This activity of cefodizime extended to pathogens against which cefodizime was less active in vitro than the comparative agents used. The in vivo superiority of cefodizime was particularly marked in immunocompromised animals. Immunomodulating effects were also demonstrated in patients [10]. Pharmacokinetic investigation of cefodizime in man has shown the elimination half-life to be 4 h [11]. 80% of the administered drug was recovered as unchanged compound from urine within 48 h of a single dose [12]. In phase I studies cefodizime was well tolerated [12]. Cefodizime was found efficacious in the treatment of lower respiratory tract infections [11,13] at a dose of 1 g b.i.d. The aim of this study was to explore the efficacy and safety of two different doses of cefodizime administered as a single i.m. injection in women having lower urinary tract infections [14].
Patients and Methods Written informed consent was obtained prior to the patient's inclusion in the study. Adult, female patients attending the outpatient clinics of Kreiskrankenhaus, Liibbecke and patients who acquired LUTI during hospital stay were allocated at random to one of the two treatment groups. Excluded from the study were patients aged under 18 years, patients with a history of hypersensitivity to 13-1actam antibiotics or receiving concomitant antibiotics, those with renal impairment (serum creatinine above 2.4 mg/dl), serious hepatic disease and pregnant women or nursing mothers. Women of childbearing age were admitted to the study only when using effective contraceptive measures. Received: 4 September 1990/Revisionaccepted: 31 October 1990
Introduction In 1967 Graneberg und Brumfitt [1] reported on single-dose antibiotic therapy in the treatment of acute lower urinary tract infections (LUTI) in females. Numerous studies have
Prof. Dr. med. H. W. Asbach, Kreiskrankenhaus, Urologische Klinik, W-4490 Liibbecke, Germany. Reprint requests to: Dr. med. H. W. Asbach, Theodor-Heuss-Platz 8, W-5630 Remscheid, Germany.
Infection 19 (1991) No. 2 © MMV Medizin Verlag GmbH Mfinchen, Miinchen 1991
85 / 31
H. W. Asbach: Cefodizime in Lower Urinary Tract Infections Patients received a single intramuscular injection of either 1 g cefodizime (group 1) or 2 g cefodizime (group 2). The antibiotic was supplied by Hoechst AG. Cefodizime was reconstituted in a 1% lignocaine hydrochloride solution immediately prior to injection. 5 ml or 10 ml respectively of the solution were administered to the patients as a slow intramuscular injection over a 3-min period. Bacteriological culture of catheter urine and the laboratory investigations listed below were performed within 48 h prior to the administration of cefodizime and five to seven days thereafter. To be admitted to the trial, at least one single pathogen at a concentration of --> 105 cfu/ml, sensitive to cefodizime in vitro, had to be isolated from urine. Susceptibility of the organisms to cefodizime was determined by disc sensitivity testing using a 30 ~tg cefodizime disc (produced by Oxoid). Organisms were regarded as sensitive to cefodizime if the inhibition zone was -> 22 mm, an inhibition zone of -< 15 mm indicated resistance to cefodizime. Urinalysis was performed to screen for proteinuria, gluc0suria, hematuria, pyuria and nitrite. In addition to a complete blood count, serum creafinine, urea and total bilirubin were determined. Body temperature and symptoms of the infection as well as antibiotic tolerance were followed up daily. Results
Abdominal surgery Age over 65 years Creatinine > 1.5 mg/dl Glucosuria Recurrent/chronic LUTI Oral antibiotic pretreatment Cystoscopy Sphincterotomy TUR of bladder tumor Bladder neck suspension Urethral stenosis (no OP) Residual urine Bladder tumor Neurogenic bladder
1 6 2 1" 10 2 2 1 0 3 1 4 1 1
0 8 5 3# 10 2 0 1 2 1 1 2 2 0
Number of aggravating factors Number of patients Patients with uncomplicated LUTI
35 17 8
37 17 8
Patient had diabetes mellitus. 4~ Mild glucosuria - no diabetes mellitus. Table 2: Causative organisms isolated at baseline.
Patient Population
A total of 50 Caucasian women with L U T I entered the study, 25 being randomly allocated to each of the two treatment groups. No major differences between groups were present on entry to the study in terms of age, weight or height. Three patients in group 1 and six in group 2 had congestive heart failure. In group 1 one patient presented with oedema, in group 2 three patients were reported to have arterial hypertension and one had cerebrovascular insufficiency. Concomitant medication comprised oral contraceptives in 14 patients, digitalis in nine, heparin in three, furosemide in two and antihypertensives in three. General medical condition on entry to the study was assessed as "good" in 39 patients (22 in group 1 and 17 in group 2) and as " p o o r " in 11 (three in group 1 and eight in group 2). None of the patients was critically ill, The history of L U T I was an acute episode in 15 patients in both groups and recurrent or chronic in the remainder. The eight outpatients in each group had acute uncomplicated LUTI. Table 1 depicts the aggravating factors and complications found in the other patients on entry into the study (35 complications among 17 patients in group 1 and 37 complications among 17 patients in group 2). The causative organisms isolated from the four patients who had received unsuccessful antimicrobial pretreatment were resistant to the antibiotics given. No evidence of upper urinary tract infection was demonstrable. On admission to the study almost all the patients reported frequency, urgency and dysuria. T h r e e patients in group 1 and four patients in group 2 complained additionally of suprapubic pain and in seven and six patients, respectively, macrohaematuria was present. Pyuria and microhaematuria as well as urinary nitrite were present in virtually all pa32 / 86
Table 1: Complicating factors of lower urinary tract infection present on entry into the study.
Escherichia coli Citrobacterfreundii Proteus mirabilis Proteus vulgaris Klebsiella pneumoniae Staphylococcus aureus Enterococcus faecalis*
17
10
0 6 1 2 1 1
1 8 0 6 0 1
No. of organisms No. of patients
28 25
26 25
Resistant to cefodizime (CDZ). tients at baseline. One patient in group 1 and four patients in group 2 had a body temperature above 37.5°C. Leucocytosis (total W B C > 11.2 x 109/1) was found in four patients in group 1 and in 11 patients in group 2. One patient in group 1 had asymptomatic bacteriuria. Clinical and Bacteriological Response
The causative organisms are shown in Table 2.95% of the pathogens were enterobacteriaceae, all of which were sensitive to cefodizime in vitro. Eighteen patients in group 1 and 22 patients in group 2 showed satisfactory clinical and bacteriological response [14]. At the follow-up visit five to seven days after therapy these patients reported remission of all clinical symptoms. Urinalysis had considerably improved or become normal. Eradication of the causative pathogens was demonstrated in every case. Seven patients in group 1 were bacteriological "non-responders". In two cases with residual urine Proteus mirabi-
Infection 19 (1991) No. 2 © MMV Medizin Verlag GmbH Miinchen, Mfinchen 1991
H. W. Asbach: Cefodizime in Lower Urinary Tract Infections l/s and a resistant Enterococcus faecalis persisted, in two other cases with residual urine the original infecting organism was replaced by a resistant E. faecalis. In one patient having a neurogenic bladder Escherichia coli was eradicated but P. mirabilis developed resistance to cefodizime and a resistant E. faecalis was found at follow-up. In one patient with diabetes mellitus and moderate glucosuria E. coli persisted. In another case E. coli persisted in a patient who developed LUTI after a cystoscopy, where a bladder tumor was found. Three patients in group 2 were bacteriological "non-responders". In one patient with urethral stenosis and residual urine a resistant E. faecalis persisted. One patient with residual urine showed complete relief of symptoms and initial eradication of P. mirabilis but had a relapse two weeks later. In one patient who had undergone transurethral resection of a bladder malignancy Klebsiella pneumoniae was only reduced from 106 to 103 cfu/ml, with persisting pyuria four days after the administration of 2 g cefodizime.
Antibiotic Tolerance All 50 patients were evaluable for tolerance of cefodizime. Several patients in both groups complained of mild pain at the injection site. No systemic adverse reactions were documented. Laboratory data showed no clinically significant changes in haematological and biochemical parameters when initial and follow-up results were compared. Discussion
This open, randomized, dose comparison study showed
similar efficacy of 1 g and 2 g cefodizime given as single intramuscular doses in the treatment of uncomplicated lower urinary tract infections. Moreover cefodizime proved effective in recurrent and in postoperative LI_YI'I,in the elderly, in patients with mild renal impairment and in patients with mild glucosuria. However, a single shot of cefodizime does not appear to be an adequate treatment when residual urine is present or in patients with underlying urinary tract pathology, such as urethral stenosis or a bladder malignancy. The findings of this study are in accordance with the results published for cefotaxime [6] and ceftriaxone [15,16]. The "non-responders" proved to require further urological care [4]. The relatively small numbers of patients studied precludes any conclusions being drawn as to which dose regimen is most efficacious; indeed, both regimens showed similar clinical and microbiological efficacy against infections caused by cefodizime-sensitive pathogens. No systemic adverse reactions were observed in either group. Localized adverse reactions, notably pain at the injection site were probably related to injection of the full dose within less than the 3-min period laid down in the study protocol for the intramuscular injection. In summary, we conclude that cefodizime was effective in all patients treated for uncomplicated LUTI when administered as a single 1 g or 2 g intramuscular dose. Cefodizime was also effective in patients suffering recurrent or postoperative LUTI and in the elderly, even with mild renal impairment or mild glucosuria. Tolerance of cefodizime was good.
References 1. Griineberg, R. N., Brumfltt, W.: Single-dose treatment of acute urinary tract infection: A controlled trial. Br. Med. J. 3 (1967) 649-651. 2. Philbrick, J. T., Bracikowskl, J. P.: Single-dose treatment for uncomplicated urinary tract infections. Arch. Intern. Med. 145 (1985) 1672-1678. 3. Gleckman, R. A.: Treatment duration for urinary tract infections in adults. Antimicrob. Agents Chemother. 31 (1987) 1-5. 4. Naber, K. G.: Single-dose therapy of uncomplicated urinary tract infections in females - treatment of choice? Infection 17 (1989) 119-120. 5. Porpaczy, P.: Cefotaxime in the treatment of urinary tract infections. J. Antimicrob. Chemother. 18 (1984) 311-315. 6. Brumfitt, W., Faiers, M. C., Franklin, I. N. S.: The treatment of urinary infection by means of a single dose of cephaloridine. Postgrad. Med. J. 46 (1970) 65-69. 7. Limbert, M., Klesel, N., Seeger, K., Seibert, G., Winkler, I., Schrinner, E.: Cefodizime, an aminothiazolyl-cephalosporine, I. In vitro activity. J. Antibiotics 37 (1984) 1719-1726. 8. Kasai, K., Tsuji, A., Miyazakl, S., Goto, S., Fujimoto, K., Masuyoshi, S., Arai, S.: In vitro antibacterial activity and [3-1actamase stability of cefodizime, a new cephalosporine antibiotic. Jap. J. Antibiotics 37 (1984) 1294-1305. 9. Limbert, M., Bartlett, 1L, Dickniete, G., Klesel, M., Schnorlemmer, H. U., Seibert, G., Winkler, I., Schrinner, E.: Cefodizime, an amino-
Infection 19 (1991) No. 2
10.
11.
12.
13.
14. 15.
16.
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