J. Reynaert, D. Van Eyck, J. Vandepitte
Single Dose Fosfomycin Trometamol versus Multiple Dose Norfloxacin over Three Days for Uncomplicated UTI in General Practice Summary: The aim of this study was to carry out a small-scale bacteriological comparison between a standard therapy with norfloxacin 400 mg twice daily, and fosfomycin trometamol (3 g) in single dose in uncomplicated urinary tract infections (UTI) in women. Only patients with UTI with cultures showing a bacterial count of 105 or more bacteria/ml were included in the study (n = 32; ages 16-75 years). After one week sterile cultures were obtained in 14 of 16 cases in the fosfomycin trometamol group, and in 14 of 16 cases in the norfloxacin group. After one month eradication was confirmed
in 13 of 16 patients in the fosfomycin trometamol group, and in nine of 16 patients in the norfloxacin group. Recurrence was seen in one case in the fosfomycin trometamol group, and in five cases in the norfloxacin group. The reinfection and persistence rates were identical (1/16) in both groups. The main clinical symptoms disappeared very rapidly after initiating treatment, and the correlation with the bacteriological data after one week was excellent. Both drugs were well tolerated and the compliance for fosfomycin trometamol was 100%.
Zusammenfassung: Einzeldosis Fosfomycin Trometamol im Vergleich zu Mehrfachdosen Norfloxacin far drei Tage zur Therapie der unkomplizierten Hamwegsinfektion in der Allgemeinpraxis. Die Standardtherapie Norfloxacin,
je 14 der 16 Patientinnen der beiden Therapiegruppen steril. Nach einem Monat hatten in der Fosfomycin Trometamol-Gruppe weiterhin 13 und in der Norfloxacin-Gruppe neun der 16 Patientinnen eine negative Urinkultur. Rezidive traten in einem Fall unter Fosfomycin Trometamol und in fiinf FNlen unter Nortloxacin auf. In beiden Gruppen kam es je einmal zu einer Reinfektion und Erregerpersistenz, Nach Therapiebeginn verschwanden die klinischen Symptome sehr rasch, was gut mit den bakteriologischen Daten nach einer Woche iibereinstimmte. Beide Medikamente wurden gut vertragen, die Compliance in der Fosfomycin Trometamol-Gruppe betrug 100%.
400 mg zweimal t/iglich, sollte in einer bakteriologisch iiberwachten Studie an einer ldeinen Fallzahl mit einer Einzeldosis von 3 g Fosfomycin Trometamol in der Therapie der unkomplizierten Harnwegsinfektion (HWI) bei Frauen verglichen werden. In die Studie wurden nur Patientinnen aufgenommen, bei denen eine HWI mit positiver Urinkultur mit 105 KBE/ml oder dariiber festgestellt wurde (n = 32; Alter 16-75 Jahre). Eine Woche nach Therapie waren die Urinkulturen bei
Introduction
Patients and Methods
Fosfomycin trometamol is a new formula of fosfomycin which is much better absorbed following oral administration than the existing forms [1]. Administration of a single dose has been shown to lead to highly effective urinary concentrations. These concentrations are maintained for 48 hours [2]. "Single-Dose" antibiotic therapy for uncomplicated urinary tract infections offers several advantages compared to therapy during 5 to 10 days necessitating repeated administration. These advantages are: convenience, a high degree of compliance, less side-effects [3] and less selection of resistant strains [4]. The favourable characteristics of "single dose" therapy in the treatment of uncomplicated UTI as well as the encouraging pharmacokinetic features of fosfomycin trometamol stimulated us to set up this study. The study consisted of evaluating the clinical and bacteriological effectiveness and safety of one single dose of 3 g fosfomycin trometamol compared to norfloxacin 400 mg twice daily for 3 days in patients with uncomplicated urinary tract infection.
Patient selection: 32 female patients with clear symptoms of uncomplicated UTI (dysuria, pollakisuria without fever) were included in the study. The patients were aged between 16 and 75 and were all residents of a university psychiatric centre. Our extensive experience indicated that urinary infections in psychiatric in-patients are comparable to infections in general practice and are clearly different from urinary infections in a general hospital. Patients were excluded from the study on the basis of: - renal insufficiencyor other renal abnormalities - a history of norfloxacin hypersensitivityor allergic reactions - a history of chronic urinary tract infection - liver disease - pregnancy. Clinical status of the patients: UTI was classified as a) acute cystitis b) recurrent cystitis. Based on subjective symptoms such as Prof. Dr. Z Reynaert, M.D., 19. Van Eyck, Universitair Psychiatrisch Centrum St. Jozef, Int. Med. Dept., Leuvensesteenweg 517, B-3070 Kortenberg; J. Vandepitte, University Hospital Gasthuisberg, Butt. Dept., B-Leuven, Belgium. Correspondence to: Prof. Dr. J. Reynaert, Abdijdreef 13, B-3070 Kortenberg, Belgium.
Infection 18 (1990) Suppl. 2 © MMV Medizin Verlag GmbH MiJnchen, Miinchen 1990
S 77
J. Reynaert et al.: Fosfomycin Trometamol Versus N0rfloxacin in Urinary Tract Infections pollakisuria and dysuria, the status of the infection was further classified as serious, moderate or mild. Laboratory findings:: A midstream urine sample from potential patients for this trial was examined using a N-Labstick for nitrate reduction, a sediment examination for leucocyturia and a dipslide for culture. Only when the dipslide showed more than 105 bacteria a new urine sample was taken, and a conventional culture and bacteriological identification was carried out. Only patients in which this culture showed 105 bacteria per mI were randomized and included in the study. Treatment and follow-up: After randomization either fosfomycin trometamol or norfloxacin was administered. The full dose of fosfomycin trometamol (3 g) was administered as a single dose. Norfloxacin was administered in two 400 mg tablets daily for three days. In all patients a follow-up examination with routine midstream urine sample for culture was carried out 5 to 10 days after initiation of the treatment. A second follow-up examination was carried out in order to determine possible side-effects, and to investigate the clinical and bacteriological effectiveness of the administered antibiotics. Safety evaluation: Any signs or symptoms of local or systemic intolerance and/or side-effects were reported and specified by the patients as follows: when did the symptoms start (how long did they last), what is the severity, have measures been taken, and if yes, which. Evaluation of effectiveness: The bacteriological effectiveness was expressed as eradication (if the culture was negative after therapy or if the bacterial count of the original bacteria was < 10~/ml), reinfection (eradication of the original pathogen, but growth of a different species > 104/ml at the control examination), recurrence (if the original pathogen had disappeared at the time of the first control visit, but reappeared at consecutive control examinations > 104/ml) or persistence (if the initially isolated microorganisms remained present in all cultures > 104/ml.). Clinical effectiveness was expressed as follows: - cure: total disappearance of subjective symptoms - improvement: clear improvement of symptoms (or improvement better than 50%) - failure: little or no improvement in symptoms. Results
32 female patients were finally selected for the study, i. e. 16 in each group. The general condition of these patients was satisfactory. Nearly all patients suffered from acute cystitis (14/16), and only two patients in each group showed acute recurrent cystitis. In the fosfomycin trometamol group 13 patients showed serious symptoms of acute UTI while three patients showed moderate symptoms of acute UTI. In the fosfomycin trometamol group age varied between 16 and 73 years, body weight between 40 and 99 kg and height between 147 and 170 cm. In the norfloxacin group the age varied between 18 and 65 years, the body weight between 42 and 118 kg and the height between 150 and 170 cm. These demographic data were statistically processed (Table 1). It can be concluded on the basis of these data that there are no significant differences between both groups with respect to both weight and height. However, with respect to mean age there is a significant difference (p = 0.04).
S 78
The organism that was most frequently isolated (Table 2) was Escherichia coli both in the fosfomycin trometamol group (14/16), and in the norfloxacin group (12/16). This finding was also consistent with expectations in the case of uncomplicated UTI. Other organisms that were isolated included Proteus mirabilis (1/16 in the fosfomycin trometamol group, and 2/16 in the norfloxacin group). In the fosfomycin trometamol group one of the infections was a mixed infection compared to two in the norfloxacin group where one case of Enterococcus with E. coli was observed. The first bacteriological control in the fosfomycin group was carried out 6.6 days after initiating treatment, and 7.4 days after initiating treatment in the norfloxacin group. Bacteriological results (Table 3) show eradication of the infection in 14 of 16 patients treated with fosfomycin trometamol, and in 14 of the 16 patients treated with norfloxacin. In the fosfomycin trometamol group one organism persisted namely P. mirabilis. There was one case of reinfection (mixed flora: E. coli plus Streptococcus sp.). In the norfloxacin group one case of reinfection was noted with Streptococcus haemolyticus and one Case of persistence with Enterococcus. In the fosfomycin trometamol group the second and last control was on the average carried out after 35.4 days compared to 36.0 days in the norfloxacin group. The bacteriological results (Table 3) show eradication of the causative infecting organisms in 13 out of 16 patients in the fosfomycin trometamol group, and in nine out of 16 patients in the norfloxacin group. Recurrence occurred in one c a s e (6.2%) in the fosfomycin trometamol group, a n d in five cases (31.3%) in the norfloxacih group. In these five cases P. mirabilis was found twice while one case of mixed infection (E. coli plus P. mirabilis) was observed. Reinfection and persistence both occurred once in each group. The clinical evaluation of the two most important symptoms associated with acute UTI, i. e. dysuria and pollakisuria, led to practically identical results for both treatments (Table 4). In all cases the clinical symptoms disappeared rapidly (usually within 24 hours) after initiating treatment.
Table 1: Demographic data.
Age (year)
mean SD
16 43.1 15.9
16 52.8 13.1
0.04(*)
Weight n = (kg) mean SD
16 61.7 11.8
16 65.9 17.5
0.38(*)
Height n = (cm) mean SD
16 160.6 5.7
16 161.1 6~1
0.77(*)
n
=
(*) T-test of grouped data.
Infection 18 (1990) Suppl. 2
© MMV Medizin Verlag GmbH Miinchen, Miinchen 1990
J. Reynaert et al.: Fosfomycin Trometamol Versus Norfloxacin in Urinary Tract Infections Table 2: Distribution of isolated bacteria. ~ !~.I::Ii£I~!II]IIII11111)11111; ' .~i~171ilIi#I!I~i I~i11~Ii iii*£-~l ~ > l l l l : - > I i ! I I I ! illIill I;i ;I
Discussion ~:i!:~ I
Escherichia cot Proteus mirabilis Escherichia coli + Proteus mirabilis Escherichia coli +
i~,!i:;"?~i Iiiii
11/16 1/16
12/16 2/16
1/16
1/16
Enterococcus sp.
1/16
Table 3: Bacteriological evaluation. .¢11~ i:,~,< ,./~!~i::!.~ti.,i!..I~::~1.I,~!1~-×]£,.i:,t;:.
Single Dose Fosfomycin Trometamol versus Multiple Dose Norfloxacin over Three Days for Uncomplicated UTI in General Practice Summary: The aim of this study was to carry out a small-scale bacteriological comparison between a standard therapy with norfloxacin 400 mg twice daily, and fosfomycin trometamol (3 g) in single dose in uncomplicated urinary tract infections (UTI) in women. Only patients with UTI with cultures showing a bacterial count of 105 or more bacteria/ml were included in the study (n = 32; ages 16-75 years). After one week sterile cultures were obtained in 14 of 16 cases in the fosfomycin trometamol group, and in 14 of 16 cases in the norfloxacin group. After one month eradication was confirmed
in 13 of 16 patients in the fosfomycin trometamol group, and in nine of 16 patients in the norfloxacin group. Recurrence was seen in one case in the fosfomycin trometamol group, and in five cases in the norfloxacin group. The reinfection and persistence rates were identical (1/16) in both groups. The main clinical symptoms disappeared very rapidly after initiating treatment, and the correlation with the bacteriological data after one week was excellent. Both drugs were well tolerated and the compliance for fosfomycin trometamol was 100%.
Zusammenfassung: Einzeldosis Fosfomycin Trometamol im Vergleich zu Mehrfachdosen Norfloxacin far drei Tage zur Therapie der unkomplizierten Hamwegsinfektion in der Allgemeinpraxis. Die Standardtherapie Norfloxacin,
je 14 der 16 Patientinnen der beiden Therapiegruppen steril. Nach einem Monat hatten in der Fosfomycin Trometamol-Gruppe weiterhin 13 und in der Norfloxacin-Gruppe neun der 16 Patientinnen eine negative Urinkultur. Rezidive traten in einem Fall unter Fosfomycin Trometamol und in fiinf FNlen unter Nortloxacin auf. In beiden Gruppen kam es je einmal zu einer Reinfektion und Erregerpersistenz, Nach Therapiebeginn verschwanden die klinischen Symptome sehr rasch, was gut mit den bakteriologischen Daten nach einer Woche iibereinstimmte. Beide Medikamente wurden gut vertragen, die Compliance in der Fosfomycin Trometamol-Gruppe betrug 100%.
400 mg zweimal t/iglich, sollte in einer bakteriologisch iiberwachten Studie an einer ldeinen Fallzahl mit einer Einzeldosis von 3 g Fosfomycin Trometamol in der Therapie der unkomplizierten Harnwegsinfektion (HWI) bei Frauen verglichen werden. In die Studie wurden nur Patientinnen aufgenommen, bei denen eine HWI mit positiver Urinkultur mit 105 KBE/ml oder dariiber festgestellt wurde (n = 32; Alter 16-75 Jahre). Eine Woche nach Therapie waren die Urinkulturen bei
Introduction
Patients and Methods
Fosfomycin trometamol is a new formula of fosfomycin which is much better absorbed following oral administration than the existing forms [1]. Administration of a single dose has been shown to lead to highly effective urinary concentrations. These concentrations are maintained for 48 hours [2]. "Single-Dose" antibiotic therapy for uncomplicated urinary tract infections offers several advantages compared to therapy during 5 to 10 days necessitating repeated administration. These advantages are: convenience, a high degree of compliance, less side-effects [3] and less selection of resistant strains [4]. The favourable characteristics of "single dose" therapy in the treatment of uncomplicated UTI as well as the encouraging pharmacokinetic features of fosfomycin trometamol stimulated us to set up this study. The study consisted of evaluating the clinical and bacteriological effectiveness and safety of one single dose of 3 g fosfomycin trometamol compared to norfloxacin 400 mg twice daily for 3 days in patients with uncomplicated urinary tract infection.
Patient selection: 32 female patients with clear symptoms of uncomplicated UTI (dysuria, pollakisuria without fever) were included in the study. The patients were aged between 16 and 75 and were all residents of a university psychiatric centre. Our extensive experience indicated that urinary infections in psychiatric in-patients are comparable to infections in general practice and are clearly different from urinary infections in a general hospital. Patients were excluded from the study on the basis of: - renal insufficiencyor other renal abnormalities - a history of norfloxacin hypersensitivityor allergic reactions - a history of chronic urinary tract infection - liver disease - pregnancy. Clinical status of the patients: UTI was classified as a) acute cystitis b) recurrent cystitis. Based on subjective symptoms such as Prof. Dr. Z Reynaert, M.D., 19. Van Eyck, Universitair Psychiatrisch Centrum St. Jozef, Int. Med. Dept., Leuvensesteenweg 517, B-3070 Kortenberg; J. Vandepitte, University Hospital Gasthuisberg, Butt. Dept., B-Leuven, Belgium. Correspondence to: Prof. Dr. J. Reynaert, Abdijdreef 13, B-3070 Kortenberg, Belgium.
Infection 18 (1990) Suppl. 2 © MMV Medizin Verlag GmbH MiJnchen, Miinchen 1990
S 77
J. Reynaert et al.: Fosfomycin Trometamol Versus N0rfloxacin in Urinary Tract Infections pollakisuria and dysuria, the status of the infection was further classified as serious, moderate or mild. Laboratory findings:: A midstream urine sample from potential patients for this trial was examined using a N-Labstick for nitrate reduction, a sediment examination for leucocyturia and a dipslide for culture. Only when the dipslide showed more than 105 bacteria a new urine sample was taken, and a conventional culture and bacteriological identification was carried out. Only patients in which this culture showed 105 bacteria per mI were randomized and included in the study. Treatment and follow-up: After randomization either fosfomycin trometamol or norfloxacin was administered. The full dose of fosfomycin trometamol (3 g) was administered as a single dose. Norfloxacin was administered in two 400 mg tablets daily for three days. In all patients a follow-up examination with routine midstream urine sample for culture was carried out 5 to 10 days after initiation of the treatment. A second follow-up examination was carried out in order to determine possible side-effects, and to investigate the clinical and bacteriological effectiveness of the administered antibiotics. Safety evaluation: Any signs or symptoms of local or systemic intolerance and/or side-effects were reported and specified by the patients as follows: when did the symptoms start (how long did they last), what is the severity, have measures been taken, and if yes, which. Evaluation of effectiveness: The bacteriological effectiveness was expressed as eradication (if the culture was negative after therapy or if the bacterial count of the original bacteria was < 10~/ml), reinfection (eradication of the original pathogen, but growth of a different species > 104/ml at the control examination), recurrence (if the original pathogen had disappeared at the time of the first control visit, but reappeared at consecutive control examinations > 104/ml) or persistence (if the initially isolated microorganisms remained present in all cultures > 104/ml.). Clinical effectiveness was expressed as follows: - cure: total disappearance of subjective symptoms - improvement: clear improvement of symptoms (or improvement better than 50%) - failure: little or no improvement in symptoms. Results
32 female patients were finally selected for the study, i. e. 16 in each group. The general condition of these patients was satisfactory. Nearly all patients suffered from acute cystitis (14/16), and only two patients in each group showed acute recurrent cystitis. In the fosfomycin trometamol group 13 patients showed serious symptoms of acute UTI while three patients showed moderate symptoms of acute UTI. In the fosfomycin trometamol group age varied between 16 and 73 years, body weight between 40 and 99 kg and height between 147 and 170 cm. In the norfloxacin group the age varied between 18 and 65 years, the body weight between 42 and 118 kg and the height between 150 and 170 cm. These demographic data were statistically processed (Table 1). It can be concluded on the basis of these data that there are no significant differences between both groups with respect to both weight and height. However, with respect to mean age there is a significant difference (p = 0.04).
S 78
The organism that was most frequently isolated (Table 2) was Escherichia coli both in the fosfomycin trometamol group (14/16), and in the norfloxacin group (12/16). This finding was also consistent with expectations in the case of uncomplicated UTI. Other organisms that were isolated included Proteus mirabilis (1/16 in the fosfomycin trometamol group, and 2/16 in the norfloxacin group). In the fosfomycin trometamol group one of the infections was a mixed infection compared to two in the norfloxacin group where one case of Enterococcus with E. coli was observed. The first bacteriological control in the fosfomycin group was carried out 6.6 days after initiating treatment, and 7.4 days after initiating treatment in the norfloxacin group. Bacteriological results (Table 3) show eradication of the infection in 14 of 16 patients treated with fosfomycin trometamol, and in 14 of the 16 patients treated with norfloxacin. In the fosfomycin trometamol group one organism persisted namely P. mirabilis. There was one case of reinfection (mixed flora: E. coli plus Streptococcus sp.). In the norfloxacin group one case of reinfection was noted with Streptococcus haemolyticus and one Case of persistence with Enterococcus. In the fosfomycin trometamol group the second and last control was on the average carried out after 35.4 days compared to 36.0 days in the norfloxacin group. The bacteriological results (Table 3) show eradication of the causative infecting organisms in 13 out of 16 patients in the fosfomycin trometamol group, and in nine out of 16 patients in the norfloxacin group. Recurrence occurred in one c a s e (6.2%) in the fosfomycin trometamol group, a n d in five cases (31.3%) in the norfloxacih group. In these five cases P. mirabilis was found twice while one case of mixed infection (E. coli plus P. mirabilis) was observed. Reinfection and persistence both occurred once in each group. The clinical evaluation of the two most important symptoms associated with acute UTI, i. e. dysuria and pollakisuria, led to practically identical results for both treatments (Table 4). In all cases the clinical symptoms disappeared rapidly (usually within 24 hours) after initiating treatment.
Table 1: Demographic data.
Age (year)
mean SD
16 43.1 15.9
16 52.8 13.1
0.04(*)
Weight n = (kg) mean SD
16 61.7 11.8
16 65.9 17.5
0.38(*)
Height n = (cm) mean SD
16 160.6 5.7
16 161.1 6~1
0.77(*)
n
=
(*) T-test of grouped data.
Infection 18 (1990) Suppl. 2
© MMV Medizin Verlag GmbH Miinchen, Miinchen 1990
J. Reynaert et al.: Fosfomycin Trometamol Versus Norfloxacin in Urinary Tract Infections Table 2: Distribution of isolated bacteria. ~ !~.I::Ii£I~!II]IIII11111)11111; ' .~i~171ilIi#I!I~i I~i11~Ii iii*£-~l ~ > l l l l : - > I i ! I I I ! illIill I;i ;I
Discussion ~:i!:~ I
Escherichia cot Proteus mirabilis Escherichia coli + Proteus mirabilis Escherichia coli +
i~,!i:;"?~i Iiiii
11/16 1/16
12/16 2/16
1/16
1/16
Enterococcus sp.
1/16
Table 3: Bacteriological evaluation. .¢11~ i:,~,< ,./~!~i::!.~ti.,i!..I~::~1.I,~!1~-×]£,.i:,t;:.
