J. B. J. B o e r e m a , F. Th. C. W i l l e m s

Fosfomycin Trometamol in a Single Dose versus Norfloxacin for Seven Days in the Treatment of Uncomplicated Urinary Infections in General Practice Summary: The efficacy and tolerability of fosfomycin trometamol in a single dose of 3 g was compared with norfloxacin 400 mg b.i.d, for seven days in the treatment of adult female patients with uncomplicated urinary infections. 158 female patients with a mean age of 30 years who presented symptoms of dysuria and frequency with documented pyuria and bacteriuria on urinalysis (--> 105 cfu/ml of urine) were initially included in the study. The total number of clinically and bacteriologically evaluable patients was 111, of which 61 received fosfomycin trometamol and 50 norfloxacin. One to two days after the double blind medication schedule for seven days, 55 of 60 patients (92%) in the fosfomycin trometamol group and 48 of 50 patients (96%) in the norfloxacin group were clinically cured. 37 patients without significant bacteriuria showed a clinical cure rate of over 90% in both therapy groups. Two to t h r e e days after the single dose treatment with fosfomycin trometamol the initial infecting pathogen was eradicated in 60 of the 61 patients (98%). One to two days after a seven day treatment with norfloxacin 48 of 50 patients

(96%) showed an eradication of the initial infecting pathogen. Six weeks after the start of therapy 39/60 patients (65%) and 32/49 (65%) in the fosfomycin trometamol and norfloxacin groups respectively, remained free from urinary infection. The reinfection rate in both treatment groups was approximately 25%. The relapse rate in the post treatment evaluation period of four weeks was relatively low in both therapy groups, 5/49 patients (10%) in the norfloxacin group and 3/55 patients (6%) in the fosfomycin trometamol group, respectively. Adverse effects, which were classified as 'probably' drug related, were mentioned by 10/79 of the patients (13%) and by 2/79 of the patients (3%) in the fosfomycin trometamol and norfloxacin groups, respectively. In 3/79 (3%) of the patients in the fosfomycin trometamol group the side effects were reported on the actual day of (single dose) treatment. Fosfomycin trometamol in a single dose of 3 g is as effective as norfloxacin 400 mg b.i.d, for seven days in the treatment of adult female patients with uncomplicated urinary infections.

Zusammenfassung: Einzeldosis-Therapie mit Fosfomy, cin Trometamol verglichen mit siebentiigigerNorfloxacinTherapie bei unkomplizierten Harnwegsinfektionen in der Allgemeinpraxis. Die Wirksamkeit und Vertr/iglichkeit

60 der 61 F~ille (98%) der Erreger nicht mehr nachzuweisen. Die Eradikation des initial identifizierten Erregers wurde ein bis zwei Tage nach der siebent~igigen Norfloxacin-Behandlung ftir 48 der 50 Patientinnen einer Einzeldosis yon 3 g Fosfomycin Trometamol wur- (96%) gesichert. Die Harnwegsinfektion war auch de mit derjenigen einer siebent/igigen Behandlung mit sechs Wochen nach Therapiebeginn bei 39/60 Patienzweimal t~iglich 400 mg Norfloxacin bei erwachsenen tinnen (65%) der Fosfomycin Trometamol-Gruppe Patientinnen mit unkomplizierter Harnwegsinfektion und 32/49 Patientinnen (65%) der Norfloxacin,Gruppe verglichen. Die Zahl der in die Studie einbezogenen beseitigt. In beiden Gruppen kam es bei etwa 25% der Patientinnen (mittleres Alter: 30 Jahre; Symptomatik: Frauen zu einer Reinfektion. Rezidive traten hingegen Dysurie und Polyurie; Harnbefund: Pyurie, Bakteriurie in der Beobachtungsphase von vier Wochen nach The(_> 105 KBE/ml Urin) betrug 158. Insgesamt konnten rapieende nur selten auf bei 5/49 Patientinnen der davon 111 klinisch und bakteriologisch ausgewertet Norfloxacin-Gruppe (10%) und 3/55 der Fosfomycin werden, von diesen erhielten 61 Fosfomycin Trometa- Trometamol-Gruppe (6%). l]-ber Nebenwirkungen, die mol und 50 Norfloxacin. Die Medikation wurde nach ,,wahrscheinlich" im Zusammenhang mit der Therapie Doppelblindverfahren sieben Tage lang durchgeffihrt. standen, klagten 10/79 Patientinnen der Fosfomycin Ein bis zwei Tage nach Therapieende wurden 55 der 60 Trometamol-Gruppe (13%) und 2/79 Patientinnen der mit Fosfomycin Trometamol behandelten Patientinnen Norfloxacin-Gruppe (3%). In 3/79 F/illen der Fosfomy(92%) und 48 der 50 mit Norfloxacin behandelten Pa- cin Trometamol Gruppe (3%) wurde am Therapietag tientinnen (96%) als klinisch geheilt beurteilt. 37 Pa- (Einzeldosis) selbst von Nebenwirkungen berichtet. In tientinnen, bei denen zu Therapiebeginn keine signifi- der Therapie unkomplizierter Harnwegsinfektionen kante Bakteriurie nachgewiesen werden konnte, waren bei erwachsenen Frauen ist eine Einzeldosis von 3 g in beiden Therapiegruppen zu 90% von ihren Be- Fosfomycin Trometamol ebenso wirksam wie eine sieschwerden befreit. Zwei bis drei Tage nach Verabrei- bent~igige Behandlung mit zweimal t/iglich 400 mg Norchung der Fosfomycin Trometamol Einzeldosis war in floxacin.

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Infection 18 (1990) Suppl. 2 © MMV MedizinVerlagGmbH Miinchen,Miinchen1990

J. B. J. Boerema et al.: Fosfomycin Trome'amol in Uncomplicated Urinary Infections Introduction

The duration of treatment of uncomplicated urinary infections in adult female patients still ranges from a single dose t o a dosage schedule of many weeks. The use of shorter courses of antimicrobial agents in these common infections arose from studies which suggest a comparable efficacy in appropriate patient populations, more adherence to patient compliance, fewer side effects, less alteration of the normal resident flora in the rectum, vagina and peri-urethral region and more cost effectiveness [1-6]. The efficacy rate of single dose treatment in urinary infections is primarily dependent on an accurate subdivision into the various categories of urinary infections. Major determinants of response to therapy are factors associated with sex and age of the patient, underlying disease, structural (anatomic) and functional (neurologic) abnormalities in the urinary tract, symptomatic or asymptomatic infections, infections restricted to the bladder ("bacterial cystitis") or involvement of the upper urinary tract (pyelitis, pyelonephritis). In general single dose therapy is thought to be effective in adult female patients with luminal or superficial mucosal infections without complications. The appropriate antimicrobial agent for single dose treatment should have a broad spectrum against both gram-negative and gram-positive uropathogens (low MICs) and be preferably bactericidal (low MBCs). The preferred pharmacokinetic profile of the drug used as a single dose agent in urinary infection is one with high concentrations in the urine and a slow excretion rate, which will guarantee a level of the antimicrobial agent above the minimal inhibitory concentration (MIC) for uropathogens for a prolonged period of time (24 hours or more). Studies showed that the single dose administration of agents with a prolonged antibacterial activity in the urine, co-trimoxazole, trimethoprim [7-9] and some fluorinated quinolones [10, 11], achieve a sufficient cure rate. Most beta-lactam antibiotics are less effective [5]. The new trometamol salt of fosfomycin has a favourable pharmacokinetic pattern and shows antibacterial activity against uropathogens which will probably lead to a promising cure rate of uncomplicated urinary infections if used as a single dose treatment [12-15]. Norfloxacin is a fluorinated 4-quinolone which shows remarkable activity against Enterobacteriaceae associated with urinary infections (MIC90 < 0.5 mg/1). Norfloxacin is also active against Pseudomonas aeruginosa (MIC90 < 2 mg/l) and Staphylococcus saprophyticus (MIC90 < 4 mg/l) [16-17]. In this study we compared the efficacy and tolerability of orally administered fosfomycin trometamol in a single dose of 3 g versus norfloxacin in a dose of 400 mg b.i.d, for seven days. Patients and Methods

Patients: Adult female patients aged 16 to 50 years visiting their

general practitioners were eligible for inclusion in this comparative randomised double blind study. The patients had symptomatic urinary infections supported by a finding of pyuria and of --> 105 cfu/m of a "clean-catch" midstream urine specimen. Patients were excluded if they had known structural (anatomical) or functional (neurological) abnormalities in the urinary tract, were pregnant or lactating, had concomitant infection or allergy to the test drugs or derivatives, or were receiving concomitant antibiotics or antimicrobial treatment seven days or less prior to the start of the study. Patients were randomised and numbered consecutively in order of acceptance into the study and were assigned to treatment with either fosfomycin trometamol or norfloxacin according to a double blind schedule (double dummy technique). Group A (fosfomycin trometamol): day 1-one sachet Monuril® (fosfomycin trometamol 3 g active agent), two tablets norfloxacin-placebo (one tablet b.i.d.); days 2-7-two tablets norfloxacin placebo (one tablet b.i.d.). Group B (norfloxacin): day 1-one sachet Monuril ® placebo, two tablets Noroxin® (norfloxacin verum; 400 mg b.i.d.); days 2-7-two tablets norfloxacin verum (400 mg b.i.d.). Patients started on the study medication before the results of culture were available, but were dropped from the study if baseline urine culture subsequently revealed less than 105 cfu/ml or if a resistant pathogen was isolated from the initial urine specimen. Approval for the study had been obtained from an academic institutional review board and patients had given informed consent before treatment with either fosfomycin trometamol or norfloxacin. The study was conducted accordir~g to the Declaration of Helsinki 1964 and the Amendments of Tokyo (1975) and Venice (1983). Clinical and bacteriological evaluations of the patients were performed before, two to three days after the first day of treatment and eight to nine days after the first day of therapy. A final evaluation was conducted six weeks after the start of therapy. During the seven day treatment period the patient kept her own diary card for registration of symptoms: many complaints, few complaints, occasional complaints or no complaints. Adverse effects from treatment were elicited at each patient visit. This information was derived from spontaneous statements made by the patient and by general questioning about her well being. The general practitioner was asked to evaluate all adverse experiences as to their severity (mild, moderate, severe) and relation to the study drug (probable, possible; remote, none). Patient compliance was assessed using a tablet count method. Microbiology: At the first visit a dipslide (URICULT~) was inoculated by the gerieral practitioner and sent in special envelopes to one central laboratory on the same day. The dipslide was incubated at 37°C and the colony count was assessed; --> 105 cfu/ml urine was considered significant bacteriuria. Aerobic cultures including gram-positive and gram-negative bacteria were inoculated on blood agar and EMB (eosin-methylene-blue) agar. These were incubated at 37°C for 24 h. Susceptibility to both study drugs was determined by diffusion using Neosensitabs on Isosensitest agar (Oxoid), as recommended by the International Collaborative Study [18]. Inocula were made to produce semiconfluent growth and equivalent to approximately

J. B. J. Boerema, M.D., Ph.D., Medical Research Bureau International, "Rijnpoort" Building, Groningensingel 1, 6835 EA Arnhem; F. Th. C. Willems, M.D., Laboratory for Medical Microbiology,P.O. Box 90157, 4800 RL Breda, The Netherlands.

Infection 18 (1990) Suppl. 2 © MMV Medizin Verlag GmbH Mtinchen, Miinchen 1990

S 81

J. B. J. Boerema et al.: Fosfomycin Trometamol in Uncomplicated Urinary Infections 5 x103 cfu/ml. Each disk contained 10 ~xgnorfloxacin or 200 Ixg fosfomycin trometamol plus 50 Ixgglucose-6-phosphate. Zones of inhibition of < 16 mm for norfloxacin and -20 mm for norfloxacin and --> 16 mm for fosfomycin trometamol indicated susceptibility. MICs were determined with Isosensitest broth (Oxoid) containing 25 mg/l glucose-6phosphate in microtitre trays containing 100 ~tl per well and a final bacterial concentration of approximately 5 x 103 cfu/ml. MICs were read after overnight incubation at 37°C and taken as the lowest concentration without visible growth. An organism was considered susceptible to norfloxacin if the MIC did not exceed 4 rag/1 and susceptible to fosfomycin trometamol ff the MIC did not exceed 128 mg~. Organisms isolated in initial and recurrent infections were identified using a biochemical identification system (API 20E). Assessment of efficacy: Clinical assessment was defined as cure (disappearance of all baseline signs and symptoms), improvement (marked or moderate reduction of signs and symptoms) or failure (persistence or worsening of initial signs and symptoms) compared with the assessment at the second and third visit. Bacteriological evaluation included cure (a concentration of ~< 103 cfu/ml urine in follow-up cultures at the second, third and fourth visit), persistence (positive culture with initial infecting strain two to three days following therapy), relapse (positive culture after therapy with the same strain as the initial one with a negative culture two to three days following therapy) and reinfection (positive culture after therapy with a different strain from the initial infecting one with a negative culture two to three days following therapy). Reinfection was not considered a therapeutic failure. The distinction between strains was based on species and antibiogram differences. Analysis of data: Key variables for analysis of efficacy were the clinical and bacteriological responses on the second, third and fourth visit. The Chi-square test was used to evaluate the difference between the two treatments with regard to the clinical and bacteriological response. An a-value of 0.05 was taken as significant. The clinical response was dichotomized into the response "cure" (cured and strong improvement) versus "failure" (some improvement and the same or worse) for the second and third visit.

Results 158 patients were initially included in the study. 47 patients were considered drop-outs: 37 had an initial negative culture (not significant bacteriuria 10-104 cfu/ml urine) and were followed for clinical assessment, six were lost to follow-up, three were considered protocol violation (exclusion criteria) and one patient had an initial infecting pathogen resistant to the study drug. All 158 patients were followed for safety assessment. The total number of clinically and bacteriologically evaluable patients included in this studv was 111; 61 were assigned to treatment with fosfomycin trometamol and 50 to norfloxacin. The distribution of age, weight and sex of both study groups is shown in Table 1.

S 82

Table 1: Characteristics of patients evaluable for efficacy (n =

Age (years) Mean S.D. Minimum Maximum

30 7.2 16 46

30 7.0 17 45

Height (cm) Mean S.D. Minimum Maximum

169 6.5 154 182

169 5.1 155 179

Weight (kg) Mean S.D. Minimum Maximum

65 9.1 45 95

64 8.3 49 83

Number of valid cases

50

61

Bacteriological Evaluation Table 2 lists the initial infecting pathogens in both treatment groups. In 86 of 111 (77%) of the patients the organism responsible for the urinary tract infection was Escherichia coil In the urine specimen of seven patients two different pathogens were isolated. Gram-positive infections were found in ten out of 111 (9%) of the patients. The cumulative minimal inhibitory concentrations (MICs) of fosfomycin trometamol and norfloxacin for the initially isolated pathogens are shown in T a b l e s 3 a and 3b, respectively. Two to three days after the single dose treatment with fosfomycin trometamol 60 of the 61 patients (98%) were cured of the initial infecting strain. This included five patients with reinfection. One patient had a persistent infection with E. coil This pathogen maintained its susceptibility for fosfomycin trometamol. Eight to nine days after the single dose of fosfomycin trometamol 51 of the 57 patients (90%) were cured from the initial infecting strain, including 14 reinfections. Shortly after therapy with norfloxacin (two to three days) 48 of the 50 patients (96%) were cured of the initial infecting strain, and two (4%) relapsed (E. coli, Klebsiella pneumoniae). Six weeks after the start of therapy (day 42) in the fosfomycin group 49 of 55 patients (89%) were cured of the initial infection, including 15 patients (27%) with reinfection. T h r e e patients (5%) had a relapse. In the norfioxacin group 44 of 49 patients (90%) were cured of the initial infection, including 12 patients (25%) with reinfection. Three more patients had a relapse resulting in a total of five relapses (10%) in the post treatment period. A survey of the bacteriological response to therapy is given in Table 4.

Infection 18 (1990) Suppl. 2 © MMV Medizin Verlag GmbH Mtinchen, Mtinchen 1990

J. B. J. Boerema et al.: Fosfomycin Trometamol in Uncomplicated Urinary Infections

Approximately 50% of reinfections were caused by gram-positive pathogens. Pseudomonas spp. were involved in three patients in each therapy group. The majority of reinfecting pathogens were susceptible to the study drugs according to the MIC values (Tables 5a, 5b). A comparison was made between the bacteriological resuits with fosfomycin trometamol obtained from the disk diffusion method and the microdilution method. A suffi-

Table 2: Initial infecting organisms.

cient correlation was found between the two methods up to and including a breakpoint of 32 mg/1. At a breakpoint of 64 mg/1, eight out of 37 strains (22%) were considered intermediately susceptible (12-15 mm) and two out of 37 strains (5%) were resistant ( - 11 mm) according to the disk diffusion method. At a breakpoint of 128 mg/l, five out of 27 (18%) and seven out of 27 (26%) of the strains were considered intermediately susceptible and resistant, respectively (Figure 1). It was obvious that a prediction of clinical and bacteriological efficacy was not affected by using a breakpoint of 128 mg/1. Table 3b: Cumulative MtCs of norfloxacin for the initially cultured microorganisms in 111 patients.

Escherichia coli Proteus mirabilis l~Tebsiellapneumoniae Staphylococcus saprophyticus Staphylococcus epidermidis Staphylococcus aureus Escherichia cell + Escherichia coli Escherichia cob + Staphylococcus saprophyticus Escherichia coli + Proteus mirabilis Escherichia coli + Pasteurella putida Escherichia coli + Morganella morganii Proteus mirabilis + BEebsiella oxytoca Enterobacter aerogenes + Pseudomonas fluorescens

40 2

46 3

1

2

2

2

-

2

2

2

1

1

-

1

-

1

1

Total

-

1

-

1

50

61

Table 3a: Cumulative MICs of fosfomycin trometamol for the initially cultured microorganisms in 111 patients.

Escherichia coli Proteus mirabilis Pseudomonas fluorescens Morganella morganii Klebsiella ~ytoca Klebsiella pneumoniae Enterobacter aerogenes Enterobacter sp. Pasteurella putida Staphylococcus aureus Staphylococcus epidermidis Staphylococcus saprophyticus

25 71 77 80 84 86 90 2

6

1

91

7

7

1

1

1

1 1

1 3 1 1

1 1

1 2

3

4

2

2

4

5

5

Total

118"

Including patients with two initially isolated microorganisms. Escherichiacoli Proteus mirabilis Pseudomonas luorescens Morganella morganu Klebsiella oxytoca Klebsiella pneurnoniae Enterobacter aerogenes Enterobacter sp. PasteureUa putida Staphylococcus aureus Staphylococcus epidermidis Staphylococcus saproph}~icus

Total

39 80 88 4

5 1 1

1

90

1

91

3

1 3 1 1 1 4

7 1 1 1 3 1 1 1 4

1

2

2

4

7

5

5

118"

Table 4: Microbiological response.

Eradication Reinfection Persistence Relapse Relapse + reinfection Eradication + relapse

55/61 (90%) 5/61 (8%)

1/61 (2%)

34/55 (62%) 40/50 (80%) 32/49 (65%) 15/55 (27%)[ 8/50 (16%) 12/49 (25%) 1/55 (2%)

I

-

3/55 (5%)

2/50(4%)

1/55 (2%)

-

~/55 (2%)

-

5/49 (10%)

Including seven patients with two initially isolated microorganisms.

Infection 18 (1990) Suppl. 2 © MMV Medizin Verlag GmbH Mfinchen, MLinchen 1990

S

J. B. J. Boerema et al.: Fosfomycin Trometamol in Uncomplicated Urinary Infections

Table 5a: Overview of reinfecting pathogens with susceptibility pattern (fosfomycin trometamol). ::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::

7 45 ~ 48 50 52 68 74 85 87 91 142 146 153 160 161

:~::::~::~::~ :::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::

Staphylococcus epidermidis

Klebsiella pneumoniae Escherichia coli Escherichia coli Staphylococcus epidermidis Klebsiella pneumoniae Proteus mirabilis Escherichia coil Escherichia coil Proteus mirabilis Staphylococcus saprophyticus Escherichia coli Proteus mirabilis Staphylococcus aureus Staphylococcus aureus Proteus mirabilis

8-9 42 8-9 8-9 8-9 8-9 8-9 8-9 8-9 8-9 8-9 8-9 8-9 8-9 8-9

Mixed flora

Staphylococcus epidermidis Staphylococcus saprophyticus Staphylococcus saprophyticus Staphylococcus saprophyticus Pseudomonas fluorescens Klebsiella pneumoniae Acinetobacter sp. Pseudomonas sp. Pseudomonas sp. Acinetobacter sp. Morganella morganii Staphylococcus saprophyticus Staphylococcus epidermidis

R

8

R R S R S S S S S S R S S

64 64 64 128 64 64 64 64 64 64 128 64 32

S = Susceptible; R = Resistant.

Table 5b: Overview of reinfecting pathogens with susceptibility pattern (norfloxacin).

il ii ..............................

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6

Staphylococcus aureus

42 44 46 75 76 88 99

.Escherichia coil Escherichia coli Escherichia cog Escherichia coli Escherichia coli Escherichia coli Proteus rnorganii Enterobacter sp. Eschericttia coli Escherichia coli (2 x ) Escherichia coli Escherichia coli

152 158 159

171

......................

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......................

Pasteurella putida Pseudomonas sp. Pseudomonas maltophilia

iii

...............................................................................................

2-3

Enterococci

Staphylococcus aureus Alcaligenes faecalis Pseudomonas sp. Enterococci

Proteus mirabilis Alcaligenes sp. Enterococci

Staphylococcus epidermidis Staphylococcus epidermidis

iii

2-3 42 42 2-3 2-3 2-3 42

S S S R R R R R S

0.50 0.25 4 4 2 4 64 2 0.06

2-3 2-3 2-3 42

S R S S

0.5 32 0.25 2

S = -Sensitive; R = Resistant.

Clinical Evaluation

Side Effects

Figures 2a and 2b show the frequency and percentages of clinical signs and symptoms in the two treatment groups during the drug administration period of seven days in patients evaluable for efficacy as reported in the patient diary. One or two days after cessation of the double blind medication schedule 55 of the 60 patients in the fosfomycin trometamol group (92%) and 48 of the 50 patients in the norfloxacin group (96%) were classified as clinically cured.

The overall incidence of side effects was 25% in the fosfomycin trometamol group and 10% in the norfloxacin group. An overview of the incidence of side effects is presented in Figure 3 and Table 6. In the fosfomycin trometamol group 10/79 (12.7%) of the patients experienced "probably related" side effects. In 3/79 (3.8%) of the patients these side effects were reported on the actual day of (single dose) treatment. In the norfloxacin group 2/79 (2.5%) of the patients reported "probably related" side effects.

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Infection 18 (1990) Suppl. 2

© MMV Medizin Verlag GmbH Miinchen, Miinchen 1990

J. B. J. Boerema et al.: Fosfomycin Trometamol in Uncomplicated Urinary Infections sensitive

8o

Intermediate

resistant

number of strains

[] [] [] [] [] [] [] •A

60

[] [] [] []

40

[] I

0.5

2

8

4

16

32

64

128

>128

1st day of intake

M.I.C.

occasional

no

P-/-/77~

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