02. Rudenko N (2005)

Prevention of Recurrent
Lower Urinary Tract Infections
by Long-term Administration
of Fosfomycin Trometamol
Double blind, randomized, parallel group,
placebo controlled study
Nikolay Rudenko and Andrey Dorofeyev
Department of Internal Medicine II, Medical University of Donetsk (Ukraine)
Arzneim.-Forsch./Drug Res. 55, No. 7, 420–427 (2005)

ArzneimForschDrugRes
Prevention of Recurrent Lower
Urinary Tract Infections by Long-term
Administration of Fosfomycin Trometamol
Double blind, randomized, parallel group, placebo controlled study
Nikolay Rudenko and Andrey Dorofeyev
Department of Internal Medicine II, Medical University of Donetsk (Ukraine)
Summary
Three hundred and seventeen non pregnant
females, suffering of recurrent
lower urinary tract infections (UTIs; at
least three episodes in the preceding 12
months) were enrolled in a double blind,
randomized placebo (PL) controlled, parallel
group clinical study, addressed to
evaluate the efficacy and safety of fosfomycin
trometamol (CAS 78964-85-9,
FT, Monuril ® ) in the prevention of infectious
recurrences of lower urinary tract.
One hundred and sixty six and 151
patients were allocated at random to FT
or to PL treatment. The assigned treatment,
i.e. one sachet containing FT equivalent
to 3 g. of fosfomycin or PL, was
taken by patients every 10 days during 6
months; thereafter they were followed up
for another 6 consecutive months. Three
hundred and two evaluable patients,
completed the study as per protocol, 158
in the FT and 144 in the PL group, respectively.
The analysis of the number of
urinary tract infections/patient-year
(primary end point) showed a result of
0.14 infections/patient-year in the FT
group and of 2.97 infections/patient-year
in the PL group. The difference was
highly significant (p < 0.001).
The time to first infection recurrence
was significantly longer in the FT (38
days) than in the PL group (6 days);
p < 0.01.
The number of patients with at least
one episode of recurrent infection and
the number of episodes/patient during
the treatment as well as during the follow-up
period were statistically significantly
lower in the FT group than in the
PL group.
Both treatments were well tolerated;
only one adverse reaction possibly treatment
related, i.e. an allergic skin reaction,
was reported in both groups.
Haematology and blood chemistry
variables explored for safety at the end
of the study did not show any significant
difference between the two groups.
The compliance with the treatment in
the 302 evaluable patients was excellent.
The results of this trial indicate that FT
is higly effective in the prophylaxis of
UTI recurrences; this beneficial effect is
evident also in the 6 months of the follow-up.
Key words
CAS 78964-85-9
Fosfomycin trometamol
Lower urinary tract
infections, prevention
of recurrences
Monuril ®
Arzneim.-Forsch./Drug Res.
55, No. 7, 420−427 (2005)
Arzneim.-Forsch./Drug Res. 55, No. 7, 420−427 (2005)
© ECV · Editio Cantor Verlag, Aulendorf (Germany) Rudenko et al. − Fosfomycin trometamol 1

Zusammenfassung
Prävention rezidivierender Infektionen
der unteren Harnwege durch Langzeitbehandlung
mit Fosfomycin-Trometamol /
Doppelblinde, randomisierte, Plazebokontrollierte
Studie an Parallelgruppen
317 nicht-schwangere Patientinnen
mit rezidivierenden Infektionen der unteren
Harnwege (mindestens drei Episoden
innerhalb der vergangenen 12 Monate)
wurden in eine doppelblinde, randomisierte,
Plazebo (PL)-kontrollierte Parallelgruppenstudie
aufgenommen mit dem
Ziel, die Wirksamkeit und Sicherheit von
Fosfomycin-Trometamol (CAS 78964-85-
9, FT, Monuril ® ) in der Prävention rezidivierender
Infektionen der unteren Harnwege
zu bewerten.
166 und 151 Patientinnen wurden randomisiert
den beiden Gruppen − FT bzw.
PL − zugeteilt. Die entsprechende Behandlung,
d. h. Einnahme eines Sachet
mit FT, entsprechend 3 g Fosfomycin,
oder PL, wurde 10 Tage lang über 6 Monate
durchgeführt. Danach folgte eine
among normal women [8]. When vaginal, buccal, and
voided uroepithelial cells were collected from women
with a history of recurrent UTIs and tested in bacterial
adherence assays, three-fold more E. coli adhered to
these women’s cells as compared with cells from control
women without a history of recurrent UTIs [9].
Interestingly Foxman et al. [10], who studied the risk
factors for recurrent UTIs, observed a higher rate of
second UTI when the first UTI was caused by E. coli
than when it was caused by bacteria other than E. coli.
Women with a baseline rate of more than two infections
per year, over many years, are likely to continue
to have recurrent infections [34].
Many evidences support the use of short-term or
even single dose treatment of uncomplicated urinary
tract infections with appropriate antimicrobial agents
and the trometamol salt of fosfomycin (FT), given orally
as single dose, proved effective and well tolerated and
comparable with antimicrobial agents of reference
given in standard or in short treatment [12−17].
Even though single infectious episodes can be managed
by short courses of appropriate antibacterial
drugs, in some women, however, reinfections occur at
frequent intervals and the prophylaxis may be preferable
to the treatment of each individual symptomatic
episode [18]. A long-term prevention treatment lasting
6 months to 1 year has been recommended [7]. In the
last decade, antimicrobial agents such as trimethoprim,
co-trimoxazole, nitrofurantoin, and quinolones, proved
effective in the long-term prophylactic treatment of rekung
in Form einer allergischen Hautreaktion
berichtet, die möglicherweise auf
die Behandlung zurückzuführen war.
Hämatologische und Blutchemie-
Werte, die nach Beendigung der Studie
im Hinblick auf die Sicherheit ermittelt
wurden, zeigten keine signifikanten Unterschiede
in den beiden Gruppen.
Die Compliance der 302 evaluierbaren
Patientinnen war ausgezeichnet. Die
Ergebnisse dieser Studie deuten darauf
hin, daß FT in der Prävention rezidivierender
Infektionen der unteren Harnwege
hochwirksam ist und die positive
Wirkung auch im 6-monatigen Nachbeobachtungszeitraum
vorhanden ist.
1. Introduction
Acute uncomplicated urinary tract infections (UTIs) are
among the most common urologic and bacterial diseases
[1]. On a global basis, around 150 million UTIs
occur annually, and in the United States, UTIs account
for > 6 billion dollars in direct health care costs [2].
The microorganism mainly responsible for these infections
is Escherichia coli, which represents the 70−
90 % of all uropathogens [3, 5]. Occasionally also other
enterobacteriacee, i.e. Proteus mirabilis or Klebsiella
spp., are found in urinary samples [3, 6]. Among Grampositive
bacteria, enterococci are rarely isolated from
patients with cystitis.
The vast majority of acute symptomatic infections
involve young women; an annual incidence of 0.5−0.7
infections per patient-year was found in this group [11].
Between one and two fifth of women will experience
cystitis during their life time. Of these women 20 % will
have recurrences, almost all of which (90 %) are caused
by reinfection rather than relapse [7].
In recurrent cystitis both host and bacterial virulence
factors are involved. Colonization of the vaginal and
periurethral mucosa with the infecting bacteria appears
to be a necessary prerequisite to E. coli urinary tract
infections. Several lines of evidence suggest that susceptibility
to colonization and other aspects of the interaction
between the infecting uropathogenic E. coli
and women’s uroepithelial cells are the key to understanding
the increased susceptibility to recurrent UTIs
Nachbeobachtung von 6 aufeinanderfolgenden
Monaten. 302 evaluierbare Patientinnen
beendeten die Studie protokollgemäß,
158 in der FT-Gruppe und
144 in der PL-Gruppe. Die Analyse der
Anzahl von Harnwegsinfektionen pro Patientenjahr
(primärer Endpunkt) ergab
0,14 Infektionen pro Patientenjahr in der
FT-Gruppe und 2,97 Infektionen pro Patientenjahr
in der PL-Gruppe. Der Unterschied
war hochsignifikant (p < 0,001).
Die Zeit bis zum ersten Infektionsrezidiv
war in der FT-Gruppe signifikant länger
(38 Tage) als in der PL-Gruppe (6
Tage); p < 0,01.
Die Anzahl der Patientinnen mit mindestens
einer Rezidivepisode und die Anzahl
der Episoden pro Patientin während
der Behandlung sowie während des Nachbeobachtungszeitraums
waren in der FT-
Gruppe signifikant niedriger als in der
PL-Gruppe.
Die Verträglichkeit war bei beiden Behandlungen
gut; in beiden Gruppen
wurde nur eine unerwünschte Nebenwir-
2 Rudenko et al. − Fosfomycin trometamol
Arzneim.-Forsch./Drug Res. 55, No. 7, 420−427 (2005)
© ECV · Editio Cantor Verlag, Aulendorf (Germany)

current UTIs [18, 19]; however, the emergence of uropathogen
strains with resistance to well established antibacterial
drugs represent a reason of concern. In the
US, more than 20−25 % of E. coli, responsible for cystitis,
showed bacterial resistance against amoxycillin, cephalexin,
and sulpha drugs; the combination of trimethoprim
with sulphamethoxazole (co-trimoxazole) is
approaching this level of resistance. E. coli uropathogenic
strains resistant to quinolones have been isolated
in significant percentage in selected geographical
areas [20].
FT at 3 g (as fosfomycin) single dose is now enjoying
a leading position in the treatment of lower UTIs, being
considered as a first line drug [21] because of:
− its bactericidal activity against E. coli and other uropathogens;
moreover in vitro studies showed that the
product retains its complete activity against quinolone
resistant urinary isolates of E. coli including strains
also resistant to amoxicillin, chloramphenicol, co-trimoxazole,
netilmicin, nitrofurantoin and tetracycline
[22];
− its extremely low index of bacterial resistance [5, 23,
24, 6, 20];
− its activity on important virulence factors at subminimal
inhibitory concentrations [36];
− its safety. An overall safety assessment carried out in
over 8700 patients treated with this product in therapeutic
clinical trials showed that only a modest incidence
of adverse events, mainly confined to the digestive
system, was reported [37]. In 10 children with
recurrent UTIs associated with abnormalities of the
urinary tract, treated with a dose of fosfomycin trometamol
equivalent to 1−2 g of fosfomycin twice a
week for 3 weeks up to 9 months, no clinical or biological
side effects were reported [25].
These features prompted us to evaluate the potential of
FT in the long-term prevention of recurrent UTIs.
2. Material and methods
Among the female population taken care of by the outpatient
departments of the Department of Internal Medicine II of the
Medical University of Donetsk (Ukraine), 326 non pregnant females
suffering from recurrent episodes of lower UTIs were
subjected to a screening.
Before the beginning of the study all patients gave their
written informed consent to participate in this clinical trial
which was duly approved by the local Ethical Committee.
Main criteria of inclusion:
Non pregnant patients, aged between 18−65 years, with a
history of recurrent bacteriuria and 3 monomicrobic lower
UTIs infections documented by urine cultures (cfu/ml
10 3 ) in the preceding 12 months.
Women in fertile age were asked to prevent conception
throughout the study and for another 3 months following
its end.
Ability to communicate with the study personnel and to read
and understand the information provided and confirmation
in writing of the willingness to participate in the study.
Main criteria of exclusion:
Known hypersensitivity to any component of the study compounds.
Concomitant or preventive antimicrobial treatment in the
15 days preceding the beginning of the study.
Symptoms suggesting an infection of the upper urinary tract
(fever >38.5 °C, back pain, loin tenderness, nausea, malaise).
Patients with symptoms of UTI but with negative urine cultures
during the screening period.
Patients with evidence of active vaginitis.
Patients under treatment with metoclopramide.
Patients with indwelling catheter.
Patients with urolythiasis or renal tumour.
Patients with known history of severe renal impairment.
Presence of diabetes or other severe underlying diseases.
Patients with malignancies.
Immunosuppressed patients.
Patient with granulocytopenia (< 500 /mm 3 polymorphonucleocytes).
Pregnancy/lactation.
Predictable poor compliance.
Participation in a clinical trial with a different, non registered
drug within 30 days of the beginning of the study.
Hormone replacement therapy users and women with topical
(genital) hormonal treatment.
Patients with severe post void residual urine.
Patients with recent urological surgery (less than three
months).
2.1. Experimental design
Double blind, placebo (PL) controlled, randomized, parallel
group study lasting 12 months (6 months of treatment and 6
months of follow-up).
2.1.1. Treatments tested in the study
Fosfomycyn trometamol (CAS 78964-85-9, Monuril ® ; manufacturer:
Zambon Italia Srl., Bresso, Italy): sachet containing
the equivalent of 3 g of fosfomycin.
Placebo.
The two treatments were indistinguishable in appearance and
flavour.
2.1.2. Dosage and administration
Patients were instructed to take orally on an empty stomach at
bed time the content of one sachet dissolved in 100 ml of tap
water every 10 days for 6 consecutive months.
2.1.3. Primary objective of the trial
To evaluate the decrease in the number of UTI recurrences.
2.1.4. Secondary objectives
To evaluate the time to the first recurrence of UTI (infectionfree
period from randomisation).
To evaluate the frequency of patients infected during the prophylaxis
and post prophylaxis periods.
To evaluate the treatment compliance.
To evaluate the overall tolerability.
2.1.5. Patient population
Out of 326 patients screened, 317 were admitted to the trial
and 166 out of 317 were allocated at random to the FT group
Arzneim.-Forsch./Drug Res. 55, No. 7, 420−427 (2005)
© ECV · Editio Cantor Verlag, Aulendorf (Germany) Rudenko et al. − Fosfomycin trometamol 3

and 151 to the PL group. The two groups were homogeneous
with regard to demographic characteristics and underlying diseases.
At the admission visit all patients were neither pregnant
nor lactating. Patients in fertile age were practicing birth control
(oral contraceptives, diaphragm, intrauterine device, condom).
Patients of the PL group had a mean (± SD) number of
infectious urinary recurrences of 4.07 (1.39), in the 12 months
preceding the study; similar figures (4.06; 1.40) were found in
the FT group. The 58 % of the women considered the recurrences
not related or unlikely related to sexual intercourse.
E. coli was the most frequent uropathogen isolated in the
visits preceding the study (72.8 % in FT patients and 75.0 % in
PL patients). Other agents such as K. pneumoniae, C. freundii,
E. cloacae, and P. mirabilis were isolated with a similar frequency
in the two groups.
2.2. Methodology
The patients enrolled in the study were submitted at visit 0
(screening) to a clinical evaluation to ascertain the presence, if
any, of specific symptoms such as dysuria, frequency and urgency,
suprapubic pain; at visit 1 (day 0), performed after about
two weeks, they were randomized after a re-check of the inclusion/exclusion
criteria. Thereafter the patients were examined
at 60 days (visit 2), 120 (visit 3),180 days (visit 4, end of study
treatment), and at 360 days (visit 6, end of follow-up period).
At 270 days (visit 5) patients were questioned only by phone
on their clinical conditions and on the treatment’s tolerability.
If necessary, additional visits were carried out.
At visits 0-2-3-4-6 (and at additional visits, if necessary, due
to the presence of UTI symptoms), a clean voided midstream
urine specimen was obtained for urinalysis and urine cultures;
an identification of genus and species and susceptibility testing
of all significant strains were carried out at the hospital’s laboratory
according to standard methods as suggested by the National
Committee for Clinical Laboratory Standards (NCCLS)
[26]. Urine samples were collected under the usual aseptic conditions.
When an UTI episode was present at visit 0 or occurred
during the visits’ intervals, a urine culture was performed and
the patients were treated according to the indications of the
susceptibility tests and the investigator’s judgement and readmitted
to the study only if cleared from the infection.
At the beginning and at the end of the study, routine haematology
and blood chemistry tests were carried out at the hospital’s
laboratory. At baseline visit, the β-HCG (human chorionic
gonadotropin) test was performed and, subsequently, a
pregnancy test at each visit.
Adverse events spontaneously reported by the patients or
following a question or observed by the investigators were recorded
at each visit.
The patient’s compliance with the treatment was assessed
by the returned empty or unused sachet count.
Primary end-point was the number of episodes/year of uncomplicated
urinary tract infections calculated in each
patients.
Statistics: The first type error was set at 0.05, and the power
of the test with 150 patients/ group is 90 %.
3. Results
3.1. Efficacy
Out of 317 patients, 302 (158/166 in the FT group and
144/151 in the PL group) completed the study and were
evaluable subjects as per protocol. Table 1 reports the
age and BMI (Body Mass Index) distribution by treatment
group.
Statistical analysis for efficacy data was carried out
in the per protocol population (n = 302).
The preventive effect of FT was already evident at the
control visit performed after 60 days of the treatment
(visit 2) where both the number of urinary infectious
episodes and the number of patients with infectious
episodes were significantly lower in the FT group than
in the PL group (p < 0.001) (Tables 2 and 3). A similar
pattern was observed throughout the treatment period.
At visit 4 (end of the treatment period), it was found
that only 11 patients (7 %; cumulative number) in the
FT group experienced infectious urinary episodes in the
period 0−180 days, while in the PL group in the same
period 108 patients (75 %) had at least one infectious
urinary recurrence (p< 0.001) (Table 2).
The same pattern was observed in the number of
total infections from baseline to the end of the treatment
(0−180 days) where in the FT group 11 UTI
episodes (0.07 episodes/patient) and in the PL group
207 episodes (1.44 episodes/patient) were reported
(p < 0.001) (Table 3).
The urinary tract infections/patient-year analysis
(primary end point) showed a result of 0.14 infections/
patient-year in the FT group versus 2.97 infections/
patient-year in the PL group.(p < 0.001) (Table 4).
The time to the first urinary tract infection (infection-free
period from randomisation) for patients enrolled
in the FT group was 38 days, while for those of
the PL group it was 6 days (Kaplan-Meyer analysis
p < 0.01).
During the first 3 months of the follow-up period
(181−270 days) the total number of UTI episodes in the
FT group was 68 (0.43 episodes/patient) and in the PL
group 147 (1.02 episodes/patient) (p < 0.001) (Table 3).
60 patients (38.0 %) (cumulative number) reported
UTI episodes in the FT group while in the PL group the
corresponding figure was 91 patients (63.2 %) and the
difference between the two groups is still significantly
in favour of FT (p < 0.001) (Table 2).
At the end of the follow-up the cumulative number
of subjects with infectious urinary episodes in the entire
period (181−360 days) and the total number of UTI
episodes were still lower in the FT in comparison to the
PL group, (p < 0.001 and p < 0.01) (Tables 2 and 3).
During the treatment period E. coli was the most frequently
represented microorganism (83.0 % in the FT
group and 84.0 % in the PL group) among the isolates
from the patients’ urine.
Antibiotic susceptibility tests carried out in uropathogens
isolated both during the treatment periods and
the follow-up showed that 100 % of the isolated E. coli
strains were susceptible to fosfomycin (Tables 5 and 6).
3.2. Treatments’ safety
All 317 enrolled patients were considered for the assessment
of the safety of the two treatments.
4 Rudenko et al. − Fosfomycin trometamol
Arzneim.-Forsch./Drug Res. 55, No. 7, 420−427 (2005)
© ECV · Editio Cantor Verlag, Aulendorf (Germany)

In the FT group, two patients reported adverse
events (one episode of mild dyspnoea judged not drug
related and a moderate allergic skin reaction regarded
as possibly drug related and found 108 days from the
beginning of the study). This adverse event was resolved
after the administration of a topical corticosteroid.
The patient was withdrawn from the study.
Table 1: Age and BMI distribution by treatment group.
Age
FT (n = 158) PL (n = 144)
Mean (± SD): years 44.59 (10.30)* 44.47 (10.69)
Median 44.52 45.66
Min : Max 25.8 : 63.2 28.1 : 62.6
BMI
Mean (± DS) 25.55 (4.30)* 25.77 (5.80)
Median 25.39 24.47
Min : Max 18.55 : 34.01 17.71 : 39.26
t-Test: * p > 0.05. FT = fosfomycin trometamol; PL = placebo.
Table 2: Cumulative number (and percentage) of patients with
infectious episodes during treatment period and follow-up.
Treatment period (days)
FT (n = 158) PL (n = 144)
0−60 days (visit 2) 8 (5.1 %)* 85 (59.0 %)
0−120 days (visit 3) 10 (6.3 %)** 100 (69.4 %)
0−180 days (visit 4) 11 (7.0 %)*** 108 (75.0 %)
Follow-up period (days)
181−270 days (visit 5) 60 (38.0 %)° 91 (63.2 %)
181−360 days (visit 6) 76 (48.1 %)°° 103 (71.5 %)
Pearson’s chi square test: * p < 0.001, ** p < 0.001, *** p < 0.001,
°p < 0.001, °°p < 0.001. FT = fosfomycin trometamol; PL = placebo.
Table 3: Total number of lower urinary tract infections (UTIs).
FT
PL
Total UTI Total UTI
UTI episodes/ UTI episodes/
episodes patient episodes patient
Table 5: Antibiotic susceptibility (%) of 218 uropathogens isolated
in the treatment period.
Pathogens (n)
Drugs
FOF CIP SXT NOR AMC
E. coli (181) 100 84 72 79 88
K. pneumoniae (8) 50 100 87.5 87.5 100
S. saprophyticus (8) 100 100 0 87.5 87.5
C. freundii (10) 100 100 60 70 30
P. mirabilis (7) 100 100 85.5 100 100
Others (4) 50 75 75 75 100
Total (218)
FOF = fosfomycin; CIP = ciprofloxacin; SXT = co-trimoxazole;
NOR = norfloxacin; AMC = amoxicillin + clavulanic acid.
Table 6: Antibiotic susceptibility (%) of 357 uropathogens isolated
in the follow-up period.
Pathogens (n)
Drugs
FOF CIP SXT NOR AMC
E. coli (299) 100 84 71 79 82
E. cloacae (10) 70 40 20 40 0
S. saprophyticus (18) 100 100 0 94 94
E. fecalis (2) 100 50 100 50 0
P. mirabilis (11) 100 100 82 100 100
K. pneumoniae (9) 67 100 89 100 100
Others (8) 63 75 75 75 87.5
Total (357)
FOF = fosfomycin; CIP = ciprofloxacin; SXT = co-trimoxazole;
NOR = norfloxacin; AMC = amoxicillin + clavulanic acid.
In the PL group, after 88 days from the beginning
of the study, one patient had a moderate allergic skin
reaction judged possibly treatment related; the patient
was treated with a topical corticosteroid and was withdrawn
from the study.
Three other patients reported adverse events in the
PL arm judged unrelated to the treatment: moderate
gastritis and duodenitis, mild cough, mild pain in the
joints.
No differences were found between the two groups
in haematology and blood chemistry variables explored
for safety.
Treatment period
0−60 days Visit 2 8* 0.05 91 0.63
0−120 days Visit 3 10** 0.06 169 1.17
0−180 days Visit 4 11*** 0.07 207 1.44
Follow-up period
181−270 days Visit 5 68° 0.43 147 1.02
181−360 days Visit 6 87°° 0.55 221 1.54
Chi square test: * p < 0.001, ** p < 0.001, *** p < 0.001, °p < 0.001,
°°p < 0.01. FT = fosfomycin trometamol; PL = placebo.
Table 4: Total number of lower urinary tract infections/patientyear.
FT
PL
0,14 2,97
Chi square test: p < 0.001. FT = fosfomycin trometamol; PL = placebo.
4. Discussion
The results obtained in this PL controlled trial are concurrent
in supporting the long-term administration of
FT in female patients with a high index of infectious
urinary recurrences and confirm the findings obtained
in a previous trial with the same prevention scheme
[31].
Throughout the 6 months of treatment 75 % of the
patients (cumulative percentage) in the PL group complained
of lower UTIs (documented by urinary cultures),
while only 7 % of the patients treated with FT
reported infectious recurrences. The difference between
groups is highly significant (p < 0.001). The number of
episodes/patient is significantly lower in FT than in PL
patients (0.07 versus 1.44; p < 0.001).
Arzneim.-Forsch./Drug Res. 55, No. 7, 420−427 (2005)
© ECV · Editio Cantor Verlag, Aulendorf (Germany) Rudenko et al. − Fosfomycin trometamol 5

The urinary tract infections/patient-year analysis
(primary end point) showed a result of 2.97 infections/
patient-year in PL versus 0.14 in FT patients (p< 0.001).
A significant difference in the rate of infections in the
two groups was apparent already in the first two
months and persisted throughout the treatment period.
A favourable effect of the antibiotic, even if less marked
than in the treatment period, was present also in
the 6 months of follow-up where both the total number
of infections and the cumulative number of patients
with at least one infective recurrence were still significantly
lower in the FT group in comparison with the
PL group.
The protection afforded by FT has a particular meaning
considering the patients admitted to the study had
at least 3 urinary infectious episodes in the previous
12 months; moreover the reduction in the number of
subjects with infections and in the number of episodes/
patient even in the follow-up period certainly improved
the patients’ quality of life.
We rated as excellent the safety of FT and this feature,
in addition to the simplicity of the treatment
schedule, were strong motivations for the patients to
comply with the assigned treatment. The compliance
was excellent in all patients.
A prerequisite for an effective prevention treatment
of recurrent UTIs is the use of an antibiotic highly active
on the urophatogens responsible for the disease. The
clinical failures observed in patients with recurrent
UTIs are due, with the exception of the cases of poor
compliance, to the presence of bacterial resistance [27].
The level of resistance found in uropathogens present
in specific geographical areas determines therefore the
degree of usefulness of antibiotic therapy schemes, in
the past well established, but often no longer suitable
for the increasing emergence of resistant strains.
Microbiological in vitro tests performed in this study
confirmed the high susceptibility of E. coli to fosfomycin
as also reported by other authors [6, 20, 22, 29]; it is
remarkable that this antibiotic is the only drug which
did not suffer of an increase in the incidence of bacterial
resistance [29, 32].
The problem of the emergence of resistant strains to
widely used antibiotics induced significant changes in
therapeutic habits of the medical community. Ampicillin
and co-trimoxazole due to the high index of resistant
E. coli found in several countries [5] are no longer recommended
in the empiric therapeutic treatment of
UTIs when the level of resistance of this uropathogen is
higher than 10−20 % [21, 29, 32]; obviously the same
principle should be extended to the prevention treatment.
The problem of resistance to fluoroquinolones of
E. coli is highly variable with sites. Just emerging in the
US and Japan, an increasing trend has been found in
several geographic areas such as Southern Europe [33],
Latin America [28], and in Asia; the situation has reached
a worrying dimension with a rate of 20−30 % [20].
This class of molecules has been used in a broad range
of indications in human medicine, but also in other settings
such as veterinary medicine, animal husbandry
etc, and this overuse may generate a strong selective
pressure on all pathogens, including those circulating
in the community, through a genetic mechanism that
involves chromosomal mutation and acquisition of
plasmids.
FT has kept its in vitro activity against E. coli practically
unchanged in spite of its wide use in the treatment
of uncomplicated lower UTIs since many years in several
European and extra European countries. In all epidemiological
surveys carried out internationally more
than 97−99 % of E. coli strains were susceptible to the
bactericidal activity of FT [5, 6, 20, 39, 40, 41]. Other
studies have shown the lack of a cross-resistance between
FT and other antimicrobial drugs because of its
specific mechanism of action; this antibiotic, therefore,
was shown to be active even against uropathogens resistant
to other agents including fluoroquinolones [22].
The favourable characteristics of FT remained unchanged
for several reasons, including its specific field
of application. Unlike other antibiotics, now less effective
because of the emergence of resistant strains (e. g.
co-trimoxazole, β-lactams, and, in prospect, even
fluoroquinolones), FT has been used almost exclusively
for the treatment of uncomplicated lower UTIs in single
dose for one day only, while other antibacterial drugs
are usually prescribed in a broader range of indications,
in multiple doses and for protracted periods. The effect
on the normal flora is therefore different, FT being
hardly the cause of any modification (the faecal flora of
humans does not host FT resistant strains [29]), while
other antibiotics have a strong selective effect often inducing
persistent alterations of the normal microbial
pattern.
In addition, it should be pointed out that FT is not
used in animal feeding, while fluoroquinolones in some
countries are given as auxinic or anti-infective agents
in animal husbandry.
Microbiological resistance to FT is most frequently
acquired by chromosomal mutation while the plasmid
mediated resistance, very common with co-trimoxazole
and β-lactamic drugs, is very rare; The spreading index
is therefore very modest and the co-selection frequently
present with co-trimoxazole is absent.
The bactericidal potency of FT against E. coli, the
most common causative agent of uncomplicated urinary
tract infections, and the high and sustained fosfomycin
levels in the urinary bladder quickly reduce the
number of the uropathogens thus preventing an easy
selection of mutant strains [29, 42].
The rare emergence of fosfomycin resistant mutants
is mainly caused by a mutation of the genes controlling
the α-glycerophosphate transport; the consequent alteration
of such mechanism, however, leads to an impairment
of the physiological fitness of E. coli [45]. It
has clearly been shown that such mutants became in-
6 Rudenko et al. − Fosfomycin trometamol
Arzneim.-Forsch./Drug Res. 55, No. 7, 420−427 (2005)
© ECV · Editio Cantor Verlag, Aulendorf (Germany)

adequate to perform a pathogenic role. Li Pira et al.
[30] found in such clones a significant reduction in their
multiplication rate and this finding has been recently
confirmed also in media containing urine [6].
Other factors help in impairing the virulence of fosfomycin
resistant mutants such as a reduced adherence
to uroepithelial cells (up to 60 %) and to urinary catheters,
a diminished cell surface hydrophobicity (up to
50 %), a higher susceptibility to polymorphonuclear
cells present in the patients’ bladder with symptomatic
or asymptomatic UTIs. A greater sensitivity to serum
complement killing activity has also been observed in
mutants in comparison with fosfomycin sensitive
strains [6]. In addition, a reduced plasmid transfer has
been found in fosfomycin resistant bacteria [6].
Because of all these factors and probably of other
co-existing alterations of the physiology of the bacterial
cells due to mutations of the genes controlling the
transport of α-glycerophosphate, fosfomycin resistant
bacteria do not exert their usual pathogenic effects.
They are rapidly washed out due to the reduced adhesiveness
to uroepithelial cells, do not survive and are
not easily spread in the environment. All these limitations
explain the very low incidence of fosfomycin resistant
strains as reported in the literature [6, 29, 30].
Recent studies have shown that in cystitis, the sessile
forms of the offending pathogens are organized in
biofilms in the bladder’s walls [43, 38]. These forms
modify phenotypically the susceptibility to the antibiotics
of the bacteria which are thus less sensitive to the
treatment [44].
These biofilms maintain symptomatic cystitis by
shredding waves of planktonic cells that replicate in the
urine [38]. It was shown that fosfomycin has the ability
to inhibit the formation and even to promote the disruption
of biofilms, thus helping to prevent recurrences
and development of chronic infections [29, 35].
FT for its microbiological and pharmacokinetic characteristics
and the proven clinical activity is considered
a first choice drug for the treatment of uncomplicated
UTIs in adults [21, 29]. The results we have obtained
in our study suggest that this product deserves a preeminent
position also in the prevention of recurrences
of uncomplicated lower urinary tract infections.
The excellent tolerability shown by the product in
our long-term study warrants the development of prevention
clinical trials with a longer duration of treatment.
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Correspondence:
Prof. Nicolay Rudenko,
Clinical Pharmacology Unit,
Ovnataniana str., 16,
83017 Donetsk (Ukraine)
E-mail: nicolaij.rudenko@mediservice.it
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