Antibiotika · Chemotherapeutika · Virustatika · Zytostatika

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)

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Summary

Three hundred and seventeen non preg-
nant 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, par-
allel group clinical study, addressed to
evaluate the efficacy and safety of fos-
fomycin trometamol (CAS 78964-85-9,
FT, Monuril) in the prevention of infec-
tious 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 treat-
ment, i.e. one sachet containing FT equi-
valent 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
Key words
in the FT and 144 in the PL group, re-
spectively. The analysis of the number of
䊏 CAS 78964-85-9
urinary tract infections/patient-year
䊏 Fosfomycin trometamol
(primary end point) showed a result of
䊏 Lower urinary tract 0.14 infections/patient-year in the FT
infections, prevention group and of 2.97 infections/patient-year
of recurrences in the PL group. The difference was
䊏 Monuril highly significant (p < 0.001).
The time to first infection recurrence
Arzneim.-Forsch./Drug Res. was significantly longer in the FT (38
55, No. 7, 420−427 (2005) 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 fol-
low-up period were statistically signifi-
cantly lower in the FT group than in the
PL group.
Both treatments were well tolerated;
only one adverse reaction possibly treat-
ment related, i.e. an allergic skin reac-
tion, 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 fol-
low-up.

Arzneim.-Forsch./Drug Res. 55, No. 7, 420−427 (2005)

420 Rudenko et al. − Fosfomycin trometamol
 Antibiotics · Antiviral Drugs · Chemotherapeutics · Cytostatics

Zusammenfassung

Prävention rezidivierender Infektionen
der unteren Harnwege durch Langzeitbe-
handlung mit Fosfomycin-Trometamol /
Doppelblinde, randomisierte, Plazebo-
kontrollierte Studie an Parallelgruppen
317 nicht-schwangere Patientinnen
mit rezidivierenden Infektionen der unte-
ren Harnwege (mindestens drei Episoden
innerhalb der vergangenen 12 Monate)
wurden in eine doppelblinde, randomi-
sierte, Plazebo (PL)-kontrollierte Parallel-
gruppenstudie aufgenommen mit dem
Ziel, die Wirksamkeit und Sicherheit von
Fosfomycin-Trometamol (CAS 78964-85-
9, FT, Monuril) in der Prävention rezidi-
vierender Infektionen der unteren Harn-
wege zu bewerten.
166 und 151 Patientinnen wurden ran-
domisiert den beiden Gruppen − FT bzw.
PL − zugeteilt. Die entsprechende Be-
handlung, d. h. Einnahme eines Sachet
Nachbeobachtung von 6 aufeinanderfol-
genden Monaten. 302 evaluierbare Pa-
tientinnen beendeten die Studie proto-
kollgemäß, 158 in der FT-Gruppe und
144 in der PL-Gruppe. Die Analyse der
Anzahl von Harnwegsinfektionen pro Pa-
tientenjahr (primärer Endpunkt) ergab
0,14 Infektionen pro Patientenjahr in der
FT-Gruppe und 2,97 Infektionen pro Pa-
tientenjahr in der PL-Gruppe. Der Unter-
schied war hochsignifikant (p < 0,001).
Die Zeit bis zum ersten Infektionsrezi-
div war in der FT-Gruppe signifikant län-
ger (38 Tage) als in der PL-Gruppe (6
Tage); p < 0,01.
Die Anzahl der Patientinnen mit min-
destens einer Rezidivepisode und die An-
zahl der Episoden pro Patientin während
der Behandlung sowie während des Nach-
beobachtungszeitraums waren in der FT-
Gruppe signifikant niedriger als in der
PL-Gruppe.
kung in Form einer allergischen Hautre-
aktion 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 Un-
terschiede in den beiden Gruppen.
Die Compliance der 302 evaluierba-
ren Patientinnen war ausgezeichnet. Die
Ergebnisse dieser Studie deuten darauf
hin, daß FT in der Prävention rezidivie-
render Infektionen der unteren Harn-
wege hochwirksam ist und die positive
Wirkung auch im 6-monatigen Nachbeob-
achtungszeitraum vorhanden ist.

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mit FT, entsprechend 3 g Fosfomycin, Die Verträglichkeit war bei beiden Be-
oder PL, wurde 10 Tage lang über 6 Mo- handlungen gut; in beiden Gruppen
nate durchgeführt. Danach folgte eine wurde nur eine unerwünschte Nebenwir-

1. Introduction among normal women [8]. When vaginal, buccal, and

Acute uncomplicated urinary tract infections (UTIs) are
among the most common urologic and bacterial dis-
eases [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 in-
fections 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 Gram-
positive 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 sus-
ceptibility to colonization and other aspects of the in-
teraction between the infecting uropathogenic E. coli
and women’s uroepithelial cells are the key to under-
standing the increased susceptibility to recurrent UTIs
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 infec-
tions 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 man-
aged by short courses of appropriate antibacterial
drugs, in some women, however, reinfections occur at
frequent intervals and the prophylaxis may be prefer-
able 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 re-

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Rudenko et al. − Fosfomycin trometamol 421
Antibiotika · Chemotherapeutika · Virustatika · Zytostatika
current UTIs [18, 19]; however, the emergence of uropa-
thogen strains with resistance to well established anti-
bacterial drugs represent a reason of concern. In the
US, more than 20−25 % of E. coli, responsible for cyst-
itis, showed bacterial resistance against amoxycillin, ce-
phalexin, and sulpha drugs; the combination of trime-
thoprim with sulphamethoxazole (co-trimoxazole) is
approaching this level of resistance. E. coli uropathog-
enic 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 uro-
pathogens; 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-tri-
moxazole, netilmicin, nitrofurantoin and tetracycline
[22];
− its extremely low index of bacterial resistance [5, 23,
24, 6, 20];
− its activity on important virulence factors at submini-
mal inhibitory concentrations [36];
− its safety. An overall safety assessment carried out in
over 8700 patients treated with this product in thera-
peutic clinical trials showed that only a modest inci-
dence of adverse events, mainly confined to the di-
gestive system, was reported [37]. In 10 children with
recurrent UTIs associated with abnormalities of the
urinary tract, treated with a dose of fosfomycin tro-
metamol equivalent to 1−2 g of fosfomycin twice a
week for 3 weeks up to 9 months, no clinical or bio-
logical 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 fe-
males 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:
䊊
Non pregnant patients, aged between 18−65 years, with a
history of recurrent bacteriuria and ⱖ 3 monomicrobic lower
UTIs infections documented by urine cultures (cfu/ml ⱖ
103) in the preceding 12 months.
䊊
Women in fertile age were asked to prevent conception
throughout the study and for another 3 months following
its end.
䊊 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.
422 Rudenko et al. − Fosfomycin trometamol
Main criteria of exclusion:
䊊 Known hypersensitivity to any component of the study com-
pounds.
䊊 Concomitant or preventive antimicrobial treatment in the
15 days preceding the beginning of the study.
䊊 Symptoms suggesting an infection of the upper urinary tract
(fever >38.5 °C, back pain, loin tenderness, nausea, malaise).
䊊 Patients with symptoms of UTI but with negative urine cul-
tures during the screening period.
䊊 Patients with evidence of active vaginitis.
䊊 Patients under treatment with metoclopramide.
䊊 Patients with indwelling catheter.
䊊 Patients with urolythiasis or renal tumour.
䊊 Patients with known history of severe renal impairment.
䊊 Presence of diabetes or other severe underlying diseases.
䊊 Patients with malignancies.
䊊 Immunosuppressed patients.
䊊 Patient with granulocytopenia (< 500 /mm3 polymorphonu-
cleocytes).
䊊 Pregnancy/lactation.
䊊 Predictable poor compliance.
䊊 Participation in a clinical trial with a different, non registered
drug within 30 days of the beginning of the study.
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䊊 Hormone replacement therapy users and women with top-
ical (genital) hormonal treatment.
䊊 Patients with severe post void residual urine.
䊊 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
䊊 Fosfomycyn trometamol (CAS 78964-85-9, Monuril; manu-
facturer: Zambon Italia Srl., Bresso, Italy): sachet containing
the equivalent of 3 g of fosfomycin.
䊊 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 (infection-
free period from randomisation).
To evaluate the frequency of patients infected during the pro-
phylaxis 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)

and 151 to the PL group. The two groups were homogeneous
with regard to demographic characteristics and underlying dis-
eases. At the admission visit all patients were neither pregnant
nor lactating. Patients in fertile age were practicing birth con-
trol (oral contraceptives, diaphragm, intrauterine device, con-
dom). 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 recur-
rences 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 fre-
quency 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 ur-
gency, suprapubic pain; at visit 1 (day 0), performed after about
two weeks, they were randomized after a re-check of the inclu-
sion/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 labo-
ratory according to standard methods as suggested by the Na-
tional Committee for Clinical Laboratory Standards (NCCLS)
[26]. Urine samples were collected under the usual aseptic con-
ditions.
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 read-
mitted to the study only if cleared from the infection.
At the beginning and at the end of the study, routine haem-
atology and blood chemistry tests were carried out at the hos-
pital’s laboratory. At baseline visit, the β-HCG (human chori-
onic 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 re-
corded 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 un-
complicated 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
Arzneim.-Forsch./Drug Res. 55, No. 7, 420−427 (2005)
Antibiotics · Antiviral Drugs · Chemotherapeutics · Cytostatics
evaluable subjects as per protocol. Table 1 reports the
age and BMI (Body Mass Index) distribution by treat-
ment 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 treat-
ment (0−180 days) where in the FT group 11 UTI
episodes (0.07 episodes/patient) and in the PL group
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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 (infec-
tion-free period from randomisation) for patients en-
rolled 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 en-
tire 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 fre-
quently 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 uropa-
thogens 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 assess-
ment of the safety of the two treatments.
Rudenko et al. − Fosfomycin trometamol 423
Antibiotika · Chemotherapeutika · Virustatika · Zytostatika

In the FT group, two patients reported adverse Table 5: Antibiotic susceptibility (%) of 218 uropathogens isolated
in the treatment period.
events (one episode of mild dyspnoea judged not drug
related and a moderate allergic skin reaction regarded Drugs
Pathogens (n)
as possibly drug related and found 108 days from the FOF CIP SXT NOR AMC
beginning of the study). This adverse event was re-
E. coli (181) 100 84 72 79 88
solved after the administration of a topical corticos- K. pneumoniae (8) 50 100 87.5 87.5 100
teroid. The patient was withdrawn from the study. 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
Table 1: Age and BMI distribution by treatment group. Total (218)

FT (n = 158) PL (n = 144) FOF = fosfomycin; CIP = ciprofloxacin; SXT = co-trimoxazole;

NOR = norfloxacin; AMC = amoxicillin + clavulanic acid.
Age

Mean (± SD): years 44.59 (10.30)* 44.47 (10.69)

Median 44.52 45.66 Table 6: Antibiotic susceptibility (%) of 357 uropathogens isolated
Min : Max 25.8 : 63.2 28.1 : 62.6 in the follow-up period.
BMI Drugs
Pathogens (n)
Mean (± DS) 25.55 (4.30)* 25.77 (5.80) FOF CIP SXT NOR AMC
Median 25.39 24.47
Min : Max 18.55 : 34.01 17.71 : 39.26 E. coli (299) 100 84 71 79 82
E. cloacae (10) 70 40 20 40 0
t-Test: * p > 0.05. FT = fosfomycin trometamol; PL = placebo. S. saprophyticus (18) 100 100 0 94 94
E. fecalis (2) 100 50 100 50 0

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P. mirabilis (11) 100 100 82 100 100
Table 2: Cumulative number (and percentage) of patients with K. pneumoniae (9) 67 100 89 100 100
infectious episodes during treatment period and follow-up. Others (8) 63 75 75 75 87.5
Total (357)
FT (n = 158) PL (n = 144)
FOF = fosfomycin; CIP = ciprofloxacin; SXT = co-trimoxazole;
Treatment period NOR = norfloxacin; AMC = amoxicillin + clavulanic acid.

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 In the PL group, after 88 days from the beginning

of the study, one patient had a moderate allergic skin
181−270 days (visit 5) 60 (38.0 %)° 91 (63.2 %)
181−360 days (visit 6) 76 (48.1 %)°° 103 (71.5 %) reaction judged possibly treatment related; the patient
was treated with a topical corticosteroid and was with-
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. drawn from the study.
Three other patients reported adverse events in the
PL arm judged unrelated to the treatment: moderate
Table 3: Total number of lower urinary tract infections (UTIs). gastritis and duodenitis, mild cough, mild pain in the
FT PL joints.
No differences were found between the two groups
Total UTI Total UTI
UTI episodes/ UTI episodes/ in haematology and blood chemistry variables explored
episodes patient episodes patient 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 4. Discussion
0−180 days Visit 4 11*** 0.07 207 1.44 The results obtained in this PL controlled trial are con-
Follow-up period current in supporting the long-term administration of
FT in female patients with a high index of infectious
181−270 days Visit 5 68° 0.43 147 1.02
181−360 days Visit 6 87°° 0.55 221 1.54 urinary recurrences and confirm the findings obtained
in a previous trial with the same prevention scheme
Chi square test: * p < 0.001, ** p < 0.001, *** p < 0.001, °p < 0.001,
°°p < 0.01. FT = fosfomycin trometamol; PL = placebo. [31].
Throughout the 6 months of treatment 75 % of the
patients (cumulative percentage) in the PL group com-
Table 4: Total number of lower urinary tract infections/patient- plained of lower UTIs (documented by urinary cul-
year.
tures), while only 7 % of the patients treated with FT
FT PL reported infectious recurrences. The difference between
0,14 2,97 groups is highly significant (p < 0.001). The number of
episodes/patient is significantly lower in FT than in PL
Chi square test: p < 0.001. FT = fosfomycin trometamol; PL = placebo.
patients (0.07 versus 1.44; p < 0.001).

Arzneim.-Forsch./Drug Res. 55, No. 7, 420−427 (2005)

424 Rudenko et al. − Fosfomycin trometamol

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 mar-
ked 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 signifi-
cantly lower in the FT group in comparison with the
PL group.
The protection afforded by FT has a particular mean-
ing 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 fea-
ture, 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 fosfomy-
cin 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 bac-
terial 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. Ampicil-
lin and co-trimoxazole due to the high index of resistant
E. coli found in several countries [5] are no longer re-
commended 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 treat-
ment.
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 re-
ached a worrying dimension with a rate of 20−30 % [20].
Arzneim.-Forsch./Drug Res. 55, No. 7, 420−427 (2005)
Antibiotics · Antiviral Drugs · Chemotherapeutics · Cytostatics
This class of molecules has been used in a broad range
of indications in human medicine, but also in other set-
tings 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 practic-
ally unchanged in spite of its wide use in the treatment
of uncomplicated lower UTIs since many years in sev-
eral European and extra European countries. In all epi-
demiological 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 be-
tween FT and other antimicrobial drugs because of its
specific mechanism of action; this antibiotic, therefore,
was shown to be active even against uropathogens res-
istant to other agents including fluoroquinolones [22].
The favourable characteristics of FT remained un-
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changed for several reasons, including its specific field
of application. Unlike other antibiotics, now less effec-
tive 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 in-
ducing 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 urin-
ary tract infections, and the high and sustained fos-
fomycin 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 al-
teration of such mechanism, however, leads to an im-
pairment of the physiological fitness of E. coli [45]. It
has clearly been shown that such mutants became in-
Rudenko et al. − Fosfomycin trometamol 425
Antibiotika · Chemotherapeutika · Virustatika · Zytostatika
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 fos-
fomycin resistant mutants such as a reduced adherence
to uroepithelial cells (up to 60 %) and to urinary cath-
eters, 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 adhe-
siveness to uroepithelial cells, do not survive and are
not easily spread in the environment. All these limita-
tions explain the very low incidence of fosfomycin res-
istant 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 antibi-
otics 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 dis-
ruption of biofilms, thus helping to prevent recurrences
and development of chronic infections [29, 35].
FT for its microbiological and pharmacokinetic char-
acteristics 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 pre-
eminent 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 pre-
vention clinical trials with a longer duration of treat-
ment.
5. References
[1] Hooton, T. M., Pathogenesis of urinary tract infection: an
up-date. J. Antimicrob. Chemother. 46, Suppl. S1, 1 (2000)
[2] Raz, R., Gennesin, Y., Wasser, J. et al., Recurrent urinary
tract infections in post menopausal women. Clin. Infect. Dis.
30, 152 (2000)
[3] Naber, K. G., Survey on antibiotic usage in the treatment
of urinary tract infections. J. Antibiot. Chemother. 46, Suppl.
S1, 49 (2000)
426 Rudenko et al. − Fosfomycin trometamol
[4] Naber, K., G., Treatment options for acute uncomplic-
ated cystitis in adults. J. Antimicrob. Chemother. 46, Suppl. 1,
23 (2000)
[5] Kahlmeter, G., The ECO SENS Project: A prospective,
multinational, multicentre epidemiological survey of the pre-
valence and antimicrobial susceptibility of urinary tract patho-
gens- interim report. J. Antimicrob.Chemother. 46, Suppl. S 1,
15 (2000)
[6] Marchese, A., Gualco, L., Debbia, E. A. et al., In vitro
activity of fosfomycin against Gram negative urinary pathogens
and the biological cost of fosfomycin resistance. Int. J. Anti-
microb. Agents 22, S 53 (2003)
[7] Chew, L. D., Fihn, S. D., Recurrent cystitis in non preg-
nant women. West J. Med. 170, 274 (1999)
[8] Schaeffer, A. J., Rajan, N., Wright, E. T. et al., Role of
vaginal colonization in urinary tract infections (UTIs), in: Ad-
vances in Bladder Research, Baskin and Hayward (eds.), Kluwer
Academic/Plenum, New York (1999)
[9] Schaeffer, A. J., Jones J. M., Dunn J. K., Association of in
vitro E. coli adherence to vaginal and buccal epithelial cells
with susceptibility of women to recurrent urinary tract infec-
tions. N. Engl. J. Med. 304,1062 (1981)
[10] Foxmann, B., Gillespie B., Koopman J. et al., Risk factors
for secondary urinary tract infections among college women.
Downloaded by: NYU. Copyrighted material.
Am. J. Epidemiol. 151, 1194 (2000)
[11] Stamm, W. E., Urinary tract infections and pye-
lonephritis, in: Harrison’s Principles of Internal Medicine, 16th
edition, pp. 1715−1721, McGraw-Hill, New York (August 2004)
[12] Naber K. G., Johnson N. F., The safety and tolerability
of fosfomycin trometamol. Rev. Contemp. Pharmacother. 6,
63 (1995)
[13] Richaud, C., Single dose treatment of lower urinary tract
infection in women: Results of a trial with fosfomycin trometa-
mol versus pefloxacin. Med. Mal. Infect. 25, 154 (1995)
[14] Boerema, J. B. J., Willelms F. T. C., Fosfomycin trometa-
mol in a single dose versus norfloxacin for seven days in the
treatment of uncomplicated urinary tract infections in general
practice. Infection 18 (Suppl. 2), 80 (1990)
[15] Van Pienbroek, E., Hermans, J., Kaptein, A. A. et al.,
Fosfomycin trometamol in single dose versus seven days nitro-
furantoin in the treatment of acute uncomplicated urinary
tract infections in women. Pharm. World Sci. 15, 257 (1993)
[16] Reynaert, J., Van Eyc, D., Vandepitte, J., Single dose fos-
fomycin trometamol versus multiple dose norfloxacin over
three days for uncomplicated UTI in general practice. Infection
18, S77 (1990)
[17] Lobel, B., Short term therapy for uncomplicated urinary
tract infections to day. Clinical outcome upholds the theories.
Int. J. Antimicrob. Agents 22, 85 (2003)
[18] Stamm, W. E., Cunts, G. W., Wagner, K. F. et al., Antimi-
crobial prophylaxis of Recurrent Urinary Tract Infections. A
double blind PL controlled trial. Ann. Intern. Med. 2, 770 (1980)
[19] Melekos, M. D., Asbach, H. W., Gerharz, E. et al., Post
intercourse versus daily Ciprofloxacin in prophylaxis for recur-
rent urinary tract infections in pre menopausal women. J. Urol.
157, 935 (1997)
[20] Fadda, G., Nicoletti, G., Schito, G. C. et al., Resistenza
agli antibiotici nei patogeni delle infezioni urinarie non com-
plicate: un importante parametro nell’impostazione della prat-
ica terapeutica clinica. GIMMOC, Quad. Microbiol. Clin. X, Q1,
1 (2005)
[21] Cersosimo, L., Catanzaro, F., Imparato, E. et al., Racco-
mandazioni per il trattamento delle vie urinarie non complic-
ate nell’adulto. SIGO Soc. Ital. Ostet. Ginecol. XVI, 14 (2003)
Arzneim.-Forsch./Drug Res. 55, No. 7, 420−427 (2005)

[22] Ungheri, D., Albini, E., Belluco, G., In vitro susceptibility
of quinolone-resistant clinical isolates of Escherichia coli to
fosfomycin trometamol. 12th Mediterranean Congress of Che-
motherapy, Marrakesh, Marocco (2000)
[23] Chomarat, M., Resistance of bacteria in urinary tract
infections. Int. J. Antimicrob. Agents 16, 483 (2000)
[24] Arzouni, J. P., Builloux J. P., de Mouy, D. et al., Urinary
tract infections in women aged 15 to 65 years in open care
practice: monitoring of Escherichia coli sensitivity to fosfomy-
cin trometamol on the basis of the previous study. Med. Mal.
Infect. 30, 699 (2000)
[25] Careddu, P., Borzani M., Varotto F. et al., Trometamol
salt of fosfomycin (Monuril) Preliminary pharmacokinetic
and clinical experience in the treatment of urinary tract infec-
tions in children. Eur. Urol. 13, Suppl. 1, 114 (1987)
[26] National Committee for Clinical Laboratory Standards
Methods for dilution antimicrobial susceptibility tests for bac-
teria that grow aerobically, 4th ed., Approved standard M7−A5
(2002) and M100−S12 (2002), NCCLS, Wayne, PA (USA)
[27] Nicolle, L. E., The optimal management of lower urin-
ary tract infections. Infection 18, Suppl. 2, S50 (1990)
[28] Kiffer, C. R. V., Mendes, C., Kuti, J. L. et al., Pharmaco-
dynamic comparison of antimicrobials against nosocomial
isolates of E. coli, K. pneumoniae, A. baumannii and P. aeurogi-
nosa from the MYSTIC surveillance program: the OPTAMA Pro-
gram, South America 2002. Diagn. Microb. Infect. Dis. 49, 109
(2004)
[29] Schito, G. C., Why fosfomycin trometamol as first line
therapy for uncomplicated UTI ? Int. J. Antimicrob. Agents 22,
S79 (2003)
[30] Li Pira, G., Pruzzo, C., Schito, G. C., Monuril and modi-
fication of pathogenicity traits in resistant microorganisms.
Eur. Urol. 13, Suppl.1, 92 (1987)
[31] Miniello, G., Urocitogramma a fresco: strumento dia-
gnostico nelle infezioni urinarie ricorrenti. Lett. Urol. 1, 3
(1996)
[32] Fadda, G., Nicoletti, G., Schito, G. C. et al., Antimicro-
bial susceptibility patterns of contemporary pathogens from
uncomplicated urinary tract infections isolated in a multi-
center italian survey: possibile impact on guidelines. J. Chem-
other. (accepted) (2005)
[33] Kahlmeter, C., An international survey of the antimicro-
bial susceptibility of pathogens of uncomplicated urinary tract
infections: The ECO-SENS Project. J. Antimicrob. Chemother.
51, 69 (2003)
[34] Stamm, W. E., Counts, G. W., McKevitt, M. et al., Urinary
prophylaxis with trimethoprim and trimethoprimsulfamethox-
azole: efficacy, influence on the natural history o recurrent bac-
teriuria, and cost control. Rev. Infect. Dis. 4, 450 (1982)
Arzneim.-Forsch./Drug Res. 55, No. 7, 420−427 (2005)
Antibiotics · Antiviral Drugs · Chemotherapeutics · Cytostatics
[35] Marchese, A., Bozzolasco, M., Gualco, L. et al., Effect of
fosfomycin alone and in combination with N-acetylcysteine on
E. coli biofilms. Int. J. Antimicrob. Agents 22, (Suppl. 2), S95
(2003)
[36] Fadda, G., Cattani, P., Rossi, A. et al., Atlante fotografico
sugli effetti di fosfomicina trometamolo nei confronti dell’ade-
sività batterica. GIMMOC VI, Luglio 2002
[37] Fosfomycin trometamol, product monograph, Excerpta
Medica, December 2002
[38] Kumon, H., Management of biofilm infections in the
urinary tract. World J. Surg. 10, 1193 (2000)
[39] Schito G. C., Chezzi C., Nicoletti G. et al., Susceptibility
of frequent urinary pathogens to fosfomycin trometamol and
eight other antibiotics: results of Italian Multicenter Survey.
Infection 20 (Suppl. 4), S291 (1995)
[40] Fuchs, P. C., Barry, A. L., Brown, S. D., Fosfomycin tro-
methamine susceptibility of outpatient urine isolates of
Escherichia coli and Enterococcus faecalis from ten North
American medical centres by three methods. J. Antimicrob.
Chemother. 43, 137 (1999)
[41] Daza, R., Gutierrez, J., Piedrola, G., Antibiotic susceptib-
ility of bacterial strains isolated from patients with community-
acquired urinary tract infections. Int. J. Antimicrob. Agents 18,
211 (2001
Downloaded by: NYU. Copyrighted material.
[42] Zhao, X., Drlica, K., Restricting the Selection of Antibi-
otic-Resistant Mutants: A General Strategy Derived from
Fluoroquinolone Studies. CID 33, S147 (2001)
[43] Nickel, J. C., Costerton, J. W., McLean, R. J. C. et al.,
Bacterial biofilms: influence on the pathogenesis, diagnosis
and tretament of urinary tract infections. J. Antimicrob. Chem-
other. 33, Suppl. A, 31 (1994)
[44] Dunne, W. M., Jr., Bacterial adhesion: seen any good
biofilms lately? Clin. Microbiol. Rev. 15, 155 (2002)
[45] Reeves, D. S., Fosfomycin trometamol. J. Antimicrob.
Chemother. 34, 853 (1994)
Correspondence:
Prof. Nicolay Rudenko,
Clinical Pharmacology Unit,
Ovnataniana str., 16,
83017 Donetsk (Ukraine)
E-mail: nicolaij.rudenko@mediservice.it
Rudenko et al. − Fosfomycin trometamol 427