Formulary Forum

Single-Dose Treatment of Acute Cystitis with Fosfomycin Tromethamine

Gary E Stein

OBJECTIVE: To review the clinical pharmacology of fosfomycin

tromethamine, a new antimicrobial agent for the treatment of
uncomplicated lower urinary tract infections (UTIs). H H
DATA SOURCE: Publications in English on fosfomycin, fosfomycin
tromethamine, and fosfomycin trometamol (MEDLINE,
1970–1997), as well as unpublished studies submitted to the Food
and Drug Administration (FDA), were reviewed. C C
STUDY SELECTION: Comparative, randomized, controlled studies were
used to analyze the efficacy and safety of fosfomycin tromethamine.
DATA SYNTHESIS: Fosfomycin tromethamine is an oral antimicrobial H3C O PO3H2
indicated for the treatment of uncomplicated lower UTIs. This agent
is active in the urine against common uropathogens that are
associated with cystitis in women, including organisms resistant to Figure 1. Graphic formula of fosfomycin.
other antibiotics. A single dose of fosfomycin tromethamine is well
absorbed and produces therapeutic concentrations in the urine for
2–4 days. Comparative clinical trials suggest that a single dose of
fosfomycin tromethamine 3.0 g is as clinically effective as 7- to 10- fomycin, fosfomycin tromethamine. Fosfomycin trometh-
day treatment regimens of standard agents used to treat UTIs, such amine is indicated only for the treatment of uncomplicated
as nitrofurantoin, norfloxacin, and trimethoprim/sulfamethoxazole. urinary tract infections (UTIs) in women. A parenteral for-
Fosfomycin tromethamine is well tolerated and appears safe to use mulation will not be available in the US. Publications in
during pregnancy. English and unpublished studies submitted to the Food and
CONCLUSIONS: Fosfomycin tromethamine is the only antimicrobial to Drug Administration are reviewed in this article.
be approved by the FDA for single-dose therapy in women with
acute cystitis. It is as effective and safe as multidose comparators
and appears safe to use during pregnancy. The acquisition cost of Microbiology
this new drug will need to be weighed against the improved
compliance and convenience associated with its use in the treatment MECHANISM OF ACTION
of uncomplicated UTIs.
The bactericidal effect of fosfomycin is due to blocking
KEY WORDS: acute cystitis, fosfomycin tromethamine.
bacterial wall synthesis.1 Two main transport systems, the
Ann Pharmacother 1998;32:215-9. L-α-glycerophosphate transport system and the hexose
phosphate uptake system, promote fosfomycin passage
across the bacterial cell wall to reach its target site. The
FOSFOMYCIN, a derivative of phosphonic acid, is an an- blocking of cell wall synthesis is accomplished by the inhi-
tibacterial agent (mol. wt. = 138) that contains unusual bition of pyruvyl transferase, an enzyme necessary for the
chemical features in its structure, such as an epoxide ring first step in the synthesis of bacterial cell walls.
and a carbon–phosphorus bond (Figure 1). The most clini-
cally useful oral preparation contains a soluble salt of fos- ANTIBACTERIAL ACTIVITY

Fosfomycin is rapidly bactericidal and possesses activi-

Gary E Stein PharmD, Associate Professor of Medicine and Pharmacology, De-
partment of Medicine, Michigan State University, B-320 Life Sciences Bldg.,
E. Lansing, MI 48824, FAX 517/353-1922
Reprints: Gary E Stein PharmD
Fosfomycin tromethamine (Monurol, Forest Laboratories).
ty against many gram-negative and gram-positive bacteria.2
The spectrum of activity of fosfomycin may include iso-
lates of Escherichia coli, Enterobacter spp., Citrobacter
spp., Klebsiella spp., Proteus spp., Providencia spp., Pseu-

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domonas aeruginosa, Enterococcus spp., and Staphylococ-
cus spp.3 The high inhibitory concentrations of this antibiot-
ic limit its clinical utility to the urinary tract. Uropathogens
inhibited by concentrations of 64 mg/L or less are consid-
ered susceptible, 128 mg/L are intermediate, and 256 mg/L
or greater are resistant to fosfomycin (Table 1).3 Corre-
sponding zone diameter break points are 16 mm or more
(susceptible), 13–15 mm (intermediate), and 12 mm or
less (resistant).
The pharmacodynamic potential of fosfomycin has
been investigated in urinary bladder models of infection. In
a study of antibacterial activity,4 fosfomycin exhibited
more than 99.9% bacterial killing within 4 hours against
common uropathogens following exposure to therapeutic
concentrations of the drug.
RESISTANCE
Both chromosomal- and plasmid-mediated resistance to
fosfomycin have been observed. Chromosomal-mediated
mutations result in a reduction of fosfomycin uptake into
the bacterial cell.5 Plasmid-mediated resistance is not com-
mon and involves inactivation of fosfomycin by glu-
tathione.6
The emergence of resistant bacterial strains to fosfo-
mycin depends on the conditions under study.7 In an in vit-
ro bladder model,8 emergence of resistant strains of E. coli
at 24 – 48 hours were observed only after low peak con-
centrations (≤250 mg/L) of fosfomycin were reached. The
development of resistant strains during therapy of UTI
does not appear to occur following single-dose (3.0 g)
therapy with fosfomycin tromethamine. In addition, there
is a relative lack of cross-resistance to other antibiotics. In
an investigation comprising 500 isolates, more than 70%
of the strains resistant to ampicillin, sulfamethoxazole, or
trimethoprim were sensitive to fosfomycin.9
Pharmacokinetics
The bioavailability of oral fosfomycin tromethamine in
adults is approximately 40%.10 Fosfomycin attains maxi-
mum serum concentrations (Cmax) in about 2 hours. A
mean Cmax of 26 mg/L is attained following a dose of 50
mg/kg in healthy volunteers.10
Fosfomycin has a large apparent volume of distribution
(140 L) and is not highly bound to plasma proteins.11 Con-
centrations attained in the prostate, bladder wall, and the
seminal vesicles are similar to serum concentrations. The
cerebrospinal fluid concentrations in infected meninges are
one-third of the simultaneously determined serum concen-
trations.12 In human milk, the concentrations of fosfomycin
are one-tenth those of simultaneous serum concentra-
tions.12 Fosfomycin has also been shown to cross the pla-
cental barrier in humans.13 Urine concentrations following
a dose of fosfomycin tromethamine 3.0 g are very high.
Peak concentrations occur in 2– 4 hours and range from
3000 to 5000 mg/L in young adults.12 Urine concentrations
decrease to a mean of 480 mg/L by 16 –24 hours and 50
mg/L by 36– 48 hours. Urine concentrations in the elderly
can decrease by as much as 50% compared with those in
young adults.14
Fosfomycin is primarily excreted unchanged in the
urine, and active metabolites have not been observed. Non-
renal clearance is negligible (<1%). The clearance of fos-
fomycin is similar to the glomerular filtration rate.15 The
mean serum half-life ranges from 4 hours in young adults
to 8 hours in the elderly and is not dose-dependent.10,14 In
patients with severe renal insufficiency (creatinine clear-
ance <10 mL/min), the elimination half-life increased to
50 hours and the percent of fosfomycin excreted in the
urine decreased by two-thirds.14 The pharmacokinetics in
pregnant women and children are similar to those in non-
pregnant young adults.16,17
FOOD AND DRUG INTERACTIONS

Table 1. In Vitro Activity of Fosfomycin3 Food impairs both the rate and extent of absorption of
a a a
fosfomycin tromethamine. Both the peak plasma concen-
ORGANISM MIC50 MIC90 RANGE tration and overall bioavailability were reduced when fos-
(isolates tested) (mg/L) (mg/L) (mg/L)
fomycin tromethamine was administered with food to
Gram-negative bacteria healthy volunteers.18 Mean urinary concentrations taken
Citrobacter diversus (50) ≤2 4 ≤2–16
Citrobacter freundii (100) ≤2 ≤2 ≤2–64
approximately 2 hours after the dose were decreased by
Enterobacter aerogenes (102) 16 64 ≤2–512 about 8%, but the cumulative amount excreted over 4 days
Enterobacter agglomerans (48) 6 256 ≤2–>512 was similar to that in fasting conditions. This effect of food
Enterobacter cloacae (102) 16 128 ≤2–>512 does not appear to be of clinical importance, and the pre-
Escherichia coli (1597) ≤2 ≤2 ≤2–128 scribing information from the manufacturer19 states that
Klebsiella oxytoca (51) 8 32 4–64 fosfomycin can be given without regard to meals.
Klebsiella pneumoniae (184) 16 128 ≤2–>512 Few drug– drug interactions with fosfomycin trometh-
Proteus mirabilis (102) ≤2 32 ≤2–>512
Proteus vulgaris (49) ≤2 8 ≤2–256
amine have been studied. Metoclopramide has been found
Providencia rettgeri (41) 8 64 ≤2–512 to significantly reduce the absorption and urinary concen-
Providencia stuartii (44) 16 128 ≤8–>512 trations of fosfomycin.20 Coadministration with other pro-
Pseudomonas aeruginosa (100) 32 64 4–>512 kinetic drugs, such as cisapride, should also be avoided.
Gram-positive bacteria
Enterococcus faecalis (196) 32 64 16–64 Clinical Studies
Enterococcus faecium (33) 32 64 16–128
Staphylococcus saprophyticus (128) 64 >512 ≤2–>512 Fosfomycin tromethamine has been evaluated in wom-
MIC = minimum inhibitory concentration. en with acute uncomplicated UTIs in numerous compara-
a
Susceptible isolates have an MIC ≤64 mg/L. tive studies.21

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 Fosfomycin Tromethamine

In two randomized, double-blind studies, single-dose PREGNANT WOMEN

fosfomycin tromethamine 3.0 g was compared with 7-day
treatment regimens of norfloxacin22 and nitrofurantoin.23
Clinical and bacteriologic cures were similar in the two
treatment groups in both studies (Table 2).16,19,22-27 Fos-
fomycin tromethamine has also been compared with single
doses of norfloxacin 800 mg24 and trimethoprim 200 mg25
in double-blind, randomized studies. No differences in
clinical or bacteriologic outcomes were observed in these
single-dose clinical trials (Table 2). Numerous nonblinded
treatment studies comparing single-dose fosfomycin tro-
methamine with comparative agents given as single- or
multiple-dose regimens have resulted in similar outcomes.18,26
The efficacy of fosfomycin tromethamine has been
evaluated in pregnant women with asymptomatic and
symptomatic bacteriuria.21 In a multicenter, randomized
study,16 single-dose fosfomycin tromethamine was com-
pared with a 7-day course of pipemidic acid, a quinolone
antibiotic, in 182 patients. One week after completion of
treatment with fosfomycin tromethamine and pipemidic
acid, bacteriologic cure rates were similar in the two
groups (Table 2).
ELDERLY PATIENTS

In two small, randomized studies,27,28 a single dose of

US TRIALS fosfomycin tromethamine 3.0 g was compared with nor-
floxacin 400 mg twice daily for 7 and 10 days in elderly
Three randomized, double-blind, placebo-controlled patients with UTI. The subjects had no known pathology
clinical trials of single-dose (3.0 g) fosfomycin trometh- of the urinary tract. Clinical and bacteriologic outcomes
amine have been conducted in the US,19 but none of these were similar in the two treatment groups in both studies
studies has been published. Fosfomycin tromethamine was (Table 2).
compared with nitrofurantoin (7 d), ciprofloxacin (7 d),
and trimethoprim/sulfamethoxazole (10 d) in women who Adverse Effects
had uncomplicated UTIs with symptoms of less than 4
days’ duration (Table 2). These studies found that clinical Fosfomycin tromethamine is well tolerated and causes
cures were similar for fosfomycin and the comparative few untoward effects. The overall incidence of adverse ef-
agents. Microbiologic eradication was superior for cipro- fects in European trials was approximately 6% in women
floxacin and trimethoprim/sulfamethoxazole compared treated with a 3.0-g dose.29 Common adverse effects in-
with fosfomycin. volve the gastrointestinal tract, with diarrhea reported most
often.30 Serious adverse events were rarely re-
ported and have included angioedema, aplastic
anemia, cholestatic jaundice, and optic neuri-
Table 2. Comparative Clinical Trials of Single-Dose (3.0 g) tis. In clinical trials conducted in the US, the
Fosfomycin Tromethamine in the Treatment of most common adverse effects included diar-
Women with Uncomplicated UTIs rhea (9%), vaginitis (5.5%), nausea (4.1%),
CLINICAL BACTERIOLOGIC headache (3.9%), dizziness (1.3%), and dys-
PTS. SUCCESS ERADICATION
REFERENCE REGIMENS (n) (%)
a
(%)
a pepsia (1.1%).
The safety of fosfomycin tromethamine in
Boerema and fosfomycin 60 92 90
Williams (1990)22 norfloxacin × 7 d 50 96 80
pregnant women has been studied in only a
Van Pienbroek et al. fosfomycin 102 95 81
small number of patients. Preliminary data on
(1993) 23
nitrofurantoin × 7 d 109 94 90 about 200 pregnant women found this drug to
31
24
Selvaggi et al. (1990) fosfomycin 28 80 75 be well tolerated. In one multicenter study,16
norfloxacin × 1 dose 25 84 84 nausea and epigastric pain were reported by
Harvard Davis et al. fosfomycin 26 96 86 9% of the patients. Fosfomycin tromethamine
(1990)25 TMP × 1 dose 25 76 59 does not exhibit teratogenic effects in animals
Elhanan et al. (1994)26 fosfomycin 58 91 91 (pregnancy category B). Moreover, no terato-
cephalexin × 5 d 54 91 83 genic effects have been associated with the use
US studies of fosfomycin tromethamine in clinical stud-
Forest Laboratories fosfomycin 260 69 83 ies.16,21
(1997) 19
nitrofurantoin × 7 d 237 70 76
fosfomycin 268 76 83
ciprofloxacin × 7 d 245 82 97 Dosage and Administration
fosfomycin 273 73 86
TMP/SMX × 10 d 239 75 93 The recommended dosage for women 18
Pregnant women years of age and older is one 3.0-g sachet
Ragni et al. (1988)16 fosfomycin 108 84 95 (powder) of fosfomycin tromethamine mixed
pipemidic acid × 7 d 74 81 92 with 4 ounces of water.19 Only a single dose of
Elderly patients fosfomycin tromethamine is recommended for
Ferraro et al. (1990)27 fosfomycin 30 77 the treatment of acute cystitis. Additional dos-
norfloxacin × 7 d 30 73 es do not improve clinical success or microbi-
SMX = sulfamethoxazole; TMP = trimethoprim; UTIs = urinary tract infections. ologic eradication rates. Elderly patients and
a
One week posttreatment. pregnant women are also treated with a single

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dose of fosfomycin tromethamine 3.0 g. A dosage adjust- References
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metamol with trimethoprim in the treatment of uncomplicated urinary
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EXTRACTO
OBJETIVO: Revisar la farmacología de la fosfomicina trometamina, un
agente antimicrobiano nuevo indicado para el tratamiento de las
infecciones leves del tracto urinario.
FUENTES DE INFORMACIÓN: Publicaciones en inglés sobre la fosfomicina,
fosfomicina trometamina, y fosfomicina trometamol identificadas a
través de MEDLINE. Además, estudios sin publicar suministrados a la
Administración de Drogas y Alimentos de los Estados Unidos.
SELECCIÓN DE FUENTES DE INFORMACIÓN: Estudios comparativos,
controlados, y de asignación aleatoria del tratamiento de prueba,
empleados para analizar la eficacia, y la seguridad de la fosfomicina
trometamina.
SÍNTESIS: La fosfomicina trometamina es un agente antimicrobiano oral
indicado para el tratamiento de las infecciones leves del tracto urinario.
Este agente es activo en la orina contra uropatógenos que están
asociados con la cistitis en la mujer, incluyendo organismos resistentes a
otros antibióticos. Una dosis única de la fosfomicina trometamina se
absorbe bién y produce concentraciones terapéuticas en la orina for un
período de 2–4 días. Estudios clínicos comparativos sugieren que una
dosis única de 3.0 g de fosfomicina trometamina es tan efectiva
clínicamente como un régimen de tratamiento de 7–10 días con agentes
comúnmente usados en esta condición tales como la nitrofurantoína, la
norfloxacina, y el sulfametoxazol con trimetoprim. La fosfomicina
trometamina se tolera bién y no parecer ocasionar efectos adversos
durante el embarazo.
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Fosfomycin Tromethamine
CONCLUSIONES: La fosfomicina trometamina es el único agente
antimicrobiano a ser aprobado por la Administración de Drogas y
Alimentos de los Estados Unidos como terapia de dosis única en
mujeres con cistitis aguda. Este agente es tan efectivo y seguro como los
agentes competidores usados en dosis múltiples. Además, su uso durante
el embarazo parece seguro. El costo elevado de adquisición de este
nuevo medicamento debe pesarse contra sus ventajas sobretodo en lo
referente la mejoramiento del cumplimiento del tratamiento y
conveniencia de administración en pacientes con infecciones leves del
tracto urinario.
ENCARNACIÓN C SUÁREZ
RÉSUMÉ
OBJECTIF: Revoir la pharmacologie clinique du trométhamine de
fosfomycine, un nouvel agent antimicrobien pour le traitement des
infections urinaires basses non compliquées.
REVUE DE LITTÉRATURE: Les publications en langue anglaise sur la
fosfomycine, le trométhamine de fosfomycine, et le trométamol de
fosfomycine ont été recherchées dans la banque informatisée
MEDLINE aussi bien que les études non publiées soumises à
l’Administration des Drogues et Alimentaires (ADA).
SÉLECTION DES ÉTUDES: Les études comparatives, randomisées, et
contrôlées ont été retenues pour analyser l’efficacité et l’innocuité du
trométhamine de fosfomycine.
RÉSUMÉ: Le trométhamine de fosfomycine est un antibiotique oral
indiqué pour le traitement des infections urinaires basses non
compliquées. Cet agent est actif dans l’urine contre les pathogènes du
tractus urinaire responsables de la cystite chez la femme, incluant des
organismes résistants à d’autres antibiotiques. Une dose unique de
trométhamine de fosfomycine est bien absorbée et produit des
concentrations thérapeutiques dans l’urine pour une période de 2–4
jours. Des essais cliniques comparatifs suggèrent qu’une dose unique de
3 g de trométhamine de fosfomycine est aussi efficace cliniquement
qu’un traitement standard de 7–10 jours avec les agents habituellement
utilisés pour le traitement des infections urinaires basses, comme la
nitrofurantoïne, la norfloxacine, et le triméthoprime–sulfaméthoxazole.
Le trométhamine de fosfomycine est bien toléré et semble sécuritaire
lors de grossesse.
CONCLUSIONS: Le trométhamine de fosfomycine est le seul antibiotique
approuvé par la ADA pour la thérapie unidose de la cystite aiguë chez la
femme. Il est aussi efficace et sécuritaire que les agents comparateurs à
doses multiples et semble sécuritaire lors de grossesse. Le coût
d’acquisition de ce nouveau médicament peut se justifier par une
meilleur observance du traitement et la facilité associée à son emploi
lors de traitement des infections urinaires basses non compliquées.
DENYSE DEMERS
■ 1998 February, Volume 32 ■ 219