Fosfomycin tromethamine is
rapidly absorbed following oral administration and converted to the free acid,
fosfomycin. Absolute oral bioavailability under fasting conditions is 37%.
After a single 3-gram dose of MONUROL, the mean (± 1 SD) maximum serum
concentration (Cmax) achieved was 26.1 (± 9.1) mcg/mL within 2 hours. The oral
bioavailability of fosfomycin is reduced to 30% under fed conditions. Following
a single 3-gram oral dose of MONUROL with a high-fat meal, the mean Cmax achieved
was 17.6 (± 4.4) mcg/mL within 4 hours.
Cimetidine does not affect
the pharmacokinetics of fosfomycin when coadministered with MONUROL.
Metoclopramide lowers the serum concentrations and urinary excretion of
fosfomycin when coadministered with MONUROL. (See DRUG
The mean apparent
steady-state volume of distribution (Vss) is 136.1 (±44.1) L following oral
administration of MONUROL. Fosfomycin is not bound to plasma proteins.
Fosfomycin is distributed to
the kidneys, bladder wall, prostate, and seminal vesicles. Following a 50 mg/kg
dose of fosfomycin to patients undergoing urological surgery for bladder
carcinoma, the mean concentration of fosfomycin in the bladder, taken at a
distance from the neoplastic site, was 18.0 mcg per gram of tissue at 3 hours
after dosing. Fosfomycin has been shown to cross the placental barrier in
animals and man.
Fosfomycin is excreted
unchanged in both urine and feces. Following oral administration of MONUROL,
the mean total body clearance (CLTB) and mean renal clearance (CLR) of
fosfomycin were 16.9 (± 3.5) L/hr and 6.3 (± 1.7) L/hr, respectively.
Approximately 38% of a 3-gram dose of MONUROL is recovered from urine, and 18%
is recovered from feces. Following intravenous administration, the mean CLTB and
mean CLR of fosfomycin were 6.1 (±1.0) L/hr and 5.5 (± 1.2) L/hr, respectively.
A mean urine fosfomycin
concentration of 706 (± 466) mcg/mL was attained within 2-4 hours after a
single oral 3-gm dose of MONUROL under fasting conditions. The mean urinary
concentration of fosfomycin was 10 mcg/mL in samples collected 72-84 hours
following a single oral dose of MONUROL.
Following a 3-gram dose of
MONUROL administered with a high fat meal, a mean urine fosfomycin
concentration of 537 (± 252) mcg/mL was attained within 6-8 hours. Although the
rate of urinary excretion of fosfomycin was reduced under fed conditions, the
cumulative amount of fosfomycin excreted in the urine was the same, 1118 (±
201) mg (fed) vs. 1140 mg (± 238) (fasting). Further, urinary concentrations
equal to or greater than 100 mcg/mL were maintained for the same duration, 26
hours, indicating that MONUROL can be taken without regard to food.
Following oral administration
of MONUROL, the mean half-life for elimination (t½) is Â 5.7 (± 2.8) hours.
Based on limited data
regarding 24-hour urinary drug concentrations, no differences in urinary
excretion of fosfomycin have been observed in elderly subjects. No dosage
adjustment is necessary in the elderly.
There are no gender
differences in the pharmacokinetics of fosfomycin.
In 5 anuric patients
undergoing hemodialysis, the t½ of fosfomycin during hemodialysis was 40
hours. In patients with varying degrees of renal impairment (creatinine
clearances varying from 54 mL/min to 7 mL/min), the t½ of fosfomycin
increased from 11 hours to 50 hours. The percent of fosfomycin recovered in
urine decreased from 32% to 11% indicating that renal impairment significantly
decreases the excretion of fosfomycin.
Fosfomycin (the active
component of fosfomycin tromethamine) has in vitro activity against a broad
range of gram-positive and gram-negative aerobic microorganisms which are
associated with uncomplicated urinary tract infections. Fosfomycin is
bactericidal in urine at therapeutic doses. The bactericidal action of
fosfomycin is due to its inactivation of the enzyme enolpyruvyl transferase,
thereby irreversibly blocking the condensation of uridine
diphosphate-N-acetylglucosamine with p-enolpyruvate, one of the first steps in
bacterial cell wall synthesis. It also reduces adherence of bacteria to
There is generally no
cross-resistance between fosfomycin and other classes of antibacterial agents
such as beta-lactams and aminoglycosides.
Fosfomycin has been shown to
be active against most strains of the following microorganisms, both in vitro and
in clinical infections as described in the INDICATIONS AND USAGE section:
The following in vitro data
are available, but their clinical significance is unknown.
Fosfomycin exhibits in vitro minimum inhibitory
concentrations (MIC's) of 64 mcg/mL or less against most (≥ 90%) strains
of the following microorganisms; however, the safety and effectiveness of
fosfomycin in treating clinical infections due to these microorganisms has not
been established in adequate and well-controlled clinical trials:
Quantitative methods are used to determine minimum
inhibitory concentrations (MIC’s). These MIC’s provide estimates of the
susceptibility of bacteria to antimicrobial compounds. One such standardized
procedure uses a standardized agar dilution method1 or equivalent
with standardized inoculum concentrations and standardized concentrations of
fosfomycin tromethamine (in terms of fosfomycin base content) powder
supplemented with 25 mcg/mL of glucose-6-phosphate. BROTH DILUTION METHODS
SHOULD NOT BE USED TO TEST SUSCEPTIBILITY TO FOSFOMYCIN. The MIC values
obtained should be interpreted according to the following criteria:
A report of “susceptible”
indicates that the pathogen is likely to be inhibited by usually achievable
concentrations of the antimicrobial compound in the urine. A report of
“intermediate” indicates that the result should be considered equivocal, and,
if the microorganism is not fully susceptible to alternative, clinically
feasible drugs, the test should be repeated. This category provides a buffer
zone that prevents small uncontrolled technical factors from causing major
discrepancies in interpretation. A report of “resistant” indicates that usually
achievable concentrations of the antimicrobial compound in the urine are
unlikely to be inhibitory and that other therapy should be selected.
test procedures require the use of laboratory control microorganisms. Standard
fosfomycin tromethamine powder should provide the following MIC values for agar
dilution testing in media containing 25 mcg/mL of glucose-6-phosphate. [Broth
dilution testing should not be performed].
|Enterococcus faecalis ATCC 29212
|Escherichia coli ATCC 25922
|Pseudomonas aeruginosa ATCC 27853
|Staphylococcus aureus ATCC 29213
Quantitative methods that require measurement of zone
diameters also provide reproducible estimates of the susceptibility of bacteria
to antimicrobial agents. One such standardized procedure2 requires
the use of standardized inoculum concentrations. This procedure uses paper
disks impregnated with 200-mcg fosfomycin and 50-mcg of glucose-6-phosphate to
test the susceptibility of microorganisms to fosfomycin.
Reports from the laboratory
providing results of the standard single-disk susceptibility tests with disks
containing 200-mcg of fosfomycin and 50-mcg of glucose-6-phosphate should be
interpreted according to the following criteria:
|Zone Diameter (mm)
Interpretation should be
stated as above for results using dilution techniques. Interpretation involves
correlation of the diameter obtained in the disk test with the MIC for
As with standardized dilution
techniques, diffusion methods require use of laboratory control microorganisms
that are used to control the technical aspects of the laboratory procedures.
For the diffusion technique, the 200-mcg fosfomycin disk with the 50-mcg of
glucose-6-phosphate should provide the following zone diameters in these
laboratory quality control strains:
||Zone Diameter (mm)
|Escherichia coli ATCC 25922
|Staphylococcus aureus ATCC 25923
In controlled, double-blind
studies of acute cystitis performed in the United States, a single-dose of
MONUROL was compared to three other oral antibiotics (See table below). The
study population consisted of patients with symptoms and signs of acute
cystitis of less than 4 days duration, no manifestations of upper tract
infection (e.g., flank pain, chills, fever), no history of recurrent urinary
tract infections (20% of patients in the clinical studies had a prior episode
of acute cystitis within the preceding year), no known structural
abnormalities, no clinical or laboratory evidence of hepatic dysfunction, and
no known or suspected CNS disorders, such as epilepsy, or other factors which
would predispose to seizures. In these studies, the following clinical success
(resolution of symptoms) and microbiologic eradication rates were obtained.
||Treatment Duration (days)
||Microbiologic Eradication Rate
||Clinical Success Rate
||Outcome (based on difference in microbiologic eradication rates 5-11 days post therapy)
|5-11 days post therapy
||Study day 1221
||Fosfomycin inferior to ciprofloxacin
||Fosfomycin inferior to trimethoprim/ sulfamethoxazole
||Fosfomycin equivalent to nitrofurantoin
||Fosfomycin 3 gram single dose
||Ciprofloxacin 250 mg bid x 7 days
||Trimethoprim/ sulfamethoxazole 160 mg/800 mg bid x 10 days
||Nitrofurantoin 100 mg bid x 7 days
1. National Committee for
Clinical Laboratory Standards, Methods for Dilution. Antimicrobial
Susceptibility Tests for Bacteria that Grow Aerobically – Third Edition;
Approved Standard NCCLS Document M7-A3, Vol. 13, No. 25 NCCLS, Villanova, PA,
2. National Committee for
Clinical Laboratory Standards, Performance Standard for Antimicrobial Disk
Susceptibility Tests – Fifth Edition; Approved Standard NCCLS Document M2-A5,
Vol. 13, No. 24 NCCLS, Villanova, PA, December, 1993.