See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/285420987

Fosfomycin: Uses and potentialities in veterinary medicine

Article  in  Open Veterinary Journal · March 2014

CITATIONS READS
25 5,100

3 authors, including:

Denisa Soledad Pérez Alejandro Luis Soraci

National University of the Center of the Buenos Aires Province National University of the Center of the Buenos Aires Province
33 PUBLICATIONS   176 CITATIONS    113 PUBLICATIONS   1,004 CITATIONS   

SEE PROFILE SEE PROFILE

Some of the authors of this publication are also working on these related projects:

1. Rational use of antibiotics in pigs: Impact of food and water quality on the bioavailability of antibiotics View project

All content following this page was uploaded by Alejandro Luis Soraci on 18 May 2016.

The user has requested enhancement of the downloaded file.

Open Veterinary Journal, (2014), Vol. 4(1): 26-43
ISSN: 2226-4485 (Print)
ISSN: 2218-6050 (Online) Review Article
_____________________________________________________________________________________
Submitted: 29/11/2013 Accepted: 22/02/2014 Published: 16/03/2014

Fosfomycin: Uses and potentialities in veterinary medicine

D.S. Pérez1,2,*, M.O. Tapia1,2 and A.L. Soraci1,2
1
Laboratorio de Toxicología, Centro de Investigación Veterinaria de Tandil, Departamento de Fisiopatología,
Facultad de Ciencias Veterinarias, Universidad Nacional del Centro de la Provincia de Buenos Aires, Tandil,
Buenos Aires, Argentina
2
Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
_____________________________________________________________________________________________
Abstract
Fosfomycin (FOS) is a natural bactericidal broad-spectrum antibiotic which acts on proliferating bacteria by
inhibiting cell wall and early murein/peptidoglycan synthesis. Bactericidal activity is evident against Gram positive
and Gram negative bacteria and can also act synergistically with other antibiotics. Bacterial resistance to FOS may
be natural or acquired. Other properties of this drug include inhibition of bacterial adhesion to epithelial cells,
exopolysaccharide biofilm penetration, immunomodulatory effect, phagocytosis promotion and protection against
the nephrotoxicity caused by other drugs. FOS has chemical characteristics not typically observed in organic
phosphoric compounds and its molecular weight is almost the lowest of all the antimicrobials. It tends to form salts
easily due to its acidic nature (disodium salt, for intravenous (IV), intramuscular (IM) and subcutaneous (SC)
administration; calcium and trometamol salt: for oral (PO) administration). FOS has a very low protein binding
(<0.5%) which, along with its low molecular weight and water solubility, contributes to its good diffusion into fluids
(cerebrospinal fluid, aqueous and vitreous humor, interstitial fluid) and tissues (placenta, bone, muscle, liver, kidney
and skin/fat). In all species, important differences in the bioavailability have been found after administration in
relation to the various derivatives of FOS salts. Pharmacokinetic profiles have been described in humans, chickens,
rabbits, cows, dogs, horses and weaning piglets. The low toxicity and potential efficacy of FOS are the main factors
that contribute to its use in humans and animals. Thus, it has been used to treat a broad variety of bacterial infections
in humans, such as localized peritonitis, brain abscesses, severe soft tissue infections, cystitis and other conditions.
In veterinary medicine, FOS is used to treat infectious diseases of broiler chickens and pigs. In broilers, it is
administered for the treatment of E. coli and Salmonella spp. infections. In piglets, the drug is prescribed to treat a
wide variety of bacterial infections. FOS penetration is demonstrated in phagocytic, respiratory (HEP-2) and
intestinal (IPEC-J2) cells. Although not widely used in animals, the drug has shown good results in human
medicine. The potentialities of FOS suggest that this drug is a promising candidate for the treatment of infections in
veterinary medicine. For these reasons, the aim of this work is to provide animal health practitioners with
information on a drug that is not extensively recognized.
Keywords: Antibiotic, Clinical uses, Fosfomycin, Pharmacodynamics, Pharmacokinetics.
_____________________________________________________________________________________________

Introduction country of origin (Vargas et al., 1987; Gudiol, 2007).

Fosfomycin (FOS) (cis-1,2-epoxyphosphonic acid), FOS is being used in veterinary medicine for over 40
initially known as ‘phosphonomycin’ (Hendlin et al., years. However, it is usually considered a second line
1969), is a natural bactericidal broad-spectrum antibiotic (Vargas et al., 1987), mainly due to the lack
antibiotic that is not structurally related to other of knowledge among veterinary professionals. This
classes of antimicrobial agents (Escolar Jurado et al., unrecognition of the drug reflects the fact that most of
1998; Popovic et al., 2010). the studies are performed in humans and they are
It was isolated in 1966 from a Streptomyces fradiae scarce and only recently applied to domestic animal
strain, obtained from a soil sample, and later, from medicine. Nevertheless, FOS is a good antibiotic, with
Streptomyces viridochromogenes, Streptomyces a fast effect, good tolerance (Ilender, 1998) and
wedmorensis (Hendlin et al., 1969; Grassi, 1990), physicochemical and pharmacokinetic characteristics
Pseudomona viridiflava and Penicillum strains that allow its enteral and parenteral administration
(Hidaka et al., 1992; Hidaka et al., 1995; Shi et al., (Dámaso et al., 1990; Mensa et al., 1994).
2001). Currently, it is exclusively produced by FOS has a very low protein binding (<0.5%). Thus, it
chemical synthesis (Gobernado, 2003). has good diffusion in corporal tissues, interstitial and
FOS is a Spanish antibiotic, undervalued in the intracellular fluids, coming through the blood brain
English medical literature and not regularly used in its barrier into the amniotic fluid, aqueous humor, lymph

________________________________________________________________________________________________________
*Corresponding Author: Denisa Soledad Pérez. Facultad de Ciencias Veterinarias, Universidad Nacional del Centro de la
Provincia de Buenos Aires, Tandil, Buenos Aires, Argentina. Email: [email protected] 26
http://www.openveterinaryjournal.com
D.S. Pérez et al. Open Veterinary Journal, (2014), Vol. 4(1): 26-43
________________________________________________________________________________________________________
tissue, purulent bronchial secretions and fluids while trometamol salt (tromethamine
(Gobernado, 2003). In pharmacokinetics studies, due [trihydroxymethyl aminomethane]) and the calcium
to the almost undetectable protein binding, the salt are used for oral administration (Escolar Jurado et
obtained plasma values represent almost all FOS al., 1998). Disodium and calcium salts, which are
available at a given moment (Zozaya et al., 2008). parenterally and orally used, respectively, are obtained
FOS has been shown to exert a time dependant by substituting the two hydrogen atoms of the
microbial growth inhibition (Sauermann et al., 2005). phosphoric radical by two atoms of sodium and one of
Thus, it has been speculated that its optimal calcium.
bactericidal effect can be obtained at three to four Trometamol salt, available since 1990 (Gudiol, 2007)
times the concentration that inhibits 90% (MIC90) of and commercially available for oral use, is obtained by
bacterial isolates (Pfausler, 2004) and not necessarily adding a molecule of tromethamine to the phosphoric
linked to high maximum plasma concentration (C max) radical. Tromethamine (tris-hydroxymethyl-
values (McKellar et al., 2004). aminomethane) is a synthetic buffer for short term use
Mazzei et al. (2006) have also described a (Gomis et al., 1992), which leads to a molecular
postantibiotic effect (PAE) of 3.4-4.7 h. It is important weight of FOS that is nearly the double of the original
to note that drugs acting by concentration peak drug, without contributing or interfering with its
(Cmax/MIC) and antimicrobial dependent AUC/MIC antibacterial action. Figure 2 shows FOS different
concentration have higher PAE, such as salts.
aminoglycosides and ciprofloxacin which have PAE
of 2 to 6 h in Gram negatives. The b-lactams do not
have PAE in Gram negatives and it is only 2 h in
Gram positives. Then, considering the PAE of other
drugs, FOS can be considered to have a significant Fig. 2. Fosfomycin different salts. (A): Disodium FOS, (B):
PAE (Labarca, 2002). Calcium FOS and (C): Trometamine FOS. Chemicals
properties make FOS a peculiar antibiotic and substitutions
Chemical structure
of its H atoms by other radicals (Na+1 or Ca+2) gives rise to
FOS is a propionic acid derivative which corresponds the different salts.
to the formula of an epoxide. The simple water-
soluble molecule is similar to phosphoenolpyruvate Spectrum of action
(PEP). It has only three carbon atoms and no nitrogen. FOS has bactericidal activity against Gram positive
The antibacterial activity is due to the epoxy bond and Gram negative bacteria (Mata et al., 1977;
(Gobernado, 2003). Gobernado, 2003) and when compared to penicillins
The molecule has a number of chemical characteristics and semi-synthetic cephalosporins, it has a broader
which are not typically observed in organo spectrum of action (Mata et al., 1977).
phosphorous compounds. On one hand, it is formed by FOS bactericidal effect is fast which has been
an epoxy group to which the negatively charged demonstrated by laboratory assays, such as turbidity
phosphoric group binds and which is decisive for its reduction in liquid culture media and colony reduction
antibacterial action. On the other hand, it presents a on solid media passes (Rodicio et al., 1978; Schmid,
direct bond between the carbon and phosphorus 1979; Schmid, 1980; Carlone et al., 1982; Schmid,
without an oxygen intermediate bridge, as is usual in 1985). Minimum inhibitory concentration (MIC) and
organo phosphorus compounds (Baron and Drugeon, Minimum bactericidal concentration (MBC) values
1985) (Fig. 1). Its molecular weight is almost the are similar to the majority of gram-positive and gram-
lowest of all the antimicrobials (138 '1) (Moritz, 1986; negative bacteria, being lower when incubated under
Neuman, l990; Gutiérrez et al., 2008), which added to anaerobic conditions, probably reflecting a lower FOS
its low protein binding, favors the spread of the drug transport through the cell membrane under these
to tissues and fluids. conditions (Inouye et al., 1989; Hamilton-Miller,
1992).
In intensive productions (poultry and swine
production), FOS is used for the treatment of
infections caused by sensitive Gram positives and
Gram negatives germs, such as Salmonella sp.,
Escherichia coli, Pasteurella sp., Staphylococcus sp.,
Fig. 1. Fosfomycin chemical structure. Streptococcus sp., Haemophilus sp., Klebsiella sp.
(good activity) and Pseudomona sp. (moderate
FOS tends to form salts easily due to its acidic nature. activity). Its activity against Listeria, Leptospira,
Its chemical structure is presented in different salts: Clostridium spp. and Vibrio spp. is moderate. It is not
disodium salt is used for IV and SC administration, active against bacteroids (García-Rodríguez, 1984),

27
http://www.openveterinaryjournal.com
D.S. Pérez et al. Open Veterinary Journal, (2014), Vol. 4(1): 26-43
________________________________________________________________________________________________________
Mycobacterium spp., Leggionella spp., Borrelia spp.,
and, naturally, against bacteria without cell wall such
as Coxiella burnetii, Rickettsia, Chlamydia,
Mycoplasma and Ureaplasma, which are insensible to
FOS.
FOS spectrum of action is shown in Table 1. MICs for
microorganisms most commonly found in animals, for
which FOS was used in their treatment are in the
range of 0.25-0.5 g/mL (Fernández et al., 1995)
(Streptococcus spp., S. aureus, Enterococcus sp., E.
coli, among others).
Note that these microorganisms are in the first column
of Table 1 that represents species for which FOS has a
good in vitro activity. FOS has a fast bactericidal
effect against a broad spectrum of animal and human
pathogens.
Mechanism of action
FOS penetrates bacteria by two systems of permeases,
one that transports L α glycerol phosphate, and other,
which is inducible and takes D-glucose-6-phosphate Fig. 3. FOS (F) is transported inside the cell by glycerol-3-
phosphate transporter (GlpT) and glucose-6-phosphate
inside the bacterial cytoplasm (Popovic et al., 2010).
transporter (UhpT) blocking the UDP-GlcNac-3-O-
FOS acts in proliferating bacteria by inhibition of cell enolpyruvate synthesis by mimicking the original substrate
wall and early murein/peptidoglycan synthesis (Kahan of UDP-GlcNAc enolpyruvyl transferase (MurA),
et al., 1974). phosphoenolpyruvate (PEP), and in the process avoiding cell
It inhibits an initial step in peptidoglycan synthesis wall synthesis and leading to cell death.
(Mensa et al., 1994), which is triggered by an analog
of FOS (Kahan et al., 1974; Popovic et al., 2010), EFFECT OF THE ASSOCIATION WITH OTHER
uridine diphosphate N-acetyl-glucosamine-enol- ANTIBIOTICS
pyruvyl-transferase and its co-enzyme, phosphoenol- Due to its mechanism of action in the first steps of cell
pyruvate (PEP). wall production, FOS can act synergistically with
FOS acts on bacteria in the growth phase without other antibiotics, especially those which inhibit the
interfering with the reactions requiring PEP in animal late stages in the cell wall synthesis (Gudiol, 2007). It
cells. This is because, in animals, enzymatic attack shows a synergistic partnership with other
occurs at a different place from PEP and the enzyme antimicrobials, mainly, with beta-lactams,
does not recognize FOS as a substrate. FOS inhibits aminoglycosides, chloramphenicol, tetracycline,
the binding of PEP to N-acetylglucosamine. For wall erythromycin, cotrimoxazole and quinolones (Salhi et
synthesis, the group-O-PO3H2 of PEP is separated, al., 1986; Damaso et al., 1990; Ilender, 1998).
binding the pyruvate C2 to the oxygen of an N- In association with penicillin it has a synergistic effect
acetylglucosamine. on S. aureus and S. pneumoniae, with ampicillin it is
However, in eukaryotic cells, the oxygen remains synergic on S. aureus and E. coli and with
attached to C2, separating only the phosphate PO3H2. cephalosporins, it has synergistic effect on S. aureus
FOS has in its molecule the -OCP-sequence, which is and P. aeruginosa. Furthermore, synergism with
different from the -COP sequence of PEP. This fact vancomicin has been demonstrated on S. aureus and S.
explains the high selectivity of FOS, which inhibits epidermidis, with imipenem on S. epidermidis and K.
the use of PEP in the cell wall synthesis (where the pneumoniae, with rifampicin on S. epidermidis and E.
enzyme cleaves OL binding) and not in the faecalis, with ciprofloxacin, on S. aureus, S.
metabolism of eukaryotic cells (where enzymes break epidermidis and E. faecalis with streptomycin it is
the union OP). Figure 3 shows FOS mechanism of synergic on E. coli and has a synergistic-additive
action. effect on S. aureus, and P. aeruginosa (Gobernado,
FOS inhibits cell wall synthesis due to its analogy 2003). Table 2 shows FOS synergistic partnership
with uridine diphosphate N-acetyl-glucosamine-enol- with other antimicrobials.
pyruvyl-transferase. PEP is the coenzime of the FOS acts synergistically with antibiotics which inhibit
reaction. However, FOS does not interfere with the the late stages of cell wall synthesis. The pathogens
reactions requiring PEP in animal cells. In animals, mainly affected by this synergistic effect are S.
enzymatic attack occurs at a different place from PEP aureus, S. epidermidis, K. pneumoniae, P. aeruginosa
and the enzyme does not recognize FOS as a substrate. and E. coli.

28
http://www.openveterinaryjournal.com
D.S. Pérez et al. Open Veterinary Journal, (2014), Vol. 4(1): 26-43
________________________________________________________________________________________________________
Table 1. Fosfomycin spectrum of action.
Good Activity Moderate Activity Without Activity
MIC < 16 mL/L MIC < 16-64 mL/L MIC < 64 mL/L
Staphylococcus aureus
Staphylococcus epidermidis
Streptococcus pyogenes Other Staphilococcus spp.
Staphylococcus haemolyticus
Aerobic Gram-positive Streptococcus viridans Mycobacterium spp.
Staphylococcus agalactiae
bacteria Streptococcus pneumoniae Nocardia sp.
Listeria monocytogenes
Streptococcus (groups C-F-G)
Enterococcus faecalis
Enterococcus faecium
Moraxella spp.
Aerobic Gram negative
- - Bordetella spp.
bacteria
Legionella spp.
Histophilus somni
Escherichia coli
Klebsiella pneumoniae
Serratia spp.
Facultative aerobic - Citrobacter spp. Corynebacterium spp.
anaerobic Gram-negative Proteus mirabilis Brucella spp.
bacteria Proteus vulgaris
Salmonella spp.
Shigella spp.
Aeromonas spp.
Yersinia enterocolitica
Microaerophilic bacteria Campylobacter jejuni
Anaerobic Gram-negative Peptococcus spp. Mycobacterium spp.
bacteria Fusobacterium spp. Bacteroides
Coxiella burnetti (Ae)
Rickettsia spp. (Ae)
Gram-negative, without cell
Chlamydia spp. (Ae)
wall
Mycoplasma spp. (FAA)
Ureaplasma spp. (FAA)
A= Aerobic
FAA = Facultative aerobic anaerobic

Table 2. Effect of Fosfomycin in association with other and, rarely, to enzymatic breakage (Gobernado, 2003).
antibiotics. Besides this natural resistance, acquired resistance
FOS associated associated with transport or chromosomic alterations
Microorganism Effect
with has also been reported (Damaso et al., 1990).
Staphylococcus aureus Extrachromosomal resistance, governed by plasmids,
Penicillin Synergistic
Staphylococcus pneumoniae
Staphylococcus aureus has also been described (Obaseiki-Ebor, 1986; Villar
Ampicillin Synergistic et al., 1986). Castañeda-García et al. (2013) considers
Escherichia coli
Cephalosporins
Staphylococcus aureus
Synergistic three different possible mechanisms leading to FOS
Pseudomonas aeruginosa resistance: a) reduced permeability to FOS, b)
Staphylococcus aureus
Vancomicin
Staphylococcus epidermidis
Synergistic modification of the antibiotic target MurA (UDP-
Staphylococcus epidermidis GlcNAc enolpyruvyl transferase), c) antibiotic
Imipenem Synergistic
Klebsiella pneumoniae modification.
Staphylococcus epidermidis Chromosomal resistance is manifested by the
Rifampicin Synergistic
Enterococcus faecalis
Staphylococcus aureus production of the enzyme FOS glutathione S-
Ciprofloxacin Staphylococcus epidermidis Synergistic transferase, which inactivates the antibiotic by
Enterococcus faecalis producing a bond between glutathione and FOS (Arca
Streptomycin Escherichia coli Synergistic et al., 1990). The enzyme is located in the periplasmic
Streptomycin
Staphylococcus aureus Synergistic space. This kind of resistance has been described in
Pseudomonas aeruginosa -Additive both gram-positive and gram-negative bacteria
(Venkateswaran and Wu, 1972; Kurashige et al.,
RESISTANCE 1975; Cordaro et al., 1976; Gershanovich et al., 1980;
Bacterial resistance to FOS has been related to Hardisson et al., 1984; Mlynarczyk et al., 1985;
transport alteration through cell wall, target alteration Ravdonikas et al., 1988; Corso et al., 1998).

29
http://www.openveterinaryjournal.com
D.S. Pérez et al. Open Veterinary Journal, (2014), Vol. 4(1): 26-43
________________________________________________________________________________________________________
Transferable plasmid resistance is conditioned by sites. FOS, macrolides and fluoroquinolones penetrate
permeability of the cell membrane alteration and acceptably into biofilms, and the association of FOS
enzymatic modification of the antibiotic (Llaneza et with macrolides or quinolones improve the
al., 1985). Another described mechanism of resistance penetration. Furthermore, it has been shown that FOS
is FOS inactivation by opening of the bond between produces significant alterations in cell morphology
carbon and phosphorus by the C-P-lyase enzyme and in the outer membrane of P. aeruginosa
(Quinn, 1989). incorporated into biofilms (Kumon et al., 1995;
In almost all susceptible bacterial populations, FOS Moden et al., 2002).
single step resistant spontaneous mutants exist with a Phagocytosis
high frequency (1/104 to 1/106). This resistance is due It has been shown that FOS, at concentrations equal to
to the inability of FOS to penetrate the bacterial cell or above the MIC, kill microorganisms located within
by a deficiency of transport systems, such as L-alpha- phagocytes (Traub and Spohr, 1983). An increased
glycerol phosphate and D-glucose-6-phosphate (Baron neutrophil bactericidal activity has been described in
and Drugeon, 1985; Damaso et al., 1990). There is no the presence of FOS (Krause et al., 2001). Studies in
evidence of cross-resistance to any other antibiotic or rabbits have shown that somatic antibody titers in
chemotherapeutic (Baron and Drugeon, 1985; Damaso flagellar bacteria exposed to FOS- immunized animals
et al., 1990; Patel et al., 1997; Gobernado, 2003; were higher than those observed in animals
Gudiol, 2007; Gutiérrez et al., 2008). immunized with bacteria not exposed to the drug
Similar to other antibiotics, shortly after the beginning (Viano et al., 1979). In vitro, it has been shown that
of FOS commercialization, the concern for the FOS promotes migration and chemotaxis of
evolution of resistance started. However, after several polymorphonuclear phagocytes, probably by
studies conducted in vitro from the '70s to the present inhibiting respiratory enzymes, the presence of
using human isolated bacteria demonstrated that the inactive metabolites of drugs and Adenine
activity against common pathogens causing infections monophosphate-Guanosine monophosphate (APM-
in which this antibiotic is indicated has not GMP) cycle alteration (De Simone et al., 1980).
significantly changed (Gobernado, 2003). Immunomodulation
FOS natural bacteria resistance may be due to Numerous immunomodulatory effects of FOS have
transport alteration through cell wall, target alteration been reported. It has been shown to inhibit human
and enzymatic breakage. Acquired resistance is also lymphocyte proliferation and to decrease the release of
associated with transport chromosomic alteration. IL-2, probably by blocking cell division T (Morikawa
Extrachromosomal resistance, governed by plasmids, et al., 1993). It has been demonstrated the inhibition
also has been described. Three other different possible of the B cell proliferative response stimulated by S.
mechanisms leading to FOS resistance are the aureus and the production of immunoglobulins
reduction of permeability, modification of the without altering the expression or activation of
antibiotic target MurA and antibiotic modification. antigens, such as CD25 and CD71 (Morikawa et al.,
OTHER EFFECTS 1996). Some authors consider that FOS modifies the
In addition to the antibacterial activity, FOS has other acute inflammatory response due to decreased
properties, such as inhibition of the adhesion of synthesis of TNF-α, IL-1 α, IL-1β, the receptor
bacteria to epithelial cells, exopolysaccharide biofilm antagonist of IL-1 and granulocyte colony stimulating
penetration, immunomodulation, phagocytosis factor (Morikawa et al., 1996; Matsumoto et al.,
promotion and protection against the nephrotoxicity 1999). It has also been shown that the sensitivity of
caused by other drugs (Gobernado, 2003). cells to TNF-β increases in the presence of FOS
Bacterial adhesion (Ishizaka et al., 1998). FOS has been shown to
While some antibiotics at concentration under the suppress LB4 production in neutrophils and to
MIC induce the formation of filamentous bacteria, decrease the expression of IL-8 (Honda et al., 1998).
favoring adherence to the urothelial cells, FOS The antiallergic property was based on its ability to
reduces this phenomenon. In addition to its anti- suppress, in vitro, histamine release (Ida et al., 1987).
adhesive effect, at concentrations under the MIC, FOS Studies on a murine experimental model have
also decreases hemolysin production and the confirmed the overall favorable immunomodulatory
hydrophobicity of E. coli, which is important in the effect of FOS (Matsumoto et al., 1997).
prophylaxis and treatment of repeated urinary tract Protection against nephrotoxicity and ototoxicity
infections (Gismondo et al., 1994). Studies in animals and humans have shown that the
Biofilms concomitant use of FOS with drugs that cause
For most antibiotics it is very difficult to penetrate the nephrotoxicity and ototoxicity, such as cisplatin,
infected exopolysaccharide biofilms that are formed cyclosporine (antitumor) (Sack et al., 1987; Suzuki et
on catheters, prosthetics, kidneys and other organ al., 1991; Nakamura et al., 1998), aminoglycosides,

30
http://www.openveterinaryjournal.com
D.S. Pérez et al. Open Veterinary Journal, (2014), Vol. 4(1): 26-43
________________________________________________________________________________________________________
vancomycin, amphotericin B and polymyxin nonsaturable passive diffusion, as determined by in
(antibiotics) (Inouye et al., 1982; Morin et al.; 1984) situ and in vivo experiments in rats (Ishizawa et al.,
protects against the undesirable effects of the other 1991).
drugs. It is suggested that the carrier-mediated transport is
The great variety of effects, in addition to its more important for absorption, especially at
antibacterial capacity, makes FOS a multifaceted drug. concentrations of less than 1 mM FOS. Studies carried
PHARMACODINAMICS out in rats, rabbits and humans show that the
In all species, important differences in the phosphate transport might be important for the
bioavailability (F) have been found after oral intestinal absorption of this antibiotic.
administration in relation to the various derivatives of Relatively small molecules which include phosphate
FOS salts, such as disodium FOS (41-85%), calcium within their structure may be the substrates for the
FOS (20%) and trometamol FOS (34-41%) (Segre et sodium-ion-dependent transporter, enhancing the
al., 1987; Patel et al., 1997). Furthermore, the IM intestinal absorption (Tamai and Tsuji, 1996).
administration of disodium FOS offers a more Distribution
predictive route of dose absorption than PO As previously described, low protein binding (<0.5%)
administration. This difference may be associated with along with its low molecular weight and water
two facts: a) absorption from the gastrointestinal tract solubility, allows good diffusion of FOS in interstitial
is a saturable process associated with the phosphate fluid and tissues.
system and b) there is degradation of disodium FOS in Cerebrospinal fluid (CSF)
acid gastric pH (Gutiérrez et al., 2008). The IM route No animal studies have been conducted regarding the
is more predictive for dose absorption. Nevertheless, concentration of FOS in CSF. In humans, it has been
PO administration is useful for the treatment of found that it readily crosses the blood brain barrier,
intestinal infections, especially when the drug has diffusing to CSF (Gallego et al., 1971). Several
poor bioavailability. studies have shown that FOS is useful in the treatment
There are differences in the bioavailability of FOS of meningitis caused by S. pneumoniae,
after IM and PO administrations, which are related Staphylococcus, E. coli and other Gram negative
with the type of salts used. sensitive bacilli (Drobnic et al., 1997; Falagas et al.,
PHARMACOKINETICS 2008) when it is IV administered (1-12 g/day). FOS
Routes of administration concentrations in CSF were determined to be 27.7% of
For PO administration, FOS is used as a calcium salt, that obtained in blood, lower than the concentrations
whereas IV, IM and SC routes require the more water- found for chloramphenicol (32%), but higher than the
soluble disodium salt. FOS-tromethamine salt is values found for penicillin (7.9%) and ampicillin (15.9
highly hydro-soluble and has good bioavailability %) (Sicilia et al., 1981). Furthermore, several authors
after oral administration (Patel et al., 1997; Popovic et have found that the penetration of FOS in CSF is
al., 2010). higher (300%) in inflamed meninges compared to
Absorption non-inflamed (Boulard et al., 1983; Pfeifer et al.,
After PO administration, absorption of FOS occurs 1985; Kuhnen et al., 1987).
throughout the digestive tract. However, it is higher in Interstitial fluid
the duodenum. In humans, it has been demonstrated that FOS reaches
IM administration of disodium FOS shows fast and values between 34-43% of plasma concentrations in
complete absorption. Absorption after PO interstitial fluid and cellular subcutaneous tissue in
administration has demonstrated to be variable and to patients with cellulite and diabetic foot syndrome after
differ between species. In mice, rats and dogs the an IV infusion (Legat et al., 2003). In addition, when
range of absorption of the administered dose is of 50- IV administered, it has been demonstrated to penetrate
80%, whereas in humans, its absolute bioavailability is the interstitial fluid of patients with burns (Koh et al.,
37-40%. 1986) and to reach the muscular interstitial fluid
Furthermore, differences are also observed, depending (Joukhadar et al. 2003). In animals, the only known
on whether the calcium salt or Trometamol is studies were performed by Fernández Lastra et al.
administered. Calcium salt absorption is not affected (1987) in interstitial fluid of rabbits and by Soraci et
by the presence of food, although its bioavailability al. (2011c) in the fluid lining the bronchial epithelial
(F%) is lower (20-30). Tromethamine salt should be of pigs. Fernandez Lastra et al. (1987) observed that
administered on empty stomach since the presence of after IV administration the half-life of FOS in
food reduces the rate of absorption and, therefore, its interstitial fluid is 1.9 h, either with single or multiple
F. However, F (40) is higher than that found with the dosages. After IM administration (15/mg/kg b.w.) of
calcium salt. FOS absorption occurs through a disodium FOS, Soraci et al. (2011a) showed that the
saturable carrier-mediated mechanism and by drug reaches concentrations above the MIC90 of

31
http://www.openveterinaryjournal.com
D.S. Pérez et al. Open Veterinary Journal, (2014), Vol. 4(1): 26-43
________________________________________________________________________________________________________
pathogens such as Streptococcus, for more than 8 h in glomerular filtration (10% to 60%) without tubular
bronchial epithelial lining fluid. These results secretion or reabsorption. Thus, its renal clearance is
demonstrate that FOS is useful for treating diseases similar to creatinine (Eardley et al., 2006). Although,
caused by extracellular microorganisms that are the excreted amount depends mainly on the
involved in swine respiratory disease. administration form, when parenteral administration is
Placenta employed 85 to 95% of the dose is excreted in urine
No animal studies regarding FOS passage through reaching urinary concentrations in the order of 1000 to
placenta have been conducted. It has been 3000 mcg/mL (Roussos et al., 2009). Its high
demonstrated in humans that after IM administration concentration in urine is maintained for at least 36 h.
at a dose of 1 g, FOS crosses the placental tissue, and When orally administered, one third of the absorbed
reaches fetal maternal blood at ratios of 0.9; 0.27 and amount is excreted in urine and the remaining amount
0.68 at 30, 90 and 120 minutes (Ferreres et al., 1977). is eliminated in feces.
Although it is apparent that the drug is safe to be When trometamol salt is parenterally or orally
administered during pregnancy, trometamol FOS has administered, it shows some biliary unmetabolized
not been approved in all European countries for it use elimination (20%) and is actively reabsorbed back to
in pregnant women (Raz, 2012). Studies in animals the intestine. This enterohepatic circulation explains
have not shown trometamol FOS teratogenicity the appearance of a secondary serum peak (Segre et
(Ferreres et al., 1977). In contrast to prolonged al., 1987).
therapy the administration as a single dose in In renal failure, when the glomerular filtration rate is
pregnancy reduces the risk to the fetus. However, it is between 20-40 mL/min, it is advisable to administer
recommended to be used in pregnancy only in cases 75% of the normal dosage, and when it is less than 10
where favorable risk/benefit is deemed. mL/min a dosage reduction to 25 % is recommended.
Aqueous and vitreous humor Bioavailability after parenteral administration
Most studies were performed in humans (Radda et al., corresponds to a two compartment open model. FOS
1985; Adenis et al., 1987; Robert and Tassy, 2000). does not bind to plasma proteins and, therefore, it
Only a pilot study conducted in rabbits (Adenis et al., becomes available as a fully active molecule.
1987) is available. In all cases, it was found that FOS Pharmacokinetic (PK) profiles of the various
reaches concentrations which are enough to inhibit derivatives of FOS have been described in humans
most pathogens that cause endophthalmitis after IV (Kirby, 1977; Segre et al., 1987; Vargas et al., 1987),
infusion. Its use in patients with cataracts (Forestier et chickens (Aramayona et al., 1997; Soraci et al.,
al., 1996) has also been shown. 2011b), rabbits (Fernández Lastra et al., 1987), cows
Bone (Sumano et al., 2007), dogs (Gutiérrez et al., 2008),
In humans it has been demonstrated that FOS horses (Zozaya et al., 2008) and weaning piglets
penetrates into the cortical and cancellous bone area (Soraci et al., 2011a).
after IV administration. High concentrations have FOS pharmacokinetics in broiler chickens:
been found in both zones (15% of plasma Three FOS pharmacokinetic studies have been
concentration) (Sirot et al., 1983; Meissner et al., conducted in broiler chickens (Aramayona et al.,
1989). An experimental study in rats has been 1997, Gutiérrez et al., 2010; Soraci et al., 2011b).
conducted using 200 mg of FOS, SC administered, in Aramayona et al. (1997) studied the pharmacokinetics
patients with osteomyelitis caused by Pseudomonas of FOS in chickens after a single IV dose (10 mg/kg
aeruginosa. This study concludes that FOS reaches b.w.). Gutiérrez et al. (2010) studied the kinetics of
good concentrations in bone and that concentrations FOS after IV administration (10, 20, 40 and 80 mg/kg
are higher in infected bones of rats with chronic b.w.) and PO administration (10, 20, 40 and 80 mg/kg
osteomyelitis (Fe Marques, 1994). b.w.). Soraci et al. (2011b) studied the kinetics of
Colostrum and milk disodium FOS after IV (40 mg/kg b.w.) and IM (10
A small proportion of FOS is eliminated by milk and mg/kg b.w.) administration and calcium FOS after PO
colostrum. Fernandez Paggi et al. (2010) studied the administration (40 mg/kg b.w.). The authors found an
distribution of disodium FOS in sow colostrum after increased bioavailability of FOS when administered
the IM administration of 15 mg/kg b.w. in pigs during IM (82%) compared to PO administration (39.3%).
the peri-partum. FOS distribution in breast fluid is low The volume of distribution determined by Soraci et al.
and of short-term (8 h). Therefore, it could be (2011b) for FOS IV administration (231 mL / kg), is
administered to the sow during lactation without side comparable to that found by Aramayona et al. (1997)
effects in the piglets. (575 mL / kg) and by Gutiérrez et al. (2010) (250-220
Metabolism and Excretion mL/kg). The elimination half-life of FOS after IV
FOS has no metabolic transformation (Roussos et al, bolus administration (1.4 h; Soraci et al., 2011b, 1.8 h,
2009). It is excreted in urine in active form, mainly by Aramayona et al., 1997) is similar to that observed

32
http://www.openveterinaryjournal.com
D.S. Pérez et al. Open Veterinary Journal, (2014), Vol. 4(1): 26-43
________________________________________________________________________________________________________
after PO (1.3 h) and IM (1.1 h) administration. The T1/2β=2.09+/-0.06 µg/mL and a bioavailability of 84-
clearance is comparable to the percentage of 85%.
glomerular filtration rate (2.1 ml. min-1.kg-1) (Soraci FOS pharmacokinetics in horses:
et al., 2011b) and similar to that reported by In 2008, Zozaya et al. studied FOS pharmacokinetic
Aramayona et al. (1997) (2.65 to 3.69 ml. min-1.kg-1). parameters in horses after the administration of
FOS pharmacokinetics in rabbits: disodium FOS at 10 mg/kg b.w. and 20 mg/kg b.w. by
There are few pharmacokinetic studies conducted in IV, IM and SC routes. Bioavailability after the SC
rabbits. In 1978, Yaginuma et al., studied the administration was 84 and 86% for the 10 mg/kg b.w.
pharmacokinetics of IV sodium salt preparation of and the 20 mg/kg b.w. dose, respectively. It was
FOS in this species. In 1986, Fernandez Lastra et al. concluded that clinically effective plasma
studied the linearity of the pharmacokinetics of FOS concentrations might be obtained for up to 10 h
in serum and interstitial tissue fluid in rabbits, after administering 20 mg/kg b.w. SC.
administration of doses of 20, 30 and 60 mg/kg b.w. of FOS pharmacokinetics in pigs:
the antibiotic by SC implantation of spiral steel cages. At present the only documented clinical experience of
The elimination half-lives of FOS ranged between the use of FOS in pigs are the studies of Soraci et al.
1.16 and 1.57 h. In 1987, Fernández Lastra et al., (2011a) and Pérez et al. (2012b). Soraci et al. (2011a)
studied FOS levels in serum and tissue interstitial fluid studied the pharmacokinetics and the bioavailability of
in a multiple dosage regimen in rabbits, after the disodium FOS in post-weaning piglets after IV and IM
administration of a single dose of 60 mg/kg b.w. and administration of 15 mg/kg b.w. After IV
during a multiple dosage regimen of 60 mg/kg/6h over administration, the area under the FOS
three days. The elimination half-life of the drug from concentration:time curve in plasma was AUC(0-12) of
the systemic circulation after a single dose had a value 120.00 ± 23.12 μg h/mL and the volume of
of 1.6 h, and was not significantly different from the distribution (Vd) of 273.00 ± 40.70 ml/kg.
value found for the same parameter in the multiple Plasma clearance was of 131.50 ± 30.07 ml/kg/h and a
dosage regimens. T1/2 of 1.54 ± 0.40 h. Peak serum concentration (C max),
FOS pharmacokinetics in cattle: Tmax, AUC(0-12) and bioavailability for the IM
There is only one pharmacokinetic study of FOS in administration were 43.00 ± 4.10 μg/ml, 0.75 ± 0.00 h,
cattle. It was performed in 2007 by Sumano et al. 99.00 ± 0.70 μg h/ml and 85.5 ± 9.90%, respectively.
They have studied the IV and IM pharmacokinetics of Pérez et al. (2012b) studied the pharmacokinetics and
a single-daily dose of disodium FOS (20 mg/kg/day), the bioavailability of calcium FOS in post-weaning
administered for 3 days. The calculated concentrations piglets after PO administration of 30 mg/kg b.w. The
at time zero and maximum serum concentrations were T1/2 was of 1.80 ± 0.89 h. C max, Tmax and
34.42 and 10.18 µg/mL (T max: 2.98 h), respectively. bioavailability were 3.60 ± 0.96 µg/mL, 3.00 ± 0.00 h
The elimination half-life of the drug remained and 20.0 ± 1.85 %, respectively. The area under the
unchanged during the 3 days (= 1.33 +/- 0.3 h for the FOS concentration:time curve in plasma AUC(0-∞)
IV route and = 2.17 +/- 0.4 h for the IM route). was 45.48 ± 9.20 µg h/mL. Table 3 shows a summary
Apparent volumes of distribution suggest moderated of the pharmacokinetics parameters of FOS in animal
distribution out of the central compartment (V (d area) = species. For PO administration, FOS is used as
673 mL +/- 27 mL / kg and V (dss) = 483 +/- 11 calcium and tromethamine salts, whereas for IV, IM
mL/kg). Bioavailability after IM administration was and SC administrations FOS is used as the more
74.52%. water-soluble disodium salt. After PO administration,
FOS pharmacokinetics in dogs: absorption occurs throughout the digestive tract.
In 1978, Yaginuma et al., studied the Disodium salt presents a fast and complete absorption
pharmacokinetics of an IV preparation of disodium (IM), which occurs through both a saturable carrier-
FOS salt in dogs. Gutiérrez et al. (2008) also studied mediated mechanism and a nonsaturable passive
FOS pharmacokinetics in mongrel dogs. Nevertheless, diffusion process.
they studied the variables after the administration of Low protein binding, along with its low molecular
buffered disodium FOS by IV, IM, SC and PO routes weight and water solubility, allow good diffusion into
at 40 and 80 mg/kg/day for three days. A non- interstitial fluid and tissues. It has no metabolic
accumulative kinetic behavior was observed after transformation. Therefore, it is excreted in urine in
three days with both doses and most pharmacokinetic active form by glomerular filtration. PK profiles of the
variables remaining unaltered. The authors concluded various derivates of FOS have been described in
that useful plasma concentrations can only be humans, chickens, rabbits, cows, dogs, horses and
achieved after the SC injection of 80 mg/kg b.w. every weaning piglets with the differences and similarities
12h, having a Cmax=18.96+/-0.3 µg/mL; a mentioned above.

33
 http://www.openveterinaryjournal.com
D.S. Pérez et al. Open Veterinary Journal, (2014), Vol. 4(1): 26-43
________________________________________________________________________________________________________
Table 3. Fosfomycin pharmacokinetics parameters in animals

SPECIES BROILER CHICKENS PIGS CATTLE

Aramayona et al. Soraci et al. Pérez et al. Sumano et al.

AUTHOR Soraci et al. (2011b)
(1997) (2011a) (2012b) (2007)
DETERMINATION Microbiologic HPLC MS/MS HPLC MS/MS HPLC MS/MS Microbiologic
METHOD DL: 0.5 ppm DL: 0.1 ppm DL: 0.1 ppm DL: 0.1 ppm DL: 0.4 ppm
FOS Disodium (IV, IM) and
Disodium Disodium Calcium Disodium
FORMULATION Calcium (PO)
ADMINISTRATION
IV IV IM PO IV IM PO IV IM
ROUTE

DOSE (mg/kg) - 40 40 10 15 15 30 20 20

F (%) - - 39.3 81.75 - 85.50 20.00 - 74.52

AUC (µg.h/mL) - 318 125.00 65.10 120 99.00 45.48 78.35 56.49

Cmax (µg/mL) - - 29.79 20.70 - 43.00 3.60 - 10.18

Tmax (h) - - 2.00 0.80 - 0.75 3.00 - 2.98

T1/2 1.86 1.39 - - 1.54 - 1.80 2.50 2.17

Vd (mL/kg) 575 231 - - 273 - - 483 -

Cl (mL/kg/h) 3.12 115 - - 131.5 - - 11.20 -

Table 3. Fosfomycin pharmacokinetics parameters in animals. Cont.

SPECIES DOGS HORSES

AUTHOR Gutiérrez et al. (2008) Zozaya et al. (2008)

DETERMINATION Microbiologic Microbiologic

METHOD DL: 0.4 ppm DL: 1.05 ppm

FOS
Disodium Disodium
FORMULATION

ADMINISTRATION
IV PO IM SC IV IM SC
ROUTE

DOSE (mg/kg) 40 80 40 80 40 80 40 80 10 20 10 20 10 20

F (%) - - 30 29 41 43 84 85 - - 38.00 58.00 84.00 86.00

315.0
AUC (µg.h/mL) 92.54 176.26 22.50 48.72 36.41 82.12 78.25 143.14 307 410 115.00 224.00 249.00
0

Cmax (µg/mL) - - 5.20 10.84 9.61 21.71 9.46 13.96 - - 24.00 46.00 55.00 72.00

Tmax (h) - - 2.04 1.75 1.08 1.19 2.63 2.51 - - 2.37 2.46 3.32 3.24

T1/2 1.28 1.30 2.18 2.18 1.54 1.55 2.06 2.09 1.33 1.34 1.54 1.57 3.43 3.46

Vd (mL/kg) 690 700 - - - - - - 215 220 - - - -

Cl (mL/kg/h) 14.20 14.90 - - - - - - 16.00 24.00 - - - -

34
http://www.openveterinaryjournal.com
D.S. Pérez et al. Open Veterinary Journal, (2014), Vol. 4(1): 26-43
________________________________________________________________________________________________________
Treatment protocols for different species Chickens:
It is important to note that FOS can be used both 150 pg/mL for 5 consecutive days (drinking water);
therapeutically and prophylactically and different initial loading dose of 40 mg/kg b.w., followed by an
protocols of use have been suggested in several ad libitum medication of 40 mg/kg b.w. 8 h later (80
species. mg/kg per d); IM (10 mg/kg b.w.), PO (40 mg/kg
Broiler chickens: b.w).
Aramayona et al. (1997) suggest that PO Rabbits:
administration of FOS in drinking water at a dose of 20-60 mg /kg b.w, SC. Cattle: 20 mg/kg b.w., IM.
150 pg/mL for 5 consecutive days provides potentially Dogs: 80 mg/kg every 12h, SC. Horses: 20 mg/kg
therapeutic concentrations of the drug in chickens. b.w., SC. Pigs: 15 mg/kg b.w., IM; 30 mg/kg b.w.,
Gutiérrez et al. (2010) suggest that useful serum PO.
concentrations of disodium FOS to treat outbreaks of Pharmacoeconomics
susceptible E. coli require an initial loading dose of 40 Several studies suggest that a single dose of FOS is
mg/kg b.w., followed by an ad libitum medication of cost effective compared to other antibiotics for the
40 mg/kg b.w. 8 h later (80 mg/kg per d). Soraci et al. treatment of similar infections. However, cost may be
(2011b) concluded that effective plasma increased with repeated dosing (Shrestha and
concentrations of FOS for sensitive bacteria can be Tomford, 2001; Pullukcu et al., 2007; Popovic et al.,
obtained following PO and IM administration. They 2010).
suggest a useful dose of 10 mg/kg b.w. of disodium FOS is cost effective.
FOS by IM administration. After PO administration of Clinical use
calcium FOS at a dose of 40 mg/kg b.w. and an IM Although the Food and Drug Administration (FDA)
dose of disodium FOS at 10 mg/kg b.w., authors has only approved the use of FOS for the treatment of
consider that there is an insufficient therapeutic infectious cystitis, it has been used to treat a broad
efficacy in vivo in a single dose at an interval of 24 variety of bacterial infections in humans, such as
hrs. localized peritonitis, brain abscesses caused by
Rabbits: Staphylococcus spp., Streptococcus spp. and E. coli
Fernandez Lastra (1986, 1987) has found good results (Sauermann et al., 2005), severe soft tissue infections
using doses between 20-60 mg/kg b.w, after SC caused by S. aureus and S. epidermidis and other
administration (single and multiple dose dosage). conditions (Krause et al., 2001; Joukhadar et al.,
Cattle: 2003).
Sumano et al. (2007) suggest that clinically effective In veterinary medicine, FOS is an antibiotic widely
plasma concentrations of disodium FOS could be used in farms in Argentina, Brazil and Central
obtained for up to 8 h following IV administration and America, being mainly prescribed in the treatment of
for approximately 10 h after IM injection of 20 mg/kg infectious diseases of broiler chickens and pigs. Other
b.w., for susceptible bacteria. In addition to residue antibiotics used for this purpose in poultry and pig
studies in milk and edible tissues, a series of clinical production are chlortetracycline, oxytetracycline,
assessments, using FOS at 20 mg/kg b.w., are tiamulin, tylosin, tilmicosin, enrofloxacin, sulfadiazine
warranted before this antibacterial drug can be and penicillin, which are more used than FOS in other
considered for use in cattle. countries. In broilers, FOS has been used to treat E.
Dogs: coli and Salmonella spp. infections (Fernández et al.,
Gutiérrez et al. (2008) concluded that useful plasma 1998, 2001, 2002). Particularly in piglets, FOS is
concentrations can only be achieved after the SC indicated to treat a wide variety of bacterial infections
injection of 80 mg/kg every 12h. (Haemophilus parasuis, Streptococcus suis,
Horses: Pasteurella multocida, Bordetella brochiseptica,
Zozaya et al. (2008) determined that clinically Staphylococcus hyicus, Escherichia coli), associated
effective plasma concentrations might be obtained for with stress and/or to different viral diseases
up to 10 h administering 20 mg/kg b.w. of disodium (Martineau, 1997).
FOS, SC administered. The use of FOS in dogs has only been suggested based
Pigs: on its low toxicity and potential efficacy (Pickrell et
Soraci et al. (2011a) conclude that effective plasma al., 1993; Gutiérrez et al., 2008). Presently,
concentrations of disodium FOS for sensitive bacteria documented clinical experience of the use of FOS in
of piglets can be obtained following IV and IM horses (Zozaya et al., 2008) and cattle (Sumano et al.,
administration of 15 mg/kg b.w. Pérez et al. (2012b), 2007) is not available.
determined that effective plasma concentrations of FOS has been used to treat a broad variety of bacterial
calcium FOS for sensitive bacteria can be obtained infections in humans. In veterinary medicine, it is
following PO administration of 30 mg/kg b.w. widely used in farms in Argentina, Brazil and Central

35
http://www.openveterinaryjournal.com
D.S. Pérez et al. Open Veterinary Journal, (2014), Vol. 4(1): 26-43
________________________________________________________________________________________________________
America, being mainly prescribed in the treatment of deoxinivalenol (DON) on the penetration of the
infectious diseases of broiler chickens and pigs. antibiotic. The results showed that intracellular
Toxicity and side effects antibiotic concentrations in HEp-2 cells incubated
The low toxicity and potential efficacy of FOS are the with 130 ppm of calcium FOS oscillated between 0.4
main factors that contribute to its use in humans and and 1.12 mg/ml with a T max of 8 h. When HEp-2 cells
animals (Gallego et al., 1974). Side effects are rare were incubated with FOS and DON, a significant
and not serious. LD50 in mice (intraperitoneally) is 4 variation was not observed in the cellular penetration
g/kg for the sodium salt and 20 g/kg for calcium FOS of the antibiotic, according to the Cmax (1.10 ppm) and
(Gallego et al., 1971). In humans, it can occasionally Tmax (12 h). Authors concluded that the presence of
produce loose stools, diarrhea, nausea and vomiting the mycotoxin would not alter the cellular distribution
when administered PO. The administration of 2 g per of FOS in pigs.
day divided into 4 doses for 28 days in dogs only Pérez et al. (2013a) studied the penetration of FOS in
caused intestinal disbacteriosis, fully recovered within an in vitro model of intestinal cells (IPEC-J2 cells).
two weeks of completion of treatment (Damaso et al., Cells cultures were subjected to 580 µg/mL of calcium
1990). It has also been described eosinophilia, FOS. Intracellular concentrations of the antibiotic
thrombocytosis and discrete transaminase elevations. were analyzed by HPLC MS/MS and they ranged
IV infusion may promote the development of from 23.48 to 45.81 µg/mL (T max: 4 h). FOS
hypernatremia or hypokalemia (Baron and Drugeon, concentrations exceeded the MIC90 for the most
1985). Allergies, anaphylaxis or severe important pathogens in swine intestinal infections
hypersensitivity have not been recorded. A few cases (Escherichia coli: 0.50 µg/mL, Salmonella enterica
of slight rash or hives which usually did not force subsp. enterica: 4 µg/mL). Therefore, it is apparent
discontinuing the treatment have been reported that FOS is an alternative choice for the treatment of
(Damaso et al., 1990). Its lack of teratogenic action intestinal infections in pigs.
for rabbit and mouse, lead to consideration that FOS a Martínez et al. (2012) cultured intestinal explants
safe drug to be administered during infancy and, from the jejunum of pigs and applied the model to
probably, during pregnancy (Prieto, 1986). Parenteral study the intracellular penetration of FOS in the
administration is painful. Thus, the solution is presence or absence of DON. The results suggest that
prepared with lidocaine. In humans, induration at the there was no statistically significant difference in the
injection site and IV phlebitis have been described. intracellular concentration of FOS between explants
FOS has low toxicity and side effects are rare and not incubated with 580 ppm FOS and explants incubated
serious. with 580 ppm FOS and 1ppm DON. The C max was 12
Intracellular penetration ppm and the Tmax was 2 h. Only 2 % of the antibiotic
FOS penetration is demonstrated in phagocytic cells, is intracellularly accumulated and the intracellular
where high concentrations are reached, presenting an concentration of FOS is not affected by the presence
intracellular activity close to that of rifampicin (Baron of non-toxic concentrations of DON.
and Drugeon, 1985; Trautmann et al., 1992). Pérez et FOS penetration is demonstrated in phagocytic,
al. (2012a) studied FOS concentrations in respiratory respiratory and intestinal cells, where adequate
cells (HEP-2). Intracellular concentrations of FOS concentrations are reached.
were analyzed by HPLC MS/MS. Two formulations FOS determination in biological matrices
of FOS were assayed (disodium FOS: 280 and 130 There are only a few methods for FOS detection in
μg/mL; calcium FOS: 130 μg/mL). Concentrations in biological matrices (Pianetti 1997; Loste et al.,
HEp-2 cells incubated with 280μg/mL of disodium 2002; Petsch et al., 2005; Gutiérrez et al., 2008;
FOS ranged from 0.74 to 2.79μg/mL (T max: 12 h). Zozaya et al., 2008).
When incubated with the same formulation of FOS at In 1980, FOS dosage by a stationary phase of
a concentration of 130 μg/mL, intracellular octadecylsilane chemically bonded with the formation
concentrations ranged between 0.31 and 1.60 μg/mL of an ion pair, or using an ion-exchange column
(Tmax: 12 h). Calcium FOS reached intracellular connected to a detector anionic by flame photometry
concentrations that varied between 0.46 and 1.11 selective phosphorus atom were proposed (Chester et
μg/mL (Tmax: 8 h). FOS concentrations exceeded the al., 1981). Its low molecular weight, low UV
MIC90 for the most important pathogens in swine absorption and lack of fluorescence, are characteristics
respiratory infections (Streptococcus spp.; that hinder its analysis (Yu-Ling et al., 1999). For this
0.25μg/mL). Therefore, it is apparent that FOS is an reason, for gas chromatography analysis FOS should
alternative drug for the treatment of intracellular be derivatized, meaning that a chemical modification
respiratory infections in pigs. must be introduced into FOS to facilitate its analysis
Martínez et al. (2011) have studied FOS penetration in and detection (Loste et al., 2002). However, the
cell culture lines and evaluated the interactive effect of limitation of this method is that is time consuming due

36
http://www.openveterinaryjournal.com
D.S. Pérez et al. Open Veterinary Journal, (2014), Vol. 4(1): 26-43
________________________________________________________________________________________________________
to derivatization steps. Other studies determine FOS detection limit. WDT for FOS in muscle and liver
by microbiological methods (Sumano et al., 2007) or were determined by 1.4 WT program, being 7 and 5
by capillary electrophoresis (Petsch et al., 2005). days, respectively (Mestorino et al., 2011). Pérez et al.
Currently, high resolution liquid chromatography (2011) determined FOS residual concentrations by
coupled to a mass spectrometer (HPLC MS/MS) is the HPLC MS/MS and WDT in muscle (pectoral, thigh
method of choice for xenobiotics determination. Its and injection site), liver and kidney of broiler chickens
use has been described for FOS determination in after PO and IM administrations.
serum of humans (Li, 2007), chickens (Dieguez et al., In this study, the WDTs of FOS were determined
2011; Soraci et al., 2011b) and piglets (Soraci et al., considering also the Maximum Residue Limit (MRL)
2011a; Pérez et al., 2012b) and in broiler chicken and defined by Japan. Concentrations of FOS in muscle,
pig tissues (Pérez et al., 2011, 2013b). liver and kidneys were always below the MRL. In
Compared with the methods mentioned above, HPLC addition, after 72 h of FOS food withdrawal and IM
MS/MS is the method of choice to perform these administration, the values of the residual
determinations due to its specificity and the lack of concentrations of the drug in tissues were below the
need for derivatization. 0.1 mg/g detection limit. FOS WDT in muscle was 1-2
There are only a few methodologies for FOS detection days, being of 1.12 days for calcium FOS (PO assay)
in biological matrices. HPLC MS/MS is the method of and 1.72 days for disodium salt (IM assay).
choice for FOS determination due to its specificity and Differences between FOS WDTs in muscle may be
the lack of need for derivatization. due to the distinct formulations and routes of
FOS concentrations in different tissues administration.
As mentioned above, it has been shown that FOS has a The same applies to WDTs in liver and kidney, which
very low protein binding, and this, along with its low are also longer after FOS PO calcium food
molecular weight and water solubility, allow good consumption (1.27 vs. 0.42 days and 2.55 vs. 0.92
tissue diffusion. days, respectively). Authors conclude that a WDT of 2
FOS concentrations in animal tissues for human days after IM administration and of 3 days after PO
consumption administration could be assigned as a precautionary
FOS tissue residues studies have been conducted in principle for public health, without a significant
broiler chickens and swines. Aramayona et al. (1997), economic impact for broiler producers.
determined, by microbiological assay, FOS residual Perez et al. (2013b) have also determined FOS
concentrations in various tissues (kidney, liver, lung, residual concentrations and WDT in swine muscle,
muscle, heart, fat, gizzard) after chronic liver, kidney and skin/fat, after PO and IM
administration of the antibiotic in drinking water (150 administration. In both assays, FOS concentrations in
micrograms/mL, during 5 days). At day 6 of the assay, all the matrices were below the MRL after 48 h of
FOS was detected in all tissues, except in muscle, in FOS food withdrawal and IM administration. After 72
concentrations between 0.63 mg/g in fat to 13.48 mg/g h, the values of the residual concentrations of the drug
in kidney. 24 hrs later, concentrations were below the in the analyzed tissues were below the 0.1 mg/mL
detection limit of the method. Mestorino et al. (2011) detection limit of the method. FOS WDT in muscle
studied the residual profile of FOS in broiler chickens was 2-3 days, being of 2.78 days for calcium FOS (PO
after PO administration of calcium FOS (10 mg/kg assay) and 1.48 days for disodium salt (IM assay).
b.w.) in water, for 5 days. WDTs in liver and kidney are longer for FOS after PO
FOS concentrations were determined in muscle, administration of calcium FOS in food (2.69 vs. 1.73
skin/fat, liver, kidney and feathers, by microbiological days and 2.95 vs. 1.38 days, respectively) (Pérez et al.,
assay. To determine FOS withdrawal time (WDT), 2013b). No significant differences were found
Mestorino et al. (2011) have used the only MRL between the WDTs for skin-fat after the PO assay (0.9
established by The Japan Food Chemical Research days) and the IM assay (1.27). A WDT of 3 days for
Foundation for bovine tissues (0.5 ppm). the PO administration and of 2 days for the IM
In muscle, FOS concentrations were below the method administration were assigned.
detection limit (0.0625 mg/g) from the fourth day of FOS tissue residue studies have been conducted in
discontinuation of FOS administration. In skin/fat broiler chickens and swines for WDT determination,
concentrations of 0.337 mg/g were obtained the first after PO and IM administration of calcium and
day after administration, and from the second day, disodium FOS, respectively (Pérez et al., 2011,
values were below the detection limit. The highest 2013b). For both species a WDT of 3 days after PO
concentrations were found in liver, falling below the administration and of 2 days after IM administration
detection limit, from the fourth day after ending the could be assigned as a precautionary principle for
treatment. In kidney, they found concentrations of public health, without a significant economic impact
0.447 mg/g, which, on the second day, were below the for producers.

37
http://www.openveterinaryjournal.com
D.S. Pérez et al. Open Veterinary Journal, (2014), Vol. 4(1): 26-43
________________________________________________________________________________________________________
Conclusion physiological fluids by ion-exchange
FOS is a good antibiotic, with a fast effect, good chromatography with phosphorus-selective
tolerance and physicochemical and pharmacokinetic detection. J. Chromatogr. 225, 1725.
characteristics that allow its enteral and parenteral Cordaro, J.C., Melton, T., Stratis, J.P., Atagün, M.,
administration. Its pharmacokinetics has been studied Gladding, C., Hartman, P.E. and Roseman, S.
in most domestic animal species. However, it is not 1976. Fosfomycin resistance: selection method for
widely used in veterinary medicine, being almost internal and extended deletions of the
limited to intensive production of broiler chickens and phosphoenolpyruvate:sugar phosphotransferase
pigs. The low toxicity and potential efficacy of FOS genes of Salmonella typhimurium. J. Bacteriol.
are the main factors that contribute to its use in 128, 785-793.
humans and animals. This, together with the additional Corso, A., Santos Sanches, I., Aires de Sousa, M.,
properties of the drug (inhibition of bacterial adhesion Rossi, A. and de Lencastre, H. 1998. Spread of a
to epithelial cells, penetration in exopolysaccharide methicillin-resistant and multiresistant epidemic
biofilm, immunomodulatory effect, promotion of the clone of Staphylococcus aureus in Argentina.
phagocytosis and protection against the nephrotoxicity Microb. Drug. Resist. 4(4), 277-288.
caused by other drugs, intracellular penetration and Damaso, D., Moreno-López, M. and Daza, R.M. 1990.
diffusion into bacteria biophases), gives an extra value Antibióticos y Quimioterápicos. Antibacterianos.
to FOS and make it a good option in the treatment of Uso Clínico. Ed. Marketing Pharm, S.A., Madrid.
infectious diseases caused by sensitive organisms. De Simone, C., Manganaro, M., Meli, D., Ricca, D.
___________________________________________ and Capozzi, C. 1980. Influenza degli antibiotici
References sulla migrazione leucocitaria. Boll. Ist. Sieroter.
Adenis, J.P., Franco, J.L., Mathon, C., Peigne, G. and Milan. 59, 612-618.
Denis, F. 1987. Etude du passage intra-oculaire de Dieguez, S.N., Soraci, A.L., Tapia, M.O., Carciochi,
la fosfomycine chez l'homme et chez le lapin. Bull. R.A., Pérez, D.S., Harkes, R. and Romano, O.
Soc. Ophtalmol. Fr. 87(12), 1415-1418. 2011. Determination of antibiotic fosfomycin in
Aramayona, J.J, Bregante, M.A., Solans, C., Rueda, chicken serum by liquid chromatography-tandem
S., Fraile, L.J and García, M.A. 1997. mass spectrometry. J. Liq. Chrom. Rel. Technol.
Pharmacokinetics of fosfomycin in chickens after a 34, 116-128.
single intravenous dose and tissue levels following Drobnic, L., Quiles, M. and Rodríguez, A. 1997. A
chronic oral administration. Vet. Res. 28(6), 581- study of the levels of fosfomycin in the
588. cerebrospinal fluid in adult meningitis. Chemother.
Arca, P., Hardisson, C. and Suárez, J.E. 1990. 23(1), 180-188.
Purification of a glutathione S-transferase that Eardley, I., Whelan, P., Kirby, R. and Schaeffer, A.
mediates fosfomycin resistance in bacteria. 2006. Drug treatment in urology. Blackwell
Antimicrob. Agents. Chemother. 34(5), 844-848. Publishing Ltd. Massachusetts USA. Chapter 5.
Baron, D. and Drugeon, H. 1985. Fosfomycine. Sem. pp: 86.
Hop. Paris. 61, 2341-2349. Escolar Jurado, M., Azanza Perea, J.R., Sádaba Díaz
Boulard, G., Quentin, C., Scontrini, G., Dautheribes, de Rada, B. and Honorato Pérez, J. 1998.
M., Pouguet, P. and Sabathie, M. 1983. Treatment Tetraciclinas, cloranfenicol y fosfomicina. Med.
of ventriculitis caused by Staphylococcus 7(76), 3524-3532.
epidermidis on equipment with the combination of Falagas, M.E., Giannopoulou, K.P., Kokolakis, G.N.,
fosfomycin and an aminoglycoside: course of Petros I.R. 2008. Fosfomycin: Use beyond urinary
ventricular levels of fosfomycin. Pathol. Biol. 31, tract and gastrointestinal infections. Invited
525-527. Article. Reviews of anti-infective agents. CID, 46:
Carlone, N.A., Cuffini, A.M. and Cattaneo, O. 1982. 1069-1077.
Structural changes induced by subinhibitory Fe Marques, A. 1994. Terapéutica experimental de
concentrations of fosfomycin on Staphylococcus osteomielitis por Pseudomonas aeruginosa:
aureus and Bacillus cereus. Microbios. 33(132), estudio de fosfomicina. Tesis Doctoral.
119-128. Universidad Complutense de Madrid.
Castañeda-García, A., Blázquez, J. and Rodríguez- Fernández, A., Payuelo, R., Gómez, J., Ramos, J.,
Rojas, A. 2013. Molecular Mechanisms and Loste, A. and Marca, M. 1998. Efficacy of
Clinical Impact of Acquired and Intrinsic phosphomycin in the control of Escherichia coli
Fosfomycin Resistance. Antibiot. 2(2), 217-236. infection of broiler chickens. Res. Vet. Sci. 65,
Chester, T.L., Lewis, E.C., Benedict, J.J., Sunberg, 201-204.
R.J. and Tettenhorst, W.C. 1981. Determination of Fernández, A., Lara, C., Loste, A., Calvo, S. and
(dichloromethylene) diphosphonate in Marca, M. 2001. Control of Salmonella enteritidis

38
http://www.openveterinaryjournal.com
D.S. Pérez et al. Open Veterinary Journal, (2014), Vol. 4(1): 26-43
________________________________________________________________________________________________________
phage type 4 experimental infection by fosfomycin Gobernado, M. 2003. Fosfomicina. Rev. Esp.
in newly hatched chicks. Comp. Immunol. Quimioter. 16, 15-40.
Microbiol. Infect. Dis. 24, 207-216. Gomis, M., Barberán, J., Herranz, A., Aparicio, P., Fe,
Fernández, A., Lara, C., Loste, A. and Marca, M. A. and Alonso, M. 1992. Short guide lines of
2002. Efficacy of calcium fosfomycin for the treatment in experimental osteomyelitis. Sth
treatment of experimental infections of broiler International Congress for Infectious Diseases.
chickens with Escherichia coli O78: k80. Vet. Res. Nairobi.
Comm. 26, 427-436. Grassi, G.G. 1990. Fosfomycin Trometamol:
Fernández, P., Herrera, I., Martínez, P., Gómez, L. and Historical Background and Clinical Development.
Prieto, J. 1995. Enhancement of the susceptibility Discussion 1: Fosfomycin Trometamol. Preclinical
of Staphylococcus aureus to phagocytosis after Studies. Infect. 18, 57-59.
treatment with fosfomycin compared with other Gudiol, F. 2007. Facts and myths about fosfomycin.
antimicrobial agents. Chemother. 41, 45-49. Oral presentations. 17th European Congress of
Fernández Lastra C., Mariño E.L., Dominguez-Gil A. Clinical Microbiology and Infectious Diseases and
1986. Linearity of the pharmacokinetics of 25th International Congress of Chemotherapy 17th
phosphomycin in serum and interstitial tissue fluid ECCMID/25th ICC. Munich, Germany.
in rabbits. Arzneim. Forsch. 36(10):1518-20. Gutiérrez, O.L., Ocampo C.L., Aguilera J.R., Luna J.,
Fernández Lastra, C., Mariño, E.L. and Dominguez- Sumano, L.H. 2008. Pharmacokinetics of disodium
Gil, A. 1987. Phosphomycin levels in serum and - fosfomycin in mongrel dogs. Res. Vet. Sci.
interstitial tissue fluid in a multiple dosage 85(1):156-161.
regimen in rabbits. Arzneim. Forsch. 37, 927-929. Hamilton-Miller, J.M.T. 1992. In vitro activity of
Fernandez Paggi, M.B., Soraci, A. and Amanto, F. fosfomycin against problem gram-positive cocci.
2010. Estudio de la distribución de Fosfomicina en Microbios. 71, 95-103.
calostro de cerdas. Tesis. Facultad de Ciencias Hardisson, C., Villar, C.J., Llaneza, J. and Mendoza,
Veterinarias. Universidad Nacional del Centro de M.C. 1984. Prédominance et dispersion des
la Provincia de Buenos Aires. plasmides conférant la résistance á la fosfomycine
Ferreres, L., Paz, M., Martin, G. and Gobernado, M. chez des entérobactéries. Pathol. Biol. 32(7), 755-
1977. New studies on placental transfer of 758.
fosfomycin. Chemother. 23(1), 175-179. Hendlin, D., Stapley, E.O., Jackson, M., Wallick, H.,
Forestier, F., Salvanet-Bouccara, A., Leveques, D., Miller, A.K., Wolf, F.J., Miller, T.W., Chaiet, L.,
Junes, P., Rakotondrainy, C., Dublanchet, A. and Kahan, F.M., Foltz, E.L., Woodruff, H.B., Mata,
Jehl, F. 1996. Ocular penetration kinetics of J.M., Hernandez, S. and Mochales, S. 1969.
fosfomycin administered as a one-hour infusion. Phosphonomycin, a new antibiotic produced by
Eur. J. Ophthalmol. 6(2), 137-142. strains of Streptomyces. Science 166(3901), 122-
Gallego, A., Rodríguez, A. and Marín, B. 1971. 123.
Farmacodinamia de la fosfomicina Estudios en Hidaka, T., Iwakura, H., Imai, S. and Seto, H. 1992.
animales. An. Inst. Farm. Esp. 20, 397-402. Studies on the biosynthesis of fosfomycin. 3.
Gallego, A., Rodríguez, A. and Mata, J.M. 1974. Detection of phosphoenol-pyruvate
Fosfomycin: pharmacological studies. Drugs phosphomutase activity in a fosfomycin high-
Today 10, 161-168. producing strain of Streptomyces wedmorensis and
García-Rodríguez, J.A. 1984. Antimicrobianos. En: characterization of its blocked mutant NP-7. J.
Microbiología y Parasitología Médica. Pumarola, Antibiot. 45(6), 1008-1010.
A., Rodríguez-Torres, A., García-Rodríguez, J.A., Hidaka, T., Goda, M., Kuzuyama, T., Takei, N.,
Piédrola-Angulo, G. Salvat Editores, S.A. Hidaka, M. and Seto, H. 1995. Cloning and
Barcelona. 118-150. nucleotide sequence of fosfomycin biosynthetic
Gershanovich, V.N., Umiarov, A.M., Burd, G.I., genes of Streptomyces wedmorensis. Molec. and
Bolshakova, T.N. and Lycheva, T.A. 1980. Gen. Gen. MGG. 249(3), 274-280.
Shigella flexneri mutation giving rise to the Honda, J., Okubo, Y., Kusaba, M., Kumagai, M.,
appearance of fosfomycin-resistant avirulent forms Saruwatari, N. and Oizumi, K. 1998. Fosfomycin
with disordered carbohydrate utilization. Zh. (FOM: 1 R-2S-epoxypropylphosphonic acid)
Mikrobiol. Epidemiol. Immunobiol. 11, 83-88. suppress the production of IL-8 from monocytes
Gismondo, M.R., Drago, L., Fassina, C., Garlaschi, via the suppression of neutrophil function.
M.L., Rosina, M. and Lombardi, A. 1994. Immunopharmacol. 39(2), 149-155.
Escherichia coli: effect of fosfomycin trometamol Ida, S., Shindoh, Y. and Takishima, T. 1987. Effect of
on some urovirulence factors. J. Chemother. 6, antibiotics on immediate hypersensitivity reactions
167-172. in vitro: suppression of IgE-mediated histamine

39
http://www.openveterinaryjournal.com
D.S. Pérez et al. Open Veterinary Journal, (2014), Vol. 4(1): 26-43
________________________________________________________________________________________________________
release from peripheral blood basophils by Labarca, J. 2002. Nuevos conceptos en
fosfomycin. Microbiol. Immunol. 31(10), 975-984. farmacodinamia ¿debemos repensar cómo
Ilender. 1998. Promotores de crecimiento. Notas administramos antimicrobianos?. Rev. Chil.
Científicas 1, 1-4. Disponible en: Infectol. 19(1), 28-32.
www.ilendercorp.com Legat, F.J., Maier, A., Dittrich, P., Zenahlik, P., Kern,
Inouye, S., Niizato, T., Komiya, I., Yuda, Y. and T., Nuhsbaumer, S., Frossard, M., Salmhofer, W.,
Yamada, Y. 1982. Mode of protective action of Kerl, H. and Müller, M. 2003. Penetration of
fosfomycin against dibekacin-induced fosfomycin into inflammatory lesions in
nephrotoxicity in the dehydrated rats. J. patients with cellulitis or diabetic foot
Pharmacobiodyn. 5(12), 941-950. syndrome. Antimicrob. Agents. Chemother. 47(1),
Inouye, S., Watanabe, T., Tsuruoka, T. and Kitasato, I. 371-374.
1989. An increase in the antimicrobial activity in Li, L., Chen, X., Dai, X., Hui Chen, X.M. and Zhong,
vitro of fosfomycin under anaerobic conditions. J. D. 2007. Rapid and selective liquid
Antimicrob. Chemother. 24(5), 657-666. chormatographic/tandem mass spectrometric
Ishizaka, S., Takeuchi, H., Kimoto, M., Kanda, S. and method for the determination of fosfomycin in
Saito, S. 1998. Fosfomycin, an antibiotic, human plasma. J. Chrom. B. 856, 171-177.
possessed TGF-beta-like immunoregulatory Llaneza, J., Villar, C.J., Salas, J.A., Suarez, J.E.,
activities. Int. J. Immunopharmacol. 20(12), 765- Mendoza, M.C. and Hardisson, C. 1985. Plasmid-
779. mediated fosfomycin resistance is due to
Ishizawa, T., Hayashi, M. and Awazu, S. 1991. enzymatic modification of the antibiotic.
Paracellular and transcellular permeabilities of Antimicrob. Agents. Chemother. 28(1), 163-164.
fosfomycin across small intestinal membrane of rat Loste, A., Hernández, E., Bregante, M.A., García,
and rabbit by voltage-clamp method. J. M.A. and Solans, C. 2002. Development and
Pharmacobiodyn. 14 (10), 583-589. validation of a gas chromatographic method for
Joukhadar, C., Klein, N., Dittrich, P., Zeitlinger, M., analysis of fosfomycin in chicken muscle samples.
Geppert, A., Skhirtladze, K., Frossard, M., Heinz, Chromatogr. 56, 3-4.
G. and Müller, M. 2003. Target site penetration of Martineau, G.P. 1997. Maladies d'élevage des porcs,
fosfomycin in critically ill patients. J. Antimicrob. manuel practique. Editions France Agricole. Paris.
Chemother. 51(5), 1247-1252. Martínez, G., Soraci, A.L. and Tapia, M.O. 2011.
Kahan, F.M., Kahan, J.S., Cassidy, P.J. and Kropp, H. Penetración de fosfomicina en células HEP-2 y su
1974. The mechanism of action of fosfomycin interacción con deoxinivalenol. Analec. Vet. 31(2),
(phosphonomycin). Ann. N. Y. Acad. Sci. 235, 23-27.
364-386. Martínez, G., Pérez, D.S., Soraci, A.L. and Tapia,
Kirby, W.M. 1977. Pharmacokinetics of fosfomycin. M.O. 2012. Penetración de fosfomicina en
Chemother. 23, 141-151. explantes intestinales. Analec. Vet. 3(2), 11-16
Koh, B., Izawa, Y., Sugiyama, H., Aoyama, H. and Mata, J., Rodríguez, A. and Gallego, A. 1977.
Komiya, I. 1986. Transfer of fosfomycin into Fosfomycin: in vitro activity. Chemother. 23, 23-
human burn blister fluid and its pharmacokinetic 24.
analysis. Jpn. J. Antibiot. 39(11), 2863-2868. Matsumoto, T., Tateda, K., Miyazaki, S., Furuya, N.,
Krause, R., Patruta, S., Daxböck, F., Fladerer, P. and Ohno, A., Ishii, Y., Hirakata, Y. and Yamaguchi,
Wenisch, C. 2001. The effect of fosfomycin on K. 1997. Immunomodulating effect of fosfomycin
neutrophil function. J. Antimicrob. Chemother. on gut-derived sepsis caused by Pseudomonas
47(2), 141-146. aeruginosa in mice. Antimicrob. Agents.
Kuhnen, E. Pfeifer, G. and Frenkel, C. 1987. Chemother. 41(2), 308-313.
Penetration of fosfomycin into cerebrospinal fluid Matsumoto, T., Tateda, K., Miyazaki, S., Furuya, N.,
across non-inflamed and inflamed meninges. Ohno, A., Ishii, Y., Hirakata, Y. and Yamaguchi,
Infect. 15, 422-424. K. 1999. Fosfomycin alters lipopolysaccharide-
Kumon, H., Ono, N. and Iida, M. 1995. Combination induced inflammatory cytokine production in
effect of fosfomycin and ofloxacin against mice. Antimicrob. Agents Chemother. 43(3), 697-
Pseudomonas aeruginosa growing in a biofilm. 698.
Antimicrob. Agents. Chemother. 39, 1038-1044. Mazzei, T., Cassetta, M.I., Fallani, S., Arrigucci, S.
Kurashige, S., Yamaguchi, N., Hiraishi, H., Teshima, and Novelli, A. 2006. Pharmacokinetic and
C. and Mitsuhashi, S. 1975. Decrease in the pharmacodynamic aspects of antimicrobial agents
virulence of fosfomycin-resistant Salmonella for the treatment of uncomplicated urinary tract
enteritidis strains. En: Mitsuhashi, S., Hashimoto, infections. Int. J. Antimicrob. Agents. Suppl. 1,
J (Eds). Microb. Drug Res. 535-538. S35-41.

40
http://www.openveterinaryjournal.com
D.S. Pérez et al. Open Veterinary Journal, (2014), Vol. 4(1): 26-43
________________________________________________________________________________________________________
McKellar, Q.A., Bruni, S.F. and Jones, D.G. 2004. Patel, S.S., Balfour, J.A. and Bryson, H.M. 1997.
Pharmacokinetic/Pharmacodynamic relationships Fosfomycin tromethamine. A review of its
of antimicrobial drugs used in veterinary medicine. antibacterial activity, pharmacokinetic properties
J. Vet. Pharmacol. Ther. 27, 503-514. and therapeutic efficacy as a single-dose oral
Meissner, A., Haag, R. and Rahmanzadeh, R. 1989. treatment for acute uncomplicated lower urinary
Adjuvant fosfomycin medication in chronic tract infections. Drugs. 53, 637-656.
osteomyelitis. Infect. 17(3), 146-151. Pérez, D.S., Soraci, A.L., Dieguez, S.N. and Tapia,
Mensa, J., Gatelí, J.M., Corachán, M., Escofel, M.C., M.O. 2011. Determination and withdrawal time of
Martínez, J.A. and Zamora, L. 1994. Guía de fosfomycin in chicken muscle, liver and kidney.
Terapéutica Antimicrobiana. Eds. Científicas y Int. J. Poult. Sci. 10, 644-655.
Técnicas, S.A. 4ed. Barcelona. Pérez, D.S., Soraci, A.L. and Tapia, M.O. 2012a. In
Mestorino, N., Daniele, M., Moncada Cárdenas, A., vitro penetration of fosfomycin in respiratory cells.
Dadé, M. and Errecalde, J.O. 2011. Perfil residual The Pig Journal, 67, 43-53.
de fosfomicina tras su administración oral a pollos Pérez, D.S., Soraci, A.L. and Tapia, M.O. 2012b.
parrilleros. XXII Latin American Poultry Pharmacokinetics and bioavailability of calcium
Congress. fosfomycin in post weaning piglets. Int. J. Agro-
Mlynarczyk, A., Młynarczyk, G., Bardowski, J. and Vet. Med. Sci. 6(6), 424-435.
Osowiecki, H. 1985. Chromosomal localization of Pérez, D.S., Martínez, G., Soraci, A.L. and Tapia,
resistance to fosfomycin and aminocyclitol M.O. 2013a. In vitro penetration of fosfomycin in
antibiotics in hospital strains of Staphylococcus IPEC J2 cells. Int. J. of Med. and Pharm. Sci. In
aureus. Acta. Microbiol. Pol. 34(2), 145-154. Press.
Moden, K., Ando, E., Iida, M. and Kumon, H. 2002. Pérez, D.S., Soraci, A.L. and Tapia, M.O. 2013b.
Role of fosfomycin in a synergistic combination Tissue disposition and withdrawal time of
with ofloxacin against Pseudomonas aeruginosa fosfomycin in swines after oral and intramuscular
growing in a biofilm. J. Infect. Chemoter. 8, 216- administration. J. Anim. Prod. Adv. 3(4), 107-119.
226. Petsch, M., Mayer-Helmb, B.X., Sauermannb, R.,
Morikawa, K., Oseko, F., Morikawa, S. and Sawada, Joukhadarb, C. and Kenndlera, E. 2005.
M. 1993. Immunosuppressive activity of Determination of fosfomycin in pus by capillary
fosfomycin on human T-lymphocyte function in zone electrophoresis. J. Chrom. A. 1081(1), 55-59.
vitro. Antimicrob. Agents. Chemother. 37(12), Pfausler, B. 2004. Concentrations of fosfomycin in the
2684-2687. cerebrospinal fluid of neurointensive care patients
Morikawa, K., Watabe, H., Araake, M. and Morikawa, with ventriculostomy-associated ventriculitis. J.
S. 1996. Modulatory effect of antibiotics on Antimicrob. Chemother. 53, 848-852.
cytokine production by human monocytes in vitro. Pfeifer, G., Frenkel, C. and Entzian, W. 1985.
Antimicrob. Agents. Chemother. 40(6), 1366- Pharmacokinetic aspects of cerebrospinal fluid
1370. penetration of fosfomycin. Int. J. Clin. Pharmacol.
Morin, J.P., Olier, B., Viotte, G. and Fillastre, J.P. Res. 5(3), 171-174.
1984. La fosfomycine peut- elle reduire la Pianetti, G.A. 1997.- Determinação cromatográfica da
nephrotoxicite des aminoglycosides? Pathol. Biol. Fosfomicina em amostras biológicas. Cad. Farm.
Paris. 32, 338-342. 13, 129.
Moritz, A.J. 1986. Clinical pharmacology of Pickrell, J.A., Oehme, F.W. and Cash, W.C. 1993.
fosfomycin. Proceedings of the International Ototoxicity in dogs and cats. Semin. Vet. Med.
Symposium. Mexico. Libro Resumen. 63-76. Surg. (Small Anim). 8(1), 42-49.
Shrestha, N.K. and Tomford, J.W. 2001. Fosfomycin: Popovic, M., Steinort, D., Pillai, S. and Joukhadar, C.
A Review. Infect. Dis. in Clin. Pract. 10, 255-260. 2010. Fosfomycin: an old, new friend? Eur. J.
Nakamura, T. Hashimoto, Y., Kokuryo T. and Inui, K. Clin. Microbiol. Infect. Dis. 29, 127-142.
I. 1998. Effects of Fosfomycin and Imipenem/ Prieto, A. 1986. Fosfomycin: first phosphonic
Cilastatin on Nephrotoxicity and Renal Excretion antibiotic used in the clinic. Proceedings of the
of Vancomycin in Rats. Pharm. Res. 15, 734-738. International Symposium. Mexico. Libro
Neuman, M. 1990. Farmacología clínica de los Resumen. 1-5.
antibióticos. Rl. Mayo, S.A. Barcelona. Pullukcu, H., Tasbakan, M. and Sipahi, O.R. 2007.
Obaseiki-Ebor, E.E. 1986. Activity of fosfomycin and Fosfomycin in the treatment of extended spectrum
R-plasmid conferring fosfomycin resistance among beta-lactamase-producing Escherichia coli-related
some clinical bacteria isolates in Nigeria. Chem. lower urinary tract infections. Int. J. Antimicrob.
32, 31-36. Agents 29, 62-65.

41
http://www.openveterinaryjournal.com
D.S. Pérez et al. Open Veterinary Journal, (2014), Vol. 4(1): 26-43
________________________________________________________________________________________________________
Quinn, J.P. 1989. Carbon-phosphorus lyase activity-a Pencillium sp. Wei Sheng Wu Xue Bao. 41(3),
novel mechanism of bacterial resistance to the 353-356.
phosphonic acid antibiotics? Lett. in Appl. Micr. Sicilia, T., Estévez, E. and Rodríguez, A. 1981.
8(3), 113-116. Fosfomycin penetration into the cerebrospinal
Radda, T.M., Gnad, H.D. and Paroussis, P. 1985. fluid of patients with bacterial meningitis.
Fosfomycin levels in human aqueous humor after Chemother. 27(6), 405-413.
intravenous administration. Arzneim. Forsch. Sirot, J., Lopitaux, R., Dumont, C., Rampon, S. and
35(8), 1329-1331. Cluzel, R. 1983. Diffusion of fosfomycin into bone
Ravdonikas, L.E., Grabovskaya, K.B. and Totolian, tissue in man. Pathol. Biol. 31(6), 522-524.
A.A. 1988. Isolation and study of fosfomycin- Soraci, A.L., Pérez, D.S., Martínez, G., Dieguez, S.N.,
resistant mutants of group A and B Streptococci. Tapia, M.O., Amanto, F., Harkes, R. and Romano,
Folia. Microbiol. 33(6), 507-512. O. 2011a. Disodium-fosfomycin pharmacokinetics
Raz, R. 2012. Fosfomycin: an old-new antibiotic. and bioavailability in post weaning piglets. Res.
Clin. Microbiol. Infect. 18, 4-7. Vet. Sci. 90(3), 498-502.
Robert, P.Y. and Tassy, A. 2000. Biodisponibilite des Soraci, A.L., Pérez, D.S., Tapia, M.O., Martínez, G.,
antibiotiques. J. Fr. Ophtalmol. 23, 510-523. Dieguez, S.N., Buronfosse-Roque, F., Harkes, R.,
Rodicio, M.R., Manzanal, M.B. and Hardisson, C. Colusi, A. and Romano, O. 2011b.
1978. Protoplast-like structures formation from Pharmacocinétique et biodisponibilité de
two species of Enterobacteriaceae by fosfomycin fosfomycine chez le poulet de chair. Rev. Méd.
treatment. Arch. Microbiol. 118(2), 219-221. Vét. 162, 358-363.
Roussos, N., Karageorgopoulos, D., Samonis, G. and Soraci, A.L., Pérez, D.S., Martínez, G., Amanto, F.,
Falaga, M. 2009. Clinical significance of the Tapia, M.O., Dieguez, S. and Fernández Paggi,
pharmacokinetic and pharmacodynamics M.B. 2011c. Fosfomycin concentrations in
characteristics of fosfomycin for the treatment of epithelial lining fluid in weaning piglets. J. Vet.
patients with systemic infections. Int. J. of Pharm. and Ther. 35(4), 406-409.
Antimicr. Agents. 34(6), 506-515. Sumano, L.H., Ocampo, C.L. and Gutiérrez, O.L.
Sack, K., Schulz, E., Marre, R. and Kreft, B. 1987. 2007. Intravenous and intramuscular
Fosfomycin protects against tubulotoxicity induced pharmacokinetics of a single-daily dose of
byCis-diaminedichloroplatin and cyclosporin A in disodium-fosfomycin in cattle, administered for 3
the rat. Klin. Wochenschr. 65, (11), 525-527. days. J. Vet. Pharm. Ther. 30, 49.
Salhi, A., Combes, T., Roche, G. and Roncucci, R. Suzuki, M., Sekiguchi, I., Tamada, T. and Tsuru, S.
1986. In vitro combinations studies with 1991. Protective effect of elastase on cis-platinum-
fosfomycin. Proceedings of the International induced renal toxicity. Oncol. 48(6), 474-479.
Symposium. Mexico. Libro Resumen pp: 34-45. Tamai, I. and Tsuji, A. 1996. Carrier-mediated
Sauermann, R., Karch, R., Langenberger, H., approaches for oral drug delivery. Adv. Drug
Kettenbach, J., Mayer-Helm, B., Petsch, M., Deliv. Rev. 20, 5-32.
Wagner, C., Sautner, T., Gattringer, R., Karanikas, Traub, W.H. and Spohr, M. 1983. Fosfomycin:
G., Joukhadar, C. 2005. Antibiotic abscess interpretation of inhibition zones obtained with the
penetration: fosfomycin levels measured in pus Bauer-Kirby agar disk diffusion susceptibility test.
and simulated concentration-time profiles. Chemother. 29(3), 208-212.
Antimicrob. Agents. Chemother. 49(11), 4448- Trautmann, M., Meincke, C., Vogt, K., Ruhnke, M.
4454. and Lajous-Petter, A.M. 1992. Intracellular
Schmid, E.N. 1979. Ultrastructure and viability of E. bactericidal activity of fosfomycin against
coli treated fosfomycin. Zentralbl. Bakteriol. Orig. Staphylococci: a comparison with other antibiotics.
A. 245(1-2), 48-54. Infect. 20(6), 350-354.
Schmid, E.N. 1980. Ultrastructure and viability of K. Vargas, E., Pacheco, E. and Beneit, J.A. 1987.
pneumoniae treated with fosfomycin. Zentralbl. Antibióticos (V): Misceláneos: Fosfomicina. In:
Bakteriol. A. 247(3), 339-346. Farmacología y su proyección a la clínica.
Schmid, E.N. 1985. Unstable L-form of Proteus Velázquez, B. L. Ed. Oteo. Madrid. 840-841.
mirabilis induced by fosfomycin. Chemother. Venkateswaran, P.S. and Wu, H.C. 1972. Isolation
31(4), 286-291. and characterization of a phosphonomycin-
Segre, G., Bianchi, E., Cataldi, A. and Zannini, G. resistant mutant of Escherichia coli K-12. J.
1987. Pharmacokinetic profile of fosfomycin Bacteriol. 110(3), 935-944.
trometamol (Monuril). Eur. Urol. 13(1), 56-63. Viano, I., Martinetto, P., Valtz, A., Santiano, M. and
Shi, J., Cui, F. and Ge, M. 2001. The epoxidation of Barbaro, S. 1979. Aspects of immune response
cis-propenylphophonic acid to fosfomycin by induced by bacteria treated with subinhibiting

42
 http://www.openveterinaryjournal.com
D.S. Pérez et al. Open Veterinary Journal, (2014), Vol. 4(1): 26-43
________________________________________________________________________________________________________
doses of fosfomycin. G. Ital. Chemioter. 26(1-2), 465-473.
281-284. Yu-Ling, H., Yu-Qi, F., Ping-He, Z. and Shi-Lu, D.
Villar, C.J., Hardisson, C. and Suárez, J.E. 1986. 1999. Determination of fosfomycin by
Cloning and molecular epidemiology of plasmid- indirect spectrophotometric method. Talanta.
determined fosfomycin resistance. Antimicrob. 49(1), 47-52.
Agents. Chemother. 29(2), 309-314. Zozaya, D.H., Gutiérrez, O.L., Ocampo, C.L. and
Yaginuma, K., Murata, S., Umemura, K., Tomono, N., Sumano, L.H. 2008. Pharmacokinetics of a single
Kikai, S. and Fujita, M. 1978. Pharmacokinetics of bolus intravenous, intramuscular and subcutaneous
intravenous preparation of fosfomycin sodium salt dose of disodium fosfomycin in horses. J. Vet.
in the rabbit and the dog. Jpn. J. Antibiot. 31(8), Pharmacol. Ther. 31(4), 321-327.

43

View publication stats