Review Article Fosfomycin: A First-Line Oral Therapy for...

Review ArticleFosfomycin A First-Line Oral Therapy forAcute Uncomplicated Cystitis

George G Zhanel Andrew J Walkty and James A Karlowsky

Department of Medical Microbiology College of Medicine University of Manitoba Winnipeg MB Canada R3A 1R9

Correspondence should be addressed to George G Zhanel ggzhanelpcsmbca

Received 13 November 2015 Accepted 31 March 2016

Academic Editor Daniele Focosi

Copyright copy 2016 George G Zhanel et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Fosfomycin is a new agent to Canada approved for the treatment of acute uncomplicated cystitis (AUC) in adult women infectedwith susceptible isolates of E coli and Enterococcus faecalis We reviewed the literature regarding the use of oral fosfomycinfor the treatment of AUC All English-language references from 1975 to October 2015 were reviewed In Canada fosfomycintromethamine is manufactured as Monurol and is available as a 3-gram single dose sachet Fosfomycin has a unique chemicalstructure inhibiting peptidoglycan synthesis at an earlier site compared to 120573-lactams with no cross-resistance with other agentsFosfomycin displays broad-spectrum activity against ESBL-producing AmpC-producing carbapenem-non-susceptible andmultidrug-resistant (MDR) E coli Resistance to fosfomycin in E coli is rare (lt1) Fosfomycin is excreted unchanged in the urineby glomerular filtration with peak urinary concentration sim4000 120583gmL and remains at concentrations gt100120583gmL for 48 hoursafter a single 3-gram oral dose No dosage adjustments are required in elderly patients in pregnant patients or in either renal orhepatic impairment Fosfomycin demonstrates a favorable safety profile and clinical trials have demonstrated efficacy in AUC thatis comparable to ciprofloxacin nitrofurantoin and trimethoprim-sulfamethoxazole Fosfomycinrsquos in vitro activity against commonuropathogens includingMDR isolates its favorable safety profile including pregnancy patients drug interactions and clinical trialsdata demonstrating efficacy in AUC has resulted in Canadian US and European guidelinesauthorities recommending fosfomycinas a first line agent for the treatment of AUC

1 Introduction

Urinary tract infections (UTIs) are among the most com-monly occurring human infections [1 2] It is estimated thatapproximately 50ofwomenwill experience at least oneUTIduring their lifetime and that 25 will suffer recurrent infec-tion [3] Uncomplicated cystitis the most common presen-tation for UTI occurs in adult premenopausal women witha normal unobstructed genitourinary tract where symptomsare confined to the urinary bladder and urethra Females withcystitis typically present with dysuria and increased urinaryurgency and frequency aswell as suprapubic pain hematuriaand nocturia Pyelonephritis is distinct from cystitis and iscommonly associated with fever (gt38∘C) and flank painThe majority of cases of community-acquired cystitis areattributable to uropathogenic Escherichia coli (75ndash90) andStaphylococcus saprophyticus (5ndash15) with Klebsiella spp

Enterococcus spp Streptococcus agalactiae and Proteusmirabilis accounting for most other cases [1 2 4 5] Pseu-domonas aeruginosa Staphylococcus aureus and Candidaspp are infrequent causes of acute uncomplicated UTIs

Current guidelines published by the Infectious DiseasesSociety of America (IDSA) and the European Society forClinical Microbiology and Infectious Diseases (ESCMID)recommend fosfomycin nitrofurantoin and trimethoprim-sulfamethoxazole (TMP-SMX) as first-line agents to treatacute uncomplicated UTIs in adult females reserving fluoro-quinolones amoxicillin-clavulanate and other 120573-lactams assecond-line agents [6] Elevated rates of resistance (gt10ndash20)to TMP-SMX as well as fluoroquinolones are now widelyreported for uropathogenic isolates of E coli in Canadaand elsewhere [7 8] The most recently published Canadianstudy describing antimicrobial resistance rates among E coliisolated from patients with urinary tract infections reported

Hindawi Publishing CorporationCanadian Journal of Infectious Diseases and Medical MicrobiologyVolume 2016 Article ID 2082693 10 pageshttpdxdoiorg10115520162082693

2 Canadian Journal of Infectious Diseases and Medical Microbiology

on isolates collected from 2010 to 2013 and found suscep-tibility rates of 747 to TMP-SMX 774 to ciprofloxacin813 to amoxicillin-clavulanate 961 to nitrofurantoinand 994 to fosfomycin [9] The increasing identificationof extended-spectrum beta-lactamase- (ESBL-) producingE coli across Canada and internationally has been associ-ated with concomitant resistance to amoxicillin-clavulanateciprofloxacin and TMP-SMX [7 8] Rates of susceptibilityamong E coli of lt80 for one or more first- or second-lineagents should prompt local reevaluation of empiric treatmentstrategies for acute uncomplicated UTIs [6]

This review endeavoured to summarize peer-reviewedpublished data on the development of fosfomycin its chem-istrymechanisms of action and resistance in vitromicrobiol-ogy pharmacokinetic and pharmacodynamic properties effi-cacy demonstrated in clinical trials for acute cystitis adverseeffects drug interactions and its role in therapy of acutecystitis

2 Development of Fosfomycin

In 1969 laboratories at MSD (Merck Sharp and Dohme)and CEPA (Compania Espanola de Penicilina y Antibioticos)were the first to successfully isolate fosfomycin a phosphonicacid derivative from cultures of Streptomyces spp (S fradiaeS viridochromogenes and S wedomorensis) [10 11] Fos-fomycin was initially synthesized as a calcium salt [11] how-ever this formulation was later identified to be responsiblefor discrepancies reported by in vitro studies and for delayedverification of therapeutic effectiveness in animal modelsand patients and its commercial production was discontin-ued Fosfomycin was subsequently reformulated into a newsalt fosfomycin tromethamine also known as fosfomycintrometamol Fosfomycin tromethamine demonstrated thesame spectrum of activity and safety profile as the calciumsalt as well as producing improved oral bioavailability andconsistency for in vitro antimicrobial susceptibility testing[12 13]

Fosfomycin has been available to physicians in manyEuropean countries as well as Japan South Africa and Brazilin both oral and parenteral formulations for up to fourdecades [12 13] Parenteral fosfomycin is formulated as adisodium salt Oral fosfomycin first entered the Canadianand American markets in 1997 [3] but was withdrawn inCanada several years later due to lack of use It was recentlyreintroduced in Canada and has been added to severalprovincial formularies with an indication for the treatmentof acute uncomplicated cystitis in adult women infected withsusceptible isolates of E coli and Enterococcus faecalis [14]In Canada and the United States fosfomycin tromethamineis manufactured exclusively under the brand name Monuroland is available as a 57-gram powder sachet of which 3 gramsis fosfomycin [14]

3 Chemistry

The chemical structure of fosfomycin ([minus] [1R 2S]-12-eposipropylphosphonic acid or cis-12-epoxypropyl

H3C

H

O

H

P

O

OH

OH H2N C

CH2OH

CH2OH

CH2OH

∙

Figure 1 Chemical structure of fosfomycin tromethamine

phosphoric acid) was published in 1969 shortly after itsinitial isolation [10] (Figure 1) It has a molecular mass of138059 gmol (C

3H7O4P) The structure of fosfomycin has

two distinguishing features a stable epoxide group and aphosphonic acid moiety both are key components of itstherapeutic activity Its carbon-phosphorous bond is alsounique to a minority of naturally occurring compounds andis an indication that it is the product of a distinct and complexbiosynthetic processThe biosynthetic pathway of fosfomycinwas initially described in S wedomorensis and leads to thedevelopment of an in vitro chemical synthesis process usingphosphonic acid as starting material which is currently usedin commercial production [15]

4 Mechanism of Action

Fosfomycinrsquos mechanism of action results from its irre-versible inhibition of MurA (UDP-N-acetylglucosamine-3-enolpyruvyl transferase) the cytosolic enzyme responsiblefor the first step in the peptidoglycan biosynthesis pathwaythat produces UDP-N-acetylmuramic acid [16] More specif-ically fosfomycin is a phosphoenolpyruvate (PEP) analogMurA is responsible for ligating PEP to the 31015840-hydroxyl groupof UDP-N-acetylglucosamine in the pathway that producesUDP-N-acetylmuramic acid [16] The inhibition of MurAis the result of direct nucleophilic attack by a catalytic sitecysteine residue on the C-2 carbon of fosfomycin resultingin blockage of the catalytic site [16] Fosfomycin has minimalto no effect on other enzymes utilizing PEP such as enolasepyruvate kinase and PEP carboxykinase [16] Fosfomycinrsquosmechanism of action is unique and distinct from otherbacterial cell wall inhibitors (120573-lactams and glycopeptides) aswell as other classes of antibacterial agents suggesting that thelikelihood of cross-resistance to these other agents should beminimal

Fosfomycin enters the bacterial cytosol by two transportsystems the constitutively expressed L-120572-glycerophosphate(or glycerol-3-phosphate) uptake (GlpT) system and theglucose-6-phosphate- (G6P-) inducible hexose-monophos-phate transport (UhpT) system Of the two systems the G6P-inducible UhpT system serves as the primary portal of entryfor fosfomycin [16] In 1983 Andrews and coworkers [17]demonstrated that a G6P concentration of 25 120583gmL opti-mizes induction of the UhpT system and it was subsequentlyadded to standardized in vitro susceptibility testing methods

Canadian Journal of Infectious Diseases and Medical Microbiology 3

for fosfomycin to facilitate reproducibleMIC generation [18]Most Enterobacteriaceae (excluding Proteus spp) Enterococ-cus spp and Staphylococcus spp possess the UhpT transportsystem in their cell membrane [16 17]

5 Mechanisms of Resistance

In vitro resistance to fosfomycin has been associated mostcommonly with chromosomal mutations in GlpT and lessfrequently with mutations in UhpT [16 19ndash22] However thepresence of a functional G6P-inducible UhpT transport sys-tem frequently overrides resistance produced bymutations inGlpT and results in a fosfomycin susceptible phenotype [16]Resistance to fosfomycinmay also result less commonly froma myriad of other mechanisms including modification inac-tivation or overexpression of MurA fosfomycin kinases orthe inactivation via plasmid-mediated enzymes such as fosAfosB fosC and fosX [23]

Plasmid-mediated fos enzymes aremembers of the glyox-alase superfamily and inactivate fosfomycin by catalyzing itsconjugation with glutathione or another nucleophile Theseenzymes function by nucleophilic attack on carbon 1 of fos-fomycin which opens the epoxide ring and inactivates itThefos enzymes differ by the identity of the nucleophile utilized inthe reaction glutathione is used by FosA bacillithiol by FosBand water by FosX [21 24 25] In general FosA and FosXenzymes are produced by Gram-negative bacteria and FosBis produced by Gram-positive bacteria [21] Another enzymeFosC utilizesATP and adds a phosphate group to fosfomycinwhich also neutralizes its antibacterial properties [26]

Resistance development during therapy is a confoundingissue for fosfomycin In vitro studies have shown that fos-fomycin can be associated with the development of resistanceat a frequency of 10minus8 to 10minus6 [23 27ndash29] However thefrequency of mutational resistance in vitro is not observed inclinical studies suggesting that there may be a biological costassociated with common mutations that confer resistanceto fosfomycin in vitro [22 23] Experimental studies withfosfomycin-resistant E coli isolates have also demonstratedreduced epithelial cell adherence increased susceptibility topolymorphonuclear cell and serum complement killing andslower growth rates [12 22 30] Overall declines in bacterialvirulence associated with fosfomycin-resistant E coli mayexplain the low rates of resistance observed in vivo for thisagent despite decades of use [12]Data from theAntimicrobialResistance Epidemiological Survey on Cystitis study showedthat resistance to fosfomycin remains rare in regions whereit is widely used (sim2) [31] Other reasons for fosfomycinrsquoslow resistance rate in urinary tract infections may include itsshort contact time high urine concentration and potentiallyhigher compliance compared with agents dosed for 3ndash7days Lower frequencies of resistance development have beenobserved at higher fosfomycin concentrations and in mediawith an acidic pH [23] In vitro resistance developmentin E coli is less frequent than in K pneumoniae and Paeruginosa [23] Although the limited resistance in E coli tofosfomycin from a variety of regions across the world (despiteintensive use of this agent) is encouraging we need toremain vigilant with ongoing surveillance studies to assess

susceptibility to fosfomycin in Canada Most worrisomewould be the emergence of plasmid-mediated enzymes suchas fosA fosB fosC and fosX [23]

6 In Vitro Microbiology

Standardizedmethods for antimicrobial susceptibility testingof fosfomycin are published by the Clinical and LaboratoryStandards Institute (CLSI) [18] and the European Committeeon Antimicrobial Susceptibility Testing (EUCAST) [32] Itis important to recognize that differences exist betweenthese two standards Specifically there are differences in theorganisms for which fosfomycin MIC and zone diameterbreakpoints apply in the two standards as well as numericaldifferences in fosfomycin MIC and zone diameter break-points

Currently CLSI-approved agar dilution susceptibilitybreakpoints for fosfomycin exist only for E coli and Efaecalis with a MIC le64 120583gmL considered susceptible(resistance ge256120583gmL) and are approved only for test-ing isolates from urinary tract infections [18] EUCASTbreakpoints for fosfomycin apply to all Enterobacteriaceaewith a MIC le32 120583gmL considered susceptible (resistancegt32 120583gmL) for both oral (uncomplicated urinary tract infec-tion only) and parenteral (systemic infections) fosfomycin[32] EUCAST also publishes parenteral fosfomycin break-points for staphylococci but no breakpoints for enterococciBased on our own data with E coli the difference in fos-fomycin susceptibility using CLSI or EUCAST breakpoints islt1 [9]

Antimicrobial susceptibility testing (agar dilution or diskdiffusion) requires agar supplementation with 25120583gmL ofG6P to ensure induction of the UhpT pathway [18 32] Stud-ies reporting in vitro susceptibility testing of fosfomycin priorto 1983 should be disregarded as the importance of addingphysiological levels of G6P to testing media was unknownbefore that time [12 17] Further studies based upon brothdilution MIC testing should not be considered because ofthe relatively high likelihood of spontaneous mutation to fos-fomycin resistance in broth [12] Presently we are not awareof efforts by automated susceptibility systems such as Vitek intesting fosfomycin in Canada or the US but these efforts arerequired

In general fosfomycin demonstrates moderate in vitropotency against both Gram-negative and Gram-positive bac-terial pathogens including those most commonly associatedwith cystitis (E coli Klebsiella spp Enterococcus spp andProteus spp but not S saprophyticus) [9 12 32ndash42]

Table 1 presents the in vitro activity of fosfomycin againstaerobic and facultative Gram-negative bacteria from variousspecimen sources including urine isolates In all studiesMICswere determined using either theCLSI [18] or EUCAST[32] standard method Fosfomycin has higher MICs forKlebsiella spp Enterobacter spp and Serratia spp than forE coli Citrobacter spp and Proteus spp The activity of fos-fomycin against Klebsiella spp and Enterobacter spp demon-strates some variability Fosfomycin may be active againstsome isolates of P aeruginosa with MICs ranging from 4to gt512 120583gmL Acinetobacter baumannii appear inherently


Table 1 In vitro activity of fosfomycin against aerobic and facultative Gram-negative bacteriaa

Bacteria Number tested FosfomycinMIC50

(120583gmL) MIC90

(120583gmL) Range (120583gmL)Acinetobacter spp 185 64ndash128 128ndash512 025ndash512Citrobacter spp (C diversus and C freundii) 251 1-2 4ndash16 003ndash128Enterobacter spp (E agglomerans E aerogenes and E cloacae) 779 8ndash64 32ndash256 012ndashgt512Escherichia coli 9338 05ndash4 2ndash16 003ndash512Escherichia coli ESBL-producing 362 05ndash2 2ndash32 003ndash512Escherichia coli AmpC-producing 135 2 4ndash16 le1ndashgt512Haemophilus influenzae 50 1 4 1ndash128Klebsiella oxytoca 51 8 32 4ndash64Klebsiella pneumoniae 392 16ndash32 32ndashgt128 05ndash512Klebsiella pneumoniae ESBL-producing 74 16 64 2ndash256Klebsiella spp 995 8ndash16 32ndash128 le2ndash512Morganella morganii 98 128ndash256 512 8ndashgt512Proteus mirabilis 1472 le2ndash4 32ndashgt128 le1ndashgt512Proteus vulgaris (indole-positive Proteus) 341 le2ndash16 8ndash256 le2ndash256Providencia spp (P rettgeri and P stuartii) 164 2ndash16 8ndash128 le2ndash512Pseudomonas aeruginosa 1518 32ndash256 64ndash256 4ndashgt512Pseudomonas spp 35 128 256 le05ndash512Serratia marcescens 307 8ndash16 16ndash128 le2ndash128Shigella spp 185 2 2 05ndash64Stenotrophomonas maltophilia 49 64 128 16ndash512aData compiled from [9 12 32ndash41]AmpC chromosomal AmpC 120573-lactamase ESBL extended-spectrum 120573-lactamaseMIC50 minimum concentration (120583gmL) required to inhibit the growth of 50 of isolates MIC

90 minimum concentration (120583gmL) required to inhibit the

growth of 90 of isolates

resistant to fosfomycin However studies combining fos-fomycin with other agents such as cefepime and meropenemversus A baumannii or an aminoglycoside for P aeruginosahave demonstrated additivity between the two agents [43]Gram-negative anaerobic bacteria have been reported to notbe a part of fosfomycinrsquos antibacterial spectrum [12] but thereasons for this are cryptic

Fosfomycin retains its in vitro activity against ESBL-producing AmpC-producing carbapenem-non-susceptibleand multidrug-resistant (MDR) E coli as well as KPC-producingK pneumoniae [9 38ndash41 44] Kaase et al tested 80isolates of Enterobacteriaceae with various carbapenemases(KPC VIM NDM and OXA-48) and reported that 78 hadMICs le32 120583gmL and would thus be considered susceptibleaccording to the EUCAST breakpoint [45] In another studyFalagas and others tested 152 MDR Enterobacteriaceae (76K pneumoniae 17 E coli 5 P mirabilis and 2 others)and determined that 93 of isolates were susceptible tofosfomycin by CLSI breakpoints (MIC le64 120583gmL) [46]Subgroup analysis in the Falagas et al study showed that 9594 and 83 of carbapenemase-producing (119899 = 79) ESBL-producing (119899 = 34) andmetallo-120573-lactamase-producing (119899 =24) isolates were susceptible to fosfomycin [46]

Table 2 summarizes data presented in the most recentlypublished Canada-wide surveillance study of E coli isolates

collected frompatients withUTIs from 2010 to 2013 [9] Ratesof susceptibility to fosfomycin were 994 979 991100 100 and 100 for all isolates ciprofloxacin-resistantTMP-SMX-resistant ESBL-producing AmpC-producingand MDR isolates respectively superior to nitrofurantoinand other frequently prescribed oral empiric agents [9]

The in vitro activity of fosfomycin against Gram-positivebacteria from various specimen sources including urineisolates is summarized in Table 3 Fosfomycin appearsmore active in vitro against S aureus including methicillin-resistant S aureus (MRSA) and S pneumoniae than otherGram-positive bacteria The majority (gt50) of isolatesof S aureus enterococci (including vancomycin-resistantenterococci (VRE)) and streptococci have fosfomycin MICsle32 120583gmL Some streptococci Staphylococcus saprophyticuscorynebacteria Chlamydia andmycoplasmas are resistant tofosfomycin likely due to the absence or low abundance ofthe G6P-inducible UhpT system or an altered MurA target[12 47]

7 Pharmacokinetic Properties

Fosfomycin is freely soluble in water demonstrates negligibleplasma protein binding and distributes widely into tissues


Table 2 In vitro activities of orally prescribed antimicrobial agents against E coli isolated from urine specimens in clinical laboratories acrossCanada from 2010 to 2013a

E coli isolate phenotypeb (number tested) Antimicrobial agent MIC interpretation susceptible resistant

All E coli (868)

Fosfomycin 994 01Amoxicillin-clavulanate 813 57

Ciprofloxacin 774 225Nitrofurantoin 961 15TMP-SMXc 747 253

TMP-SMX-resistant (219)


Ciprofloxacin 516 479Nitrofurantoin 918 32TMP-SMX 0 100

Ciprofloxacin-resistant (195)



ESBL-producing (42)



AmpC-producing (16)



Multidrug-resistant (15)



aData adapted from [9]bESBL extended-spectrum 120573-lactamase AmpC chromosomal AmpC 120573-lactamase multidrug-resistant was defined as isolates resistant to ge3 agents fromdifferent antimicrobial classes (amoxicillin-clavulanate ciprofloxacin nitrofurantoin and TMP-SMX)cTMP-SMX trimethoprim-sulfamethoxazole

Table 3 In vitro activity of fosfomycin against facultative Gram-positive bacteriaa

Organism Number tested FosfomycinMIC50

(120583gmL) MIC90

(120583gmL) Range (120583gmL)Enterococcus faecalis 1862 32 64 05ndash512Enterococcus faecium 516 32ndash64 64ndash128 05ndash128Enterococcus spp 137 16ndash32 64 025ndashgt256Staphylococcus aureus 2213 4 16 012ndash512Staphylococcus aureus MRSA 162 4 64 05ndash512Staphylococcus epidermidis 896 8 128 05ndash256Staphylococcus saprophyticus 227 64ndash128 256ndashgt512 le2ndashgt512Streptococcus pneumoniae 57 8 16 4ndash32Streptococcus pyogenes 50 32 64 2ndash64Streptococcus agalactiae 50 32 64 2ndash64aData compiled from [12 32ndash34 38 42]


Table 4 Pharmacokinetic properties of fosfomycin following a single 3-gram oral dosea

Parameter Mean value or rangeSerumplasma

Bioavailability (119865) 34ndash41Maximum plasma concentration 119862max 22ndash32 120583gmLTime to maximum concentration in the blood (119879max) 2ndash25 hArea under the curve (AUC) 145mgLsdothVolume of distribution (119881

119889

) 1361 LHalf-life (119905

12

) 57 hClearance (CL) 169 Lh

UrineMaximum urinary concentration (119880max) 1053ndash4415 120583gmLTime to maximum concentration in the urine (urinary 119905max) 4 hUrinary concentration at 48 h sim100 120583gmL

Dosage adjustmentsDose adjustment in elderly None requiredDose adjustment in pregnancy None requiredDose adjustment for renal impairment None requiredHepatic adjustment None required

aData adapted from [14 48 49]

(steady state volume of distribution is 1361 plusmn 441 L) [12 1423 27 43 48ndash50]

Table 4 summarizes the pharmacokinetic properties forfosfomycin tromethamine following oral administration of asingle 57-gram (3-gram fosfomycin) dose The oral bioavail-ability of fosfomycin is 34ndash41 18 is recovered from fecesand 54ndash65 of absorbed fosfomycin is recovered unaltered inthe urine [14 48]

Fosfomycinrsquos distribution follows a two-compartmentmodel [48 51] Upon absorption from the gut fosfomycinis rapidly distributed to the kidneys bladder prostate andseminal vesicles [14 49] A 3-gram oral dose of fosfomycinresults in serum 119862max of 22ndash32120583gmL achieved within 2ndash25 hours Animal studies have demonstrated that fosfomycinpenetrates fluids and tissue of the central nervous system andcardiac respiratory and urinary systems supporting its use innoncystitis indications such as prostatitis [52]

Fosfomycin is not metabolized but rather is excretedunchanged in the urine by glomerular filtration [14 49] Itsserum half-life is 57 hours [12 14] Peak urinary concen-trations reach sim4000 120583gmL and remain at concentrationsgt100 120583gmL for 48 hours [49] A fosfomycin urinary con-centration above the MIC

90of E coli (4 120583gmL) has been

reported for 80 hours [48]No dosage adjustments are required in elderly patients

pregnant patients or either renal or hepatic impairment[14 48 49] Studies have reported an increase in 119879maxand 119862max larger AUC and reduced rates of eliminationfor renally impaired patients regardless no dosage adjust-ment is recommended for patients with a creatinine clear-ance (CrCL) gt10mLmin [14 48 49] A study of patientswith (CrCL) of 7ndash54mLmin demonstrated increased serum11990512

from 11 h to 50 h accompanied by the observation thatonly 30 of orally absorbed fosfomycin was excreted within

24 hours [49] Another study of patients with mean CrCLof 40mLmin demonstrated lower mean urinary concentra-tions for the first 24 hours but similar concentrations after48ndash60 hours [14] Limited data exists for both children andpregnant women Studies have demonstrated slightly higherelimination rates in children as well as an increase in meanurinary fosfomycin concentrations in pregnant patientsalthough the differences were considered insignificant anddid not warrant dose adjustments [14]

8 Pharmacodynamic Properties

Fosfomycin has demonstrated concentration-dependentkilling in two different in vitro models Mazzei andcolleagues assessed fosfomycin activity using kill curvesat concentrations from 1x MIC to 64x MIC for isolates ofE coli and P mirabilis [53] When bacterial growth wasassessed from time 0 to 24 hours bacterial inhibition wasdirectly proportional to fosfomycin concentration [53] ForE coli complete eradication was observed at 6ndash8 hours atfosfomycin concentrations ge4x MIC [53]

In a hollow fiber infection model that simulated humanpharmacokinetics of fosfomycin three isolates of ESBL-producing E coli (Ec2974 fosfomycin MICs 1 120583gmL Ec46MIC 1 120583gmL and Ec4244 MIC 64 120583gmL resp) were chal-lenged with varying dosage regimens to assess bacterial inhi-bition including 4 g q8h (12 gday) 8 g q8h (24 gday) and12 g q8h (36 gday) and concentration-dependent activitywas observed [54] Fosfomycin 119891AUC

0ndash24MIC ratios (MIC1 120583gmL) were determined to be 174494 3313603 and428782 for 12 gday 24 gday and 36 gday doses respectively[54] While growth of highly resistant mutants in the 12 gdaydose was observed after 24 hours higher dosages (24 gdayand 36 gday) resulted in complete bacterial eradication


and suppression of resistant mutants [54] Furthermore nodifference in the rate and extent of fosfomycinrsquos bactericidalactivity was observed with different dosage intervals sug-gesting that fosfomycinrsquos pharmacodynamic activity was nottime-dependent [54]

The postantibiotic effect (PAE) for fosfomycin has alsobeen assessed [53] Following two-hour exposures to varyingconcentrations of fosfomycin (025x MIC 1x MIC 4x MICand 8x MIC) and subsequent removal E coli and P mirabilisdemonstrated long concentration-dependent PAEs rangingfrom 34 hours at 025xMIC to 34 hours at 1x MIC to 42 h at8x MIC [49 53]

9 Clinical Trials

In 2010 Falagas and others published a meta-analysis ofall available randomized controlled trials comparing fos-fomycin and other antimicrobial agents for effectivenessand safety in the treatment of acute uncomplicated cystitis[46] Following screening they included 27 trials from 1987to January 2010 in their analysis [46] They reported nodifference in clinical successmicrobiological success relapseor reinfection with single dose fosfomycin and comparatorsusing multidose regimens in trials involving nonpregnantfemales (119899 = 16 trials) and trials involving adult mixed popu-lations (119899 = 3 trials) They were unable to draw conclusionsfrom trials involving pediatric patients (119899 = 3 trials) andpregnant patients (119899 = 5 trials) because of insufficient dataFosfomycin was shown to possess a comparable safety profilewith the comparators prescribed for nonpregnant womenadult mixed populations and pediatric patients and to have asignificantly lower rate of adverse events in pregnant women[46] The authors concluded that fosfomycin may provide avaluable alternative therapy for the treatment of acute cystitisin nonpregnant and pregnant women as well as in the elderlyand pediatric patients

To further the work of Falagas et al we performeda review of randomized controlled trials from 2010 to2015 that compared fosfomycin and other antimicrobialagents for the treatment of acute uncomplicated cystitis andone additional study was identified Ceran and colleaguesconducted a randomized comparative study of single-dosefosfomycin and 5-day ciprofloxacin in 260 female patientsaged between 18 and 65 years with uncomplicated lowerurinary tract infections [55] Of the 260 patients enrolled 142completed the study In the 142 patients E coli (823) andEnterobacter spp (84) were the pathogens most frequentlyisolated from urine cultures Patients were evaluated ondays 7ndash10 for clinical and microbiological cure Clinical curerates were 83 for fosfomycin and 81 for ciprofloxacinmicrobiological cure rates were 83 for fosfomycin and 78for ciprofloxacin Patients were reevaluated on day 60 forrecurrence or reinfection only five patients of 142 patientsdemonstrated relapse The authors concluded that a single3-gram dose of fosfomycin was as effective as ciprofloxacinat 500mg twice a day for 5 days in the treatment of acuteuncomplicated cystitis

Table 5 Adverse effects of fosfomycin following a single 3-gramoraldosea

Adverse effect Frequency ()Diarrhea 4ndash10Vaginitis 58Headache 2Nausea 2ndash5Epigastricabdominal pain 13ndash2Dyspepsia 1-2Dizziness 12Asthenia 1Fatigue 02Mild backache 02aData adapted from [47 48 56]

10 Adverse Effects

Most adverse effects described for fosfomycin have beenmild and transient [48] Table 5 summarizes the mostcommonly reported adverse effects of fosfomycin Seriousadverse reactions such as angioedema asthma exacerbationcholestatic jaundice hepatic necrosis and toxic megacolonhave been extremely rare [48] As with other antimicro-bial agents prolonged use of fosfomycin may be associ-ated with fungal or bacterial super-infections includingClostridium difficile infection [47] A postmarketing study inJapan (reporting on fosfomycin calcium) documented only2 cases of super-infection within 6 years [56] Laboratorychanges (including increased eosinophil count increasedor decreased white blood cell count increased biliru-bin increased alanine aminotransferase increased aspartateaminotransferase increased alkaline phosphatase decreasedhematocrit decreased hemoglobin and alterations in plateletcount) have also been reported however they have beentransient and clinically insignificant [47]

11 Drug Interactions

The only confirmed drug interaction for fosfomycin iswith metoclopramide [14 47 49 57] Metoclopramidersquosmechanism of action (increase in gastrointestinal mobil-ity) decreases the absorption of fosfomycin tromethamineresulting in a 25 reduction in 119862max and 20-minute shorter119905max [47 48] Recent data also suggest that fosfomycin mayhave a protective effect against nephrotoxicity induced byaminoglycosides or cisplatin which may be due to fos-fomycinrsquos inhibition ofmedication-induced histamine releasefrom mast cells [56] Lastly no drug interactions have beenreported between fosfomycin and commonly used agentssuch as analgesics anticonvulsants bronchodilators diuret-ics spasmolytics and antipyretics [14]

12 Role of Fosfomycin in Therapy ofAcute Cystitis

In vitro studies have demonstrated increasing rates ofresistance among E coli urinary isolates to trimethoprim-sulfamethoxazole and ciprofloxacin antimicrobial agents


frequently prescribed for the treatment of cystitis [7 57 58]Community-acquired UTIs caused by ESBL-producing Ecoli are also being reported with increasing frequency [59]These isolates are oftenMDR leaving clinicians with few oraltreatment options [59] Fosfomycin demonstrates excellentin vitro activity against common uropathogens includingMDR isolates [9] Fosfomycin demonstrates a favorable safetyprofile and clinical trials have demonstrated efficacy in thetreatment of uncomplicated cystitis that is comparable toother first-line antimicrobials [46 48 60] Fosfomycin has aunique chemical structure that is distinct from all other mar-keted antimicrobial classes (ie 120573-lactams glycopeptidesfluoroquinolones macrolides lincosamides tetracyclinesaminoglycosides etc) and there is no cross-resistance withother agents used to treat cystitis [12] Resistance to fos-fomycin most commonly arises by chromosomal mutationswhich do not spread easily and the biological cost of thesegeneticmutations is high [22 23] As an additional advantagewhen used for the treatment of acute uncomplicated cystitisfosfomycin is conveniently administered as a single 3 g oraldose [6] CurrentUTI guidelines from the InfectiousDiseasesSociety of America the European Society for Microbiol-ogy and Infectious Diseases the European Association ofUrology and the Canadian Anti-Infective Guidelines forCommunity Acquired Infections (the Ontario Orange Book)all recommend fosfomycin as a first-line antimicrobial forthe treatment of acute uncomplicated cystitis [6 60ndash62]This recommendation is supported by the data reviewedhere Given the rising antimicrobial resistance rates amongcommon uropathogens it is likely that fosfomycin will beused with increasing frequency over the coming years

Competing Interests

Drs James A Karlowsky and Andrew J Walkty declare thatthey have no competing interests Dr George G Zhaneldeclares receiving research funding from Paladin labs

Acknowledgments

The authors would like to thank Camille Manansala for hercontributions to the initial literature review and to the paperoutline

References

[1] A SultanM Rizvi F KhanH Sami I Shukla andHMKhanldquoIncreasing antimicrobial resistance among uropathogens isfosfomycin the answerrdquo Urology Annals vol 7 no 1 pp 26ndash30 2015

[2] M A Pezzlo ldquoLaboratory diagnosis of urinary tract infectionsguidelines challenges and innovationsrdquo Clinical MicrobiologyNewsletter vol 36 no 12 pp 87ndash93 2014

[3] S A Mehnert-Kay ldquoDiagnosis and management of uncompli-cated urinary tract infectionsrdquo American Family Physician vol72 no 3 pp 451ndash458 2005

[4] A Wang P Nizran M A Malone and T Riley ldquoUrinary tractinfectionsrdquo Primary Care Clinics in Office Practice vol 40 no3 pp 687ndash706 2013

[5] L Nicolle P A M Anderson J Conly et al ldquoUncomplicatedurinary tract infection in women Current practice and theeffect of antibiotic resistance on empiric treatmentrdquo CanadianFamily Physician vol 52 pp 612ndash618 2006

[6] K Gupta T M Hooton K G Naber et al ldquoInternationalclinical practice guidelines for the treatment of acute uncom-plicated cystitis and pyelonephritis in women A 2010 update bythe Infectious Diseases Society of America and the EuropeanSociety for Microbiology and Infectious Diseasesrdquo ClinicalInfectious Diseases vol 52 no 5 pp e103ndashe120 2011

[7] J A Karlowsky P R S Lagace-Wiens P J Simner et al ldquoAnti-microbial resistance in urinary tract pathogens in Canada from2007 to 2009 CANWARD surveillance studyrdquo AntimicrobialAgents and Chemotherapy vol 55 no 7 pp 3169ndash3175 2011

[8] A Sorlozano A Jimenez-Pacheco J de Dios Luna del Castilloet al ldquoEvolution of the resistance to antibiotics of bacteriainvolved in urinary tract infections a 7-year surveillance studyrdquoAmerican Journal of Infection Control vol 42 no 10 pp 1033ndash1038 2014

[9] J A Karlowsky A J Denisuik P R S Lagace-Wiens et al ldquoInvitro activity of fosfomycin againstEscherichia coli isolated frompatients with urinary tract infections in Canada as part of theCANWARD surveillance studyrdquo Antimicrobial Agents andChemotherapy vol 58 no 2 pp 1252ndash1256 2014

[10] B G Christensen W J Leanza T R Beattie et al ldquoPhosphon-omycin structure and synthesisrdquo Science vol 166 pp 123ndash1251969

[11] G G Grassi ldquoFosfomycin trometamol historical backgroundand clinical developmentrdquo Infection vol 18 supplement 2 ppS57ndashS59 1990

[12] M Popovic D Steinort S Pillai and C Joukhadar ldquoFos-fomycin an old new friendrdquo European Journal of ClinicalMicrobiology and Infectious Diseases vol 29 no 2 pp 127ndash1422010

[13] P J Bergen C B Landersdorfer H J Lee J Li and R L NationldquolsquoOldrsquo antibiotics for emerging multidrug-resistant bacteriardquoCurrent Opinion in Infectious Diseases vol 25 no 6 pp 626ndash633 2012

[14] Monurol Fosfomycin Trometamol Product MonographSpringer Healthcare Italia Srl Milano Italia 2012

[15] R D Woodyer Z Shao P M Thomas et al ldquoHeterologousproduction of fosfomycin and identification of the minimalbiosynthetic gene clusterrdquo Chemistry and Biology vol 13 no 11pp 1171ndash1182 2006

[16] F M Kahan J S Kahan P J Cassidy and H Kropp ldquoThemechanismof action of fosfomycin (phosphonomycin)rdquoAnnalsof the NewYork Academy of Sciences vol 235 pp 364ndash386 1974

[17] J M Andrews F Baquero J M Beltran et al ldquoInternationalcollaborative study on standardization of bacterial sensitivity tofosfomycinrdquo Journal of Antimicrobial Chemotherapy vol 12 no4 pp 357ndash361 1983

[18] Clinical and Laboratory Standards Institute ldquoPerformancestandards for antimicrobial susceptibility testing Twenty-fifthinformational supplementrdquo Tech Rep M100-S25 2015

[19] P-L Ho J Chan W-U Lo et al ldquoPrevalence and molecularepidemiology of plasmid-mediated fosfomycin resistance genesamong blood and urinary Escherichia coli isolatesrdquo Journal ofMedical Microbiology vol 62 no 11 pp 1707ndash1713 2013

[20] J Navas J Leon M Arroyo and J M Garcıa Lobo ldquoNucleotidesequence and intracellular location of the product of the


fosfomycin resistance gene from transposon Tn2921rdquo Antimi-crobial Agents and Chemotherapy vol 34 no 10 pp 2016ndash20181990

[21] R E Rigsby K L Fillgrove L A Beihoffer and R N Arm-strong ldquoFosfomycin resistance proteins a nexus of glutathionetransferases and epoxide hydrolases in a metalloenzyme super-familyrdquoMethods in Enzymology vol 401 pp 367ndash379 2005

[22] M Ballestero-Tellez F Docobo-Perez J M Rodriguez-Martinez et al ldquoContribution of specific resistancemechanismsof fosfomycin resistance and its biological cost in Escherichiacolirdquo in Proceedings of the Interscience Conference on Antimicro-bial Agents and Chemotherapy (ICAAC rsquo15) September 2015

[23] D E Karageorgopoulos R Wang X-H Yu and M E FalagasldquoFosfomycin evaluation of the published evidence on the emer-gence of antimicrobial resistance in gram-negative pathogensrdquoJournal of Antimicrobial Chemotherapy vol 67 no 2 Article IDdkr466 pp 255ndash268 2012

[24] S V Sharma V K Jothivasan G L Newton et al ldquoChemicaland chemoenzymatic syntheses of bacillithiol a unique low-molecular-weight thiol amongst low G + C gram-positivebacteriardquo Angewandte ChemiemdashInternational Edition vol 50no 31 pp 7101ndash7104 2011

[25] A A Roberts S V Sharma A W Strankman S R DuranM Rawat and C J Hamilton ldquoMechanistic studies of FosB adivalent-metal-dependent bacillithiol-S-transferase that medi-ates fosfomycin resistance in Staphylococcus aureusrdquo Biochemi-cal Journal vol 451 no 1 pp 69ndash79 2013

[26] P Garcıa P Arca and J Evaristo Suarez ldquoProduct of fosC a genefrom Pseudomonas syringae mediates fosfomycin resistance byusing ATP as cosubstraterdquo Antimicrobial Agents and Chemo-therapy vol 39 no 7 pp 1569ndash1573 1995

[27] FGudiol ldquoS55 Facts andmyths about fosfomycinrdquo InternationalJournal of Antimicrobial Agents vol 29 supplement 2 pp S12ndashS13 2007

[28] J Oteo V Bautista N Lara et al ldquoParellel increase in commu-nity use of fosfomycin and resistance to fosfomycin in extended-spectrumbeta-lactamase-producingEscherichia colirdquo Journal ofAntimicrobial Chemotherapy vol 65 pp 2459ndash2463 2010

[29] J Oteo V Bautista N Lara et al ldquoParallel increase in com-munity use of fosfomycin and resistance to fosfomycin inextended-spectrum 120573-lactamase (ESBL)-producing Escherichiacolirdquo Journal of Antimicrobial Chemotherapy vol 65 no 11Article ID dkq346 pp 2459ndash2463 2010

[30] A Marchese L Gualco E A Debbia G C Schito and A MSchito ldquoIn vitro activity of fosfomycin against Gram-negativeurinary pathogens and the biological cost of fosfomycin resis-tancerdquo International Journal of Antimicrobial Agents vol 22 no2 pp S53ndashS59 2003

[31] G C Schito K G Naber H Botto et al ldquoThe ARESCstudy an international survey on the antimicrobial resistance ofpathogens involved in uncomplicated urinary tract infectionsrdquoInternational Journal of Antimicrobial Agents vol 34 no 5 pp407ndash413 2009

[32] European Committee on Antimicrobial Susceptibility TestingClinical breakpoints-bacteria version 50 2015

[33] A L Barry andP C Fuchs ldquoIn vitro susceptibility testing proce-dures for fosfomycin tromethaminerdquo Antimicrobial Agents andChemotherapy vol 35 no 6 pp 1235ndash1238 1991

[34] A L Barry and S D Brown ldquoAntibacterial spectrum of fos-fomycin trometamolrdquo Journal of Antimicrobial Chemotherapyvol 35 no 1 pp 228ndash230 1995

[35] L V Perdigao-Neto M S Oliveira C F Rizek C M D MCarrilho S F Costa and A S Levin ldquoSusceptibility of multire-sistant gram-negative bacteria to fosfomycin and performanceof different susceptibility testingmethodsrdquoAntimicrobial Agentsand Chemotherapy vol 58 no 3 pp 1763ndash1767 2014

[36] A Alhambra J A Cuadros J Cacho J L Gomez-Garces andJ I Alos ldquoIn vitro susceptibility of recent antibiotic-resistanturinary pathogens to ertapenem and 12 other antibioticsrdquo Jour-nal of Antimicrobial Chemotherapy vol 53 no 6 pp 1090ndash10942004

[37] S Rajenderan V Balaji S Anandan et al ldquoDeterminationof MIC distribution of arbekacin cefminox fosfomycin bia-penem and other antibiotics against gram-negative clinicalisolates in South India a prospective studyrdquo PLoS ONE vol 9article 7 Article ID e103253 2014

[38] H Hayami S Takahashi K Ishikawa et al ldquoNationwidesurveillance of bacterial pathogens from patients with acuteuncomplicated cystitis conducted by the Japanese surveillancecommittee during 2009 and 2010 antimicrobial susceptibilityof Escherichia coli and Staphylococcus saprophyticusrdquo Journal ofInfection and Chemotherapy vol 19 no 3 pp 393ndash403 2013

[39] K S Ko J Y Suh K R Peck et al ldquoIn vitro activity of fos-fomycin against ciprofloxacin-resistant or extended-spectrum120573-lactamase-producing Escherichia coli isolated from urine andbloodrdquo Diagnostic Microbiology and Infectious Disease vol 58no 1 pp 111ndash115 2007

[40] M Kresken Y Pfeifer D Hafner R Wresch and B Korber-Irrgang ldquoOccurrence of multidrug resistance to oral antibioticsamong Escherichia coli urine isolates from outpatient depart-ments in Germany extended-spectrum 120573-lactamases and therole of fosfomycinrdquo International Journal of AntimicrobialAgents vol 44 no 4 pp 295ndash300 2014

[41] M-S Hsu C-H Liao C-Y Liu C-J Yang Y-T Huangand P-R Hsueh ldquoIn vitro susceptibilities of clinical isolatesof ertapenem-non-susceptible Enterobacteriaceae to nemono-xacin tigecycline fosfomycin and other antimicrobial agentsrdquoInternational Journal of Antimicrobial Agents vol 37 no 3 pp276ndash278 2011

[42] M B Perri EHershbergerM Ionescu C Lauter andM J Zer-vos ldquoIn vitro susceptibility of vancomycin-resistant enterococci(VRE) to fosfomycinrdquo Diagnostic Microbiology and InfectiousDisease vol 42 no 4 pp 269ndash271 2002

[43] M E Falagas K P Giannopoulou G N Kokolakis and P IRafailidis ldquoFosfomycin use beyond urinary tract and gastroin-testinal infectionsrdquoClinical Infectious Diseases vol 46 no 7 pp1069ndash1077 2008

[44] A Endimiani G Patel K M Hujer et al ldquoIn vitro activityof fosfomycin against 119887119897119886KPC-containing Klebsiella pneumoniaeisolates including those nonsusceptible to tigecycline andorcolistinrdquo Antimicrobial Agents and Chemotherapy vol 54 no1 pp 526ndash529 2010

[45] M Kaase F Szabados A Anders and S G GatermannldquoFosfomycin susceptibility in carbapenem-resistant Enterobac-teriaceae from Germanyrdquo Journal of Clinical Microbiology vol52 no 6 pp 1893ndash1897 2014

[46] M E Falagas SMaraki D E Karageorgopoulos A C KastorisE Mavromanolakis and G Samonis ldquoAntimicrobial suscep-tibility of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Enterobacteriaceae isolates to fosfomycinrdquoInternational Journal of Antimicrobial Agents vol 35 no 3 pp240ndash243 2010


[47] A S Michalopoulos I G Livaditis and V Gougoutas ldquoTherevival of fosfomycinrdquo International Journal of Infectious Dis-eases vol 15 no 11 pp e732ndashe739 2011

[48] S S Patel J A Balfour and H M Bryson ldquoFosfomycinTromethamine A review of its antibacterial activity pharma-cokinetic properties and therapeutic efficacy as a single-doseoral treatment for acute uncomplicated lower urinary tractinfectionsrdquo Drugs vol 53 no 4 pp 637ndash656 1997

[49] G M Keating ldquoFosfomycin trometamol a review of its use asa single-dose oral treatment for patients with acute lower uri-nary tract infections and pregnant women with asymptomaticbacteriuriardquo Drugs vol 73 no 17 pp 1951ndash1966 2013

[50] N Roussos D E Karageorgopoulos G Samonis and M EFalagas ldquoClinical significance of the pharmacokinetic and phar-macodynamics characteristics of fosfomycin for the treatmentof patients with systemic infectionsrdquo International Journal ofAntimicrobial Agents vol 34 pp 506ndash515 2009

[51] WMM Kirby ldquoPharmacokinetics of fosfomycinrdquo Chemother-apy vol 23 pp 141ndash151 1977

[52] M E Falagas and P I Rafailidis ldquoFosfomycin the current statusof the drugrdquo Clinical Infectious Diseases vol 61 no 7 pp 1144ndash1146 2015

[53] TMazzei M I Cassetta S Fallani S Arrigucci and A NovellildquoPharmacokinetic and pharmacodynamic aspects of antimicro-bial agents for the treatment of uncomplicated urinary tractinfectionsrdquo International Journal of Antimicrobial Agents vol28 supplement 1 pp 35ndash41 2006

[54] F Docobo-Perez G L Drusano A Johnson et al ldquoPharmaco-dynamics of fosfomycin insights into clinical use for antimicro-bial resistancerdquoAntimicrobial Agents andChemotherapy vol 59no 9 pp 5602ndash5610 2015

[55] NCeranDMert F Y Kocdogan et al ldquoA randomized compar-ative study of single-dose fosfomycin and 5-day ciprofloxacinin female patients with uncomplicated lower urinary tractinfectionsrdquo Journal of Infection and Chemotherapy vol 16 no6 pp 424ndash430 2010

[56] J L Reffert and W J Smith ldquoFosfomycin for the treatment ofresistant gram-negative bacterial infectionsrdquo Pharmacotherapyvol 34 no 8 pp 845ndash857 2014

[57] G V Sanchez R N Master J A Karlowsky and J M BordonldquoIn vitro antimicrobial resistance of urinary Escherichia coli iso-lates among US outpatients from 2000 to 2010rdquo AntimicrobialAgents and Chemotherapy vol 56 no 4 pp 2181ndash2183 2012

[58] AWalkty P R S Lagace-Wiens J A Karlowsky et al ldquoChangein antimicrobial susceptibility of escherichia coli urinary tractisolates at a single institution over a period of 10 yearsrdquoCanadian Journal of Microbiology vol 58 no 3 pp 345ndash3492012

[59] Y Doi Y S Park J I Rivera et al ldquoCommunity-associatedextended-spectrum 120573-lactamase-producing Escherichia coliinfection in the United Statesrdquo Clinical Infectious Diseases vol56 no 5 pp 641ndash648 2013

[60] L Grigoryan B W Trautner and K Gupta ldquoDiagnosis andmanagement of urinary tract infections in the outpatient set-ting a reviewrdquoThe Journal of the AmericanMedical Associationvol 312 no 16 pp 1677ndash1684 2014

[61] M Grabe R Bartoletti T E Bjerklund Johansen et al Guide-lines on Urological Infections European Association of Urology2015

[62] Anti-Infective Review Panel Anti-Infective Guidelines for Com-munity Acquired Infections Anti-Infective Review Panel 2014

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


on isolates collected from 2010 to 2013 and found suscep-tibility rates of 747 to TMP-SMX 774 to ciprofloxacin813 to amoxicillin-clavulanate 961 to nitrofurantoinand 994 to fosfomycin [9] The increasing identificationof extended-spectrum beta-lactamase- (ESBL-) producingE coli across Canada and internationally has been associ-ated with concomitant resistance to amoxicillin-clavulanateciprofloxacin and TMP-SMX [7 8] Rates of susceptibilityamong E coli of lt80 for one or more first- or second-lineagents should prompt local reevaluation of empiric treatmentstrategies for acute uncomplicated UTIs [6]

This review endeavoured to summarize peer-reviewedpublished data on the development of fosfomycin its chem-istrymechanisms of action and resistance in vitromicrobiol-ogy pharmacokinetic and pharmacodynamic properties effi-cacy demonstrated in clinical trials for acute cystitis adverseeffects drug interactions and its role in therapy of acutecystitis

2 Development of Fosfomycin

In 1969 laboratories at MSD (Merck Sharp and Dohme)and CEPA (Compania Espanola de Penicilina y Antibioticos)were the first to successfully isolate fosfomycin a phosphonicacid derivative from cultures of Streptomyces spp (S fradiaeS viridochromogenes and S wedomorensis) [10 11] Fos-fomycin was initially synthesized as a calcium salt [11] how-ever this formulation was later identified to be responsiblefor discrepancies reported by in vitro studies and for delayedverification of therapeutic effectiveness in animal modelsand patients and its commercial production was discontin-ued Fosfomycin was subsequently reformulated into a newsalt fosfomycin tromethamine also known as fosfomycintrometamol Fosfomycin tromethamine demonstrated thesame spectrum of activity and safety profile as the calciumsalt as well as producing improved oral bioavailability andconsistency for in vitro antimicrobial susceptibility testing[12 13]

Fosfomycin has been available to physicians in manyEuropean countries as well as Japan South Africa and Brazilin both oral and parenteral formulations for up to fourdecades [12 13] Parenteral fosfomycin is formulated as adisodium salt Oral fosfomycin first entered the Canadianand American markets in 1997 [3] but was withdrawn inCanada several years later due to lack of use It was recentlyreintroduced in Canada and has been added to severalprovincial formularies with an indication for the treatmentof acute uncomplicated cystitis in adult women infected withsusceptible isolates of E coli and Enterococcus faecalis [14]In Canada and the United States fosfomycin tromethamineis manufactured exclusively under the brand name Monuroland is available as a 57-gram powder sachet of which 3 gramsis fosfomycin [14]

3 Chemistry

The chemical structure of fosfomycin ([minus] [1R 2S]-12-eposipropylphosphonic acid or cis-12-epoxypropyl

H3C

H

O

H

P

O

OH

OH H2N C

CH2OH

CH2OH

CH2OH

∙

Figure 1 Chemical structure of fosfomycin tromethamine

phosphoric acid) was published in 1969 shortly after itsinitial isolation [10] (Figure 1) It has a molecular mass of138059 gmol (C

3H7O4P) The structure of fosfomycin has

two distinguishing features a stable epoxide group and aphosphonic acid moiety both are key components of itstherapeutic activity Its carbon-phosphorous bond is alsounique to a minority of naturally occurring compounds andis an indication that it is the product of a distinct and complexbiosynthetic processThe biosynthetic pathway of fosfomycinwas initially described in S wedomorensis and leads to thedevelopment of an in vitro chemical synthesis process usingphosphonic acid as starting material which is currently usedin commercial production [15]

4 Mechanism of Action

Fosfomycinrsquos mechanism of action results from its irre-versible inhibition of MurA (UDP-N-acetylglucosamine-3-enolpyruvyl transferase) the cytosolic enzyme responsiblefor the first step in the peptidoglycan biosynthesis pathwaythat produces UDP-N-acetylmuramic acid [16] More specif-ically fosfomycin is a phosphoenolpyruvate (PEP) analogMurA is responsible for ligating PEP to the 31015840-hydroxyl groupof UDP-N-acetylglucosamine in the pathway that producesUDP-N-acetylmuramic acid [16] The inhibition of MurAis the result of direct nucleophilic attack by a catalytic sitecysteine residue on the C-2 carbon of fosfomycin resultingin blockage of the catalytic site [16] Fosfomycin has minimalto no effect on other enzymes utilizing PEP such as enolasepyruvate kinase and PEP carboxykinase [16] Fosfomycinrsquosmechanism of action is unique and distinct from otherbacterial cell wall inhibitors (120573-lactams and glycopeptides) aswell as other classes of antibacterial agents suggesting that thelikelihood of cross-resistance to these other agents should beminimal

Fosfomycin enters the bacterial cytosol by two transportsystems the constitutively expressed L-120572-glycerophosphate(or glycerol-3-phosphate) uptake (GlpT) system and theglucose-6-phosphate- (G6P-) inducible hexose-monophos-phate transport (UhpT) system Of the two systems the G6P-inducible UhpT system serves as the primary portal of entryfor fosfomycin [16] In 1983 Andrews and coworkers [17]demonstrated that a G6P concentration of 25 120583gmL opti-mizes induction of the UhpT system and it was subsequentlyadded to standardized in vitro susceptibility testing methods

















(120583gmL) MIC90














All E coli (868)









ESBL-producing (42)



AmpC-producing (16)









(120583gmL) MIC90






119889

) 1361 LHalf-life (119905

12





















9 Clinical Trials





10 Adverse Effects








Competing Interests


Acknowledgments


References







































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
































(120583gmL) MIC90














All E coli (868)









ESBL-producing (42)



AmpC-producing (16)









(120583gmL) MIC90






119889

) 1361 LHalf-life (119905

12





















9 Clinical Trials





10 Adverse Effects








Competing Interests


Acknowledgments


References







































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



















All E coli (868)









ESBL-producing (42)



AmpC-producing (16)









(120583gmL) MIC90






119889

) 1361 LHalf-life (119905

12





















9 Clinical Trials





10 Adverse Effects








Competing Interests


Acknowledgments


References







































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




















119889

) 1361 LHalf-life (119905

12





















9 Clinical Trials





10 Adverse Effects








Competing Interests


Acknowledgments


References







































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



















9 Clinical Trials





10 Adverse Effects








Competing Interests


Acknowledgments


References







































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















Competing Interests


Acknowledgments


References







































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















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