G

A

R

Wts

SGa

b

c

ARA

KPATII

1

imranat�roiE

RA

0h

ARTICLE IN PRESS Model

NTAGE-4129; No. of Pages 5

International Journal of Antimicrobial Agents xxx (2013) xxx– xxx

Contents lists available at SciVerse ScienceDirect

International Journal of Antimicrobial Agents

jou rn al hom epage : ht tp : / /www.e lsev ier .com/ locate / i jant imicag

eview

hat is the relevance of fosfomycin pharmacokinetics in thereatment of serious infections in critically ill patients? Aystematic review

uzanne Parkera,∗, Jeffrey Lipmana,b, Despoina Koulenti a,b,c,eorge Dimopoulosc, Jason A. Robertsa,b

Burns, Trauma and Critical Care Research Centre, The University of Queensland, Brisbane, AustraliaRoyal Brisbane and Women’s Hospital, Brisbane, AustraliaAttikon University Hospital, Athens, Greece

a r t i c l e i n f o

rticle history:eceived 31 May 2013ccepted 31 May 2013

eywords:harmacodynamicsntibiotic resistanceherapeutic drug monitoringntensive care

a b s t r a c t

As treatment options for critically ill patients with multidrug-resistant bacteria diminish, older antibioticssuch as fosfomycin are being investigated for use as last-resort drugs. Fosfomycin is a broad-spectrumantibiotic with activity both against Gram-positive and Gram-negative bacteria. The aim of this reviewwas to examine the effectiveness of current fosfomycin dosing strategies in critically ill patients. Thesepatients can be subject to pathophysiology that can impact antibiotic pharmacokinetic (PK) profiles andpotentially the effectiveness of their treatment. As a hydrophilic drug with negligible protein binding,fosfomycin is eliminated almost entirely by glomerular filtration and is subject to patient renal function. Ifaltered as seen in augmented renal clearance, renal function in a critically ill patient may lead to low blood

CU concentrations and predispose patients to the risk of treatment failure. If altered as seen in acute kidneyinjury, toxic blood concentrations may develop. Fosfomycin has a volume of distribution comparablewith �-lactams and aminoglycosides and may therefore increase in critically ill patients. Altered dosingstrategies may be required to optimise dosing given these PK changes, although the current paucity ofdata on fosfomycin in critically ill patients prevents accurate dosing guidance being recommended at thistime.

lsevie

© 2013 E

. Introduction

The escalation of antibiotic resistance is a significant andmmediate global health concern. An increasing prevalence of

ultidrug-resistant (MDR) Gram-negative bacteria is steadilyeducing the number of antibiotics available that can be useds effective treatment for many infections. Whilst serious Gram-egative infections are commonly treated with carbapenemntibiotics, infections are caused by resistant bacteria, such ashose producing the increasingly described New Delhi metallo--lactamase (NDM), meaning that normal treatment options will

esult in an increased likelihood of treatment failure [1,2]. Reports

Please cite this article in press as: Parker S, et al. What is the relevance of focritically ill patients? A systematic review. Int J Antimicrob Agents (2013),

f NDM-producing and similarly resistant bacteria are becomingncreasingly common in the USA, Europe, Asia-Pacific and Middleast regions.

∗ Corresponding author. Present address: Burns, Trauma and Critical Careesearch Centre, Level 7, Block 6, Royal Brisbane and Women’s Hospital, QLD 4029,ustralia. Tel.: +61 7 3346 5104; fax: +61 7 3646 3542.

E-mail address: suzanne.parker@uq.edu.au (S. Parker).

924-8579/$ – see front matter © 2013 Elsevier B.V. and the International Society of Chemttp://dx.doi.org/10.1016/j.ijantimicag.2013.05.018

r B.V. and the International Society of Chemotherapy. All rights reserved.

Fosfomycin is a broad-spectrum antibiotic with bactericidalactivity against Gram-negative and Gram-positive bacteria. It wasfirst discovered in Spain in 1969 and was used for the treatment ofurinary tract infections [3]. Fosfomycin is structurally unrelated toother antibiotics: it is a small (138 Da), highly hydrophilic phospho-nic acid and, with negligible protein binding [2], exhibits excellentpenetration into tissue [4].

The bacterial killing mechanism of fosfomycin is to inhibit thesynthesis of peptidoglycan found in the inner cell wall of bacteria.Fosfomycin is very well tolerated, with only minor adverse effects,with hypokalaemia being the most frequent [5]. These character-istics support the effectiveness of fosfomycin for the treatment ofMDR pathogens as a last-line antibiotic and, as such, it has beenused extensively in critically ill patients in some countries in thesecircumstances [6].

Despite its favourable chemical characteristics, there has beensome debate over what appears to be the rapid development of

sfomycin pharmacokinetics in the treatment of serious infections in http://dx.doi.org/10.1016/j.ijantimicag.2013.05.018

in vitro resistance with fosfomycin monotherapy [7]. However, incountries where fosfomycin has been used in clinical practice formany years, little change in resistance patterns has been described[8]. Resistance may also be driven by low drug exposures, as has

otherapy. All rights reserved.

ING Model

A

2 of Ant

bam

faewne

2

2

a‘cEcprc

3n

pPtab

3

fvwfcfi

cooipn

3

a(t

w[fcb[

ARTICLENTAGE-4129; No. of Pages 5

S. Parker et al. / International Journal

een demonstrated for quinolones and �-lactams [9], especially inssociation with what can be the relatively long duration of treat-ent with fosfomycin [6].As a treatment reserved for the critically ill, changes in fos-

omycin pharmacokinetics can significantly impact concentrationst the site of infection, thus dose alterations may be required tonsure that optimal exposures are achieved. The aim of this paperas to examine the published data describing the pharmacoki-etics of fosfomycin in critically ill patients and to review theffectiveness of current dosing strategies.

. Methodology

.1. Literature search

The Web of Knowledge and PubMed databases were system-tically searched up to October 2012. The keyword searches were

fosfomycin’ OR ‘phosphomycin’ OR ‘phosphonomycin’ AND ‘criti-al care’ OR ‘intensive care’ OR ‘sepsis’, with the search limited tonglish language papers only. The bibliographies of relevant arti-les were also reviewed. Studies were selected if they includedharmacokinetic (PK) data on fosfomycin as well as a review of cur-ent microbiological or clinical data to report a summary of currentlinical practice of fosfomycin and susceptibility patterns (Fig. 1).

. Pharmacokinetics in intensive care unit (ICU) versuson-ICU patients

The effect of pathophysiological changes in critical illness onharmacokinetics can be described via the changes that occur toK parameters, specifically to clearance (CL) and the volume of dis-ribution (Vd). Such changes can impact fosfomycin concentrationst the site of infection, which in turn may potentially reduce itsactericidal activity.

.1. Clearance

Clearance of hydrophilic, renally cleared antibiotics such as fos-omycin is subject to changes in patient renal function, which mayary dynamically in critically ill patients. Being hydrophilic andith negligible protein binding (ca. 0% [10,11]), elimination of fos-

omycin is almost entirely via glomerular filtration [12] and totallearance of fosfomycin is highly correlated with the glomerularltration rate (as measured by creatinine clearance) [10].

An increase in clearance is likely to lead to reduced blood con-entrations of fosfomycin, thereby exposing the patient to the riskf treatment failure. As seen in Fig. 1 and Table 1, there is a paucityf information on fosfomycin clearance in critically ill patients withmpaired renal function. More research in this area is necessary torovide clinicians with evidence-based dosing strategies for ratio-al adjustment of fosfomycin dosing.

.2. Volume of distribution

An increase in the Vd of fosfomycin will prolong the half-lifend reduce the maximum concentrations during a dosing intervalCmax). Whilst a reduced Cmax is not problematic, the time to reachherapeutic concentrations may be problematic.

Like most hydrophilic drugs, fosfomycin has a Vd consistentith extracellular body water (ca. 0.3 L/kg) in healthy volunteers

10]. Like aminoglycosides and �-lactam antibiotics, the Vd of

Please cite this article in press as: Parker S, et al. What is the relevance of fcritically ill patients? A systematic review. Int J Antimicrob Agents (2013),

osfomycin is likely to increase in critically ill patients, whichould result in a decreased Cmax. As seen in Table 1, the Cmax cane reduced by as much as 35% compared with healthy patients4,14]. An increase in Vd (by as much as 50%) is likely due to the

PRESSimicrobial Agents xxx (2013) xxx– xxx

pathogenesis of bacterial infections and resulting changes tothe vascular endothelium with increased capillary permeability[15–17]. An increased Vd may suggest that the use of loading dosesto ensure target concentrations are met is necessary where theymay not traditionally be used [18].

3.3. Tissue penetration

The apparent high penetration ability of fosfomycin manifestsas favourable distribution into many tissue types, including inter-stitial fluid of muscle, infected lung tissue, abscess fluid, heartvalves, urinary bladder wall, prostate and cerebral spinal fluid (CSF)[14,19–22].

Joukhadar et al. used the microdialysis technique to comparefosfomycin concentrations in the interstitial fluid of muscles withplasma concentrations in nine sepsis patients. Maximum concen-trations of fosfomycin in plasma were similar to those found inthe original study of healthy patients (357 mg/L and 395 mg/L,respectively). The concentrations found in muscle were higher insepsis patients compared with healthy volunteers (247 mg/L vs.156 mg/L), which suggests that sepsis may not adversely affectfosfomycin penetration [23], as has been found for other antibi-otics (e.g. piperacillin, meropenem) [24,25], although the effect ofmicrovascular failure on fosfomycin tissue penetration has not yetbeen fully investigated. The authors also found that muscle concen-trations rapidly equilibrated with plasma in critically ill patients(within 80 min), which is important given that the interstitial fluidof tissues is typically the site of most infections [20].

Using microdialysis, Matzi et al. examined the ability of fos-fomycin to penetrate both infected and healthy lung tissue in sepsispatients. The authors found that severe lung inflammation dur-ing bacterial pneumonia did not impair fosfomycin penetration.This supports the use of fosfomycin in achieving clinically relevantconcentrations in severe pulmonary infection [19].

Another study of 39 patients by Pfeifer et al. examined fos-fomycin pharmacokinetics in patients undergoing neurosurgicalprocedures resulting in CSF drainage in the presence of an intactblood–brain barrier. The authors concluded that there was ade-quate penetration of fosfomycin in these patients for treatmentof infections caused by susceptible organisms. Furthermore, theauthors observed increased CSF penetration in the presence ofinflamed meninges [26]. Another study by Pfausler et al. also foundthat penetration of fosfomycin into the CSF in six ventriculitispatients with extraventricular drainage was unaffected over 5 days,despite progressive healing and improvement of ventriculitis [14].

These studies support the favourable penetration of fosfomycininto tissues sites traditionally considered to be associated withlow penetration, thereby supporting its potential for use in manydifficult-to-treat infection sites.

4. Pharmacodynamics

Bacterial killing by fosfomycin is categorised pharmacodynam-ically as time-dependent and, as such, maintaining concentrationsabove the minimum inhibitory concentration (MIC) of the targetpathogen for extended periods is required for optimum activity[12]. Static time–kill studies of fosfomycin tromethamine suggestthat it kills 99% of Staphylococcus aureus, Escherichia coli, Klebsiellapneumoniae, Enterobacter cloacae and Citrobacter freundii within2.9 h when fosfomycin concentrations are 2× MIC [27]. Increasing

osfomycin pharmacokinetics in the treatment of serious infections in http://dx.doi.org/10.1016/j.ijantimicag.2013.05.018

the concentrations to 8× MIC slightly reduced this time to 2.2 h [27],however this is not likely to be clinically significant. Bactericidalactivity against E. coli, Proteus mirabilis or K. pneumoniae is seen ateven 1× MIC with no evidence of recovery by 5 h of incubation [28].

Please cite

this

article in

press

as: Parker

S, et

al. W

hat

is th

e relevan

ce of

fosfomycin

ph

armacokin

etics in

the

treatmen

t of

serious

infection

s in

critically ill

patien

ts? A

systematic

review.

Int

J A

ntim

icrob A

gents

(2013), h

ttp://d

x.doi.org/10.1016/j.ijan

timicag.2013.05.018

AR

TIC

LE

IN P

RE

SS

G M

odel

AN

TAG

E-4129;

No.

of Pages

5

S. Parker

et al.

/ International

Journal of

Antim

icrobial A

gents xxx (2013) xxx– xxx

3

Table 1Review of literature for pharmacokinetic (PK) data on intensive care unit (ICU) patients receiving fosfomycin.

Reference Study population No. ofpatients

Fosfomycin dose PK parameter

Vd (L) t1/2 (h) CL (L/h) Cmax (mg/L) Tmax (h) AUC (mg h/L)

Bergan et al. [13] Healthy volunteers 12 3 g i.v. 20.6a 2.1 ± 0.1 6.8b 370.6 ± 92 0.02 ± 0 443.6 ± 48.9

Frossard et al. [4] Healthy volunteers 6 4 g i.v., once nd nd 9.0b (serum) 97 ± 13 (muscle) 201.7 ± 56.7 (muscle)144 ± 1 (subcutis) 313.3 ± 43.3 (subcutis)202 ± 20 (serum) AUC0–8, 443.3 ± 41.7 (serum)

8 g i.v., once nd nd 9.0b

(serum)156 ± 16 (muscle) 460 ± 40 (muscle)209 ± 30 (subcutis) 596.7 ± 48.3 (subcutis)395 ± 46 (serum) 886.7 ± 70 (serum)

Gattringer et al.[33]

Anuric ICU patients(CVVH)

12 8 g (CVC) 33.7 ± 12.7 12.1 ± 5.2 6.4 ± 7.6 (total) 442.8 ± 124.0 0.4 ± 0.1 AUC0–12,2159.4 ± 609.81.1 ± 0.2 (HF)c

Joukhadar et al.[23]

Sepsis 9 8 g i.v. 31.5 ± 4.5 3.9 ± 0.9 7.2 ± 1.3 357 ± 28 (plasma) 0.4 ± 0.1 (plasma) AUC0–4, 721 ± 66 (plasma)4.1 ± 0.6 (muscle) 247 ± 38 (muscle) 1.2 ± 0.2 (muscle) AUC0–4, 501 ± 69 (muscle)

Pfausler et al. [14] Bacterialventriculitis

6 8 g i.v. 30.8 ± 10.2 3.0 ± 1.0 7.4 ± 2.3 260 ± 85 (plasma) 1.2 ± 0.4 (plasma) 929 ± 280 (plasma)43 ± 20 (CSF) 3.8 ± 1.8 (CSF) 225 ± 131 (CSF)

8 gt.i.d.

26.3 ± 9.7 4.0 ± 0.5 5.0 ± 2.0 307 ± 101 (plasma) 1.5 ± 1.2 (plasma) 1035 ± 383 (plasma)62 ± 38 (CSF) 4.5 ± 2.7 (CSF) 295 ± 179 (CSF)

Pfeifer et al. [26] Perioperativeneurosurgicalpatients

39 5 g i.v. 15.4 2 7.2 253 ± 108 0.259–10 (CSF) 3–6

10 g i.v. nd nd nd 14–17 (CSF) 2–65 g i.v. t.i.d. nd nd nd 32 (CSF) Between 2 days and 5 days

Matzi et al. [19] Sepsis 7 4 g i.v. 31.7a 2.5 ± 0.5 (plasma) 8.8b 243.3 ± 58.5(plasma)

0.3 ± 0 (plasma) AUC0–4, 453.0 ± 113.4(plasma)

n = 7 healthylung

nd 2.2 ± 0.8d nd 131.6 ± 110.6d 1.1 ± 0.4d AUC0–4, 242.4 ± 101.6d

n = 5 infectedlung

nd 2.7 ± 1.5e nd 107.5 ± 60.2e 1.4 ± 0.5e AUC0–4, 203.5 ± 118.4e

Vd, volume of distribution; t1/2, terminal elimination half-life; CL, clearance; Cmax, maximum concentration; Tmax, time to reach Cmax; AUC, area under the concentration–time curve; i.v., intravenous; nd, not described; AUC0–x ,AUC from time 0–x h; CVVH, continuous venovenous haemofiltration; CVC, central venous catheter; HF, haemofiltration; t.i.d., three times daily; CSF, cerebral spinal fluid.

a Calculated based on the approximation that ke = 0.693/t1/2 = CL/Vd.b Calculated based on the approximation CL = dose/AUC.c The clearance of haemofiltration (CLHF) was calculated with the formula CLHF = (UFR × CUF)/CA, where UFR refers to the ultrafiltration rate and CUF and CA refer to the ultrafiltrate and arterial (dialyser inlet) serum fosfomycin

concentrations, respectively.d Healthy lung.e Infected lung.

ARTICLE IN PRESSG Model

ANTAGE-4129; No. of Pages 5

4 S. Parker et al. / International Journal of Antimicrobial Agents xxx (2013) xxx– xxx

f the

mftt(0cwf

4

TbtiHsff

fsdicpo

mthn

Fig. 1. Summary o

When comparing results from studies reporting the oral for-ulation fosfomycin tromethamine with the intravenous (i.v.)

ormulation (fosfomycin sodium), it is important to be awarehat the inactive salt component (tromethamine) of fosfomycinromethamine contributes to almost one-half of the dose reportedi.e. 1 g of fosfomycin tromethamine = 0.53 g of fosfomycin and.47 g of tromethamine). Intravenous fosfomycin (as a sodium salt)ontains 76% of the active material fosfomycin. This is of relevancehen interpreting what doses of drug should be used based on the

ormulation to be administered and the study used.

.1. Relevance of microbiology data

The European Committee on Antimicrobial Susceptibilityesting (EUCAST) MIC breakpoints for i.v. fosfomycin for Entero-acteriaceae and Staphylococcus spp. are 32 mg/L (irrespective ofhe site of infection), whilst there is insufficient evidence to nom-nate breakpoints for Enterococcus spp., Streptococcus pneumoniae,aemophilus influenzae and Moraxella catarrhalis. For Pseudomonaspp., anecdotally these should be considered resistant to fos-omycin and would require treatment with another agent orosfomycin as part of combination therapy.

A considerable difference exists in the definition of breakpointsor fosfomycin by various breakpoint committees and professionalocieties and this may be due to the susceptibility testing proce-ures. In vitro studies have found that the activity of fosfomycin

s potentiated by the presence of the physiologically availableompound glucose-6-phosphate (G6P), and the addition of G6Produces results that more closely correlate to the in vivo activityf fosfomycin [12].

Fosfomycin also exhibits a high level of spontaneous bacterial

Please cite this article in press as: Parker S, et al. What is the relevance of fcritically ill patients? A systematic review. Int J Antimicrob Agents (2013),

utation rates when tested in vitro [29]. However, little resistanceo fosfomycin has been described in countries where fosfomycinas been used routinely [30,31], suggesting that in vitro data mayot correlate with clinical observations. However, there is a recent

literature review.

report of three ICU patients developing resistance to fosfomycinduring K. pneumoniae infections associated with K. pneumoniae car-bapenemase (KPC) when fosfomycin was used as adjunct therapy.Additional data are required to determine the role of fosfomycin incombination therapy for infections mediated by MDR bacteria [32].

4.2. Interpretative pharmacokinetics/pharmacodynamics

Fosfomycin has been used in the past for the treatment of avariety of infections (urinary, central nervous system, neurosurgi-cal, etc.) due to MDR pathogens where doses up to 12 g/daily wereused. During recent years, because of the increasing incidence ofMDR/pandrug-resistant infections in critically ill patients, a dose of24 g/daily was considered adequate in order to treat these infec-tions.

A study by Joukhadar et al. into tissue penetration of fosfomycinfound that the concentrations in the interstitium and plasmaremained at >70 mg/L during a 4-h observation period. However,with a half-life of ≥2.5 h (as has been found in critically ill patients)and a MIC of 32 mg/L, twice-daily dosing is unlikely to provide ade-quate concentrations of fosfomycin in the interstitial fluid of sometissues [23]. This highlights the need for further investigations intodosing with fosfomycin, particularly where altered pathophysio-logical changes are impacting on drug distribution.

Supporting the need for further investigations are the studiesby Matzi et al. [19] and Pfausler et al. [14]. Matzi et al. also foundthat whilst a single i.v. dose of 4 g administered was suitable forpathogens with a MIC of up to 32 mg/L there was considerableinterpatient variability in tissue and plasma PK profiles, and theyhypothesised that there was a potential risk of underdosing individ-ual patients [19]. Pfausler et al. found that penetration of fosfomycin

osfomycin pharmacokinetics in the treatment of serious infections in http://dx.doi.org/10.1016/j.ijantimicag.2013.05.018

into the CSF at 8 g three times daily was potentially unsuitable foreradicating pathogens with a MIC90 (MIC required to inhibit thegrowth of 90% of the organisms) of 32 mg/L, with CSF concentra-tions generally four-fold lower than observed in plasma [14]. In

ING Model

A

of Ant

mVn

Tb2tcsuaaaipot

5

tpsWieifcnt

sitA

R

[

[

[

[

[

[

[

[[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

ARTICLENTAGE-4129; No. of Pages 5

S. Parker et al. / International Journal

ost of these studies the critically ill patients exhibited higherd values and a high level of interpatient variability than seen inon-critically ill patients.

From these studies and a review of the data available (seeable 1), a reasonable approach to dosing critically ill patients maye to provide frequent, higher doses of fosfomycin over the first4–48 h (to counter the increased Vd observed) and then to con-inue frequent but lower doses, based on estimates of creatininelearance using urinary collection. Fosfomycin has a favourableafety profile and appears well tolerated [33] and this dosing sched-le may be suitable. However, the data to categorically support thispproach are not available and further investigations on dosingre required. There are also no strong data available in the liter-ture on the suggested duration of treatment for different sites ofnfection. An advanced description of the PK and pharmacodynamicarameters of fosfomycin in critically ill patients would ensure thatptimal dosing is achieved for successful therapeutic outcomes ando prevent the development of resistance.

. Conclusion

This systematic review has found that there is limited informa-ion available on the pharmacokinetics of fosfomycin in critically illatients. The lack of data could be considered problematic given theerious nature of infections requiring use of this last-line antibiotic.

hen comparing the PK data of healthy volunteers with criticallyll patients, significant changes in the Vd and CL of fosfomycin arevident. These data emphasise that standard dosing, particularlyn line with the earliest PK studies, is likely to be inappropriateor critically ill patients and that revised dosing strategies must beonsidered. A more advanced understanding of the pharmacoki-etics and pharmacodynamics is clearly required to ensure optimalherapy for fosfomycin for critically ill patients.

Funding: SP is supported by a PhD Scholarship by The Univer-ity of Queensland Research Scholarship (UQRS). JAR is supportedn part by a Career Development Fellowship from the Aus-ralian National Health and Medical Research Council [NHMRCPP1048652].

Competing interests: None declared.Ethical approval: Not required.

eferences

[1] Popovic M, Steinort D, Pillai S, Joukhadar C. Fosfomycin: an old, new friend?Eur J Clin Microbiol Infect Dis 2010;29:127–42.

[2] Roussos N, Karageorgopoulos DE, Samonis G, Falagas ME. Clinical significanceof the pharmacokinetic and pharmacodynamic characteristics of fosfomycinfor the treatment of patients with systemic infections. Int J Antimicrob Agents2009;34:506–15.

[3] Raz R. Fosfomycin: an old–new antibiotic. Clin Microbiol Infect 2012;18:4–7.[4] Frossard M, Joukhadar C, Erovic BM, Dittrich P, Mrass PE, Van Houte M, et al.

Distribution and antimicrobial activity of fosfomycin in the interstitial fluid ofhuman soft tissues. Antimicrob Agents Chemother 2000;44:2728–32.

[5] Florent A, Chichmanian R-M, Cua E, Pulcini C. Adverse events associated withintravenous fosfomycin. Int J Antimicrob Agents 2011;37:82–3.

[6] Dinh A, Salomon J, Bru JP, Bernard L. Fosfomycin: efficacy against infectionscaused by multidrug-resistant bacteria. Scand J Infect Dis 2012;44:182–9.

[7] Nilsson AI, Berg OG, Aspevall O, Kahlmeter G, Andersson DI. Biological costsand mechanisms of fosfomycin resistance in Escherichia coli. Antimicrob AgentsChemother 2003;47:2850–8.

Please cite this article in press as: Parker S, et al. What is the relevance of focritically ill patients? A systematic review. Int J Antimicrob Agents (2013),

[8] Falagas ME, Giannopoulou KP, Kokolakis GN, Rafailidis PI. Fosfomycin:use beyond urinary tract and gastrointestinal infections. Clin Infect Dis2008;46:1069–77.

[9] Roberts JA, Kruger P, Paterson DL, Lipman J. Antibiotic resistance—what’s dosinggot to do with it? Crit Care Med 2008;36:2433–40.

[

PRESSimicrobial Agents xxx (2013) xxx– xxx 5

10] Kirby WMM. Pharmacokinetics of fosfomycin. Chemotherapy 1977;23(Suppl.1):141–51.

11] Zeitlinger MA, Sauermann R, Traunmüller F, Georgopoulos A, Müller M,Joukhadar C. Impact of plasma protein binding on antimicrobial activity usingtime-killing curves. J Antimicrob Chemother 2004;54:876–80.

12] Patel SS, Balfour JA, Bryson HM. Fosfomycin tromethamine. A review of itsantibacterial activity, pharmacokinetic properties and therapeutic efficacy as asingle-dose oral treatment for acute uncomplicated lower urinary tract infec-tions. Drugs 1997;53:637–56.

13] Bergan T, Thorsteinsson SB, Albini E. Pharmacokinetic profile of fosfomycintrometamol. Chemotherapy 1993;39:297–301.

14] Pfausler B, Spiss H, Dittrich P, Zeitlinger M, Schmutzhard E, JoukhadarC. Concentrations of fosfomycin in the cerebrospinal fluid of neurointen-sive care patients with ventriculostomy-associated ventriculitis. J AntimicrobChemother 2004;53:848–52.

15] Udy AA, Roberts JA, De Waele JJ, Paterson DL, Lipman J. What’s behind thefailure of emerging antibiotics in the critically ill? Understanding the impactof altered pharmacokinetics and augmented renal clearance. Int J AntimicrobAgents 2012;39:455–7.

16] Lipman J, Udy AA, Roberts JA. Do we understand the impact of alteredphysiology, consequent interventions and resultant clinical scenarios in theintensive care unit? The antibiotic story. Anaesth Intensive Care 2011;39:999–1000.

17] van der Poll T. Immunotherapy of sepsis. Lancet Infect Dis 2001;1:165–74.18] Roberts JA, Taccone FS, Udy AA, Vincent J-L, Jacobs F, Lipman J. Vancomycin dos-

ing in critically ill patients: robust methods for improved continuous-infusionregimens. Antimicrob Agents Chemother 2011;55:2704–9.

19] Matzi V, Lindenmann J, Porubsky C, Kugler SA, Maier A, Dittrich P, et al. Extracel-lular concentrations of fosfomycin in lung tissue of septic patients. J AntimicrobChemother 2010;65:995–8.

20] Ryan DM. Pharmacokinetics of antibiotics in natural and experimentalsuperficial compartments in animals and humans. J Antimicrob Chemother1993;31(Suppl. D):1–16.

21] Michalopoulos AS, Livaditis IG, Gougoutas V. The revival of fosfomycin. Int JInfect Dis 2011;15:e732–9.

22] Miró JM, Entenza JM, Del Río A, Velasco M, Castaneda X, Garcia de la MàriaCG. High-dose daptomycin plus fosfomycin is safe and effective in treatingmethicillin-susceptible and methicillin-resistant Staphylococcus aureus endo-carditis. Antimicrob Agents Chemother 2012;56:4511–15.

23] Joukhadar C, Klein N, Dittrich P, Zeitlinger M, Geppert A, Skhirtladze K, et al.Target site penetration of fosfomycin in critically ill patients. J AntimicrobChemother 2003;51:1257–352.

24] Roberts JA, Kirkpatrick CMJ, Roberts MS, Robertson TA, Dalley AJ, Lipman J.Meropenem dosing in critically ill patients with sepsis and without renaldysfunction: intermittent bolus versus continuous administration? MonteCarlo dosing simulations and subcutaneous tissue distribution. J AntimicrobChemother 2009;64:142–50.

25] Roberts JA, Roberts MS, Robertson TA, Dalley AJ, Lipman J. Piperacillin pene-tration into tissue of critically ill patients with sepsis—bolus versus continuousadministration? Crit Care Med 2009;37:926–33.

26] Pfeifer G, Frenkel C, Entzian W. Pharmacokinetic aspects of cerebrospinal fluidpenetration of fosfomycin. Int J Clin Pharmacol Res 1985;5:171–4.

27] Reeves DS, Holt HA, Bywater MJ. In vitro study of fosfomycin trometamol. In:Neu HC, Williams JD, editors. New trends in urinary tract infections. Basel,Switzerland: Karger; 1988. p. 224–31.

28] Lerner SA, Price S, Kulkarni S. Microbiological studies of fosfomycin trometa-mol against urinary isolates in vitro. In: Neu HC, Williams JD, editors.New trends in urinary tract infections. Basel, Switzerland: Karger; 1987.p. 121–9.

29] Ellington MJ, Livermore DM, Pitt TL, Hall LMC, Woodford N. Mutators amongCTX-M �-lactamase-producing Escherichia coli and risk for the emergence offosfomycin resistance. J Antimicrob Chemother 2006;58:848–52.

30] Falagas ME, Kastoris AC, Kapaskelis AM, Karageorgopoulos DE. Fosfomycinfor the treatment of multidrug-resistant, including extended-spectrum �-lactamase producing, Enterobacteriaceae infections: a systematic review.Lancet Infect Dis 2010;10:43–50.

31] Lee SY, Park YJ, Yu JK, Jung S, Kim Y, Jeong SH, et al. Prevalence ofacquired fosfomycin resistance among extended-spectrum �-lactamase-producing Escherichia coli and Klebsiella pneumoniae clinical isolates in Koreaand IS26-composite transposon surrounding fosA3. J Antimicrob Chemother2012;67:2843–7.

32] Karageorgopoulos DE, Miriagou V, Tzouvelekis LS, Spyridopoulou K, Daikos GL.Emergence of resistance to fosfomycin used as adjunct therapy in KPC Kleb-

sfomycin pharmacokinetics in the treatment of serious infections in http://dx.doi.org/10.1016/j.ijantimicag.2013.05.018

siella pneumoniae bacteraemia: report of three cases. J Antimicrob Chemother2012;67:2777–9.

33] Gattringer R, Meyer B, Heinz G, Guttmann C, Zeitlinger M, Joukhadar C, et al.Single-dose pharmacokinetics of fosfomycin during continuous venovenoushaemofiltration. J Antimicrob Chemother 2006;58:367–71.