J Antimicrob Chemother 2010; 65: 995 998

doi:10.1093/jac/dkq070 Advance publication 12 March 2010

Extracellular concentrations of fosfomycin in lung tissue

of septic patients
Veronika Matzi 1, Jorg Lindenmann 1, Christian Porubsky 1, Sylvia A. Kugler 2, Alfred Maier 1, Peter Dittrich 3,
Freyja M. Smolle-Juttner 1 and Christian Joukhadar 1,2,4,5*
1

Division of Thoracic and Hyperbaric Surgery, Medical University of Graz, Graz, Austria; 2J&P Medical Research Ltd, Vienna, Austria;
3
Institute of Pharmacology and Toxicology, Karl-Franzens University, Graz, Austria; 4Beth Israel Deaconess Medical Center,
Boston, MA 02215, USA; 5Harvard Medical School, Boston, MA 02115, USA

Received 10 January 2010; returned 10 February 2010; revised 13 February 2010; accepted 15 February 2010
Objectives: The present investigation explored the ability of fosfomycin to penetrate lung tissue of septic
patients by utilizing the microdialysis technique.
Methods: After microdialysis probe insertion into healthy and infected lung tissue, a single intravenous dose of
4 g of fosfomycin was administered.
Results: The mean Cmax, Tmax, AUC0 4 and AUC0 1 for healthy lung were 131.6+110.6 mg/L, 1.1+0.4 h,
242.4+101.6 mg.h/L and 367.6+111.9 mg.h/L, respectively. The corresponding values for infected lung
were 107.5+60.2 mg/L, 1.4+0.5 h, 203.5+118.4 mg.h/L and 315.1+151.2 mg.h/L. The half-life of fosfomycin
ranged from 2.2 to 2.7 h between compartments. The magnitude of lung tissue penetration, as determined by
the ratios of the AUC0 1 for lung to the AUC0 1 for plasma, was 0.63+0.31 and 0.53+0.31 for healthy and
infected lung, respectively.
Conclusions: We conclude that fosfomycin achieves antimicrobially effective concentrations in infected lung
tissue.
Keywords: tissue, penetration, human, microdialysis

Introduction
Previous studies investigating interstitial levels of fosfomycin in
adipose soft tissue, skeletal muscle tissue or cerebrospinal fluid
were performed in diabetic patients and in critically ill subjects.1 4 Other studies examined the concentrations of fosfomycin in the interstitial space fluid of healthy, unaffected soft tissue
in healthy men.5 From these studies, we learned that concentrations of fosfomycin in unaffected and infected soft tissues
or bone are sufficiently high to kill relevant bacteria.1 5
Another important finding was that interstitial tissue levels of
fosfomycin were largely comparable to corresponding free concentrations in plasma or serum.
Hence, the pharmacokinetic profile of fosfomycin is excellently
described for many tissues and clinical conditions except for lung
tissue. Against this background, the ability of fosfomycin to penetrate into human pulmonary tissue is still controversial. Therefore,
the present investigation aimed to address this important clinical

question, particularly at times of increasing resistance rates of

bacteria to traditional anti-methicillin-resistant Staphylococcus
aureus (MRSA) and anti-extended-spectrum b-lactamase (ESBL)
agents. Intravenous fosfomycin is frequently used in Austria,
Brazil, France, Germany, Spain, South Africa and Japan for the
therapy of severe and life-threatening Gram-positive infections
and was recently reported to be a therapeutic option in the
therapy of MRSA and ESBL-producing Enterobacteriaceae
infections.6

Methods
The study was approved by the Ethics Committee of the Medical University of Graz, Austria. All patients were given a detailed description of the
study and their written informed consent was obtained prior to the start
of study-related procedures. The study was performed in accordance
with the Declaration of Helsinki and the Good Clinical Practice Guidelines
of the European Commission.

# The Author 2010. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.
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*Corresponding author. Tel: +43-1-8760432-10; Fax: +43-1-8760432-33; E-mail: christian.joukhadar@jp-medical-research.com

or cjoukhad@bidmc.harvard.edu

Matzi et al.

Sepsis was diagnosed according to the criteria from the American College
of Chest Physician/Society of Critical Care Medicine (ACCP/SCCM) Consensus Conference Committee.7 Conservative treatment options failed to
work well in all patients scheduled for surgical intervention. In these subjects, lateral thoracotomy, decortication, debridement and pulmonary
wedge resection in the case of lung abscess were considered the treatments of choice.

Measurement of interstitial fosfomycin concentrations

and chemical analysis

Pharmacokinetic calculations
Non-compartmental pharmacokinetic analysis was employed for the calculation of missing data points. The main pharmacokinetic parameters
such as half-life at the b-phase (t1/2b), peak concentration (Cmax), time
to reach peak concentration (Tmax) and the area under the
concentration-versus-time curves from time zero to n (AUC0 n) were calculated by use of the linear trapezoidal rule. Commercially available computer software (KineticaTM, version 4.4.1; Thermo Electron Corporation,
Waltham, MA, USA) was employed.

Results and discussion

In total, eight patients (five males and three females) were
studied in the present investigation. The pharmacokinetic
profile of one subject was not eligible for further evaluation,
because of malfunction of microdialysis probes. The mean age
was 58.7 years (range 26 80). Subjects had a mean body
weight of 74.3 kg (range 60 90) and a mean body mass index
of 24 kg/m2 (range 21 28).
Mean values of Cmax, Tmax and AUC0 1 for healthy lung
were 131.6+110.6 mg/L, 1.1+0.4 h and 367.6+111.9 mg.h/L,
respectively, after administration of a single intravenous
dose of 4 g of fosfomycin. The corresponding values for
infected lung were 107.5+60.2 mg/L, 1.4+0.5 h and
315.1+151.2 mg.h/L. The half-life of fosfomycin varied from
2.2 to 2.7 h between compartments. The degree of lung tissue
penetration, as determined by the ratio of the AUC0 1 for lung
to the AUC0 1 for plasma, was 0.53+0.31 and 0.63+0.31 for
infected and healthy tissue, respectively. Fosfomycin was well
tolerated in all subjects. No adverse events related to the study
drug or to microdialysis probe insertion were observed.
In the present study, we were able to show that fosfomycin
penetrates well into the interstitial space fluid of healthy and
infected lung tissue in patients scheduled to undergo elective
thoracotomy due to severe complications of bacterial

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plasma
healthy lung
infected lung

100
32 mg/L
16 mg/L
10

8 mg/L

1
0

2
Hours

Figure 1. Mean pharmacokinetic profiles of fosfomycin in plasma,

infected lung tissue and healthy lung tissue in eight patients after
single intravenous administration of 4.0 g. Error bars are standard
deviations. Horizontal lines indicate different MICs ranging from 8 to
32 mg/L.

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The principles of microdialysis are described in detail elsewhere.8 After a

20 min equilibration period, a single dose of 4 g of fosfomycin (Fosfomycin
SandozTM ; Sandoz, Kundl, Austria) was administered to the patient intravenously over 30 min. Microdialysates and plasma aliquots collected
from venous blood after centrifugation at 1600 g for 10 min were
stored at approximately 708C until analysis.
Fosfomycin concentrations in specimens were determined by the use
of a previously published and modified method using capillary gas
chromatography with nitrogen phosphorous detection following derivatization with N,O-BIS(trimethylsilyl)trifluoroacetamide (BSTFA).9 The limit
of quantification for fosfomycin was 1 mg/L. The intra-day and inter-day
coefficients of variation were ,0.07.

pneumonia. The concentration-versus-time profiles of fosfomycin

in plasma, infected lung tissue and healthy lung tissue are
depicted in Figure 1. The main pharmacokinetic parameters are
summarized in Table 1. Thus, severe inflammation exerted no
clinically relevant effect on the ability of fosfomycin to penetrate
into infected lung tissue (Figure 1), i.e. a finding that is consistent
with reported data from previous investigations in patients presenting either with severe sepsis, cellulitis, deep seated infections, diabetic foot syndrome and bacterial osteomyelitis, or
cerebral infections.1 5,10 Hence, we provide strong evidence
that free fosfomycin in plasma equilibrates almost completely
with the extracellular space fluid of tissues under inflammatory
and normal conditions (Figure 1). The reasons for the ability of
fosfomycin to penetrate into the interstitium of tissues are not
yet fully understood, but may be partly related to its high hydrophilicity, small molecular weight of only 138 g/mol and negligible
plasma protein binding.6
From previous pharmacokinetic/pharmacodynamic experiments, we learned that effective bacterial killing for timedependent antibiotics such as fosfomycin, may be expected when
the MIC for the pathogen is exceeded for at least 40% of the
dosing interval.1,11 With regard to the relatively low dose of 4 g
applied in the present study and considering our pharmacokinetic/
pharmacodynamic calculations (Table 2), these data show that
this criterion is met for infected and healthy lung tissue for
MICs of up to 32 mg/L. However, there was considerable intersubject variability in tissue and plasma pharmacokinetic profiles,
exposing individual subjects to the potential risk of under-dosing.
Such patients may require optimization of fosfomycins dosing
regimen, where shorter dosing intervals or higher doses of up
to 8 g of fosfomycin given two or three times a day should be
considered as an alternative, if subjects present with severe
infection and have a creatinine clearance of .40 mL/min. Total
daily doses of 24 g of fosfomycin are approved for the therapy
of severe and life-threatening infections in Austria, Germany,
Spain, France and elsewhere in the European Union. This
dosing regimen will cover pathogens for which the MIC is

Fosfomycin concentration (mg/L)

Patients

JAC

Fosfomycin in lung tissue

Table 1. Non-compartmental analysis of fosfomycin parameters after administration of a

single intravenous dose of 4 g
Parameter

Plasma (n7)

Healthy lung (n7)

Infected lung (n5)

Cmax (mg/L)
Tmax (h)
AUC0 4 (mg.h/L)
AUC0 1 (mg.h/L)
t1/2b (h)

243.3+58.5
0.33+0
453.0+113.4
665.9+179.5
2.5+0.5

131.6+110.6
1.1+0.4
242.4+101.6
367.6+111.9
2.2+0.8

107.5+60.2
1.4+0.5
203.5+118.4
315.1+151.2
2.7+1.5

Dosing interval (t)

MIC (mg/L)

Plasma (%)

Healthy lung (%)

Infected lung (%)

12 h

8
16
32

104
84
63

78
61
44

74
57
41

8h

8
16
32

157
126
94

116
91
65

110
86
61

32 mg/L for periods much longer than 40% of the dosing interval
in most subjects.
The potential for the development of resistance to fosfomycin
after mono-therapeutic use is an important limitation. Fosfomycin
given at total daily doses of up 24 g may be linked to increased
sodium load and could lead to oedema and augmented potassium excretion necessitating its replacement. On rare occasions
allergic reactions may be observed. Headache, loss of appetite,
thrombophlebitis, visual impairment, nausea and other clinically
less relevant untoward effects may also occur.6
In summary, we demonstrated that the free concentrationversus-time profile of fosfomycin in the interstitium of infected
lung tissue mimics closely the pharmacokinetic profiles determined in plasma and healthy lung tissue indicating that fosfomycin penetrates infected lung tissue effectively.

Acknowledgements
We very much appreciate Dieter Steinorts personal input and significant
dedication to make this interdisciplinary clinical investigation possible.

for pharmaceutical companies. All other authors declare having no

relationship with companies that make products relevant to the manuscript and have no conflicts of interest with the present work.

References
1 Pfausler B, Spiss H, Dittrich P et al. Concentrations of fosfomycin in the
cerebrospinal
fluid
of
neurointensive
care
patients
with
ventriculostomy-associated ventriculitis. J Antimicrob Chemother 2004;
53: 84852.
2 Joukhadar C, Klein N, Dittrich P et al. Target site penetration of
fosfomycin in critically ill patients. J Antimicrob Chemother 2003; 51:
1247 52.
3 Schintler MV, Traunmuller F, Metzler J et al. High fosfomycin
concentrations in bone and peripheral soft tissue in diabetic patients
presenting with bacterial foot infection. J Antimicrob Chemother 2009;
64: 5748.
4 Legat FJ, Maier A, Dittrich P et al. Penetration of fosfomycin into
inflammatory lesions in patients with cellulitis or diabetic foot
syndrome. Antimicrob Agents Chemother 2003; 47: 371 4.

Funding

5 Frossard M, Joukhadar C, Erovic BM et al. Distribution and antimicrobial

activity of fosfomycin in the interstitial fluid of human soft tissues.
Antimicrob Agents Chemother 2000; 44: 272832.

The present work was supported by an unrestricted grant from Sandoz

GmbH, Vienna, Austria.

6 Popovic M, Steinort D, Pillai S et al. Fosfomycin: an old, new friend? Eur J

Clin Microbiol Infect Dis 2010; 29: 127 42.

Transparency declarations
S. A. K. is an employee of J&P MEDICAL RESEARCH LTD, which is an international independent research institute basically operating according to
the PublicPrivate-Partnership concept. C. J. is managing director of
J&P MEDICAL RESEARCH Ltd, owns 100% options, and is also a consultant

7 Bone RC, Balk RA, Cerra FB et al. Definitions for sepsis and organ failure
and guidelines for the use of innovative therapies in sepsis. The ACCP/
SCCM Consensus Conference Committee. American College of Chest
Physicians/Society of Critical Care Medicine. Chest 1992; 101: 1644 55.
8 Joukhadar C, Muller M. Microdialysis: current applications in clinical
pharmacokinetic studies and its potential role in the future. Clin
Pharmacokinet 2005; 44: 895 913.

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Table 2. Calculated values for %T. MIC for plasma, healthy lung and infected lung after
administration of a single intravenous dose of 4 g of fosfomycin for dosing intervals of 12
and 8 h

Matzi et al.

9 Dios-Vieitez MC, Goni MM, Renedo MJ et al. Determination of fosfomycin

in human urine by capillary gas chromatography: application to clinical
pharmacokinetic studies. Chromatographia 1996; 43: 2935.
10 Sauermann R, Karch R, Langenberger H et al. Antibiotic abscess
penetration: fosfomycin levels measured in pus and simulated

concentration-time profiles. Antimicrob Agents Chemother 2005; 49:

4448 54.
11 Craig WA. Pharmacokinetic/pharmacodynamic parameters: rationale
for antibacterial dosing of mice and men. Clin Infect Dis 1998; 26:
1 10.

Downloaded from http://jac.oxfordjournals.org/ at Chulalongkorn University on November 9, 2016

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