Journal of Antimicrobial Chemotherapy (2004) 53, 848–852

DOI: 10.1093/jac/dkh158
Advance Access publication 31 March 2004

Concentrations of fosfomycin in the cerebrospinal fluid of

neurointensive care patients with ventriculostomy-associated
ventriculitis

Bettina Pfausler1, Heinrich Spiss1, Peter Dittrich2, Markus Zeitlinger3, Erich Schmutzhard1 and
Christian Joukhadar3,4*
1Department
of Neurology, University Hospital, Innsbruck; 2Department of Pharmacology and Toxicology,
Karl-Franzens-University, Graz; 3Department of Clinical Pharmacology, Division of Clinical Pharmacokinetics,
University of Vienna Medical School, Allgemeines Krankenhaus, Waehringer Guertel 18-20, A-1090 Vienna;
4Institute of Pharmacology, University of Vienna, Vienna, Austria

Received 1 December 2003, returned 23 December 2003; revised 26 January 2004; accepted 2 February 2004

Objective: The present study was performed to test the ability of fosfomycin to penetrate into the CSF of
neurointensive care patients with ventriculostomy-associated ventriculitis.
Patients and methods: Six patients requiring neurointensive care monitoring, including extraventricular
drainage due to secondary obstructive hydrocephalus, were enrolled into the study. All patients received 8 g
of fosfomycin intravenously three times a day over a period of at least 5 days. Concentrations of fosfomycin
in the CSF and plasma were measured after single-dose administration and at steady state.
Results: Mean values of the fosfomycin area under the time–concentration curves for the dosing interval of
8 h (AUC8) were 929 ± 280 and 225 ± 131 mg·h/L for plasma and CSF after single-dose administration, respect-
ively (P < 0.03). The ratios of the AUC8 for CSF to the AUC8 for plasma were 0.23 ± 0.07 after a single dose and
0.27 ± 0.08 following multiple doses (P > 0.05, not significant). Additional in vitro experiments have shown
that fosfomycin exerts non-concentration-dependent microbial growth inhibition. At steady state, the time
above MIC (t > MIC) values were 98%, 92% and 61% for pathogens with MIC values of 8, 16 and 32 mg/L,
respectively.
Conclusion: The present pharmacokinetic study indicates that 8 g of fosfomycin three times per day should
provide sufficient antimicrobial concentrations in the CSF for the overall treatment period. Thus, the
co-administration of fosfomycin could be useful for the treatment of ventriculitis caused by susceptible
pathogens.

Keywords: CSF, intensive care, pharmacokinetics, humans

Introduction Fosfomycin is a bactericidal antimicrobial agent with high in vitro

activity against a range of Gram-positive and distinct Gram-negative
Severe brain infections require immediate administration of anti- bacteria, such as Pseudomonas aeruginosa,2 Escherichia coli3 and
biotics that effectively combat prevalent pathogens. However, in other Enterobacteriaceae.4 Tissue concentrations of fosfomycin were
some cases empirical antibiotic therapy fails to kill the causative identical to plasma levels in healthy volunteers,5 and differed only
pathogen. This can be attributed to an inadequate choice of anti- moderately in critically ill patients and diabetics.6,7 Thus, although
microbial agent, impaired penetration of the drug into tissues, or to there was almost complete plasma-to-tissue equilibration for tissues
the development of bacterial resistance during antimicrobial therapy. in these patients, we had no knowledge of concentrations of fosfo-
In particular, impaired penetration of antibiotics into brain tissue and mycin in the CSF of patients with ventriculitis. Previous pharmaco-
CSF has been observed in patients with extraventricular drainage kinetic (PK)/pharmacodynamic (PD) simulations have raised the
(EVD) and presenting with ventriculitis.1 speculation that optimal microbial killing by fosfomycin in tissues is
..................................................................................................................................................................................................................................................................

*Corresponding author. Tel: +43-1-40400-2981; Fax: +43-1-40400-2998; E-mail: christian.joukhadar@univie.ac.at

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848
JAC vol.53 no.5 © The British Society for Antimicrobial Chemotherapy 2004; all rights reserved.
 CSF kinetics of fosfomycin
not necessarily linked to high Cmax values, as fosfomycin exerts
non-concentration-dependent microbial growth inhibition.5,6,8 These
PK/PD characteristics of fosfomycin would, theoretically, compen-
sate for impaired penetration of fosfomycin into brain tissues as
long as concentrations in brain tissue and CSF exceed MIC values for
causative pathogens for a distinct period.
Thus, the present study addressed the ability of fosfomycin to
penetrate into the CSF of patients with EVD-associated ventriculitis
after single-dose administration and at steady state. In addition, we
aimed to show in vitro that fosfomycin exerts concentration-
independent growth inhibition of a select model strain of methicillin-
susceptible Staphylococcus aureus.
Materials and methods
The study protocol was approved by the Ethics Committee of the University
of Innsbruck Medical School and was performed in accordance with the
Declaration of Helsinki (1964) in the revised version of 1996 (Somerset-
West), the Guidelines of the International Conference of Harmonization,
the Good Clinical Practice Guidelines and the Austrian drug law. The
study met all criteria set by the local ethics committee for patients who
were unable to give written consent because of incapacity or being
comatose.
Patients
Six Caucasian patients (two women and four men) with severe haemor-
rhage infarction (n = 1) or acute subarachnoid haemorrhage (n = 5)
requiring EVD due to obstructive hydrocephalus were treated with
broad-spectrum intravenous antibiotic therapy. Patients’ demographic
and laboratory data are shown in Tables 1 and 2. Bacterial ventriculitis
was diagnosed based on the isolation of pathogens in the CSF, on inflam-
matory parameters in plasma, and elevated counts of leucocytes and pro-
tein levels in the CSF. Methicillin-susceptible Staphylococcus aureus
(MSSA) was identified in two patients, and methicillin-susceptible
Staphylococcus epidermidis (MSSE) was found in two other patients. No
pathogen was isolated in the CSF of two patients (Table 2). In these two
patients, ventriculitis was diagnosed based on a significant increase in
granulocytes in the liquor, a decrease in the ratio of glucose in liquor to
serum, an increase in protein concentration in liquor and positive MSSE
blood cultures. Fosfomycin was administered at a dosage of 8 g three
times a day. No interaction of fosfomycin with concomitantly adminis-
tered drugs occurred. Each patient underwent common diagnostic and
therapeutic intensive care measures.
Measurement of fosfomycin concentrations
Total fosfomycin levels in plasma and CSF were determined by a
previously published but modified gas chromatography method.9 The
coefficients of variation were 7.0% at 6 mg/L, 6.6% at 240 mg/L and
2.2% at 480 mg/L (n = 4). The limit of detection was 1 mg/L. Intra-day
and inter-day coefficients of variations were <7%.
Study protocol
Patients received 8.0 g of fosfomycin three times a day over a period of at
least 5 days. Eight grams of fosfomycin dry powder (Fosfomycin
‘Biochemie’, 8.0 g, Trockenstechampulle, Biochemie, Vienna, Austria)
was reconstituted with 200 mL of sterile water just before dosing and
administered to patients. Study drug was administered over a period of
∼30 min. The sampling interval was 1–2 h over a period of 8 h after the
first drug administration of fosfomycin. Thereafter, the blood and CSF
samples were collected at 2 h intervals. After 24 h of treatment, steady-
state conditions of fosfomycin were reached and the sampling interval
849
was extended to 4 h. Sampling of CSF and plasma was continued for up to
180 h after first drug administration. All samples were stored at –80°C
until analysis.
PK calculations
PK analysis was performed using the commercially available computer
software Kinetica 3.0 (Innaphase Sarl, Paris, France). All parameters
were calculated using non-compartmental analysis. Area under the con-
centration time–curve (AUC) values for plasma and CSF were calculated
from non-fitted data by employing the linear trapezoidal rule. The
volume of drug distribution (V) and clearance (CL) were calculated for
plasma by use of standard formulae as follows: V = dose/AUCtotal × kel,
CL = kel × V; where kel represents the elimination rate constant. The half-
life calculated for the terminal slope (t1/2β) was calculated by the equation
t1/2β = ln(2)/kel.
The following PK parameters were determined: AUC, maximum
concentration (Cmax) and time to maximum concentration (Tmax). Main
PK data are summarized in Table 3.
In vitro experiments
Bacterial strain and antibiotic. S. aureus was obtained from the American
Type Culture Collection (ATCC 29213). Between experiments,
S. aureus was stored in liquid nitrogen until use. Fosfomycin was
purchased from Biochemie (Austria) and was stored, handled and
prepared according to the manufacturer’s guidelines. In all experiments,
glucose-6-phosphate (Boehringer Mannheim, Germany) was added at a
concentration of 25 mg/L according to the NCCLS guidelines.10
Susceptibility tests. The MIC was determined by a two-fold serial Muel-
ler–Hinton microdilution method, according to NCCLS criteria.10 S.
aureus was pre-cultured overnight on a Columbia agar plate (Columbia +
5% sheep blood; bioMérieux, France) and then introduced into Mueller–
Hinton broth (MHB; Mikrobiologie Mueller-Hinton Bouillon, Merck,
Germany) at an initial inoculum of ∼5 × 105 cfu/mL. The lowest concen-
tration of fosfomycin, which inhibited visible bacterial growth after 20 h
of incubation at 37°C, was defined as the MIC value.
Time–kill curves. Bacterial growth inhibition curves were obtained by
inoculating MHB with ∼5 × 105 cfu/mL of S. aureus ATCC 29213 at
defined fosfomycin concentrations. Samples were drawn and bacteria
counted at defined time-points over a period of 8 h. The bacterial growth
inhibition period of 8 h was chosen because of the three-times daily
dosing regimen of fosfomycin with a dosing interval of 8 h. After vortex-
ing the culture tubes, two 50 µL samples were drawn and serially diluted
with 0.9% sodium chloride. Twenty microlitres of each fraction was
plated onto Columbia agar plates, which were incubated for 24 h at 37°C.
Afterwards the colonies were counted and back-extrapolated to the
original volume to determine the number of cfu/mL. Controls present
bacterial growth in MHB when no antibiotic was added.
Statistical calculations
For statistical comparison of PK parameters, paired Wilcoxon tests were
employed. All PK data are presented as means ± S.D. A two-sided P value
<0.05 was considered significant.
Results
Patients
Six patients were enrolled in the study. Patient diagnosis on admis-
sion identified pathogens for EVD ventriculitis; the demographic and
 B. Pfausler et al.

Table 1. Demographic data are presented as means ± S.D. concentrations following single- and multiple-dose administration
(Table 3 and Figure 1; P < 0.03). Steady-state conditions of fosfo-
Parameters Pre-treatment Post-treatment mycin were reached in plasma and CSF after administration of the
third intravenous dose. The mean ratios of the AUC8 for CSF to the
Sex (female/male) 2/4 2/4 AUC8 for plasma were 0.23 ± 0.07 and 0.27 ± 0.08 after single and
Age (years) 53 ± 8 53 ± 8 multiple doses, respectively (Table 3; P = 0.17, not significant).
Weight (kg) 71 ± 9 ND Mean Cmax values were 260 ± 85 mg/L and 43 ± 20 mg/L for plasma
Body mass index (kg/m2) 24.0 ± 1.6 ND and CSF, respectively, following single dose administration of 8 g of
Leucocyte count (109/L) 12.5 ± 2.4 9.1 ± 1.5 fosfomycin (P < 0.03). After multiple doses of fosfomycin, mean
Fibrinogen (mg/dL) 616 ± 72 470 ± 46 Cmax values were 307 ± 101 mg/L for plasma and 62 ± 38 mg/L for
Serum creatinine (mg/dL) 0.82 ± 0.24 0.82 ± 0.23 CSF (P < 0.03). Main PK parameters of fosfomycin for plasma and
C-reactive protein (mg/dL) 13.2 ± 4.5 1.9 ± 1.0 CSF are presented in Table 3.
Cell count in liquor/mm3 757 ± 421 26 ± 8
Protein in liquor (g/L) 146 ± 35 64 ± 27
Glucose liquor/serum ratio 0.39 ± 0.08 0.77 ± 0.07 Safety and tolerability
Study drug administration was well tolerated by all patients. No study
ND, not determined.
drug-related severe adverse events were observed during the
patients’ stay at the neurointensive care unit.

laboratory data are presented in Tables 1 and 2. All patients com-
pleted the study and were included in safety analysis.
In vivo experiment
Specimens were collected at defined time-points. However, in some
individuals, sampling of specimens was incomplete or deviated
somewhat from the time schedule. The ‘sawtooth’ levels of fosfo-
mycin in the CSF (Figure 1) resulted from the flushing of the CSF
drain every 2 h with ∼3 mL of physiological saline solution. This was
carried out to avoid blocking of the drainage system by blood cells.
For this reason, 3 mL of CSF was drawn every 2 h and the drain was
subsequently rinsed with saline solution. This procedure, however, is
not routine in all intensive care units and concentrations of fosfo-
mycin are expected to be ∼15% higher in liquor if the EVD is not
periodically flushed with saline solution.
The time–concentration courses of fosfomycin for plasma as well
as for CSF were not significantly different after single and multiple
doses (Figure 1; P > 0.12; not significant). Concentrations of fosfo-
mycin in CSF were consistently lower than corresponding plasma
Bacterial growth inhibition experiment
Bacterial growth inhibition of S. aureus ATCC 29213 by fosfomycin
at different concentrations is presented in Figure 2. Initial inhibition
of growth of S. aureus was observed for all fosfomycin concen-
trations used. Similar and effective bacterial growth inhibition was
detected for all fosfomycin concentrations that were equal to or
higher than the strain’s MIC value (2 mg/L), which indicates that
fosfomycin exerts non-concentration-dependent antimicrobial effects.
At steady state, the calculated time above MIC (t > MIC) values
for CSF were 98%, 92% and 61% for pathogens with MIC values of
8, 16 and 32 mg/L, respectively.
Discussion
One of the most important mainstays in the therapy of severe brain
infections is the administration of antimicrobial agents that are
known to reach effective concentrations in the CSF and brain tissue.
This issue becomes particularly important when looking at recent
reports that have linked the development of bacterial resistance to

Table 2. Patients’ characteristics and concomitant therapya

Duration of Duration of
Age Antibiotic Haemodynamically fosfomycin therapy ventriculitis
Patient no. Sex (years) Underlying disease Pathogen co-treatment active drugs (days) (days)

1 F 47 subarachnoid MSSA amikacin dopamine, dobutamine, 9 5

haemorrhage ceftazidime phenylephrine
2 M 61 subarachnoid MSSE penicillin G dopamine, dobutamine, 9 7
haemorrhage clindamycin norepinehrine
3 M 50 subarachnoid MSSE amikacin dopamine, norepinephrine 10 6
haemorrhage ceftazidime
4 F 63 subarachnoid none netilmicin dopamine, phenylephrine 8 4
haemorrhage ceftazidime
5 M 43 cerebral infarction none penicillin G none 10 5
clindamycin
6 M 56 subarachnoid MSSA clindamycin none 10 4
haemorrhage ceftazidime

aSix
patients were studied.
MSSA, methicillin-susceptible Staphylococcus aureus.
MSSE, methicillin-susceptible Staphylococcus epidermidis.

850
 CSF kinetics of fosfomycin

with single-dose administration, although the limited number of

Figure 1. Time–concentration profiles of fosfomycin for plasma (open circles)
and CSF (filled squares) after single and multiple intravenous doses of 8 g over 30
min in neurointensive care patients (n = 6). Each arrow indicates intravenous
administration of fosfomycin. The solid horizontal lines represent MIC values for
pathogens. Data are shown as means ± S.D.
subinhibitory antibiotic concentrations11–13 at the target site. Against
this background, we set out the present study and addressed the pene-
tration properties of fosfomycin into the CSF in neurointensive care
patients with EVD-associated ventriculitis.
In the present study, we found that fosfomycin exerts non-concen-
tration-dependent bacterial growth inhibition of S. aureus (Figure 2).
The antimicrobial effect of fosfomycin on Gram-negative bacteria
has not been explored in the present study, but previous experiments
from our group have shown that fosfomycin kills strains of Entero-
bacter cloacae and Serratia marcescens comparable with S. aureus.5
Thus, we expect that the antimicrobial effect of fosfomycin on
susceptible Gram-negative bacteria is comparable with Gram-posi-
tive pathogens. Steady-state conditions were observed after the third
intravenous dose of fosfomycin, but the plasma-to-CSF equilibration
was not complete (Figure 1). Concentrations of fosfomycin in the
CSF were ∼four-fold lower in comparison with plasma (P < 0.03).
This is indicated by the ratio of the AUC8 for CSF to the AUC8 for
plasma of 0.23 ± 0.07 and 0.27 ± 0.08 after single and multiple dose
administration, respectively. Peak concentrations of fosfomycin
increased by ∼18%–40% in plasma and CSF at steady state compared
patients and the high inter-individual variability did not allow for sta-
tistical confirmation of this trend (P not significant).
This important finding confirms previous data derived from
patients with brain infections.14,15 Thus, there is evidence that pene-
tration of fosfomycin into the CSF is restricted. This, most probably,
is due to the hydrophilic character of fosfomycin, the partially intact
blood–brain barrier and the presence of transport pumps, such as
P-glycoprotein that actively act against plasma-to-tissue equilibration.
Our observation of incomplete fosfomycin plasma-to-CSF equili-
bration might be of clinical relevance because β-lactams and fosfo-
mycin exert optimal bacterial killing when the time above the MIC
(t > MIC) of the respective target is optimized (Figure 2). Exceeding
the MIC over a dosing interval of 60%–70% (t > MIC) is considered
the lower threshold value for favourable clinical and bacteriological
outcome.16,17 Several recent clinical studies suggested that t > MIC
should almost cover 100% of the dosing interval for ‘difficult-to-
treat’ pathogens, although studies in animal infection models have
found that t > MIC does not necessarily need to reach this value to
exert a significant antimicrobial effect,18–21 providing that unbound
drug levels are used for these calculations. Thus, at steady state,
fosfomycin appears to be highly effective when considering calcu-
lated t > MIC values of unbound fosfomycin in the CSF as values of
98%, 92% and 61% will be reached for bacteria with MIC values of
8, 16 and 32 mg/L, respectively. These MIC values do not include
MSSE, but cover frequently isolated bacteria such as methicillin-
resistant S. aureus (MRSA),22 MSSA,22 Streptococcus species6,22,23
and Enterobacteriaceae.15 Nevertheless, it is recommended to
administer fosfomycin in combination with other classes of anti-
microbial agents to improve antimicrobial activity and to avoid the
development of resistance.24 Cephalosporins as a class have been
suggested for combined use with fosfomycin2,25 because of their
similar tissue and plasma PK profiles in healthy volunteers5 and
critically ill patients.6 The antimicrobial efficacy of the simultaneous
administration of cephalosporins with fosfomycin versus mono-
therapy with fosfomycin to intensive care patients has currently been
demonstrated in vitro.2
One might expect the ability of hydrophilic compounds such as
fosfomycin—and the class of cephalosporins—to penetrate the CSF

Table 3. Main PK parameters calculated for the study population (n = 6)

Single dose Multiple doses

Parameters plasma CSF plasma CSF

AUC8 CSF/AUC8 plasma 0.23 ± 0.07 0.27 ± 0.08

AUC8 (mg·h/L) 929 ± 280a 225 ± 131 1035 ± 383b 295 ± 179
Cmax (mg/L) 260 ± 85a 43 ± 20 307 ± 101b 62 ± 38
Tmax (h) 1.2 ± 0.4a 3.8 ± 1.8 1.5 ± 1.2 4.5 ± 2.7
t1/2β (h) 3.0 ± 1.0 ND 4.0 ± 0.5 ND
CL (L/h) 7.4 ± 2.3 ND 5.0 ± 2.0 ND
V (L) 30.8 ± 10.2 ND 26.3 ± 9.7 ND

Data are presented as means ± S.D.

aP < 0.05 compared with CSF single dose.
bP< 0.05 compared with CSF multiple dose.

Cmax, the maximum concentration of fosfomycin; Tmax, the time to reach Cmax; t1/2β, the termi-
nal elimination half-life; AUC, area under the concentration–time curve; CL, total body clear-
ance; V, apparent volume of distribution; ND, not determined.

851
 B. Pfausler et al.
Figure 2. Growth inhibition versus time curves of a select S. aureus ATCC 29213
strain, which was exposed to different fosfomycin concentrations over a period of
8 h.
and brain tissue, to decrease in the course of treatment because of the
reconstitution of the blood–brain barrier. As a consequence, the
combination of fosfomycin with lipophilic antimicrobial agents,
such as the fluoroquinolones,26 appears to be a particularly important
approach to assure that at least one antimicrobial agent sufficiently
penetrates the CSF, even if the blood–brain barrier has recovered.
However, we have demonstrated that the ability of the hydrophilic
agent fosfomycin to penetrate into the CSF remains unaffected over a
period of more than 5 days, despite progressive healing and the
improvement of ventriculitis (Table 3 and Figure 1).
In conclusion, the present study has shown that, with the exception
of MSSE, effective concentrations of fosfomycin can be demon-
strated in the CSF, covering a range of clinically relevant bacteria,
including MRSA, MSSA, Streptococcus species and Enterobac-
teriaceae. Thus, CSF pharmacokinetics of fosfomycin indicate that
fosfomycin might qualify for the management of severe brain
infections in neurointensive care patients with ventriculostomy-
associated ventriculitis. Nevertheless, fosfomycin should be admin-
istered in combination with other classes of antimicrobial agents to
avoid the development of bacterial resistance.
References
1. Pfausler, B., Spiss, H., Beer, R. et al. (2003). Treatment of
staphylococcal ventriculitis associated with external cerebrospinal fluid
drains: a prospective randomized trial of intravenous compared with
intraventricular vancomycin therapy. Journal of Neurosurgery 98, 1040–4.
2. Zeitlinger, M. A., Marsik, C., Georgopoulos, A. et al. (2003). Target
site bacterial killing of cefpirome and fosfomycin in critically ill patients.
International Journal of Antimicrobial Agents 21, 562–7.
3. Ungheri, D., Albini, E. & Belluco, G. (2002). In-vitro susceptibility of
quinolone-resistant clinical isolates of Escherichia coli to fosfomycin
trometamol. Journal of Chemotherapy 14, 237–40.
4. Garcia-Rodriguez, J. A., Trujillano, M. I., Baquero, F. et al. (1997).
In vitro activity of fosfomycin trometamol against pathogens from urinary
tract infections: a Spanish multicenter study. Journal of Chemotherapy 9,
394–402.
5. Frossard, M., Joukhadar, C., Erovic, B. M. et al. (2000). Distribution
and antimicrobial activity of fosfomycin in the interstitial fluid of human
soft tissues. Antimicrobial Agents and Chemotherapy 44, 2728–32.
6. Joukhadar, C., Klein, N., Dittrich, P. et al. (2003). Target site penetra-
tion of fosfomycin in critically ill patients. Journal of Antimicrobial Chemo-
therapy 51, 1247–52.
852
7. Legat, F. J., Maier, A., Dittrich, P. et al. (2003). Penetration of
fosfomycin into inflammatory lesions in patients with cellulitis or diabetic
foot syndrome. Antimicrobial Agents and Chemotherapy 47, 371–4.
8. Grif, K., Dierich, M. P., Pfaller, K. et al. (2001). In vitro activity of
fosfomycin in combination with various antistaphylococcal substances.
Journal of Antimicrobial Chemotherapy 48, 209–17.
9. Dios-Vieitez, M. C., Goni, M. M., Renedo, M. J. et al. (1996).
Determination of fosfomycin in human urine by capillary gas chromato-
graphy: application to clinical pharmacokinetic studies. Chromatographia
43, 293–5.
10. National Committee for Clinical Laboratory Standards. (2002).
Performance Standards for Antimicrobial Susceptibility Testing—Twelfth
Informational Supplement M100-S12. NCCLS, Wayne, PA, USA.
11. Gould, I. M. & MacKenzie, F. M. (2002). Antibiotic exposure as a
risk factor for emergence of resistance: the influence of concentration.
Journal of Applied Microbiology 92, Suppl., 78S–84S.
12. Huovinen, P. (2002). Macrolide-resistant group A Streptococcus—
now in the United States. New England Journal of Medicine 346, 1243–5.
13. Dagan, R., Klugman, K. P., Craig, W. A. et al. (2001). Evidence to
support the rationale that bacterial eradication in respiratory tract infection
is an important aim of antimicrobial therapy. Journal of Antimicrobial
Chemotherapy 47, 129–40.
14. Brunner, M., Reinprecht, A., Illievich, U. et al. (2002). Penetration
of fosfomycin into the parenchyma of human brain: a case study in three
patients. British Journal of Clinical Pharmacology 54, 548–50.
15. Kuhnen, E., Pfeifer, G. & Frenkel, C. (1987). Penetration of fosfo-
mycin into cerebrospinal fluid across non-inflamed and inflamed menin-
ges. Infection 15, 422–4.
16. Hyatt, J. M., McKinnon, P. S., Zimmer, G. S. et al. (1995). The
importance of pharmacokinetic/pharmacodynamic surrogate markers to
outcome. Focus on antibacterial agents. Clinical Pharmacokinetics 28,
143–60.
17. Scaglione, F. (2002). Can PK/PD be used in everyday clinical
practice? International Journal of Antimicrobial Agents 19, 349–53.
18. Craig, W. A. (1995). Interrelationship between pharmacokinetics
and pharmacodynamics in determining dosage regimens for broad-
spectrum cephalosporins. Diagnostic Microbiology and Infectious Disease
22, 89–96.
19. Vogelman, B., Gudmundsson, S., Leggett, J. et al. (1988). Corre-
lation of antimicrobial pharmacokinetic parameters with therapeutic
efficacy in an animal model. Journal of Infectious Diseases 158, 831–47.
20. Leggett, J. E., Fantin, B., Ebert, S. et al. (1989). Comparative anti-
biotic dose-effect relations at several dosing intervals in murine pneumo-
nitis and thigh-infection models. Journal of Infectious Diseases 159, 281–
92.
21. Roosendaal, R., Bakker-Woudenberg, I. A., van den Berg, J. C.
et al. (1985). Therapeutic efficacy of continuous versus intermittent
administration of ceftazidime in an experimental Klebsiella pneumoniae
pneumonia in rats. Journal of Infectious Diseases 152, 373–8.
22. Van der Auwera, P., Godard, C., Denis, C. et al. (1990). In vitro
activities of new antimicrobial agents against multiresistant Staphylo-
coccus aureus isolated from septicemic patients during a Belgian
national survey from 1983 to 1985. Antimicrobial Agents and Chemo-
therapy 34, 2260–2.
23. Takahashi, A., Yomoda, S., Tanimoto, K. et al. (1998). Strepto-
coccus pyogenes hospital-acquired infection within a dermatological
ward. Journal of Hospital Infection 40, 135–40.
24. Pardo, Z. A., Gimeno, B. L. & Andonegui, O. J. (1977). Evaluation
of fosfomycin in an intensive care unit. Chemotherapy 23, Suppl. 1, 411–5.
25. Borowski, J. & Linda, H. (1977). Combined action of fosfomycin
with β-lactam and aminoglycoside antibiotics. Chemotherapy 23, Suppl.
1, 82–5.
26. Pea, F., Pavan, F., Nascimben, E., et al. (2003). Levofloxacin dis-
position in cerebrospinal fluid in patients with external ventriculostomy.
Antimicrobial Agents and Chemotherapy 47, 3104–8.
–