Article Title: Current fluconazole
dosing regimens in critically ill adults result in under-exposure during
early
therapy
Short Title: Fluconazole dosing in
critically ill
adults
Indy SANDARADURA1,2,3,4 *, Debbie
MARRIOTT2,3, Richard O DAY3,5, Ross
L G NORRIS5,6,7 Edna PANG5, Sophie
STOCKER3,5 and Stephanie E REUTER8
1 Centre for Infectious Diseases and Microbiology.
Westmead Hospital, Sydney, NSW, AUSTRALIA
2 Department of Microbiology, St Vincent’s Hospital,
Sydney, NSW, AUSTRALIA
3 St Vincent’s Clinical School, University of New
South Wales, Sydney, NSW, AUSTRALIA
4 School of Medicine, University of Sydney, NSW.
AUSTRALIA
5 Clinical Pharmacology & Toxicology, St Vincent’s
Hospital, Sydney, NSW, AUSTRALIA
6 Discipline of Clinical Pharmacology, School of
Medicine & Public Health, University of Newcastle, Newcastle, NSW,
Australia.
7 Hunter Medical Research Institute, Kookaburra
Circuit, New Lambton Heights, NSW, Australia8 UniSA Clinical & Health Sciences, University of
South Australia, Adelaide, SA, AUSTRALIA
*Corresponding author. Email
indy.sandaradura@health.nsw.gov.au
Telephone +61 2 8890 6012 Fax +61 2 9891 5317
Principal Investigator statement: The authors confirm that the
Principal Investigator for this paper is Indy Sandaradura and that he
had direct clinical responsibility for patients.
Word count: 3437 (excluding abstract, references, figures and
supplementary material)
Word count (Abstract): 247
Tables: 2
Figures: 2
References: 32
Electronic supplementary material: 1 table, 4 figures and 1
appendix
Key words: fluconazole, population pharmacokinetics, target
attainment, critical illness
What is already known about this subject:
- A free fluconazole 24 hour area-under-the-curve to minimum inhibitory
concentration (fAUC24/MIC) ratio of ≥100 is associated
with a high clinical cure rate.
- Fluconazole pharmacokinetics in the critically ill demonstrate
significant interpatient variability, particularly in patients
undergoing continuous renal replacement therapy (CRRT) and obese
patients.
What this study adds:
- Early (0-48h) pharmacodynamic target attainment with current
fluconazole dosing regimens in critically ill patients is poor,
particularly in patients who are overweight, have higher renal
function or are undergoing dialysis.
- In general, organisms with an MIC of ≥4 mg/L are not adequately
treated with fluconazole using current dosing strategies.
Abstract:
Aim: To evaluate current
fluconazole dosing regimens against established pharmacodynamic targets
in critically ill adults.
Methods: Data from critically ill adults treated with
fluconazole (n=30) were used to develop a population pharmacokinetic
model. Probability of target attainment (PTA)
(fAUC24/MIC >100) was determined from
simulations for four previously proposed dosing regimens; (i) 400 mg
once daily (ii) a 800 mg loading dose followed by 400 mg once daily,
(iii) 400 mg twice daily and (iv) a 12 mg/kg loading dose followed by 6
mg/kg once daily. The effect of body weight (40, 70, 120 kg) and renal
function (continuous renal replacement therapy (CRRT), 20, 60, 120, 180
mL/min glomerular filtration rates) on PTA was assessed.
Results: Early (0-48 h) fluconazole target attainment for
patients with Minimum Inhibitory Concentrations (MIC) of 2 mg/L was
highly variable. PTA was highest with an 800 mg loading dose for
underweight (40 kg) patients and with a 12 mg/kg loading dose for the
remainder. End-of-treatment PTA was highest with 400 mg twice daily
maintenance dosing for patients who were under- or normal- weight and 6
mg/kg maintenance dosing for overweight (120 kg) patients. None of the
fluconazole regimens reliably attained early targets for MICs of ≥4
mg/L.
Conclusion: Current fluconazole dosing regimens do not achieve
adequate early target attainment in critically ill adults, particularly
in those who are overweight, have higher renal function or are
undergoing CRRT. Current fluconazole dosing strategies are generally
inadequate to treat organisms with an MIC of ≥4 mg/L.
Introduction
Bloodstream infections with Candida spp. are associated with
approximately 28% crude and 11% attributable mortalities.1 In the
critically ill, Candida spp. infections are reported to have
crude and attributable mortalities of up to 60 and 40%, respectively.2Initiation of adequate antifungal therapy within 48h in critically ill
patients with candidemia has been demonstrated to lower mortality,
especially when combined with other therapeutic measures such as removal
of central venous catheters.3Conversely, inadequate dosing of antifungal agents may contribute to
treatment failure and increased mortality.4,5The highly variable drug pharmacokinetics (PK) reported in critically
ill patients attributed to changes in physiology and the use of
extracorporeal devices such as renal replacement therapy6 results
in inadequate exposure from standard doses of antifungal agents.
Since approval by the FDA and European drug licensing authorities in
1990, fluconazole has been the antifungal agent of choice for fungal
infections caused by Candida spp. Fluconazole exhibits linear PK
in the recommended dose range and demonstrates excellent distribution
into various tissues and body fluids.7–9The free drug 24 hour area under the curve to minimum inhibitory
concentration ratio (fAUC24/MIC) is the pharmacodynamic
(PD) parameter which best correlates with clinical outcome with a ratio
of ≥100 being associated with a high clinical cure rate.10 The
fluconazole product information recommends maintenance doses of 50 to
400 mg per day and consideration of a loading dose of double the
maintenance dose to achieve steady state by 48 h.11 By
contrast, treatment guidelines for severe Candida spp. infections
recommend loading doses of 800 mg and maintenance doses of 400 mg per
day. 12Weight based dosing (12 mg/kg loading; 6 mg/kg per day maintenance) has
also been suggested in some treatment guidelines and may be required to
ensure adequate exposure particularly in obese patients.13Finally, renal failure and the use of renal replacement therapies are
common in critically ill patients. Fluconazole doses of 800 mg per day
for patients receiving continuous renal replacement therapy (CRRT) have
been suggested.14–17Generally, the recommended treatment duration for a critically ill
patient with invasive candidiasis is 14 days.12
The efficacy of fluconazole has been questioned after a patient-level
quantitative review of randomized trials investigating treatment
strategies in patients with bloodstream infections.18Patients with Candida albicans infection treated with
echinocandins, on multivariate analysis, had much lower mortality (OR
0.55, 95% CI 0.32-0.95, p=0.03,) than those treated with other agents
to which these organisms were susceptible including fluconazole. In one
of the included studies 44% of patients treated with fluconazole were
critically ill and had a higher chance of death (OR 3.8, 95% CI
1.5-9.6, p=0.006).19Although most of the other studies included in this review did not
report patient status, given what is known about the epidemiology of
candidaemia it is likely that many patients were critically ill.
Therefore, these findings may potentially be attributable to the
favourable PK profile of echinocandins in critical illness20 and
raise the possibility that current fluconazole dosing regimens may be
suboptimal for these patients. Whilst there has been examination of
fluconazole pharmacokinetics in subsets of the critically ill population
such as those with renal failure21 and
those who are obese,22 to
date no study has comprehensively assessed fluconazole exposure across a
heterogenous critically ill population over the entire treatment course.
The objective of this study was to characterise the population PK of
fluconazole during the first 14 days of treatment in a diverse but
representative cohort of adult patients with critical illness. Further,
the product information standard and 3 additional, previously proposed
dosing regimens were evaluated against established PD targets across a
range of minimum inhibitory concentrations (MICs).
Patients and methods
Patients and data
collection
Clinical data, including demographics (age, gender, and weight), routine
clinical biochemistry data such as serum creatinine (Scr) and serum
albumin (ALB) concentrations, and the use of CRRT and extracorporeal
membrane oxygenation (ECMO), were obtained from the medical records of
consecutive adult patients who were treated in the intensive care unit
(ICU) of a tertiary-level teaching hospital in Sydney, Australia between
January 2014 and December 2015. Patients received fluconazole doses
chosen by their treating physician. Each fluconazole dose was infused at
a rate of 200 mg/h in all patients. Blood samples were collected
throughout the dosing interval as part of routine care. For patients not
undergoing CRRT, creatinine clearance (CLCr) was
calculated by the Cockroft-Gault formula using total body weight.23
Biological sample analysis
Total fluconazole concentrations were determined by a validated assay in
a laboratory accredited by the National Association of Testing
Authorities against the ISO 15189 standard. In brief, plasma samples
were prepared by liquid/liquid extraction followed by gas chromatography
with a flame thermionic detector for quantitation. The lower limit of
quantification of fluconazole was 1.0 mg/L, with an accuracy (recovery)
of 100.5% and a coefficient of variation (CV) of 9.0% at this
concentration and 98.7% accuracy, and CV 5.6% at 45 mg/L. Other
biochemical data, including serum creatinine and albumin were determined
by the routine pathology service.
Population PK analysis
The PK model development, evaluation, and validation generally followed
recent guidelines for PKPD modelling.24 The
analysis was conducted in NONMEM® version 7.3 (ICON Development
Solutions, Ellicott City, MD, USA) with a GNU Fortran compiler version
6.1 (GNU Fortran Project, Free Software Foundation, Boston, MA, USA) and
PLT Tools interface version 5.4.0 (PLT Soft San Francisco, CA, USA).
Model visualisation and evaluation was done in R® version 3.4.4 (R
Foundation for Statistical Computing, Vienna, Austria). The model
incorporated population parameter variability and residual unexplained
variability (comprising proportional and/or additive error). Covariance
between population parameter variability was assessed. Biologically
plausible covariates were tested successively for their influence on PK
parameters. Free fluconazole exposure (fAUC24) was
calculated based on unbound plasma concentrations, assuming protein
binding of 12%.25
Model selection was based on a combination of (1) a reduction in
objective function value (OFV) of 3.84 units (Chi-square
[χ2], p < 0.05) for nested models with
one degree of freedom; (2) graphical goodness-of-fit plots; (3) Akaike’s
Information theoretic Criterion (AIC); (4) Bayesian Information
Criterion (BIC); (5) the biological plausibility of the parameter
estimates; and (6) parameter precision. As a visual predictive check
(VPC), 1000 simulated datasets and the 5th, 50th and 95th percentiles of
model-predicted fluconazole concentrations were plotted against observed
data to evaluate the suitability of the final model. For external
validation, the final model was also compared with predictions from 2
other published models in critically ill populations.21,26Published, observed concentration-time data21 were
scanned, extracted using DigitizeIt software (I Bormann, Braunschweig,
Germany) and overlaid on the model predictions for equivalent
populations.
Dosing simulations
To examine current and proposed fluconazole dosing regimens in patients
with critical illness, the final population PK model was used to
simulate datasets for 15,000 patients with representative body weights
(40, 70, 120 kg) and renal function (CRRT, 20, 60, 120, 180 mL/min).
Pharmacodynamic target attainment was defined as
fAUC24/MIC >100. Probability of target
attainment (PTA) was determined for four different dosing regimens at
0-24 h, 24-48 h and at 312-336 h. Daily target attainment was also
determined for an MIC of 2 mg/L over the entire treatment course. The
dosing regimens examined were (i) 400 mg once daily (ii) an 800 mg
loading dose followed by 400 mg once daily, (iii) 400 mg twice daily and
(iv) a 12 mg/kg loading dose followed by 6 mg/kg once daily. A range of
MICs from 0.5 to 8 mg/L were examined, with a focus on the upper limits
of the susceptible range as defined by European Committee on
Antimicrobial Susceptibility Testing (EUCAST), 2 mg/L and Clinical and
Laboratory Standards Institute (CLSI), 4 mg/L. Organisms with these MICs
are deemed by these organisations to be treatable with the standard
fluconazole regimen. Simulations were performed using NONMEM. Data
processing was conducted using R®️.27
Results
Study population and patient
characteristics
A total of 30 critically ill patients were enrolled in the study for
which 130 plasma fluconazole concentrations (median 4, range 2-11
observations per patient) were reported and included in the analysis. No
samples were excluded from the analysis dataset. The characteristics of
the patients are presented in Table 1. Loading doses (800 mg to 1600 mg)
were administered to 63% (19/30) of patients and fluconazole
maintenance doses ranged from 200 mg to 800 mg per day. Albumin
concentrations were low (<36 g/L) in the majority (87%
[26/30]) of patients. Reduced renal function (CLCr<90 mL/min) was documented in 63% (19/30) of patients and 6
of these patients received continuous renal replacement therapy (CRRT).
Extracorporeal membrane oxygenation (ECMO) was undertaken in 17% (5/30)
of patients.
Population PK model building and
evaluation
A one compartment model with first order elimination and a combined
error model was found to best describe fluconazole concentration-time
data (Table S1). Introduction of covariates into the structural model
identified a significant effect of total body weight on volume of
distribution (Vc) and creatinine clearance (CLCr) and
the use of CRRT on clearance (CL). No significant relationships were
observed between fluconazole PK parameters and gender, age and the use
of ECMO. A variance-covariance matrix for the variability in CL and Vd
was included in the final model.
The final model control stream is presented in Appendix S1. The
diagnostic plots used to confirm the appropriateness of the final model
are presented in Figures S1, S2 and S3. Additional model validation
comparing predictions from our model to predicted and observed data from
2 other published population PK models21,26for identical test populations demonstrated good agreement. The final
population PK model is illustrated in Figure 1 and the final model
parameters are summarised in Table 2.
Assessment of dose-exposure
relationship
Probability of target attainment (PTA) at (a) 48 h and (b) end of
treatment for the 4 different fluconazole regimens examined for a range
(0.5 to 8 mg/L) of MICs, stratified by weight and renal function is
presented in Figure S4. For simplicity the results for the two 400 mg
once daily maintenance regimens are presented together in Figure S4 (b)
as their end of treatment PTA is identical. PTA over time for organisms
with an MIC of (a) 2 mg/L and (b) 4 mg/L for the same fluconazole
regimens and patient groups is presented in Figure 2.
Early (0-48h) target
attainment
MIC 2 mg/L
Early target attainment for an isolate with an MIC of 2 mg/L in the
absence of a loading dose was suboptimal (<95%) for most
patients except those who were underweight (40 kg). Target attainment at
0-24 h was highest (97 - 100%) with an 800 mg loading dose for
underweight patients and with a 12 mg/kg loading dose for the remainder.
Even with a 12 mg/kg loading dose target attainment decreased as weight
and CLCr increased and amongst patients with the highest
renal function (CLCr 180 mL/min), only 86% of those who
weighed 70 kg and 90% of those who weighed 120 kg met targets. Target
attainment at 24-48 h for an isolate with an MIC of 2 mg/L was highest
(≥98%) with 400 mg twice daily for patients who were under- or normal-
weight. Overweight patients had the highest target attainment (≥99%)
with 6 mg/kg maintenance dosing. These findings were replicated in
patients on CRRT at 24-48 h.
With the commonly prescribed guideline dose of 800 mg loading dose
followed by 400 mg once daily early target attainment was poor in the
most extreme simulated patients (120 kg, CLCr 120 mL/min
and 120 kg, CLCr 180 mL/min) where only 79 and 72% of
patients respectively met targets at 24-48 h. With this regimen, it took
until 96 h for patients who were 120 kg with a CLCr of
120 mL/min and 288 h for patients who were 120 kg with a
CLCr of 180 mL/min for >95% target
attainment. At 24-48 h target attainment for CRRT patients was variable
(17-61%) after 800 mg loading followed by 400 mg once daily and
decreased over time as the impact of the loading dose was lost.
MIC 4 mg/L
For an isolate with an MIC of 4 mg/ the probability of early target
attainment was low for all the tested fluconazole regimens. At 0-24 h
target attainment was highest (44-77%) with an 800 mg loading dose for
underweight patients and with a 12 mg/kg loading dose for the remainder
(11-31%). Target attainment at 24-48 h for an isolate with an MIC of 4
mg/L was highest (56-99%) with 400 mg twice daily for patients who were
under- or normal- weight. Overweight patients had the highest target
attainment (58-84%) with 6 mg/kg maintenance dosing. Target attainment
decreased with increasing CLCr.
With the commonly prescribed guideline dose of 800mg loading dose
followed by 400 mg once daily early target attainment was negligible in
the most extreme simulated patients (120 kg, CLCr 120
mL/min and 120 kg, CLCr 180 mL/min) where only 1 and 0%
of patients respectively met targets at 24-48 h. With this regimen
>95% target attainment was not achieved during the
treatment course in these patients.
All the tested fluconazole regimens resulted in <7% target
attainment in patients on CRRT at 0-48 h.
End of treatment (336h) target
attainment
End of treatment target attainment was 100% for an isolate with an MIC
of 2 mg/L with 400 mg twice daily maintenance dosing for all patient
groups. The standard maintenance fluconazole dose of 400 mg also
performed well in patients who were not on CRRT with ≥95% target
attainment at the end of treatment. In CRRT patients 400 mg once daily
resulted in ≤24% target attainment whilst 6mg/kg only led to
satisfactory target attainment in overweight patients.
For an isolate with an MIC of 4 mg/L the 400 mg twice daily fluconazole
regimen resulted in >95% of patients who were not
receiving CRRT meeting PD targets. Although this regimen also performed
the best in CRRT patients, <24% met targets. Whilst the
standard maintenance regimen of 400 mg once daily resulted in patients
with impaired renal function (CLCr 20 mL/min) meeting
targets, it proved to be suboptimal in those with normal or augmented
renal function and those on CRRT.
MIC ≤ 1 mg/L target
attainment
The tested fluconazole regimens were found to result in reliable target
attainment for organisms with an MIC of ≤ 1 mg/L in all but the most
extreme CRRT patients. Early target attainment for 120 kg patients
receiving 400 mg once daily was 88% and end of treatment target
attainment for 40 kg patients receiving 6mg/kg maintenance dosing was
79% for isolates with an MIC of 1 mg/L.
Discussion
To date there has been limited study of the population PK of fluconazole
in the critically ill despite the widespread use of the drug in this
population to treat serious infections. Significant interpatient
variability in fluconazole PK has been demonstrated in intensive care
patients (n=57),26 anuric
patients undergoing CRRT (n=10)21 and
obese intensive care patients (n=37)22.
Although each of these studies examined the pharmacokinetics of
fluconazole in a subset of critically ill patients the prevalence of
altered body weight (both malnourishment and obesity), altered renal
function (both augmented and diminished) and the prevalence of renal
replacement therapies and their frequent coexistence in intensive care
patients means that these studies inadequately describe the PK of
fluconazole across the entire critical care population.
In our study the population PK of intravenous fluconazole in critically
ill adult patients was characterised using a one-compartment model.
Although Patel et al fitted their data to a 2 compartment model,
our model adequately describes their data. Consistent with previous
studies,22,26total body weight was a covariate for Vc and CLcr a covariate for CL.
The final parameters in our model for Vc and CL and
CLCRRT are similar to those reported previously.21,26Consistent with this, the model was able to accurately predict the
observed concentrations of fluconazole in intensive care patients and
patients on CRRT. This indicates the generalisability and robustness of
the model to predict fluconazole drug exposure across a broad range of
critically ill patient populations.
Subsequently, the model was used to examine the pharmacodynamic target
attainment of previously described dosing regimens. We have demonstrated
that pharmacodynamic targets are not consistently achieved at 0-48 h in
overweight patients, those with higher renal function or those
undergoing CRRT despite administration of the currently recommended
loading dose (800 mg). Patients with these characteristics are commonly
treated in the intensive care unit and made up 13/30 (43%) of our study
population. Poor early target attainment with standard fluconazole
dosing in a substantial proportion of patients who are critically ill
may in part explain the worse outcomes described in these patients.1,2It is likely that a 12 mg/kg loading dose would perform better in
patients who are not underweight.
We have also demonstrated that whilst 400 mg/day maintenance dosing is
sufficient to reliably treat infections caused by organisms with an MIC
≤2 mg/L, higher doses (400 mg twice daily) are required for patients
receiving CRRT. Although other authors have also suggested higher doses
during CRRT,14–17existing treatment guidelines12 and
drug monographs28,29including the fluconazole product information11 do not
yet make this recommendation. Therefore, most clinicians are unlikely to
be aware of the need to administer higher doses of fluconazole in these
clinical circumstances.
From our data it is apparent that an fAUC24/MIC of
>100 for organisms with an MIC of 4 mg/L would not be
achieved reliably during the early stages of therapy with any one
current or proposed fluconazole dosing regimen in patients with critical
illness. Higher maintenance doses (400 mg twice daily) than those
currently in use would also be required for end of treatment target
attainment in patients who are not receiving CRRT. Although the use of
several different dosing regimens based on weight, renal function and
fluconazole MIC may improve target attainment across the population,
successful implementation of dosing advice for the variable regimens
needed to accommodate the relevant, individual covariates of critically
ill patients’ will present logistic challenges.
In a recent multicentre Australian study, organisms with MICs of 2 and 4
mg/L accounted for 12% and 2% respectively of all Candida
albicans bloodstream infections.30 In
current laboratory practice these organisms are deemed to be amenable to
treatment with the standard fluconazole regimen, indicating to
clinicians a high probability of success. Given the significant risk of
mortality associated with these infections, clinicians treating
critically ill patients need to be mindful of the poor early target
attainment in some patients with current and proposed fluconazole dosing
regimens.
Several potential limitations of this study must be considered. The
first is our choice of fAUC/MIC >100 as the PD threshold
predictive of a good outcome. Although this is used by many clinicians
and supported by EUCAST, other authors have proposed thresholds ranging
from ≥11.519 to
≥400. 31Utilising a higher PD threshold would mean that even fewer patients
would attain targets with current dosing regimens, whilst a lower PD
threshold would result in most patients being adequately treated. A
second limitation is that we estimated free fluconazole concentrations
rather than measuring them. Changes in protein binding are known to
occur during critical illness. However, it is those drugs which are the
most highly bound where free drug concentrations become the most
difficult to predict and small absolute changes may result in large
proportional changes.32 Given
the relatively low extent of fluconazole protein binding, the impact on
the results is unlikely to be significant.
Conclusions
This population pharmacokinetic analysis strongly indicates that
fluconazole dosage should be optimized in terms of weight,
CLCr and CRRT in critically ill patients in order to
ensure pharmacodynamic target attainment for organism MICs of 2 mg/L.
Whilst we were able to support the EUCAST clinical breakpoint of
>2 mg/L when only considering end of treatment target
attainment, it was apparent that patients with higher renal function,
those undergoing CRRT and those who are overweight require increased
doses to attain these same targets early and maximise the chance of
achieving a good clinical outcome. Conversely, it is likely that lower
doses would be sufficient to attain these targets in underweight
patients and those with lower renal function. In the interests of
stewardship of existing antimicrobial agents, it is critical to ensure
that the use of established drugs such as fluconazole is optimised
before relegation in favour of newer (and usually more expensive)
options. As no single current or proposed fluconazole dosing regimen
resulted in optimal exposure across the studied critically ill
population, further clinical studies with optimised dosing of
fluconazole using population PK are warranted.
Transparency
declarations:
Ethical approval and consent to participate
The study was approved by the Institutional Human Research Ethics
Committee (LNR/14/SVH/148).
Availability of supporting data
The data used for this research are available from the corresponding
author on reasonable request and subject to Institutional Ethics
Committee guidelines.
Competing interests
None to declare
Funding
This research was supported by an Australian Government Research
Training Program (RTP) Scholarship to IS. Work undertaken by S.E.R. is
with the financial support of Cancer Council’s Beat Cancer Project on
behalf of its donors, the State Government through the Department of
Health, and the Australian Government through the Medical Research
Future Fund.
Authors’ contributions
IS designed the study, collected data, conducted pharmacokinetic
modelling, performed data analysis and prepared the manuscript. ROD
assisted with study design. DM conceived the study. EP and RLGN
supervised analysis of plasma concentrations and assisted with data
collection. SER supervised pharmacokinetic modelling and data analysis.
All of the authors reviewed the manuscript.
Acknowledgements
The preliminary results of this study were presented at the World
Conference of Pharmacometrics 2016 (Poster 217).
The authors wish to thank the Department of Intensive Care, St Vincent’s
Hospital and the TDM laboratory, Sydpath for their assistance with
collection and assaying of specimens respectively.
References:
1. Chen S, Slavin M, Nguyen
Q, et al. Active surveillance for candidemia, Australia.Emerg Infect Dis 2006; 12: 1508–16.
2. Eggimann P, Garbino J,
Pittet D. Epidemiology of Candida species infections in critically ill
non-immunosuppressed patients. Lancet Infect Dis 2003;3: 685–702.
3. Puig-Asensio M, Pemán J,
Zaragoza R, et al. Impact of therapeutic strategies on the
prognosis of candidemia in the ICU. Crit Care Med 2014;42: 1423–32.
4. Labelle AJ, Micek ST,
Roubinian N, Kollef MH. Treatment-related risk factors for hospital
mortality in Candida bloodstream infections. Crit Care Med 2008;36: 2967–72.
5. Zilberberg MD, Kollef MH,
Arnold H, et al. Inappropriate empiric antifungal therapy for
candidemia in the ICU and hospital resource utilization: a retrospective
cohort study. BMC Infect Dis 2010; 10: 150.
6. Roberts JA, Abdul-Aziz MH,
Lipman J, et al. Individualised antibiotic dosing for patients
who are critically ill: challenges and potential solutions. Lancet
Infect Dis 2014; 14: 498–509.
7. Pappas PG, Kauffman CA,
Andes D, et al. Clinical practice guidelines for the management
of candidiasis: 2009 update by the Infectious Diseases Society of
America. Clin Infect Dis 2009; 48: 503–35.
8. Charlier C, Hart E, Lefort
A, et al. Fluconazole for the management of invasive candidiasis:
where do we stand after 15 years? J Antimicrob Chemother 2006;57: 384–410.
9. Thaler F, Bernard B, Tod
M, et al. Fluconazole penetration in cerebral parenchyma in
humans at steady state. Antimicrob Agents Chemother 1995;39: 1154–6.
10. Rodriguez-Tudela JL,
Almirante B, Rodriguez-Pardo D, et al. Correlation of the MIC and
Dose/MIC Ratio of Fluconazole to the Therapeutic Response of Patients
with Mucosal Candidiasis and Candidemia. Antimicrob Agents
Chemother 2007; 51: 3599–604.
11. Anon. DIFLUCAN.Product Information 2014. Available at:
http://labeling.pfizer.com/ShowLabeling.aspx?id=575.
Accessed January 5, 2017.
12. Pappas PG, Kauffman CA,
Andes DR, et al. Clinical Practice Guideline for the Management
of Candidiasis: 2016 Update by the Infectious Diseases Society of
America. Clin Infect Dis 2016; 62: e1–50.
13. Alobaid AS, Wallis SC,
Jarrett P, et al. What is the effect of obesity on the population
pharmacokinetics of fluconazole in critically ill patients?Antimicrob Agents Chemother 2016. Available at:
http://dx.doi.org/10.1128/AAC.01088-16.
14. Bergner R, Hoffmann M,
Riedel K-D, et al. Fluconazole dosing in continuous veno-venous
haemofiltration (CVVHF): need for a high daily dose of 800 mg.Nephrol Dial Transplant 2006; 21: 1019–23.
15. Muhl E, Martens T, Iven
H, Rob P, Bruch H-P. Influence of continuous veno–venous
haemodiafiltration and continuous veno–venous haemofiltration on the
pharmacokinetics of fluconazole. Eur J Clin Pharmacol 2000;56: 671–8.
16. Pittrow L, Penk A. Dosage
adjustment of fluconazole during continuous renal replacement therapy
(CAVH, CVVH, CAVHD, CVVHD). Mycoses 1999; 42: 17–9.
17. Yagasaki K, Gando S,
Matsuda N, et al. Pharmacokinetics and the most suitable dosing
regimen of fluconazole in critically ill patients receiving continuous
hemodiafiltration. Intensive Care Med 2003; 29:
1844–8.
18. Andes DR, Safdar N,
Baddley JW, et al. Impact of treatment strategy on outcomes in
patients with candidemia and other forms of invasive candidiasis: a
patient-level quantitative review of randomized trials. Clin
Infect Dis 2012; 54: 1110–22.
19. Baddley JW, Patel M,
Bhavnani SM, Moser SA, Andes DR. Association of fluconazole
pharmacodynamics with mortality in patients with candidemia.Antimicrob Agents Chemother 2008; 52: 3022–8.
20. Muilwijk EW, Schouten JA,
van Leeuwen HJ, et al. Pharmacokinetics of caspofungin in ICU
patients. J Antimicrob Chemother 2014; 69: 3294–9.
21. Patel K, Roberts JA,
Lipman J, Tett SE, Deldot ME, Kirkpatrick CM. Population
pharmacokinetics of fluconazole in critically ill patients receiving
continuous venovenous hemodiafiltration: using Monte Carlo simulations
to predict doses for specified pharmacodynamic targets. Antimicrob
Agents Chemother 2011; 55: 5868–73.
22. Alobaid AS, Wallis SC,
Jarrett P, et al. Population Pharmacokinetics of Piperacillin in
Nonobese, Obese, and Morbidly Obese Critically Ill Patients.Antimicrob Agents Chemother 2017; 61. Available at:
http://dx.doi.org/10.1128/AAC.01276-16.
23. Cockcroft DW, Gault MH.
Prediction of creatinine clearance from serum creatinine. Nephron1976; 16: 31–41.
24. Nguyen THT, Mouksassi
M-S, Holford N, et al. Model Evaluation of Continuous Data
Pharmacometric Models: Metrics and Graphics. CPT Pharmacometrics
Syst Pharmacol 2017; 6: 87–109.
25. Debruyne D, Ryckelynck
JP. Clinical pharmacokinetics of fluconazole. Clin Pharmacokinet1993; 24: 10–27.
26. Aoyama T, Hirata K,
Hirata R, et al. Population pharmacokinetics of fluconazole after
administration of fosfluconazole and fluconazole in critically ill
patients. J Clin Pharm Ther 2012; 37: 356–63.
27. R Development Core Team.
R: A language and environment for statistical computing. 2017. Available
at:
https://www.R-project.org/.
28. Nett J, Andes D.
Fluconazole. In: Kucers’ The Use of Antibiotics Sixth Edition.
CRC Press, 2010; 1806–23.
29. Anon. Fluconazole:
Dosing/Administration. Micromedex 2016. Available at:
http://www.micromedexsolutions.com/.
Accessed January 5, 2017.
30. van Hal SJ, Chen SC-A,
Sorrell TC, Ellis DH, Slavin M, Marriott DM. Support for the EUCAST and
revised CLSI fluconazole clinical breakpoints by Sensititre® YeastOne®
for Candida albicans: a prospective observational cohort study. J
Antimicrob Chemother 2014; 69: 2210–4.
31. Brosh-Nissimov T, Ben-Ami
R. Differential association of fluconazole dose and dose/MIC ratio with
mortality in patients with Candida albicans and non-albicans bloodstream
infection. Clin Microbiol Infect 2015; 21: 1011–7.
32. Roberts JA, Pea F, Lipman
J. The clinical relevance of plasma protein binding changes. Clin
Pharmacokinet 2013; 52:
1–8.