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CE: Swati; QCO/310603; Total nos of Pages: 11;

QCO 310603

REVIEW
URRENT
C
OPINION

How to optimize antibiotic pharmacokinetic/
pharmacodynamics for Gram-negative
infections in critically ill patients
Aaron J. Heffernan a,b, Fekade B. Sime b,
Fabio S. Taccone c, and Jason A. Roberts b,d,e

Purpose of review
Optimized antibiotic dosing regimens improve survival rates in critically ill patients. However, dose
optimization is challenging because of fluctuating antibiotic pharmacokinetics both between patients and
within a single patient. This study reviews the pharmacokinetic changes that occur in critically ill patients,
along with the pharmacodynamics and toxicodynamics of antibiotics commonly used for the treatment of
Gram-negative bacterial infections to formulate a recommendation for antibiotic dosing at the bedside.
Recent findings
Recent studies highlight that critically ill patients do not achieve therapeutic antibiotic exposures with
standard antibiotic dosing. Although dose increases are required, the method of administration, such as the
use of b-lactam antibiotic continuous infusions and nebulized aminoglycoside administration, may improve
efficacy and limit toxicity. In addition, the increased availability of therapeutic drug monitoring and
antibiotic dosing software allow the formulation of individualized dosing regimens at the bedside.
Summary
When prescribing antibiotic doses, the clinician should consider antibiotic pharmacokinetic and
pharmacodynamic principles. Before initiating high-dose antibiotic therapy, therapeutic drug monitoring
may be considered to assist the clinician to optimize antibiotic treatment and minimize potential toxicity.
Keywords
antibiotics, dose optimization, pharmacodynamics, pharmacokinetic, sepsis, septic shock

INTRODUCTION
Many advances in the management of Gram-negative bacterial sepsis are related to enhanced recognition and prompt administration of an appropriate
antibiotic [1,2]. The importance of an appropriate
antibiotic dose cannot be understated. There is a clear
association between antibiotic exposure and probability of treatment success, although robust prospective clinical evidence is lacking [3 ,4]. However,
selecting the antibiotic dose that achieves the target
exposure is challenging in critically ill patients [5].
Antibiotic doses recommended in the product information are often derived from studies in healthy
volunteers. These dosing regimens are unlikely to
achieve therapeutic antibiotic concentrations in critically ill patients in the ICU because of profound and
variable physiological changes that occur in patients
that may be infected with pathogens that are less
susceptible to antibiotic therapy [6,7].
We will review the pharmacokinetics of commonly prescribed antibiotics used for the treatment
&

of critically ill patients with Gram-negative bacterial
infections and the antibiotic exposures (concentrations) required for both therapeutic efficacy and
toxicity. These concepts will be integrated to provide methods to optimize antibiotic dosing.

a
School of Medicine, Griffith University, Gold Coast, bCentre for Translational Anti-Infective Pharmacodynamics, School of Pharmacy, The
University of Queensland, Woolloongabba, Queensland, Australia,
c
Department of Intensive Care, Erasme Hospital, Universite Libre de
Bruxelles, Bruxelles, Belgium, dFaculty of Medicine, University of Queensland Centre for Clinical Research, The University of Queensland and
e
Department of Intensive Care Medicine and Pharmacy Department,
Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia

Correspondence to Professor Jason A. Roberts, PhD, Faculty of Medicine, Level 8 University of Queensland Centre for Clinical Research,
The University of Queensland, Royal Brisbane and Women’s Hospital
Campus, Butterfield St, Herston, QLD 4029, Australia.
E-mail: j.roberts2@uq.edu.au
Curr Opin Infect Dis 2018, 31:000–000
DOI:10.1097/QCO.0000000000000494

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QCO 310603

Gram-negative infections

KEY POINTS
Clinicians should consider using supranormal doses to
ensure therapeutic exposures are achieved in critically
ill patients.
TDM will assist with dose selection and mitigate
toxicity risks.

killing and clinical efficacy are related to the ratio
of the maximum concentration to the MIC (Cmax/
MIC) [6]. For time-dependent antibiotics, such as
b-lactam antibiotics, bacterial killing is optimized
when the unbound (or free) antibiotic concentration exceeds the MIC throughout the dosing interval ( fT>MIC) [3 ]. When bacterial killing and clinical
outcomes are described by a mixed concentration
and time-dependent effect, as with the fluoroquinolones, the relevant PK/PD ratio is the area under
the antibiotic concentration–time curve, typically
over a 24-h period, to the MIC (AUC0–24/MIC)
(Table 1, Fig. 1) [19].
At initial patient presentation, the causative
pathogen and the associated MIC are generally
unknown. Thus, we would recommend setting the
target PK/PD ratio considering an MIC equal to the
clinical breakpoint, which will have the greatest
probability of ensuring a therapeutic exposure
against pathogens for which the antibiotic is
intended to be effective [39 ]. This approach allows
the implementation of PK/PD targets in settings that
do not provide a pathogen MIC. If an MIC less than
the clinical breakpoint is identified, it is not advised
to reduce the dose because of the variability in
the MIC assay, particularly as the MIC may not
represent resistant subpopulations, which may
contribute to treatment failure in some patients
[39 ,40]. Although knowledge of the specific MIC
of a susceptible bacterial pathogen should not
&

Altered dosing strategies that consider the infection
target site may improve therapeutic outcomes.

PHARMACOKINETIC/
PHARMACODYNAMIC RATIOS AND THE
MINIMUM INHIBITORY CONCENTRATION
Pharmacokinetic/pharmacodynamic (PK/PD) ratios
relate the antibiotic concentration–time curve to
the bacterial minimum inhibitory concentration
(MIC) and are correlated with improved clinical
outcomes or enhanced bacterial killing (Table 1)
[19,38]. Given that antibiotic therapy cannot be
guided by a clinical endpoint (measurable marker
of effectiveness) in a timely manner, PK/PD ratios
provide the clinician with an appropriate target to
guide antibiotic dosing; however, the exact PK/PD
target in plasma for a specific antibiotic varies with
the pathogen and site of infection (Fig. 1) [3 ,4].
Aminoglycosides are an example of a concentration-dependent antibiotic whereby the bacterial
&

&&

&&

Table 1. Pharmacokinetic/pharmacodynamic ratios associated with clinical efficacy and toxicity
Type of PK/PD ratio and minimum target
value for clinical efficacy
Antibiotic class

PK/PD ratio

Aminoglycoside

Cmax/MIC

>8

[8–10]

AUC/MIC

>70

[8–10]

fT>MIC

100% 1–4xMIC

[3 ,19–21]

Penicillins

Target value

References

&

PK/PD toxicity threshold
Toxicity
Nephrotoxicity

Threshold

References

Gentamicin/tobramycin
Cmin >1 mg/l; Amikacin
Cmin >5 mg/l

[11–18]

Neurotoxicity

Piperacillin Cmin >64–361 mg/l

[22–24]

Nephrotoxicity

Piperacillin Cmin >452 mg/l

[22]

Cephalosporins

fT>MIC

100% 1–4xMIC

[3 ,21,25,26]

Neurotoxicity

Cefepime Cmin 22 mg/L

[27]

Carbapenems

fT>MIC

100% 1–4xMIC

[19,20,28]

Neurotoxicity

Meropenem Cmin> 64 mg/l

[22]

Nephrotoxicity

Meropenem Cmin >44 mg/l

[22]

Fluoroquinolones

&

AUC/MIC

>125

[29–31]

N/A

Cmax/MIC

>8

[10]

Colistin

AUC/MIC

>50

[32] a

Nephrotoxicity

Css 1.88 mg/l; Cmin 2.42 mg/l

[33]

Polymyxin B

AUC/MIC

N/A

[34]

Nephrotoxicity

Daily dose 250 mg

[35]

Tigecycline

AUC/MIC

>4.5

[36,37]

N/A

AUC, area-under the concentration–time curve over 24 h; Cmax, maximum antibiotic concentration over the dosing interval; Cmin, minimum antibiotic concentration
over the dosing interval; Css, average steady-state antibiotic concentration; f, free drug concentration; MIC, minimum inhibitory concentration; N/A, data
unavailable; PK/PD, pharmacokinetic/pharmacodynamic.
a
Based on animal models of bactericidal activity.

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Optimising antibiotic PK/PD Heffernan et al.

FIGURE 1. Clinical response rates relative to pharmacokinetic/pharmacodynamic targets. BSI, bloodstream infection; cIAI,
complicated intra-abdominal infection; GNB, Gram-negative bacillary infection; HAP, hospital-acquired pneumonia; LRTI, lower
respiratory tract infection; Psa, Pseudomonas aeruginosa; VAP, ventilator-associated pneumonia. Clinical response determined
by clinical cure. §Clinical response determined by microbiological cure. zClinical response determined by survival rates.

change dosing, rapid identification and susceptibility determination are critical for timely antibiotic
selection [41].

Pharmacokinetics in the critically ill
Prescribing a therapeutic antibiotic dose is challenging given the pharmacokinetic changes that occur
in critically ill patients (Supplementary Figure 1,
http://links.lww.com/COID/A26).
The volume of distribution relates the drug
dose following a bolus intravenous injection to
the peak plasma concentration. For hydrophilic
antibiotics, the volume of distribution is often
increased in critically ill patients, potentially necessitating loading doses [5]. The volume of distribution is also influenced by the degree of antibiotic
protein binding. Hypoalbuminaemia occurs in
50% of patients, possibly affecting protein binding
that results in an increased unbound antibiotic
fraction that can change both the volume of distribution and clearance [42–44]. Additionally, extracorporeal membrane oxygenation may increase
the antibiotic volume of distribution; however,
current evidence suggests that dosing recommendations for extracorporeal membrane oxygenation
are equivalent with other critically ill patients
(Table 2) [70].
To facilitate determination of the maintenance
dose, the clearance of the antibiotic should be
considered. Renally cleared antibiotics may have a

decreased clearance in the case of an acute kidney
injury (AKI), or increased in approximately 50% of
patients admitted to the ICU because of augmented
renal clearance (ARC; creatinine clearance 130 ml/
min/1.73 m2) [71,72]. Patients with ARC are more
likely to be younger (age 50 years), male, have a
modified Sequential Organ Failure Assessment score
4 or less, and be admitted because of trauma [72].
Identifying patients with AKI and ARC is challenging. Renal function is mostly estimated using equations based on a serum creatinine concentration;
however, in critically ill patients, these equations
can overestimate the renal function by up to 80% in
patients with AKI [73] and underestimate the renal
function by up to 42% in patients with ARC [74,75].
If available, urine creatinine clearance may improve
renal function estimates to guide antibiotic dosing
[76]. Antibiotic dosing is also influenced by renal
replacement therapy (RRT). RRT is complicated by
the type, duration, dose, and filter used for RRT [77].
Given the complexity and variability in antibiotic
dosing in patients receiving RRT, the reader is
referred to the cited review that provides in-depth
dosing guidance [78].

DOSE OPTIMIZATION AT THE BEDSIDE
Empiric dosing regimens should consider the pharmacokinetic changes in critically ill patients and the
likely target site of the infection [79 ]. A suggested
work flow is outlined in Fig. 2.

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31250–62500 IU CMS/kg
in two to four divided doses daily

Amikacin

Colistin

LD 100 mg; 50 mg q12h

Tigecycline

LD 4/0.5 g, 0.5 h
infusion; 12/1.5 g
continuous infusion over
24 h

LD 2 g, 0.5 h infusion; 3 g
continuous infusion over
24 h

LD 2 g, 0.5 h infusion;
2 g continuous infusion
over 24 h

LD 2 g, 0.5 h infusion; 6 g
LD 2 g, 0.5 h infusion;
continuous infusion over
4 g continuous infusion
24 h
over 24 h
1–2 g q12h

LD 4/0.5 g, 0.5 h infusion;
16/2 g continuous infusion
over 24 h

CLCr 40–60 ml/
min/1.73 m2

400 mg q8h
750 mg q24h #
LD 200 mg; 100 mg q12h

1000 mg q24h or 500 mg q12h

600 mg q8h for up to 48 h
followed by 400 mg q8h

LD 2.5 mg/kg; 1.3–1.5 mg/kg q12h (max daily dose 250 mg)

LD 9 MIU CMS;
3.325 MIU CMS q12h

750 mg q24h #

400 mg q12h

LD 9 MIU CMS;
2.2 MIU CMS q12h

LD 2 g, 0.5 h infusion;
1 g continuous infusion
over 24 h

LD 2 g, 0.5 h infusion;
2 g continuous infusion
over 24 h

30 mg/kg q; dosing interval and subsequent doses dependent on TDM

7 mg/kg q; dosing interval and subsequent doses dependent on TDM
LD 9 MIU CMS; maintenance dose 5.45 MIU CMS q12h

CLCr 20–40 ml/min/
1.73 m2
LD 4/0.5 g, 0.5 h
infusion; 8/1 g
continuous infusion over
24 h

7 mg/kg q; dosing interval and subsequent doses dependent on TDM

LD 2 g, 0.5 h infusion; 4 g
continuous infusion over
24 h

LD 2 g, 0.5 h infusion; 8 g
continuous infusion over
24 h

LD 4/0.5 g, 0.5 h infusion;
24/3 g continuous infusion
over 24 h

CLCr 60–130 ml/
min/1.73 m2

Minimum recommended dose in critically ill patients

[67–69]

[65,66]

[61–64]

[60]

[58,59]

[56,57]

[53–55]

[50–52]

[48,49]

&&

[57 ,58,59]

References

Recommended doses are likely to achieve the desired PK/PD target for most patients with a Gram-negative bacterial pathogen (Enterobacterales for tigecycline and ceftriaxone or Pseudomonas aeruginosa for other listed
antibiotics) with an MIC at the clinical breakpoint.
CMS, colistin methanesulfonate; CLCr, creatinine clearance; IU, international units; LD, loading dose; MIU, million international units; TDM, therapeutic drug monitoring; q36 h, administered every 36 h; q24 h,
administered every 24 h; q12 h, administered every 12 h; q8 h, administered every 8 h; q6 h, administered every 6 h.

500 mg q24h, 0.5–1 h infusion

Levofloxacin

400 mg q12h

15 mg/kg q24h

Tobramycin

0.75–1.25 mg/kg q12h

5 mg/kg q24h

Gentamicin

Ciprofloxacin

5 mg/kg q24h

Meropenem

Polymyxin B

1–2 g q24h

1 g q8h, 0.5 h infusion

Ceftriaxone

2 g q12h, 0.5 h infusion

4/0.5 g q6h, 0.5 h infusion

Current recommended dose

Cefepime

Piperacillin/
tazobactam

Antibiotic

CLCr >130 ml/min/
1.73 m2

Table 2. Suggested empiric dosing regimens for common antibiotics used for the treatment of critically ill patients with Gram-negative bacterial infections

CE: Swati; QCO/310603; Total nos of Pages: 11;

QCO 310603

Gram-negative infections

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Optimising antibiotic PK/PD Heffernan et al.

Diagnosis of infec ous syndrome and likely pathogen(s)

Collec on of pa ent specific informa on:
Pa ent demographics height, weight
Appropriate biological specimens for bacterial culture; crea nine clearance es mates, and markers of illness severity

Selec on of a likely effec ve an bio c for the likely pathogen based on local suscep bility pa erns and considering
pa ent specific factors (e.g. allergy).

Consider the local ins tute an biogram/likely pathogen clinical suscep bility breakpoint in combina on with the
an bio c PK/PD ra o for the minimum dosing target

Prompt administra on of a likely effec ve an bio c at the highest tolerable dose (e.g. meropenem 2 g)

Consider the following when selec ng an appropriate dosing regimen:






An bio c Dosing Programs
Pharmacokine c studies with validated dosing nomograms in cri cally-ill pa ents
Infec on site and an bio c penetra on
Pa ent factors: crea nine clearance, weight, illness severity, intravenous access
Toxicity thresholds limi ng dosing

Therapeu c Drug Monitoring

Toxicity 862

An bio c plasma or
target site concentra on

Elimina ng organ
func on (e.g. crea nine)

Dose adjustment or an bio c cessa on

FIGURE 2. Suggested steps for dose optimization.

Aminoglycosides
Current regimens for empiric sepsis treatment are
unlikely to achieve PK/PD targets for commonly
encountered pathogens in many patients (Table 2)
[57,80,81]. High-dose therapy (Table 2), potentially
in combination with RRT, has been shown to
improve the rate of PK/PD target attainment,
although the safety of high-dose therapy is yet to
be extensively studied [56,82–84]. Where high

doses are used, further doses should be separated
by 36–48 h with therapeutic drug monitoring
(TDM) guiding future dose selection [57].

b-lactam antibiotics
The serum PK/PD target of 100% fT>4xMIC results in
maximal killing against most Gram-negative bacterial pathogens; however, clinical studies have

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Gram-negative infections

shown improved survival rates following exposures
of 100% fT>MIC (Table 1). Achievement of the 100%
fT>1–4xMIC target may be as low as 16% using conventional dosing regimens [85]. One potential strategy includes a loading dose to achieve therapeutic
concentrations within 15 min of treatment initiation, followed by the commencement of a continuous infusion (Table 2) [86–88]. The total daily dose
may be determined using previously published
nomograms or antibiotic dosing software (see below)
and should not be altered when a loading dose is
administered [53,89,90]. This dosing approach has
been associated with improved survival rates in clinical trials [91].
Importantly, the use of a continuous infusion
with standard daily doses may not provide a therapeutic b-lactam antibiotic concentration in patients
with ARC, and thus may require a higher than
standard dose to avoid treatment failure [92]. Furthermore, clinicians must consider the practicalities
of continuous b-lactam antibiotic infusions such as
drug stability (meropenem is stable in 0.9% sodium
chloride for only up to 8 h) and the ‘dead space’ in
the infusion tubing to ensure that the full dose is
administered [93].

Polymyxins
Colistin has complex pharmacokinetics, partly as it
is administered as the prodrug colistin methanesulfonate. Given the delay in conversion of the inactive
prodrug, colistin methanesulfonate, to colistin, a
loading dose is required (Table 2) [58,94]. Maintenance doses are determined by creatinine clearance
and may be administered every 12 h; however, the
optimal dosing interval remains uncertain [58].
Given that the recommended maximum colistin
dose of 4.5 million international units failed to
achieve the target steady-state concentration in
60% of patients with a creatinine clearance at least
80 ml/min/1.73 m2, current dosing strategies are
unlikely to be maximally effective in patients with
ARC [58]. However, the optimal polymyxin PK/PD
target associated with improved clinical outcomes is
yet to be confirmed, although preclinical infection
model data are likely to be predictive [32]. Polymyxin B is an alternative to colistin with more
predictable pharmacokinetics, although clinical
and in-vitro PK/PD data are limited [60,95 ]. For
critically ill patients, an optimal simulated dose of
polymyxin B (1.5 mg/kg twice daily) based on the
colistin PK/PD target (Table 1) exceeds current dosing recommendations [60]. High doses are likely
necessary for optimal clinical outcomes given that
a daily dose of less than 200 mg or less than 1.3 mg/
kg have been associated with increased mortality
&

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[35,60,96]. Given the high rates of nephrotoxicity,
further studies are required to elucidate the benefits
and risks of high-dose polymyxin B [96].

Fluoroquinolones
Ciprofloxacin and levofloxacin may be considered
for the management of Gram-negative bacillary
infections. Most patients receiving ciprofloxacin
400 mg administered intravenously thrice daily
are likely to achieve a therapeutic exposure against
a susceptible pathogen (Table 1) [61–63,81]. However, up to 30% of patients may require at least
600 mg administered thrice daily [61,62,81]. In contrast, levofloxacin at currently studied doses of up
to 1000 mg administered once-daily are unlikely to
achieve therapeutic PK/PD ratios for many Gramnegative pathogens [65,81].

Tigecycline
Currently recommended tigecycline doses are likely
to be insufficient for critically ill patients (Table 2),
and may be a contributing factor to the increased
mortality observed in patients with a bacteraemia
receiving tigecycline compared with other active
antibiotics [97]. Recent evidence suggests that a
200 mg loading dose followed by 100 mg twice daily
are more likely to meet PK/PD targets and is supported by a six-fold increased clinical cure rate in
critically ill patients, predominantly with ventilator-associated pneumonia [67–69].

THE IMPORTANCE OF THE INFECTION
SITE AND ALTERNATIVE ROUTES OF
ADMINISTRATION
It is often assumed that the antibiotic concentration
in the plasma approximates that at the infection
site; however, recent evidence suggests this assumption may be incorrect in certain infectious pathologies (Supplementary Table 1, http://links.lww.com/
COID/A26) [98–128].

Lung
Hydrophilic antibiotics such as aminoglycosides,
polymyxins, and most b-lactam antibiotics have
impaired penetration into the epithelial lining fluid
(ELF), the site of bacterial infection in pneumonia
(Supplementary Table 1, http://links.lww.com/
COID/A26). It is difficult to meet the optimal PK/
PD targets associated with improved outcomes in
the ELF of many patients [129–131]. Nebulized
antibiotic administration is an alternative delivery
method, which can achieve exposures up to 100Volume 31 Number 00 Month 2018

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Optimising antibiotic PK/PD Heffernan et al.

fold that possible with intravenous administration
[132–136]. Small clinical trials have shown
improved clinical cure rates with this approach,
although recent phase III clinical trials of nebulized
amikacin and the combination of amikacin and
fosfomycin have not shown reduced mortality;
however, this may in part be related to trial design
[137 ,138,139 ]. In contrast, lipophilic antibiotics
such as fluoroquinolones and tigecycline achieve
high ELF concentrations with standard therapeutic
dosing.
&

&

Interstitial fluid
Infection most commonly occurs within tissue
interstitial fluid (ISF), and achieving therapeutic
concentrations here is likely to be important for
patient outcomes [140]. Microdialysis methods
allow the determination of unbound antibiotic concentrations in the ISF [141,142]. This method has
been used in clinical studies to demonstrate the
increased ISF concentrations of meropenem and
piperacillin/tazobactam when administered as a
continuous infusion compared with intermittent
bolus dosing [141,142].

Cerebrospinal fluid
Achieving therapeutic antibiotic exposures in the
cerebrospinal fluid is limited by the blood–brain
barrier and pharmacokinetic alterations in critical
illness (Supplementary Table 1, http://links.lww.
com/COID/A26) [143]. To overcome the reduced
penetration, intraventricular administration of preservative-free antibiotics improves the achievement
of target PK/PD ratios at the site of infection and has
been successfully used for aminoglycosides and colistin [144,145]. Given the severity of nosocomial meningitis and difficulties in intraventricular antibiotic
dosing, expert opinion should be sought [146].

THERAPEUTIC DRUG MONITORING AND
ANTIBIOTIC TOXICITY
Although TDM has been traditionally used for monitoring toxicity, it may be implemented to increase
the rate of attainment of therapeutic antibiotic concentrations. The advantages of such an approach
have been demonstrated in a cohort study of
patients with nosocomial pneumonia receiving
dose optimization for aminoglycosides, fluoroquinolones, and b-lactam antibiotics [147]. In this
nonrandomized study, clinical failure (18 vs. 32%;
P < 0.001), mortality (10 vs. 24%; P < 0.001), and
length of stay (12 vs. 15 days; P < 0.008) were significantly less for patients receiving antibiotic TDM

(n ¼ 205) compared with patients not receiving TDM
(n ¼ 433) [147].
TDM is widely available for aminoglycosides;
however, there are variable monitoring practices
[148]. We would recommend peak (1-h postinfusion
cessation) and trough sampling, which may be combined with Bayesian dosing optimization or dose
optimization based on the calculated AUC [149]. In
addition to improving the Cmax/MIC target attainment rate, TDM reduces nephrotoxicity risk, which
is associated with prolonged therapy duration (>3
days) and elevated trough concentrations (Table 1)
[11–18,150]. However, the risk of aminoglycosideinduced nephrotoxicity in patients with severe sepsis or septic shock receiving aminoglycosides dosed
once daily for up to 3 days is similar to those not
receiving aminoglycosides [151].
b-lactam antibiotic TDM is becoming increasingly common, particularly for piperacillin and meropenem [152]. Current protocols dose-adjust based
on a trough concentration taken at steady state
(between 24–48 h after treatment onset) [152].
Some clinical sites have incorporated b-lactam
Bayesian dose adjustment; however, most sites perform a linear dose adjustment, or reduce the dosing
interval to increase the exposure. This approach
has been shown in a randomized controlled trial
to improve the PK/PD target attainment rate for
piperacillin and meropenem [153]. Dose-dependent
b-lactam antibiotic neurotoxicity may limit dose
escalation (Table 1) [22–24,154]. However, the
threshold concentrations for dose-dependent toxicity are generally high, allowing the use of supranormal empiric dosing regimens that can then be
refined with TDM (Table 2).
TDM for other drug classes is not currently widespread. Fluoroquinolones are subject to interpatient
variability like b-lactam antibiotics [61,62]. Patients
with extracorporeal circuits such as RRT or severe
infections may benefit from peak and trough monitoring for AUC determination if this is available
[147,155]. Fluoroquinolones have been associated
with QT interval prolongation and subsequent Torsade de Pointes, the risk of which may be increased
with drug interactions and cardiac disease, albeit there
is no clear dose-response effect [156]. When high-dose
fluoroquinolone therapy is employed, both the QT
interval relative to the heart rate and electrolytes
should be monitored accordingly [157,158].
Colistin is also a likely candidate for TDM,
although complicated laboratory analytical methods limit its clinically feasibility [159]. Further supporting the potential utility of colistin, TDM is the
association of colistin-induced nephrotoxicity in
approximately 10% of patients with a steady-state
concentration 2 mg/l (Table 1) [33,160].

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ANTIBIOTIC DOSING SOFTWARE
Antibiotic dosing software, such as ID-ODS (Optimum Dosing Strategies, Bloomingdale, New Jersey,
USA) [161] and DoseMe (DoseMe Pty Ltd, Houston,
Texas, USA), can assist clinicians by providing a userfriendly interface to utilize previously published
pharmacokinetic models for more accurate antibiotic dosing [38]. A clinician enters patient-specific
data, including antibiotic concentrations, weight,
and creatinine concentration, thus enabling the
prediction of an individualized dosing regimen.
Despite the potential issues outlined in Supplementary Table 2, http://links.lww.com/COID/A26, the
use of pharmacokinetic models incorporated in
readily available packages, combined with clinician
experience, provides a significant advancement in
personalized antibiotic dosing [162].

CONCLUSION
Antibiotic dosing in the critically ill patient is complex. Integrating knowledge about the patient’s
pharmacokinetics, the infecting bacterial pathogen
MIC and site of infection, and antibiotic PK/PD can
improve dosing practices in critically ill patients.
Combining these principles with TDM can provide
individualized dosing that optimizes the probability
of achieving therapeutic exposures, whereas minimizing toxicity.
Acknowledgements
A.J.H. would like to acknowledge funding from a Griffith
School of Medicine Research Higher degree scholarship.
J.A.R. would like to recognize funding from the Australian National Health and Medical Research Council for a
Centre of Research Excellence (APP1099452) and a
Practitioner Fellowship (APP1117065). F.B.S. would like
to acknowledge funding from a University of Queensland
Post-Doctoral Fellowship.
Financial support and sponsorship
None.
Conflicts of interest
There are no conflicts of interest.

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