Abdul Aziz2015 PDF

136
Applying Pharmacokinetic/Pharmacodynamic
Principles in Critically Ill Patients: Optimizing
Efficacy and Reducing Resistance Development
Mohd H. Abdul-Aziz, BPharm1 Jeffrey Lipman, MD1,2 Johan W. Mouton, PhD3,4 William W. Hope, PhD5
Jason A. Roberts, PhD1,2,5
1 Burns, Trauma and Critical Care Research Centre, The University of Address for correspondence Jason A. Roberts, PhD, Burns, Trauma
Queensland, Brisbane, Queensland, Australia and Critical Care Research Centre, The University of Queensland, Level
2 Department of Intensive Care Medicine, Royal Brisbane and Women’s 3, Ned Hanlon Building, Royal Brisbane and Women’s Hospital,
Hospital, Brisbane, Queensland, Australia Herston, Queensland 4029, Australia (e-mail: j.roberts2@uq.edu.au).
Downloaded by: IP-Proxy University_Queensland, University of Queensland. Copyrighted material.

3 Department of Medical Microbiology, Radboud University, Nijmegen
Medical Centre, Nijmegen, The Netherlands
4 Department of Medical Microbiology and Infectious Diseases,
Erasmus MC, Rotterdam, The Netherlands
5 Department of Molecular and Clinical Pharmacology, University of
Liverpool, Liverpool, United Kingdom,
Semin Respir Crit Care Med 2015;36:136–153.
Abstract The recent surge in multidrug-resistant pathogens combined with the diminishing
antibiotic pipeline has created a growing need to optimize the use of our existing
antibiotic armamentarium, particularly in the management of intensive care unit (ICU)
patients. Optimal and timely pharmacokinetic/pharmacodynamic (PK/PD) target at-
tainment has been associated with an increased likelihood of clinical and microbiological
success in critically ill patients. Emerging data, mostly from in vitro and in vivo studies,
suggest that optimization of antibiotic therapy should not only aim to maximize clinical
outcomes but also to include the suppression of resistance. The development of
Keywords antibiotic dosing regimens that adheres to the PK/PD principles may prolong the
► antibiotic clinical lifespan of our existing antibiotics by minimizing the emergence of resistance.
► resistance This article summarizes the relevance of PK/PD characteristics of different antibiotic
► pharmacodynamics classes on the development of antibiotic resistance. On the basis of the available data,
► pharmacokinetics we propose dosing recommendations that can be adopted in the clinical setting, to
► antibiotic dosing maximize therapeutic success and limit the emergence of resistance in the ICU.
Severe infections leading to severe sepsis and septic shock are 54.1%, respectively.2 Despite an emerging trend for improved
prominent causes of morbidity and mortality in critically ill survival over recent years,3–5 the mortality rate in this patient
patients. In a large multicenter point prevalence study in- cohort remains unacceptably high worldwide.6 In the context
volving 1,265 intensive care units (ICUs) across 75 countries, of the financial burden incurred, the United States is currently
51% of ICU patients were classified as infected on the day of spending between $121 and $263 billion annually on critical-
study with a mortality rate of 25.3%.1 Data from a large ly ill patients, which represents more than 8% of the country’s
European ICU study has further corroborated the diagnosis total healthcare expenditure.7
of severe sepsis as a global healthcare crisis, whereby the To address these persisting poor patient outcomes, signif-
condition accounted for 26.7% of ICU admissions.2 In this icant amounts of research have been directed toward opti-
study, the corresponding mortality in patients with severe mizing the provision of care for the critically ill patient.
sepsis and septic shock was of concern, with rates of 32.2 and Indeed, improving antibiotic therapy is a core focus of
Issue Theme Antimicrobial Resistance: Copyright © 2015 by Thieme Medical DOI http://dx.doi.org/
Management of Superbugs; Guest Editor, Publishers, Inc., 333 Seventh Avenue, 10.1055/s-0034-1398490.
David L. Paterson, MBBS, PhD, FRACP, New York, NY 10001, USA. ISSN 1069-3424.
FRCPA Tel: +1(212) 584-4662.
Applying Pharmacokinetic/Pharmacodynamic Principles in Critically Ill Patients Abdul-Aziz et al. 137
treatment of infection-driven pathologies such as sepsis. crease the likelihood of treatment success as well as minimize
There is strong evidence to suggest that optimal antibiotic the emergence of resistance.
therapy may have a greater impact on patients’ survival when
compared with novel treatment strategies such as the use of
Applied Clinical Pharmacology of Antibiotics
activated protein C,8 antithrombin III,9 and intensive insulin
therapy in these patients.10–13 However, the process of Pharmacology is the science of drugs including the study of
optimizing antibiotic therapy can be a daunting challenge drug actions. Two principle areas of pharmacology are PK and
in the ICU for a variety of reasons. Extreme physiological PD. Traditionally, antibiotic dosing and administration were
derangements that can occur from either pharmacological only optimized, in accordance with the PK/PD principles, for
interventions or the natural course of critical illness may alter clinical efficacy (i.e., clinical and microbiological cure) with an
antibiotic concentrations and consequently reduce antibiotic associated collateral damage being the selection of resistant
exposure in critically ill patients.14 In addition, pathogens pathogens. Emerging data are suggesting that the PD-based
that are usually isolated in the ICU differ from the general dosing approach should not only aim to maximize clinical
wards, as they are commonly less susceptible to common outcomes but also to include the suppression of resistance.

antibiotics.15,16 Indeed, antibiotic dosing that does not ac- Indeed, the application of PK/PD principles has been shown to
count for these features is likely to lead to suboptimal minimize the risk of emergence of resistance by avoiding
antibiotic exposure and therapeutic failures. In addition, ineffective antibiotic exposure, which consequently exerts a
suboptimal antibiotic exposure is also highly implicated as selective pressure to pathogens, rather than to eradicate
a contributing factor to the escalation of antibiotic resistance. them.25 This selective pressure causes the elimination of
Resistance to antibiotics certainly is considered a global highly susceptible, but not the more resistant colonies, lead-
healthcare crisis which currently threatens the advances of ing to future colonization and potential infection with poorly
modern medicine.17 susceptible pathogens.
The recent surge in multidrug-resistant (MDR) pathogens
combined with the diminishing antibiotic pipeline has creat- Pharmacokinetic Considerations
ed a growing need to optimize the use of the existing PK refers to the study of concentration changes of a drug over
antibiotic armamentarium, particularly in the ICU. Although a given time period. This branch of pharmacology describes
critically ill patients constitute fewer than 10% of all hospital the rates and processes from absorption to distribution of
admissions, their antibiotic consumption is 10 times greater drugs to elimination mechanism via metabolism or excretion.
compared with patients in all other wards.18–20 The rampant Some of the examples of important PK parameters are (1)
antibiotic use (or misuse) has therefore, in part, contributed volume of distribution (Vd), (2) clearance (CL), (3) maximum
to the alarming increase in the MDR pathogens such as the drug concentration over a dosing interval (Cmax), (4) mini-
extended spectrum β-lactamases and carbapenemase-pro- mum drug concentration during a dosing interval (Cmin), and
ducing gram-negative pathogens. Notably, gram-negative (5) area under the concentration–time curve from 0 to
pathogens such as Acinetobacter baumannii and Pseudomonas 24 hours (AUC0–24). Among these however, alterations in
aeruginosa, as well as members of the Enterobacteriaceae the primary PK parameters, namely Vd and CL, are probably
family such as Escherichia coli and Klebsiella pneumoniae, the most influential in determining altered antibiotic dosing
which were previously considered relatively innocuous, have and exposure. Changes in antibiotic Vd and CL have been
impressively out-maneuvered our current antibiotics. Previ- commonly observed in critically ill patients and the relevance
ously simple infections have become increasingly difficult to of the two phenomena in influencing effective antibiotic
treat over a short period of time.21 Moreover, infections exposure has been reviewed in detail elsewhere.26
caused by these pathogens frequently result in poor clinical
outcomes, including higher mortality and prolonged hospi- Pharmacodynamic Considerations
talisation.22–24 The healthcare community concerns are legit- PD describes the relationship between PK exposure and
imate, as the emergence of resistance is likely to far outpace pharmacological effect. For antibiotics, PD relates the antibi-
the rate of development of new antibiotics. In light of these otic concentration to the ability of an antibiotic to kill or
grim prospects, clinicians are currently forced to reintroduce inhibit the growth of a pathogen. In general, this relationship
older antibiotics as treatment options (e.g., colistin and is often described by linking the concentration of an antibiotic
fosfomycin) and vigorously search for new strategies that with the corresponding minimum inhibitory concentration
can optimize the use of our presently available antibiotics. (MIC) of the offending pathogen. For an antibiotic, it is the free
The aim of this article is to describe the relevance of or unbound concentration that is responsible for the antibi-
pharmacokinetic (PK) exposure and pharmacodynamic (PD) otic activity.27 Numerous studies have demonstrated that
characteristics of different antibiotic classes on the develop- different antibiotics have different PD properties and can
ment of antibiotic resistance. We will discuss the relevant be readily categorized as the following: (1) the duration of
antibiotic resistance descriptors and review how target drug time that free drug concentration remains above the MIC
exposures differ between predicting treatment success and during a dosing interval (fT>MIC), (2) the ratio of Cmax to MIC,
suppressing resistance development. On the basis of these and (3) the ratio of AUC0–24 to MIC. These fundamental PK/PD
current data, we will also suggest dosing strategies that indices for antibiotics’ activity are further illustrated
ultimately exploit antibiotic pharmacodynamics which in- in ►Fig. 1. It should be noted that the AUC/MIC was never
Seminars in Respiratory and Critical Care Medicine Vol. 36 No. 1/2015

138 Applying Pharmacokinetic/Pharmacodynamic Principles in Critically Ill Patients Abdul-Aziz et al.
Concentration-dependent antibiotics (Cmax/MIC)

Cmax e.g. Aminoglycosides, quinolones
Concentration- with/without time-dependence (AUC/MIC)

e.g. Quinolones, aminoglycosides & glycopeptides
AUC
MIC

T>MIC Time-dependent antibiotics (T>MIC)
e.g. Beta-lactams
Cmin
Time (hours)
Fig. 1 The graphical illustration of fundamental pharmacokinetic and pharmacodynamic parameters of antibiotics on a hypothetical
concentration–time curve. AUC, area under the concentration–time curve; Cmax , maximum drug concentration; C min , minimum drug
concentration; MIC, minimum inhibitory concentration; T >MIC , duration of time that drug concentration remains above MIC.
considered in earlier studies, and that many data retrieved cure and not on minimization of the emergence of antibiotic
from older literature established only the relationship be- resistance. To date, most of the data describing PK/PD and its
tween Cmax/MIC and effect parameter. From a theoretical association with antibiotic resistance comes from preclinical,
point of view, most of the antibiotics should show a relation- albeit advanced, PK/PD infection models. However, the anti-
ship with AUC and effect rather than Cmax. biotic exposure required for clinical efficacy and resistance
Based on the PK/PD indices, antibiotics can be classified suppression is markedly different. For instance, the antibiotic
into three categories that, by and large reflect their modes of exposure–response relationship for clinical efficacy is mono-
bacterial killing.28–30 The first category includes antibiotics tonic or can also be described as a sigmoidal relationship in
where the difference between the maximum effect and which no measurable antibiotic effect is expected at lower
minimum effect is relatively large, and increasing concen- drug exposures while larger exposures are expected to aug-
trations result in progressively increased killing. Therefore, ment the bactericidal effect up to a certain threshold. In
these are also sometimes called concentration-dependent contrast, the relationship between antibiotic exposure and
antibiotics, and include aminoglycosides and quinolones. the selection of resistant mutants is markedly non-monotonic
For these antimicrobials, AUC/MIC describes their antibiotic and has the shape of an inverted “U,” where resistant mutants
activity best, and, mainly because AUC/MIC is closely corre- are amplified with initial antibiotic exposure and then slowly
lated to Cmax/MIC, Cmax/MIC as well.31,32 On the other hand, decline with increasing exposure up to an optimal threshold
time-dependent antibiotics’ activity, such as the β-lactams, is that ultimately prevents resistance amplifications.36–39 The
strongly correlated with fT>MIC and as such, prolonging the inverted U-shape seems to follow a log normal distribution.40
duration of effective drug exposure should be the priority In addition, Jumbe et al40 found that an AUC0–24/MIC of 110
when this antibiotic class is used.33,34 However, some anti- for levofloxacin, which was twice that was necessary for
biotics such as the glycopeptides are more complex where optimal bactericidal effect, was required to suppress drug-
they are found to display both concentration- and time- resistant population of P. aeruginosa in a mouse thigh infec-
dependent kill characteristics.34 For these antibiotics, the tion model.41 This information, among other similar obser-
ratio of AUC0–24/MIC describes their antibiotic activity best vations, has indicated that the magnitude of the PK/PD indices
and higher thresholds are closely related to successful clinical for resistance suppression is generally different and higher
outcome.35 than the thresholds required for clinical success.37,42–44
Therefore, antibiotic dosing that only aims to optimize clinical
efficacy may potentially amplify resistance formation by
Pharmacokinetic/Pharmacodynamic
selecting mutant bacterial strains with reduced drug suscep-
Considerations and the Resistance
tibility. With enhanced knowledge on antibiotic PK/PD over
Descriptors
recent years, important hypotheses and concepts, such as the
Most of the earlier research on optimizing antibiotic dosing mutant selection window (MSW) and mutant prevention
was focused only on maximizing clinical and microbiological concentrations (MPCs), have been proposed to provide

potential explanations as to how suboptimal antibiotic expo- The MSW hypothesis is potentially important, as contem-
sure may amplify the selection of resistant bacterial strains. In porary antibiotic dosing tends to produce drug concentra-
addition, the dynamics of bacterial populations under various tions within the critical zone where they selectively amplify
dosing regimens can be described using mixture models, the growth of resistant mutants. Essentially, the higher the
where changes in susceptible and resistant subpopulations percentage of time (t) spent by an antibiotic within the MSW
in relation to drug concentrations are quantified.38,41,42,45,46 (tMSW), the greater the opportunity for resistant mutants to
be selected and amplified. Furthermore, the continuous and
Mutant Selection Window prolonged “careless” practice of “dosing to only cure” in the
The term “selective window” (SW), which was first coined by ICU eventually leads to the resistant mutants being the
Baquero,47,48 refers to a critical range of antibiotic concen- dominant bacterial population and it is only at this point
trations in which drug-resistant bacterial mutants could be that surveillance studies would be alerted to the emergent
selectively enriched and amplified when exposed to concen- resistant isolates. The MSW has been defined for many of the
trations in this zone. Subsequent in vitro studies, utilizing quinolones and some of the β-lactams against various micro-
mycobacteria treated with quinolones, were able to define the organisms.60–62 Nevertheless, this concept is currently con-

boundaries for the critical zone of antibiotic concentrations sidered as a relatively new idea and has not been investigated
and this concept was later renamed as the MSW.49–51 Studies in many infective pathologies, nor its relevance at the site of
that attempted to describe MSW further suggested that these infection. Hence, its clinical relevance in optimizing antibiotic
concentration zones are those between the MIC of the dosing to avoid the MSW remains unclear and warrants
susceptible pathogens and that of the least susceptible further investigation.
mutants. ►Fig. 2 illustrates the concept of MSW and its
relevance in the development of resistant mutants. In addi- Mutant Prevention Concentration
tion to this, the formation of the resistant mutants was The concept of MPC, which was derived from the MSW
observed to be most intense in the bottom portion as opposed hypothesis, refers to the antibiotic concentration that corre-
to the upper portion of the selection window.52 The existence sponds to the MIC of the least susceptible mutants in a
of such “dangerous” concentration zones was further corrob- colony.49,51 While MIC refers to the lower boundary, the
orated by several in vitro39,53–55 and in vivo experimental MPC essentially represents the upper boundary of concen-
studies.56–59 trations in the MSW in which the enrichment of resistant
Fig. 2 Graphical illustration of the mutant selection window and mutant prevention concentration on a hypothetical concentration–time curve.
The MSW describes the range of antibiotic concentrations where resistant mutants may be selectively amplified and these concentration zones are
those between the MIC of the susceptible pathogens and that of the least susceptible mutants, i.e., MPC. In area (A), which is below the MIC, no
resistant mutants are expected to grow, as there is no selective pressure in this area. In area (C), which is above the MPC, the growth of resistant
mutants is severely restricted and highly unlikely as the exposure in the area is able to suppress the growth of the least susceptible pathogens. On
the contrary, the selection of resistant mutants would be most intense in area (B) which is also known as MSW. Conversely, the longer the time
spent by an antibiotic in this concentration zone, the greater the opportunity for resistant mutants to be selected and amplified. Cmax , maximum
drug concentration; C min, minimum drug concentration; MIC, minimum inhibitory concentration; MPC, mutant prevention concentration; MSW,
mutant selection window.

mutants are expected to be severely hindered. Conversely, indices that have been shown to correlate with both outcomes
antibiotic dosing that aims to achieve concentrations higher are presented in ►Table 1.
than the MPC, as opposed to MIC, theoretically provides both
an optimal bactericidal effect and resistance suppression. Quinolones
Furthermore, the ratio of AUC0–24 to MPC (AUC0–24/MPC) as Quinolones are mostly lipophilic antibiotics and display largely
opposed to AUC0–24/MIC is also suggested as a predictor of the concentration-dependent kill characteristics but with some
development of resistance in several in vitro and in vivo time-dependent effects. Previous in vitro studies have shown
evaluations as MIC quantifications generally ignore mutant that the achievement of a Cmax/MIC ratio of at least 8 to 12 is
subpopulations.36,60,63,64 The argument has been mostly important for optimal bactericidal activity.68,69 Given the half-
tested in in vitro studies for quinolones where the mutant- life of most quinolones, this corresponds to AUC0–24/MIC
restrictive thresholds of AUC0–24/MPC were approximately values that correlate to efficacy. More important, however, is
one-third of those AUC0–24/MIC values.39,65 that the index has also been associated with the reduction of
The MPC has been described mostly for quinolones, al- resistant mutants in several experimental studies.70–72
though data for other classes of antibiotics are emerg- Several studies found that the ratio of AUC0–24/MIC is

ing.60,66,67 Quantifying MPC thresholds for individual important for its bactericidal effect, as an even more signifi-
antibiotics should be one of the priorities in the development cant index as compared with the Cmax/MIC ratio, and a ratio of
of dosing guidelines especially earlier in the process of 125 and 30 has been advocated for clinical success in the
evaluation and screening of new compounds. Although the treatment of gram-negative and -positive infections, respec-
concept seems appealing, the application, however, is not tively.71,73–77 In the context of antibiotic resistance, an in-
straightforward, as the doses needed to achieve the MPC are verse relationship has been described between this index and
usually higher than those for curing patients and exceed those the probability of developing resistance.78 Accordingly, quin-
that are registered for those antibiotics. There are also olone dosing regimens that ensure higher ratios of AUC0–24/
examples where these concentrations are unattainable for MIC are currently recommended to maximize bactericidal
some antibiotic–pathogen combination.50,67 In addition, a exposure as well as minimizing the development of resis-
trade-off between an increased risk of adverse effects with tance.38,41,78 Several investigators have further elucidated the
minimizing antibiotic resistance is a difficult consideration in critical AUC0–24/MIC thresholds as being between >100 and
clinical practice. In such cases, combining two or three anti- 200 to suppress the formation of resistant mutants when
biotics with overlapping PD properties may be warranted. these antibiotics are used for gram-negative infec-
tions.41,78,79 However, owing to intrinsic differences between
Application of Experimental Mixture Models various quinolones in selecting resistant strains, the sug-
Mixture models examine resistance development by describ- gested AUC0–24/MIC ratio for resistance suppression may
ing the population dynamics of antibiotic-susceptible and vary between individual agents.71,80
-resistant bacteria during the course of treatment. Suscepti- The AUC0–24/MPC index is also being investigated and the
ble and resistant subpopulations respond differently to dif- advantages over AUC0–24/MIC in the prediction of resistance
ferent antibiotic concentrations. development have been documented in several in vitro
In a murine thigh infection model, Jumbe et al investigated studies.60,63,64 To date, this remains a controversial argument
the impact of bacterial inoculum on the required levofloxacin as most authors found that both indices were similar in their
exposure for the eradication of the total P. aeruginosa popu- predictive potentials of resistance development.57,81 Never-
lation.41 The mice were inoculated with either 107 or 108 theless, higher ratios of AUC0–24/MPC are associated with
bacteria per thigh and levofloxacin was initiated after 2 hours. minimizing the emergence of resistance.
The investigators demonstrated that the exposure intensity Recently, increasing interest and efforts have been focused
which is required for maximal levofloxacin activity increases on the application of MSW concept in the evaluation of
(by two- to fivefold) as the size of the inoculum increases by 1 quinolones dosing regimens. Based on the current data,
log. This phenomenon occurs as a larger bacterial challenge tMSW of 30% should restrict mutant amplification and
constitutes larger population of resistant mutants, which are the index has been studied in several in vitro55,82 and in
less susceptible to antibiotic therapy. The investigators also vivo studies.57,61 Khachman et al further extended this
employed a complex mathematical model to analyze their concept into clinical practice by investigating the appropri-
findings and simultaneously calculate an exposure that ateness of the currently recommended ciprofloxacin dosing
would amplify resistant population and restrict the enrich- in 102 critically ill patients.83 Using Monte Carlo simulations,
ment of the population. A free AUC/MIC ratio of 110 and 36 the probability of target attainment (i.e., 20% tMSW) for the
was predicted to prevent and amplify resistant P. aeruginosa currently recommended ciprofloxacin dosing regimens (i.e.,
mutants in the study, respectively. 800 mg or 1,200 mg/daily) was less than 50% and when
higher doses such as 2,400 mg/daily were used, only minor
improvements were observed, that is, probability of target
Specific Antibiotic Classes
attainment of 61%. More importantly, the risk of selecting
This section discusses individual antibiotic classes and their resistant A. baumannii and P. aeruginosa strains were ex-
pharmacodynamic characteristics, which influence antibiotic tremely high with the recommended regimens, thus chal-
activity and the prevention of resistance. The relevant PD lenging their appropriateness in critically ill patients. As it

Table 1 Optimal pharmacokinetic/pharmacodynamic indices for antibiotic activity and the magnitudes associated with maximal
therapeutic outcomes and resistance suppressiona
Antibiotic class Optimal PK/PD PK/PD magnitude PK/PD magnitude Optimal PK/PD PK/PD magnitude
index for bacterial for clinical efficacyc index for for resistance
killingb resistance suppressiond
suppression
Aminoglycosides AUC0–24/MIC AUC0–24/MIC: 80– AUC0–24/MIC: 50– Cmax/MIC Cmax/MIC 2094
16086,88,90 10089
Cmax/MIC – Cmax/MIC 831,66,87 Cmax/MIC 3094
Penicillins T>MIC 40–50% T>MIC34 40–50% T>MIC T>MIC 40–50% T>MIC62
Cephalosporins T>MIC 60–70% T>MIC34 45–100% tMSW 40% tMSW112
T>MIC32,99,102,103
Carbapenems T>MIC 40% T>MIC34 50–75% T>MIC 40% T>MIC116

T>MIC105,107
tMSW 45% tMSW117
Quinolones AUC0–24/MIC AUC0–24/MIC: 30– AUC0–24/MIC: 35– AUC0–24/MIC AUC0–24/MIC: 100–
20029,76,77 25071,73–75 20038,41
Cmax/MIC Cmax/MIC Cmax/MIC 888 Cmax/MIC Cmax/MIC 470
868,69,72
AUC0–24/MPC AUC0–24/MPC
2260
tMSW 30%
tMSW53,55,59,82
Vancomycin AUC0–24/MIC AUC0–24/MIC: 86– AUC0–24/MIC: 400– AUC0–24/MIC AUC0–24/MIC:
46034 60034,128 20053
Linezolid AUC0–24/MIC AUC0–24/MIC: 50– AUC0–24/
80136 MIC 80137
T>MIC 40% T>MIC136,138 85% T>MIC137
Daptomycine AUC0–24/MIC AUC0–24/MIC: – AUC0–24/MIC AUC0–24/MIC:
388–537149 20053
Cmax/MIC Cmax/MIC: 59– –
94149
Fosfomycin Unknown – – – –
Colistin AUC0–24/MIC AUC0–24/MIC: 50– – – –
65175,176
Abbreviations: AUC0–24/MIC, ratio of area under the concentration–time curve during a 24-hour period to minimum inhibitory concentration;
AUC0–24/MPC, ratio of area under the concentration–time curve during a 24-hour period to the concentration that prevents mutation; Cmax/MIC, ratio
of maximum drug concentration to minimum inhibitory concentration; T>MIC, duration of time that drug concentration remains above the minimum
inhibitory concentration during a dosing interval; tMSW, percentage of time spent by an antibiotic within the mutant selection window.
a
All values refer to the nonprotein bound, free fraction except when indicated otherwise.
b
Data have been summarized from in vivo animal studies and may utilize different infection models employing different bacteria. Where the index is
reported as a range, specific data for the contributing indices, which may have been derived from different studies, can be found in the associated
references. The data also reflect the 2-log kill and in some cases 1-log kill which may or may not coincide with maximum kill.
c
Data have been summarized from clinical studies and may recruit different patient population. Where the index is reported as a range, specific data
for the contributing indices, which may represent PK/PD thresholds for clinical or microbiological cure, can be found in the associated references.
d
Data have been summarized from preclinical studies, which may include in vitro and in vivo experimental infection models employing different
bacteria. Specific data for the contributing indices can be found in the associated references.
e
Values reported here refer to total drug concentration.
stands, a quinolone dosing regimen that maximizes the Aminoglycosides

AUC0–24/MIC ratio should be considered in critically ill pa- Aminoglycosides are hydrophilic in nature and they demon-
tients and by citing ciprofloxacin as an example; the objective strate concentration-dependent kill characteristics.31,84 Al-
may be achieved with a 400 mg 8-hour or 600 mg 12-hour though previous studies have mainly suggested that
regimen. When treating pathogens with high MICs, dose achieving a high Cmax/MIC ratio predicts optimal out-
escalation should be considered while being observant of come,32,85–88 Craig argued that the ratio of AUC0–24/MIC
possible occurrence of dose-related adverse effects. would be more appropriate in describing the antibiotic’s

activity.34 In the 1980s, Moore et al32 suggested that an the gram-positive pathogens. However, clinical data from
aminoglycoside dose that provided a Cmax/MIC ratio of 8 to critically ill patients have not consistently supported these
10 was associated with a higher probability of clinical success targets. Some studies recommend these in vitro exposures to
against gram-negative infections. However, the investigators be the minimum antibiotic exposures required, with patients
chose the index due to their sparse PK sampling times and potentially benefiting from higher and longer antibiotic ex-
consequently, AUC0–24/MIC ratio was not considered in the posures than those previously described in in vitro and in vivo
study. Importantly, high collinearity existed between Cmax studies.33,102–106 It has also been demonstrated that maximal
and AUC. Several investigators have since suggested that the bactericidal activity occurs when drug concentrations are
ratio of AUC0–24/MIC is more likely to be a “better” PD maintained at four to five times the MIC, with higher con-
descriptor for aminoglycosides activity,29,89 in which an centrations providing little added benefit.106–108 Therefore, it
AUC0–24/MIC ratio of 80 to 160 has been advocated for its has been suggested that β-lactam concentrations should be
efficacy.89,90 maintained at least four to five times the MIC for extended
Although higher concentrations enhance aminoglycoside periods during each dosing interval to ensure clinical success,
activity, prolonged exposure of such concentrations may lead particularly in severely ill patients.109

to drug toxicity as well as the development of bacterial It is still inconclusive whether the fT>MIC index predicts
resistance. This type of resistance is known as adaptive β-lactam resistance, although the potential link has been
resistance and is characterized by a slow, but reversible, described in several in vitro44 and in vivo experimental
concentration-independent killing.91–93 Maximizing the studies.62,110 Fantin et al utilized an in vivo animal model
Cmax/MIC ratio seems to reduce the development of adaptive to suggest that the development of resistance against cefta-
resistance and the objective is likely achieved with extended zidime might arise should the drug concentration fall below
daily dosing (EDD) as opposed to the traditional dosing the MIC for more than half of the dosing interval.110 The risk
schemes (i.e., twice or thrice daily dosing).93 In a PD model of developing resistance against a cephalosporin has also
designed to predict aminoglycosides activity against A. bau- been linked to a low AUC0–24/MIC ratio.111 This was further
mannii and P. aeruginosa, Tam et al further quantified the demonstrated by Stearne et al who found that an AUC0–24/
required Cmax/MIC ratio to prevent the resistance develop- MIC of 1,000 was required with ceftizoxime to prevent the
ment.94 In this study, a Cmax/MIC ratio of 20 for a once-daily emergence of resistant Enterobacter cloacae strains.40 In
amikacin dosing regimen and 30 for a 12-hour gentamicin another murine lung infection model, Goessens et al found
dosing regimen was required for suppressing A. baumannii that the growth of resistant E. cloacae strains was correlated
and P. aeruginosa regrowth, respectively. Based on these with prolonged ceftazidime’s tMSW.112
results, it could be inferred that the Cmax/MIC and AUC0–24/ Based on the limited data on resistance suppression,
MIC ratios are the PD indices to consider for suppressing A. β-lactams dosing that targets concentrations greater than
baumannii and P. aeruginosa resistant mutants, respectively. four times the MIC for extended periods would be most
Based on the available data, EDD rather than the tradi- appropriate.113 Importantly, research has shown that the
tional multiple daily dosing of aminoglycosides is currently objective can be obtained via frequent dosing or by utilizing
advocated in an attempt to maximize their therapeutic extended infusion (EI) or continuous infusion (CI). However,
potential and minimize resistance development. Further- the altered dosing schemes may potentially drive the emer-
more, it has been shown in numerous clinical studies95,96 gence of resistance with suboptimal dosing, at least in theory,
and several meta-analyses97,98 that the dosing recommenda- as these approaches tend to increase β-lactams tMSW. In a
tion is indeed appropriate and valid in reducing aminoglyco- recent in vitro hollow-fiber infection model (HFIM) of P.
sides toxicity and may increase the likelihood of successful aeruginosa, Felton et al suggested that EI of piperacillin/
treatment outcomes. Clinical data on these dosing effects on tazobactam was equivalent to intermittent bolus (IB) dosing
development of resistance remain sparse. in terms of the bactericidal effect and the prevention of
resistance.14 However, the target concentration for the two
Beta-Lactams approaches should be different in which the ratio of Cmin/MIC
The β-lactam antibiotics are made up of penicillins, cepha- of 10.4 and 3.4 was required by EI and IB to suppress resistant
losporins, monobactams, and carbapenems. Because of their mutants, respectively.
different spectrum and PD properties, carbapenems will be
discussed separately in the following section. Beta-lactam Carbapenems
antibiotics are generally hydrophilic in nature and display In general, carbapenems have similar PK/PD characteristics
time-dependent kill characteristics. The percentage of fT>MIC when compared with other β-lactam antibiotics. Some stud-
(% fT>MIC) is regarded as the optimal PD index for their activity ies have suggested that unlike other β-lactams, carbapenems
and, as such, maintaining effective drug exposure above the possess a postantibiotic effect (PAE) against gram-negative
MIC should be the priority when this antibiotic class is used.30 bacilli, including P. aeruginosa strains,114 although this could
It has been generally suggested that the % fT>MIC required for not be confirmed in another study.115 This PAE property of
bactericidal effect is 50, 60 to 70, and 40% for penicillins, carbapenems may explain a shorter % fT>MIC for optimal
cephalosporins, and carbapenems, respectively.99–101 In ad- bactericidal activity. Li et al further quantified the % fT>MIC
dition, relatively higher fT>MIC exposures are needed for as >54% to achieve optimal microbiological outcome when
maximal activity against the gram negatives as opposed to meropenem is used in patients with lower respiratory tract

infections.107 In addition, only a ratio of Cmin/MIC of >5 was also described that higher exposures are needed, specifically
significantly associated with clinical and microbiological cure a ratio of AUC0–24/MIC of 578, when treating critically ill
in this cohort of patients. Further, Tam et al used an in vitro patients with septic shock.128 Owing to common clinical
HFIM to demonstrate that a Cmin/MIC of >6.2 was required to practice of measuring trough concentrations when vancomy-
suppress the development of resistant P. aeruginosa mu- cin is used, a trough concentration ranging between 15 and 20
tants.108 The finding was later corroborated by the same mg/L is recommended for optimal outcome in hospital-
group of investigators in a neutropenic mouse infection acquired pneumonia and complicated infections.129,130
model, and in this current analysis, % fT>MIC of >40% was Although scarce data exist, it could be assumed that the
also associated with the selection of resistant mutants.116 development of resistance is linked to suboptimal vancomy-
Recently in an in vitro dynamic model simulating doripenem cin exposure. Through their in vitro PD model, Tsuji et al were
concentrations, Zinner et al found that resistant P. aeruginosa able to conclude that the development of vancomycin-inter-
mutants were likely to be selected at drug concentrations that mediate susceptible S. aureus (VISA) strains was driven by
fell 45% within the MSW (45% tMSW).117 suboptimal vancomycin exposure in the setting of dysfunc-
Similar to the other β-lactam antibiotics, maintaining tional agr locus in S. aureus.131 In addition, the investigators

carbapenem concentrations at four to six times the MIC for also found that the AUC0–24/MIC ratio needed to suppress
extended periods is currently advocated to suppress the resistance for the strains was fourfold higher than that in the
selection of resistant mutants. To achieve this objective, parent strains. Charles et al observed that patients with VISA
prolonging the duration of infusion is generally recom- infections were more likely to present with low vancomycin
mended when the antibiotic is used. However, EI instead of trough concentrations (i.e., <10 mg/L).132 Based on similar
CI is the currently preferred dosing method when carbape- findings to Charles et al’s retrospective data evaluation,133,134
nems are used considering the group’s inherent drug insta- and considering the recommended trough concentrations for
bility in aqueous solutions. With increasing information and successful clinical outcomes in severe infections, vancomycin
emerging data, clear distinction, in the context of stability trough concentrations should also be maintained between
problems, needs to be emphasized between the different 15 and 20 mg/L at all times to suppress resistance emer-
members of the carbapenem group. While imipenem is gence.129 Thus, loading doses of 25 to 30 mg/kg should be
indeed less stable, there are currently no practical reasons considered in critically ill patients to rapidly attain the target
to oppose continuous meropenem infusion, as it has been concentration and certainly, higher vancomycin doses of up
successfully administered up to 8 hours (in a hospital envi- to 40 mg/kg may be important to minimize resistance devel-
ronment) in numerous clinical studies without drug instabil- opment. In addition, doses in excess of 5 g/daily were
ity or degradation reports.118–120 In an in vitro HFIM estimated to be necessary to achieve the target AUC0–24/
examining cell-kill and resistance suppression for three P. MIC ratio when treating VISA infections.135 Increasing knowl-
aeruginosa strains, Louie et al demonstrated that a doripenem edge of the relationship between higher vancomycin expo-
dosing regimen of 1 g infused over 4 hours was the solitary sures and drug toxicities may limit the dosing of this drug to
regimen that was able to completely suppress resistance for limit the emergence of resistance.
the full period of 10 days for wild-type isolates.121 Impor-
tantly, the investigators also reported that the dosing regimen Linezolid
produces concentrations at >6.2 times the MIC which were Linezolid belongs to a class of antibiotics known as oxazoli-
significantly associated with maximal resistance suppression dinones, which was developed for the treatment of gram-
in other evaluations.44,117 In addition, Chastre et al also positive infections. In a murine infection model, Andes et al
observed lower occurrence of resistant P. aeruginosa strains demonstrated that optimal linezolid activity correlates well
arising in patients treated with EI of doripenem when com- with the ratio of AUC0–24/MIC, with a ratio of between 50 and
pared with patients who received conventional imipenem 80 predicting the likelihood of successful treatment out-
dosing in a multicenter, randomized controlled trial of criti- come.136 However, higher clinical success rates may occur
cally ill patients with ventilator-associated pneumonia.122 at AUC0–24/MIC ratio of 80 to 120 for bacteremia, lower
respiratory tract infections and skin structure infections as
Vancomycin reported by Rayner et al.137 Importantly, the investigators
Vancomycin is a glycopeptide antibiotic and is a relatively also showed that the drug exposure required for optimal
hydrophilic drug. Some in vitro123,124 and in vivo animal treatment outcome was also dependent on the site and types
studies125 suggest that the bactericidal activity of the antibi- of infection. In addition, the probability of treatment success
otic is time dependent, whereas some have shown the ratio of appeared likely when linezolid concentrations were main-
Cmax/MIC to be equally important.126 Recently, it has been tained above the MIC for the entire dosing interval. The
generally accepted that achieving a high ratio of AUC0–24/MIC finding corroborated two earlier rabbit endocarditis experi-
would be more predictive of its clinical success. Studies by mental models, which described linezolid as a time-depen-
Moise-Broder et al were the earliest to quantify that a ratio of dent antibiotic where an fT>MIC of 40% is needed for optimal
AUC0–24/MIC of 400 is needed for an optimal bacteriological antibiotic activity.136,138 A 600-mg 12-hour dose is currently
and clinical outcome when treating patients with S. aureus suggested to achieve these PD indices and hence, predicts
respiratory infections.35,127 The findings are consistent with successful treatment outcome. However, it is also imperative
the retrospective data evaluation of Zelenitsky et al and they to emphasize that the antibiotic’s PK is highly

variable,27,115,139–141 particularly in patients with severe resistance is driven by low drug exposures and prolonged
infections, and the phenomenon has, in part, contributed to duration of antibiotic course.162 There has also been some
treatment failures as well as the increased occurrence of debate concerning the rapid development of fosfomycin
adverse events in such patients.137,142 As such, therapeutic resistance when it is used as a monotherapy particularly
drug monitoring (TDM) of linezolid is beneficial in this in nonurinary tract infections. In a murine endocarditis
respect and emerging data are suggesting that general TDM model, Thauvin et al found that the combination of fosfo-
may optimize patient outcomes when linezolid is used in mycin and pefloxacin was more effective in suppressing
critically ill patients. In the context of antibiotic resistance, resistant S. aureus strains emergence when compared
low-dose linezolid (200 mg 12 hourly) has been associated with fosfomycin alone.163 In several in vitro and in vivo
with the development of E. faecium and E. faecalis resistant experimental studies, instances of synergism were also
strains.143 In addition, prior exposure and prolonged line- demonstrated against MRSA when fosfomycin was com-
zolid administration have been suggested to increase the bined with the β-lactams,164,165 linezolid,166 and moxiflox-
likelihood of resistance development.144–146 Nevertheless, acin.167 Combining fosfomycin with β-lactams is also
the development of resistance against the antibiotic has not strongly supported by in vitro data, which describe syner-

been widely reported.147,148 gism between the two antibiotics against P. aeruginosa
infections.168–170 However, whether the in vitro synergism
Daptomycin would translate to increased clinical efficacy remains to be
Daptomycin is the first approved member of the cyclic lip- demonstrated. In a recent prospective study, fosfomycin, in
opeptides with a potent activity against gram-positive patho- combination with colistin, gentamicin, or piperacillin/
gens including methicillin-resistant S. aureus (MRSA) and tazobactam, provided promising bacteriological and clinical
vancomycin-resistant enterococci. In vivo experimental stud- outcome data in the treatment of 11 critically ill patients
ies describe daptomycin to be a concentration-dependent with ICU-acquired infections caused by carbapenem-
antibiotic. The ratio of Cmax/MIC in concert with AUC0–24/MIC resistant K. pneumoniae.171 Based on limited clinical data
has been correlated with its efficacy in several in vivo animal in treating serious infections in the ICU and its high tendency
studies.149–151 Safdar et al used a neutropenic murine thigh for developing resistance, fosfomycin should not be used as a
infection model to characterize the PD characteristics of single agent and the choice of adjunctive antibiotic should be
the antibiotic.149 In the infection model, the Cmax/MIC and appropriately evaluated in future studies.
AUC0–24/MIC ratio required for bacteriostasis ranged from
59 to 94 and 388 to 537 (total drug concentration), respective- Colistin
ly. Similar ratios were required for bacteriostasis in two other Colistin is a polymyxin antibiotic, which is administered
clinical studies, which recruited healthy volunteers.152,153 parenterally as colistin methanesulfonate (CMS). The antibi-
Based on these suggested indices, optimal daptomycin expo- otic has concentration-dependent kill characteristics with a
sure could be expected in most patients with modest dosing significant in vitro PAE against gram-negative pathogens.172
(4–6 mg/kg/d). However, the emergence of daptomycin-resis- In vivo murine studies suggested that the most predictive PD
tant strains has been reported with such dosing regi- index for its bacterial activity, particularly against A. bau-
mens154,155 and some experts recommend the use of higher mannii and P. aeruginosa, is AUC0–24/MIC.173,174 Based on
dosing to curb this issue (i.e., 8–12 mg/kg/d),156 which was observations in several lung infection models, the ratio of
shown to be safe in one retrospective data evaluation157 and AUC0–24/MIC between 50 and 65 has been suggested as the
several case reports.158,159 A duration of therapy exceeding optimal PD target, although higher exposures were also
2 weeks has also been documented to increase the likelihood of described in thigh infection models.175 The heteroresistance
daptomycin resistance.155 phenomenon, the situation whereby resistant subpopula-
tions are present within a strain-considered susceptible
Fosfomycin based on MIC, is an emerging problem for the antibiotic
Fosfomycin, which was discovered more than 40 years ago and has been observed in clinical isolates of A. bauma-
but then forgotten, is a phosphonic acid derivative that nii,176,177 K. pneumoniae,178 and P. aeruginosa.179 Further to
possesses promising in vitro activity against carbapenem- this, rapid resistant mutants formation was demonstrated
resistant K. pneumoniae.160 The introduction of fosfomycin following colistin exposure in two recent in vitro PK/PD
into our current armamentarium of antibiotics was greeted studies mimicking clinical dosing regimens in humans.180,181
with some skepticism due to major setbacks in its initial in This is particularly worrying as Garonzik et al suggested that
vitro evaluation and this has, in part, contributed to its the currently recommended CMS dosing regimen is subopti-
limited acceptance for clinical use. Although there are sug- mal in a population PK analysis of 105 critically ill patients182
gestions that fosfomycin’s bacterial killing appears to be and their findings were corroborated by other investigators
driven by fT>MIC, the optimal PK/PD index relating to its who recruited smaller number of patients.183,184 With in-
activity remains to be established and requires further creasing PK knowledge on the drug, Garonzik et al182 and
investigations.161 In addition, rapid bacterial killing was Plachouras et al184 further described optimized CMS dosing
observed in several static-time kill studies when drug con- regimens in patients with varying degrees of renal function.
centrations were maintained at two to eight times the MIC. The dosing proposed by Plachouras et al184 has now been
Similar to the β-lactams, the development of fosfomycin validated in a critical care setting by Dalfino et al in the

treatment of MDR infections.185 Among the relevant recom- ies,53,200,202,208,209 no randomized clinical trials to date have
mendations concerning CMS dosing is the need for an initial shown that the approach reduces the emergence of resis-
loading dose, as the conversion of the prodrug CMS to the tance. Furthermore, the benefit is particularly difficult to be
active entity of colistin is very slow and adequate colistin demonstrated in clinical evaluations, which frequently re-
exposure may be delayed for a few days. Although theoreti- cruit heterogeneous patient population and are not con-
cally plausible based on its PD characteristics, the adoption of ducted long enough to detect the emergence of resistance.
EDD is not suitable on the basis of the resultant prolonged In the face of rapidly evolving resistance phenomenon, it is
periods of low colistin concentrations leading to the forma- likely that we have to turn our attention to the concept of
tion of heteroresistance.173,174,180 Based on current PK data of rationally optimized combination antibiotic therapy, partic-
critically ill patients182–184,186,187 and in vivo PK/PD experi- ularly in the treatment of severely ill patients in the ICU. In
mental studies,173,174 colistin monotherapy would not be addition, the approach is likely to be important early in the
beneficial in maximizing therapeutic success and preventing course of infection when the inoculum of the infecting
resistance, particularly in patients with moderate-to-good pathogens is the highest.
renal function and for pathogens with MICs of 1. In addition,

a treatment course lasting more than 12 days has been found Duration of Therapy
to be associated with the development of colistin resistance in It has been increasingly shown in preclinical studies that
two recent clinical studies.188,189 prolonged antibiotic administration may play an important
role in the formation of resistant mutants. Conversely, the
longer antibiotic therapy persists, the more challenging it is to
Modifying Treatment Approaches to Prevent
curtail the emergence of resistant pathogens. It has been
Emergence of Resistance
suggested that an antibiotic regimen that lasts for only 4 to
Combination Antibiotic Therapy 5 days should be sufficient to produce maximal bactericidal
Although combining antibiotics is common during the effect with an added benefit of resistance suppression. Ex-
treatment of infection, the relevance of the practice has tending antibiotic exposure to more than 10 days is risky on
been the matter of debate with conflicting conclusions. the basis of resistance development whereby higher drug
Proponents of combination therapy will strongly suggest exposures are needed to suppress resistant mutants in this
that the approach will increase antibiotic exposure via situation and if this threshold is not achieved, treatment
extending coverage across a wider range of potential failure ensues as the resistant population dominates. This
pathogens and, in some clinical evaluations, has been found phenomenon has been described by Tam et al in their in vitro
to improve survival in severely ill patients.190–193 Further model of S. aureus infection which investigated two gare-
strong theoretical reasons to seriously consider a combi- noxin dosing regimens with different intensity, one with an
nation antibiotic approach include antibiotic synergism AUC0–24/MIC ratio of 280 and the other with 100.42 The
which enhances killing potency; combined activity against investigators demonstrated that once the duration of gare-
biofilm-growing pathogens; increasing tissue penetration; noxin exposure increased beyond 5 days, the magnitude of
inhibition of pathogen’s toxin and enzyme production; and dosing needed for suppressing resistant mutants also in-
prevention of resistance development. However, there is creased. The higher dosing regimen was found to suppress
also clinical evidence indicating that combination therapy resistance amplification for 10 days, while the less intense
may not be superior, even harmful in some instan- regimen was only able to demonstrate the ability for 4 to
ces,194–196 as opposed to monotherapy in the treatment 5 days.
of gram-negative bacilli infections.197–199 Based on the At best, the common practice of administering an antibi-
current data, it could be deduced that combination antibiotic for 10 to 14 days is currently based on limited data and
otic therapy may not benefit all patients but rather a select expert opinion rather than it being an evidence-based ap-
patient population with select infections. While monother- proach. However, for some deep-seated infections such as
apy may be sufficient for most patients, critically ill pa- osteomyelitis and endocarditis, prolonged antibiotic courses
tients with severe infections may benefit the most from are essential. Instances of potential benefits from shortening
rationally optimized combination therapy. Although some the duration of antibiotic therapy in reducing the emergence
in vitro infection models200,201 and animal studies202 of resistance while maintaining clinical efficacy have been
clearly indicated benefits behind the approach, unfortu- increasingly described.210–213 Among these findings, Singh et
nately, the vast majority of combination schemes were al demonstrated that patients who received shortened anti-
chosen randomly without considering the preclinical biotic courses (i.e., 3 days) had reduced ICU stays, lower
findings.203 superinfection and resistance rates, as well as lower mortality
In the context of resistance suppression, rationally opti- rates compared with patients who received standard
mized combination therapy may restrict the amplification of courses.213 Further investigations are warranted to elucidate
resistant mutants. Epstein et al204 suggest that the presence the exact duration of therapy that maximizes therapeutic
of more than two antibiotics at the infection loci (with drug outcome and suppresses resistance development. Until con-
concentrations above the MIC), each with a different killing clusive findings are made, antibiotic therapy should “hit
mechanism, would “shut” the MSW and thereby suppress hard” in the early course of infection and “stop early” to
mutant growth.205–207 Apart from several preclinical stud- assist in resistance prevention.

Altered Dosing Approaches cure and not on minimization of the emergence of antibiotic
Optimal and timely PK/PD target attainment has been associ- resistance. With numerous preclinical data indicating that the
ated with the likelihood of clinical success and resistance magnitude of the PK/PD indices for resistance suppression is
suppression in critically ill patients.6 However, organ func- generally higher than the thresholds required for clinical
tion changes that may result from either infectious or nonin- success, antibiotic dosing that only aims to optimize clinical
fectious pathologic processes may alter antibiotics exposure. efficacy may potentially amplify resistance formation by se-
For example, the increase in Vd for hydrophilic antibiotics lecting mutant bacterial strains with reduced drug suscepti-
such as aminoglycosides,214,215 β-lactams,216 glycopepti- bility. Furthermore, the relevance of commonly prescribed
des,135 and linezolid,217 has been extensively documented antibiotic dosing is questionable in severely ill patients as
in critically ill patients. Importantly, this phenomenon leads most dosing recommendations have been derived from studies
to suboptimal antibiotic concentration and may impair the that do not consider the occurrence of pathophysiological
attainment of desired PK/PD targets for optimal activity, changes in critical illness. Therefore, with enhanced knowl-
particularly in the early phase of severe sepsis and septic edge on antibiotic PK/PD over recent years, emerging data are
shock. In this setting, higher initial loading doses of hydro- suggesting that the PD-based dosing approach should not only

philic antibiotics should be applied to compensate for the aim to maximize clinical outcomes but also to include the
volume expansion. In the context of resistance prevention, suppression of resistance. In some antibiotics such as the
the approach may have the potential utility to rapidly reduce quinolones, the PD thresholds needed to prevent the emer-
bacterial burden in the early stage of infection. Tsuji et al gence of resistance is readily described but, unfortunately, is
recently tested the impact of a front-loaded linezolid-dosing often neglected and not implemented in clinical practice,
regimen on bacterial killing and resistance suppression in a while for most antibiotic classes specific research is urgently
HFIM of MRSA infection.218 From a PD standpoint of bacterial needed. To curb the development of resistance, it is likely that
eradication, their findings suggest potential benefits of in- we have to administer “the highest tolerated antibiotic dose”
creasing doses of linezolid early in therapy, although no via alternative dosing strategies and should also consider the
differences were observed in terms of resistance suppression. combined use of multiple antibiotics (that are rationally opti-
Further preclinical studies are necessary to investigate this mized), particularly early in the course of infection in severely
promising dosing strategy particularly in the context of ill patients.
resistance suppression, before it can be fully applied in clinical
practice.
For the β-lactams, maintaining effective exposure for Financial Support
extended periods or increasing % fT>MIC would be especially None.
appropriate in the prevention of resistance particularly in
critically ill patients. Research has shown that the traditional Conflict of Interest
bolus dosing produces suboptimal antibiotic concentrations None.
for much of the dosing interval, which may consequently
favor resistant bacterial strains development.109 Numerous
preclinical and clinical PK/PD studies have demonstrated that Acknowledgment
improved β-lactams exposure could be achieved via EI or CI Jason Roberts is funded by a Career Development Fellow-
administration.219 These altered dosing approaches may be ship from the National Health and Medical Research
especially important in patients who develop severe patho- Council of Australia (APP1048652).
physiological derangements and when less susceptible
pathogens are present. However, more clinical studies are
urgently needed to evaluate the relative ability of EI and CI
References
versus IB dosing of β-lactam antibiotics in reducing the
1 Vincent JL, Rello J, Marshall J, et al; EPIC II Group of Investigators.
emergence of resistance if a global practice change is to be International study of the prevalence and outcomes of infection
expected. in intensive care units. JAMA 2009;302(21):2323–2329
2 Vincent JL, Sakr Y, Sprung CL, et al; Sepsis Occurrence in Acutely Ill
Patients Investigators. Sepsis in European intensive care units:
Conclusion results of the SOAP study. Crit Care Med 2006;34(2):344–353
3 Kaukonen KM, Bailey M, Suzuki S, Pilcher D, Bellomo R. Mortality
For decades now, clinicians have overused antibiotics and
related to severe sepsis and septic shock among critically ill
apparently did so with the notion that our continuous supply patients in Australia and New Zealand, 2000-2012. JAMA 2014;
of new antibiotics would adequately address any emerging 311(13):1308–1316
resistance concerns. That thought did not materialize and on 4 Stevenson EK, Rubenstein AR, Radin GT, Wiener RS, Walkey AJ.
the contrary, as our current antibiotic pipeline is nearly dry, Two decades of mortality trends among patients with severe
sepsis: a comparative meta-analysis. Crit Care Med 2014;42(3):
infecting pathogens have tremendously outperformed our
625–631
existing armamentarium thus far and they are becoming 5 ARISE; ANZICS APD Management Committee. The outcome of
increasingly difficult to treat. The current situation that we patients with sepsis and septic shock presenting to emergency
are in is not surprising, as most of our treatment goals were departments in Australia and New Zealand. Crit Care Resusc
previously focused on maximizing clinical and microbiological 2007;9(1):8–18

6 Dellinger RP, Levy MM, Rhodes A, et al; Surviving Sepsis Cam- 25 Roberts JA, Kruger P, Paterson DL, Lipman J. Antibiotic resistance—
paign Guidelines Committee including the Pediatric Subgroup. what’s dosing got to do with it? Crit Care Med 2008;36(8):
Surviving sepsis campaign: international guidelines for manage- 2433–2440
ment of severe sepsis and septic shock: 2012. Crit Care Med 2013; 26 Roberts JA, Abdul-Aziz MH, Lipman J, et al; International Society
41(2):580–637 of Anti-Infective Pharmacology and the Pharmacokinetics and
7 Coopersmith CM, Wunsch H, Fink MP, et al. A comparison of Pharmacodynamics Study Group of the European Society of
critical care research funding and the financial burden of critical Clinical Microbiology and Infectious Diseases. Individualised
illness in the United States. Crit Care Med 2012;40(4):1072–1079 antibiotic dosing for patients who are critically ill: challenges
8 Ranieri VM, Thompson BT, Barie PS, et al; PROWESS-SHOCK Study and potential solutions. Lancet Infect Dis 2014;14(6):498–509
Group. Drotrecogin alfa (activated) in adults with septic shock. N 27 Zeitlinger MA, Derendorf H, Mouton JW, et al. Protein binding: do
Engl J Med 2012;366(22):2055–2064 we ever learn? Antimicrob Agents Chemother 2011;55(7):
9 Warren BL, Eid A, Singer P, et al; KyberSept Trial Study Group. 3067–3074
Caring for the critically ill patient. High-dose antithrombin III in 28 Drusano GL. Pharmacokinetics and pharmacodynamics of anti-
severe sepsis: a randomized controlled trial. JAMA 2001;286(15): microbials. Clin Infect Dis 2007;45(1, Suppl 1):S89–S95
1869–1878 29 Mouton JW, Jacobs N, Tiddens H, Horrevorts AM. Pharmacody-
10 Finfer S, Chittock DR, Su SY, et al; NICE-SUGAR Study Investi- namics of tobramycin in patients with cystic fibrosis. Diagn
gators. Intensive versus conventional glucose control in critically Microbiol Infect Dis 2005;52(2):123–127

ill patients. N Engl J Med 2009;360(13):1283–1297 30 Craig WA. Pharmacokinetic/pharmacodynamic parameters: ra-
11 Garnacho-Montero J, Aldabo-Pallas T, Garnacho-Montero C, et al. tionale for antibacterial dosing of mice and men. Clin Infect Dis
Timing of adequate antibiotic therapy is a greater determinant of 1998;26(1):1–10, quiz 11–12
outcome than are TNF and IL-10 polymorphisms in patients with 31 Craig WA, Redington J, Ebert SC. Pharmacodynamics of amikacin
sepsis. Crit Care 2006;10(4):R111 in vitro and in mouse thigh and lung infections. J Antimicrob
12 Kumar A, Roberts D, Wood KE, et al. Duration of hypotension Chemother 1991;27(Suppl C):29–40
before initiation of effective antimicrobial therapy is the critical 32 Moore RD, Lietman PS, Smith CR. Clinical response to amino-
determinant of survival in human septic shock. Crit Care Med glycoside therapy: importance of the ratio of peak concentration
2006;34(6):1589–1596 to minimal inhibitory concentration. J Infect Dis 1987;155(1):
13 Garnacho-Montero J, Garcia-Garmendia JL, Barrero-Almodovar 93–99
A, Jimenez-Jimenez FJ, Perez-Paredes C, Ortiz-Leyba C. Impact of 33 McKinnon PS, Paladino JA, Schentag JJ. Evaluation of area under
adequate empirical antibiotic therapy on the outcome of patients the inhibitory curve (AUIC) and time above the minimum inhibi-
admitted to the intensive care unit with sepsis. Crit Care Med tory concentration (T>MIC) as predictors of outcome for cefe-
2003;31(12):2742–2751 pime and ceftazidime in serious bacterial infections. Int J
14 Felton TW, Hope WW, Roberts JA. How severe is antibiotic Antimicrob Agents 2008;31(4):345–351
pharmacokinetic variability in critically ill patients and what 34 Craig WA. Basic pharmacodynamics of antibacterials with clinical
can be done about it? Diagn Microbiol Infect Dis 2014;79(4): applications to the use of beta-lactams, glycopeptides, and line-
441–447 zolid. Infect Dis Clin North Am 2003;17(3):479–501
15 Zhanel GG, DeCorby M, Laing N, et al; Canadian Antimicrobial 35 Moise-Broder PA, Forrest A, Birmingham MC, Schentag JJ. Phar-
Resistance Alliance (CARA). Antimicrobial-resistant pathogens in macodynamics of vancomycin and other antimicrobials in pa-
intensive care units in Canada: results of the Canadian National tients with Staphylococcus aureus lower respiratory tract
Intensive Care Unit (CAN-ICU) study, 2005-2006. Antimicrob infections. Clin Pharmacokinet 2004;43(13):925–942
Agents Chemother 2008;52(4):1430–1437 36 Firsov AA, Strukova EN, Shlykova DS, et al. Bacterial resistance
16 Rhomberg PR, Fritsche TR, Sader HS, Jones RN. Antimicrobial studies using in vitro dynamic models: the predictive power of
susceptibility pattern comparisons among intensive care unit and the mutant prevention and minimum inhibitory antibiotic con-
general ward Gram-negative isolates from the Meropenem Yearly centrations. Antimicrob Agents Chemother 2013;57(10):
Susceptibility Test Information Collection Program (USA). Diagn 4956–4962
Microbiol Infect Dis 2006;56(1):57–62 37 Tam VH, Louie A, Deziel MR, Liu W, Drusano GL. The relationship
17 Mouton JW, Ambrose PG, Canton R, et al. Conserving antibiotics between quinolone exposures and resistance amplification is
for the future: new ways to use old and new drugs from a characterized by an inverted U: a new paradigm for optimizing
pharmacokinetic and pharmacodynamic perspective. Drug Resist pharmacodynamics to counterselect resistance. Antimicrob
Updat 2011;14(2):107–117 Agents Chemother 2007;51(2):744–747
18 Dulhunty JM, Paterson D, Webb SA, Lipman J. Antimicrobial 38 Tam VH, Louie A, Deziel MR, Liu W, Leary R, Drusano GL.
utilisation in 37 Australian and New Zealand intensive care units. Bacterial-population responses to drug-selective pressure: ex-
Anaesth Intensive Care 2011;39(2):231–237 amination of garenoxacin’s effect on Pseudomonas aeruginosa. J
19 Singh N, Yu VL. Rational empiric antibiotic prescription in the ICU. Infect Dis 2005;192(3):420–428
Chest 2000;117(5):1496–1499 39 Firsov AA, Vostrov SN, Lubenko IY, Drlica K, Portnoy YA, Zinner
20 Fridkin SK, Gaynes RP. Antimicrobial resistance in intensive care SH. In vitro pharmacodynamic evaluation of the mutant selection
units. Clin Chest Med 1999;20(2):303–316, viii window hypothesis using four fluoroquinolones against Staphy-
21 Livermore DM. Fourteen years in resistance. Int J Antimicrob lococcus aureus. Antimicrob Agents Chemother 2003;47(5):
Agents 2012;39(4):283–294 1604–1613
22 Ben-David D, Kordevani R, Keller N, et al. Outcome of carbapenem 40 Stearne LE, Goessens WH, Mouton JW, Gyssens IC. Effect of dosing
resistant Klebsiella pneumoniae bloodstream infections. Clin Mi- and dosing frequency on the efficacy of ceftizoxime and the
crobiol Infect 2012;18(1):54–60 emergence of ceftizoxime resistance during the early develop-
23 Lye DC, Earnest A, Ling ML, et al. The impact of multidrug ment of murine abscesses caused by Bacteroides fragilis and
resistance in healthcare-associated and nosocomial Gram-nega- Enterobacter cloacae mixed infection. Antimicrob Agents Chemo-
tive bacteraemia on mortality and length of stay: cohort study. ther 2007;51(10):3605–3611
Clin Microbiol Infect 2012;18(5):502–508 41 Jumbe N, Louie A, Leary R, et al. Application of a mathematical
24 Shorr AF. Review of studies of the impact on Gram-negative model to prevent in vivo amplification of antibiotic-resistant
bacterial resistance on outcomes in the intensive care unit. Crit bacterial populations during therapy. J Clin Invest 2003;112(2):
Care Med 2009;37(4):1463–1469 275–285

42 Tam VH, Louie A, Fritsche TR, et al. Impact of drug-exposure 59 Andes D, Craig WA. Pharmacodynamics of the new fluoroquino-
intensity and duration of therapy on the emergence of Staphylo- lone gatifloxacin in murine thigh and lung infection models.
coccus aureus resistance to a quinolone antimicrobial. J Infect Dis Antimicrob Agents Chemother 2002;46(6):1665–1670
2007;195(12):1818–1827 60 Olofsson SK, Marcusson LL, Komp Lindgren P, Hughes D, Cars O.
43 LaPlante KL, Rybak MJ, Tsuji B, Lodise TP, Kaatz GW. Fluoroquin- Selection of ciprofloxacin resistance in Escherichia coli in an in
olone resistance in Streptococcus pneumoniae: area under the vitro kinetic model: relation between drug exposure and mutant
concentration-time curve/MIC ratio and resistance development prevention concentration. J Antimicrob Chemother 2006;57(6):
with gatifloxacin, gemifloxacin, levofloxacin, and moxifloxacin. 1116–1121
Antimicrob Agents Chemother 2007;51(4):1315–1320 61 Croisier D, Etienne M, Bergoin E, et al. Mutant selection window
44 Tam VH, Schilling AN, Neshat S, Poole K, Melnick DA, Coyle EA. in levofloxacin and moxifloxacin treatments of experimental
Optimization of meropenem minimum concentration/MIC ratio pneumococcal pneumonia in a rabbit model of human therapy.
to suppress in vitro resistance of Pseudomonas aeruginosa. Anti- Antimicrob Agents Chemother 2004;48(5):1699–1707
microb Agents Chemother 2005;49(12):4920–4927 62 Knudsen JD, Odenholt I, Erlendsdottir H, et al. Selection of
45 Drusano GL, Bonomo RA, Bahniuk N, et al. Resistance emergence resistant Streptococcus pneumoniae during penicillin treatment
mechanism and mechanism of resistance suppression by tobra- in vitro and in three animal models. Antimicrob Agents Chemo-
mycin for cefepime for Pseudomonas aeruginosa. Antimicrob ther 2003;47(8):2499–2506
Agents Chemother 2012;56(1):231–242 63 Liang B, Bai N, Cai Y, Wang R, Drlica K, Zhao X. Mutant prevention

46 Gumbo T, Louie A, Deziel MR, Parsons LM, Salfinger M, Drusano concentration-based pharmacokinetic/pharmacodynamic indi-
GL. Selection of a moxifloxacin dose that suppresses drug resis- ces as dosing targets for suppressing the enrichment of levoflox-
tance in Mycobacterium tuberculosis, by use of an in vitro acin-resistant subpopulations of Staphylococcus aureus.
pharmacodynamic infection model and mathematical modeling. Antimicrob Agents Chemother 2011;55(5):2409–2412
J Infect Dis 2004;190(9):1642–1651 64 Firsov AA, Smirnova MV, Strukova EN, Vostrov SN, Portnoy YA,
47 Baquero F, Negri MC. Strategies to minimize the development of Zinner SH. Enrichment of resistant Staphylococcus aureus at
antibiotic resistance. J Chemother 1997;9(Suppl 3):29–37 ciprofloxacin concentrations simulated within the mutant selec-
48 Baquero F. Resistance to quinolones in gram-negative micro- tion window: bolus versus continuous infusion. Int J Antimicrob
organisms: mechanisms and prevention. Eur Urol 1990;17 Agents 2008;32(6):488–493
(Suppl 1):3–12 65 Firsov AA, Vostrov SN, Lubenko IY, Arzamastsev AP, Portnoy YA,
49 Zhao X, Drlica K. Restricting the selection of antibiotic-resistant Zinner SH. ABT492 and levofloxacin: comparison of their phar-
mutants: a general strategy derived from fluoroquinolone stud- macodynamics and their abilities to prevent the selection of
ies. Clin Infect Dis 2001;33(3, Suppl 3):S147–S156 resistant Staphylococcus aureus in an in vitro dynamic model. J
50 Dong Y, Zhao X, Kreiswirth BN, Drlica K. Mutant prevention Antimicrob Chemother 2004;54(1):178–186
concentration as a measure of antibiotic potency: studies with 66 Gugel J, Dos Santos Pereira A, Pignatari AC, Gales AC. beta-Lactam
clinical isolates of Mycobacterium tuberculosis. Antimicrob MICs correlate poorly with mutant prevention concentrations for
Agents Chemother 2000;44(9):2581–2584 clinical isolates of Acinetobacter spp. and Pseudomonas aerugi-
51 Dong Y, Zhao X, Domagala J, Drlica K. Effect of fluoroquinolone nosa. Antimicrob Agents Chemother 2006;50(6):2276–2277
concentration on selection of resistant mutants of Mycobacteri- 67 Hansen GT, Metzler K, Drlica K, Blondeau JM. Mutant prevention
um bovis BCG and Staphylococcus aureus. Antimicrob Agents concentration of gemifloxacin for clinical isolates of Streptococcus
Chemother 1999;43(7):1756–1758 pneumoniae. Antimicrob Agents Chemother 2003;47(1):
52 Zhou J, Dong Y, Zhao X, et al. Selection of antibiotic-resistant 440–441
bacterial mutants: allelic diversity among fluoroquinolone-resis- 68 Drusano GL, Johnson DE, Rosen M, Standiford HC. Pharmacody-
tant mutations. J Infect Dis 2000;182(2):517–525 namics of a fluoroquinolone antimicrobial agent in a neutropenic
53 Firsov AA, Smirnova MV, Lubenko IY, Vostrov SN, Portnoy YA, rat model of Pseudomonas sepsis. Antimicrob Agents Chemother
Zinner SH. Testing the mutant selection window hypothesis with 1993;37(3):483–490
Staphylococcus aureus exposed to daptomycin and vancomycin in 69 Blaser J, Stone BB, Groner MC, Zinner SH. Comparative study with
an in vitro dynamic model. J Antimicrob Chemother 2006;58(6): enoxacin and netilmicin in a pharmacodynamic model to deter-
1185–1192 mine importance of ratio of antibiotic peak concentration to MIC
54 Campion JJ, Chung P, McNamara PJ, Titlow WB, Evans ME. for bactericidal activity and emergence of resistance. Antimicrob
Pharmacodynamic modeling of the evolution of levofloxacin Agents Chemother 1987;31(7):1054–1060
resistance in Staphylococcus aureus. Antimicrob Agents Chemo- 70 Thorburn CE, Edwards DI. The effect of pharmacokinetics on the
ther 2005;49(6):2189–2199 bactericidal activity of ciprofloxacin and sparfloxacin against
55 Zinner SH, Lubenko IY, Gilbert D, et al. Emergence of resistant Streptococcus pneumoniae and the emergence of resistance. J
Streptococcus pneumoniae in an in vitro dynamic model that Antimicrob Chemother 2001;48(1):15–22
simulates moxifloxacin concentrations inside and outside the 71 Forrest A, Nix DE, Ballow CH, Goss TF, Birmingham MC, Schen-
mutant selection window: related changes in susceptibility, tag JJ. Pharmacodynamics of intravenous ciprofloxacin in seri-
resistance frequency and bacterial killing. J Antimicrob Chemo- ously ill patients. Antimicrob Agents Chemother 1993;37(5):
ther 2003;52(4):616–622 1073–1081
56 Cui J, Liu Y, Wang R, Tong W, Drlica K, Zhao X. The mutant 72 Peloquin CA, Cumbo TJ, Nix DE, Sands MF, Schentag JJ. Evaluation
selection window in rabbits infected with Staphylococcus aureus. of intravenous ciprofloxacin in patients with nosocomial lower
J Infect Dis 2006;194(11):1601–1608 respiratory tract infections. Impact of plasma concentrations,
57 Croisier D, Etienne M, Piroth L, et al. In vivo pharmacodynamic organism, minimum inhibitory concentration, and clinical con-
efficacy of gatifloxacin against Streptococcus pneumoniae in an dition on bacterial eradication. Arch Intern Med 1989;149(10):
experimental model of pneumonia: impact of the low levels of 2269–2273
fluoroquinolone resistance on the enrichment of resistant mu- 73 Zelenitsky SA, Ariano RE. Support for higher ciprofloxacin AUC
tants. J Antimicrob Chemother 2004;54(3):640–647 24/MIC targets in treating Enterobacteriaceae bloodstream infec-
58 Etienne M, Croisier D, Charles PE, et al. Effect of low-level tion. J Antimicrob Chemother 2010;65(8):1725–1732
resistance on subsequent enrichment of fluoroquinolone-resis- 74 Drusano GL, Preston SL, Fowler C, Corrado M, Weisinger B, Kahn J.
tant Streptococcus pneumoniae in rabbits. J Infect Dis 2004; Relationship between fluoroquinolone area under the curve:
190(8):1472–1475 minimum inhibitory concentration ratio and the probability of

eradication of the infecting pathogen, in patients with nosoco- 91 Xiong YQ, Caillon J, Kergueris MF, et al. Adaptive resistance of
mial pneumonia. J Infect Dis 2004;189(9):1590–1597 Pseudomonas aeruginosa induced by aminoglycosides and killing
75 Ambrose PG, Grasela DM, Grasela TH, Passarell J, Mayer HB, Pierce kinetics in a rabbit endocarditis model. Antimicrob Agents Che-
PF. Pharmacodynamics of fluoroquinolones against Streptococcus mother 1997;41(4):823–826
pneumoniae in patients with community-acquired respiratory 92 Barclay ML, Begg EJ, Chambers ST. Adaptive resistance following
tract infections. Antimicrob Agents Chemother 2001;45(10): single doses of gentamicin in a dynamic in vitro model. Anti-
2793–2797 microb Agents Chemother 1992;36(9):1951–1957
76 Mattoes HM, Banevicius M, Li D, et al. Pharmacodynamic assess- 93 Daikos GL, Lolans VT, Jackson GG. First-exposure adaptive resis-
ment of gatifloxacin against Streptococcus pneumoniae. Antimi- tance to aminoglycoside antibiotics in vivo with meaning for
crob Agents Chemother 2001;45(7):2092–2097 optimal clinical use. Antimicrob Agents Chemother 1991;35(1):
77 Bédos JP, Azoulay-Dupuis E, Moine P, et al. Pharmacodynamic 117–123
activities of ciprofloxacin and sparfloxacin in a murine pneumo- 94 Tam VH, Ledesma KR, Vo G, Kabbara S, Lim TP, Nikolaou M.
coccal pneumonia model: relevance for drug efficacy. J Pharmacol Pharmacodynamic modeling of aminoglycosides against Pseudo-
Exp Ther 1998;286(1):29–35 monas aeruginosa and Acinetobacter baumannii: identifying dos-
78 Thomas JK, Forrest A, Bhavnani SM, et al. Pharmacodynamic ing regimens to suppress resistance development. Antimicrob
evaluation of factors associated with the development of bacterial Agents Chemother 2008;52(11):3987–3993
resistance in acutely ill patients during therapy. Antimicrob 95 Marik PE, Lipman J, Kobilski S, Scribante J. A prospective ran-

Agents Chemother 1998;42(3):521–527 domized study comparing once- versus twice-daily amikacin
79 Schentag JJ, Gilliland KK, Paladino JA. What have we learned from dosing in critically ill adult and paediatric patients. J Antimicrob
pharmacokinetic and pharmacodynamic theories? Clin Infect Dis Chemother 1991;28(5):753–764
2001;32(1, Suppl 1):S39–S46 96 Prins JM, Büller HR, Kuijper EJ, Tange RA, Speelman P. Once versus
80 Burgess DS, Hall RG II. Simulated comparison of the pharmaco- thrice daily gentamicin in patients with serious infections. Lancet
dynamics of ciprofloxacin and levofloxacin against Pseudomonas 1993;341(8841):335–339
aeruginosa using pharmacokinetic data from healthy volunteers 97 Bailey TC, Little JR, Littenberg B, Reichley RM, Dunagan WC. A
and 2002 minimum inhibitory concentration data. Clin Ther meta-analysis of extended-interval dosing versus multiple daily
2007;29(7):1421–1427 dosing of aminoglycosides. Clin Infect Dis 1997;24(5):786–795
81 Gebru E, Choi MJ, Lee SJ, Damte D, Park SC. Mutant-prevention 98 Munckhof WJ, Grayson ML, Turnidge JD. A meta-analysis of
concentration and mechanism of resistance in clinical isolates studies on the safety and efficacy of aminoglycosides given either
and enrofloxacin/marbofloxacin-selected mutants of Escherichia once daily or as divided doses. J Antimicrob Chemother 1996;
coli of canine origin. J Med Microbiol 2011;60(Pt 10):1512–1522 37(4):645–663
82 Firsov AA, Vostrov SN, Lubenko IY, Zinner SH, Portnoy YA. 99 Crandon JL, Bulik CC, Kuti JL, Nicolau DP. Clinical pharmacody-
Concentration-dependent changes in the susceptibility and kill- namics of cefepime in patients infected with Pseudomonas aer-
ing of Staphylococcus aureus in an in vitro dynamic model that uginosa. Antimicrob Agents Chemother 2010;54(3):1111–1116
simulates normal and impaired gatifloxacin elimination. Int J 100 Mouton JW, Punt N, Vinks AA. Concentration-effect relationship
Antimicrob Agents 2004;23(1):60–66 of ceftazidime explains why the time above the MIC is 40 percent
83 Khachman D, Conil JM, Georges B, et al. Optimizing ciprofloxacin for a static effect in vivo. Antimicrob Agents Chemother 2007;
dosing in intensive care unit patients through the use of popula- 51(9):3449–3451
tion pharmacokinetic-pharmacodynamic analysis and Monte 101 Ong CT, Tessier PR, Li C, Nightingale CH, Nicolau DP. Comparative
Carlo simulations. J Antimicrob Chemother 2011;66(8): in vivo efficacy of meropenem, imipenem, and cefepime against
1798–1809 Pseudomonas aeruginosa expressing MexA-MexB-OprM efflux
84 MacArthur RD, Lolans V, Zar FA, Jackson GG. Biphasic, concentra- pumps. Diagn Microbiol Infect Dis 2007;57(2):153–161
tion-dependent and rate-limited, concentration-independent 102 Muller AE, Punt N, Mouton JW. Exposure to ceftobiprole is
bacterial killing by an aminoglycoside antibiotic. J Infect Dis associated with microbiological eradication and clinical cure in
1984;150(5):778–779 patients with nosocomial pneumonia. Antimicrob Agents Che-
85 Mouton JW, Vinks AA. Pharmacokinetic/pharmacodynamic mother 2014;58(5):2512–2519
modelling of antibacterials in vitro and in vivo using bacterial 103 Muller AE, Punt N, Mouton JW. Optimal exposures of ceftazidime
growth and kill kinetics: the minimum inhibitory concentration predict the probability of microbiological and clinical outcome in
versus stationary concentration. Clin Pharmacokinet 2005;44(2): the treatment of nosocomial pneumonia. J Antimicrob Chemo-
201–210 ther 2013;68(4):900–906
86 Vogelman B, Gudmundsson S, Leggett J, Turnidge J, Ebert S, Craig 104 Roberts JA, Paul SK, Akova M, et al; DALI Study. DALI: defining
WA. Correlation of antimicrobial pharmacokinetic parameters antibiotic levels in intensive care unit patients: are current β-
with therapeutic efficacy in an animal model. J Infect Dis 1988; lactam antibiotic doses sufficient for critically ill patients? Clin
158(4):831–847 Infect Dis 2014;58(8):1072–1083
87 Kashuba AD, Nafziger AN, Drusano GL, Bertino JS Jr. Optimizing 105 Ariano RE, Nyhlén A, Donnelly JP, Sitar DS, Harding GK, Zelenitsky
aminoglycoside therapy for nosocomial pneumonia caused by SA. Pharmacokinetics and pharmacodynamics of meropenem in
gram-negative bacteria. Antimicrob Agents Chemother 1999; febrile neutropenic patients with bacteremia. Ann Pharmacother
43(3):623–629 2005;39(1):32–38
88 Zelenitsky SA, Harding GK, Sun S, Ubhi K, Ariano RE. Treatment 106 Mouton JW, den Hollander JG. Killing of Pseudomonas aeruginosa
and outcome of Pseudomonas aeruginosa bacteraemia: an anti- during continuous and intermittent infusion of ceftazidime in an
biotic pharmacodynamic analysis. J Antimicrob Chemother 2003; in vitro pharmacokinetic model. Antimicrob Agents Chemother
52(4):668–674 1994;38(5):931–936
89 Drusano GL, Ambrose PG, Bhavnani SM, Bertino JS, Nafziger AN, 107 Li C, Du X, Kuti JL, Nicolau DP. Clinical pharmacodynamics of
Louie A. Back to the future: using aminoglycosides again and how meropenem in patients with lower respiratory tract infections.
to dose them optimally. Clin Infect Dis 2007;45(6):753–760 Antimicrob Agents Chemother 2007;51(5):1725–1730
90 Smith PF, Ballow CH, Booker BM, Forrest A, Schentag JJ. Pharma- 108 Tam VH, McKinnon PS, Akins RL, Rybak MJ, Drusano GL. Phar-
cokinetics and pharmacodynamics of aztreonam and tobramycin macodynamics of cefepime in patients with Gram-negative in-
in hospitalized patients. Clin Ther 2001;23(8):1231–1244 fections. J Antimicrob Chemother 2002;50(3):425–428

109 Abdul-Aziz MH, Dulhunty JM, Bellomo R, Lipman J, Roberts JA. efficacy of teicoplanin in a rabbit model of endocarditis. Anti-
Continuous beta-lactam infusion in critically ill patients: the microb Agents Chemother 1990;34(4):510–514
clinical evidence. Ann Intensive Care 2012;2(1):37 126 Knudsen JD, Fuursted K, Raber S, Espersen F, Frimodt-Moller N.
110 Fantin B, Farinotti R, Thabaut A, Carbon C. Conditions for the Pharmacodynamics of glycopeptides in the mouse peritonitis
emergence of resistance to cefpirome and ceftazidime in experi- model of Streptococcus pneumoniae or Staphylococcus aureus
mental endocarditis due to Pseudomonas aeruginosa. J Antimi- infection. Antimicrob Agents Chemother 2000;44(5):1247–1254
crob Chemother 1994;33(3):563–569 127 Moise PA, Forrest A, Bhavnani SM, Birmingham MC, Schentag JJ.
111 Olofsson SK, Geli P, Andersson DI, Cars O. Pharmacodynamic Area under the inhibitory curve and a pneumonia scoring system
model to describe the concentration-dependent selection of for predicting outcomes of vancomycin therapy for respiratory
cefotaxime-resistant Escherichia coli. Antimicrob Agents Chemo- infections by Staphylococcus aureus. Am J Health Syst Pharm
ther 2005;49(12):5081–5091 2000;57(2, Suppl 2):S4–S9
112 Goessens WH, Mouton JW, ten Kate MT, Bijl AJ, Ott A, Bakker- 128 Zelenitsky S, Rubinstein E, Ariano R, et al; Cooperative Antimi-
Woudenberg IA. Role of ceftazidime dose regimen on the selec- crobial Therapy of Septic Shock-CATSS Database Research Group.
tion of resistant Enterobacter cloacae in the intestinal flora of rats Vancomycin pharmacodynamics and survival in patients with
treated for an experimental pulmonary infection. J Antimicrob methicillin-resistant Staphylococcus aureus-associated septic
Chemother 2007;59(3):507–516 shock. Int J Antimicrob Agents 2013;41(3):255–260
113 Tam VH, Schilling AN, Melnick DA, Coyle EA. Comparison of beta- 129 Rybak MJ, Lomaestro BM, Rotschafer JC, et al. Vancomycin thera-

lactams in counter-selecting resistance of Pseudomonas aerugi- peutic guidelines: a summary of consensus recommendations
nosa. Diagn Microbiol Infect Dis 2005;52(2):145–151 from the infectious diseases Society of America, the American
114 Gudmundsson S, Vogelman B, Craig WA. The in-vivo postanti- Society of Health-System Pharmacists, and the Society of Infec-
biotic effect of imipenem and other new antimicrobials. J Anti- tious Diseases Pharmacists. Clin Infect Dis 2009;49(3):325–327
microb Chemother 1986;18(Suppl E):67–73 130 American Thoracic Society; Infectious Diseases Society of Amer-
115 Fuentes F, Martín MM, Izquierdo J, Gomez-Lus ML, Prieto J. In vivo ica. Guidelines for the management of adults with hospital-
and in vitro study of several pharmacodynamic effects of mer- acquired, ventilator-associated, and healthcare-associated pneu-
openem. Scand J Infect Dis 1995;27(5):469–474 monia. Am J Respir Crit Care Med 2005;171(4):388–416
116 Tam VH, Ledesma KR, Schilling AN, et al. In vivo dynamics of 131 Tsuji BT, Rybak MJ, Lau KL, Sakoulas G. Evaluation of accessory
carbapenem-resistant Pseudomonas aeruginosa selection after gene regulator (agr) group and function in the proclivity towards
suboptimal dosing. Diagn Microbiol Infect Dis 2009;64(4): vancomycin intermediate resistance in Staphylococcus aureus.
427–433 Antimicrob Agents Chemother 2007;51(3):1089–1091
117 Zinner SH, Gilbert D, Greer K, Portnoy YA, Firsov AA. Concentra- 132 Charles PG, Ward PB, Johnson PD, Howden BP, Grayson ML.
tion-resistance relationships with Pseudomonas aeruginosa ex- Clinical features associated with bacteremia due to heteroge-
posed to doripenem and ciprofloxacin in an in vitro model. J neous vancomycin-intermediate Staphylococcus aureus. Clin In-
Antimicrob Chemother 2013;68(4):881–887 fect Dis 2004;38(3):448–451
118 Roberts JA, Kirkpatrick CM, Roberts MS, Robertson TA, Dalley AJ, 133 Sakoulas G, Gold HS, Cohen RA, Venkataraman L, Moellering RC,
Lipman J. Meropenem dosing in critically ill patients with sepsis Eliopoulos GM. Effects of prolonged vancomycin administration
and without renal dysfunction: intermittent bolus versus con- on methicillin-resistant Staphylococcus aureus (MRSA) in a pa-
tinuous administration? Monte Carlo dosing simulations and tient with recurrent bacteraemia. J Antimicrob Chemother 2006;
subcutaneous tissue distribution. J Antimicrob Chemother 57(4):699–704
2009;64(1):142–150 134 Howden BP, Ward PB, Charles PG, et al. Treatment outcomes for
119 Lorente L, Lorenzo L, Martín MM, Jiménez A, Mora ML. Merope- serious infections caused by methicillin-resistant Staphylococcus
nem by continuous versus intermittent infusion in ventilator- aureus with reduced vancomycin susceptibility. Clin Infect Dis
associated pneumonia due to gram-negative bacilli. Ann Phar- 2004;38(4):521–528
macother 2006;40(2):219–223 135 del Mar Fernández de Gatta Garcia M, Revilla N, Calvo MV,
120 Krueger WA, Bulitta J, Kinzig-Schippers M, et al. Evaluation by Domínguez-Gil A, Sánchez Navarro A. Pharmacokinetic/pharma-
monte carlo simulation of the pharmacokinetics of two doses of codynamic analysis of vancomycin in ICU patients. Intensive Care
meropenem administered intermittently or as a continuous Med 2007;33(2):279–285
infusion in healthy volunteers. Antimicrob Agents Chemother 136 Andes D, van Ogtrop ML, Peng J, Craig WA. In vivo pharmacody-
2005;49(5):1881–1889 namics of a new oxazolidinone (linezolid). Antimicrob Agents
121 Louie A, Bied A, Fregeau C, et al. Impact of different carbapenems Chemother 2002;46(11):3484–3489
and regimens of administration on resistance emergence for 137 Rayner CR, Forrest A, Meagher AK, Birmingham MC, Schentag JJ.
three isogenic Pseudomonas aeruginosa strains with differing Clinical pharmacodynamics of linezolid in seriously ill patients
mechanisms of resistance. Antimicrob Agents Chemother 2010; treated in a compassionate use programme. Clin Pharmacokinet
54(6):2638–2645 2003;42(15):1411–1423
122 Chastre J, Wunderink R, Prokocimer P, Lee M, Kaniga K, Friedland 138 Buchanan LV, Dailey CF, LeMay RJ, Zielinski RJ, Kuo MS, Gibson JK.
I. Efficacy and safety of intravenous infusion of doripenem versus Time-dependent antibacterial effects of linezolid in experimen-
imipenem in ventilator-associated pneumonia: a multicenter, tal rabbit endocarditis. J Antimicrob Chemother 2002;50(3):
randomized study. Crit Care Med 2008;36(4):1089–1096 440–442
123 Löwdin E, Odenholt I, Cars O. In vitro studies of pharmacody- 139 Zoller M, Maier B, Hornuss C, et al. Variability of linezolid
namic properties of vancomycin against Staphylococcus aureus concentrations after standard dosing in critically ill patients: a
and Staphylococcus epidermidis. Antimicrob Agents Chemother prospective observational study. Crit Care 2014;18(4):R148
1998;42(10):2739–2744 140 Dong H, Wang X, Dong Y, et al. Clinical pharmacokinetic/
124 Larsson AJ, Walker KJ, Raddatz JK, Rotschafer JC. The concentra- pharmacodynamic profile of linezolid in severely ill intensive
tion-independent effect of monoexponential and biexponential care unit patients. Int J Antimicrob Agents 2011;38(4):
decay in vancomycin concentrations on the killing of Staphylo- 296–300
coccus aureus under aerobic and anaerobic conditions. J Anti- 141 Adembri C, Fallani S, Cassetta MI, et al. Linezolid pharmacokinet-
microb Chemother 1996;38(4):589–597 ic/pharmacodynamic profile in critically ill septic patients: inter-
125 Chambers HF, Kennedy S. Effects of dosage, peak and trough mittent versus continuous infusion. Int J Antimicrob Agents
concentrations in serum, protein binding, and bactericidal rate on 2008;31(2):122–129

142 Cattaneo D, Orlando G, Cozzi V, et al. Linezolid plasma concen- 161 Patel SS, Balfour JA, Bryson HM. Fosfomycin tromethamine. A
trations and occurrence of drug-related haematological toxicity review of its antibacterial activity, pharmacokinetic properties
in patients with gram-positive infections. Int J Antimicrob Agents and therapeutic efficacy as a single-dose oral treatment for acute
2013;41(6):586–589 uncomplicated lower urinary tract infections. Drugs 1997;53(4):
143 Livermore DM. Linezolid in vitro: mechanism and antibacterial 637–656
spectrum. J Antimicrob Chemother 2003;51(Suppl 2):ii9–ii16 162 Dinh A, Salomon J, Bru JP, Bernard L. Fosfomycin: efficacy against
144 Sánchez García M, De la Torre MA, Morales G, et al. Clinical infections caused by multidrug-resistant bacteria. Scand J Infect
outbreak of linezolid-resistant Staphylococcus aureus in an in- Dis 2012;44(3):182–189
tensive care unit. JAMA 2010;303(22):2260–2264 163 Thauvin C, Lemeland JF, Humbert G, Fillastre JP. Efficacy of
145 Hentschke M, Saager B, Horstkotte MA, et al. Emergence of pefloxacin-fosfomycin in experimental endocarditis caused by
linezolid resistance in a methicillin resistant Staphylococcus methicillin-resistant Staphylococcus aureus. Antimicrob Agents
aureus strain. Infection 2008;36(1):85–87 Chemother 1988;32(6):919–921
146 Pai MP, Rodvold KA, Schreckenberger PC, Gonzales RD, Petrolatti 164 Portier H, Kazmierczak A, Lucht F, Tremeaux JC, Chavanet P, Duez
JM, Quinn JP. Risk factors associated with the development of JM. Cefotaxime in combination with other antibiotics for the
infection with linezolid- and vancomycin-resistant Enterococcus treatment of severe methicillin-resistant staphylococcal infec-
faecium. Clin Infect Dis 2002;35(10):1269–1272 tions. Infection 1985;13(Suppl 1):S123–S128
147 Wunderink RG, Niederman MS, Kollef MH, et al. Linezolid in 165 Komatsuzawa H, Suzuki J, Sugai M, Miyake Y, Suginaka H. Effect of

methicillin-resistant Staphylococcus aureus nosocomial pneumo- combination of oxacillin and non-beta-lactam antibiotics on
nia: a randomized, controlled study. Clin Infect Dis 2012;54(5): methicillin-resistant Staphylococcus aureus. J Antimicrob Chemo-
621–629 ther 1994;33(6):1155–1163
148 Herrmann DJ, Peppard WJ, Ledeboer NA, Theesfeld ML, Weigelt 166 Sahuquillo Arce JM, Colombo Gainza E, Gil Brusola A, Ortiz
JA, Buechel BJ. Linezolid for the treatment of drug-resistant Estévez R, Cantón E, Gobernado M. In vitro activity of linezolid
infections. Expert Rev Anti Infect Ther 2008;6(6):825–848 in combination with doxycycline, fosfomycin, levofloxacin, ri-
149 Safdar N, Andes D, Craig WA. In vivo pharmacodynamic activity of fampicin and vancomycin against methicillin-susceptible Staph-
daptomycin. Antimicrob Agents Chemother 2004;48(1):63–68 ylococcus aureus. Rev Esp Quimioter 2006;19(3):252–257
150 Dandekar PK, Tessier PR, Williams P, Zhang C, Nightingale CH, 167 Ferrara A, Dos Santos C, Cimbro M, Gialdroni Grassi G. Effect of
Nicolau DP. Determination of the pharmacodynamic profile of different combinations of sparfloxacin, oxacillin, and fosfomycin
daptomycin against Streptococcus pneumoniae isolates with vary- against methicillin-resistant staphylococci. Eur J Clin Microbiol
ing susceptibility to penicillin in a murine thigh infection model. Infect Dis 1997;16(7):535–537
Chemotherapy 2004;50(1):11–16 168 Okazaki M, Suzuki K, Asano N, et al. Effectiveness of fosfomycin
151 Louie A, Kaw P, Liu W, Jumbe N, Miller MH, Drusano GL. combined with other antimicrobial agents against multidrug-
Pharmacodynamics of daptomycin in a murine thigh model of resistant Pseudomonas aeruginosa isolates using the efficacy time
Staphylococcus aureus infection. Antimicrob Agents Chemother index assay. J Infect Chemother 2002;8(1):37–42
2001;45(3):845–851 169 Hayami H, Goto T, Kawahara M, Ohi Y. Activities of beta-lactams,
152 Dvorchik BH, Brazier D, DeBruin MF, Arbeit RD. Daptomycin fluoroquinolones, amikacin and fosfomycin alone and in combi-
pharmacokinetics and safety following administration of escalat- nation against Pseudomonas aeruginosa isolated from complicat-
ing doses once daily to healthy subjects. Antimicrob Agents ed urinary tract infections. J Infect Chemother 1999;5(3):
Chemother 2003;47(4):1318–1323 130–138
153 Woodworth JR, Nyhart EH Jr, Brier GL, Wolny JD, Black HR. Single- 170 Reguera JA, Baquero F, Berenguer J, Martinez-Ferrer M, Martinez
dose pharmacokinetics and antibacterial activity of daptomycin, JL. Beta-lactam-fosfomycin antagonism involving modification of
a new lipopeptide antibiotic, in healthy volunteers. Antimicrob penicillin-binding protein 3 in Pseudomonas aeruginosa. Anti-
Agents Chemother 1992;36(2):318–325 microb Agents Chemother 1990;34(11):2093–2096
154 Gould IM, David MZ, Esposito S, et al. New insights into meticillin- 171 Michalopoulos A, Virtzili S, Rafailidis P, Chalevelakis G, Damala M,
resistant Staphylococcus aureus (MRSA) pathogenesis, treatment Falagas ME. Intravenous fosfomycin for the treatment of nosoco-
and resistance. Int J Antimicrob Agents 2012;39(2):96–104 mial infections caused by carbapenem-resistant Klebsiella pneu-
155 Fowler VG Jr, Boucher HW, Corey GR, et al; S. aureus Endocarditis moniae in critically ill patients: a prospective evaluation. Clin
and Bacteremia Study Group. Daptomycin versus standard ther- Microbiol Infect 2010;16(2):184–186
apy for bacteremia and endocarditis caused by Staphylococcus 172 Li J, Turnidge J, Milne R, Nation RL, Coulthard K. In vitro pharma-
aureus. N Engl J Med 2006;355(7):653–665 codynamic properties of colistin and colistin methanesulfonate
156 Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by against Pseudomonas aeruginosa isolates from patients with
the Infectious Diseases Society of America for the treatment of cystic fibrosis. Antimicrob Agents Chemother 2001;45(3):
methicillin resistant Staphylococcus aureus infections in adults 781–785
and children: executive summary. Clin Infect Dis 2011;52(3): 173 Dudhani RV, Turnidge JD, Coulthard K, et al. Elucidation of the
285–292 pharmacokinetic/pharmacodynamic determinant of colistin ac-
157 Moise PA, Hershberger E, Amodio-Groton MI, Lamp KC. Safety tivity against Pseudomonas aeruginosa in murine thigh and lung
and clinical outcomes when utilizing high-dose (> or ¼8 mg/kg) infection models. Antimicrob Agents Chemother 2010;54(3):
daptomycin therapy. Ann Pharmacother 2009;43(7):1211–1219 1117–1124
158 Bassetti M, Nicco E, Ginocchio F, Ansaldi F, de Florentiis D, Viscoli 174 Dudhani RV, Turnidge JD, Nation RL, Li J. fAUC/MIC is the most
C. High-dose daptomycin in documented Staphylococcus aureus predictive pharmacokinetic/pharmacodynamic index of colistin
infections. Int J Antimicrob Agents 2010;36(5):459–461 against Acinetobacter baumannii in murine thigh and lung infec-
159 Figueroa DA, Mangini E, Amodio-Groton M, et al. Safety of high-dose tion models. J Antimicrob Chemother 2010;65(9):1984–1990
intravenous daptomycin treatment: three-year cumulative experi- 175 Lim LM, Ly N, Anderson D, et al. Resurgence of colistin: a review of
ence in a clinical program. Clin Infect Dis 2009;49(2):177–180 resistance, toxicity, pharmacodynamics, and dosing. Pharmaco-
160 Falagas ME, Maraki S, Karageorgopoulos DE, Kastoris AC, Mavro- therapy 2010;30(12):1279–1291
manolakis E, Samonis G. Antimicrobial susceptibility of multi- 176 Yau W, Owen RJ, Poudyal A, et al. Colistin hetero-resistance in
drug-resistant (MDR) and extensively drug-resistant (XDR) multidrug-resistant Acinetobacter baumannii clinical isolates
Enterobacteriaceae isolates to fosfomycin. Int J Antimicrob from the Western Pacific region in the SENTRY antimicrobial
Agents 2010;35(3):240–243 surveillance programme. J Infect 2009;58(2):138–144

177 Hawley JS, Murray CK, Jorgensen JH. Colistin heteroresistance in 193 Chamot E, Boffi El Amari E, Rohner P, Van Delden C. Effectiveness
acinetobacter and its association with previous colistin therapy. of combination antimicrobial therapy for Pseudomonas aerugi-
Antimicrob Agents Chemother 2008;52(1):351–352 nosa bacteremia. Antimicrob Agents Chemother 2003;47(9):
178 Poudyal A, Howden BP, Bell JM, et al. In vitro pharmacodynamics 2756–2764
of colistin against multidrug-resistant Klebsiella pneumoniae. J 194 Cosgrove SE, Vigliani GA, Fowler VG Jr, et al. Initial low-dose
Antimicrob Chemother 2008;62(6):1311–1318 gentamicin for Staphylococcus aureus bacteremia and endocardi-
179 Bergen PJ, Forrest A, Bulitta JB, et al. Clinically relevant plasma tis is nephrotoxic. Clin Infect Dis 2009;48(6):713–721
concentrations of colistin in combination with imipenem en- 195 Riedel DJ, Weekes E, Forrest GN. Addition of rifampin to standard
hance pharmacodynamic activity against multidrug-resistant therapy for treatment of native valve infective endocarditis
Pseudomonas aeruginosa at multiple inocula. Antimicrob Agents caused by Staphylococcus aureus. Antimicrob Agents Chemother
Chemother 2011;55(11):5134–5142 2008;52(7):2463–2467
180 Bergen PJ, Li J, Nation RL, Turnidge JD, Coulthard K, Milne RW. 196 Falagas ME, Matthaiou DK, Bliziotis IA. The role of aminoglyco-
Comparison of once-, twice- and thrice-daily dosing of colistin on sides in combination with a beta-lactam for the treatment of
antibacterial effect and emergence of resistance: studies with bacterial endocarditis: a meta-analysis of comparative trials. J
Pseudomonas aeruginosa in an in vitro pharmacodynamic model. Antimicrob Chemother 2006;57(4):639–647
J Antimicrob Chemother 2008;61(3):636–642 197 Vardakas KZ, Tansarli GS, Bliziotis IA, Falagas ME. β-Lactam plus
181 Tan CH, Li J, Nation RL. Activity of colistin against heteroresistant aminoglycoside or fluoroquinolone combination versus β-lactam

Acinetobacter baumannii and emergence of resistance in an in monotherapy for Pseudomonas aeruginosa infections: a meta-
vitro pharmacokinetic/pharmacodynamic model. Antimicrob analysis. Int J Antimicrob Agents 2013;41(4):301–310
Agents Chemother 2007;51(9):3413–3415 198 Peña C, Suarez C, Ocampo-Sosa A, et al; Spanish Network for
182 Garonzik SM, Li J, Thamlikitkul V, et al. Population pharmacoki- Research in Infectious Diseases (REIPI). Effect of adequate single-
netics of colistin methanesulfonate and formed colistin in criti- drug vs combination antimicrobial therapy on mortality in
cally ill patients from a multicenter study provide dosing Pseudomonas aeruginosa bloodstream infections: a post hoc
suggestions for various categories of patients. Antimicrob Agents analysis of a prospective cohort. Clin Infect Dis 2013;57(2):
Chemother 2011;55(7):3284–3294 208–216
183 Marchand S, Frat JP, Petitpas F, et al. Removal of colistin during 199 Marcus R, Paul M, Elphick H, Leibovici L. Clinical implications of β-
intermittent haemodialysis in two critically ill patients. J Anti- lactam-aminoglycoside synergism: systematic review of ran-
microb Chemother 2010;65(8):1836–1837 domised trials. Int J Antimicrob Agents 2011;37(6):491–503
184 Plachouras D, Karvanen M, Friberg LE, et al. Population pharma- 200 Louie A, Grasso C, Bahniuk N, et al. The combination of merope-
cokinetic analysis of colistin methanesulfonate and colistin after nem and levofloxacin is synergistic with respect to both Pseudo-
intravenous administration in critically ill patients with infec- monas aeruginosa kill rate and resistance suppression.
tions caused by gram-negative bacteria. Antimicrob Agents Che- Antimicrob Agents Chemother 2010;54(6):2646–2654
mother 2009;53(8):3430–3436 201 den Hollander JG, Horrevorts AM, van Goor ML, Verbrugh HA,
185 Dalfino L, Puntillo F, Mosca A, et al. High-dose, extended-interval Mouton JW. Synergism between tobramycin and ceftazidime
colistin administration in critically ill patients: is this the right against a resistant Pseudomonas aeruginosa strain, tested in an
dosing strategy? A preliminary study. Clin Infect Dis 2012;54(12): in vitro pharmacokinetic model. Antimicrob Agents Chemother
1720–1726 1997;41(1):95–100
186 Karvanen M, Plachouras D, Friberg LE, et al. Colistin methanesul- 202 Mouton JW, van Ogtrop ML, Andes D, Craig WA. Use of
fonate and colistin pharmacokinetics in critically ill patients pharmacodynamic indices to predict efficacy of combination
receiving continuous venovenous hemodiafiltration. Antimicrob therapy in vivo. Antimicrob Agents Chemother 1999;43(10):
Agents Chemother 2013;57(1):668–671 2473–2478
187 Markou N, Fousteri M, Markantonis SL, et al. Colistin pharmaco- 203 Zavascki AP, Bulitta JB, Landersdorfer CB. Combination therapy
kinetics in intensive care unit patients on continuous venovenous for carbapenem-resistant Gram-negative bacteria. Expert Rev
haemodiafiltration: an observational study. J Antimicrob Chemo- Anti Infect Ther 2013;11(12):1333–1353
ther 2012;67(10):2459–2462 204 Epstein BJ, Gums JG, Drlica K. The changing face of antibiotic
188 Matthaiou DK, Michalopoulos A, Rafailidis PI, et al. Risk factors prescribing: the mutant selection window. Ann Pharmacother
associated with the isolation of colistin-resistant gram-negative 2004;38(10):1675–1682
bacteria: a matched case-control study. Crit Care Med 2008; 205 Zhanel GG, Mayer M, Laing N, Adam HJ. Mutant prevention
36(3):807–811 concentrations of levofloxacin alone and in combination with
189 Mentzelopoulos SD, Pratikaki M, Platsouka E, et al. Prolonged use azithromycin, ceftazidime, colistin (Polymyxin E), meropenem,
of carbapenems and colistin predisposes to ventilator-associated piperacillin-tazobactam, and tobramycin against Pseudomonas
pneumonia by pandrug-resistant Pseudomonas aeruginosa. In- aeruginosa. Antimicrob Agents Chemother 2006;50(6):
tensive Care Med 2007;33(9):1524–1532 2228–2230
190 Martínez JA, Cobos-Trigueros N, Soriano A, et al. Influence of 206 Lister PD, Wolter DJ. Levofloxacin-imipenem combination pre-
empiric therapy with a beta-lactam alone or combined with an vents the emergence of resistance among clinical isolates of
aminoglycoside on prognosis of bacteremia due to gram-negative Pseudomonas aeruginosa. Clin Infect Dis 2005;40(2, Suppl 2):
microorganisms. Antimicrob Agents Chemother 2010;54(9): S105–S114
3590–3596 207 Firsov AA, Vostrov SN, Lubenko IY, Portnoy YA, Zinner SH.
191 Kumar A, Zarychanski R, Light B, et al; Cooperative Antimicrobial Prevention of the selection of resistant Staphylococcus aureus
Therapy of Septic Shock (CATSS) Database Research Group. Early by moxifloxacin plus doxycycline in an in vitro dynamic model:
combination antibiotic therapy yields improved survival com- an additive effect of the combination. Int J Antimicrob Agents
pared with monotherapy in septic shock: a propensity-matched 2004;23(5):451–456
analysis. Crit Care Med 2010;38(9):1773–1785 208 Drusano GL, Liu W, Fregeau C, Kulawy R, Louie A. Differing effects
192 Kumar A, Safdar N, Kethireddy S, Chateau D. A survival benefit of of combination chemotherapy with meropenem and tobramycin
combination antibiotic therapy for serious infections associated on cell kill and suppression of resistance of wild-type Pseudomo-
with sepsis and septic shock is contingent only on the risk of nas aeruginosa PAO1 and its isogenic MexAB efflux pump-over-
death: a meta-analytic/meta-regression study. Crit Care Med expressed mutant. Antimicrob Agents Chemother 2009;53(6):
2010;38(8):1651–1664 2266–2273

209 Mendes RE, Fritsche TR, Sader HS, Jones RN. Increased antimicro- 214 Taccone FS, Laterre PF, Spapen H, et al. Revisiting the loading dose
bial susceptibility profiles among polymyxin-resistant Acineto- of amikacin for patients with severe sepsis and septic shock. Crit
bacter baumannii clinical isolates. Clin Infect Dis 2008;46(8): Care 2010;14(2):R53
1324–1326 215 Rea RS, Capitano B, Bies R, Bigos KL, Smith R, Lee H. Suboptimal
210 Mantzarlis K, Makris D, Manoulakas E, Karvouniaris M, Zakyn- aminoglycoside dosing in critically ill patients. Ther Drug Monit
thinos E. Risk factors for the first episode of Klebsiella pneumoniae 2008;30(6):674–681
resistant to carbapenems infection in critically ill patients: a 216 Gonçalves-Pereira J, Póvoa P. Antibiotics in critically ill patients: a
prospective study. Biomed Res Int 2013;2013:850547 systematic review of the pharmacokinetics of β-lactams. Crit Care
211 Micek ST, Ward S, Fraser VJ, Kollef MH. A randomized controlled 2011;15(5):R206
trial of an antibiotic discontinuation policy for clinically suspected 217 Buerger C, Plock N, Dehghanyar P, Joukhadar C, Kloft C. Pharma-
ventilator-associated pneumonia. Chest 2004;125(5):1791–1799 cokinetics of unbound linezolid in plasma and tissue interstitium
212 Chastre J, Wolff M, Fagon JY, et al; PneumA Trial Group. Compari- of critically ill patients after multiple dosing using microdialysis.
son of 8 vs 15 days of antibiotic therapy for ventilator-associated Antimicrob Agents Chemother 2006;50(7):2455–2463
pneumonia in adults: a randomized trial. JAMA 2003;290(19): 218 Tsuji BT, Brown T, Parasrampuria R, et al. Front-loaded linezolid
2588–2598 regimens result in increased killing and suppression of the
213 Singh N, Rogers P, Atwood CW, Wagener MM, Yu VL. Short- accessory gene regulator system of Staphylococcus aureus. Anti-
course empiric antibiotic therapy for patients with pulmonary microb Agents Chemother 2012;56(7):3712–3719

infiltrates in the intensive care unit. A proposed solution for 219 Mohd Hafiz AA, Staatz CE, Kirkpatrick CM, Lipman J, Roberts JA.
indiscriminate antibiotic prescription. Am J Respir Crit Care Med Continuous infusion vs. bolus dosing: implications for beta-
2000;162(2, Pt 1):505–511 lactam antibiotics. Minerva Anestesiol 2012;78(1):94–104

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Concentration-dependent antibiotics (Cmax/MIC)

Concentration- with/without time-dependence (AUC/MIC)

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stands, a quinolone dosing regimen that maximizes the Aminoglycosides

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