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REVIEWS OF ANTI-INFECTIVE AGENTS

INVITED ARTICLE

Louis D. Saravolatz, Section Editor

Recent Updates on the Role of Pharmacokineticspharmacodynamics in Antimicrobial


Susceptibility Testing as Applied to Clinical
Practice
Matthew J. Labreche,1 Christopher J. Graber,2 and Hien M. Nguyen1
1

Kaiser Permanente Northwest, Portland, Oregon; 2Infectious Diseases Section, VA Greater Los Angeles Healthcare System and the David Geffen School of
Medicine at the University of California

Given current challenges in antimicrobial resistance and drug development, infectious diseases clinicians must
rely on their own ingenuity to effectively treat infections while preserving the current antimicrobial armamentarium. An understanding of pharmacokinetics (PK), pharmacodynamics (PD), antimicrobial susceptibility
testing (AST), and how these concepts relate, is essential to this task. In this review, we discuss how and why
PK-PD impacts AST and the way infectious diseases are being treated, with a particular focus on vancomycin for
methicillin-resistant Staphylococcus aureus, penicillin for Streptococcus pneumoniae, and an update on cephalosporins for Enterobacteriaceae. Finally, we address how new ideas to exploit PK-PD can promote innovative
study design and bring about more rapid regulatory review of new antimicrobials.
Keywords. pharmacokinetics; pharmacodynamics; breakpoints; susceptibility testing.

OVERVIEW OF PK-PD
Pharmacokinetics (PK) describes drug concentrations
over time in the host and at the site of action, whereas
pharmacodynamics (PD) describes the effect of the
drug on the targeted disease and the patient [1]. PKPD describes the triangular relationship between the
effect of the antimicrobial on the infecting organism,
typically measured in vitro (PD), antimicrobial exposure to the infecting organism in vivo (PK), and clinical
and microbiological outcomes in the host [2]. Bacterial
killing is best described by indices that incorporate
the antimicrobials PK and PD parameters and the
minimum inhibitory concentration (MIC), the lowest

Received 20 January 2015; accepted 13 June 2015; electronically published 23


June 2015.
Correspondence: Hien M. Nguyen, MD, 9900 SE Sunnyside Rd, Clackamas, OR
97015 (hien.m.nguyen@kp.org).
Clinical Infectious Diseases 2015;61(9):144652
The Author 2015. Published by Oxford University Press on behalf of the Infectious
Diseases Society of America. All rights reserved. For Permissions, please e-mail:
journals.permissions@oup.com.
DOI: 10.1093/cid/civ498

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REVIEWS OF ANTI-INFECTIVE AGENTS

concentration of an antimicrobial required to prevent


the growth of the target organism. These indices include: duration of time the free drug concentration remains above the MIC ( f T > MIC), the ratio of the peak
free drug concentration to the MIC ( f Cmax:MIC), and
the ratio of the area under the 24 hour free drug concentration time-curve to the MIC ( fAUC:MIC) (Figure 1)
[3, 4]. Antimicrobials are linked to PK-PD indices that
best describe their antimicrobial effects: in particular,
f T > MIC for -lactams, fAUC:MIC for vancomycin,
uoroquinolones, and aminoglycosides, of which uoroquinolones and aminoglycosides have both also been
linked with the f Cmax:MIC index [5]. PK-PD indices can
be further categorized as time-dependent ( f T > MIC),
concentration-dependent ( f Cmax:MIC), or some combination of the 2 ( fAUC:MIC). These indices are evaluated both in vivo and in vitro, and through population
modeling using Monte Carlo simulations (computer
algorithms in which repeated random sampling is done
to obtain a probability distribution) to predict the probability of target attainment at different index thresholds
using different dosing regimens [6].

Diseases Society of America (IDSA) guidelines in 1997 [13], is


dened as the optimal selection, dose, and duration of an antimicrobial that results in the best clinical outcome, for the
treatment or prevention of infection, with minimal toxicity
to the patient and minimal impact on subsequent resistance
development [8]. Modern-day antimicrobial stewardship
aims to employ the clinical application of PK-PD principles
while providing the narrowest coverage for the infection at
hand.
ANTIMICROBIAL SUSCEPTIBILITY TESTING
AND BREAKPOINTS

Figure 1. Pharmacokinetics-pharmacodynamics (PK-PD) Indices. Graphical representation of three commonly used PK-PD indices. f Cmax/MIC: ratio
of peak drug concentration to the organism minimum inhibitory concentration (MIC); commonly employed index for the aminoglycosides. fAUC/MIC:
ratio of the area under the 24 hour concentration curve to the organism
MIC; commonly employed index for vancomycin and the uoroquinolones.
f T > MIC: percent time of the dosing interval the drug concentration
remains above the organism MIC; commonly employed index for the
-lactams.

HISTORY OF PK-PD
Harry Eagle is considered the founder of antimicrobial PK-PD
through his investigations of the time-dependent killing of penicillin in the 1940s1950s [7]. In the 1970s, Shah and colleagues
introduced the concept of classifying the activity of an antimicrobial as time- or concentration-dependent [8]. Antimicrobial
PK-PD underwent a renaissance in the mid-1970s when Craig
and others discovered its potential for predicting therapeutic
outcome in animal models [9]. From the 1990s to 2000s, Forrest, Drusano, and Ambrose evaluated clinical data from
human subjects to characterize antimicrobial PK-PD relationships for efcacy [1012]. These PK-PD targets for efcacy in
humans were subsequently shown to be concordant with
those based on animal data, thus, demonstrating the utility of
preclinical PK-PD targets for efcacy [4]. Using such targets, together with population pharmacokinetics and Monte Carlo
simulation, dosing regimens associated with high probabilities
of PK-PD target attainment can be identied [6].
Meanwhile, clinicians identied the need for promotion of
appropriate antimicrobial utilization to improve clinical outcomes and prevent adverse effects, including the development
of antimicrobial resistance. The term antimicrobial stewardship, introduced by Dale Gerding and rst appearing in
Society for Healthcare Epidemiology of America and Infectious

The primary concern of the prescribing clinician is that the selected antimicrobial will disable the offending organism, producing a good clinical outcome. It is often assumed that this
will be the case when an organism is reported as susceptible
to the chosen antimicrobial(s) and the converse when an organism is reported as intermediate or resistant. Antimicrobial
susceptibility testing (AST), however, is often based on the response of the organism to an antimicrobial in testing media,
and the S-I-R (susceptible, intermediate, and resistant) nomenclature does not necessarily convey exclusivity in categorizing
predicted clinical response [14]. Some have proposed the 90
60 rule, to describe the observation that a favorable therapeutic
outcome is seen approximately 90% or 60% of time when an
isolate is reported as susceptible or resistant, respectively [15].
The relationship between S-I-R and clinical outcome has become more predictable in recent years, largely due to better understanding and application of PK-PD to AST [16].
Susceptibility testing provides quantitative results (usually
with MIC values). As described in examples later in this manuscript, these quantitative values may allow for greater individualization of antimicrobial therapy. However, these values are
often presented in qualitative format as S, I, or R on the basis
of interpretive criteria. Interpretive criteria for in vitro susceptibility testing, or breakpoints, have signicantly changed in
recent years, largely due to trends in bacterial resistance and advancements in the elds of microbiologic diagnostics and PKPD. The term breakpoints often creates confusion because of
its use to describe microbiologic, pharmacologic, and clinical
thresholds. In an effort to provide clarity, Turnidge and Paterson
have recommended that breakpoints be renamed and separated
into 3 categories: epidemiological cutoffs, PK-PD cutoffs, and
clinical cutoffs [3]. Epidemiological cutoffs separate the population of wild-type organisms without innate or acquired resistance mechanisms from those with such mechanisms. PK-PD
cutoffs, derived from PK-PD modeling (ie, Monte Carlo simulations), utilize knowledge of antimicrobial PK and PD parameters
to identify MICs that best predict the probability of target attainment for specic bug-drug combinations. Finally, clinical cutoffs

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identify the threshold MIC values that divide isolates with a


high vs low likelihood of clinical success upon treatment with
a particular antimicrobial agent. The authors recommend that
the term breakpoint represent the nal value selected to be
applied in AST. Unfortunately, there is no single formula that
can assist in the construction of breakpoints. An array of data is
considered, including clinical outcome studies, microbiological
outcome studies, epidemiologic studies, genotypic/phenotypic
resistance studies, and other PK-PD studies. The paucity of
PK-PD data in critically ill patients, who exhibit pathophysiologic changes not present in healthy volunteers, and clinical
outcome data in patients with specic infecting organism
MIC values, present major challenges to identifying threshold
MIC values [17, 18].
AGENCIES THAT DETERMINE ANTIMICROBIAL
BREAKPOINTS
In the United States, the Clinical and Laboratory Standards Institute (CLSI), formerly the National Committee for Clinical
Laboratory Standards, and the Food and Drug Administration
(FDA) are responsible for setting breakpoint standards. In
Europe, the main agencies are the European Union Committee
on Antimicrobial Susceptibility Testing (EUCAST) and the
European Medicines Agency (EMA). Breakpoints developed
by these agencies conict at times and have caused confusion
for clinical microbiologists, drug and equipment manufacturers,
and practicing clinicians.
The 2 main, nongovernmental agencies, CLSI and EUCAST,
differ in philosophy and approach toward setting antimicrobial
breakpoints as well as in how they report to their respective governmental counterparts, the FDA and EMA (Table 1) [19]. By

law, US manufacturers are required to follow FDA breakpoints


for drug approval and for AST systems that interpret MIC data.
All too often, CLSI and FDA breakpoints do not agree, as illustrated in Table 2 [16, 2023]. In contrast, EUCAST operates as
the breakpoint committee for the EMA.
EUCAST has employed 2 different MIC values: clinical
breakpoints and epidemiologic cutoffs, the latter of which has
greater sensitivity for detecting changes in antimicrobial susceptibility [24]. In contrast, CLSI only utilizes clinical breakpoints, which tend to be higher than those of EUCAST.
Consequently, more resistant organisms may go undetected
when CLSI breakpoints are applied [25]. When data do not
clearly support a particular PK-PD target, EUCAST will prioritize epidemiologic cutoff values to avoid splitting the MIC distribution of the wild-type population, or they will not establish a
clinical breakpoint. Hence, EUCAST clinical breakpoints are
generally lower than those of CLSI. Part of the rationale for
CLSIs higher clinical breakpoints is CLSIs use of the intermediate category. CLSI fundamentally denes the intermediate
category as being associated with a lower response rate, but clinical efcacy can be obtained if adequate drug levels are achieved
[26]. EUCAST, on the other hand, has largely done away with
the intermediate category, perceiving it as a grey zone to prevent
serious categorization errors with unpredictable therapeutic
response. More recently, CLSI has modied the intermediate
category to include susceptible dose-dependent (SDD) breakpoints for cefepime and the Enterobacteriaceae [27].
The realization that antimicrobial resistance is a global problem argues for harmonization of antimicrobial breakpoints
across agencies. Much work is still required, particularly for
CLSI and EUCAST clinical breakpoints established for older
antimicrobials [28]. In response, the National Antimicrobial

Table 1. Comparison of Clinical Laboratory Standard Institute and European Committee for Antimicrobial Susceptibility Testing
CLSI

EUCAST

Members

Representatives from different fields and agencies

Representatives from different fields and


agencies

Role of government

Recognized by FDA, but FDA still determines its own


breakpoints. Breakpoints determined by FDA can be
modified by CLSI after 2 yr

Functions as breakpoint committee for EMA

Role of industry

Part of decision process

Consultative role

Decision making
Funding

Consensus by group votes


Industry, government and sales of documents

Consensus of executive committee (no vote)


ESCMID, ECDC, government

Data and Rationale


documents
Meetings

For sale
www.clsi.org
2 per year

Free
www.eucast.org
5 per year

Breakpoints

Clinical breakpoints
Retains intermediate category, expanding concept of SDD

Epidemiological cutoffs
Clinical breakpoints
Largely abandoned intermediate category

Abbreviations: CLSI, Clinical Laboratory Standard Institute; ECDC, European Center for Disease Control and Prevention; EMA, European Medicines Agency;
ESCMID, European Society Clinical Microbiology and Infectious Diseases; EUCAST, European Union Committee for Antimicrobial Susceptibility Testing; FDA,
US Food and Drug Administration; SDD, susceptible dose-dependent.

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Table 2. Clinical Laboratory Standards Institute, European Union Committee for Antimicrobial Susceptibility Testing, and US Food and
Drug Administration Clinical Breakpoints for Enterobacteriaceae and Common Intravenous Cephalosporins
Clinical Breakpoints (Susceptible, g/mL)
CLSI
IV Agents

Pre-2010 [16]

2010 [16, 20]

Current [21]

EUCAST/EMA
Current [22]

FDA
Current [23]

Cefazolin

...

16

Cefuroxime
Ceftriaxone

8
8

8
1

8
1

8
1

8
1

Ceftazidime

16

Cefepime
Aztreonam

8
8

8
4

2, SDD (48)
4

1
1

8
4

Abbreviations: CLSI, Clinical Laboratory Standards Institute; EMA, European Medicines Agency; EUCAST, European Union Committee for Antimicrobial
Susceptibility Testing; FDA, US Food and Drug Administration; IV, intravenous; SDD, susceptible dose-dependent.

Susceptibility Testing Committee for the USA (USCAST; www.


uscast.org) was created in 2013 as a national branch of
EUCAST. The overarching goals of USCAST are to work closely
with EUCAST, the FDA. and EMA to harmonize AST, to
provide access to clinical breakpoints data and guidelines, to
educate healthcare specialists, and to facilitate new drug
development.
The following examples highlight the inuence of PK-PD
studies on breakpoint development as it applies to antimicrobial
utilization. There are many other examples in which PK-PD
studies have inuenced the approach to antimicrobial therapy
(eg, use of vancomycin loading doses, continuous infusion of
piperacillin-tazobactam, once-daily aminoglycoside dosing,
and therapeutic drug monitoring), but they are beyond the
scope of this manuscript.
RECENT IMPACT OF PK-PD ON BREAKPOINT
DEVELOPMENT
Methicillin-resistant Staphylococcus aureus (MRSA) and
Vancomycin

Until the early 2000s, when used in the treatment of staphylococcal infections, vancomycin was commonly dosed to avoid
trough levels >10 g/mL, which were thought to promote toxicity [29]. A trend toward more aggressive dosing to achieve
higher trough levels subsequently emerged, based in part on
PK-PD data suggesting that achieving an AUC/MIC 400 improved clinical outcomes in patients with Staphylococcus aureus
pneumonia [30]. In 2006, CLSI also lowered the methicillinresistant Staphylococcus aureus (MRSA) clinical breakpoint to
2 g/mL over concern for heteroresistance and worsened clinical outcomes at higher vancomycin MIC values [31]. IDSA
guidelines subsequently recommended targeting trough levels
of 1520 g/mL for severe infections caused by organisms susceptible to vancomycin within this new susceptibility range,

though there remains considerable controversy regarding the


ability of a vancomycin MIC of 1.5 to 2.0 g/mL to predict vancomycin failure and whether or not current dosing strategies can
achieve the AUC/MIC target of 400 at these MICs [3234].
Penicillin-resistant Streptococcus pneumoniae and Penicillin

Unlike the clinical breakpoints for many antimicrobials, which


have been lowered out of concerns for evolving resistance, clinical breakpoints for penicillin against Streptococcus pneumoniae
were raised in 2008 to encourage its use [35]. Penicillin clinical
breakpoints for S. pneumoniae were established in the 1970s
primarily to guide the treatment of meningitis. In the 1990s,
there was a dramatic spike in penicillin-resistant S. pneumoniae
in the United States; however, higher penicillin MIC values did
not necessarily result in poor outcomes, particularly for infections outside the central nervous system [35]. In response, CLSI
established three separate penicillin clinical breakpoint categories in 2008: meningitis (intravenous), non-meningitis (intravenous), and non-meningitis (oral). For meningitis, the pre-2008
CSF breakpoints did not change [0.06 g/mL (susceptible)
and 0.12 g/mL (resistant)]. For non-meningitis infections,
the serum breakpoints were increased to 2 g/mL (susceptible), 4 g/mL (intermediate) and 8 g/mL (resistant). The introduction of these nonserum clinical breakpoints set a new
precedent and increased the utility of IV penicillin for pneumococcal pneumonia and other upper respiratory infections when
higher doses are given (ie, at least 10 million units per day). Further, PK-PD studies suggest the use of higher doses of oral
amoxicillin (which has better bioavailability than oral penicillin) against pneumococcal isolates with higher penicillin
MICs [35, 36].
Cefazolin and Enterobacteriaceae

Particular disharmony has been seen in cefazolin AST for Enterobacteriaceae. In 2010, CLSI lowered the cefazolin susceptibility

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breakpoint against the Enterobacteriaceae from 8 to 1 g/mL


[20]. It was soon recognized that the new breakpoint was set
too low and would needlessly eliminate the use of this drug
against Escherichia coli, Klebseilla spp, and Proteus mirabilus.
In 2011, CLSI increased the cefazolin susceptibility breakpoint
to 2 g/mL, contingent upon use of cefazolin dosage of 2 gm
IV every 8 hours (based on PK-PD considerations) instead of
the typical 1 gm IV every 8 hours [20]. However, clinical microbiology laboratories are not required to report dosage suggestions and this recommendation remained unknown to many
clinicians. The FDA did not adopt the lower CLSI clinical
breakpoints and still referred to the older susceptibility breakpoint of 8 g/mL. As a result, FDA-endorsed automated
AST systems were outdated in their clinical breakpoint recommendations. In addition, many automated AST panels could
not be modied to test a cefazolin MIC of 2 g/mL. Hence,
labs were left on their own to decide how best to test for cefazolin susceptibility.
Urinary Breakpoints for Cephalosporins vs Enterobacteriaceae

-lactams and cephalosporins have long been considered inferior to other antimicrobial classes for the treatment of urinary
tract infections (UTI) caused by Enterobacteriaceae [37]. In past
CLSI guidelines, as recent as 2013, it was suggested that cephalothin susceptibility could predict that of cephalexin, cefadoxil,
loracarbef, and cefpodoxime for uncomplicated UTIs and
breakpoints for many oral cephalosporins were not established
[38]. However, as previously identied, cephalothin is a poor
class representative of these oral cephalosporins [39].
The majority of clinical microbiology laboratories and clinicians in the United States rely on the susceptibility of cefazolin
to predict the susceptibly of cephalexin, a commonly used oral
1st generation cephalosporin [39]. However, the use of the current CLSI serum cefazolin susceptibility breakpoint of 2 g/
mL would overpredict cephalexin resistance considering that
cefazolin is more potent than cephalexin [39]. Many microbiologists have lobbied for the development of separate urine breakpoints for oral antimicrobials, including oral cephalosporins,
that concentrate 1001000 higher in urine than serum [40].
From a PK-PD standpoint, these higher urinary concentrations
translate into a greater f T > MIC against urinary pathogens, including those with higher MICs. In 2014, CLSI created a urine
susceptibility breakpoint of 16 g/mL for the use of cefazolin
in uncomplicated UTIs due to E. coli, Klebsiella spp, and P. mirabilis. The cefazolin urine breakpoint can also be used to predict the susceptibility of 7 oral cephalosporins (cephalexin,
cefaclor, cefprozil, cefdinir, cefuroxime, loracarbef, cefdinir,
and cefpodoxime) [41]. Of note, cefazolin can overpredict cefdinir and cefpodoxime resistance; however, clinicians can request individual AST of these 3rd generation cephalosporins
on a case-by-case basis. It must be stressed that clinicians

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should not apply the new urine cefazolin susceptibility breakpoint to the treatment of complicated UTIs and pyelonephritis,
where the serum breakpoint (2 g/mL) may be more appropriate given involvement of disease above the bladder.
Extended-spectrum -lactamase (ESBL) and Cephalosporins

Breakpoints for cephalosporins against Enterobacteriaceae (eg,


E. coli, Klebsiella spp, P. mirabilis) were established in the 1980s
based mostly on in vitro data; clinical outcome and PK-PD data
were either not available at the time or largely not considered
[16]. Rising cephalosporin MICs in the early 2000s aroused
fear that CLSI and EUCAST clinical breakpoints could not
fully detect Enterobacteriaceae that harbor extended-spectrum
-lactamases (ESBL), which hydrolyze most cephalosporins
[27]. In the mid-2000s, CLSI and EUCAST implemented a temporary solution to detect ESBL producers that did not rely directly on MICs. This involved placing a ceftazidime or
cefotaxime disk next to a clavulanate disk (an inhibitor of
ESBLs) [42]. If clavulanate reverses ceftazidime/cefotaxime resistance, this phenotypic test is considered positive, and the isolate
is reported as an ESBL producer, resistant to all cephalosporins
(including cefepime) and aztreonam.
However, studies demonstrated that drug response in vivo
was fundamentally similar between ESBL- and non-EBSL producing isolates and could be predicted based on the MIC [43].
In response, EUCAST and CLSI both lowered clinical breakpoints for most cephalosporins against E. coli, Klebsiella spp,
and P. mirabilis (Table 2) [27]. ESBL phenotypic testing is no
longer recommended for AST in the vast majority of clinical
situations, with the dual benet of eliminating a labor-intensive
process and increasing the utility of cephalosporins ( particularly cefepime and ceftazidime) as treatment options for ESBL producers [27]. Both CLSI and EUCAST recommend that the ESBL
phenotypic test still be considered, but only for epidemiologic
purposes.
Cefepime and Susceptible Dose-dependent

Cefepime is a 4th generation cephalosporin with higher stability


against some -lactamases compared with earlier generation
cephalosporins [44]. This stability against resistant organisms
led CLSI to maintain the cefepime breakpoints while lowering
those of other cephalosporins in 2010 [27]. However, new clinical data emerged suggesting that higher cefepime MIC values
among Enterobacteriaceae were associated with worse outcomes despite susceptible MIC values 8 g/mL [45]. For comparison, EUCAST has set the cefepime susceptibility breakpoint
at 1 g/mL dating back to at least 2009. In 2014, CLSI lowered
cefepimes clinical breakpoints to 2 g/mL (susceptible) and
>8 g/mL (resistant). CLSI also created a new AST category
for cefepime known as SDD with a MIC range of 48 g/mL.
The intention of this category is to promote the use of higher

REVIEWS OF ANTI-INFECTIVE AGENTS

doses of cefepime (2 gm every 12 hours or 12 gm every 8 hour)


for elevated MICs to achieve the PK-PD index associated with
efcacy ( f T > MIC) [27]. If this trend is successful, CLSI may
apply the SDD category to other antimicrobials in the future.

Clinicians must be educated to be stewards of antimicrobials


while other invested partiesresearch, academia, industry,
and governmentmust coordinate their efforts in order to
combat antimicrobial resistance and facilitate the development
of new antimicrobials and effective treatment strategies.

PK-PD AND DRUG DEVELOPMENT


Note

As described above, PK-PD has helped clinicians to make better


use of currently available antimicrobials. However, PK-PD may
play yet another important role in the development of new antimicrobial agents. Currently, there is a critical need to expedite
the regulatory pathways for new drug development and approval [46]. Traditionally, new drugs are evaluated through
noninferiority trials using historical controls to measure the
magnitude of the treatment effect. However, regulatory uncertainty on clinical and surrogate endpoints and their ability to
appropriately capture meaningful treatment effects has undermined noninferiority designs. A Bayesian pharmacometricbased approach utilizing PK-PD provides an alternative pathway
to measure treatment effect and restore the statistical power of
noninferiority studies [47]. This pharmacometric approach utilizes available clinical and microbiological response study data, PKPD study data, and the appropriate PK-PD index (eg, f T > MIC,
fAUC: MIC, f Cmax:MIC) to estimate the placebo-response rate
(ie, when PK-PD index approaches zero). The treatment effect
is the difference in likelihood of clinical (or microbiological) success between the maximal (intervention) and minimal (placebo)
drug exposure according to the PK-PD index examined. According to Ambrose, this approach would involve 3 phases:[48, 49] in
vitro and in vivo studies to evaluate antimicrobial activity and
identify the best PK-PD index to describe antimicrobial activity;
a randomized-controlled trial of patients infected with wild-type
phenotype pathogens to collect PK-PD and clinical response
data; and nally, a noncomparative trial involving only patients
with pathogens having the resistant phenotype of interest to collect PK-PD and clinical response data. This pharmacometric approach would negate the need and difculty of recruiting for a
large randomized controlled trial in patients with resistant
organisms.
CONCLUSION
Clinicians now practice in an age where a single susceptibility
breakpoint may not accurately predict a favorable clinical outcome. Resistance mechanisms, site of infection and dosing regimen, among other variables, must be considered. Signicant
progress has been made in the elds of PK-PD and AST over
the past few decades to inform these decisions. These developments come at an auspicious time given the current crisis of
multidrug resistant organisms and the scarcity of effective
and/or safe antimicrobials to treat the infections they cause.

Potential conicts of interest. All authors: No potential conicts of


interest.
All authors have submitted the ICMJE Form for Disclosure of Potential
Conicts of Interest. Conicts that the editors consider relevant to the content of the manuscript have been disclosed.

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