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INVITED ARTICLE
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
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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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Table 1. Comparison of Clinical Laboratory Standard Institute and European Committee for Antimicrobial Susceptibility Testing
CLSI
EUCAST
Members
Role of government
Role of industry
Consultative role
Decision making
Funding
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]
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.
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,
Particular disharmony has been seen in cefazolin AST for Enterobacteriaceae. In 2010, CLSI lowered the cefazolin susceptibility
1449
-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
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