Optimizing and

Maximizing Antibiotic
Therapy
JAIME C. MONTOYA, MD, MSc, PhD
Professor V
University of the Philippines College of Medicine
Executive Director
Philippine Council for Health Research and Development
Department of Science and Technology

Optimal Antibiotic Therapy

including
resistant strains

PK-PD relationships between

antibiotics and key
nosocomial pathogens

Eur Respir Rev 2007; 16: 103, 3339

Optimal Antibiotic Therapy

Involves the use of antibiotics that achieves
maximum therapeutic effect with minimum
selective pressure for resistance
Balance between potency and efficacy with
potential for induction of antimicrobial resistance

Polk. Clin Infect Dis 1999;29:264-274

Components of Optimal
Antibiotic Therapy
Includes:
optimal selection (based on predicted
pathogens, activity and efficacy, host
characteristics, toxicity, cost)
dose and duration of treatment (based on PK/PD
of the antibiotic, site of infection, severity of
infection)
control of antibiotic use that will prevent or slow
down the emergence of resistance among
micro-organisms
Polk. Clin Infect Dis 1999;29:264-274

Need for Optimal Antibiotic

Therapy
Increasing number of cases of antibiotic failure
Decreasing number of new antibiotics in the
pipeline
Need to maximize the efficacy of existing
antibiotics
Preserve their potency and reduce the problems
of antimicrobial resistance

How to Choose the

Appropriate Antimicrobial
Therapy

Factors Affecting Choice of

Antibiotics
Defining whether it is for empiric, definitive or
prophylactic therapy
Identifying the site of infection ( for determining
antibiotic penetration)
Identifying the most probable etiologic agent/s
and the predicted susceptibilities (based on local
or unit antibiograms) and proper interpretation of
DST
Defining the immune status of the host (eg,
immunocompromised vs immunocompetent)
Defining the severity of infection

Types of Antibiotic Therapy

Type of Therapy

Description

Use of
Antibiograms

Prophylaxis

Antibiotics used to
prevent infection

Selection of antibiotic

Empiric

Organism is unknown
but syndrome is
known

Selection of antibiotic
or combination of
antibiotics

Pathogen-directed

Organism is known
but susceptibility is
unknown

Selection of antibiotic

Susceptibility-guided

Organism is known
and susceptibility is
known

Cumulative
antibiogram not
useful

Factors Affecting Choice of

Antibiotics
Defining whether it is for empiric, definitive or
prophylactic therapy
Identifying the site of infection ( for determining
antibiotic penetration)
Identifying the most probable etiologic agent/s
and the predicted susceptibilities (based on local
or unit antibiograms) and proper interpretation of
DST
Defining the immune status of the host (eg,
immunocompromised vs immunocompetent)
Defining the severity of infection

Factors Affecting Choice of

Antibiotics
Defining whether it is for empiric, definitive or
prophylactic therapy
Identifying the site of infection ( for determining
antibiotic penetration)
Identifying the most probable etiologic agent/s
and the predicted susceptibilities (based on local
or unit antibiograms) and proper interpretation of
DST
Defining the immune status of the host (eg,
immunocompromised vs immunocompetent)
Defining the severity of infection

Unit-Specific or Hospital-Specific Cumulative

Antibiotic Susceptibility Report or
"Antibiogram"
Helpful

for choosing empiric and pathogendirected treatment regimens.

antibiotic susceptibility reports on individual
patients is clearly of use to ensure that
antimicrobial treatment was adequate for
the organism causing the infection.

Unit-Specific or Hospital-Specific Cumulative

Antibiotic Susceptibility Report or
"Antibiogram"
It

also assists in antibiotic "streamlining" -the process by which excessively broadspectrum empiric antibiotic therapy can be
switched to narrower spectrum therapy
aimed only at the implicated pathogen(s).

Empiric Antibiotic Therapy

Choice of antibiotics rests on the likely organisms
causing that particular type of infection.
For example, for uncomplicated urinary tract
infection, E coli predominates; for communityacquired pneumonia, Streptococcus pneumoniae;
and
for
ventilator-associated
pneumonia,
Pseudomonas
aeruginosa,
S
aureus,
Enterobacter cloacae, and Klebsiella pneumoniae
are most frequently isolated

Difficulty of Hospital Micro Lab

It may be difficult for a microbiologist to determine
whether organisms are community-acquired or
hospital-acquired.
Hospital laboratories should know the ward in
which the patient was residing at the time when
the isolate was collected.

Importance of Appropriate
Antibiotic Therapy
For patients in ICUs, mortality rises if the empiric
antibiotic therapy chosen does not cover the
pathogens causing the infection.[1-4]
Kollef and colleagues[1] showed that infectionrelated mortality was 17.7% in those patients who
received appropriate empiric antibiotic therapy vs
42.0% in those patients who received
inappropriate empiric antibiotic therapy.
most common reason why empiric antibiotic
therapy was inappropriate was resistance of the
bacteria to the antibiotic chosen

Strategy to ensure appropriate

antibiotics
Ibrahim and colleagues[5] reviewed the
antibiogram for their particular ICU and created a
clinical guideline for antibiotic selection in that
unit.
Adequacy of empiric antibiotic selection for
ventilator-associated pneumonia for patients in
their ICU increased from 48.0% before the
creation of antibiotic guidelines to 94.2% with the
use of their guidelines.

Antibiogram-based Guideline
does not have an unlimited duration of utility.
shifts in antibiotic usage engendered by the
creation of the guideline will, over time, lead to a
change in resistance patterns.
it is prudent to update antibiograms and
antibiogram-based antibiotic guidelines on a
regular basis. A yearly review should be regarded
as a bare minimum.

Importance of Unit or Site Based

Antibiogram
Do hospital-wide antibiograms give an accurate
indication of antibiotic resistance in a particular
unit within the hospital.
Namias and colleagues[6] showed that ICU
antibiograms differed substantially from the
antibiogram for the entire hospital.
In general, unit-specific hospital antibiograms
serve more utility in showing which antibiotics
should be avoided for specific infections rather
than which antibiotics should be used.

Importance of National
Antibiograms
First, it allows for a comparison of local data with
national data to determine whether the extent of
resistance is better or worse than national
averages.
Second, it provides the ability to presage future
trends in antibiotic resistance: If resistance is
rising for a particular pathogen at a national level,
it may be only a matter of time before resistance
rates rise locally.

Criteria for Empiric Antibiotic

Therapy
likely pathogens (and their susceptibility profiles)
at any particular infection site are known.
Cumulative antibiotic susceptibility reports on
multiple patients (antibiograms) or national
susceptibility data can be useful in guiding
empiric antibiotic therapy.
recent antibiotic use and known bacterial
colonization status.

Factors Affecting Choice of

Antibiotics
Defining whether it is for empiric, definitive or
prophylactic therapy
Identifying the site of infection ( for determining
antibiotic penetration)
Identifying the most probable etiologic agent/s
and the predicted susceptibilities (based on local
or unit antibiograms) and proper interpretation of
DST
Defining the immune status of the host (eg,
immunocompromised vs immunocompetent)
Defining the severity of infection

How to Give Antimicrobial

Therapy in the Critically Ill
Patient

Dosing based on
Hemodynamic changes in the critically ill
patient (severity of infection)
Body weight of the patient (e.g. obese)
PK/PD of the antibiotic
Presence of medical comorbidities that will
affect metabolism of the antibiotic

Hemodynamic Changes in the

critically ill patient

alter the
concentration-time
relationship
reduce the
exposure of
antibiotics to
bacteria

Roberts, J. and Lipman, J. CCM 2009

Hemodynamic Changes in the

Critically Ill Patient

Patients may have augmented renal clearances

needing either higher doses or more frequent
dosing to overcome increased drug elimination
Udy AA et al. Clin Pharmacokinet 2010; 49: 116.
Udy AA et al. Chest 2012; 142: 309.

Critically ill patients often have low plasma

albumin concentrations that alters the protein
binding of drugs and has significant effects on
pharmacokinetics
Finfer S et al. BMJ 2006; 333: 1044.
Ulldemolins M et al. Clin Pharmacokinet 2011; 50: 112.
Roberts JA et al. Clin Pharmacokinet 2013; 52: 18.

PK/PD of the Antibiotic

Pharmacokinetics

(PK) is concerned
with the time course of antimicrobial
concentrations in the body
Pharmacodyamics (PD) is concerned
with the relationship between those
concentrations and the antimicrobial
effect.

PK/PD of the Antibiotic

Antibiotic

dosing regimens have

traditionally been determined by PK
parameters only.
However, PD plays an equal, if not
more important, role.
these parameters may be used to
design
dosing
regimens
which
counteract or prevent resistance.

MIC of the Antibiotic

The

primary measure of antibiotic activity is

the minimum inhibitory concentration (MIC).
The MIC is the lowest concentration of an
antibiotic that completely inhibits the growth
of a microorganism in vitro.
While the MIC is a good indicator of the
potency of an antibiotic, it indicates nothing
about the time course of antimicrobial
activity.

PK Parameters of the Antibiotic

PK parameters quantify the serum level time
course of an antibiotic.
three pharmacokinetic parameters that are most
important for evaluating antibiotic efficacy :
peak serum level (Cmax),
trough level (Cmin)
Area Under the concentration Curve (AUC).
While these parameters quantify the serum level
time course, they do not describe the killing
activity of an antibiotic.

PK/PD Parameters of the

Antibiotic
Peak/MIC ratio - Cpmax divided by the MIC
T>MIC (time above MIC) - percentage of a
dosage interval in which the serum level exceeds
the MIC
24h-AUC/MIC determined by dividing the 24hour-AUC by the MIC.

Pattern of
activity

Antibiotics

Goal of Therapy

PK/PD
Parameter

Type I
Concentrationdependent killing
and Prolonged
persistent effects

Aminoglycosides
Daptomycin
Fluoroquinolones
Ketolides

Maximize
concentrations

24h-AUC/MIC
Peak/MIC

Type II
Time-dependent
killing and
Minimal
persistent effects

Carbapenems
Cephalosporins
Erythromycin
Linezolid
Penicillins

Maximize
duration of
exposure

T>MIC

Type III
Time-dependent
killing and
Moderate to
prolonged
persistent effects.

Azithromycin
Clindamycin
Oxazolidinones
Tetracyclines
Vancomycin

Maximize amount
of drug

24h-AUC/MIC

 Time-dependent
antibiotics:
the most important
PD parameter is
T>MIC, which should
be maintained >50%
of dosing interval
( e.g. cephalosporins
(cefepime) ,
carbapenems)

Antibiotic (C)

Antimicrobial PD Parameter
to Optimize Therapy of T>MIC Antibiotics

MIC
T>MIC
Time (h)

Drusano GL Clin Infect Dis. 2007 Jul 15;45 Suppl 1:S89-95

McKinnon PS, Davis SL Eur J Clin Microbiol Infect Dis. 2004;23:271-88

Optimizing -lactam Therapy:

Maximizing Percent T>MIC

Higher dose
Increased dosing frequency
Increased duration of infusion
a. Prolonged infusion
b. Continuous infusion

Improved
Potency
(In Vivo Exposure)

Pharmacodynamics of Antimicrobial by David Nicolau , FCCP,FIDSA

Dosing of Beta-Lactams

Drug dosing in the obese patient population have to be

more precise to effectively treat infections.
Obesity alters the disposition of drugs in the body
(pharmacokinetics)
Failure to adjust doses in obesity may result either in
therapeutic failure or increased toxicity.
Total body weight greatly overestimates renal function in
obese patients.
Use of an adjusted body weight (IBW + 0.4 [TBW-IBW])
may provide a more accurate estimate in obese patients
ICAAC 2014

PK/PD changes in the Obese

Volume of distribution (Vd) of drugs may be
altered
Obesity results in increased adipose tissue
mass, which can influence medications with
lipophilic properties
Increased organ mass, lean body mass, and
blood volume in obesity also can affect
hydrophilic medications e.g. aminoglycodises
Can lead to sub- or supra-therapeutic
concentrations.

Wurtz et al.Clin Infect Dis. 1997; 25:112-118.

Blouin RA et al. J Pharm Sci. 1999; 88:1-7.
Cheymol G. Clin Pharmacokinet. 2000; 39:215-231

Optimizing -lactam Therapy:

Maximizing Percent T>MIC

Improved
Higher dose
Potency
Increased dosing frequency
(In Vivo Exposure)
Increased duration of infusion
a. Prolonged infusion
- Same dose and dosing interval,
however, change duration of
infusion (0.5 hr 3hr)
b. Continuous infusion
- Administer loading dose, then use
pump to give total daily dose IV
over 24 hr period
Pharmacodynamics of Antimicrobial by David Nicolau , FCCP,FIDSA

Prolonged Infusion VS Slow IV

Bolus
A population pharmacokinetic model of cefepime
was constructed from data from adult critical
care patients with ventilator-associated
pneumonia (VAP).
A total of 32 patients treated with high-dose
cefepime, 2 g every 8 h (3-h infusion) or a renal
function-adjusted equivalent dose, were
randomized into two groups
Serum samples of cefepime were collected at
steady state.

Nicasio AM et al. Antimicrob Agents Chemother 2009; 53(4):1476-1481

Prolonged Infusion VS Slow IV

Bolus
Among the regimens, the likelihoods of 2 g every
8 h (3-h infusion) achieving free drug
concentrations above the MIC for 50% of the
dosing interval were 91.8%, 78.1%, and 50.3%
for MICs of 8, 16, and 32 g/ml, respectively.
This study provides a pharmacokinetic model
capable of predicting cefepime concentrations in
critically ill patients with VAP.

Nicasio AM et al. Antimicrob Agents Chemother 2009; 53(4):1476-1481

Increasing Order of Optimal

Infusion
Intermittent Dosing < Prolonged
Infusion with Intermittent Dosing
< Continuous Infusion <
Continuous Infusion with Loading
Dose

Optimal Duration of Treatment

with Antibiotics

Need for Optimal Duration of

Therapy

Up to half of the antibiotic use in hospital wards and

critical care units is unnecessary or inappropriate
Excessive durations of treatment are the greatest
contributor to inappropriate use
Reduction in the length of antibiotic courses is, therefore,
a potentially viable strategy to minimize the
consequences of antibiotic overuse in critical care,
including antibiotic resistance, adverse effects,
Clostridium difficile colitis, and costs
Hecker MT et al. Arch Intern Med 2003, 163:972-978
Rice LB.Clin Infect Dis 2008, 46:491-496.
Hayashi Y et al.Clin Infect Dis 2011, 52:1232-1240.
Rubinstein E. Int J Antimicrob Agents 2007, 30:76-79.

Shorter Duration of Antibiotic

Therapy
Limited information about the optimal
duration of antibiotic treatment able to
cure disease without causing microbial
resistance.
Few antibiotic regimens have been
subjected to rigorous evaluation of
treatment duration.

Shorter Duration of Antibiotic

Therapy
Duration of antibiotic treatment necessary
for urinary tract infections in women and
for sexually transmitted diseases have
been well studied
a large series of trials established the
shortest effective antibiotic treatment
regimen for tuberculosis

Rice LB et al.Clin Infect Dis 2008, 46:491-496.

Fox W et al. Int J Tuberc Lung Dis 1999, 3:S231-279

Shorter Duration of Antibiotic

Therapy

However, data are lacking for the optimal

treatment duration for many other
diseases, including diarrhea, meningitis
and pneumonia and also for different
forms of bacteremia or BSI (Blood stream
infections)

Shorter Therapy for CAP

El Moussaoui et al compared outcomes for
cases of mild to moderate-severe
community acquired pneumonia after
treatment with antibiotics for three or
eight days.
Study involved nine hospitals in the
Netherlands and was carried out as a
randomised, double blind, placebo
controlled non-inferiority trial.

El Moussaoui R et al. BMJ 2006;332:1355-8.

Shorter Therapy for CAP

Patients who met entry criteria were treated with
intravenous amoxicillin.
Those who showed significant improvement
after 72 hours were switched to either oral
amoxicillin or placebo for five days.
Clinical and radiological outcomes assessed at
days 10 and 28 were not significantly different.
Study yields strong evidence in favour of short
course therapy for a subset of patients

El Moussaoui R et al. BMJ 2006;332:1355-8.

Optimal Duration of Therapy

Optimal duration of therapy for primary BSI and BSI

secondary to major organ system infections has been
poorly defined.
There is wide variability in antibiotic treatment duration
recommendations from infectious disease and critical
care specialists
Presence of bacteremia is often used as a justification
for extended courses of antibiotic therapy regardless of
the observed clinical response to treatment
Corona A et al. J Antimicrob Chemother 2003, 53:849-852.
Daneman N et al. Int J Antimicr Agents 2011, 38:480-485.

Optimal Duration of Therapy

Randomized controlled trials (RCTs) demonstrated that

treatment can be shortened to 1 week or less without
worsening patient outcomes
It is plausible that treatment duration could potentially be
shortened for BSIs
Kyriakidou KG et al. Clin Ther 2008, 30:1859-1868.
Dimopoulos G et al. Drugs 2008, 68:1841-1854.
Li JZ et al. Am J Med 2007, 120:783-790.

Optimal Duration of Therapy

Harvey et al. conducted a systematic review and

meta-analysis of RCTs explicitly examining the
efficacy of shorter-course versus longer-course
antibiotic therapy for patients with bacteremia as
well as comparable trials examining the organ
system infections most commonly causing
bacteremia in critically ill patients.
Harvey T et al. Critical Care 2011, 15:R267

Forest plot for outcome of clinical cure among bacteremic

subgroups of randomized trials of shorter versus longer antibiotic
treatment.

Forest plot for outcome of microbiologic cure among bacteremic

subgroups of randomized trials of shorter versus longer antibiotic
treatment

Forest plot for outcome of survival among bacteremic

subgroups of randomized trials of shorter versus
longer antibiotic treatment

Optimal Duration of Therapy

Available data from bacteremic subgroups of prior

randomized controlled trials suggest that shorterduration therapy (not more than 7 days) may be as
effective as longer-duration therapy in achieving clinical
cure, microbiologic cure, and survival among most
patients with bloodstream infections.
A large dedicated randomized trial of treatment duration
for bacteremia is urgently needed.
Harvey T et al. Critical Care 2011, 15:R267

Importance of Early
Appropriate and Potent
Antimicrobial Therapy

New Paradigm in Sepsis

Sepsis, Severe Sepsis and Septic shock are
fundamentally different diseases and not a
continuum
Microbial load drives downstream host
responses including development of organ
dysfunction and failure and not the cellular
immune response

Kumar A. Virulence 2014; 5(1):8097

New Paradigm in Sepsis

Elimination of underlying infection should
terminate downstream inflammatory process
leading to organ dysfunction and failure and not
the termination of the inflammatory cascade
But once critical threshold is exceeded,
likelihood of positive outcome is reduced and
irreversibility of organ dysfunction ensues

Kumar A. Virulence 2014; 5(1):8097

Implications
Sepsis, Severe Sepsis and Septic shock are
fundamentally different diseases and not a
continuum
Time of delivery of effective antimicrobial
therapy from onset of hypotension is a
surrogate marker for increasing microbial burden
of organism
Early and Rapid clearance of pathogens is
the most important determinant of outcome in
sepsis

Kumar A. Virulence 2014; 5(1):8097

Importance of Early Initiation of

Antibiotic Therapy

Retrospective study involving 2154 patients with septic

shock
Showed strong correlation between delays in initiating
antibiotic therapy and in-hospital mortality (adjusted odds
ratio [OR], 1.119 deaths/1-h delay; P <.0001).
Time to initiation of appropriate antibiotic therapy was
the strongest predictor of survival
If an effective antibiotic was administered within the
first hour of documented hypotension, the survival
rate was 79.9%; each 1-h delay over the next 6 h
decreased average survival rates by 7.6%.
Kumar A et al. Crit Care Med 2006; 34:158996.

Early targeted antibiotics improved outcomes in

S. aureus bloodstream infections

Appropriate antibiotics initiated within 24 hours

of a positive blood culture, and appropriate
exposure maintained for the duration of therapy
Cure rate was significantly higher (72% vs. 48%,
P = .024)

Weber and Zelenitsky, ICAAC 2014

Parameters for PK/PD Resistance

Curve
MPC (Mutant Prevention Concentration) is
defined as the lowest antibiotic concentration
that prevents growth of the least susceptible
single-step mutants.
Resistant subpopulations are proposed to be
selectively enriched in the mutant selection
window (MSW)that is, the drug concentration
range between the MIC and the MPC

Zhao X et al. Clin Infect Dis 2001; 33(Suppl 3):S14756.

Drlica K et al. Clin Infect Dis 2007; 44:6818.

Olofsson SK and Cars O. Clin Infect Dis 2007;45:S129-36

Impact of Antibiotic Therapy on

Antibiotic Resistance
Antibiotic resistance can be selected during
antibiotic treatment .
Selection takes place both at the site of infection
and in the commensal flora.
To prolong the life span of existing and new
antibiotics, it is of utmost importance that the
dosing regimens are carefully selected on the
basis of the PK/PD properties that prevent
emergence of preexisting or newly formed
mutants.

Olofsson SK and Cars O. Clin Infect Dis 2007;45:S129-36

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