Antibiotic pharmacology and

stewardship
Dr. shashikant

Moderators: Prof. Ganga

Dr. Souvik
 Seminar highlights
Antibiotics: historical perspective
Why do we need to know antibiotics?
Pharmacology: components and definition
Indices of pharmacokinetics and pharmacodynamics
Application of PKPD in critically ill patients
Antibiotic stewardship: definition
Components of antibiotic stewardship
Utility of antibiotic stewardship in critically ill
Impact of stewardship on outcome
 Antibiotics: historical perspective

Wainwright, Milton. “Moulds in Folk Medicine.” Folklore, vol.

100, no. 2, 1989, pp. 162–66. JSTOR.
Antibiotics: historical perspective

3rd September, 1928

Penicillin heralded the
dawn of the antibiotic
usage
Mold- penicillium
notatum

“Antibiotics are compounds produced by bacteria

and fungi which are capable of killing, or
inhibiting, competing microbial species”
 Why do we need to know antibiotics?
Critically ill patients:
Admitted with infection
Develop infection during stay (immunosuppression, invasive devices)
European ICU study- severe sepsis (26.7%) (Vincent JL et al. Critical care medicine.
2006) [mortality- 32.2%]
Multicentre prevalence study (75 ICUs)- infection (51%)( Vincent JL et al. Jama.
2009)[mortality- 25.3%]
US- Annual expenditure of $121 and $263 billion on treatment of critically ill
patients.(Coopersmith CM et al. Crit Care Med.2012)
Antimicrobial
associated
harm

Mitochondria
the first target of
antibiotic

Arulkumaran et al. Intensive care medicine.2020

 The growing challenges
Surge in MDR High morbidity and
pathogens mortality
(a global health crisis)
Antibiotic consumption is 10
times higher in ICU than
general ward and it’s rising
Diminishing
antibiotic pipeline Clinicians are forced
Abdul-Aziz MH et al. In Seminars in respiratory and critical care medicine 2015 to use older antibiotics
(colistin, Fosfomycin)
Critical care , 2019
 Antibiotic pharmacology
Pharmacology- the science of dealing with
drugs

Pharmacokinetics Pharmacodynamics
“what does the body do with the “ what the drug does with the
drugs” body”
ADME study (absorption, Action of drugs as well as their
distribution, metabolism, mechanisms
excretion)
Asín-Prieto E et al. Journal of Infection and Chemotherapy. 2015
Antibiotic pharmacology

It’s a complex
interaction among
host, pathogen and
the antibiotic
 PK indices

Vd and Clearance- the most

influential Pharmacokinetic
parameters in critically ill
patients
Shah S et al. Journal of the Intensive Care Society. 2015 .
 PK consideration

Shah S et al. Journal of the Intensive Care Society. 2015

 PK consideration

Shah S et al. Journal of the Intensive Care Society. 2015 .

 PD indices

Shah S et al. Journal of the Intensive Care Society. 2015 .

 PD indices

Abdul-Aziz MH et al. In Seminars in respiratory and critical care medicine;2015

 Pattern of PD indices and antibiotics
Antibiotic PK/PD index magnitude
Penicillin Cephalosporins carbapenems 50-60 60-70 40-50
f % T>MIC
f % T>MIC
f % T>MIC
10 125
Amynoglicosides Cmax/MIC
Quinolones AUC/MIC
Clarithromycin Azithromycin 25 25
f AUC/MIC
f AUC/MIC
Tetracyclines AUC/MIC 25

Asín-Prieto E et al. Journal of Infection and Chemotherapy. 2015

 Pattern of PD indices and antibiotics
Antibiotic PK/PD index magnitude

Vancomycin Teicoplanin 400 >10 (serious gram positive infections) >20 (for deep
AUC0-24/MIC seated infection)
Cmin/MIC

Daptomycin Tigecycline AUC/MIC AUC/MIC 666 17.9

Linezolid Colistin 100 27.6-45.9

AUC/MIC
f AUC/MIC

Asín-Prieto E et al. Journal of Infection and Chemotherapy. 2015

 PD indices
MPC= MIC of least susceptible
mutant

Abdul-Aziz MH et al. In Seminars in respiratory and critical

MPC- Mutant prevention
care medicine 2015
concentration
MSW- Mutant selection window Asín-Prieto E et al. Journal of Infection and Chemotherapy.
OD- optimal dosing 2015
MIC (minimum inhibitory concentration)

MIC is the lowest concentration of an antibacterial agent expressed in

mg/L (microgram/mL) which, under strictly controlled in vitro
conditions, completely prevents visible growth of the test strain of an
organism after overnight incubation.

Kowalska Krochmal B. Pathogens. 2021

 Estimation of MIC
MIC

Microbiological Clinical breakpoint PKPD breakpoint

breakpoint (MIC concentration to (tissue concentration
(in vitro MIC separate strains with with likelihood of
concentration to likelihood therapeutic therapeutic success)
differentiate wild type success vs failure)
from non-wild type
strain) Human studies Animal studies
Invitro studies

Turnidge J et al. Clinical microbiology reviews. 2007

 Estimation of MIC

Cmax = maximum serum concentration following a stated dose at steady state, and usually at 1
h post-dose.
e = factor by which the Cmax should exceed the MIC. (normal=4, Less for antibiotics which
achieve higher tissue concentration
f = protein binding (protein binding <70%, f = 1; for protein binding 70-90%,f = 0.5; and for
protein binding >90%,f = 0.2).
t = factor (normally 1) to allow for the serum elimination half-life. For a serum elimination half-
life of between 1 and 3 h, t = 1; if it is >3 h, t = 0.5; or if it is <1 h, t = 2.
s = shift (or reproducibility) factor mentioned above. Typically, s = 1 and should not normally
be <0.5 or >2.
MacGowan AP,. Journal of Antimicrobial Chemotherapy. 2001
 MIC measurement: techniques
Dilution methods Gradient method

Agar strips impregnated with a

predefined concentration
gradient of antibiotic (E-test).
Liquid
Microdilution
Macro dilution

Kowalska-Krochmal B. Pathogens. 2021.

MIC measurement techniques

Agar dilution
MIC measurement techniques

E-test
 MIC: CLSI Vs EUCAST
CLSI EUCAST

Support interchangeable broth and Broth microdilution

agar dilution

Exceptions: Exception:
Fosfomycin (agar only) Fosfomycin, Mecillinam (Agar dilution
Colistin and daptomycin (only broth for both)
dilution)
Hemophilus test medium (HTM) for MH-F (muller hinton fastidious agar)
H. influenzae for H. influenzae

Kowalska-Krochmal B. Pathogens. 2021.

 MIC interpretation
Susceptible (S) There is a high likelihood of therapeutic success using
a standard dosing regimen of the agent.
Susceptible (I)
There is a high likelihood of therapeutic success
because exposure to the agent is increased by adjusting
the dosing regimen or by its concentration at the site of
infection.

Resistant (R)
There is a high likelihood of therapeutic failure even
when there is increased exposure

Kowalska-Krochmal B. Pathogens. 2021.

MIC Interpretation

MIC alone is not

enough to choose
appropriate antibiotic

MIC must be interpretated with

reference to susceptible
breakpoint for the given
antibiotic
Susceptibility to more than one antibiotic: what
to do ???

Does Low MIC value

mean more
susceptible ????

NO
Efficacy ratio (ER)= susceptible
breakpoint / MIC [ for a given
antibiotic]
Sabu P, Indian J Pharmacol. 2018
Susceptibility to more than one antibiotic: what to
do ???
ANTIBIOTIC ER

Amikacin 8
cefepime 4
ceftazidime 2
Ciprofloxacin 4
Doripenem 16
Gentamicin 4
Imipenem 8
Levofloxacin 16
Minocycline 4
Piptaz 4
Ticarcillin/clavulanic acid 2
septran 2
 An antibiotic with higher ER
ratio had higher therapeutic
success

The subpopulation of given strain has very low

level of resistance
Standard dosing achieves therapeutic
concentration even with altered
pharmacokinetics
 MIC creep
MIC creep” is a phenomenon that describes an increase of an organism MICs over time.
Creep phenomenon is globally reported to result in:
Therapeutic failure,
Increase morbidity
Slow clinical response and
Higher relapse rate

Arshad F, Saleem S, Jahan S, Tahir R. Assessment of Vancomycin MIC Creep Phenomenon in

Methicillin-Resistant Staphylococcus aureus isolates in a Tertiary Care Hospital of Lahore. Pak J Med Sci.
2020
Sameerah A et al. Journal of Infection and Public Health.2020
MIC creep
MIC creep
736 isolates of s.
aureus

MIC
value
 MIC creep: mechanism
Acquisition of resistance over a period
of time due to antibiotic exposure
The MIC creep phenomenon may be influenced by:

The type of microbiological susceptibility test used (E-test, broth

microdilution(BMD) or automated system)
Type of S. aureus strain or
Type of patient population

R. Diaz et al. Clinical Microbiology and Infection.2018

 MIC creep

55 studies,
29 234 S. aureus isolates,
The mean MIC were 1.23 mg/L (95% CI 1.13-1.33) and 1.20 mg/L (95% CI
1.13-1.28)determined by E-test and broth microdilution method, respectively.
No significant differences were observed between these two methodologies
 Decline in MIC over
time:
Stringent application of
antibiotic stewardship
leading to appropriate
use of vancomycin
 How to choose optimal antibiotic?
Host factor

PKPD
considerations Protein
binding

Drug
availability
Local
AST report antibiogram
Site of infection Cost
Appropriate
ER ratio agent/dose
 Limitations of MIC
Measurement done in standard laboratory conditions (bacterial
inoculum and antibiotic concentration may not be the same at the site of
infection)
Does not consider albumin level, volume of distribution and organ
dysfunction
Does not tell about resistance mechanism
Effect of additional drugs is not considered
Two fold dilution (there may be many values of MIC between two fold
dilution)
The condition in body undergoes various changes till report is available

Kowalska Krochmal B. Pathogens. 2021

 Therapeutic drug monitoring (TDM)

TDM, traditionally used for drugs with narrow therapeutic index (Digoxin, aminoglycosides)
to minimize toxicity.

The spectrum is widening (voriconazole, beta- lactams, linezolid etc.)

Tabah, Alexis, et al. Journal of Antimicrobial Chemotherapy.2015

Wong G, Journal of antimicrobial chemotherapy. 2014
TDM kinetics

https://www.element.com/nucleus/2022/biomarkers-tool-for-tdm
 Why TDM in critically ill patients?
Surge in MDR- Huge inter-individual as well as
pathogens intraindividual variation in
Declining antibiotic Pharmacokinetics
pipeline
Altered PKPD PKPD data of
parameters in antimicrobials is
TDM critically ill from non- ICU
patients patients

How to decide on Under/over-

optimal dose? exposure
Therapeutic failure/toxicity
Abdul-Aziz et al.Intensive care medicine.2020
 Criteria for TDM

An antimicrobial should fulfil certain criteria for TDM:

A significant intra- and/or inter-individual PK variability;

A defined exposure range associated with pharmacological responses
(clinical responses and toxicities);
Defined relevant sampling time points; and
Accurate and timely bioanalytical assay methods for drug measurement

Abdul-Aziz et al. Intensive care medicine.2020

 TDM recommendations in critically ill

European Society of Intensive Care Medicine (ESICM)

European Society of Clinical Microbiology and Infectious Diseases
(ESCMID)
Infectious Diseases Group of International Association of Therapeutic Drug
Monitoring and Clinical Toxicology (IATDMCT)
International Society of Antimicrobial Chemotherapy (ISAC)
 TDM in critically ill
The Panel Members recommend routine TDM to be performed for:
Aminoglycosides
beta-lactam antibiotics
Linezolid
Teicoplanin
vancomycin and
voriconazole
 TDM in critically ill
Antibiotic Sampling scheme target Threshold for toxicity

Aminoglycosides AUC-based monitoring AUC: 80–120 mg h/L Amikacin (Cmin>

Two samples: 5mg/L)
One taken 30 min after the Gentamicin/Tobramycin
end of infusion and the (Cmin>1 mg/L)
other one taken between 6
and 22 h post-infusion

Cmax/MIC monitoring Cmax/MIC>8-10

One sample
30 min after the end of
infusion
 TDM in critically ill
Antibiotic Sampling scheme target Threshold for toxicity

Beta-lactams Cmin monitoring 100% fT>MIC Penicillin (Cmin> 361

One sample mg/L)
30 min or just before the Cephalosporin (Cmin>20
next dosing mg/L)
Sampling should occur Carbapenems (Cmin>
24–48 h post-initiation 44.5 mg/L)
of therapy
Css monitoring for Css > MIC
continuous infusion Css= steady state
One sample at any time concentration
point during the
infusion
 TDM in critically ill
Antibiotic Sampling scheme Target Threshold for toxicity
Teicoplanin Cmin monitoring Cmin>15-30 mg/L Teicoplanin (unclear)
One sample
30 min or just before the
next dosing
Linezolid:
Cmin>7 mg/L
Linezolid Cmin monitoring Cmin>2-7 mg/L
One sample
30 min or just before the
next dosing
Sampling should occur
48 h post-initiation of
therapy
 TDM in critically ill
Antibiotic Sampling scheme Target Threshold for toxicity
Vancomycin AUC/MIC-based monitoring AUC 0–24/MIC ≥ 400 Cmin> 20mg/L
Two samples AUC 0–24/MIC ≥ 700
One taken 1 h after the end of mg h/L
infusion and the other one
taken within 1–2 h of the next
infusion
Cmin monitoring for Cmin > 10 mg/L
intermittent infusion Cmin ≥ 15–20 mg/L
One sample (severe infections)
30 min or just before the next
dosing
Css monitoring for continuous Css: 20–25 mg/L
infusion
One sample at any time point
during the infusion
 TDM in critically ill
Antibiotic Sampling scheme Target Threshold for toxicity
Voriconazole Cmin monitoring Cmin: 2–6 mg/L Cmin ≥ 4.5–6 mg/L
One sample (prophylaxis or
30 min or just before the treatment)
next dosing
Sampling should occur
between 2 and 5 days of
initiation of therapy

TDM based dosing
New dose= old dose x (desired
concentration/old concentration)
Enara, M. MOJ Toxicol .2014.
Pitfalls and error sources
Dose administration error.
Inaccurate time of sampling, or timing
was before steady-state is reached
Lab assay error
It measures both bound and unbound
fraction of drug
It measures serum concentration (not
the tissue concentration)
 TDM and outcome

N=110 ( TDM- 55, Non-TDM- 55)

Seoul national university Hospital (2008-2011)
TDM group: (target range, 1.0–5.5 mg/L) according to the serum trough level measured on
the fourth day after initiation of voriconazole.
Non-TDM: a fixed, standard dosage.
The proportion of voriconazole discontinuation due to adverse events was significantly
lower in the TDM group than in the non-TDM group (4% vs 17%; P = .02)
A complete or partial response was observed in 81% (30 of 37) of patients in the TDM
group compared to 57% (20 of 34) in the non-TDM group (P = .04
 TDM and outcome

Multicentric study (1994-95)

TDM group (105), Non-TDM (127)
Peak concentrations in TDM patients were significantly higher (10.6 ± 2.9 mg/L; non-TDM,
7.6 ± 2.2 mg/L; p < 0.01).
Trough levels in the TDM group were significantly lower (p < 0.01).
TDM reduced the length of hospital stay for all patients in the study (20.0 ± 1.4 days; non-
TDM, 26.3 ± 2.9 days; p = 0.045).
The incidence of nephrotoxicity was reduced from 13.4% (non-TDM) to 2.9% (p < 0.01).
With TDM, total costs were reduced.
TDM and outcome

DOLPHIN TRIAL

Trial registration- 6th March, 2018

N=450 will be included, 8 ICU in Netherland
to TDM or not to TDM?
 Antibiotic stewardship
Merriam-Webster dictionary:
Stewardship refers to:
the office, duties, and obligations of a steward;’ and
the conducting, supervising, or managing of something; especially: the
careful and responsible management of something entrusted to one's care’.

In recent years, the long-established "management” sense of

stewardship has evolved a positive meaning, “careful and responsible
management”.’
 Antibiotic stewardship: Historical perspectives
1996
First article to use the term
“antimicrobial stewardship”

1997 1998- ESGAP (the European

Society for Healthcare
Epidemiology of America
(SHEA)
Infectious Diseases Society of
America (IDSA) guidelines
Society of Clinical Microbiology
and Infectious Diseases Study
Group for Antimicrobial
stewardship),
 Why antibiotic stewardship??
TOI, Sep 2021

PR Rhomberg et al. Diagn Microbiol Infect Dis. 2009

The growing concern

Ventola CL. The antibiotic resistance

crisis: part 1: causes and threats. P T.
2015
Antibiotic stewardship: the progress

Dyar, O. J et al. clinical

microbiology and infection .2017
 Antibiotic stewardship: definition

Antimicrobial stewardship involves a multifaceted and multidisciplinary

approach to achieving the following goals:
combating antimicrobial resistance,
improving clinical outcomes, and
controlling costs by improving antimicrobial use.

Kollef, Marin H et al. Intensive care medicine.2017.

Core elements of Antibiotic stewardship
Core elements of Antibiotic stewardship
Antibiotic stewardship program (ASP)

Kollef MH. Intensive care medicine. 2017.

 Antibiotic stewardship program

MALDI-TOF
Multiplex PCR (For respiratory sample)

Kollef MH. Intensive care medicine. 2017.

Antibiotic stewardship program

Kollef MH. Intensive care medicine. 2017.

 Antibiotic stewardship program

11 studies selected
Not to be 4 found to be suitable
routinely No reliable conclusion(Methodological
implemented in flaws, lack of standardization)
clinical practice
 Assessment of ASP

Antimicrobial stewardship programmes in health-care facilities in low- and middle-income countries. A

WHO practical toolkit (2019)

Structure measure
Checking national and health-care Documented indication for antibiotic use
facility core elements
Assessment of ASP
Process measure Outcome measure
Total consumption of antibiotics [per
100(0) patient-days]
Stop/review date Patient mortality
Compliance with current clinical treatment Length of stay
guidelines
Length of therapy by indication Readmission within 30 days after
discharge
48 hour review, de-escalation, switch from iv to Incidence of Cl. difficle
oral
Incidence of MDR organisms
Compliance with current guidelines of surgical
prophylaxis
 Antibiotic stewardship: efficacy and outcome

Improved prescribing pattern (appropriate antibiotic use, decreased

resistance)
Low strength of evidence
Studies not adequately designed for patient outcome
Adverse effects on patient outcome not reported
 Antibiotic stewardship: efficacy and outcome

50 studies eligible for inclusion

Medium-strength evidence:
Incorporating communication skills training and laboratory testing are associated with
reductions in antimicrobial use
low-strength evidence - improved prescribing.
Patient-centered outcomes, were infrequently reported
Medication costs were generally lower with stewardship interventions
No studies reported microbial outcomes
 Antibiotic stewardship: efficacy and outcome

N=46 studies
The pooled effect size for change in overall antimicrobial and carbapenem consumption
(% difference) was -9.74% (95% CI, -18.93% to -.99%) and -10.56% (95% CI, -19.99%
to -3.03%), respectively.
Trends toward decreases in the incidence of MDR organisms and antimicrobial
expenditure (range, 9.7%-58.1% reduction in cost in the intervention period/arm).
 Antibiotic stewardship: where are we now

Antibiotic decision-making remains sub-optimal including in hospitals.

Globally, resources remain a limiting factor in the implementation of antibiotic
stewardship programs.
Cultural boundaries in healthcare and across specialties still limit the involvement of allied
healthcare professionals in stewardship interventions.
There is variation in the social norms and antibiotic-prescribing behaviors between
specialties in hospitals.
Antibiotic stewardship program

The missing link

Over the counter

prescription of
antibiotics

As per WHO, over 50% of the antibiotic prescriptions worldwide are

inappropriate with 2/3rds of antibiotics accessible at the pharmacies being
used for self-medication (Antimicrobial Resistance Global Report on
Surveillance .World Health Organisation. 2014)
face-to-face, in-depth interviews (22 pharmacists and 14 informal dispensers from 36 retail
pharmacies in Haryana and Telangana).
Antibiotics were often dispensed (fever, cough and cold, and acute diarrhea, which are
typically viral and self-limiting).
Main drivers for OTC dispensing:
Were commercial interests,
Poor access to public healthcare,
Economic and time constraints among consumers,
Lack of stringent regulations, and
Scanty inspections
19 studies, 11197 participants
The prevalence of self-medication with antibiotics (SMA) ranged from 7.3% to
85.59% with an overall prevalence of 42.64%.
Common reasons for self medications:
common cold
sore throat
Fever
gastrointestinal tract diseases, and
respiratory diseases
 Antibiotic stewardship: future
Strict Implementation of core High quality studies aiming
elements of antibiotic impact of ASP on:
stewardship program Microbial data
Patient data
cost

Antibiotic
stewardship
program

Dilution of cultural barrier More funding, research

among different specialties and approval for
with respect to antibiotic OTC dispensing of projects to develop
prescription antibiotics newer antibiotics
Antibiotic policy at AIIMS
 Take home messages
Antibiotics are cornerstone of patient care in intensive care units
The critically ill patients have altered PKPD kinetics
The implementation of antibiotic stewardship program globally is the need
of the hour
We need more research, funding and approval for newer antibiotics
We need to focus on preventing infections as much as possible
Take home messages

One dose fits all Customized

approach
 Incidence of antimicrobial
resistance

Development of Newer
antibiotics
The fight with microbes will
continue………………….