PRINCIPLES OF ANTIBIOTIC THERAPY

D r Ya s m i n G a n i
I D p hy s i c i a n
 OVERVIEW OF PRESENTATION

UNDERSTANDING HOST FACTORS IN OPTIMIZING THE USE PRESERVING OUR

PKPD ANTIBIOTIC OF ANTIBIOTICS NATURAL RESOURCES
SELECTION
 DR CHUA

• Qualification : just passed MRCP

• Height : 170cm
• Weight : 90kg
• BMI lets not go there!
• Enthusiasm : At his highest!!!!
 C A L L F RO M E M E R G E N C Y – H A P P E N S TO
Hi Dr Chua. This is the EP. We B E D R C H UA ’S F I R S T C A L L A S A
have a case with septic shock P H YS I C I A N
secondary to a severe
pneumonia. Pt needs HFM and
inotrope support. BP 90/50 and
HR 130 on admission
COMING….
 PATIENT PROFILE

• 56 yr old Encik WTS… HPT/HPL

• On 3 AntiHpt / and statins
• Presented with 3 day history of fever
and cough with SOB.
• One week ago had URTI symptoms
that had improved
• Lives in HTK and mostly retired.
Before that he worked in bank.
• No history of travel
• Bp OA : 90/40, HR 130/ SPo2 93%
• Wcc 25 Plt 700 crp >320
• Body weight : 95kg
• Bloods : RP : creat 121/ urea 12,
• RBS-5
• LFT : Alt 78/ Ast 121/ Alb 28/ Tbil 35
• 1. What are the
factors that Dr
Chua should be
considering
before starting
an antibiotics
1. NOT ALL DRUGS ARE MADE THE SAME
 FUNDAMENTAL CONCEPT OF
ANTIMICROBIALS: PK PRINCIPLES
• PHARMACOKINETICS; absorption/ distribution/ elimination/
• 3 main parameters
• Peak serum level ( Cmax)
• Trough level (C min)
• Area under the serum concentration time curve ( AUC)

Affected by
1. Solubility and stability of the drug
2. Extend of protein binding
3. Dynamic clinical condition
4. Standard therapeutic bundles for
sepsis
 FUNDAMENTAL CONCEPT OF
ANTIMICROBIALS: PD PRINCIPLES

• Important to Integrate PD properties to PK analysis in order to

optimize the effect of antibiotics
• Cmax /MIC,: the ratio of maximal drug concentration to MIC
• AUC/MIC ratio of free drug area under the AUC curve to MIC
over a 24hr period
• T> MIC- time the [drug] remains over the MIC
 ANTIMICROBIAL PATTERNS- TYPE 1

• Concentration dependent Killing &

Prolonged post antibiotic effect
• Dosing strategy is to maximize the concentration of
the drug , the higher the concentration the faster
and effective the killing
• Maintaining concentration above MIC for longer
periods are not necessary: more SE
• Has a post antibiotic effect , where killing continues
• Aminoglycosides/ quinolones/ amphotericin

HIGH dose / Low frequency

Nicholas J.Clinical Therapeutics/vol 38, num9.2016
 ANTIMICROBIAL PATTERNS – TYPE 2

• Time dependant killing & Min/

None post antibiotic effect
• Dosing strategy: Optimise T > MIC – that refers
to the dosing interval that exceeds MIC),
• concentration of antibiotics does not matter so
much
• Eg Blactam antibiotic: Tazosin/ carbapenem/
cephalosporins/
• No post antibiotic effect
High Frequency / Prolonged
Infusion
 ANTIMICROBIAL PATTERNS – TYPE 3

• Time dependant killing +

Moderate to Prolonged Post
antibiotic effect
• Bactericidal activity continues as long as the plasma
concentration is greater than the MIC
• The concentration of these drugs should be
maintained above the MIC for the entire time
interval between repetitive doses.

Flexible Dosing regime / High

dose
Now that I know that certain
antibiotics need to be
individually prescribed, how do I
know what to star t?
2. ‘HIDDEN’ HOST FACTORS IN ANTIBIOTIC
SELECTION
 HOST FACTORS IN ANTIBIOTIC
SELECTION

• Renal impairment
• Liver impairment
• Adverse effects /Allergies
• HYPOALBUMINAEMIA
• OBESITY
• MDR RISK FACTORS
 Vd

CL

HYPOALBUMINAEMIA
 SEPSIS ALTERS DRUG ALBUMIN BINDING

• Hypoalbuminaemia ; mainly due to reduced production and increased capillary

leakage/ malnutrition/ prolonged illness etc
• Use of Inotropes / volume resuscitation further alters PkpD principles
• Enhanced Vd and faster distribution of drug and reduced available unbound
drug in the circulation & increased CL ( due to augmented renal clearance)
•

Concentration dependant
antibiotics
Time dependant antibiotics Subtherapeutic
Drug Levels Reduced Cmax to MIC may
Reduced fT/MIC
be lowered due to increased
Vd
 WHAT DOES THIS MEAN?

Case 1: 45 yr old man with DM/HPT

presented with severe pneumonia . On 3 Ceftriaxone 1-2gm BD
inotropes on CVVH is better than
Blood Culture : Kliebsiella non ESBL Ceftriaxone 2 gm dly
Pt not improving : should we escalate!

Case 2: 35 Yr old lady with HHS presented

with severe meliodosis with multiple liver and
lung abscess
Blood culture despite 10 days of antibiotics
and drainage still positive
Pt not improving : should we escalate!
IVI Ceftazidime 2gm 6hrly
continuous infusion is better
than Ceftazidime 2gm every 6hrs
 WHAT DOES THIS MEAN

80kg DM/HPT PT presented with

persistent MRSA bacteraemia
Vanco was ordered as 1 gm bd (
standard dosing)
Trough levels: 3.4→ 7.9→
11mmols/dL
Vancomycin 25mg/kg (2gm loading dose
over 2hrs) followed by 15mg/kg bd
(1250mg bd) is better than Vancomycin
1gm bd

Augmented renal clearance ( Burns/ CNS/ Sepsis) : think about increasing

frequency/ dose but Keep in view toxicity
ANTIBIOTIC DOSING IN OBESITY
 ALTERATION IN PHARMACOKINETICS
AND DYNAMIC IN OBESITY

• Volume of distribution is increased as a result of increased adipose tissue &

lean muscle mass-
• Clearance is altered by possible Hepatic dysfunction from NAFLD, renal failure
,or Augmented renal clearance

Pharmacotherapy 2017;37(11):1415–1431
UKCPA. NHS. uk
 Class Of Antbiotics Weight Used Recommendation

Aminoglycosides Adjusted BW Subsequent Dosing based on drug

levels
Blactam No Specific Should be treated with the upper end
treatment range, with continuous/
prolonged infusion
Meropenem Standard dose Should be treated with the upper end
treatment range, with continuous
infusion

RE COMME NDATI O NS
Ertapenem No specific In critically ill, more resistant bacteria
FOR DOSING
advice may need to double dose
Ciprofloxacin No specific Conflicting data
advice IV 400mg tds/ 800mg bd have been
tried
Colistin IBW Loading dose followed by dose acc to
crcl ( higher than 10Mu is not
recommended)
Vancomycin ABW Loading dose more than 2gm not
recommended- infused over 2hrs
Maintenance dosing acc to levels
 • Physicians need to identify patients who are at increased risk
for bacteria resistant tothese empirical antibiotic regimens.
more likely to receive initially inappropriate antibiotic therapy,
which has been associated with increased mortality among
these patients.

RISK FACTORS FOR MDR ORGANISM

 MDR RISK FACTORS

1. Hospitalization for more than 2 days in the last 90days

2. Nursing Home residents
3. Recent use of antibiotics / Home infusion therapy last 6 months
4. Home Wound care
5. Colonized By Drug resistant pathogens before
*Immunocompromised * Poor functional Status * NG tube feeding * Use of gastric
acid supressants Am J Respir Crit Care Med 2013;188:985-95.
N Engl J Med 2014;370:543-51
Clin Microbiol Infect 2013;19:E142-E148
IDSA 2011
OTHER FACTORS TO CONSIDER

Lee.MS. Infect Chemother 2018;50(2):160-198

 Other Factors to consider
Patient Risk factors
Thalassemia on iron Chelators
Liver Cirrhosis
Post splenectomy
Diabetic Mellitus/Farmer/ fishing/
soil and water exposures
Common Organisms Implicated
Listeria ,Vibrio sp., Ecoli/ kliebsiella
Fungal : Sporulating Mold / Mucor
Yersinia / Aeromonas
Vibrio , Enteric gm Negative ,
Kliebsiella
Capnocytophaga
Strep Pneumoniae, N. Meningitis,
Hemophilus Influenza
Capnocytophaga, Salmonella sp
Melioidosis
 AREAS OF UNCERTAINTY

• Potential to over use antibiotics and promote resistance

• Ideal approach: good clinical specimens, Improved diagnostic methods , Short duration/ de-
escalation of antibiotics shd be practiced

Clinical Infectious Diseases, Volume 54, Issue 4, 15 February 2012

PLOS ONE 10(4): e0119528.
Am J Respir Crit Care Med.2013.188:985–995.
Clin Infect Dis57:1373–1383.
3. OPTIMIZING THE USE OF ANTIBIOTICS
 MANAGEMENT

• Patient did not have any obvious

MDR risk factor apart from 2 days of
augmentin given by GP
• She was started on Piperacillin-
Tazobactam at 9gm loading dose and
4.5gm tds
• Admitted into MHDW unit

• 2 days later: Blood culture

• Kliebsiella pneumonia
• S to all antibiotics
• R ampicillin
• The antibiotics were narrowed down to
iv Augmentin 1.2gm tds
 PROGRESS

• Despite 2 days of piptazo and 4 days

of augmentin
• Spiking temperature
• Worsening pneumonia
• Intubated

RESPONSE

• Increase the antibiotics to IV

Meropenem 2 gm TDS
• Repeated Blood cultures are NG
 Ct scan @ 1 week of treatment
PROGRESS

• Despite 4 days of piptazo;

• Spiking temperature
• Worsening pneumonia
• Intubated
Mayo Clin Proc. • February 2011;86(2):156-167
 1. When agents inhibit
a synergistic activity

• Synergy = the combined effect of the agents

is greater than the sum of their
independent activities when measured
separately.
• Eg : enterococcus and strep viridans
Infective endocarditis
 2. To prevent Emergence
of resistance

• Prevents the emergence of resistant

subpopulation during treatment
• This concept can be overcome by
• Increasing drug concentration and prolonging
infusion
• Check TDM levels and keep It much higher
than MIC

• Adding a second agent

• Eg in Staph aureus / Tuberculosis treatment/
CRE treatment
 3. When Patients are critically ill and
require broad spectrum

• To Improve the likelihood of covering the offending bacteria esp when pt is

critically ill
• In a likely polymicrobial infection like intraabdominal infections: 3 rd gen CP +
metronidazole ± Gentamicin
• In a neutropenic patient who develops sepsis : limited room for error
• In a patent with significant MDR risk factors
• In a patient whom you need a bit of extra help!
• Thick walled abscess cavity
• Bone penetration ( Cipro/ Bactrim/ Clindamycin/ Rifampicin/ Doxy)
• Prosthetic material
 Pt was started on IVI Unasyn 3gm tds and
added On T levofloxacin 750mg dly

Developed Pseudomonas pneumonia and

the ab was escalated to cefepime 2gm tds (
4hrly infusion)
PTS PROGRESS
Ct scan repeated after 6 weeks of
treatment showed resolved mediastinal and
smaller left lobe necrotizing penumonia

Subsequently referred to CTS for

decortication.
4. PRESERVING OUR NATURAL RESOURCES
 SPIRALING EMPIRICISM

• Why do people favor empiricism over accurate diagnosis and specific therapy
• Fear of errors omission and potential to deteriorate without treatment
• The desire to alleviate distress ( not necessarily the patients!)
• Fear of litigation

Am J Med. 1989 Aug;87(2):201-206

 FACTORS TO CONSIDER IN EMPIRICISM

• Key to a successful antibiotic regimen: starts with an;

• Accurate infectious disease diagnosis ( know the site of infection)
• Defining the host ( DM/ Immunocompromised/ Immunocompetent)
• Defining Nature of infection : (Nosocomial Or Community acquired)
• Microbiological diagnosis : Appropriate Specimen being sent

• Avoid Spiraling Empiricism

Clinical Therapeutics/Volume38,Number9,2016
 WHAT DRIVES RESISTANCE

• Selection pressure
• Mutations/ gene transfer
• Inappropriate Antibiotic use
• Inaccurate diagnosis
• Wrong drug
• Wrong dose
• Wrong duration
• Ab usage in animal husbandry and
agriculture
 SMART EMPIRICISM

AMS STEP DOWN WHEN

CULTURES ARE AVAILABLE
STRATEGIES
STEP DOWN TO ORAL WHEN
CLINICALLY IMPROVED

USE THE SHORTEST EFFECTIVE

DURATION THERAPY
NON INFECTIOUS FEVER