This document discusses principles of antibiotic use in critical care. It notes that up to 50% of antibiotics prescribed are inappropriate and outlines consequences like increased resistance. The key principles for appropriate use are described as using the right antibiotic, at the right time, duration and dose based on the patient's condition and likely pathogens. Factors affecting pharmacokinetics and pharmacodynamics in critical illness are also reviewed to optimize dosing for better outcomes.

1. PRINCIPLES OF
ANTIBIOTIC USE IN
CRITICAL CARE
Ahmed Mohamed Abdelazeem
Critical Care Medicine Department
Benha University
2017

2. SCOPE OF ANTIBIOTIC
PRESCRIBING
 2nd Most Commonly Prescribed Drug
Class

3. ANTIBIOTIC MISUSE
 Up To 50% Of Antibiotics Prescribed Are
Inappropriate
 A Recent Study Found 30% Of All Antibiotic Days
Were Unnecessary:
 Excessive Duration
 Non-infectious Etiology
 Colonizers Or Contaminants
 Redundant Coverage
 Failure To De-escalate Abx

4. “Antibiotics Are Among The Most Potent Of All
Anxiolytics – For Prescribers” Dr. Brad Spellberg

5. CONSEQUENCES OF
ANTIBIOTIC MISUSE

6. SMART ANTIBIOTIC USE
RIGHT ANTIBIOTIC RIGHT
DURATION
RIGHT TIME RIGHT DOSE

7. RIGHT
ANTIBIOTIC

8.  Inappropriate Initial Therapy
Resulted In A 5-fold Decrease In
Survival To Hospital Discharge

9. DESIGNING EMPIRIC
ANTIMICROBIAL THERAPY
 Designing An Empiric Therapy Begins With
Identifying The Most Likely Infectious Sources For
The Patient And Knowing The Most Common
Causative Pathogens For Each Source
 Recently Used Antimicrobials, Redundant
Antibiotics (e.g Dual Anaerobic Coverage) Should
Be Avoided, And Coverage Of Resistant
Organisms Should Be Considered

10. RISK FACTORS FOR DRUG
RESISTANT PATHOGENS
 Receipt Of Antibiotics Within The Past 90
Days
 Current Hospitalization Of ≥5 Days
 Immunosuppressive Disease And/Or Therapy
 Antibiotic Resistance In The Community
 Patient Had History Of Antibiotic Resistant
Organism

11.  Because Empiric Therapy Should Cover All
Likely Pathogens, An Extended-spectrum
Penicillin With A Β-lactamase Inhibitor, A
Third- Or Fourth-generation
Cephalosporin,Or An Antipseudomonal
Carbapenem Should Be Used
 Vancomycin Should Be Added If The
Patient Is At Risk Of MRSA

12. RISK FACTORS FOR MRSA
INFECTION
 Advanced Age
 Male Gender
 Previous Hospitalization
 Long Hospitalization
 Stay In An ICU
 Chronic Medical Illness
 Prior And Prolonged Antimicrobial Use
 Presence Of Wound
 Exposure To Colonized Or Infected Patient
 Presence Of Invasive Indwelling Devices

13.  Empiric Antifungal Therapy Should Not
Routinely Be Added As Initial Empiric
Therapy Unless The Patient Is At High
Risk Of Invasive Candidiasis

14. RISK FACTORS FOR
INVASIVE CANDIDIASIS
 Immunosuppression
 Hematological Malignancy
 Neutropenia
 TPN
 CVC
 Hemodialysis
 Burn
 Necrotizing Pancreatitis
 Complicated GI Surgery

15. CANDIDA SCORE

16. PSEUDOMONAS COVERAGE
 Piperacillin/Tazobactam
 Aminoglycosides
 Ceftazidime
 Cefepime
 Fluoroquinolones
 Carbapenems (Except Ertapenem)
 Colistin

17. ANAEROBES COVERAGE
 Metronidazole
 Clindamycin
 Piperacillin/Tazobactam
 Ampicillin/ Sulbatam
 Amoxicillin/Clavulanic Acid
 Carbapenems
 Moxifloxacin
 Tigecycline

18. MRSA COVERAGE
 TMP/SMX
 Clindamycin
 Doxycyclin
 Vancomycin
 Linezolid
 Tigecycline

19. COMBINATION THERAPY
VS
MONOTHERAPY
 Combination Therapy Is The Use Of At Least Two Different
Classes OfAntimicrobials With Different Mechanisms OfAction
 Use Of A Β-lactam And Glycopeptide (i.e.Vancomycin) Is Not
Considered Combination Therapy Because Both Classes
ExertTheir BactericidalActivity OnThe Bacterial Cell Wall

20. MECHANISMS OF
ANTIBIOTICS ACTION

21.  The Rationale For Using Combination Therapy As
Initial Empiric Therapy In Patients With Sepsis Is
Based On The Following:
(1) Combinations Provide A Broader Antibacterial Spectrum
To Cover All Likely Pathogens And Resistant Pathogens
(2) Combinations (e.g., Β-lactam With An Aminoglycoside)
Can Provide Additive Or Synergistic Antibacterial Effects
(3) Combinations May Reduce The Development
Of Drug Resistance

22.  Combination Therapy Failed To Decrease The Risk Of Sepsis-
related Organ Dysfunction And Provide No Benefit Regarding
Other Clinical Outcomes
 A Survival Benefit May Be Seen In Patients With Septic Shock
At High Risk Of Death/Clinical Failure
 Combination Therapy Should Be Restricted To Patients With
Sever Infections(e.g., Endocarditis, Gram-negative
Bacteremia) And High Risk Of Death
 The SSC Guidelines Suggest Combination Therapy In
Patients With Neutropenia And Those With Difficult-to-treat,
Multidrug-resistant Organisms And Suggest Specific
Combinations According To Organ Dysfunction And
Suspected Organisms

23. RIGHT
TIME

24.  Golden Hour Of Sepsis
 With Each 1-hour Of Delay In
Antimicrobial Therapy, Patients With
Septic Shock Had A 7.6% Decrease In
Survival

26. RIGHT
DURATION

27.  Empiric Combination Therapy Should
Not Be Administered For More Than 3
To 5 Days
 De-escalation To The Most Appropriate
Single Therapy Should Be Performed
As Soon As The Susceptibility Profile Is
Known

28. WAYS OF DE-ESCALATION
 Going From A Broad Spectrum To A
Narrower Spectrum Antibiotic Based On
Culture And Sensitivity Data
 Changing From Multiple Antibiotics To A
Single Antibiotic
 Decreasing Duration Of Therapy

30.  Clinical Biomarkers Such As WBC,
CRP, And ESR Are Commonly Used
To Monitor Patients With Infection, But
They Are Nonspecific For Bacterial
Infections And Do No Correlate With
Prognosis

31. PROCALCITONIN
 Procalcitonin (PCT) Is A Prohormone That Is
Essentially Undetectable In Healthy Patients And
Elevated In Patients With Bacterial Infections
 Procalcitonin Has Been Proposed To Be A
Clinically Useful Prognostic Biomarker In Patients
With Sepsis When Measured Serially
 Falsely Elevated Concentrations Can Occur In
Patients With Autoimmune Diseases, End-stage
Renal Disease, Trauma, Underlying
Immunosuppression, And Malignancy

32.  Studies Show That Using PCT
Concentrations To Guide The
Initiation And Discontinuation Of
Empiric Antimicrobial Therapy Leads
To Shorter Antimicrobial Durations,
Shorter Hospital Lengths Of Stay,
And Less Relapse Of Infection With
No Impact On Mortality

34. SHORT VERSUS LONG
DURATION
 The Optimal Duration Of Antibiotic Therapy For
Bacteremia Is Unknown
 There Appears To Be Some Evidence That Would
Suggest That There Is No Significant Difference In
Mortality, Clinical And Microbiological Cure
Between Shorter Durations i.e. 5 – 7 Days Versus
8 -21 Days In Critically Ill Patients With Bacteremia

35. EMPIRICAL ANTIBIOTIC THERAPY OF
VENTILATOR-ASSOCIATED PNEUMONIA: 8 VS.
15 DAYS

36. RIGHT
DOSE

37. PHARMACOKINETICS

38. ABSORPTION
 Decreased Gastric Or Subcutaneous
Absorption Due To Shock And
Vasopressors

39. VOLUME OF DISTRIBUTION
 The Inflammatory Effects Of Sepsis Increase Vascular
Permeability And Vasodilation. Fluid From The Intravascular
Space Leaks Into The Interstitial Space, Causing A Third-
space Phenomenon. This Change And Redistribution Of Fluid
Increases The Vd Of Hydrophilic Antimicrobials
 Volume Is Further Affected By Aggressive Fluid Resuscitation
In The Early Stages Of Severe Sepsis And Septic Shock,
When Most Crystalloids Administered Will Reside In The
Interstitial Space Hours After Administration

40.  The Increase In Volume During The Resuscitative Period May
Lead To Subtherapeutic Antimicrobial Concentrations And
Place The Patient At Risk Of Treatment Failure, Increased
Antimicrobial Resistance, Or Both
 Hydrophilic Antimicrobials May Need Larger Doses And/Or
Loading Doses To Achieve Adequate Concentrations At The
Infection Site
 Lipophilic Antimicrobials Are Less Influenced By Changes In
Volume Because Of Their Wide Distribution In Adipose Tissues
And Intracellular Compartments

41.  Protein Binding Is A Factor That May Influence The
Vd And CL Of Many Antibiotics
 Hypoalbuminemic States (A Common Finding In
The Critically Ill) Can Result In A Higher Unbound
Concentration That Has Up To 100% Increased Cl
And 90% Greater Vd

42.  HYDROPHILIC MEDICATIONS
Β-lactams
Linezolid
Polymyxins
Vancomycin
Aminoglycosides
 LIPOPHILIC MEDICATIONS
Macrolides
Fluoroquinolones
Tetracyclines
Tigecycline
Metronidazole

43. METABOLISM
High-extraction Drugs :
Depends On Hepatic Perfusion
In Sepsis, There May Be A High Cardiac Output State
And An Increase In Perfusion To Liver, Leading To
Increased Clearance Of High-extraction Drugs By The
Liver. However, There Also Can Be A Decrease In
Perfusion In Sepsis, Leading To Decreased Clearance
Of High-extraction Drugs

44.  Low-extraction Drugs:
Depends On Hepatic (Intrinsic) function
In Sepsis, Hepatocellular Enzyme Activity
May Also Be Decreased, Leading To The
Decreased Clearance Of Antimicrobials That
Are Metabolized By Hepatocellular Enzymes

45. EXCRETION
 Progression Of Renal Dysfunction And Decreases
In Glomerular Filtration Will Decrease The
Clearance Of Antimicrobials That Are Eliminated By
The Kidney
 However, In Preserved Kidney Function, Renal
Clearance May Actually Be Increased Or
Augmented Because Of The Increase In Perfusion
To The Kidney Seen In High Output States Like
Sepsis

46. PHARMACODYNAMICS

47. CONCENTRATION DEPENDENT
 Microorganism Killing Is Optimized As The Maximum
Concentration (Cmax) At The Infection Site Increases
Above The MIC (Cmax/MIC)
 The Goal With These Antimicrobials Is To Maximize The
Concentration While Avoiding Adverse Effects
 These Drugs Should Be Given By High Doses With
Widely Separated Frequencies Of Administration
 Examples:
Aminoglycosides
Metronidazole

48. TIME DEPENDENT
 Microorganism Killingis Optimized When The Unbound
Concentration Of The Antimicrobialis Above The MIC At
The Infection Site For Most Of The Dosing Interval (T >
MIC)
 The Goal With These Antimicrobials Is To Maximize The
Duration Of Exposure
 These Drugs Should Be Given By Extended/Prolonged
Infusion (i.e., Over More Than 4 Hours) Or Continuous
Infusion
 Examples:
Β-lactams (Penicillins, Cephalosporins, Carbapenems)

49. CONCENTRATION DEPENDENT
WITH TIME DEPENDENCE
 Examples:
Fluoroquinolones
Glycopeptides
Macrolides
Tigecycline
Tetracyclines
Linezolid
Polymyxins

50. CONCLUSION
 Appropriate use of antimicrobial agents involves
obtaining an accurate diagnosis, determining the
need for and timing of antimicrobial therapy,
understanding how dosing affects the antimicrobial
activities of different agents, tailoring treatment to
host characteristics, using the narrowest spectrum
and shortest duration of therapy
 The old and famous refrain by the German
microbiologist Paul Ehrlich “hit fast and hit hard” is
still true after more than a century