1. Where can we wrong; while prescribing right dose of antibiotics
Dr. Udgeeth Thaker
MD, Medicine
Idccm
Consultant intensivist and physician

2. The serial killer  sepsis
Sepsis, severe sepsis and septic shock remains a major cause of morbidity and mortality
Mortality for severe sepsis ≥5-fold higher than that for acute coronary syndrome or for stroke.
Incidence of sepsis requiring intensive care admission of 0.25–0.38 per 1000 population, suggesting ∼2 million admissions to critical care units alone.
The EPIC study, a point prevalence study performed in 1265 critical care units in evaluated patients estimated that over half the patients in the units were infected, more than 70% of them were on antibiotics and 62% of the microbiological isolates were gram negative bacteria.

3. Antibiotics  magic  cure
Antibiotics made human race survived
Antibiotics made health care effective
Can you imagine world without antibiotics?

5. How the magic will work?

9. Principles of antibiotic prescription
Right antibiotic
guidelines
time and concentration dependent antibiotics
tissue and fluid distribution
drug bug mismatches
inappropriate or redundant antibiotics (dual anaerobic cover etc)
Right dose
loading dose
liver and renal adjustment
dose optimisation
iv to oral switch
Right time
golden hour of sepsis
Right duration
de escalation

10. We need to understand the powers…
Pharmacokinetics and pharmacodynamics
Tissue distribution
Right dose
Right choice
Bacteriocidal vs bacteriostatic antibiotics

11. Renal clearance of antiobitics
Renal clearance of antibiotics is calculated for chronic renal failure
Not for acute renal failure because in that creatinine is changed time to time
Even in renal failure patients  first dose is normal dose
Which will act as loading dose  only maintenance doses will change
How to take decision ?

12. Renal clearance for hyper filtration
Patient with Lasix ?  hydrophilic antibiotics
Patient with s. creatinine less then 0.8 ?  water soluble
Patient with ascites, severe pulmonary edema
Should we need to increase dose of antibiotics in that case?
Controversy but easily concluded with affirmation.

13. Antibiotics and dialysis
Dialysis filters some of the antibiotics  micromolecules
Dialysis retains many of antibiotics  macromolecule
Dialysis decreases cost of antibiotic therapy  dialysis is done without extra cost in septic patient.
Vancomycin  72 hours
Meropenam  repeat loading dose
As a protocol, all antibiotic doses are given post dialysis. Re-load !

14. Antibiotics and crushing them
How to administer antibiotics in Ryles tube
Crushing them together  mixing up molecules
Some part of drug is stucked up to the crusher
Ideal is to wrap them in butter paper and then crush all medicines individually.

16. Tissue concentrations
Tigecycline is not penetrated in urine
Levoflox do not cross bones
Deptomycin is not concentrated in lungs
Meropenam is poor in crossing brain then ceftriaxone.
No azithromycin above neck & below diaphragm

17. Absorption of antibiotics
Sucralfate coats gastric mucosa  many pro drugs are activated there  many tablet forms disintegrates in acidic ph of stomach. Twice a day dose of PPI  more then 90% acid suppression  antibiotics not disintegrated. Actually H2 blockers are recommended for prophylaxis Patient with RT aspiration Patient with delayed gastric emptying time Patient with RT feed if aspiration less then 50 ml. Patient with intestinal diseases, will have impaired absorption of antibiotics.

18. IV to oral switch Bioavailability Antibiotics group Cross resistance
Linezolid
Levoflox
Iron
Metronidazole
Antibiotics group
Cross resistance
Drug interaction

19. Liver clearance Any specific instructions?
Liver dysfunction cannot be measured like s. creatinine hence no specific guidelines
Almost all of antibiotics are liver metabolized.
Drug dosage has to be induvidualized.
If liver functions are compromised, there has to be higher serum level of the drug in blood as per the percentage of the liver dependency of the drug molecule.

20. Protein bound drugs
With liver disease or malnutrition  protein levels are decreased
Albumin or others
Accordingly we have to decrease or increase the drug doses
Less is the protein  less protein bound drug  more serum level

21. Drug interactions of antibiotics
Debate

22. Bacteriostatic vs bactericidal antibiotics
Only bacteriostatic drugs  flare up after stopping antibiotics
In resistance infection bacteriostatic + cidal
 linezolid requires to be combine
 colistin alone  not a good choice

23. Mis-use of antibiotics
Viral infection  no antibiotics
Prevention of infection in viral infections.
Allow antibiotic to ACT  72 hours  no frequent change
Keep an eye on plasma concentration

24. Mis –use of antibiotics

25. Inhalation antibiotics and serum level
Colistin will not work alone as nebulizer therapy. Additional serum concentration can be achieved but there has to be an above MIC colistin concentration in the serum level.
Tobramycin works alone as neb theraoy

27. Golden hour for antibiotics
Golden hour in MI
Golden hour in stroke
Golden hour in SEPSIS as well !!!
Sepsis  Treatment is antibiotics

28. Early initiation of appropriate antibiotic therapy for septic shock and survival.
Early initiation of appropriate antibiotic therapy for septic shock and survival. The survival fraction is the fraction of patients surviving to hospital discharge after receiving effective therapy initiated within the given time interval. The cumulative effective antimicrobial fraction is the cumulative fraction of patients having received effective antimicrobials at any given time point. Adapted from Kumar A, Roberts D, Wood KE, Light B, Parrillo JE, Sharma S, Suppes R, Feinstein D, Zanotti S, Taiberg L, Gurka D, Kumar A, Cheang M. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med 2006; 34(6):1589–96 [5] (with permission from Lippincott Williams & Wilkins).
Deresinski S Clin Infect Dis. 2007;45:S177-S183
© 2007 by the Infectious Diseases Society of America

30. Loading dose of antibiotics
Loading dose of antibiotics helps to reach MIC level at higher speed
Loading dose of antibiotics provides confirm tissue penetration levels at the target organ site.

31. Loading dose of antibiotics
Golden hour is missed !!

32. Therapeutic failure, definition and causes
본표는 감염병소의 항생제 노출이 적은 이유들을 정리해놓은 표입니다.
원인은 다음과 같습니다.
Drugs 2012; 72
YUMC 32

33. Infection and Chemotherapy : Vol.40, No.3, 2008

34. Drugs 2012; 72
YUMC 34

36. concentration dependent

37. time dependent

38. Antimicobial characteristics related to pK/pD behaviour involving new forms of administration
1) Concentration dependent killing activity and moderate to prolonged persistent effects (Cmax/MIC, AUC/MIC)
Aminoglycosides
Fluoroquinolones
Metronidazole
Colistin
Rifampicin
Clindamycin
2) Time dependent killing activity and minimal persistent effects (T>MIC)
Beta lactams
Linezolid
3) Time dependent killing activity and moderate to prolonged persistent effects (AUC/MIC)
Tetracyclines
Vancomycin
약동/약력학 지표와 관련하여 항생제를 분류해 보면,
농도 의존적이고, 항생제 투여후 효과가 moderate 이상인 경우,
시간 의존적이면서 항생제 투여후 효과가 미약한 경우
시간 의존적이면서 항생제 투여 후 효과가 moderate 이상인 경우. (체내의 높은 항균제 농도가 살균력을 증대시키지는 않지만, 좀더 높은 농도로 세균의 재성장을 오랫동안 억제할 수 있는 특징)
YUMC 38

39. Concentration dependent killing activity and moderate to prolonged persistent effects
More rapid killing effect against micro organisms at high concentrations than low concentrations
Allows the administrations of high doses with widely separated frequencies of administration
Aminoglycosides
Doses of these antimicrobials administered to critically ill patients are frequently insufficient
Rea RS, et al. Suboptimal aminoglycoside dosing in critically ill patients. Ther Drug Monit 2008; 30:
YUMC 39

40. Time dependent killing activity and minimal persistent effects
Maintain blood concentrations above MIC for prolonged time periods
T>MIC ratio is the pK.pD predictor of efficacy of these antibacterials and to attain the best values of this parameter
These drugs should be given by continuous infusion
B- lactams
Constant controversy
Penicillin, monobactams, cephalosporins, carbapenems
No relation to the survival, continuous infusion vs extended infusion
Continous or extended infusion of β-lactam antibacterials leads to similar clinical results
YUMC 40

41. Time dependent killing activity and minimal persistent effects
Linezolid
T>MIC and AUC/MIC are the pK/pD predictors of efficacy
With continuous infusion, AUC/MIC more frequently than with intermittent infusion
According to pK/pD parameters, continuous infusion has theoretically advantages over intermittent infusion in this population
Adembri C, et al. Linezolid pharmacokinetic/ pharmacodynamic profile in critically ill septic patients: intermittent versus continuous infusion. Int J Antimicrob Agents 2008; 31: 122-9
YUMC 41

42. Time dependent killing activity and moderate to prolonged persistent effects
Glycopeptides (Vancomycin, Teicoplanin)
Significant controversy in regarding the efficiency by which vancomycin kills GPB and the potential misuse of the drug
In humans, AUC/MIC value >350 was an independent factor associated with clinical success in patients with S.aureus proven lower respiratory tract infection
Difficulty in obtain multiple serum vancomycin concentration,
 Cmin monitoring has been recommended as the most accurate and practical method
The duration of effect is longer and the possibility of regrowth of micro-organisms during the dosing interval is more limited
YUMC 42

44. YUMC 44

45. Right Time

46. Duration of antibiotic therapy
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 days in critically ill patients with bacteremia.
Better to prove and treat with culture reports.
Prompt de-escalation is the key to shorter duration of broad spectrum cover
Procalcitonin guided antibiotic de-escalation.

47. Appropriate empirical antibiotic therapy of ventilator-associated pneumonia: 8 vs. 15 days.
Appropriate empirical antibiotic therapy of ventilator-associated pneumonia: 8 vs. 15 days. In a multicenter, randomized, double-blind trial involving patients with ventilator-associated pneumonia, the 8-day regimen achieved outcomes better than or equivalent to those associated with the 15-day regimen. “Unfavorable outcome” was defined as death, recurrence of pulmonary infection, or prescription of a new antibiotic for any reason. ICU, intensive care unit; MDR, multidrug resistance.
Deresinski S Clin Infect Dis. 2007;45:S177-S183
© 2007 by the Infectious Diseases Society of America

48. Multidrug resistance
MDR pathogens : resistant to > 3 classes of drugs
ESBL
Amp- C lactamase
Carbapenamase
Answer is
 high and optimum MIC concentration
 antibiotic stewardship

49. Multi drug resistance

51. Infectious Diseases Society of America guidelines for antimicrobial stewardship: comprehensive multidisciplinary antimicrobial management program.
Infectious Diseases Society of America guidelines for antimicrobial stewardship: comprehensive multidisciplinary antimicrobial management program.
Deresinski S Clin Infect Dis. 2007;45:S177-S183
© 2007 by the Infectious Diseases Society of America

52. Strategies to optimize the use of antimicrobials in the ICU
1) De-escalation therapy
2) Antibacterial cycling
3) Pre-emptive therapy
4) Use of pharmacokinetic/pharmacodynamic parameters for dose adjustment
YUMC 52

53. De-escalation therapy
Initial administration of broad spectrum empirical treatment
To cover pathogens, most frequently related to the infection
Rapid adjustment of antibacterial treatment once the causative pathogen has been identified
Objective
Lower morbidity and mortality by an early achievement of an appropriate empirical treatment
Limit the appearance of bacterial resistance by a reduced antibacterial pressure
Condition that needed-strategy
Epidemiolgical map of the bacterial ecosystem including susceptibility pattern of the most frequent pathogen
Rapid response of microbiological studies
Compliance with the recommendation of adjusting initial empirical treatment to definite microbiological diagnosis
YUMC 53

54. De-escalation therapy
Applicability of this strategy, failed
Absence of microbiological results
Isolation of multi-resistant pathogens preventing de-escalation
Reluctance of some clinicians to change antibacterials in patients with a favorable clinical course despite persistence of severity of illness
Despite limitations, antibacterial de-escalation therapy has been recommended
ATS guideline for the management of adults with hospital acquired, ventilator associated, and healthcare associated pneumonia, AJRCCM 2005;171:
YUMC 54

55. Recommendations for starting/stopping antibiotics based on the PRORATA study.21 Adapted from Figure 1 in Bouadma et al.21.
Recommendations for starting/stopping antibiotics based on the PRORATA study.21 Adapted from Figure 1 in Bouadma et al.21
Kibe S et al. J. Antimicrob. Chemother. 2011;66:ii33-ii40
© The Author Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please

56. Antibacterial cycling
The scheduled rotation of one class of antibacterials
One or more different classes with comparable spectra of activity
Different mechanisms of resistance
Some weeks and a few months
Objective
Reduce the appearance of resistances by replacing the antibacterial before they occur and preserving its activity to be re-introduced in the hospital in a later cycle
YUMC 56

57. Pre-emptive therapy
The administration of antimicrobials in certain patients at very high risk of opportunistic infections before the onset of clinical signs of infection
Developed in hematological patients and/or transplant recipients based on the use of serological tests that advanced the diagnosis of some infections
CMV, aspergillosis
In critical illness patients to patients at high risk of candidemia or invasive candidiasis
: In the absence of serological test to establish an early diagnosis of invasive candidiasis, different scores based on clinical and/or microbiological data
YUMC 57

58. SUMMARY
Antibiotics are amongst the most commonly used therapies in critical care
Optimising antibiotic use improves patient outcomes
Optimising antibiotic use should minimise pressures on emerging antibiotic resistance
Is antibiotic stewardship the answer?