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

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 2009 evaluated 14414 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.

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

How the magic will work?

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

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

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 ?

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.

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 !

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.

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

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.

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

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.

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

Drug interactions of antibiotics Debate

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

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

Mis –use of antibiotics

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

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

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

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.

Loading dose of antibiotics Golden hour is missed !!

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

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

Drugs 2012; 72 YUMC 34

concentration dependent

time dependent

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

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: 674-81 YUMC 39

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

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 80-120 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

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

YUMC 44

Right Time

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 8 -21 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.

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

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

Multi drug resistance

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

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

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

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;171:388-416 YUMC 54

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 2011. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com

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

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

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?