optimizing and maximizing antibiotic therapy

Optimizing and Maximizing Antibiotic

Therapy

JAIME C. MONTOYA, MD, MSc, PhDProfessor V

University of the Philippines College of MedicineExecutive Director

Philippine Council for Health Research and DevelopmentDepartment of Science and Technology

Optimal Antibiotic Therapy

Eur Respir Rev 2007; 16: 103, 33–39

PK-PD relationships between antibiotics and key

nosocomial pathogens

includingresistant strains

Optimal Antibiotic Therapy Involves the use of antibiotics that achieves

maximum therapeutic effect with minimum selective pressure for resistance

Balance between potency and efficacy with potential for induction of antimicrobial resistance

Polk. Clin Infect Dis 1999;29:264-274

Components of Optimal Antibiotic TherapyIncludes: optimal selection (based on predicted

pathogens, activity and efficacy, host characteristics, toxicity, cost)

dose and duration of treatment (based on PK/PD of the antibiotic, site of infection, severity of infection)

control of antibiotic use that will prevent or slow down the emergence of resistance among micro-organisms

Polk. Clin Infect Dis 1999;29:264-274

Need for Optimal Antibiotic Therapy Increasing number of cases of antibiotic failure Decreasing number of new antibiotics in the

pipeline Need to maximize the efficacy of existing

antibiotics Preserve their potency and reduce the problems

of antimicrobial resistance

How to Choose the Appropriate Antimicrobial

Therapy

Factors Affecting Choice of Antibiotics Defining whether it is for empiric, definitive or

prophylactic therapy Identifying the site of infection ( for determining

antibiotic penetration) Identifying the most probable etiologic agent/s

and the predicted susceptibilities (based on local or unit antibiograms) and proper interpretation of DST

Defining the immune status of the host (eg, immunocompromised vs immunocompetent)

Defining the severity of infection

Types of Antibiotic TherapyType of Therapy Description Use of

Antibiograms

Prophylaxis Antibiotics used to prevent infection

Selection of antibiotic

Empiric Organism is unknown but syndrome is known

Selection of antibiotic or combination of antibiotics

Pathogen-directed Organism is known but susceptibility is unknown

Selection of antibiotic

Susceptibility-guided Organism is known and susceptibility is known

Cumulative antibiogram not useful

Unit-Specific or Hospital-Specific Cumulative Antibiotic Susceptibility Report or "Antibiogram"

Helpful for choosing empiric and pathogen-directed treatment regimens.

antibiotic susceptibility reports on individualpatients is clearly of use to ensure thatantimicrobial treatment was adequate forthe organism causing the infection.

Unit-Specific or Hospital-Specific Cumulative Antibiotic Susceptibility Report or "Antibiogram"

It also assists in antibiotic "streamlining" --the process by which excessively broad-spectrum empiric antibiotic therapy can beswitched to narrower spectrum therapyaimed only at the implicated pathogen(s).

Empiric Antibiotic Therapy

Choice of antibiotics rests on the likely organismscausing that particular type of infection.

For example, for uncomplicated urinary tractinfection, E coli predominates; for community-acquired pneumonia, Streptococcus pneumoniae;and for ventilator-associated pneumonia,Pseudomonas aeruginosa, S aureus,Enterobacter cloacae, and Klebsiella pneumoniaeare most frequently isolated

Difficulty of Hospital Micro Lab

It may be difficult for a microbiologist to determinewhether organisms are community-acquired orhospital-acquired.

Hospital laboratories should know the ward inwhich the patient was residing at the time whenthe isolate was collected.

Importance of Appropriate Antibiotic Therapy For patients in ICUs, mortality rises if the empiric

antibiotic therapy chosen does not cover thepathogens causing the infection.[1-4]

Kollef and colleagues[1] showed that infection-related mortality was 17.7% in those patients whoreceived appropriate empiric antibiotic therapy vs42.0% in those patients who receivedinappropriate empiric antibiotic therapy.

most common reason why empiric antibiotictherapy was inappropriate was resistance of thebacteria to the antibiotic chosen

Strategy to ensure appropriate antibiotics Ibrahim and colleagues[5] reviewed the

antibiogram for their particular ICU and created aclinical guideline for antibiotic selection in thatunit.

Adequacy of empiric antibiotic selection forventilator-associated pneumonia for patients intheir ICU increased from 48.0% before thecreation of antibiotic guidelines to 94.2% with theuse of their guidelines.

Antibiogram-based Guideline

does not have an unlimited duration of utility. shifts in antibiotic usage engendered by the

creation of the guideline will, over time, lead to achange in resistance patterns.

it is prudent to update antibiograms andantibiogram-based antibiotic guidelines on aregular basis. A yearly review should be regardedas a bare minimum.

Importance of Unit or Site Based Antibiogram Do hospital-wide antibiograms give an accurate

indication of antibiotic resistance in a particularunit within the hospital.

Namias and colleagues[6] showed that ICUantibiograms differed substantially from theantibiogram for the entire hospital.

In general, unit-specific hospital antibiogramsserve more utility in showing which antibioticsshould be avoided for specific infections ratherthan which antibiotics should be used.

Importance of National Antibiograms First, it allows for a comparison of local data with

national data to determine whether the extent ofresistance is better or worse than nationalaverages.

Second, it provides the ability to presage futuretrends in antibiotic resistance: If resistance isrising for a particular pathogen at a national level,it may be only a matter of time before resistancerates rise locally.

Criteria for Empiric Antibiotic Therapy likely pathogens (and their susceptibility profiles)

at any particular infection site are known. Cumulative antibiotic susceptibility reports on

multiple patients (antibiograms) or nationalsusceptibility data can be useful in guidingempiric antibiotic therapy.

recent antibiotic use and known bacterialcolonization status.

How to Give Antimicrobial Therapy in the Critically Ill

Patient

Dosing based on Hemodynamic changes in the critically ill

patient (severity of infection) Body weight of the patient (e.g. obese) PK/PD of the antibiotic Presence of medical comorbidities that will

affect metabolism of the antibiotic

Hemodynamic Changes in the critically ill patient

Roberts, J. and Lipman, J. CCM 2009

• alter the concentration-time relationship• reduce the exposure of antibiotics to bacteria

Hemodynamic Changes in the Critically Ill Patient Patients may have augmented renal clearances

needing either higher doses or more frequent dosing to overcome increased drug elimination

Udy AA et al. Clin Pharmacokinet 2010; 49: 1–16.Udy AA et al. Chest 2012; 142: 30–9.

Critically ill patients often have low plasma albumin concentrations that alters the protein binding of drugs and has significant effects on pharmacokinetics

Finfer S et al. BMJ 2006; 333: 1044.Ulldemolins M et al. Clin Pharmacokinet 2011; 50: 1–12.

Roberts JA et al. Clin Pharmacokinet 2013; 52: 1–8.

PK/PD of the Antibiotic

Pharmacokinetics (PK) is concernedwith the time course of antimicrobialconcentrations in the body

Pharmacodyamics (PD) is concernedwith the relationship between thoseconcentrations and the antimicrobialeffect.

PK/PD of the Antibiotic

Antibiotic dosing regimens havetraditionally been determined by PKparameters only.

However, PD plays an equal, if notmore important, role.

these parameters may be used todesign dosing regimens whichcounteract or prevent resistance.

MIC of the Antibiotic

The primary measure of antibiotic activity isthe minimum inhibitory concentration (MIC).

The MIC is the lowest concentration of anantibiotic that completely inhibits the growthof a microorganism in vitro.

While the MIC is a good indicator of thepotency of an antibiotic, it indicates nothingabout the time course of antimicrobialactivity.

PK Parameters of the Antibiotic

PK parameters quantify the serum level timecourse of an antibiotic.

three pharmacokinetic parameters that are mostimportant for evaluating antibiotic efficacy :

peak serum level (Cmax),trough level (Cmin)Area Under the concentration Curve (AUC).

While these parameters quantify the serum leveltime course, they do not describe the killingactivity of an antibiotic.

PK/PD Parameters of the Antibiotic Peak/MIC ratio - Cpmax divided by the MIC T>MIC (time above MIC) - percentage of a

dosage interval in which the serum level exceedsthe MIC

24h-AUC/MIC determined by dividing the 24-hour-AUC by the MIC.

Pattern of activity

Antibiotics Goal of Therapy PK/PD Parameter

Type IConcentration-dependent killing and Prolonged persistent effects

AminoglycosidesDaptomycinFluoroquinolonesKetolides

Maximize concentrations

24h-AUC/MICPeak/MIC

Type IITime-dependent killing and Minimal persistent effects

CarbapenemsCephalosporinsErythromycinLinezolidPenicillins

Maximize duration of exposure

T>MIC

Type IIITime-dependent killing andModerate to prolonged persistent effects.

AzithromycinClindamycinOxazolidinonesTetracyclinesVancomycin

Maximize amount of drug

24h-AUC/MIC

Antimicrobial PD Parameterto Optimize Therapy of T>MIC Antibiotics● Time-dependent

antibiotics: the most important PD parameter is T>MIC, which should be maintained >50% of dosing interval( e.g. cephalosporins(cefepime) , carbapenems)

MIC

Time (h)

T>MICAn

tibio

tic (C

)

Drusano GL Clin Infect Dis. 2007 Jul 15;45 Suppl 1:S89-95McKinnon PS, Davis SL Eur J Clin Microbiol Infect Dis. 2004;23:271-88

Optimizing β-lactam Therapy: Maximizing Percent T>MIC

Higher dose Increased dosing frequency Increased duration of infusion

a. Prolonged infusionb. Continuous infusion

Pharmacodynamics of Antimicrobial by David Nicolau , FCCP,FIDSA

Improved Potency

(In Vivo Exposure)

Dosing of Beta-Lactams Drug dosing in the obese patient population have to be

more precise to effectively treat infections. Obesity alters the disposition of drugs in the body

(pharmacokinetics) Failure to adjust doses in obesity may result either in

therapeutic failure or increased toxicity. Total body weight greatly overestimates renal function in

obese patients. Use of an adjusted body weight (IBW + 0.4 [TBW-IBW])

may provide a more accurate estimate in obese patients ICAAC 2014

PK/PD changes in the Obese Volume of distribution (Vd) of drugs may be

altered Obesity results in increased adipose tissue

mass, which can influence medications with lipophilic properties

Increased organ mass, lean body mass, and blood volume in obesity also can affect hydrophilic medications e.g. aminoglycodises

Can lead to sub- or supra-therapeutic concentrations.

Wurtz et al.Clin Infect Dis. 1997; 25:112-118. Blouin RA et al. J Pharm Sci. 1999; 88:1-7.

Cheymol G. Clin Pharmacokinet. 2000; 39:215-231

Optimizing β-lactam Therapy: Maximizing Percent T>MIC

Higher dose Increased dosing frequency Increased duration of infusion

a. Prolonged infusion- Same dose and dosing interval,

however, change duration of infusion (0.5 hr 3hr)

b. Continuous infusion- Administer loading dose, then use

pump to give total daily dose IV over 24 hr period

Pharmacodynamics of Antimicrobial by David Nicolau , FCCP,FIDSA

Improved Potency

(In Vivo Exposure)

Prolonged Infusion VS Slow IV Bolus A population pharmacokinetic model of cefepime

was constructed from data from adult critical care patients with ventilator-associated pneumonia (VAP).

A total of 32 patients treated with high-dose cefepime, 2 g every 8 h (3-h infusion) or a renal function-adjusted equivalent dose, were randomized into two groups

Serum samples of cefepime were collected at steady state.

Nicasio AM et al. Antimicrob Agents Chemother 2009; 53(4):1476-1481

Prolonged Infusion VS Slow IV Bolus Among the regimens, the likelihoods of 2 g every

8 h (3-h infusion) achieving free drug concentrations above the MIC for 50% of the dosing interval were 91.8%, 78.1%, and 50.3% for MICs of 8, 16, and 32 g/ml, respectively.

This study provides a pharmacokinetic model capable of predicting cefepime concentrations in critically ill patients with VAP.

Nicasio AM et al. Antimicrob Agents Chemother 2009; 53(4):1476-1481

Intermittent Dosing < Prolonged Infusion with Intermittent Dosing

< Continuous Infusion < Continuous Infusion with Loading

Dose

Increasing Order of Optimal Infusion

Optimal Duration of Treatment with Antibiotics

Need for Optimal Duration of Therapy Up to half of the antibiotic use in hospital wards and

critical care units is unnecessary or inappropriate Excessive durations of treatment are the greatest

contributor to inappropriate use Reduction in the length of antibiotic courses is, therefore,

a potentially viable strategy to minimize the consequences of antibiotic overuse in critical care, including antibiotic resistance, adverse effects, Clostridium difficile colitis, and costs

Hecker MT et al. Arch Intern Med 2003, 163:972-978 Rice LB.Clin Infect Dis 2008, 46:491-496. Hayashi Y et al.Clin Infect Dis 2011, 52:1232-1240. Rubinstein E. Int J Antimicrob Agents 2007, 30:76-79.

Shorter Duration of Antibiotic Therapy Limited information about the optimal

duration of antibiotic treatment able to cure disease without causing microbial resistance.

Few antibiotic regimens have been subjected to rigorous evaluation of treatment duration.

Shorter Duration of Antibiotic Therapy Duration of antibiotic treatment necessary

for urinary tract infections in women and for sexually transmitted diseases have been well studied

a large series of trials established the shortest effective antibiotic treatment regimen for tuberculosis

Rice LB et al.Clin Infect Dis 2008, 46:491-496. Fox W et al. Int J Tuberc Lung Dis 1999, 3:S231-279

Shorter Duration of Antibiotic Therapy However, data are lacking for the optimal

treatment duration for many other diseases, including diarrhea, meningitis and pneumonia and also for different forms of bacteremia or BSI (Blood stream infections)

Shorter Therapy for CAP El Moussaoui et al compared outcomes for

cases of mild to moderate-severe community acquired pneumonia after treatment with antibiotics for three or eight days.

Study involved nine hospitals in the Netherlands and was carried out as a randomised, double blind, placebo controlled non-inferiority trial.

El Moussaoui R et al. BMJ 2006;332:1355-8.

Shorter Therapy for CAP Patients who met entry criteria were treated with

intravenous amoxicillin. Those who showed significant improvement

after 72 hours were switched to either oral amoxicillin or placebo for five days.

Clinical and radiological outcomes assessed at days 10 and 28 were not significantly different.

Study yields strong evidence in favour of short course therapy for a subset of patients

El Moussaoui R et al. BMJ 2006;332:1355-8.

Optimal Duration of Therapy Optimal duration of therapy for primary BSI and BSI

secondary to major organ system infections has been poorly defined.

There is wide variability in antibiotic treatment duration recommendations from infectious disease and critical care specialists

Presence of bacteremia is often used as a justification for extended courses of antibiotic therapy regardless of the observed clinical response to treatment

Corona A et al. J Antimicrob Chemother 2003, 53:849-852. Daneman N et al. Int J Antimicr Agents 2011, 38:480-485.

Optimal Duration of Therapy Randomized controlled trials (RCTs) demonstrated that

treatment can be shortened to 1 week or less without worsening patient outcomes

It is plausible that treatment duration could potentially be shortened for BSIs

Kyriakidou KG et al. Clin Ther 2008, 30:1859-1868.Dimopoulos G et al. Drugs 2008, 68:1841-1854.

Li JZ et al. Am J Med 2007, 120:783-790.

Optimal Duration of Therapy Harvey et al. conducted a systematic review and

meta-analysis of RCTs explicitly examining the efficacy of shorter-course versus longer-course antibiotic therapy for patients with bacteremia as well as comparable trials examining the organ system infections most commonly causing bacteremia in critically ill patients.

Harvey T et al. Critical Care 2011, 15:R267

Forest plot for outcome of clinical cure among bacteremic subgroups of randomized trials of shorter versus longer antibiotic treatment.

Forest plot for outcome of microbiologic cure among bacteremic subgroups of randomized trials of shorter versus longer antibiotic treatment

Forest plot for outcome of survival among bacteremic subgroups of randomized trials of shorter versus longer antibiotic treatment

Optimal Duration of Therapy Available data from bacteremic subgroups of prior

randomized controlled trials suggest that shorter-duration therapy (not more than 7 days) may be as effective as longer-duration therapy in achieving clinical cure, microbiologic cure, and survival among most patients with bloodstream infections.

A large dedicated randomized trial of treatment duration for bacteremia is urgently needed.

Harvey T et al. Critical Care 2011, 15:R267

Importance of Early Appropriate and Potent Antimicrobial Therapy

New Paradigm in Sepsis Sepsis, Severe Sepsis and Septic shock are

fundamentally different diseases and not a continuum

Microbial load drives downstream host responses including development of organ dysfunction and failure and not the cellular immune response

Kumar A. Virulence 2014; 5(1):80–97

New Paradigm in Sepsis Elimination of underlying infection should

terminate downstream inflammatory process leading to organ dysfunction and failure and not the termination of the inflammatory cascade

But once critical threshold is exceeded, likelihood of positive outcome is reduced and irreversibility of organ dysfunction ensues


Implications

Sepsis, Severe Sepsis and Septic shock are fundamentally different diseases and not a continuum

Time of delivery of effective antimicrobial therapy from onset of hypotension is a surrogate marker for increasing microbial burden of organism

Early and Rapid clearance of pathogens is the most important determinant of outcome in sepsis


Importance of Early Initiation of Antibiotic Therapy Retrospective study involving 2154 patients with septic

shock Showed strong correlation between delays in initiating

antibiotic therapy and in-hospital mortality (adjusted odds ratio [OR], 1.119 deaths/1-h delay; P <.0001).

Time to initiation of appropriate antibiotic therapy was the strongest predictor of survival

If an effective antibiotic was administered within the first hour of documented hypotension, the survival rate was 79.9%; each 1-h delay over the next 6 h decreased average survival rates by 7.6%.

Kumar A et al. Crit Care Med 2006; 34:1589–96.

Early targeted antibiotics improved outcomes in S. aureus bloodstream infections

Appropriate antibiotics initiated within 24 hours of a positive blood culture, and appropriate exposure maintained for the duration of therapy

Cure rate was significantly higher (72% vs. 48%, P = .024)

Weber and Zelenitsky, ICAAC 2014

Parameters for PK/PD Resistance Curve MPC (Mutant Prevention Concentration) is

defined as the lowest antibiotic concentration that prevents growth of the least susceptible single-step mutants.

Resistant subpopulations are proposed to be selectively enriched in the mutant selection window (MSW)—that is, the drug concentration range between the MIC and the MPC

Zhao X et al. Clin Infect Dis 2001; 33(Suppl 3):S147–56.Drlica K et al. Clin Infect Dis 2007; 44:681–8.

Olofsson SK and Cars O. Clin Infect Dis 2007;45:S129-36

Impact of Antibiotic Therapy on Antibiotic Resistance Antibiotic resistance can be selected during

antibiotic treatment . Selection takes place both at the site of infection

and in the commensal flora. To prolong the life span of existing and new

antibiotics, it is of utmost importance that the dosing regimens are carefully selected on the basis of the PK/PD properties that prevent emergence of preexisting or newly formed mutants.

Olofsson SK and Cars O. Clin Infect Dis 2007;45:S129-36

THANK YOU

optimizing and maximizing antibiotic therapy

Documents

antibiotic penetration

antibiotic therapyjaime

use of antibiotics

choice of antibiotics

prophylactic therapy

site of infection

predicted susceptibilities

unit antibiograms