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Optimizing and Maximizing Antibiotic TherapyOptimizing and Maximizing Antibiotic Therapy
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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
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
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
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.
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
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
Kumar A. Virulence 2014; 5(1):80–97
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
Kumar A. Virulence 2014; 5(1):80–97
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
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