ANTIBIOTICS IN CRITICALLY ILL PATIENTS CLINICAL PHARMACOLOGY Lenka Součková Control of infectious disease MMWR, Achievements in Public Health, 1900-1999: Control of Infectious Diseases, 1999 / 48(29);621-629 Great antibiotic Pathogen Clear solution Cure the patient Is always ATB great? Pathogen Clear solution Cure the patient Critical steps in antibiotic therapy  Determine  the right time initiating antibiotic therapy - golden hour of sepsis  ATB selection  the correct dose - dose optimisation - iv to oral switch  the correct time interval  duration of antibiotic therapy - de escalation  inappropriate or redundant antibiotics (dual anaerobic cover etc)  Recognize different types of ADRs of individual antibiotics and suitably replace  Identify where the use of antibiotics inappropriate / unwanted Normal flora  Microbes that engage in mutual or commensal associations - normal (resident) flora, indigenous flora, microbiota  Infection- a condition in which pathogenic microbes penetrate host defenses, enter tissues and multiply  Disease – any deviation from health, disruption of a tissue or organ  Caused by microbes or their products – infectious disease Normal Pathogen Conditional Pathogen Pathogen Symbiosis, natural protection Eradicate all pathogens Innate Resistance to Infection • Nonspecific physical, anatomical, and chemical barriers prevent colonization of the host by most pathogens • Lack of these defenses results in susceptibility to infection and colonization by a pathogen.  Anatomic barriers breached (IV’s, foleys, vents etc.)  Exposure to virulent pathogens  many resistant to multiple antibiotics Innate Resistance to Infection Innate Resistance to Nosocomial Infection • Many hospital patients with noninfectious diseases (for example, cancer and heart disease) acquire microbial infections because they are compromised hosts. • Host defenses depressed by underlying disease or treatment, malnutrition, age • Such hospital-acquired infections are called nosocomial infections. Where do the microbes come from? • patient's own flora • cross infection from medical personnel • cross infection from patient to patient • hospital environment- inanimate objects  air  dust  IV fluids & catheters  washbowls  bedpans  endoscopes  ventilators & respiratory equipment  water, disinfectants etc The Inanimate Environment Can Facilitate Transmission ~ Contaminated surfaces increase cross-transmission ~ Abstract: The Risk of Hand and Glove Contamination after Contact with a VRE (+) Patient Environment. Hayden M, ICAAC, 2001, Chicago, IL. X represents VRE culture positive sites SOURCES OF PATHOGENS IN NI  Reactivation of latent infection: TB, herpes viruses  Less common  Endogenous: normal commensals of the skin, respiratory, GI, GU tract  common  Exogenous  Inanimate environment: Aspergillus from hospital construction, Legionella from contaminated water  Animate environment: hospital staff, visitors, other patients  Cross transmission- common Site of infections • Pathogen invasion starts at the site of adherence and may spread throughout the host via the circulatory systems. • 4 major nosocomial infections: • UTI, VAP, SSI, BSI  Urosepsis 40% - Urinary tract  Pneumonia 20% - Lung  Surgical site 17%  Bloodstream (IV) 8% - catheter infections • GIT – salmonela, clostridum diff. • infections in the abdominal cavity • meningitis • bacterial endocarditis • localized infections, abscesses and other SEPSIS 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. Objectives  Define SIRS / sepsis / severe sepsis / septic shock  Early recognition of Sepsis  Early Goal Directed Therapy SIR S Definitions  A continuum of severity describing the host systemic inflammatory response SIRS  SIRS – systemic inflammatory response syndrome  Must have at least 2 of the following:  Temperature >38.5ºC or <36ºC  Heart rate >90 beats/min  Respiratory rate >20 breaths/min or PaCO2 <32 mmHg  WBC >12,000 cells/mm3, <4000 cells/mm3, or >10 % immature (band) forms  SIRS is the body’s response to infection, inflammation, stress. Sepsis and Severe Sepsis  Sepsis – SIRS + suspected or confirmed infection (documented via cultures or visualized via physical exam/imaging)  Severe Sepsis – Sepsis + at least one sign of organ hypoperfusion or dysfunction Areas of mottled skin Disseminated intravascular coagulation Capillary refill > 3 secs AKI UOP < 0.5cc/kg /hr ARDS or acute lung injury (ALI) Lactate > 2mmol /L Cardiac dysfunction on echo Altered mental status Plt < 100 Abnormal EEG Troponin Leak Septic Shock  Septic Shock - Severe sepsis plus one of the following conditions:  MAP <60 mm Hg (<80 mm Hg if previous hypertension) after adequate fluid resuscitation  Need for pressors to maintain BP after fluid resuscitation  Adequate fluid resuscitation = 40 to 60 mL/kg saline solution (NS 5L-10L)  Lactate > 4mmol /L Antibiotics  Cultures / Antibiotics / Labs  Cultures PRIOR to Antibiotics ( 2 Sets, one peripheral and one from any line) IV Abx within 1 hr in the ICU  Broad Spectrum, combination therapy for neutropenic and patients with pseudomonas risk factors  Consider need for Source Control ! Drainage of abscess or cholangitis, removal of infected catheters, debridement or amputation of osteomyelitis Fluid therapy  Central Line Access (Fluid hydration +/- pressor)  1st line therapy – fluids, fluids, fluids!  Crystalloid equivalent to colloid  Initial 1-2 Liters (20mg /kg) crystalloid or 500 ml colloid  Careful in CHF patients !! Pressors  See separate lecture on vasopressors  Start with norepinephrine as first line therapy +/- Vasopressin  Consider Dopamine peripherally on floor  ** This is available in crash cart ** If not responding to fluids, don’t want for pharmacy to send levophed. Corticosteroids  Use in Septic Shock, if NO response to vasopressors and fluids  HYDROCORTISONE 200mg -300mg / day Divided doses (Q6hrs)  Initial Dose 100mg IV x1  Consider for patients who received etomidate  No need for cosyntropin stim test  Wean Steroids QUICKLY once off pressors KEY TAKE HOME POINTS  Recognize Sepsis EARLY and determine SEVERITY  EARLY Antibiotics are critical to resolution of shock  RESUSCITATE severe sepsis and septic shock ASAP  EARLY GOAL DIRECTED THERAPY Antibiotics therapy Pharmacokinetics and Pharmacodynamics as steps leading to optimalization of ATB treatment Pathogen Great and clear solution PK/PD Succesfull treatment Therapeutic failure, definition and causes Drugs 2012; 72 PK/PD princip Dose of ATB A D M E Plasma concentration changing in time Concentration in non targeted site Concentration in action site Toxicity Therapeutic effect W.A. Graig Protein binding, Cmax, Cmin, Half-life, AUC, Tissue, Distribution MAX MIN PK/PD properties of ATB Plasma concentration changing in time C (max) Peak AUC C (min) Plasma concentration of ATB defines the ATB effect The phenomenon of acquired resistance Andersson DI. Nature Reviews Microbiology 12.7 (2014): 465-478. Escherichia coli and fluoroquinolones 2001 2013 http://ecdc.europa.eu/en/healthtopics/antimicrobial_resistance/database/Pages/map_reports.aspx Pseudomonas aeruginosa – carbapenems databáze EARS-Net 2008 2013 http://ecdc.europa.eu/en/healthtopics/antimicrobial_resistance/database/Pages/map_reports.aspx Klebsiella pneumoniae and fluoroquinolones 2007 2013 http://ecdc.europa.eu/en/healthtopics/antimicrobial_resistance/database/Pages/map_reports.aspx Klebsiella pneumoniae – carbapenems database EARS-Net 2007 2013 http://ecdc.europa.eu/en/healthtopics/antimicrobial_resistance/database/Pages/map_reports.aspx PK and PD parameters of ATBs on a concentration vs. time curve Key: T >MIC—The time for which a drug’s plasma concentration remains above the minimum inhibitory concentration (MIC) for a dosing period; Cmax/MIC, the ratio of the maximum plasma antibiotic concentration (C max) to MIC; AUC/MIC, the ratio of the area under the concentration time curve during a 24-hour time period (AUC0–24) to MIC. Roberts JA, Crit Care Med 37 (3) 2009 PK/PD characteris tics Time>MIC 24h AUC/MIC Cmax/MIC Antibiotics β Lactams Carbapenems Linkosamids Klindamycine Vancomycine Quinolones Tetracyclines Glykopeptidy Linezolid Aminoglycosides Metronidazole Target Maximizing time of ATB exposure Optimization of the ATB dose administered over time Optimalization Cmax ATB Pharmacodynamic properties that correlate with efficacy of selected antibiotics Roberts JA, Crit Care Med 37 (3) 2009 Leipzig 2009 43 Time > MIC MIC Half-life concentrations Time (h) 24 t1 t2  100 2 2 1 %    Ln T MICVd Dose LnMICTime β Lactams Carbapenems Lincosamids Clindamycins Vancomycine Way of administration prolonged/continuous infusion Time above the minimum inhibitory concentration (MIC) for intermittent, extended and continuous infusion of time-dependent drugs. Extended or continuous infusion of time-dependent drugs can improve the percentage of the dosing interval above the MIC... Downes KJ. International Journal of Antimicrobial Agents, Volume 43, Issue 3, 2014, 223 - 230 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 Leipzig 2009 46 Cmax / MIC PK PD • Bioavailability (%) • clearance • Rate of absorptione Rate of elimination • Accumulation factor 90 max MIC C MIC Time C-p Aminoglycosides Metronidazole Concentration dependent killing activity and moderate to prolonged persistent effects  More rapid killing effect against micro organisms 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 Leipzig 2009 48 AUC/MIC PK PD 90 / MIC ClearanceDose MIC AUC  MIC Time C-p Quinolones Tetracyclines Glykopeptidy Linezolid Concentration dependent killing activity and moderate to prolonged persistent effects  Fluoroquinolones  Cut off of 125 for the AUC/MIC ratio has been proposed  In critical ill patients, very complex given that pharmacokinetics of these and multiple variation related to changes in renal function and high inter-individual variability  Using a Monte Carlo dosing simulation, doses of 400mg every 8-12hrs givento 1-2 patients did not reach the necessary killing concentrations for P.aeruginosa, A.baumannii strains Khachman D, et al. Optimizing ciprofloxacin dosing in intensive care unit patients through the use of population pharmacokinetic-pharmacodynamic analysis and Monte Carlo simulations. J Antimicrob Chemother 2011; 66: 1798-809 YUMC 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 microorganisms during the dosing interval is more limited YUMC 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 Hydrophilic ATB Lipophilic ATB • Low Vd • Predominant renal CL • Low intracellular penetration • Inactive against intracellular pathogens • High Vd • Predominant hepatic SL (Drugdrug interactions) • Good intracellular penetration • Active against intracellular pathogens • Higher Vd • Higher or lower CL dependent on renal function • Vd largely unchanged • Higher or lower CL dependent on hepatic function β-lactams Aminoglycosides Glycopeptides Linezolid Colistin Fluoroquinolons Makcrolides Lincosamides Tigecykline Comparision of hydrophilic and lipophilic ATB related with PK properties General PK characteristics Altered ICU PK Examples Influence of basic pharmacokinetic parameters Drug clearance (CL) Volume of distribution (Vd) pathophysiology Function of elimination organs increase of cardiac output (increased flow, crystalloid / colloid NA-sepsis, burns) sepsis leakage of fluid into the third compartment volume dependence hypoalbuminemia Drug interactions induction inhibition binding to a proteins drug incompatibilites ascites Using RRT • selected method of elimination (Diffusion / convection) • technical adjustment methods (Qb, Qd, Qd predilutions / Postdilution) • physicochemical properties of ATB (Mw, lipophilicity, hydrophilicity, binding to proteins) • patient parameters (Residual filtration, nonrenal CL) obesity lipophilichydrophilic Case report  Woman, 27 years, 58 kg, 165 cm  laparoscopic appendectomy, 2nd day release at home, there colaps state, transported to ICU, massive pulmonary embolism  CPR for cardiac arrest with the development posthypoxic status epilepticus – administered valproic acid (1600 mg/day), intubated  Pneumoia treated with meropenem (1 g after 6 hours)  Unadequate concentration of valproic acid althought the daily dose was increased on 6 000 mg What is the management of this drug-drug interactions? Schematic representation of the basic pathophysiological changes that can occur during sepsis and their subsequent pharmacokinetic effects. Roberts JA, Crit Care Med 37 (3) 2009 Guidelines therapeutic range of plasma concentration aminoglycosides Shaw B.: Applied pharmacokinetics and pharmacodynamics, Lippincott Williams Wilkens, Philadelphia, 2006 distribuční objem aminoglykosidů Considering the low Vd AMG has a small change of the extracellular fluid bulky fatty tissue the great importance for Vd changes. Altered physiology in the critically ill and the impact on antibiotic PK/PD. ARC augmented renal clearance AKI acute kidney injury, CL clearance, IV intravenous, MIC minimum inhibitory concentration, Vd volume of distribution Udy, AA. Intensive Care Med (2013) 39:2070–2082 Optimalization of ATB therapy  Selection of appropriate ATB  Early initialization of ATB therapy  Choosing the correct loading and maintenance dose  The way of administration – prolonged/continual infusion Depending on factors: Patients Weight/Age Alergy Elimination organs function Disease Type / pathogen susceptibility Site of infection ATB Solubility PK/PD characteristics Guidelines therapeutic range of plasma concentration of vancomycine Guidelines therapeutic range of plasma concentration vancomycine http://www.ashp.org/doclibrary/bestpractices/tpsvanco.aspx Case report  Man, 62 years, 75 kg, 175 cm  Sepsis, septic shock  initial therapy, a huge volume dependence,  Vancomycin i.v. 1500 mg bid 12 h/1h inf. , sCr=54 umol/l.  plasma concentration (39.8 mg/l ).  Recommendations: to continue in dose regiment for four days and then to perform sample control before the next dose  plasma concentration (7 mg/l).  Then comes the worsening of renal function, creatinine is gradually increasing.  The sample control was performed on 8. day and 7.5 hours after administration was found creatinemia 416 umol/l.  Plasma concentration (71.9 mg/l).  Vancomycine was stoped and drop to a safe concentration lasted 7 days. The drug accumulation in the body during therapy required monitoring levels throughout the treatment period! Early ATB therapy  Many large, observational studies have demonstrated that early initiation of antibiotic therapy is very closely related to improved survival  Non-randomized-controlled data Gaieski DF, Mikkelsen ME, Band RA, et al. Impact of time to antibiotics on survival in patients with severe sepsis or septic shock in whom early goal-directed therapy was initiated in the emergency department*. Critical Care Medicine 2010;38(4):1045–53. Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock*. Critical Care Medicine 2006;34(6):1589–96. Time from EDGT qualification to ABX Time from hypotension to appropriate ABX Early initiation of appropriate antibiotic therapy for septic shock and survival. Deresinski S Clin Infect Dis. 2007;45:S177-S183 © 2007 by the Infectious Diseases Society of America Dose selection Loading dose:  The initial dose is typically used to ensure the achievement of therapeutic concentrations in the shortest possible time and to achieve bactericidal activity.  This applies even in the antibiotics, which subsequently administered in several hours of infusion (carbapenems). After intravenous bolus antibiotic concentration decreases very rapidly particularly for distribution of the drug. If Vd is higher than assumed, the standard dose of antibiotics is inadequate and should be increased. Recommendation:  Physicians should choose a higher initial dose with aminoglycosides, βlactams, glycopeptides and colistin in critically ill patients with sepsis.  Subsequent doses should be adjusted according to the function of elimination organs. (Moore RD, 1987, Taccone FS, 2010) Dose adjustments at AKI  Generally, in AKI the dose of ATB during the first 48 to 72 hours is not necessary to reduce. In risk ATB is necessary to adjust the dose according to the monitoring levels. (Blot, 2014).  Generally, it is recommended to reduce the initial dose ATB in patients during CVVH (Pea F, 2007 Bouman SC, 2008).  All these data show a significant correlation between disease severity and pharmacokinetics of antibiotics, which is not normally taken into account in most current dosing regimens (Udy AA, 2013).  ATB dosage recommended on the SPC is not adequate for patients with sepsis. 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. Appropriate empirical antibiotic therapy of ventilator-associated pneumonia: 8 vs. 15 days. 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 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 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 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 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 A bedside scoring system (Candida score) for preemptive antifungal treatment in nonneutropenic critically ill patients with Candida colonization. Crit Care Med 2006; 34: 730-7  In a large cohort of nonneutropenic critically ill patients in whom Candida colonization was prospectively assessed, a “Candida score” >2.5 accurately selected patients who would benefit from early antifungal treatment. YUMC How to optimize antibiotic administration in critically ill patient  1) β-lactams  Active against most organisms recovered form ICU patients  Drug levels are insufficient in patients with severe infections  Cefepime (2g taken every 12hr) concentrations were more than 70% above target concetnrations in less than half of patients with sepsis Ambrose PG, Owens Jr RC, Garvey MJ, et al. Pharmacodynamic considerations in the treatment of moderate to severe pseudomonal infections with cefepime. J Antimicrob Chemother. 2002;49:445–5  Cefepime (2g every 8hr), recently  Serum cefepime and ceftazidime levels below therapeutic levels after a few hours in most cases in septic patients with normal renal function Lipman J, Gomersall CD, Gin T, et al. Continuous infusion ceftazidime in intensive care: a randomized controlled trial. J Antimicrob Chemother. 1999;43:309–11. YUMC How to optimize antibiotic administration in critically ill patient  1) β-lactams  Piperacillin concentration, above therapeutic levels for most of the time interval in patients with sepsis  Administration of piperacillin by continuous infusion, with a loading dose, achieved superior pharmacodynamic targets compared with conventional bolus dosing in septic patients Roberts JA, et al. First-dose and steady-state population pharmacokinetics and pharmacodynamics of piperacillin by continuous or intermittent dosing in critically ill patients with sepsis. Int J Antimicrob Agents 2010, 35:156–163.  Meropenem concentration, adequate in most of the studies in critically ill patients  But in severe infection,mostly after cardiac surgery, meropenem had adequate serum concentration for at least 50% of the time in patients with normal and impaired renal function Kitzes-Cohen R, Farin D, Piva G, et al. Pharmacokinetics and pharmacodynamics of meropenem in critically ill patients. Int J Antimicrob Agents. 2002;19:105–10. YUMC How to optimize antibiotic administration in critically ill patient  Monitoring of several antibiotics in a large cohort of ICU septic patients, showing that dose adjustments are necessary to optimize drug concentrations in most of them  Early phase of sepsis, broad-spectrum β-lactams should be administered more frequently or in doses larger than suggested in non septic patients with a dramatic increased of therapy costs  Continous infusion or extended β-lactam infusion are required to optimize pathogen exposure to bactericidal concentrations of these drugs  Roberts JA, Lipman J: Pharmacokinetic issues for antibiotics in The critically ill patients. Crit Care Med 2009, 37:840–851 YUMC How to optimize antibiotic administration in critically ill patient  2) Vancomycin  Higher than recommended doses of vancomycin were necessary to optimize drug concentrations and rescue patients from septic shock d/t GPB  Administration of the conventional dose of vancomycin (15mg/kg of BW every 12hr) would probably fail to achieve therapeutic drug concentraions in the majority of critically ill patients  Continuous infusion with 30mg/kg daily dosage has been proposed to optimize PD vancomycin Pea F, Viale P. Should the currently recommended twice-daily dosing still be considered the most appropriate regimen for treating MRSA ventilator-associated pneumonia with vancomycin? Clin Pharmacokinet. 2008;47:147–52.  Continuous infusion, faster time to achieve target drug concentrations, lower daily dose, reduced therapy costs than intermittent dose Wysocki M, et al. Continuous versus intermittent infusion of vancomycin in severe Staphylococcal infections: prospective multicenter randomized study. Antimicrob Agents Chemother. 2001;45:2460–7. YUMC How to optimize antibiotic administration in critically ill patient  Clinical superiority of continuous infusion of vancomycin in a subgroup of patients with VAP d/t MRSA Rello J, Sole-Violan J, Sa-Borges M, et al. Pneumonia caused by methicillin-resistant Staphylococcus aureus treated with glycopeptides. Crit Care Med. 2005;33:1983–7.  Continuous infusion with a 30mg/kg daily dosage has been proposed to optimize PD vancomycin Pea F, Viale P. Should the currently recommended twice-daily dosing still be considered the most appropriate regimen for treating MRSA ventilator-associated pneumonia with vancomycin? Clin Pharmacokinet. 2008;47:147–52.  Slower onset of nephrotoxicity Ingram PR, Lye DC, Fisher DA, et al. Nephrotoxicity of continuous versus intermittent infusion of vancomycin in outpatient parenteral antimicrobial therapy. Int J Antimicrob Agents. 2009;34:570–4. YUMC 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 Summary • Early administration of adequate antibiotic at the right dose is crucial for the treatment of sepsis and positively influences the prognosis • In critically ill patients are often required increased doses of antibiotics than other patients • In acute organ failure the dose of antibiotics within the first 48-72 hours does not reduce • For toxic ATB (aminoglycosides, vancomycin) adjust the dose according to plasma levels of antibiotics • ATB administered according to their PK / PD properties Literature  Gilbert DN.: The Sanford guide to antimicrobial therapy, Sperryville, USA, ISBN: 978-1-930808-60-70, 2013  Aronoff, GR.: Drug Prescribing in Renal Failure, Dosing guidelines for adults and children, fifth edition,ACP, Philadelphia, USA, ISBN: 978-1-930513-76- 1, 2007 http://kdpnet.louisville.edu/renalbook/