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  • 1. Antibiotic Dosing in Multiple Organ Dysfunction Syndrome Marta Ulldemolins, Jason A. Roberts, Jeffrey Lipman and Jordi Rello Chest 2011;139;1210-1220 DOI 10.1378/chest.10-2371 The online version of this article, along with updated information and services can be found online on the World Wide Web at: http://chestjournal.chestpubs.org/content/139/5/1210.full.html Chest is the official journal of the American College of Chest Physicians. It has been published monthly since 1935. Copyright2011by the American College of Chest Physicians, 3300 Dundee Road, Northbrook, IL 60062. All rights reserved. No part of this article or PDF may be reproduced or distributed without the prior written permission of the copyright holder. (http://chestjournal.chestpubs.org/site/misc/reprints.xhtml) ISSN:0012-3692Downloaded from chestjournal.chestpubs.org by guest on June 24, 2012 © 2011 American College of Chest Physicians
  • 2. CHEST Postgraduate Education Corner CONTEMPORARY REVIEWS IN CRITICAL CARE MEDICINE Antibiotic Dosing in Multiple Organ Dysfunction Syndrome Marta Ulldemolins, PharmD; Jason A. Roberts, PhD, BPharm(Hons); Jeffrey Lipman, MD; and Jordi Rello, MD, PhD Although early and appropriate antibiotic therapy remains the cornerstone of success for the treatment of septic shock, few data exist to guide antibiotic dose optimization in critically ill patients, particularly those with multiple organ dysfunction syndrome (MODS). It is well known that MODS significantly alters the patient’s physiology, but the effects of these variations on phar- macokinetics have not been reviewed concisely. Therefore, the aims of this article are to sum- marize the disease-driven variations in pharmacokinetics and pharmacodynamics and to provide antibiotic dosing recommendations for critically ill patients with MODS. The main findings of this review are that the two parameters that vary with greatest significance in critically ill patients with MODS are drug volume of distribution and clearance. Disease- and clinician-driven changes lead to an increased volume of distribution and lower-than-expected plasma drug concentrations during the first day of therapy at least. Decreased antibiotic clearance is common and can lead to drug toxicity. In summary, “front-loaded” doses of antibiotic during the first 24 h of therapy should account for the likely increases in the antibiotic volume of distribution. Thereafter, main- tenance dosing must be guided by drug clearance and adjusted to the degree of organ dysfunction. CHEST 2011; 139(5):1210–1220 Abbreviations: AKI 5 acute kidney injury; AUC0-24 5 area under the concentration curve over 0 to 24 h; CL 5 clearance; Cmax 5 peak concentration; CrCL 5 creatinine clearance; ƒ T . MIC 5 time over minimum inhibitory concentration; GFR 5 glomerular filtration rate; MDRD 5 modified diet in renal disease; MIC 5 minimum inhibitory concentration; MODS 5 multiple organ dysfunction syndrome; PK/PD 5 pharmacokinetic/pharmacodynamic; RRT 5 renal replacement therapy; TDM 5 therapeutic drug monitoring; Vd 5 volume of distributionDespiteuse, treatment of severe infections remains biotic decades of clinical experience with anti- however, there is an absence of guidance on rational approaches to antibiotic dosing in patients with mul-a challenge for clinicians. Over the past years, two tiple organ dysfunction syndrome (MODS) who haveimportant phenomena have made even more essen- higher levels of sickness severity and whereby effec-tial the need to improve the use of presently available tive antibiotic therapy may be even more importantantibiotics and to extend the effective life of a drug: to clinical outcome. The purpose of this article is to(1) the escalation in the incidence of bacteria resis- review, using examples from the literature, the key con-tant to the available antibiotics1 and (2) the dearth of cepts likely to affect antibiotic pharmacokinetics andantimicrobial drugs with new mechanisms of action pharmacodynamics and to provide dose recommen-in development.2 One mechanism to improve optimi- dations for the treatment of critically ill patients withzation of antibiotic use may be improvement of anti- MODS.biotic dosing because a causal relationship is thoughtto exist among inappropriate dosing, clinical out- Search Strategy and Selection Criteriacome, and the development of bacterial resistance.3From a clinical perspective, optimization of antibiotic Data were identified by a systematic search inuse is particularly important for critically ill patients in PubMed (1966-October 2010) for original articleswhom early and appropriate antibiotic prescription that evaluated the variations in antibiotic pharmaco-has been shown to reduce mortality.4-10 The physio- kinetics and pharmacokinetics/pharmacodynamicslogic and pharmacokinetic derangements in antibiotics (PK/PD) in MODS. Key words used were “sepsis” orhave been reviewed previously for patients with sepsis11; “systemic inflammation response syndrome” or “septic1210 Postgraduate Education Corner Downloaded from chestjournal.chestpubs.org by guest on June 24, 2012 © 2011 American College of Chest Physicians
  • 3. shock” or “multiple organ failure” and “antibacterial lent to the extracellular water and usually correspondsagents” or “antibiotics” and “pharmacokinetics” or to a value between 0.1 L/kg and 0.3 L /kg.11 On the con-“pharmacodynamics” and “critically ill patient” or trary, lipophilic drugs can cross lipid membranes and,“intensive care unit” or “critical care.” A total of therefore, distribute intracellularly and into adipose167 articles were returned, of which only 48 were tissues. Hence, the Vd of lipophilic drugs dependsdeemed relevant for critically ill patients with MODS on the amount of adipose tissue, which generally isor some level of organ dysfunction. Numerous articles proportional to total body weight.11 There are a fewalso were identified through searches of the exten- exceptions where this approach cannot be extrapo-sive files of the authors. lated, for example, in patients with increased muscle mass, as muscle tissue is highly hydrophilic and affects the Vd of lipophilic drugs to a lesser extent. Overview of Antibiotic Physicochemistry, Pharmacokinetics, and Pharmacodynamics Pharmacokinetics The term “antibiotic” includes a variety of chemicalcompounds that exhibit great differences among them Pharmacokinetics is the study of the interrela-in terms of mechanism of action and physicochemical, tionship between drug dose and variations in con-pharmacokinetic, and pharmacodynamic characteris- centrations in plasma and tissue over time. Thetics. The uniqueness of each class makes independent most relevant pharmacokinetic parameters includestudy essential to provide accurate characterization the following12:of antibiotic behavior. • peak concentration achieved after a single dose (Cmax)Physicochemistry • Vd: the apparent volume of fluid that contains the total drug dose administered at the same A simple, but useful chemical classification for concentration as in plasmaantibiotics is by their affinity for water. Hydrophilic • clearance (CL): quantification of the irrevers-drugs predominantly distribute into intravascular ible loss of drug from the body by metabo-and interstitial water but are unable to passively cross lism and excretionthe lipid cellular membrane and, therefore, do not • elimination half-life: time required for thepenetrate intracellularly in meaningful concentrations. plasma concentration to fall by one-halfHence, their volume of distribution (Vd) is equiva- • protein binding: proportion of drug binding to plasma proteinsManuscript received September 13, 2010; revision acceptedJanuary 3, 2011. • AUC0-24: total area under the concentrationAffiliations: From the Burns, Trauma and Critical Care Research curve over 0 to 24 hCentre (Drs Ulldemolins, Roberts, and Lipman), The Universityof Queensland, Brisbane, QLD, Australia; Critical Care Depart-ment (Drs Ulldemolins and Rello), Vall d’Hebron UniversityHospital, Vall d’Hebron Institut de Recerca (VHIR), Universitat Pharmacodynamics and PK /PDAutònoma de Barcelona, Barcelona, Spain; Centro de InvestigaciónBiomédica En Red de Enfermedades Respiratorias (CIBERES) Pharmacodynamics is the study of the relationship(Drs Ulldemolins and Rello), Barcelona, Spain; and Department between drug concentrations and effect.12 The PK/PDof Intensive Care Medicine (Drs Roberts and Lipman) and Phar- approach seeks to establish a relationship betweenmacy Department (Dr Roberts), Royal Brisbane and Women’sHospital, Herston, Brisbane, QLD, Australia. dosage and pharmacological effect.12 Figure 1 repre-Funding/Support: Funded by the National Health and Medical sents the relationship among pharmacokinetics, phar-Research Council of Australia [Project Grant 519702; Australian macodynamics, and PK/PD. Antibiotics can be cate-Based Health Professional Research Fellowship 569917(to Dr Roberts)]; Australia and New Zealand College of Anaes- gorized in three different classes depending on thethetists [ANZCA 06/037 and 09/032]; Queensland Health-Health PK/PD indices associated with their optimal killingPractitioner Research Scheme; Royal Brisbane and Women’s activity.13Hospital Research Foundation (to Drs Roberts and Lipman); andCIBERES [0606036], Agència de Gestió d’Ajuts Universitaris i deRecerca [09/SGR/1226], and Fondo de Investigación Sanitaria Time-Dependent Antibiotics: Optimal activity is achieved[07/90960] (to Drs Ulldemolins and Rello). when unbound plasma concentrations are maintainedCorrespondence to: Jordi Rello, MD, PhD, Critical Care Depart- above the minimum inhibitory concentration (MIC)ment, Vall d’Hebron University Hospital, Institut de RecercaVall d’Hebron-UAB, Passeig de la Vall d’Hebron 119-129, 08035 of the bacteria (ƒ T . MIC) for a defined fraction ofBarcelona, Spain; e-mail: jrello.hj23.ics@gencat.cat the dosing interval.© 2011 American College of Chest Physicians. Reproductionof this article is prohibited without written permission from the Concentration-Dependent Antibiotics: Optimal activityAmerican College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). correlates with Cmax, quantified by its ratio with theDOI: 10.1378/chest.10-2371 MIC of the bacteria (Cmax/MIC).www.chestpubs.org CHEST / 139 / 5 / MAY, 2011 1211 Downloaded from chestjournal.chestpubs.org by guest on June 24, 2012 © 2011 American College of Chest Physicians
  • 4. Figure 1. Interrelationship among pharmacokinetics, pharmacodynamics, and pharmacokinetics/ pharmacodynamics.Concentration-Dependent Antibiotics With Time Later, typical features of septic shock may appear,Dependence: A defined ratio between the unbound including a decrease in cardiac output and BP.17 ThisAUC0-24 and the MIC of the bacteria (ƒAUC0-24/MIC) sepsis-mediated altered blood flow may have impor-correlates with optimal activity. tant effects on drug delivery to tissues. During the warm shock phase, hypoperfusion of vital organs (eg, brain or lung) occurs, whereas Pathophysiology of MODS and Effect peripheral tissues and nonvital organs still receive on Drug Vd and CL high blood flow as a consequence of peripheral vaso- dilation and increased cardiac work.17 Vital organs Sepsis-related MODS has been defined as the hypoperfusion can lead to suboptimal delivery ofworsening of organ function due to a severe infection antibiotic and subtherapeutic levels at the target sitesuch that homeostasis cannot be maintained without during the initial stages of the infection in vital organintervention, usually involving two or more organ infections (eg, respiratory tract infections). However,systems.14 Endotoxins have a cascade effect on the a challenge for interpretation is the absence of phar-production of endogenous molecules that act on the macokinetic data specifically targeting the effects ofvascular endothelium, leading to vasodilatation and warm shock on drug distribution, and more researchtranscapillary leakage of fluid and proteins into the is required in this area.extracellular space.15 Moreover, sepsis is known to Peripheral tissue hypoperfusion can occur duringproduce myocardial dysfunction.16 These hemody- the second phase of septic shock as a result of the body’snamic alterations lead to sepsis-induced tissue hypop- attempt to increase perfusion of the vital organs.18erfusion, which can affect pharmacokinetics. Because Because peripheral tissues frequently are the sourceantibiotics are a group of drugs with “silent” pharma- of infection,19 hypoperfusion can lead to a failure tocodynamics (ie, the pharmacologic effect is not per- attain therapeutic concentrations at the site of infec-ceivable immediately after administration), it is almost tion.20 A similar scenario may be observed in patientsimpossible to assess whether therapeutic concentra- with fluid shifts, capillary leak, and edema.21 In thistions are being achieved during the early phase of case, despite increased movement of plasma andtherapy. Therefore, consideration of the scenarios likely solutes (eg, hydrophilic antibiotics) to the extravas-to alter antibiotic pharmacokinetics and necessitate cular compartment, drug concentrations at the tar-dosage adjustment are necessary to enable individu- get site could decrease because of a dilution effect.21alization of antibiotic therapy. Alternative approaches to drug administration, such as continuous or extended infusion, have been shown to reach more consistent antibiotic concentrationsTissue Hypoperfusion in tissue for time-dependent antibiotics in these In the first stage of septic shock (warm shock), scenarios and should be considered when treatingarteries dilate, decreasing peripheral arterial resis- infections by poorly susceptible bacteria.22,23 Montetance and causing a reflex increase in cardiac output. Carlo simulations can be used to this end to compare1212 Postgraduate Education Corner Downloaded from chestjournal.chestpubs.org by guest on June 24, 2012 © 2011 American College of Chest Physicians
  • 5. the relative PK/PD target attainments for different related cachexia) and are rarely at steady state, thesedosing approaches for antibiotics, particularly for formulas may lead to inaccurate estimations of GFRtime-dependent antibiotics. These analyses have shown and lead to inappropriate dose adjustments.28,29 Whereconsistently that extended infusions (. 3 h) or contin- possible, it is preferable to use either 8-, 12-, oruous infusions of time-dependent antibiotics achieve 24-h urinary CrCL to estimate GFR in critically illPK/PD targets more successfully than intermittent patients.30-32infusions (Յ 30 min).24-26 Monte Carlo simulations When using urinary CrCL, dose recommendationsalso can be used to show the effect of renal dysfunc- in the product information for estimated GFR bytion on the achievement of PK/PD targets. Figure 2 MDRD or Cockroft-Gault also apply. The main issuehas been adapted from Roberts et al22 and describes here is not the change in drug CL relative to GFRhow administering the same dose of meropenem in that is problematic; rather, it is how GFR is calcu-different levels of renal dysfunction will provide dif- lated. If GFR is not accurately estimated, then anyferent levels of achievement of PK/PD targets. Use of dose adjustment is likely to be suboptimal.extended or continuous infusions in this context couldserve to further increase the achievement of PK/PD Hepatic Dysfunctiontargets. The most common causes of liver failure in criti-Renal Dysfunction cally ill patients are infection-related cholestasis and hepatocellular injury, which occur in response to bac- Several factors can precipitate acute kidney injury terial toxins and to the toxins themselves.33 In the first(AKI) in critically ill patients.27 Early identification case, bacterial toxins and released cytokines canof AKI and accurate assessment of renal function affect the uptake and excretion of bile by hepatocytes,are essential for daily dose adjustment of hydrophilic leading to jaundice. In the second case, endotoxinsantibiotics. The estimations of creatinine clearance and bacteria are phagocytized by Kupffer cells that(CrCL) as a surrogate for glomerular filtration rate release several hepatotoxic molecules, leading to cel-(GFR) using formulas such as Cockroft-Gault and lular damage.33 Hepatic dysfunction also may resultmodified diet in renal disease (MDRD) must be from organ hypoperfusion, hemolysis, or concomi-interpreted carefully in critically ill patients because tant administration of hepatotoxic drugs (eg, rifam-despite having well-documented clinical value in spe- picin).33,34 Assessment of the degree of hepatic dys-cific patient populations (eg, patients with chronic kid- function in acute liver failure is mainly clinical andney disease), they are yet to be validated in critically may include signs and symptoms such as elevations inill patients. Because plasma creatinine concentrations liver enzymes, bilirubin, or ammonia and decreases incan vary for many reasons other than renal function the concentration of liver-produced proteins (eg, albu-in these patients (eg, decreases due to immobility- min, a1-acid glycoprotein, coagulation factors). Hepatic dysfunction may impair metabolism and, therefore, lead to accumulation of hepatically cleared antibi- otics.35,36 A decrease in the hepatic production of albumin and a1-acid glycoprotein also can alter phar- macokinetics of highly protein-bound antibiotics.25,37,38 Albumin is the most frequent drug carrier in the bloodstream. The drug-protein interaction is rapid and dynamic, and an equilibrium depends on the concentration of both drug and protein.39 In the presence of hypoalbuminemia, a larger number of unbound drug molecules are able to distribute from the bloodstream into tissues to a larger extent than when there is normal protein binding; pharmacoki- netically, this is translated into a larger Vd.39Figure 2. The effect of varying levels of renal dysfunction on Furthermore, clinical management of severe hepaticthe achievement of pharmacokinetics/pharmacodynamics targets failure may include renal replacement therapy (RRT)for the same dose of meropenem. This example describes the prob- and the use of adsorbent columns for removing excessability of target attainment (fT . MIC) for meropenem administeredby intermittent bolus (infused over 5 min), in a man aged 50 years ammonia and other waste products in the blood.40and weighing 70 kg with Cr of 50, 100, 200, and 300 mmol/L. The additive effect of these interventions and endog-Cr 5 plasma creatinine concentration; f T . MIC 5 time over the enous renal function on the excretion of renallyminimum inhibitory concentration; MIC 5 minimum inhibitoryconcentration. Adapted with permission of Oxford University Press cleared antibiotics has to be considered when dosingfrom Roberts et al.22 with hydrophilic antibiotics.www.chestpubs.org CHEST / 139 / 5 / MAY, 2011 1213 Downloaded from chestjournal.chestpubs.org by guest on June 24, 2012 © 2011 American College of Chest Physicians
  • 6. Optimizing Initial Dosing of Antibiotics therapeutic concentrations.49 This is the same prin- in MODS ciple by which loading doses of drugs such as amio- darone and phenytoin are required.50,51 Further, Pharmacokinetic alterations mediated by MODS evidence supports that even the Vd of hydrophilicshould be considered during antibiotic prescription antibiotics is increased in obese patients due toin critically ill patients. During the initial phase of the increased interstitial fluid, connective tissue, andsepsis, increased Vd and CL are common, and dosing muscle mass also present in obesity.52,53 Therefore,must be adjusted,11,41,42 which has been confirmed by obesity must be a factor to consider for initial dosing.two recent studies. The first study, by Roberts et al,43 In this context, use of an equation that assists cal-was a b-lactam therapeutic drug monitoring (TDM) culation of lean body weight should be used.54evaluation in critically ill patients, including patients Table 1 provides broad recommendations for opti-with MODS, that found that ‫ %07 ف‬of patients did mizing initial dosing in patients with increased Vd.not achieve appropriate antibiotic concentrations, Table 2 provides guidance for specific drugs in thiswith requirement of 50.4% and 23.7% dose increases scenario.and decreases, respectively, on the initial phase oftherapy. The second was a multicenter study byTaccone et al44 that showed that conventional initial Optimizing Maintenance Dosingdosing for many b-lactams frequently used in criti- of Antibiotics in MODScally ill patients was insufficient for achieving PK/PD Maintenance dosing must be guided by drug CL.targets on the first day of therapy. In this study, only Depending on the organ systems impaired by MODS,28% of the patients on ceftazidime, 16% on cefepime, the effect on antibiotic CL can vary widely. The mostand 44% on piperacillin/tazobactam achieved the relevant organ systems that may affect pharmacoki-PK/PD targets on the first day of therapy. The authors netics (mainly renal and hepatic systems) will be con-found that 40% of patients receiving piperacillin/ sidered individually.tazobactam had plasma concentrations of less than Table 1 provides general principles for mainte-four times MIC within 90 min after administration. nance dosing in renal failure, hepatic failure, and The results of both studies are likely to be due to RRT. Table 2 provides guidance for specific drugs inan increased Vd for these patients.15,45 It is important these scenarios. Figure 3 summarizes the scenariosto note that in the study by Taccone et al,44 27% of the likely to alter pharmacokinetics in MODS.patients had AKI, and despite having been prescribedwith standard non-AKI initial doses, most of themhad suboptimal concentrations after the first dose. Renal DysfunctionIn contrast, in the study by Roberts et al,43 19% of Hydrophilic antibiotics are mostly renally cleared bypatients had AKI (with or without dialysis require- glomerular filtration and tubular secretion. Decreasedments), and on days 2 through 5, 72% of these patients CL of these drugs is well described in renal dysfunc-required a dose decrease. The data from both studies tion, and as such, dose reductions or extended dosingsuggest that initial antibiotic dosing needs to account intervals are required to prevent drug accumulationfor the increased Vd that occurs in critically ill patients and toxicity.55 Dose adjustments to prevent toxicitywith MODS15; therefore, higher-than-standard doses are especially relevant for antibiotics with a narrowshould be considered in the initial phase of therapy. therapeutic window, such as glycopeptides and amin-This concept will be referred throughout this review oglycosides, that can produce nephrotoxicity, and,as “front-loaded” dosing and especially applies to hence, its accumulation may lead to a vicious circle ofhydrophilic drugs whose Vd dramatically increases in injury in the damaged kidney that may lead to greaterthis scenario.22,23,46,47 This concept was demonstrated antibiotic accumulation.by Marik46 who showed a twofold increase in the When dose reducing, it is essential to consider anti-Vd of amikacin in critically ill patients with gram- biotic pharmacodynamics to ensure that targets arenegative infections. This pharmacokinetic alteration will still attained where possible. For instance, a more appro-significantly affect the achievement of therapeutic priate dose reduction of time-dependent antibioticspeak concentrations (Cmax/MIC Ն 10).46 Recent would be to reduce the dose rather than the fre-research also supports administration of front-loaded quency of administration as a strategy to preserve thedoses for aminoglycosides (eg, 25 mg/kg for amikacin) ƒ T . MIC (eg, recommended dosing of meropenemon the first day of therapy for severe sepsis and septic for an estimated GFR , 15 mL/min would be a front-shock.48 loaded dose of 1,000 mg to provide therapeutic con- For lipophilic drugs, front-loaded doses based on centrations followed by a maintenance dose of 500 mgtotal body weight should be considered for patients every 12 h to enable continued optimization of ƒ T . MICwith a higher proportion of adipose tissue to achieve without toxicity). For concentration-dependent drugs,1214 Postgraduate Education Corner Downloaded from chestjournal.chestpubs.org by guest on June 24, 2012 © 2011 American College of Chest Physicians
  • 7. www.chestpubs.org Table 1—Broad Guidelines for Loading and Maintenance Dosing of Antibiotics in Critically Ill Patients With MODS Main Organ Systems PD Parameter Associated LD in Patients With Antibiotic Solubility Responsible for Clearance With Maximal Activity Increased Vd MD in Acute Kidney Injury MD in Hepatic Failure b-Lactams Hydrophilic Renal ƒ T . MIC Administer a high LD on Dose decreases preferred Normal dosing day 1, as Vd will be to increased time between significantly increased intervals Aminoglycosides Hydrophilic Renal Cmax/MIC Administer a high LD on Increased time intervals Normal dosing day 1, as Vd will be preferred to dose decreases, significantly increased titrate dosing according to TDM results Glycopeptides Hydrophilic Renal AUC0-24/MIC Administer high LD on Titrate dosing according Normal dosing day 1, as Vd will be to TDM results significantly increased Fluoroquinolones Lipophilic Renal and hepatic AUC0-24/MIC and Administer dosing for Decrease dose based on the Decrease dose based on the (ciprofloxacin, Cmax/MIC conserved organ degree of organ dysfunction degree of organ dysfunction moxifloxacin), renal function on day 1 and principal organ system and principal organ system (levofloxacin) responsible for clearance responsible for clearance Lincosamides Lipophilic Renal and hepatic AUC0-24/MIC and Administer dosing for Decrease dose based on Decrease dose based on the ƒ T . MIC conserved organ the degree of organ degree of organ dysfunction function on day 1 dysfunction Macrolides Lipophilic Hepatic ƒ T . MIC and Normal dosing Normal dosing Normal dosing AUC0-24/MIC Nitroimidazoles Lipophilic Hepatic Cmax/MIC Normal dosing Normal dosing Decrease dosing if severe (metronidazole) hepatic failure Cyclic lipopeptides Amphiphilic Renal Cmax/MIC Administer a high LD on Increase dosing interval Normal dosing © 2011 American College of Chest Physicians (lipophilic and day 1, as Vd will be hydrophilic) significantly increased Glycylcyclines Lipophilic Hepatic AUC0-24/MIC Administer LD per Normal dosing Decrease dosing product information Oxazolidinones Lipophilic Hepatic AUC0-24/MIC and Normal dosing Normal dosing Normal dosingDownloaded from chestjournal.chestpubs.org by guest on June 24, 2012 ƒ T . MIC AUC0-24/MIC 5 area under the concentration curve over 0 to 24 h-to-minimum inhibitory concentration ratio; Cmax/MIC 5 peak concentration-to-minimum inhibitory concentration ratio; ƒT . MIC 5 time over the minimum inhibitory concentration; LD 5 front-loaded dose; MD 5 maintenance dose; MIC 5 minimum inhibitory concentration; MODS 5 multiple organ dysfunction syndrome; PD5pharmacodynamic; TDM 5 therapeutic drug monitoring; Vd 5 volume of distribution. CHEST / 139 / 5 / MAY, 2011 1215
  • 8. Table 2—Dose Recommendations for LD and MD in MODS by Individual Drugs 1216 Recommended LD for Recommended MD for Recommended MD for Recommended MD for Antibiotic Class Antibiotic Name Patients With -Vd (Day 1) Patients With Hepatic Failurea Patients With Acute Kidney Injurya Patients With RRTb b-Lactams Carbapenems Meropenem 1-2 g q8h 1 g q8h 500 mg q12h 500 mg q8h Ertapenem 1 g q12h 1 g q12h 500 mg q12h 500 mg q8-12h Penicillins Piperacillin/tazobactam 4.5 g q4-6h 4.5 g q6h 4.5 g q8h or 2.25 g q6h 4.5 g q8h Ticarcillin/clavulanate 3.1 g q4-6h 3.1 g q6h 2 g q4-6h 2 g q4-6h Isoxazolyl penicillins 2 g q4h 2 g q4h 2 g q6h-1g q4h 2 g q6h-1g q4h (cloxacillin, flucloxacillin, dicloxacillin) Cephalosporins Ceftriaxone 1-2 g q12h 1 g q12h 1 g q12h 1-2g q12h Ceftazidime 2 g q8h 2 g q8h 1 g q8h 1 g q8h Cefepime 1-2 g q8-12h 1-2 g q8-12h 500 mg-1 g q12h 1-2 g q12h Monobactams Aztreonam 1-2 g q8h 1 g q6-8h 500 mg q6-8h 500 mg q6-8h Aminoglycosides Amikacin 25 mg/kg q24h to achieve 15 mg/kg q24h; monitor Monitor Cmin after 24 h, aiming Monitor Cmin after 24 h, a Cmax/MIC 5 10 Cmin after 24 h, aiming for levels , 5 mg/L. Dosing aiming for levels , 5 mg/L for levels , 5 mg/L q48h may be required for and titrate dosing according severe renal dysfunction to results Gentamycin, 7 mg/kg as a LD on day 1 to 5 mg/kg q24h; monitor Monitor Cmin after 24 h, aiming Monitor Cmin after 24 h, tobramycin achieve a Cmax/MIC 5 10 Cmin after 24 h, aiming for levels , 0.5 mg/L. Dosing aiming for levels , 0.5 mg/L for levels , 0.5 mg/L q48h may be required for and titrate dosing according severe renal dysfunction to results Glycopeptides Vancomycin 20-30 mg/kg LDc 15-20 mg/kg q12h Use TDM (Cmin) on day 3, Use TDM (Cmin) on day 3, aiming for range 15-20 mg/L aiming for range 15-20 mg/L (20-25 mg/L if CI). Dosing (20-25 mg/L if CI). Dosing must be titrated to fit in this range should be titrated to this range Teicoplanin 12 mg/kg q12h for 3-6 mg/kg q12h, titrate Prescribe 3 mg/kg q12h from the Prescribe 3 mg/kg q12h from the © 2011 American College of Chest Physicians three doses dosing on day 4 guided fourth dose and titrate dosing fourth dose and titrate dosing by TDM, aiming for on day 4 guided by TDM, aiming on day 4 guided by TDM, Cmin . 10 mg/L for Cmin . 10 mg/L aiming for Cmin . 10 mg/L Fluoroquinolones Ciprofloxacin 400 mg q8h 400 mg q12-24h 400 mg q12-24h 400 mg q12-24h Levofloxacin 500-750 mg q24h 500-750 mg q24h 250 mg q24-48h 500 mg q48h or 250 mg q24h Moxifloxacin 400 mg q24h 400 mg q24h 400 mg q24h 400 mg q24hDownloaded from chestjournal.chestpubs.org by guest on June 24, 2012 Lincosamides Lincomycin Administer 600 mg q6-8h 600 mg q12h 600 mg q12h 600 mg q8h as an LD on day 1 Clindamycin Administer 600 mg q6-8h 600 mg q12-24h 600 mg q8h 600 mg q8h as an LD on day 1 Macrolides Clarithromycin 500 mg q12h 500 mg q12h In severe renal failure, 500 mg q12h 250 mg q12h Azithromycin 500 mg q24h 500 mg q24h 500 mg q24h 500 mg q24h (Continued) Postgraduate Education Corner
  • 9. Data are modified from the product information of each particular drug. Note that the product information for many of the hydrophilic antibiotics included in the table (except teicoplanin and the amino- glycosides) does not consider different dosing schedules for LDs and MDs and is based on studies of patients who were not critically ill. The recommended LDs are based on data from critically ill patients like aminoglycosides, it is suggested to prolong the interval between doses rather than to decrease the Recommended MD for Patients With RRTb dose so that the peak concentration required for opti- 12 h after LD, administer mal bacterial killing is still achieved.11 However, despite these theoretical recommenda- 50-100 mg q12h tions, uncertainty is always present when prescribing 6 mg/kg q48h 600 mg q12h 500 mg q8h antibiotics in patients with MODS because organ to enable rapid attainment of therapeutic concentrations. Cmin 5 trough concentration; RRT 5 renal replacement therapy. See Table 1 legend for expansion of other abbreviations. function is very likely to fluctuate from day to day during therapy. It follows that TDM is a very useful tool to titrate antibiotic dosing in MODS. TDM is widely used with aminoglycosides and glycopeptides to ensure appropriate exposure and minimize the incidence of Patients With Acute Kidney Injurya toxicity.56 However, the potential and usefulness of Recommended MD for TDM as a strategy for optimizing antibiotic doses of b-lactams (the most frequently prescribed class of anti- 12 h after LD, administer biotics) has not yet been confirmed. Recent research 50-100 mg q12h has assessed its usefulness with a broad group of criti- cally ill patients.43,44 Roberts et al43 showed that in the 6 mg/kg q48h 600 mg q12h 500 mg q8h maintenance phase of therapy, many patients with renal dysfunction required a dose decrease due to high con- cThere are few data measuring toxicity of vancomycin LDs; therefore, we would suggest not administering LDs that exceed 35 mg/kg. centrations (about 10 times MIC), despite empirical dose adjustment for renal dysfunction. However, some other patients with renal failure or on RRT exhibit sub- Patients With Hepatic Failurea optimal concentrations with this adjusted dosing, which 500 mg q12-24h in severe 12 h after LD, administer Recommended MD for evidences that concentrations do not depend exclusively Table 2—Continued on renal function but on various other factors. hepatic failure 25 mg q12h 6 mg/kg q24h 600 mg q12h Renal Replacement Therapy As renal function deteriorates, waste products will accumulate, and commencement of RRT should be considered. The main determinants of CL during RRT are the modality and settings prescribed. Hemodial- ysis, hemofiltration, hemodiafiltration, and peritoneal Patients With -Vd (Day 1) Recommended LD for dialysis all have different mechanisms of removing aActual dose prescribed will be guided by the actual level of organ dysfunction. metabolic waste and have a different effect on the extent to which each drug is cleared. Other factors 6-8 mg/kg q24h 600 mg q8-12h 100 mg dose 1 that determine the extraction ratio are drug molec- 500 mg q8h ular weight (drugs with a molecular weight greater than the pores of the filter membrane are not able to be removed), protein binding (only unbound mole- cules can be removed), drug affinity for filter adsorp- bDose depends on data available for dialysis settings. tion, whether replacement fluid is added prefilter or postfilter, and the ultrafiltration rate.57 The implica- Antibiotic Name tions of RRT on drug dosing have been reviewed Metronidazole recently,57 and a further discussion is beyond the Daptomycin Tigecycline scope of this article. However, Table 1 provides some Linezolid recommendations for dosing in RRT. Hepatic Dysfunction Cyclic lipopeptides Liver impairment may have a significant impact on Nitroimidazoles Antibiotic Class Oxazolidinones Glycylcyclines the CL of both lipophilic and hydrophilic drugs. Lipophilic drugs may undergo metabolism in the liver to increase the hydrophilicity of the compound. The CL of hepatically eliminated drugs depends onwww.chestpubs.org CHEST / 139 / 5 / MAY, 2011 1217 Downloaded from chestjournal.chestpubs.org by guest on June 24, 2012 © 2011 American College of Chest Physicians
  • 10. Figure 3. Clinical scenarios likely to alter antibiotic PK in MODS. MODS 5 multiple organ dysfunction syndrome; PK 5 pharmacokinetics.the hepatic blood flow and intrinsic clearance (ie, otics (Table 2) account for this scenario. Maintenancedegree of enzymatic activity). Therefore, two kinds of dosing should be guided by the level of organ func-scenarios can be distinguished. CL of highly extracted tion and in the context of the main elimination path-drugs is mainly correlated with hepatic blood flow ways for the drug and, where possible, guided by(eg, lidocaine), whereas in less-extracted drugs, CL TDM. Decreased plasma concentrations of a1-acidis determined by intrinsic CL and degree of pro- glycoprotein increase substantially erythromycin Vdtein binding (eg, nitroimidazoles, fluoroquinolones).12 (73%-81% protein bound), whereas CL decreasesHepatic failure may imply modification of both fac- by 60% in the presence of metabolic impairment.62tors, leading to decreased drug elimination, accumu- Other antibiotics that bind substantially to this proteinlation, and potential toxicity. For example, in liver include trimethoprim and the lincosamides.63failure, metronidazole oxidation by microsomes may As a final consideration for organ dysfunction, it isbe decreased because of reduced enzyme expression noteworthy that critically ill patients can present withand enzymatic activity,58 leading to potential toxic- underlying comorbidities, such as chronic renal orities, including seizures and peripheral neuropathy. hepatic dysfunction, unrelated to sepsis. In this case, Other drugs may be cleared by biliary excretion, the previously mentioned dosing principles for initialwhich may be substantially decreased in hepatic and maintenance dosing also should apply. Doseimpairment (eg, tigecycline). A study comparing adjustments should always be made according to thepatients with different degrees of hepatic failure degree of organ function and the estimated level offound that tigecycline CL was reduced by 55%, and drug Vd and CL present in the patient, regardless ofelimination half-life was prolonged by 43% in patients preexisting dysfunction. Preexisting dysfunction shouldwith severe hepatic impairment. In this context, a only be considered as a guide to the likely level ofdose reduction is suggested to avoid toxicity.59 organ function in the maintenance phase of therapy. Additionally, the decreased synthesis of albumin anda1-acid glycoprotein in liver dysfunction, together withthe transcapillary distribution of these proteins due Conclusionsto capillary leakage,60 may alter the pharmacokineticsof highly protein-bound antibiotics. Hypoalbuminemia Appropriate antibiotic dosing in MODS is complexhas been shown to cause significant increases in the and depends on several drug- and patient-related fac-Vd and CL of drugs such as ceftriaxone (85%-95% tors. Consideration of antibiotic physicochemical andprotein bound), ertapenem (85%-95%), flucloxacillin pharmacodynamic characteristics and disease-related(95%), and teicoplanin (90%-95%).25,37,38,61 Therefore, alterations in pharmacokinetics is essential for design-front-loaded doses should be considered when pre- ing dosing regimens that avoid suboptimal dosing.scribing these drugs in critically ill patients with There are two important phases in antibiotic therapyMODS and hypoalbuminemia.39 Initial dosing rec- in MODS. During the first day of therapy, front-ommendations for highly bound hydrophilic antibi- loaded dosing is required and must be guided by the1218 Postgraduate Education Corner Downloaded from chestjournal.chestpubs.org by guest on June 24, 2012 © 2011 American College of Chest Physicians
  • 11. predicted Vd, which is likely to be increased in critically terns in empiric antibiotic therapy for HAP/VAP [publishedill patients despite impaired organ function. From online ahead of print September 16, 2010]. Eur Respir J. doi:10.1183/09031936.00093010.day 2 onward, maintenance dosing can be adjusted in 11. Roberts JA, Lipman J. Pharmacokinetic issues for antibi-line with the CL associated with the organ dysfunc- otics in the critically ill patient. Crit Care Med. 2009;37(3):tion. The requirements for dose adjustment for anti- 840-851.biotics should be considered individually depending 12. Rowland M, Tozer TN. Clinical Pharmacokinetics: Conceptson the organ system that is failing and the drug and Applications. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 1995.CL pathway. Because of the great variability of organ 13. Craig WA. Pharmacokinetic/pharmacodynamic parameters:function during a septic insult, TDM should be rationale for antibacterial dosing of mice and men. Clin Infectregarded as a useful tool to individualize dosing and Dis. 1998;26(1):1-10.ensure appropriate exposure to the antibiotic. Further 14. American College of Chest Physicians/Society of Critical Careresearch on dose adjustment in MODS is required Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative ther-for improving patient quality of care and outcomes in apies in sepsis. Crit Care Med. 1992;20(6):864-874.this population. 15. van der Poll T. Immunotherapy of sepsis. Lancet Infect Dis. 2001;1(3):165-174. 16. Thijs LG, Schneider AJ, Groeneveld AB. The haemodynam- Acknowledgments ics of septic shock. Intensive Care Med. 1990;16(suppl 3):Financial/nonfinancial disclosures: The authors have reported S182-S186.to CHEST the following conflicts of interest: Dr Roberts serves 17. 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  • 13. Antibiotic Dosing in Multiple Organ Dysfunction Syndrome Marta Ulldemolins, Jason A. Roberts, Jeffrey Lipman and Jordi Rello Chest 2011;139; 1210-1220 DOI 10.1378/chest.10-2371 This information is current as of June 24, 2012Updated Information & ServicesUpdated Information and services can be found at:http://chestjournal.chestpubs.org/content/139/5/1210.full.htmlReferencesThis article cites 61 articles, 18 of which can be accessed free at:http://chestjournal.chestpubs.org/content/139/5/1210.full.html#ref-list-1Cited BysThis article has been cited by 2 HighWire-hosted articles:http://chestjournal.chestpubs.org/content/139/5/1210.full.html#related-urlsPermissions & LicensingInformation about reproducing this article in parts (figures, tables) or in its entirety can befound online at:http://www.chestpubs.org/site/misc/reprints.xhtmlReprintsInformation about ordering reprints can be found online:http://www.chestpubs.org/site/misc/reprints.xhtmlCitation AlertsReceive free e-mail alerts when new articles cite this article. To sign up, select the"Services" link to the right of the online article.Images in PowerPoint formatFigures that appear in CHEST articles can be downloaded for teaching purposes inPowerPoint slide format. See any online figure for directions. Downloaded from chestjournal.chestpubs.org by guest on June 24, 2012 © 2011 American College of Chest Physicians