Syed Tabish R. Zaidi · Jason A. Roberts Editors Drug Dosing in Obesity Volume I: Antimicrobials Drug Dosing in Obesity Syed Tabish R. Zaidi Jason A. Roberts (cid:129) Editors Drug Dosing in Obesity Volume I: Antimicrobials 123 Editors SyedTabish R.Zaidi Jason A.Roberts Division of Pharmacy, Schoolof Medicine Schoolof Medicine andSchool University of Tasmania ofPharmacy, Burns Trauma Hobart, TAS andCriticalCare Research Centre Australia TheUniversity of Queensland Brisbane, QLD Australia ISBN978-3-319-44032-3 ISBN978-3-319-44034-7 (eBook) DOI 10.1007/978-3-319-44034-7 LibraryofCongressControlNumber:2016947787 ©SpringerInternationalPublishingSwitzerland2016 Thisworkissubjecttocopyright.AllrightsarereservedbythePublisher,whetherthewholeorpart of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission orinformationstorageandretrieval,electronicadaptation,computersoftware,orbysimilarordissimilar methodologynowknownorhereafterdeveloped. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publicationdoesnotimply,evenintheabsenceofaspecificstatement,thatsuchnamesareexemptfrom therelevantprotectivelawsandregulationsandthereforefreeforgeneraluse. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authorsortheeditorsgiveawarranty,expressorimplied,withrespecttothematerialcontainedhereinor foranyerrorsoromissionsthatmayhavebeenmade. Printedonacid-freepaper ThisSpringerimprintispublishedbySpringerNature TheregisteredcompanyisSpringerInternationalPublishingAGSwitzerland Foreword Use of antibiotics is becoming increasingly challenging as we are required to treat differenttypesofpatients,includingtheelderlyaswellasthosethatareprofoundly immunosuppressed and/or critically ill. The presence of multi-drug resistant pathogens and the association of their emergence with suboptimal antibiotic exposures also present major challenges for clinicians. Indeed, despite all the in vitro and in vivo studies on antibiotic pharmacokinetics and pharmacodynamics over the last 30–40 years, therapeutic failures are still relatively common for some patient groups such as the critically ill. An increasingly common question that now pervades the health system and affectsourabilitytogiveoptimalantibiotictherapyis,“Howdowedoseantibiotics in obese patients?” While this issue is not significant for some countries, Western countriesincludingUSA,UK,andAustraliaallhaverelativelyhighratesofobesity inthepopulationmeaningthattheratesofpatientswithobesityissimilarlyhigh.In this book, data is presented which highlights the worse clinical outcomes for infected obese patients relative to non-obese comparators. While some physiolog- icalrationaleexistsforthis,includingmaldistributionofbloodflowintoperipheral tissuesandalteredendocrinefunction,acontrollablefactorforcliniciansisthedose of antibiotic that these patients are administered. This textbook provides a very detailed summary of the literature describing the data of altered pharmacokinetics of various antibiotics in obese patients and translates these data into dosing guid- ance. Atthesame stage,wherethere aresevere deficiencies indata, these gapsare also highlighted as areas requiring further research. Although I am biased because I have been involved in the development of this book,Ibelieveittobeahighlyvaluableresourceandrecommendittopharmacists, v vi Foreword doctors,andother antibioticprescribersaswellasbasic andtranslational scientists that have an interest in antibiotic pharmacokinetics and pharmacodynamics. Brisbane, Australia Jason A. Roberts, Ph.D. Professor of Medicine NHMRC Career Development Fellow and Professor of Pharmacy Chair of Research Strategies Committee Preface No matter how depressing it sounds, obesity is here to stay! Despite a significant increase in the awareness of causes of obesity, extensive media campaign from public health organizations and government bodies, and availability of modern medical interventions, the global incidence of obesity is rising exponentially. The official product information for medications is based on the data derived from normal weight individuals and therefore, cannot be applied to obese patients. As such, clinicians are struggling to make dosing decisions for obese patients on a daily basis. Antimicrobials are one of the most frequently used medications, and limited information is available about antimicrobials in obese patients. Like any other situation in the practice of medicine where limited information is available, clinical decisions are often guided by the best use of available data and expert advice on the matter. In a nutshell, this is all what the first clinical reference on “Drug Dosing in Obesity-Volume I: Antimicrobials” is all about. ThreeyearsagowhenImadeatransitionfromfull-timeclinicalpharmacistrole to an academic, I contemplated the idea of having a clinical drug reference for dosing medication in obesity. Springer publishers were kind enough to accept the idea, and I started contacting doctors, pharmacists, and academics to gauge the support for this idea. The response was overwhelming, and many individuals volunteered to write chapters for the antimicrobials section of the book. The response for the non-antimicrobials chapters was less encouraging. Springer was onceagainkindenoughtoallowbreakingthebookintotwovolumes;thefirstone for the antimicrobials and the second one for the rest of medications. Dosing antimicrobials in any patient population requires thoughtful considera- tions of patients, diseases, and drug factors; therefore, this book is not meant to replace clinical judgment. The aim of this book is to assist clinicians by providing an up-to-date summary of the literature coupled with the expert advice on dosing antimicrobials in obesity. Each chapter represents a summary of the relevant pharmacokineticchangesinobesepatientsfollowedbyadiscussionoftheavailable literature on the use of a particular antimicrobial in obese patients. Dosing rec- ommendations are provided based on the available literature and expert advice vii viii Preface consideringimportantpatient-relatedfactors,whereapplicable.Selectedcaseshave beenpresentedasanappendixtothebooktodemonstrateclinicaldecision-making in the dosing of antimicrobials for obese patients. To the best of our knowledge, there is no reference book available on the dosing of antimicrobials in obesity and we believe that this book will serve as a useful reference source for clinicians, academics, and researchers. Iwouldliketothankalltheauthorsfortheirtimeandeffortsinmakingthisbook a reality. Special thanks to the Division of Pharmacy, School of Medicine at the University of Tasmania for allowing me to complete this important piece of sci- entific literature. Thanks to Sarah Germans and Thijs van Vlijmen at the Springer office. Last but not least, thanks to Prof. Jason Roberts for providing two chapters forthebookandacceptingmyinvitationtobecomeaco-editorofthisbook.There is an urgent need to conduct pharmacokinetics and clinical studies on many rou- tinely used antimicrobials in obese patients where the literature is simply nonex- istent.Iwillencourageallcliniciansinvolvedinprovidingcareforobesepatientsto collaborate with the universities in conducting the necessary research. Best wishes, Hobart, Australia Syed Tabish R. Zaidi Lecturer and Course Coordinator Postgraduate Clinical Pharmacy Coursework Contents 1 Introduction... .... .... ..... .... .... .... .... .... ..... .... 1 Syed Tabish R. Zaidi 2 Penicillins. .... .... .... ..... .... .... .... .... .... ..... .... 13 Iain J. Abbott and Kelly A. Cairns 3 Cephalosporins .... .... ..... .... .... .... .... .... ..... .... 27 Carmela Corallo and Syed Tabish R. Zaidi 4 Aminoglycoside Dosing in Obesity.. .... .... .... .... ..... .... 39 Janattul-Ain Jamal and Jason A. Roberts 5 Fluoroquinolones... .... ..... .... .... .... .... .... ..... .... 45 Renee Dimond, Rahul P. Patel and Syed Tabish R. Zaidi 6 Carbapenems.. .... .... ..... .... .... .... .... .... ..... .... 53 Tara Anderson 7 Glycopeptides and Antibiotics for Gram-positive Bacterial Infections. .... .... .... ..... .... .... .... .... .... ..... .... 63 Syed Tabish R. Zaidi and Brett Janson 8 Azole Antifungal Agents. ..... .... .... .... .... .... ..... .... 77 Nicolette R. Holt and Karin A. Thursky 9 Echinocandin Antifungals..... .... .... .... .... .... ..... .... 97 Tara Anderson 10 Polyene Antifungals. .... ..... .... .... .... .... .... ..... .... 109 Janattul-Ain Jamal and Jason A. Roberts 11 Miscellaneous Agents ... ..... .... .... .... .... .... ..... .... 117 Eleanor van Dyk, Rahul P. Patel and Syed Tabish R. Zaidi Appendix 1: Clinical Cases... ..... .... .... .... .... .... ..... .... 127 Index .... .... .... .... .... ..... .... .... .... .... .... ..... .... 133 ix Abbreviations µg/ml Microgram per milliliter ABW Adjusted body weight ARC Augmented renal clearance AUC Area under the concentration–time curve AUC /AUC Tissue penetration tissue plasma BMI Body mass index BSA Body surface area C&G Cockcroft and Gault C The average plasma concentration ave CBA Colistin base activity CFR Cumulative fraction of response CK Creatinine kinase Cl Renal clearance cm Centimeter C The maximum plasma concentration or the crest max concentration C The maximum plasma concentration at steady state max,ss C The minimum plasma concentration or the trough min concentration CMS Colistimethate sodium CNS Central nervous system CPK Creatine phosphokinase CPM Clinical pharmacokinetic monitoring Crcl Creatinine clearance CSF Cerebrospinal fluid CVVH Continuous venovenous hemofiltration CVVHDF Continuous venovenous hemodiafiltration CYP Cytochrome P450 enzymes DILI Drug-induced liver injury ECMO Extracorporeal membrane oxygenation xi