Antimicrobial pharmacodynamics in theory and clinical practice

526 Pages·2007·2.88 MB·English

by  Nightingale C.H.

Antimicrobial
Pharmacodynamics
in Theory and
Clinical Practice
Second Edition
Edited by
Charles H. Nightingale
Hartford Hospital
Hartford, Connecticut, USA
Paul G. Ambrose
Institute for Clinical Pharmacodynamics
Albany, New York, USA
George L. Drusano
Ordway Research Institute
Albany, New York, USA
Takeo Murakawa
Kyoto University
Kyoto, Japan
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Antimicrobialpharmacodynamicsintheoryandclinicalpractice/[editedby]
CharlesH.Nightingale...[etal.].–2nded.
p.;cm.– (Infectiousdiseaseandtherapy;v.44)
Includesbibliographicalreferencesandindex
ISBN-13:978-0-8247-2925-7(hb:alk.paper)
ISBN-10:0-8247-2925-0(hb:alk.paper)
1. Antibiotics–Dose-responserelationship. I.Nightingale,C.H.II.Series.
[DNLM:1. Anti-BacterialAgents–pharmacology. W1IN406HMN
v.442007/QV350A63372007]
RM267.A5552007
6150.329–dc22 2006103466
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Preface
The second edition of this book assumes that to use antibiotics properly, the
clinician needs to understand fundamental concepts of pharmacodynamics. While
many infectious disease physicians do understand these concepts, they are not the
only physician group prescribing antibiotics. The objective of the second edition is
to review the scientific and medical literature concerning antibiotics and pharma-
codynamics, and then synthesize this information into an easy to understand
discussionoftheconceptsandtheory,alongwithapplicationofthesetheoriesand
concepts.
Thisbook includes adiscussion of thepharmacodynamics ofallof themajor
classes of drugs. These include penicillins, cephalosporins, cephamycins, carbape-
nems, monobactams, aminoglycosides, quinolones, macrolides, azalides, ketolides,
glycopeptides, metronidazole, clindamycin, tetracyclines, and antifungals. In addi-
tion to the topics on the antibiotics listed above, the second edition has added
chapters on malaria, some antivirals, a section on non-clinical models of infection,
a chapter on streptogramins and oxazolididones, and a section on pharmacody-
namics in drug development. In addition to an updated introductary chapter, we
include a chapter on the impact of pharmacodynamics on breakpoint selection for
susceptibility testing, while retaining and updating the chapter on resistance and
pharmacoeconomics.
This book is unique in that no other text of its kind currently exists and our
chapterauthorsareamongtheleadersinthefield.Thisbookwillfindanaudience
in a large array of healthcare disciplines including college educators; medical,
pharmacy, and microbiology students; infectious disease physicians; pharmacy
specialists; medical house staff; clinical and staff pharmacists; clinical microbiolo-
gists;andotherhealthcaredecisionmakers.
CharlesH.Nightingale
PaulG.Ambrose
GeorgeL.Drusano
TakeoMurakawa
iii

Contents
Preface iii
Contributors vii
SECTIONI: INTRODUCTION
1. PharmacodynamicsofAntimicrobials:GeneralConceptsandApplications 1
WilliamA.Craig
2. ApplyingPharmacodynamicsforSusceptibilityBreakpointSelection
andSusceptibilityTesting 21
JohanW.Mouton,PaulG.Ambrose,GunnarKahlmeter,MattWikler,
andWilliamA.Craig
SECTIONII: NON-CLINICALMODELSOFINFECTION
3. InVitroDynamicModelsasToolstoPredictAntibioticPharmacodynamics 45
AlexanderA.Firsov,StephenH.Zinner,andIreneY.Lubenko
4. AnimalModelsofInfectionfortheStudyofAntibioticPharmacodynamics 79
DavidGriffithandMichaelN.Dudley
5. ThePredictiveValueofLaboratoryTestsforEfficacyofAntibiotic
CombinationTherapy 103
JanG.denHollanderandJohanW.Mouton
SECTIONIII: ANTIBACTERIALAGENTS
6. (cid:2)-LactamPharmacodynamics 129
ZenzaburoTozukaandTakeoMurakawa
7. Aminoglycosides 147
Myo-KyoungKimandDavidP.Nicolau
8. Quinolones 177
PaulG.Ambrose,SujataM.Bhavnani,andRobertC.Owens,Jr.
9. GlycopeptidePharmacodynamics 189
ElizabethD.Hermsen,GigiH.Ross,andJohnC.Rotschafer
10. Macrolide,Azalide,andKetolides 217
SanjayJain,WilliamBishai,andCharlesH.Nightingale
11. MetronidazoleandClindamycinforAnaerobicInfections 231
ElizabethD.HermsenandJohnC.Rotschafer
v
vi Contents
12. StreptograminsandOxazolidinones 239
DarrenAbbanat,MarkMacielag,andKarenBush
13. PharmacokineticsandPharmacodynamicsofTetracyclines 267
DaveAndesandWilliamA.Craig
SECTIONIV: ANTIVIRALAGENTS
14. TheClinicalPharmacologyofNucleosideReverseTranscriptaseInhibitors 279
JenniferJ.KiserandCourtneyV.Fletcher
15. PharmacodynamicsofAntivirals 295
GeorgeL.Drusano
SECTIONV: ANTIFUNGALAGENTS
16. AntifungalAgentsPharmacokineticsandPharmacodynamicsof
AmphotericinB 315
DavidAndes
17. PharmacokineticsandPharmacodynamicsofAzoles 327
JohanW.Mouton
18. GlucanSynthaseInhibitors 355
TawandaGumbo,FumiakiIkeda,andArnoldLouie
SECTIONVI: ANTIMALARIALAGENTS
19. AntimalarialAgents 379
ElizabethA.AshleyandNicholasJ.White
SECTIONVII: PHARMACODYNAMICSINDRUGDEVELOPMENT
20. HumanPharmacodynamicsofAnti-infectives:DeterminationfromClinical
TrialData 411
GeorgeL.Drusano
21. ApplicationofPharmacokineticsandPharmacodynamicsinAntimicrobial
GlobalDrugDevelopment 433
SujataM.Bhavnani
22. ModelingofToxicitiesDuetoAntibiotics 449
AlanForrestandGeorgeL.Drusano
SECTIONVIII: PHARMACODYNAMICSANDRESISTANCE
23. PharmacodynamicsandAntibacterialResistance 463
PhilipD.Lister,NancyD.Hanson,andAntonF.Ehrhardt
SECTIONIX: APPLICATIONOFPK–PDTOCLINICALAND
FORMULARYDECISIONS
24. ThePrinciplesofPharmacoeconomics 487
CraigI.Coleman,EffieL.Kuti,andJosephL.Kuti
Index 505
AbouttheEditors 517
Contributors
DarrenAbbanat Johnson&JohnsonPharmaceuticalResearch&Development,L.L.C.,
Raritan,NewJersey,U.S.A.
PaulG.Ambrose InstituteforClinicalPharmacodynamics,OrdwayResearchInstitute,
Albany,NewYork,andUniversityofthePacificSchoolofHealthSciences,Stockton,
California,U.S.A.
DavidAndes UniversityofWisconsinandWilliamS.MiddletonMemorialVeterans
Hospital, Madison,Wisconsin,U.S.A.
ElizabethA.Ashley ShokloMalariaResearchUnit,MaeSot,Thailand;FacultyofTropical
Medicine,MahidolUniversity,Bangkok,Thailand;andCentreforClinicalVaccinologyand
TropicalMedicine,ChurchillHospital,Headington,Oxford,U.K.
SujataM.Bhavnani InstituteforClinicalPharmacodynamics,OrdwayResearchInstitute,
Albany,NewYork,U.S.A.
WilliamBishai CenterforTuberculosisResearch,JohnsHopkinsUniversitySchoolof
Medicine,Baltimore,Maryland,U.S.A.
KarenBush Johnson&JohnsonPharmaceuticalResearch&Development,L.L.C.,Raritan,
NewJersey,U.S.A.
CraigI.Coleman UniversityofConnecticutSchoolofPharmacy,Storrs,Connecticut,
andPharmacoeconomicsandOutcomesStudiesGroup,HartfordHospital,Hartford,
Connecticut,U.S.A.
WilliamA.Craig UniversityofWisconsinandWilliamS.MiddletonMemorialVeterans
Hospital,Madison,Wisconsin,U.S.A.
JanG.denHollander DepartmentofInternalMedicineandInfectiousDiseases,Medical
CenterRotterdamZuid,Rotterdam,TheNetherlands
GeorgeL.Drusano OrdwayResearchInstitute,Albany,NewYork,U.S.A.
MichaelN.Dudley MpexPharmaceuticals,SanDiego,California,U.S.A.
AntonF.Ehrhardt DepartmentofMedicalAffairs,CubistPharmaceuticals,Inc.,Lexington,
Massachusetts,U.S.A.
AlexanderA.Firsov GauseInstituteofNewAntibiotics,RussianAcademyofMedical
Sciences,Moscow,Russia
CourtneyV.Fletcher UniversityofColoradoHealthSciencesCenter,Denver,
Colorado,U.S.A.
AlanForrest OrdwayResearchInstitute,Albany,NewYorkandUniversityatBuffaloSchool
ofPharmacy,Buffalo,NewYork,U.S.A
DavidGriffith MpexPharmaceuticals,SanDiego,California,U.S.A.
TawandaGumbo UniversityofTexasSouthwesternMedicalCenter,Divisionof
InfectiousDiseases,Dallas,Texas,U.S.A.
NancyD.Hanson CenterforResearchinAnti-infectivesandBiotechnology,Departmentof
MedicalMicrobiologyandImmunology,CreightonUniversitySchoolofMedicine,Omaha,
Nebraska,U.S.A.
vii
viii Contributors
ElizabethD.Hermsen DepartmentofPharmaceuticalandNutritionCare,TheNebraska
MedicalCenter,Omaha,Nebraska,U.S.A.
FumiakiIkeda InfectiousDiseasesDepartment,PharmacologyResearchLaboratories,Drug
DiscoveryResearch,AstellasPharma,Inc.,Osaka,Japan
SanjayJain CenterforTuberculosisResearchandPediatricInfectiousDiseases,Johns
HopkinsUniversitySchoolofMedicine,Baltimore,Maryland,U.S.A.
GunnarKahlmeter ClinicalMicrobiology,CentralHospital,Växjö,Sweden
Myo-KyoungKim PharmacyPractice,UniversityofthePacificThomasJ.LongSchoolof
Pharmacy,Stockton,California,U.S.A.
JenniferJ.Kiser UniversityofColoradoHealthSciencesCenter,Denver,Colorado,U.S.A.
EffieL.Kuti UniversityofConnecticutSchoolofPharmacy,Storrs,Connecticut,U.S.A.
JosephL.Kuti ClinicalandEconomicStudies,CenterforAnti-infectiveResearchand
Development,HartfordHospital,Hartford,Connecticut,U.S.A.
PhilipD.Lister CenterforResearchinAnti-infectivesandBiotechnology,Departmentof
MedicalMicrobiologyandImmunology,CreightonUniversitySchoolofMedicine,Omaha,
Nebraska,U.S.A.
ArnoldLouie EmergingInfectionsandPharmacodynamicsLaboratory,OrdwayResearch
Institute,AlbanyMedicalCollege,Albany,NewYork,U.S.A.
IreneY.Lubenko GauseInstituteofNewAntibiotics,RussianAcademyofMedical
Sciences,Moscow,Russia
MarkMacielag Johnson&JohnsonPharmaceuticalResearch&Development,L.L.C.,
Raritan,NewJersey,U.S.A.
JohanW.Mouton DepartmentofMedicalMicrobiologyandInfectiousDiseases,Canisius
WilhelminaHospital,Nijmegen,TheNetherlands
TakeoMurakawa GraduateSchoolofPharmaceuticalSciences,KyotoUniversity,Kyoto,
Japan
DavidP.Nicolau CenterforAnti-infectiveResearchandDevelopment,Departmentof
Medicine,DivisionofInfectiousDiseasesandPharmacy,HartfordHospital,Hartford,
Connecticut,U.S.A.
CharlesH.Nightingale CenterforAnti-infectiveResearchandDevelopment,Hartford
HospitalandUniversityofConnecticutSchoolofPharmacy,Hartford,Connecticut,U.S.A.
RobertC.Owens,Jr. MaineMedicalCenter,Portland,Maine,andUniversityofVermont,
CollegeofMedicine,Burlington,Vermont,U.S.A.
GigiH.Ross Ortho-McNeilPharmaceutical,Inc.,Raritan,NewJersey,U.S.A.
JohnC.Rotschafer DepartmentofExperimentalandClinicalPharmacology,Universityof
MinnesotaCollegeofPharmacy,Minneapolis,Minnesota,U.S.A.
ZenzaburoTozuka ExploratoryADME,JCLBioassayCorporation,Hyogo,Japan
NicholasJ.White FacultyofTropicalMedicine,MahidolUniversity,Bangkok,Thailand,
andCentreforClinicalVaccinologyandTropicalMedicineChurchillHospital,Headington,
Oxford,U.K.
MattWikler PacificBeachBioscience,SanDiego,California,U.S.A.
StephenH.Zinner MountAuburnHospital,HarvardMedicalSchool,Cambridge,
Massachusetts,U.S.A.
Section I: Introduction
1
Pharmacodynamics of Antimicrobials: General
Concepts and Applications
William A. Craig
UniversityofWisconsinandWilliamS.MiddletonMemorialVeteransHospital,
Madison,Wisconsin,U.S.A.
INTRODUCTION
“Pharmacodynamics” (PDs) is the term used to reflect the relationship between
measurements of drug exposure in serum, tissues, and body fluids and the
pharmacological and toxicological effects of drugs. With antimicrobials, PDs is
focused on the relationship between concentrations and antimicrobial effect.
Studies in the past have focused on pharmacokinetics (PKs) and descriptions of
the time course of antimicrobials in serum, tissues, and body fluids. Much less
emphasis has been placed on the time course of antimicrobial activity. Studies
overthepast25yearshavedemonstratedmarkeddifferencesinthetimecourseof
antimicrobial activity among antibacterials and antifungals (1–4). Furthermore, the
pattern of antimicrobial activity over time is an important determinant of optimal
dosage regimens (5). This chapter focuses on general concepts and the application
ofPDstoantimicrobialtherapy.
MEASUREMENTSOFANTIMICROBIALACTIVITY
MinimumInhibitoryandMinimumBactericidalConcentrations
The minimum inhibitory concentration and minimum bactericidal concentration
(MIC and MBC) have been the major parameters used to measure the in vitro
activity of antimicrobials against various pathogens. Although MIC and MBC are
excellent predictors of the potency of an antimicrobial against the infecting
organism,theyprovideessentiallynoinformationonthetimecourseofantimicro-
bial activity. For example, the MBC provides minimal information on the rate of
bactericidal and fungicidal activity and on whether killing can be increased by
higher drug concentrations. In addition, MIC provides no information on growth
inhibitory effects that may persist after antimicrobial exposure. These persistent
effects are due to three different phenomena: the postantibiotic effect (PAE),
the postantibiotic sub-MIC effect (PAE-SME), and the postantibiotic leukocyte
enhancement (PALE) (6–8). The killing effects of increasing concentrations on the
bactericidalandfungicidalactivityofantimicrobialscombinedwiththemagnitude
of persistent effects give amuchbetterdescription of the timecourse of antimicro-
bialactivitythanthatprovidedbyMICandMBC.
KillingActivity
Antimicrobials exhibit two primary patterns of microbial killing. The first pattern
is characterized by concentration-dependent killing over a wide range of
1