Pharmacokinetics and Pharmacodynamics of Aerosolized Antibacterial Agents in Chronically ...

30 Pages·2014·0.59 MB·English

Pharmacokinetics and Pharmacodynamics of Aerosolized Antibacterial
Agents in Chronically Infected Cystic Fibrosis Patients
AxelDalhoff
UniversityMedicalCenterSchleswig-Holstein,InstituteforInfectionMedicine,Kiel,Germany
SUMMARY..................................................................................................................................................753
INTRODUCTION............................................................................................................................................754
CurrentChallengesinAntibioticResistance .............................................................................................................754
D
Antibacterialactivitiesofciprofloxacin,levofloxacin,tobramycin,amikacin,colistin,andaztreonam.................................................754
o
Heteroresistance,aResistanceReservoirwithoutSelectivePressureofAntibacterials...................................................................755 w
ImplicationsforSusceptibilityTesting....................................................................................................................756 n
PULMONARYPHARMACOKINETICS.......................................................................................................................756 lo
ConfoundingFactors.....................................................................................................................................756 a
d
ChemistryandFormulation..............................................................................................................................756 e
SerumandSputumPharmacokinetics...................................................................................................................757 d
Fluoroquinolones......................................................................................................................................757 f
r
Aminoglycosides......................................................................................................................................758 o
Aztreonam.............................................................................................................................................758 m
Colistin.................................................................................................................................................758 h
CorrelationofSputumConcentrationstoAntibacterialActivities........................................................................................758 t
t
PHARMACODYNAMICS....................................................................................................................................759 p
:
DefinitionofEndpointsandUseofAppropriateMatrices................................................................................................759 //
c
PreclinicalandClinicalPK/PDStudiesinCFPatients.....................................................................................................759 m
Fluoroquinolones......................................................................................................................................759
r
Aminoglycosides......................................................................................................................................760 .a
Beta-lactams...........................................................................................................................................760 s
m
Colistin.................................................................................................................................................761
EmergenceofResistanceinPK/PDStudiesandinCFPatients...........................................................................................761 .o
EmergenceofresistanceinP.aeruginosa..............................................................................................................761 rg
EmergenceofresistanceinS.aureusandH.influenzae................................................................................................763 /

Bacteriophageinductionandpromotionofresistancespread........................................................................................763 o
n
EFFECTOFAEROSOLIZEDANTIBACTERIALTHERAPYONLUNGFUNCTIONANDP.AERUGINOSASPUTUMLOAD.....................................764
D
Fluoroquinolones.........................................................................................................................................764
e
Aminoglycosides.........................................................................................................................................766 c
Aztreonam................................................................................................................................................767 e
Colistin...................................................................................................................................................767 m
CorrelationofSputumConcentrationstoAntipseudomonalEfficacyandImprovementofLungFunction.............................................768 b
e
OPENQUESTIONSANDCAVEATS..........................................................................................................................769 r
TheCFInflammasome...................................................................................................................................769 2
TheCFTransmembraneConductanceRegulatorProtein................................................................................................770 7
,
SignalingandVirulence..................................................................................................................................770 2
TheCFMicrobiome......................................................................................................................................770 0
CONCLUSIONS.............................................................................................................................................771 1
8
REFERENCES................................................................................................................................................771
b
AUTHORBIO................................................................................................................................................782
y

g
u
e
s
SUMMARY conventionalpharmacokinetic/pharmacodynamic(PK/PD)sur- t
Bacteriaadapttogrowthinlungsofpatientswithcysticfibrosis rogatescorrelatingpharmacokineticsinserumwithclinicalcure
(CF)byselectionofheterogeneouslyresistantvariantsthatarenot andpresumedorproveneradicationofthepathogenasabasisfor
detectedbyconventionalsusceptibilitytestingbutareselectedfor PK/PDinvestigationsinCFpatientsisirrelevant,asminimization
rapidlyduringantibacterialtreatment.Therefore,totalbacterial ofsystemicexposureisoneofthemainobjectivesofaerosolized
countsandantibioticsusceptibilitiesaremisleadingindicatorsof therapy; in addition, bacterial pathogens cannot be eradicated,
infection and are not helpful as guides for therapy decisions or and chronic infection cannot be cured. Consequently, conven-
efficacyendpoints.Highdrugconcentrationsdeliveredbyaerosol
may maximize efficacy, as decreased drug susceptibilities of the
pathogensarecompensatedforbyhightargetsiteconcentrations. [email protected].
However,reductionsofthebacterialloadinsputumandimprove- Copyright©2014,AmericanSocietyforMicrobiology.AllRightsReserved.
ments in lung function were within the same ranges following doi:10.1128/CMR.00022-14
aerosolizedandconventionaltherapies.Furthermore,theuseof
October2014 Volume27 Number4 ClinicalMicrobiologyReviews p.753–782 cmr.asm.org 753
Dalhoff
tional PK/PD surrogates are not applicable to CF patients. It is there is an urgent need to optimize the use of existing agents,
nonethelessobviousthatsystemicexposureofpatients,withallits consideringthelackofnewantibacterials.Highdrugconcentra-
sequelae,isminimizedandthattheburdenoforaltreatmentfor tionsdeliveredbyaerosolmayovercomethedecreasedsuscepti-
CFpatientssufferingfromchronicinfectionsisreduced. bilitiesofpathogens.Furthermore,aminoglycosidesandfluoro-
quinolonesexhibitconcentration-dependentpharmacodynamics
INTRODUCTION
(48–51), so increased drug concentrations delivered by aerosol
Aerosolized antibacterials have long been used for the treat- maytranslateintoaugmentedantibacterialactivity;thus,inhala-
mentofrespiratorytractinfectionsingeneralandofcystic tionofantibacterialsmayaugmentefficacyandreducesystemic
fibrosis(CF)inparticular.Itisassumedthatinhalationofanti- toxicities.
bacterialsdepositshighdrugconcentrationsatthefocusofinfec- Marketing authorizations for inhalation therapy have been
tion,thuscompensatingforthepoorpenetrationof,e.g.,(cid:2)-lac- grantedforcolistin,tobramycin,andaztreonam;liposomalami-
tamsoraminoglycosidesintotherespiratorytractuponenteralor kacin, liposomal ciprofloxacin, ciprofloxacin betaine, levofloxa-
parenteraladministrationsothatdifficult-to-treatpathogensare cinhemihydrate,andanewtobramycinformulationareinclini-
D
inprincipleexposedtoadequatedrugconcentrations(1–6). caldevelopmentforaerosoltherapyofGram-negativepathogens.
o
Inadditiontothepoorpenetrationofantibacterialsintothe Acombinationoftobramycinandfosfomycinisbeingdeveloped w
focusofinfection,antibacterialtherapyofCFpatientsisaggra- for treatment of patients with Pseudomonas aeruginosa and/or n
lo
vatedbyseveralfactors,suchasbiofilmformation,whichimpairs staphylococcalairwayinfections.
a
drugpenetrationandprotectsthepathogensfromimmunede- Thisreviewdescribesthepharmacokinetic/pharmacodynamic d
e
fense(7–14);thedevelopmentofhypermutatorstrains,character- (PK/PD)characteristicsofaerosolizedadministrationofantibac- d
ized by high mutation rates, which result in pronounced resis- terialstoCFpatients,withspecialemphasisonnovelformulations f
r
o
tanceagainstantimicrobialsandpathoadaptation(15–27);drug comparedtoestablishedaerosolformulationsandoralorintrave-
m
adsorptiontosputumcomponents(28,29),whichlimitsantibi- nous (i.v.) administration. PK/PD evaluations are based on the
h
oticactivities;andslowgrowthassmall-colonymorphotypes(30– indices of the MIC of an antibacterial agent for the pathogen, t
t
34),whichfacilitatesrecurrentandpersistentinfectionsandre- quantitatingitsactivity,andthepharmacokineticsoftheagentas p
:
/
ducestheantibacterialactivitiesofseveralantimicrobials(35,36). ameasureofdrugexposure,sothatPK/PDevaluationsintegrate /c
Theresultofthemultiplicityoffactorsimpairingtheactivitiesof thesetwoindices.Therefore,thesusceptibilitypatternsofthetyp- m
r
antibacterialsisthatthepathogencannotbeeliminated,andin- icalpathogensandthekineticsoftherelevantagentsaredescribed .
a
fectionpersistsinachronicstate.Nevertheless,inmanystudies, first,followedbyanevaluationofPK/PDtargetsandadiscussion s
m
treatmentofCFpatientswithantibacterialswasassociatedwith ofwhetheraerosolizedantibacterialtherapymayaugmentPK/PD
.
improvementinlungfunction(37),prolongationofthetimeto target attainment rates and, in particular, clinical efficacy. For o
r
g
thenextacuterespiratoryexacerbation(38),andamoderatere- discussionofthechangingCFairwaymicrobiome,pathophysiol-
/

duction of viable bacterial counts so that improvement of lung ogy, treatment, and infection control measures, the reader is o
n
functionismorepronouncedfollowingantibiosisthanfollowing kindlyreferredtorecentreviews(seereferences52–58andrefer-
D
chestphysiotherapyandadministrationofbronchodilators(39). encestherein). e
Duetothelackoferadication,highdosesofantibacterialsshould c
e
beadministeredtochronicallyinfectedCFpatients,whichhaveto CurrentChallengesinAntibioticResistance m
begiventoCFpatientsformostoftheirlives(6,7);furthermore, Antibacterialactivitiesofciprofloxacin,levofloxacin,tobramy- b
e
thepharmacokineticsofagentsaremodifiedinmanypatientpop- cin, amikacin, colistin, and aztreonam. Staphylococcus aureus r

ulations, including CF patients, necessitating dose adjustments andHaemophilusinfluenzaearethemostcommonbacteriaiso- 2
7
(40). lated initially from the sputum of CF patients, and thereafter, ,

2
Aggravatingthisproblemisthecontinuousincreasesinresis- Pseudomonasaeruginosaistheprevalentspecies;severalopportu- 0
tancetoanyantibacterialagentusedforthetreatmentofCFpa- nisticbacterialspecies,suchasBurkholderiacepacia,Stenotroph- 1
8
tients. Fluoroquinolone, penicillin, carbapenem, and aminogly- omonas maltophilia, and Achromobacter xylosoxidans, are occa-
b
coside resistance rates exceeding 30% and even multidrug sionally associated with CF. These species are the predominant y

resistancerateshavebeenreported(40–47).Resistancedevelop- ones,althoughtheCFmicrobiomeismuchmorecomplex(48– g
u
mentwasassociatedwithpatientage,andresistancemechanisms 50).Therefore,theantibacterialactivitiesofagentsusedforaero- e
s
accumulated sequentially, so that resistance rates gradually in- solizedtherapyagainstthesespeciesaresummarizedinTable1. t
creased over time (42). Furthermore, resistance development is TheisolatesstudiedoriginatedfromCFpatientsonly;pathogens
amplifiedbyhighmutationfrequenciesinhypermutableisolates isolatedfromnon-cysticfibrosispatientsweremoresusceptible
fromCFpatients(16).Acquisitionof(cid:2)-lactamaseexpression,in- thanwerethosefromCFpatients.
creased efflux pump activity, and permeability changes due to Ingeneral,thedatasummarizedinTable1demonstratethat
alterations of lipopolysaccharides or porins occur during the colistin,ciprofloxacin,andlevofloxacinarethemostactiveagents,
chronicstateofinfection.Nosinglemutationcompromisesevery whereastobramycin,amikacin,andaztreonamarelessactive.The
drug.Nevertheless,upregulatedeffluxcansimultaneouslycom- MIC andMIC valuesarescatteredoverabroadrange.
50 90
promisefluoroquinolonesandmost(cid:2)-lactams.Acombinationof High concentrations of these antibacterials of (cid:2)16 mg/liter
upregulatedefflux,lossofporins,andoutermembraneimperme- inhibited90%ofisolatesofS.maltophilia,A.xylosoxidans,B.ce-
ability compromises probably every drug class except the poly- pacia,andmethicillin-resistantS.aureus(MRSA)(59–70).
myxins(47). TheP.aeruginosafluoroquinoloneresistanceraterangedfrom
Inparticular,becauseofsuboptimaldrugpenetrationintothe 14% to 30%, the amikacin resistance rate ranged from 26% to
respiratory tract and continuously increasing drug resistance, 36%,thegentamicinresistanceraterangedfromalmost50%to
754 cmr.asm.org ClinicalMicrobiologyReviews
PharmacodynamicsofAerosolizedAgentsinCFPatients
TABLE1Antibacterialactivitiesofvariousagentsinhibiting50%and90%ofstrainsisolatedfromCFpatientsa
Concn(mg/liter)
CPX LVX Tobramycin Amikacin Aztreonam Colistin
Organism MIC MIC MIC MIC MIC MIC MIC MIC MIC MIC MIC MIC
50 90 50 90 50 90 50 90 50 90 50 90
P.aeruginosa 1–2 8 1–2 8 0.5–8 8–256 8–16 (cid:5)128 4–8 64–128 0.5–2 0.5–8
S.maltophilia 4 16 2 8(cid:5)32 (cid:5)32 128 (cid:5)128 (cid:5)128 (cid:5)128 2 8
B.cepacia 4 32 4 32 (cid:5)32 (cid:5)32 128 (cid:5)128 32 (cid:5)128 IR IR
A.xylosoxidans 4 16 4 16 (cid:5)32 (cid:5)32 (cid:5)128 (cid:5)128 64 (cid:5)128 8 (cid:5)16
MRSA 16 (cid:5)32 4 (cid:5)32 128 (cid:5)128 8 16 (cid:5)512 (cid:5)512 IR IR
aDatawerederivedfromreferences59–70.CPX,ciprofloxacin;LVX,levofloxacin;IR,intrinsicallyresistant.
D
40%,andthetobramycinresistanceraterangedfrom40%to10% ticed.ThestandardCLSImethodresultsinananalysisofveryfew
o
of the total isolates studied (41, 43, 47, 63, 71, 72). Almost all coloniesofthesamemorphotypeperpatientandpertimepoint w
isolatesofA.xylosoxidansweredrugresistant,althoughtheMICs only,whereasalaboriouspopulationanalysishastobeperformed n
lo
of fluoroquinolones were lower than those of the other drug to detect heteroresistance. Detection of heteroresistance, how- a
classesforS.maltophilia,A.xylosoxidans,andB.cepacia;resistance ever,isimportant,asS.aureusandP.aeruginosaadaptrapidlyto de
ratesamountedto91%to98%(61,63).Allagentsdisplayedre- growthinCFlungsasdiseaseprogresses.Duringtheearlyphases d

ducedactivitiesagainstS.maltophilia,withaztreonamandgenta- of colonization, the P. aeruginosa population is phenotypically fr
o
micinresistanceratesof96%and80%,respectively(72). homogeneousandsusceptibletoantibacterials.Heterogeneityin- m
Itisimportanttonotethatsusceptibilitytestswereperformed creasesasdiseaseprogressessothattherearediversepheno-and h
with planktonic bacteria but not with bacteria immobilized in t
genotypesthatareheterogeneouslyresistantinparallelwithinone tp
biofilms.Furthermore,criteriaclassifyingthestudiedisolatesas patient.Furthermore,ithasbeendemonstratedthatthereiscon- :/
being susceptible or resistant are based on breakpoints derived /c
siderablewithin-patientdiversitypertimepoint(82–87).Conse- m
fromPK/PDsurrogatesadaptedforenteralorparenteraltherapy,
quently, the geno- and phenotypes of strains isolated from CF r
whichdonotapplyfortreatmentwithinhaledantibacterials(73). .
a
patientsvarybothwithinanindividualpatientpertimepointand
Highlocalconcentrationsofantibacterialsfollowinginhaledther- s
with time as the disease progresses. Unfortunately, whether the m
apy were not considered. Therefore, it has been suggested that
.
strainsanalyzedinthecourseofsusceptibilitystudieshavebeen o
susceptibility testing be adapted: intermediate and resistant r
isolatedfromcolonizedorchronicallyinfectedpatientsisalmost g
strains should be retested by using high-range Etest strips and /
recategorizedinterpretivecriteria(69,74–76)sothatintermedi- neverdescribed.Thisdifferentiation,however,isofclinicalrele- o
n
ately susceptible and even resistant pathogens may be treatable vance,asthenumbersofdifferentphenotypesinchronicallyin-
D
withaerosolizedantibacterials.Itshouldalsobeconsideredthatin fected CF patients are 50% higher than those in colonized CF e
alloftheresistancesurveillancestudiesmentionedabove,theiso- patients; the resistance rates in the chronically infected groups c
e
lateswerenotstratifiedaccordingtothestatusofinfection,i.e., weretwiceashighasthoseinthecomparatorgroup(88). m
colonization or early or chronic infection. Early isolates of P. Thephenotypicandgenotypicheterogeneityofpathogensiso- b
e
aeruginosa have not yet acquired the phenotypic and genotypic latedfromCFlungsresultsinconsiderableheteroresistanceofthe r

2
responsestoachronicinfection,soalmostallP.aeruginosaiso- pathogens.Thistypeofheteroresistanceiscausedbyprocessesto 7
latesassociatedwithearlyinfectionweredrugsusceptible(76–78). adapttogrowthinahostileenvironmentandnotbyselectiondue ,
2
Thus,conventionalsusceptibilitytestingofCFisolatesispoorly toantimicrobialtherapy.Heteroresistance,assuch,isaspecies- 0
1
predictiveoftheclinicalresponse(31,79,80). specificpathoadaptationresultinginamixedpopulationofdrug- 8

resistantanddrug-susceptiblesubpopulationsofasinglebacterial b
Heteroresistance,aResistanceReservoirwithoutSelective y
strain.Ingeneral,adaptationofH.influenzae,S.aureus,P.aerugi-
PressureofAntibacterials g
nosa, and B. cepacia to growth in cystic fibrosis lungs generates u
Withinagenotypicallyhomogeneouspopulation,therearesev- e
heterogeneouspopulations,resultinginheteroresistance,ahyper- s
eralmixedpopulationsoflow-andhigh-leveldrug-resistantand t
mutator phenotype, and small colony variants (SCVs) (16–20,
-susceptible or hypersusceptible phenotypes; although the fre-
quencyofheteroresistanceisvariable,itsrateisaslowas(cid:3)10(cid:3)5to 33–36).
10(cid:3)6.Therefore,traditionalinvitrosusceptibilitytestingcharac- Carbapenem or polymyxin-colistin heteroresistance has been
describedforAcinetobacterbaumanniiandP.aeruginosa,occur-
terizestheentirepopulationasbeingsusceptible,althoughasub-
ringwithfrequenciesrangingfrom2(cid:4)10(cid:3)4to7(cid:4)10(cid:3)8;hetero-
setexpressesphenotypicresistance.Antibiosisdiminishesthesus-
resistancetobothdrugclasseswasrare(89–92),aswasheterore-
ceptiblesubpopulationwhiletheresistantpopulationincreasesin
totalnumbers,soheteroresistanceisconsideredaprecursorstage sistancetocolistininmultidrug-resistantA.baumannii(93,94).
ofresistance.Itisalsorelevantforsusceptibilitytestingthatthe Although polymyxin heteroresistance was uncommon, several
MICvaluesreportedinTable1weregeneratedbyusingstandard isolatespresentedheterogeneoussubpopulationswithincreased
methods recommended by the CLSI (81); i.e., the inoculum is andthusborderlinesusceptibleMICs,whichmightcausetreat-
preparedbyselecting“atleastthreetofivewell-isolatedcolonies mentfailures(92,95).Heteroresistancetocarboxy-andureido-
ofthesamemorphologicaltype,”yieldingafinalinoculumof105 penicillins,cephalosporins,carbapenems,aminoglycosides,colis-
CFU/ml,sotheresistantsubpopulationverylikelypassesunno- tin,fluoroquinolones,aswellasthepiperacillin-tazobactamand
October2014 Volume27 Number4 cmr.asm.org 755
Dalhoff
ticarcillin-clavulanatecombinationsinP.aeruginosahasbeenre- subpopulationstoalmost100%,comparedto(cid:6)40to60%withcon-
ported(96–101). ventionaltesting(118,119,123).
ComparativegenomesequencingofS.aureusisolatesobtained Therefore,aclearunderstandingofwithin-patientpopulationdy-
sequentiallyfromtheairwaysofCFpatientsrevealedvariationsin namicsduringtheprogressionofdiseaseaswellasduringeverytreat-
phagecontent,growthrate,hemolyticactivity,andotherpatho- mentcycleandthedevelopmentoftoolsforanalysisofintraspecies
genicity factors as well as genetic polymorphisms in genes that diversityareofutmostimportance.Furthermore,interpretivecriteria
influence antibiotic resistance. The majority of polymorphisms forsusceptibilitytestingshouldbeadaptedtorelevantconcentra-
wereisolatespecific,suggestingtheexistenceofaheterogeneousS. tionsofunboundagentsadministeredbyinhalation,andthelon-
aureuspopulationthatevolvedfromasingleinfectingstrain.The gitudinalchangeinsusceptibilityofCFbacterialisolateshastobe
increasedfrequencyofgenomicalterationsisduetophagemobi- considered.
lization(102–106).GenomicplasticityofS.aureusfacilitatesad-
aptationtovariousandchangingconditionsinCFlungs(103). PULMONARYPHARMACOKINETICS
CarriageofMRSAandinfectionarebecomingincreasinglycom-
ConfoundingFactors D
monamongCFpatients;theprevalenceofMRSAinCFpatientsin
o
theUnitedStatesisapproximately25%.Themolecularepidemi- Asreviewedrecently,druglevelsintherespiratorytractcannotbe w
ologyandPanton-Valentineleukocidingenecarriagearecomplex extrapolatedfromthenominaldoseplacedinthedeliverysystem n
(107–109).MRSApossessanintrinsicabilitytogeneratehighly (124,125).Thereasonsforthisaremanifold.First,theagentmay loa
methicillin-resistantsubclonesatafrequencyof10(cid:3)4to10(cid:3)8,so adheretothedeliverysystemsothattheemitteddoseislowerthan d
e
any MRSA population represents a heterogeneously (cid:2)-lactam- thenominaldose.Second,thefateofaparticle,onceinhaled,is d
resistantpopulation(110,111),evenintheabsenceof(cid:2)-lactam influencedbyavarietyoffactors,suchastheanatomyofthere- f
r
exposure. Glycopeptide-intermediate methicillin-susceptible S. spiratorytractandtheaerodynamiccharacteristicsofanaqueous om
aureus(MSSA)andglycopeptide-intermediateMRSAstrains,in- aerosol,whichmaybealteredbytherelativehumidityoftheair-
h
cludingheteroresistantones,havebeenisolatedfromCFpatients. way.Third,inspiratoryandexpiratorybreathingpatternsofthe t
t
Thefirstglycopeptide-intermediateS.aureusstrainwithavanco- CFpatientpopulationmayvarywithinonepatientfromdayto p
:
mycinMICof4to8mg/literwasisolatedfromaCFpatientin dayandbetweenpatients.Furthermore,reliablemeasurementsof //c
1999.Sincethen,severaladditionalcasesinCFpatientswerere- thedosedepositedaredifficulttoperform,sodifferenttechniques m
ported; vancomycin heteroresistance has been observed in ap- usedforquantitationofpulmonarydepositionmaygeneratecon- r.
a
proximately3%to5%ofCFpatientsharboringS.aureus(112– tradictorydata(124,125).Residualamountsofinhaleddrugmay s
m
117). bedepositedintheoralcavityandmayberecoveredduringspu-
.
tumsampling.Drugconcentrationsinserum,respiratorysecre- o
r
tions,aswellasurineprovideusefulinformationaboutthesys- g
ImplicationsforSusceptibilityTesting /
temic bioavailability of inhaled agents. However, analyses of o
n
Theintraindividualdiversityofbacterialpopulationshassignifi- serumconcentrationsandurinaryrecoverymaybeaffectedbythe
D
cantimplicationsforsusceptibilitytesting,selectionofresistance, swalloweddrugabsorbedfromthegastrointestinaltract,sodrug
e
andpharmacokinetic/pharmacodynamicconsiderations;thelat- concentrations in serum or urine may in part arise from swal- c
e
ter two aspects are discussed below. Basically, heteroresistance lowed drug deposited extrapulmonarily, and another part will m
impliesthatthebacterialpopulationinCFairwaysissignificantly arise from pulmonary deposition. Methods to reduce these pit- b
e
undersampled,resistanceratesareunderestimated,andthereare falls,suchastheuseofcharcoaltoabsorbresidualdruginsputum, r

subpopulationswithdifferentMICs.Therefore,routinesuscepti- havebeendescribedandusedinrecentstudies,asdescribedbe- 2
7
bilitytestingisnotapplicable,astheresultsarenotrepresentative low. Furthermore, rapid clearance via pulmonary macrophages ,

2
of a heterogeneous population of P. aeruginosa (118). Conse- andmucociliaryclearancemakeeffectivepulmonarydeposition 0
quently,datageneratedbyroutinemethodsarepoorlypredictive; difficult. 1
8
ciprofloxacin susceptibility and resistance of a mixed-morpho-
b
typestrainofP.aeruginosafromaCFpatientwerecorrectlypre- ChemistryandFormulation y

dictedin87.0%and41.7%ofcases,respectively(119),andanother Oneofthedeterminantsofintrapulmonarydistributionandab- g
u
analysis revealed that the conventional approach of susceptibility sorption as well as antibacterial activity is the solubility of an e
s
testing indicated susceptibility in 45% of the isolates studied, al- agent;onlythesolubleandfreefractiondiffusesthroughmem- t
thoughresistantsubpopulationswereidentifiedbypopulationanal- branes and reaches its target. Most fluoroquinolones are barely
ysisinallofthesesamplesclassifiedasbeingsusceptible(120).Fur- watersolubleataphysiologicalpH;theirsolubilitiesincreaseatan
thermore, conventional testing had no prognostic value for the acidicoralkalinepH,asfluoroquinolonesarezwitterions.Cipro-
clinical response to parenteral antibiotic treatment in CF patients floxacinhydrochloride,usedintheliposomalformulationofcip-
(121,122).Consequently,routinesusceptibilitytestingofCFpatho- rofloxacin,ismoderatelywatersolubleatpH7(54to86mg/liter)
gensisnotrepresentative,asthetestprovidesaconsiderableunder- (126–128),whereasciprofloxacinbetaine,usedinthedrypowder
estimationofresistance(31,118)andhasalimitedprognosticvalue formulation, is “slightly soluble,” i.e., (cid:7)50 mg/liter (129). The
for clinical efficacy. Detection of heteroresistance would probably watersolubilityoflevofloxacinatpH6.9isathousandfoldhigher,
improvethesituation.Detectionofheteroresistanceby,e.g.,popula- amountingto50g/liter,(130).Aminoglycosides,colistin,aztreo-
tionanalysisprofilingisdifficultandlabor-intensive,sothismethod nam,vancomycin,andfosfomycinarehighlywatersoluble(131).
cannotbeusedunderroutineconditions.Analternativetoconven- Ontheotherhand,watersolubilitymayaffecttherapeuticeffi-
tionaltestmethodscouldprovidedirectplatingofsputumsamples cacynegatively,asitreducestheresidencetimeoftheagentinthe
ontoagarplates;directplatingincreasedthedetectionrateofresistant respiratory tract significantly. For example, following intratra-
756 cmr.asm.org ClinicalMicrobiologyReviews
PharmacodynamicsofAerosolizedAgentsinCFPatients
TABLE2PharmacokineticsofvariousantibacterialsinadultCFpatientsfollowingoral,intravenous,oraerosolizedadministration
Urinary
C (mg/liter) t (h)in recovery
max 1/2
Agent,dose,androute C (mg/liter)inserum C (mg/liter)insputum inlungorELF serum/sputum (%) Reference(s)
max max
CPX,500mg,p.o. 2.5–3.8 0.7–1.9 3.9–29 3.7–5.1 35.7 144–146
CPX,750mg,p.o. 3.4–4.5 3.6–4.5 144,145
CPX,1,000mg,p.o. 4.6–5.6 1.8 3.7–5.1 40.8 144–147
CPX,200mg,i.v. 4.9 16.9 148
CPX,32.5mg,ae 0.056 33.0 9.5/9.04 149
LVX,200mg,p.o. 2.1 3.9 151
LVX,500mg,p.o. 4.1–5.3(4h) 9.9–15.2* 152–155
LVX,750mg,p.o. 12.0(4h) 22.1* 152–155
LVX,500mg,i.v. 6.6 18.3 156
LVX,180mg,ae 0.95–1.3 2,563-2,932 6.4–6.8/3.5–4.3 157
TOB,1.7–3.5,mg/kgq.d.i.v. 3.6–11.32 1.1-0.7 85 158,160
TOB,10mg/kg,q.d.i.v. 22–29 1.7–2.2 221,223,224,369
TOB,600mg,aeb 1.3 13 17.5 164 D
TOB,300mg,aeb (cid:7)4 489–695 3.6–5.5 8.9–11.2 5.5 165–168 o
w
TOB,112mg,aec 1.02 1,048 3.1/2.2 169
n
TAOMBI,,33000mmg/gk,ga,eib.v. 813.0–4121(AUC(cid:8)235mg·h/liter) 67.337–10.9(AUC(cid:8)83.7mg·h/liter) 03..60–/12..76 83 136699,225,299,370,371 lo
AMI,500mg,ae AUC(cid:8)8.3mg·h/liter AUC(cid:8)3,830mg·h/liter 2.9 170 ad
AMI,560mg,ae 1.29 2,286 25–50 171 e
AZM,2g 80–228 5.2 1.8 72 172–175 d
AZM,75mg,ae 0.42–0.49 324–677 2.1 176,177 f
r
COL,2.4mg/kg 2.5–10(range) 4.2 179 o
COL,66mg 0.17–0.18 (cid:6)40 4.1–4.5 4.3 180 m

aThebroadrangeofciprofloxacinlungtissueconcentrationsfollowingoral(p.o.)ori.v.administrationisduetothefactthatsomeinvestigatorsadministeredthedrugsonceand h
t
othersadministeredthemrepeatedly;thehighervaluesrepresentsteady-stateconcentrations.Therangeoflevofloxacinconcentrationsfollowingaerosolized(ae)administrationis t
p
duetothefactthatthedoseof180mgwasadministeredintwodifferentformulations(50mg/mland100mg/ml)(lung,lungtissuehomogenate;ELF,epithelialliningfluid;AUC, :
/
areaundertheconcentration-versus-timecurve;t1/2,half-life,eitherinserumorinsputum;CPX,ciprofloxacin;LVX,levofloxacin;TOB,tobramycin;AMI,amikacin;AZM, /c
aztreonam;COL,colistin).AsterisksindicatevaluesforELF. m
bTobramycinsolutionforinhalation. r
.
cTobramycindrypowderforinhalation. a
s
m
.
o
r
g
chealadministrationtoexperimentalanimals,moderatelysoluble literintheepithelialliningfluid(ELF).Thewater-solublefraction
/

ciprofloxacinhydrochloridewasrapidlyabsorbedfromthelungs is released continuously over prolonged periods of time (136). o
n
intothesystemiccirculation,withahalf-lifeofonly1h.Conse- Tobramycin(TobiPodhaler)(137,138),colistin(colistimethate)
D
quently, ciprofloxacin lung tissue concentrations declined too (Colobreathe) (139), vancomycin hydrochloride (AeroVanc) e
rapidlytoachieveeffectivetreatment.Inordertoovercomethe (140),andthecombinationoffosfomycinandtobramycin-leu- c
e
rapidclearanceofciprofloxacinhydrochloridefromthelungs,an cine(141)arealsoadministeredasdrypowders.Theseagents,in m
experimentalliposomalformulationwasdeveloped.Theelimina- contrasttociprofloxacin,arefreelywatersoluble. b
e
tionhalf-lifeofliposomallyencapsulatedciprofloxacininexperi- Aztreonam lysine (Cayston) and levofloxacin hemihydrate r

mental animals was 3 h, which resulted in therapeutic efficacy (MP-376;Aeroquin),whicharealsofreelywatersoluble,arede- 2
7
against Francisella tularensis and P. aeruginosa infections (132– liveredasaqueoussolutions(142,143). ,

2
135). 0
Twoliposomalformulationsofinhaledciprofloxacin(Pulma- SerumandSputumPharmacokinetics 1
8
quin and Lipoquin) that differ in the proportions of a rapidly Fluoroquinolones.Fluoroquinolonesingeneralarecharacterized
b
available aqueous solution of ciprofloxacin hydrochloride and by marked tissue penetration activities, surpassing the corre- y

slow-release liposomal ciprofloxacin are in development. Dual- spondingserumconcentrations2-toalmost10-folduponoralor g
u
release ciprofloxacin for inhalation (DRCFI) (Pulmaquin or intravenousadministration. e
s
ARD-3150) uses the slow-release liposomal formulation (also Concentrationsofciprofloxacininlungtissuehomogenatesor t
called ciprofloxacin for inhalation [CFI] [Lipoquin or ARD- ELFareashighas15to29mg/liter(Table2)(144–148).
3100])mixedwithasmallamountofciprofloxacinhydrochloride Following aerosolized administration of 50 mg dry powder
dissolvedinanaqueousmedium.ARD-3100wasdevelopedfor ciprofloxacin, corresponding to 32.5 mg ciprofloxacin betaine,
themanagementofinfectionsinCFpatients,andARD-3150was maximalsputumconcentrationsamountedto33.0mg/liter,de-
developedforthemanagementofinfectionsinnon-cysticfibrosis clining with a half-life of 9.04 h (149). As described previously
bronchiectasispatients.ARD-1100isaliposomalformulationfor (149), sputum concentrations following a dose of 100 mg dry
defensepurposessuchastreatmentofinhaledtularemia,pneu- powderwerenotsignificantlyhigher.Thecorrespondingserum
monicplague,andQfever(AradigmCorp.,Hayward,CA).Like- concentrations were negligibly low, with maximal concentra-
wise,aliposomalformulationofamikacin(Arikace)isinclinical tionsof0.08and0.3mg/literfollowingthe50-mgand100-mg
development. doses, respectively. Low ciprofloxacin serum concentrations
Analternativeapproachistoadministerpoorlysolublecipro- and a long half-life in sputum indicate minimal absorption
floxacinbetaineasadrypowder.Deliveryofanominaldoseof35 and, thus, minimal systemic exposition following aerosolized
mgintheorydepositsahightotaldrugconcentrationof466mg/ deliveryofciprofloxacin(149).CiprofloxacinsputumandELF
October2014 Volume27 Number4 cmr.asm.org 757
Dalhoff
concentrationsfollowingoralorintravenousadministrationof trationsaslowas1.29(cid:9)g/literandmeansputumconcentrations
ciprofloxacinhydrochlorideandaerosolizedciprofloxacinbe- of2,286(cid:9)g/gwererecordedfollowingaerosolizedadministration
taine, respectively, are comparable and are near the limit of of560mg(171).
solubilityofciprofloxacin. Aztreonam. Aztreonam displayed the typical (cid:2)-lactam phar-
Dataonthepharmacokineticsoftheliposomalciprofloxacin macokinetics, with a short half-life and slow penetration into
formulationhavenotyetbeenreported,exceptforaplasmahalf- bronchialsecretions,correspondingtoapenetrationratioof20%
lifeof10.5h(150). uponasingleintravenousadministration(172–177).Highspu-
LevofloxacinlungtissueorELFconcentrationsuponoralor tumconcentrationswereachieveduponaerosolizedadministra-
intravenousadministrationsaresimilartothoseofciprofloxacin tion;sputumconcentrationsincreaseddoseproportionallyfrom
(Table2)(151–156).However,itssputumconcentrationsmea- 383to879to985mg/kgfollowingaerosoldeliveryof75,150,and
suredfollowingaerosolizedadministrationsurpasslungtissueor 225mg.Systemicexposurewaslowbutoccurredrapidly(Table2)
ELF concentrations achieved following oral or intravenous ad- (171–177).
ministrationby100-to1,000-fold,reachingsputumconcentra- Colistin. Analysis of colistin pharmacokinetics, in particular
D
tionsofalmost3,000mg/liter(157). tissuekinetics,isproblematicandmaygenerateconflictingdata
o
Althoughserumconcentrationsfollowingaerosolizedadmin- becauseofthedifferentmethodsusedandalsoduetothefactthat w
istrationof180mglevofloxacinarelow,thelevelscorrespondtoa polymyxinsadsorbtovariousmatrices.Thepharmacokineticsof n
lo
serum concentration following oral administration of 100 mg either25mgcolistimethatedrypowderor158mgofanebulized
a
levofloxacin.Thisphenomenonislikelyduetothehighsolubility solutionwereevaluatedinacrossoverstudy(178).Maximalse- d
e
of levofloxacin and, thus, relatively good absorption from the rumconcentrationsandareaundertheconcentration-timecurve d
lung. (AUC)valuesof66.3mg/literand200.7mg·h/liter,respectively, f
r
o
Aminoglycosides. Although aminoglycosides are distributed wererecordedfollowingaerosolizedadministrationofdrypow-
m
almostfreelyintheextracellularspaceofmosttissuesbecauseof der, and the corresponding values for nebulized administration
h
their minimal protein binding and high water solubility, they were144.3mg/literand459.5mgh/liter;sputumconcentrations t
t
cross biological membranes poorly, so drug concentrations in werenotreportedinthatstudy.DatareportedinTable2(178– p
:
/
bronchialsecretionsarelow,thusrestrictingtheirefficacyinthe 180) should be interpreted with caution, and urinary recovery /c
treatmentofrespiratorytractinfections(158–162).Lowconcen- observedafteraerosolizedtherapyindicatingabsorptionfromthe m
r
trationsofaminoglycosidesintherespiratorytractuponintrave- lungisdisputed(181–183). .
a
nousdosingareduetotheirpolycationicchargeandtheirlipid s
insolubility(163).DatasummarizedinTable2demonstratethat CorrelationofSputumConcentrationstoAntibacterial m
.
sputumorlungtissueconcentrationsweresignificantlyincreased Activities o
r
g
upon ultrasonic (164), pneumatic (165), and Pari LC Plus Jet Achievabledruglevelsatthefocusofinfectionareoftencorrelated
/

(166,167)nebulizationusingthepreviousformulationsandde- to MICs of the relevant pathogens; a drug is considered to be o
n
vicescomparedtointravenousadministration.Recently,anovel effectiveandthepathogenisconsideredtobesusceptibleifthe
D
tobramycindrypowderformulationwaslaunched.Astudycom- drugconcentrationsexceedtheMIC.Ingeneral,aerosolizedad- e
paringthepharmacokineticsofthisdrypowderformulationwith ministrationoftheagentsdescribedabove,exceptforciprofloxa- c
e
the pharmacokinetics of the previous tobramycin solutions for cinbetaineadministeredwithadrypowderinhaler(ciprofloxacin m
inhalationrevealedthatmeansputumconcentrationsashighas DPI),generatessputumconcentrationsexceedingthosefollowing b
e
1,048 mg/kg of body weight were measured upon inhalation of oralorintravenousadministration,ashigherdosescanbeadmin- r

112mg,comparedto737mg/kgfollowingaerosolizedadminis- isteredtopicallythanenterallyorparenterally.Comparisonofthe 2
7
trationof300mgoftheaqueousformulation.Thesystemicbio- sputumlevelswiththeMIC valuesfortherelevantpathogens ,
90 2
availabilityoftobramycindrypowderis12%(168,169).Measur- summarizedinTable1revealsthatthesputumlevelsoflevofloxa- 0
ableandslowlydecliningtobramycinserumconcentrationswere cinandcolistinsurpasstheMIC valuesforalltherelevantspe- 1
90 8
recorded,independentofthenebulizertypeused.Thisprolonged cies by severalfold. The aminoglycoside and aztreonam sputum
b
half-lifemaylikelybeduetothedelayedabsorptionoftobramycin concentrations correspond to or exceed 2-fold MIC values y

fromthelungintothebloodstream.Comparisonsofthepharma- of(cid:5)128mg/liter. g
u
cokineticcharacteristicsoftobramycindeliveredbyeitherbypre- However,suchcorrelationsshouldbeinterpretedwithcaution, e
s
viousoractualinhalationdevicesdemonstratethatboththefor- as sputum concentrations are not a predictive marker for lung t
mulation administered as well as the inhalation device have deposition(1,2),noristherelevantsiteforantibioticpenetration
significant impacts on pharmacokinetics and the drug amounts clearly defined. Concentrations of antibacterials in sputum and
deliveredanddeposited. bronchi are presumably most relevant for bronchial infections,
NostudyresultshavebeenpostedatClinicalTrials.gov(regis- whiledruglevelsinlungparenchyma,epithelialliningfluid,and
trationno.NCT00794586)fortheevaluationofthepharmacoki- alveolarmacrophagesorneutrophilsareprobablymoreimpor-
netics of the fosfomycin-tobramycin combination as of 3 June tantforpneumonicinfections(184).Althoughlocalconcentra-
2014. tionsofanantibacterialagentarerelevantfortherapeuticefficacy,
Amikacinconcentrationsinsputumwereabout45-foldhigher itisalsoimportanttoconsiderwhethertheactivityoftheagent
uponaerosolizedadministrationof500mgofaliposomalformu- may be impaired by certain local conditions such as acidic pH,
lationthanafterparenteraladministrationof30mg/kgofbody whichprevailsinsomepneumonicareasofthelung.Growthatan
weight; mean sputum concentrations increased (cid:6)3- to 5-fold acidicpHincreasedtheMICsofaminoglycosides,commercially
fromday1today14(170,171).Insupplementalmaterialpub- available fluoroquinolones, colistin, and macrolides but not
lishedpreviously(158),itwasreportedthatmeanserumconcen- aztreonam (185–191). Furthermore, polycations such as poly-
758 cmr.asm.org ClinicalMicrobiologyReviews
PharmacodynamicsofAerosolizedAgentsinCFPatients
myxin-colistin and aminoglycosides bind to DNA, so they are roquinolone resistance. It has also been suggested that
inactivatedinthepresenceof,e.g.,pusandcelldebris(192,193). aminoglycosidesputumconcentrationsshouldexceedtheMICs
FluoroquinolonesalsobindtoDNAandcelldebris(194–197).In 25 times to achieve a bactericidal effect (205). The efficacy of
addition, infected areas with poor ventilation may be protected (cid:2)-lactams is determined predominantly by T(cid:5)MIC, which
fromaerosolizedagents.Thesefactors,inadditiontothosemen- should correspond to 30% to 50% of the dosing interval (200–
tioned briefly above in the introduction and in addition to the 204).ThesePK/PDmeasuresshouldbeattainedwithaprobability
drugconcentrationsatthefocusofinfection,haveanimpacton of(cid:2)90%.Basedontheseconceptsandwell-definedPK/PDmea-
theclinicalefficacyofantibacterialagents. sures, it is possible to preclinically identify treatment regimens
Asdiscussedin“ImplicationsforSusceptibilityTesting,”above, that will optimize the probability of clinical and bacteriological
reportedMICsofantibacterialsforpathogensisolatedfromCF outcomesasnewantimicrobialagentsornewformulationsofold
patientsarenotrepresentativeoftheheterogeneouslysusceptible agentsaredeveloped.Therefore,theseprincipleshavealsobeen
bacterialpopulationsisolatedfromCFpatients.Asdiscussedbe- appliedforthedevelopmentofaerosolizedantibacterials.
low,theexpositionofheterogeneouspopulationstofluctuating TheuseofthePK/PDsurrogatescorrelatingpharmacokinetics
D
drug concentrations simulating lung tissue levels results in the inserumwithclinicalcureandpresumedorproveneradicationof
o
elimination of susceptible but selection of resistant subpopula- thepathogenasabasisforPK/PDinvestigationsinCFpatientsis w
tions.Notonlypopulationdynamicsbutalsophysicalstructure, problematicfortworeasons.First,clinicalcureand/oreradication n
lo
suchasbiofilmformationanddepositionofDNAandcelldebris, ofP.aeruginosa,withtheexceptionofearlyP.aeruginosainfection
a
haveanimpactontheactivitiesofantibacterialagents(198). (77),cannotbeachievedinCFpatients.Second,serumconcen- d
e
trationsareirrelevantinCFpatientstreatedbyinhalation,asthe d
PHARMACODYNAMICS minimization of systemic exposure but optimization of target- fr
o
site-specificexposureisoneoftheprimaryobjectivesofaerosol-
m
DefinitionofEndpointsandUseofAppropriateMatrices izedtherapy.Therefore,itmaybeobviousthatsputuminsteadof
h
Duringthepast20years,investigatorshavebeenabletoidentify serumkineticsshouldbeusedasabasisforPK/PDconsiderations. t
t
clinicaloutcomepredictorsbasedonthecorrelationofthephar- Sofar,however,asystematicanalysisoftarget-site-specificdata p
:
/
macokineticsandpharmacodynamics(PK/PD)ofanagent;phar- generatedinvitro,invivo,andinclinicalstudiesandacorrelation /c
macokinetic parameters are derived from serum kinetics, and ofPK/PDmeasureswithclinicalefficacyhavenotbeendone. m
r
pharmacodynamicparametersarederivedfromMICvalues.Sur- Therefore,theendpointsclinicalcureand/oreradicationofthe .
a
rogatesforclinicalcureanderadicationofpathogenshavebeen pathogenthataretobeevaluatedclinicallyandcorrelatedtodrug s
m
defined,andquantitativevaluesthatpredicttheprobabilitiesof exposuredifferbetweennon-CFpatientsandCFpatients,sothe
.
successorfailureofantibioticregimenshavebeenassigned(199– endpointtobemetshouldberedefined.Furthermore,thematrix, o
r
g
204).Inaddition,PK/PDparametersofferawaytoexpeditethe i.e.,serumorsputum,tobeusedforpharmacokineticevaluations
/

antibioticdevelopmentprocessandtoprovidearationaleforthe andthePK/PDtargettobeachievedinCFpatientstreatedwith o
n
doseselected. aerosolizedantibacterialsshouldbereconsidered.Actually,phar-
D
Ingeneral,antimicrobialagentscanbecategorizedonthebasis macokineticanalysisofaerosolizedantibacterialsisbasedondrug e
ofthePK/PDsurrogatesthatcorrelatebestwithclinicalorbacte- measurementsinsputum.However,drugconcentrationsinspu- c
e
riologicalefficacy.ThethreemostfrequentlyusedPK/PDsurro- tumprovideonlyanapproximation,assputumisnotahomoge- m
gatesforantibacterialsarethedurationoftimethatadrugcon- neous matrix. Sputum viscosity and contents of cell debris and b
e
centration remains above the MIC (T(cid:5)MIC), the ratio of the pus,etc.,arevariable,andtheoriginofexpectoratedsputumis r

maximaldrugconcentrationtotheMIC(C /MICratio),and unknown. 2
max 7
theratiooftheareaundertheconcentration-timecurveat24hto ,

theMIC(AUC/MICratio).BasedonthecompilationofPK/PD PreclinicalandClinicalPK/PDStudiesinCFPatients 20
targetsderivedfrominvitromodelssuchasexposureofindicator Fluoroquinolones.BasedonthepioneeringstudiesofForrestet 1
8
strains to fluctuating drug concentrations simulating serum or al.,PK/PDsurrogatesforintravenousciprofloxacintreatmentof
b
target site concentrations, animal infection models, computer- respiratorytractinfectionsinseriouslyillpatientshavebeende- y

based modeling, and clinical data, the magnitudes of exposure fined (206). Serum samples for pharmacokinetic analysis and g
u
necessary for clinical and bacteriological efficacy were defined. specimens from the site of infection for microbiological assess- e
s
Theendpointsanalyzedinclinicalstudieswereclinicalcureand ments were withdrawn from every patient daily so that kinetic t
presumedorproveneradicationofthepathogen.ThePK/PDsur- parameters,thepresenceorabsenceofthepathogen,andtheMIC
rogates most predictive of the efficacy of aminoglycosides and couldbedetermined.Bycorrelatingexposuretototaldruglevels
fluoroquinolonesaretheC /MICandAUC/MICratios,andthe (AUC[mg·h/liter])andsusceptibilityofthepathogen(MIC[mg/
max
mostpredictivePK/PDmeasurefor(cid:2)-lactamsisT(cid:5)MIC(199– liter]) to clinical and bacteriological responses, it was demon-
204).Inprinciple,theantibacterialactivityandclinicalefficacyof strated that an AUC/MIC ratio of (cid:2)125 h (corresponding to
aminoglycosidesandfluoroquinolonesareconcentrationdepen- about75hforthefreefraction)wasassociatedwithahighprob-
dent, so increasing concentrations are paralleled by increasing ability of clinical response and in particular eradication of the
activities.Consequently,highmaximalserumconcentrationsand pathogenfromthelung.Thoseauthorsstatedclearlyinthedis-
high AUCs correlate best with their activity profiles. C /MIC cussionofthesedatathatitisdifficulttoachieveanAUC/MIC
max
andAUC/MICratiosof(cid:2)10and(cid:2)125h,respectively,werefound ratioof(cid:2)125hforbacteriawithciprofloxacinMICsof0.5mg/
to be predictive of the efficacy of aminoglycosides and fluoro- literandabove,suchasStaphylococcusspp.andPseudomonasspe-
quinolonesinthetreatmentofGram-negativeinfections.AC / cies(206).
max
MICratioof(cid:2)10wasfoundtominimizetheemergenceoffluo- SubsequentstudieswithciprofloxacinconfirmedthatanAUC/
October2014 Volume27 Number4 cmr.asm.org 759
Dalhoff
MICratioof(cid:2)125hwasassociatedwithclinicalandbacteriolog- topredictthelikelihoodofefficacyinthetreatmentofnosocomial
icalefficacyagainsthighlysusceptibleP.aeruginosaisolatesonly infections,includingrespiratorytractinfections(217–220).The
(207–211).TheprobabilityofmeetingthePK/PDtarget,i.e.,an mostpredictivePK/PDefficacyparameterinCFpatientswasthe
AUC/MICratioof(cid:2)125hforisolateswithMICsof(cid:5)0.3mg/liter, C /MICratio(221).
max
wassuboptimal,resultinginatargetattainmentrateof53to59% Inamouselunginfectionmodelcomparingaerosolizedtobra-
forroutinelyisolatedP.aeruginosastrainsin2002(212).There- mycin and levofloxacin, it was shown that bacterial loads of P.
fore,anAUC/MICtargetof(cid:5)350hhasbeensetforP.aeruginosa aeruginosa in the lungs of chronically infected animals were re-
(206,207).However,althoughthePK/PDtargetoffluoroquino- ducedfollowingtwice-dailytreatmentfor3dayswith60mg/kgof
lonesforP.aeruginosahasbeenincreasedfrom(cid:2)125hto(cid:5)350h, levofloxacinortobramycinby3.33log titersand2.94CFU/lung,
10
anAUC/MICratioof(cid:2)125hisstillusedbyalmosteveryauthoras respectively,comparedtothepreexposurelevel(216).
a predictor of clinical or bacteriological efficacy in patients in- IntravenoustobramycintreatmentofCFpatientswithchronic
fectedwithP.aeruginosa,includingCFpatients(213,214),orin P.aeruginosainfectionsrevealedthattheC /MICratiocorre-
max
preclinicalmodels(215).TheuseofanincreasedPK/PDtargetof latedbestwithclinicalefficacy,withalog-linearrelationshipbe-
(cid:5)350himpliesthatonlyhighlysusceptibleisolatesaretreatable: tweentheC /MICratioandpercentforcedexpiratoryvolume D
max o
theserumAUCsofciprofloxacinfollowinganoraladministration in1s(FEV )beingpredicted.However,P.aeruginosawasrecov- w
1
of500mgor750mgtoCFpatientsamountto11mg·h/literand eredinallpatientstreated,andaPK/PDanalysisofbacteriological n
lo
19 mg · h/liter, respectively (144, 146), and the serum AUC of outcomehasnotbeenreported(154).Thesefindingsareinagree-
a
levofloxacinfollowinganoraldoseof500mgadministeredtoCF mentwithfindingsofotherclinicaltobramycinstudies(164,209, d
e
patientsis71.3mg·h/liter(155).Consequently,thePK/PDtarget 210).AerosolizedadministrationofliposomalamikacintoCFpa- d
of(cid:5)350hwouldbeattainedforisolateswithaciprofloxacinMIC tientsdidnotresultinaPK/PD-drivenchangeinlungfunction f
r
of (cid:7)0.05 mg/liter to be treated with 750 mg ciprofloxacin and tests,butaconcentration-dependentreductionofbacterialload o
m
isolates with a levofloxacin MIC of (cid:7)0.2 mg/liter to be treated wascorrelatedtotheAUC/MICratio(170,171,222).
h
with 500 mg levofloxacin. Susceptibility data compiled by the AssumingthatanAUC/MICratioof100ispredictiveofthe t
t
EUCAST reveal that the susceptible wild-type population of P. likelihoodofclinicalsuccess,andbasedonAUCvaluesof110.5 p
:
aeruginosa (n (cid:8) 19,046) is characterized by ciprofloxacin MICs and 235 mg · h/liter for tobramycin (223) and amikacin (224), //c
rangingfrom0.125to4mg/literandamedianMICof1mg/liter, respectively,isolateswithatobramycinMICof(cid:3)1mg/literand m
thusindicatingthatanAUC/MICratioof(cid:5)350hcanbeattained anamikacinMICof(cid:3)2mg/litercanbetreatedeffectivelywiththe r.
a
foronlyasmallminorityofsusceptiblewild-typestrains(203). standarddosesadministeredintravenously.TheMICsoftobra- s
m
Nevertheless,orallyadministeredciprofloxacinandlevofloxacin mycin and amikacin for the P. aeruginosa wild-type population
.
wereandstillareclinicallyeffectiveinthetreatmentofP.aerugi- rangefrom0.016to512mg/literand0.25to256mg/liter,respec- o
r
g
nosainfectionsinnon-CFandCFpatients.Astheminimizationof tively,withmedianMICsof0.5mg/literand4mg/liter,respec-
/

systemicexposureandtheoptimizationoftargetsiteexposureare tively(http://www.escmid.org/),thusindicatingthattheactivities o
n
thebasicprinciplesforaerosolizedadministration,pharmacoki- of the two aminoglycosides are suboptimal, particularly against
D
netic parameters derived from serum concentrations cannot be strainsisolatedfromCFpatients;theMIC90valuesfortheseiso- e
used, but it seems to be obvious that parameters derived from lates are as high as 8 to (cid:5)256 mg/liter (Table 1). The AUC of c
e
sputumconcentrationsshouldbeusedforPK/PDinvestigations. amikacin in sputum following aerosolized administration in- m
IfsputumAUCsof72.5mg·h/literandapproximately2,000mg· creased almost 45-fold compared to that following i.v. dosing b
e
h/liter following aerosolized administration of 32.5 mg cipro- (225), so isolates with MICs of up to 32 mg/liter could be ade- r

floxacinDPIand180mglevofloxacinhemihydrate,respectively, quatelyexposed.IfPK/PDassessmentsarebasedonthesugges- 2
7
areusedasthebasisforthesecalculations,thePK/PDtargetwould tion that aminoglycoside sputum concentrations should exceed ,

2
beattainedforstrainswithciprofloxacinMICsof0.2mg/literand the MICs 25-fold, aerosolized tobramycin and amikacin would 0
levofloxacinMICsof5.0mg/liter.Theseratiosaremuchhigher coverpathogenswithMICsofupto16mg/liter. 1
8
thanthosecalculatedfororaltherapy,butstill,borderlinesuscep- Beta-lactams.InachronicP.aeruginosalunginfectionmodel,
b
tibleandresistantisolateswillnotbecoveredbyaerosolizedad- aztreonam (400 mg/kg) reduced the lung burden by 1.25 CFU/ y

ministrationoffluoroquinolones.AssummarizedinTable1,the lungcomparedtothepreexposurelevel(216).Theprobabilitiesof g
u
MIC valueofciprofloxacinandlevofloxacinforaggregatedCF clinicalsuccesswerecalculatedfornon-CFandCFpatientsdosed e
90 s
isolatesis8mg/liter;earlycolonizersshouldbemoresusceptible, intravenouslywith1gaztreonamevery8husingaPK/PDtarget t
while isolates from chronically infected patients should have of50to60%T(cid:5)MIC(172).IsolateswithMICsofupto1mg/liter
higherMICvalues. and2mg/liter,respectively,werereliablytreatedwith1gaztreo-
An in vitro study (215) and an in vivo mouse lung infection namfourtimesaday(q.i.d.).
model(216)revealedthatlevofloxacinexhibitedaconcentration- Three additional PK/PD studies are worth mentioning, al-
ordose-dependentreductionofviableP.aeruginosacounts.Aero- though neither piperacillin nor ceftazidime has been developed
solizedlevofloxacindosesof15,30,and60mg/kgofbodyweight foraerosolizedtherapy.TimeabovetheMICistherelevantpa-
inachroniclunginfectionmodelreducedviablecountsby0.07, rameterforthese(cid:2)-lactams.ThePK/PDofpiperacillinhasbeen
0.62,and1.25CFU/lung,whereastheantibacterialeffectsofin- studiedinhospitalizednon-CFpatientsandinCFpatients(226,
traperitoneallyappliedidenticaldosesoflevofloxacinweresignif- 227). A PK/PD target of 50% T(cid:5)MIC was set for both patient
icantlylower. populations, who were dosed with two different regimens. The
Aminoglycosides.Evaluationsofthepharmacodynamicchar- MIC that was covered for 50% of the dosing interval by either
acteristics of aminoglycosides are scarce. C /MIC and AUC/ regimenwasevaluated;aPK/PDanalysisofdrugeffectshasnot
max
MICratiosof8to10and80hto100h,respectively,arereasonable beenperformed.Inthenon-CFpopulation,thetargetwasmetby
760 cmr.asm.org ClinicalMicrobiologyReviews
PharmacodynamicsofAerosolizedAgentsinCFPatients
administrationof3gpiperacillinevery6hforhypotheticaliso- ceptibilitypatternofthecausativepathogen.Datageneratedby
lateswithanumericalMICof(cid:3)8mg/liter,whileadministration usingthedeterministicmethodtendtobetoofavorable,asonly
every4hresultedinamorerobusttargetattainmentandcovered discrete numerical values (i.e., mean C or MIC ) are used.
max 90
hypotheticalisolateswithnumericalMICsof(cid:2)16mg/liter(226), Datageneratedbyprobabilisticmethodstendtobemoredisad-
which corresponds to the resistance breakpoint set by the vantageous,astheentirepatientandpathogenpopulations,with
EUCAST. A piperacillin dose of 3 g every 4 h achieved robust alltheirvariabilities,suchashighandlowdrugexposuresorhigh
target attainment in CF patients for hypothetical isolates with andlowMICs,areconsidered(203).Therefore,itcannotbecon-
MICsof(cid:3)12mg/liter(227).Thesecalculationssuggestthatpip- cludedonthebasisofthesecalculationsthatonedrugclassmay
eracillincanbeusedfortheempiricaltreatmentofCFpatients. provideabettertargetattainmentratethantheother.
However,theprobabilitiesoftargetattainmentweredifferentfor
a population of clinical isolates of P. aeruginosa sampled from EmergenceofResistanceinPK/PDStudiesandinCF
both non-CF and CF patients. The target of 50% T(cid:5)MIC was Patients
attainedforP.aeruginosaisolatesfrompatientsadmittedtoone Invitromutationalresistancetoantibacterialsinpathogensiso-
D
hospital in North America, while surveillance isolates collected latedfromCFpatientswillnotbereviewed.Thefrequencywith
o
throughoutNorthorSouthAmericaandtwoGermaninstitutions whichresistancetoantibacterialsemergesinvitroisroutinelyde- w
werenotreliablycovered.Targetattainmentratesdifferedby50% termined by the exposure of a bacterial population to a given n
lo
between North and South American isolates and by 30 to 35% concentration of the test agent. This procedure results in the
a
betweenisolatesfromthetwoGermaninstitutions(227). quantificationofthenumberofmutantbacteriainapopulation d
e
AnanalysisofPK/PDcharacteristicsofceftazidimeinnon-CF anddescribesthefrequencywithwhichresistantbacterialpheno- d
andCFpatientsresultedinananalogousoutcome(228).These typesariseinvitro,expressedasmutationratesormutationfre- f
r
o
datasuggestthatPK/PDanalysisandcalculationoftargetattain- quencies.Suchdataareconsideredtoprovideimportantinforma-
m
mentratesshouldbeperformedonaregional/locallevelbyusing tion about the risk of resistance emerging in a treated patient.
h
“real-life”PKandPDdatafromtherelevantpatientgroup.Target However,pathoadaptiveprocessesfavortheemergenceofbacte- t
t
attainment rates should be recalculated regularly, as the MICs riadisplayingahypermutatorphenotype(15–27),exhibitingsig- p
:
/
shiftovertimeinparallelwithacontinuousincreaseinresistance nificantlyincreasedratesofmutation,orasmall-colonymorpho- /c
rates. type(30–34),facilitatingrecurrentandpersistentinfections.Both m
r
Colistin.PK/PDparametersofcolistinwerederivedfromanin adaptiveresponsesconferantibioticresistance,which,however,is .
a
vitro model simulating 5 different intermittent administrations not analyzed by routine procedures. Therefore, in vitro studies s
m
andacontinuousinfusionregimenofthedrug. assessing mutation rates or mutation frequencies are not re-
.
TheAUC/MICratiofittedbestwithantibacterialactivity.The viewed. o
r
g
AUC/MICratiosrequiredfor2-logreductionsofviablecountsof Emergence of resistance in P. aeruginosa. In general, resis-
/

P.aeruginosarangedfromapproximately36hto7h,althoughthe tancetoantibacterialsdevelopedrapidlyinP.aeruginosa.Thisfact o
n
MICsofcolistinforthethreeindicatorstrainstestedwerealmost ismirroredbyanalysesofstrainsisolatedeitherfrompatientswith
D
identical(0.5to1mg/liter).Thereductionofviablecountswas long-termadministrationoffluoroquinolones,aminoglycosides, e
independentofthedosingschedule,withonce-daily(q.d.)twice- and(cid:2)-lactams,includingcarbapenemsandaztreonam,orfrom c
e
daily(b.i.d.),andthree-times-daily(t.i.d.)administrationsbeing colonizedCFpatients.Amarkedincreaseofresistancewasdem- m
equallyactive.However,thet.i.d.regimenminimizedtheemer- onstratedinthelong-term-treatedpatientsbutnotinthecolo- b
e
genceofresistancemosteffectively(229,230).Thesefindingswere nizedpatients(232).GrowthofahighlyadaptivebacteriumlikeP. r

confirmedinamurinethighandlunginfectionmodel(231).The aeruginosainCFlungsischaracterizedbyavariablenutrientand 2
7
MICs of colistin for the susceptible wild-type population range oxygen supply resulting in decreased oxygen consumption and ,

2
from0.032to8mg/liter,withamedianMICof0.25mg/liter(http: increasednitrogenutilization.Thesemetabolicshiftsconferresis- 0
//www.escmid.org/).TheserumAUCsfollowingaerosolizeddry tance to tobramycin and ciprofloxacin even without preceding 1
8
powderorliquidsolutionadministrationamountto200.7mg· exposuretotheseantibacterials(233).Inadditiontogrowthina
b
h/literand459.5mg·h/liter,respectively,soAUC/MICratiosof hostileenvironment,fluctuatinginflammatoryandimmunolog- y

20h(approximationfromthereportedrangesofcolistinPK/PD icalresponsestriggerthedevelopmentofvariousgrowthmorpho- g
u
surrogates)provideexposuresofisolateswithMICsofupto10 types,suchasabiofilmmodeofgrowthandsmallcolonyvariants e
s
mg/literfollowingdrypowderinhalationandapproximately20 (SCVs), and the establishment of a hypermutation phenotype t
mg/literfollowingadministrationofanebulizedsolution.Thus, (234).Highermutationratesinbiofilm-associatedP.aeruginosa
colistinmaylikelyexposetheentirewild-typepopulationtoade- havealsobeenfound(235).Dormantpersistingbacteriaaretol-
quatedrugconcentrations. eranttoantibacterialagentsbecauseofthereducedratesofDNA
ItisworthmentioningthatcalculationsofPK/PDtargets,i.e., replication,translation,cellwallsynthesis,andmetabolism.Per-
AUC/MIC ratios of fluoroquinolones, aminoglycosides, and sistersisolatedfromCFpatientswerefoundtocontributetore-
colistinontheonehandandT(cid:5)MICof(cid:2)-lactamsontheother lapsingchronicinfectionsandmayrepresentapoolofadaptively
hand,havebeenperformedbyusingtwodifferentmethods:the evolving organisms from which resistant mutants can emerge.
formerbydeterministicandthelatterbyprobabilisticmethods. The molecular mechanisms relating to antibiotic tolerance and
Thedeterministicmethodcorrelatesmeanpharmacokineticpa- resistance were reviewed recently (235–237). In general, muta-
rameterstoonenumericalvalue,usuallytheMIC value,sothat tionsplayanimportantroleintheadaptationofP.aeruginosato
90
variabilities in drug exposures are not taken into account. The thespecificenvironmentalconditionsinthelungsofCFpatients,
probabilisticmethodconsidersthevariabilitiesofdrugexposures and hypermutators can be isolated frequently. It was demon-
oftherelevantpatientpopulationsandthevariabilitiesofthesus- stratedthat37%ofCFpatientschronicallyinfectedwithP.aerugi-
October2014 Volume27 Number4 cmr.asm.org 761
Dalhoff
TABLE3PopulationanalysisoffourP.aeruginosastrainsisolatedin1983fromadultCFpatientstreatedtwicedailywith500mgciprofloxacin
orallya
Bacterialloaddeterminedbypopulationanalysis(log CFU/ml)
CLSIMIC 10
Strain Day (mg/liter) 1(cid:4)CLSIMIC 2(cid:4)CLSIMIC 4(cid:4)CLSIMIC 16(cid:4)CLSIMIC 64(cid:4)CLSIMIC
1 1 0.25 7.6 6.3 6.8 5.5 ND
3 1.0 ND ND 7.3 7.3 ND
5 2.0 ND ND 4.1 8.3 8.8
9 1 0.03 6.6 6.5 ND ND ND
3 1.0 ND 6.0 6.7 5.5 ND
5 1.0 ND ND 6.2 7.7 ND
19 1 0.12 8.3 8.6 8.6 6.5 ND
3 0.5 ND 7.5 7.5 6.3 5.9 D
5 1.0 ND 7.3 7.3 8.1 8.3 o
w
n
36 1 0.03 8.0 7.2 6.9 5.3 ND lo
3 0.25 ND 8.3 7.3 6.0 5.9 a
d
5 0.5 ND 5.5 6.9 9.1 9.3
e
aTheseisolateswereexposedinvitrotofluctuatingciprofloxacinconcentrationssimulatinganoraltwice-dailydoseof500mg.TheCLSIMICwasgeneratedbyselectingatleast d

threetofivewell-isolatedcoloniesofthesamemorphologicaltypeforpreparationoftheinoculum.Populationanalysiswasperformedbyselectingonlyonecolonyforthe fr
o
inoculumpreparation(viablecountsrepresentthenumberofcoloniesgrownonagarplatescontainingaciprofloxacinconcentrationoneortwotimes,etc.,theconcentration m
equivalenttotheCLSIMIC)(ND,notdetected;i.e.,viablecountswerebelowthelimitofdetectabilityof2log CFU/ml).Seereference97forthemethodusedtoanalyzethedata.
10
h
t
t
p
:
/
nosaharborhypermutators(16,20–22).Allthesefeaturesconsis- weretreatedin1983forthefirsttimeintheirliveswith500mg /c
tent with adaptive responses to growth in CF lungs create an ciprofloxacinorallytwicedaily(145)revealedthatthepreexpo- m
r
environment facilitating pathoadaptive mutations as well as in- sure isolates were heterogeneously susceptible to ciprofloxacin, .
a
creasedratesofresistanceacquisitionandperhapsalsotransmis- with MICs for the subpopulations ranging from (cid:3)1- to up to s
m
sibility(237,238).Althoughexposuretoeitherciprofloxacinor 16-fold the MIC of ciprofloxacin, as determined for the entire
.
tobramycin was adequate, hypermutator strains not only per- populationbytheCLSImethod(97).Thesestrainswereexposed o
r
g
sistedbutalsomultiplied(50,000-fold),incontrasttothenonhy- invitrofor5daystofluctuatingciprofloxacinconcentrationssim-
/

permutatorstrains(239),andacquiredantibioticresistancemore ulatinganoral500-mgb.i.d.dose.Viablecountsofsubpopula- o
n
frequently,followedbydeteriorationoflungfunction(240).Ex- tionswithMICsofonetofourtimestheoverallMICwereeither
D
posureofP.aeruginosatosubinhibitoryconcentrationsof(cid:2)-lac- reducedortotallyeliminatedduringexposuretofluctuatingdrug e
tams,aminoglycosides,andfluoroquinolonesledto3-to14-fold concentrationsover5days,whiletheviablecountsofhighlyre- c
e
increasesinmutationfrequencies(241).Thepracticalimpactof sistantsubpopulationswithMICsupto64timestheinitialMIC m
thepresenceofhypermutatorsinCFpatientsisthatwithinalarge increasedcontinuously(97).DatasummarizedinTable3illus- b
e
populationofpathogensintheCFlung,resistantsubpopulations tratetheshiftsinpopulationdensitiesofthevarioussubpopula- r

arepresentpriortothecommencementoftreatmentandwillbe tions.Althoughonday1,thehighlysusceptiblesubpopulations 2
7
rapidlyselectedassoonasthepatientistreated. withMICsrangingfrom0.03to0.25mg/literwerepredominant, ,

2
In addition, exposure of biofilm-grown P. aeruginosa to the lesssusceptiblesubpopulationswithMICs2,4,and16timesas 0
optimizedPK/PDparameterofanAUC/MICratioof384hfor high were isolated in smaller numbers. On consecutive days of 1
8
ciprofloxacinfailedtoreducetotalviablecountsandrapidlyse- exposuretofluctuatingciprofloxacinconcentrations,thesuscep-
b
lectedforresistancedevelopment(242).Thisstudysuggeststhat, tible subpopulations were eradicated, and the moderately resis- y

inagreementwiththedatadiscussedin“PreclinicalandClinical tantandresistantsubpopulationsprevailed(Table3).Thisfinding g
u
PK/PDStudiesinCFPatients,”above,conventionalandevenop- isremarkableinsofarastheseCFpatientsweretreatedwithcipro- e
s
timizedPK/PDmeasuresarenotpredictiveofantibacterialactiv- floxacinforthefirsttimeintheirlivesandyearspriortothelaunch t
ityinCFpatientsandfailtosuppressresistancedevelopment.As ofciprofloxacinandlevofloxacin,butstill,resistancealreadyex-
summarizedin“PreclinicalandClinicalPK/PDStudiesinCFPa- istedinthepretherapyisolates.Similarresultsweregeneratedfor
tients,”above,almostallisolates,exceptforthehighlysusceptible tobramycin;however,thepropensityforresistanceselectionwas
subpopulationsthatmayprevailduringtheearlyphasesofcolo- (cid:6)2ordersofmagnitudelowerthanforciprofloxacin(myunpub-
nization, are exposed to suboptimal concentrations of the anti- lisheddata).Thesedatawereconfirmedrecently:threeclinicalP.
bacterialsstudiedsofar,exceptprobablycolistin. aeruginosaisolateswereexposedtofluctuatingciprofloxacincon-
Furthermore,pathogenheterogeneitycontributessignificantly centrationssimulatingAUC/MICratiosrangingfrom55hto180
toresistancedevelopment.InvitroexposureofP.aeruginosato h.Resistantsubpopulationsalreadyexistedpriortoexposureand
fluctuatingenoxacinserumconcentrationsfollowingoraldosesof wereenrichedduringexposure(234).Agenomicanalysisofone
500 mg/day administered either once or twice daily for 2 days P.aeruginosastrainrevealedthat35differentgeneswereinvolved
resultedinrapidemergenceofresistanceduetotheselectionof inciprofloxacinresistance;10ofthesewereregulatedbycipro-
moderatelyresistantsubpopulations(243).Apopulationanalysis floxacin(235).Threestudies(145,243,244)demonstratedthat
offourP.aeruginosastrainsisolatedfromadultCFpatientswho heterogeneousbacterialpopulationsprovideareservoirforresis-
762 cmr.asm.org ClinicalMicrobiologyReviews