Vancomycin in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infection: End of an era?

Review

Vancomycin

in

the

treatment

of

meticillin-resistant

Staphylococcus

aureus

(MRSA)

infection:

End

of

an

era?

A.M.

Bal

a,

*

,

J.

Garau

b

,

I.M.

Gould

c

,

C.H.

Liao

d

,

T.

Mazzei

e

,

G.R.

Nimmo

f

,

A.

Soriano

g

,

S.

Stefani

h

,

F.C.

Tenover

i

a

DepartmentofMicrobiology,UniversityHospitalCrosshouse,NHSAyrshireandArran,Kilmarnock,UK

b

InfectiousDiseaseUnit,ServiceofInternalMedicine,HospitalUniversitariMu´tuadeTerrassa,Terrassa,Spain

c

DepartmentofMedicalMicrobiologyAberdeenRoyalInfirmary,Aberdeen,UK

d_{DepartmentofInternalMedicine,FarEasternMemorialHospital,Taipei,Taiwan}

e

DepartmentofPreclinicalandClinicalPharmacology,UniversityofFlorence,Florence,Italy

f

PathologyQueenslandCentralLaboratory,BrisbaneandGriffithUniversity,GoldCoast,Queensland,Australia

g

DepartmentofInfectiousDiseases,HospitalClinicofBarcelona,Barcelona,Spain

h

DepartmentofBio-MedicalScience,SectionofMicrobiology,UniversityofCatania,Catania,Italy

i

Cepheid,Sunnyvale,CA,USA

Contents

1. Introduction... 24

2. PlaceofvancomycininthetreatmentofMRSA... 24

3. Developmentofnewantistaphylococcalagents... 25

4. NeweragentsforthetreatmentofMRSA... 25

4.1. Oxazolidinones... 25

4.1.1. Linezolidandtedizolid ... 25

4.2. Cephalosporins... 26 4.2.1. Ceftaroline... 26 4.3. Newerglycopeptides ... 26 4.3.1. Telavancin... 26 4.3.2. Oritavancin ... 27 4.4. Lipopeptides... 27 4.4.1. Daptomycin... 27 5. Olderagents ... 27 6. Conclusions... 28 Acknowledgements... 28 References... 28 A R T I C L E I N F O Articlehistory: Received12December2012 Accepted24January2013 Keywords: hVISA MICcreep VISA A B S T R A C T

Infectionwithmeticillin-resistantStaphylococcusaureus(MRSA)continuestohavesignificantmorbidity andmortality.Vancomycin,whichhasbeenthemainstayoftreatmentofinvasiveMRSAinfections,has severaldrawbacksrelatedtoitspharmacologicalpropertiesaswellasvaryingdegreesofemerging resistance.Theseresistantsubpopulationsaredifficulttodetect,makingtherapywithvancomycinless reliable.Thenewer agentssuchaslinezolid,daptomycin, ceftaroline,andthenewerglycopeptides telavancinandoritavancin areusefulalternativesthatcouldpotentiallyreplace vancomycininthe treatment ofcertain conditions. By summarisingthe discussionsthat took place atthe III MRSA ConsensusConferenceinrelationtothecurrentplaceofvancomycinintherapyandthepotentialofthe neweragentstoreplacevancomycin,thisreviewfocusesonthechallengesfacedbythelaboratoryand bycliniciansinthediagnosisandtreatmentofMRSAinfections.

ß2013InternationalSocietyforChemotherapyofInfectionandCancer.PublishedbyElsevierLtd.All rightsreserved.

*Correspondingauthor.Tel.:+441563827422;fax:+441563825000.

E-mailaddress:abhijit.bal@nhs.net(A.M.Bal).

ContentslistsavailableatSciVerseScienceDirect

Journal

of

Global

Antimicrobial

Resistance

j our na l ho me pa g e : ww w . e l se v i e r . com / l oca t e / j ga r

2213-7165/$–seefrontmatterß2013InternationalSocietyforChemotherapyofInfectionandCancer.PublishedbyElsevierLtd.Allrightsreserved.

1. Introduction

Meticillin-resistant Staphylococcus aureus (MRSA) remains a keypathogenbothincommunityandhospitalsettings.Despitethe availability of antimicrobial agents such as vancomycin and teicoplanin, and more recently linezolid and daptomycin, both morbidityandmortalityfromMRSAinfectionsremainsubstantial

[1,2].Thepreviousexpertconsensusconference,whichtookplace

inFlorence,Italy,publishedapaperin2012[3].Thisreviewisa summaryofthediscussionsthat tookplaceattheInternational SocietyofChemotherapyMRSApanelmeetingheldinNaplesin March2012.

The last few years have seen a surge in the availability of antimicrobialagents active against MRSA, e.g. linezolid, dapto-mycin,tigecycline,telavancinandceftaroline.However,thespread of resistance determinants among MRSA has continued. Fortu-nately, there are still only a small number of reports of fully vancomycin-resistant MRSA. The spread of MRSA has been reducedinmanyareasoftheworld(e.g.theUK,USA),butserious MRSAinfectionsoftenstillresultinpooroutcomes[4].Thus,there isacontinuingneedtodevelopnewer,moreeffective antimicro-bialagentsandtoexplorestrategiesthatmayenhancethepotency ofexistingagents.Thismayinclude pharmacokinetic/pharmaco-dynamic (PK/PD) modelling studies, the use of combination therapy, and revisiting the current breakpoints. Antimicrobial susceptibilitytestingandtheuseofgenotypictestsforresistance gene detection need to be standardised and must include all appropriateresistance genealleles(e.g.mecAandmecC).Bovine andhumanstrainsofMRSAisolatedinDenmarkandtheUKwere reportedtocarryanovelmecAhomologue(originallypublishedas LGA251butnowrenamedmecC)inanoveltypeXIstaphylococcal cassettechromosome.Thisallelewaspresentinca.70%of mecA-negativeMRSAisolates[5].Howwidelythisgenewillspreadstill hastobedetermined.Furthercomplicatingantimicrobial suscep-tibilitytestingarereportsofmecA-positiveinvasiveisolatesofS. aureusthatappear tobesusceptible tooxacillinby phenotypic testing[6].Reasonsforsuchdiscrepanciesmayincludeinducible oxacillinresistanceandheteroresistance,oranon-functionalmecA determinantowingtomutation.Suchdiscrepanciesmayberare but,giventhelargedenominatorofMRSAinfections,theirimpact onclinicalmanagementcouldbesignificant.

2. PlaceofvancomycininthetreatmentofMRSA

S. aureus has evolved from susceptibility to virtually all antimicrobialagents,includingpenicillin,tomultidrugresistance, includingresistancetotheneweragentsdaptomycinandlinezolid. Thisincludesvaryingdegreesofresistance,suchas vancomycin-intermediateS. aureus(VISA) and heteroresistantVISA (hVISA), thatareachallengeboth tolaboratorydetectionand toclinical care.Itis likely that theemergence ofVISA from vancomycin-susceptibleMRSAisamultistepprocess.VISAemergesfromhVISA, atermthatisnotformallydefined[7].Thesephenotypicchanges areorchestratedatthegeneticlevelthroughaseriesofevents[8]. A paper by Cafiso et al. underlines the complex genetic mechanismsthatoccurinthetransitionof vancomycin-suscepti-ble MRSA to hVISA and VISA [9]. One mechanism of reduced susceptibilityinVISAstrainsisathickenedcellwall.Thisistheend resultofaprocessthatisachievedeitherbyproducingexcesscell wallprecursors,byreductioninautolysis,orboth[10].Thegenetic mechanismsthat underlie thesealterations include loss of agr functions(the agr locuscontains thehld gene encoding the

d

-haemolysin)andalterationsinatl,lytMandsceD,amongothers. Phenotypic changes include a high rate of cell wall turnover (enhancedexpressionofsceD)andachangetoapositivesurface charge(mprFupregulation).Theyresultinreducedsurfacebinding

of antimicrobial agents such as vancomycin and daptomycin. Furtherchangestotheregulatorymechanismsthat controlcell wallautolysis(i.e.downregulationofatlandlytM)giverisetocells with the VISA phenotype. Moreover, antimicrobial agents can induce these responses. For example, daptomycin leads to upregulationofthemprFgeneleadingtoitsexclusionfromthe cell by the increase in cell wall positive charges. Daptomycin-resistantmutantsadditionallydemonstrateincreasedexpression ofthedltoperon,whichincreasesthenetsurfacechargeonthecell. Acquisitionofa positivesurfacechargein daptomycin-resistant cellsisadynamicprocessduetoseveralmechanismsthatoperate inoppositedirections.Mishraetal.hypothesisedthattheinitial negative charge is a result of glutamate amidation on the cell surface, which leadstorapid entrapment of positivelycharged daptomycin molecules,followed bytheoverexpression ofmprF (perhapsasaresultofdaptomycin-mediatedinduction)leadingto acquisitionofpositivechargesonthesurface[11].

Whatever the genetic mechanisms, the ultimate biological outcome is reduced in vitro susceptibility to vancomycin. The extenttowhichthesechangesresultinclinicallyrelevantlevelsof resistance is uncertain, although cumulative data and opinion suggestthattheutilityofvancomycininclinicalpracticemaybe limited as a result of these evolutionary changes. Thus, in an observationalstudyof1994episodesofbacteraemiaduetoeither MRSAormeticillin-susceptibleS.aureus(MSSA),treatmentwitha glycopeptidewas anindependent predictor ofhigher mortality irrespectiveofmeticillinresistance[12].However,asubstudyof 532episodesfoundthatmortalitywassignificantlyhigherifthe vancomycinE-testminimuminhibitoryconcentration(MIC)ofthe causalisolatewas>1.5

m

g/mLregardlessof whethertreatment was with vancomycin or flucloxacillin [13]. The latter finding suggeststhatthecomplexchangesassociatedwiththeVISAand hVISA phenotypeshave aninfluenceon thecourseof infection quiteapartfromtheefficacyofglycopeptides.

EvidenceforareductioninvancomycinefficacyagainstMRSA strainsforwhichthevancomycinMICis2

m

g/mLis accumulat-ing; hence, the potential of clinical failure of vancomycin for treatinginfectionscausedbysuchstrainsshouldbeconsidered. Risk factors for infection caused by MRSA strains with higher vancomycinMICsincludeexposuretovancomycininthemonth prior toinfection,recent hospitalisationorsurgery,and bacter-aemiapriortoadmissiontoanintensivecareunit(ICU)[14,15]. Overcoming highvancomycin MICs by targeting higher trough levels has not been successful. In a prospective cohort study, Hidayatet al.reported thatdespiteachievingthetargettrough levelofatleastfourtimesthevancomycinMICoftheinfecting isolate, patientsinthehigh(2

m

g/mL) vancomycinMICgroup hadsignificantlylowerend-of-treatmentresponses(62%vs.85%; P=0.02)andanumericallyhighermortality(24%vs.10%;P=0.16) comparedwithpatientsinthelow(<2

m

g/mL)vancomycinMIC group,withhighvancomycinMICbeinganindependentpredictor ofpooroutcome[16].

The global emergence of strains of S. aureus with reduced susceptibility to vancomycin within what is considered the susceptible range is widely acknowledged. However, there is debateaboutwhether therehasbeenagradual increasein the MICsofvancomycinagainstS.aureusstrains,i.e.‘MICcreep’.The phenomenonofvancomycinMICcreep,mostlyinthesusceptible range, was first observed in the last decade, with several independentstudiesreportedincreasingMICsinS.aureusstrains over a variableperiod oftime [17–20]. However, othercentres foundnoevidenceofMICcreep[21,22]orevidenceofreductionin MICs over time [15]. Alo´s et al. demonstrated that such MIC changeswerenotobservedinareasoflowvancomycinuse[23]. Kehrmannetal.suggestedthatthephenomenonwasregional[24], whilst storage may result in reduced MICs, thus calling into

question theinterpretation of studies including stored isolates

[25,26].Finally,theideallaboratorymethodfordetectionofhVISA, whichisconceivablyresponsibleforevenhigherratesoffailureof vancomycin therapy, has yet to be established. van Hal et al. compared the macromethod E-test (MET), the glycopeptide resistance detection (GRD) E-test, the standard vancomycin E-test,vancomycinbrothmicrodilution(BMD)andVITEK1

2testing using population analysisprofiling utilising thearea under the concentration–time curve (PAP-AUC) as the standard. The sensitivitiesandspecificities ofMET,GRD E-test,BMD(withan MICcut-off2

m

g/mL)andstandardvancomycinE-test(alsowith anMICcut-off2

m

g/mL)were89%and55%,71%and94%,82%and 97%, and 71% and 94% respectively. The most cost-effective strategywasBMDsinglyorincombinationwithPAP-AUC[27].On theotherhand,therearepracticaldifficultiesincarryingour PAP-AUConaroutinebasis,andscreeningofisolatesonbrain–heart infusionagarcontainingteicoplanin5

m

g/mLfollowedbyMEThas beensuccessfullyusedfordeterminingtheprevalenceofhVISA

[28].Asistrueforanyothertest,thesensitivityandspecificity dependupontheprevalenceofhVISA.Althoughnomethodologyis perfect,itcouldbearguedthatthelikelihoodofhVISAisgreater whenthevancomycinMICis2

m

g/mLbyE-test,andlesserifthe MICislower,e.g.0.5

m

g/mL[29].

Loss of the

d

-haemolysin, referred to earlier as a potential geneticmarkerforhVISAdetection,andthediagnosticutilityof this phenomenon has been evaluated recently. Cafiso et al. investigated 37 clinical isolates of MRSA and found a high (>90%)degreeof sensitivity for discriminating hVISA and VISA strains from vancomycin-susceptible strains [30]. This method maybesuitableforcentreswithlimitedfacilitiestocarryout PAP-AUC.

ThequestionofwhethervancomycinMICcreepisassociated withclinicalfailureiscritical.Somepublishedstudiesreportan association between therapeutic failure and vancomycin MICs

[31–33].Incontrast,deSanctisetal.foundnoassociationbetween elevated vancomycin MICs and treatment failure for MRSA infections [34]. Walraven et al. notedthat the site of infection (e.g.endocarditisandpneumonia)ratherthanthevancomycinMIC waspredictiveoftreatmentfailure,presumablyreflectingthepoor tissuedistributionofvancomycin.Itisofnotethatthevancomycin MIC90(MICatwhich90%ofstrainsareinhibited)oftheMRSA strainsisolatedfrompatientsincludedinthisstudywas2

m

g/mL, makingtheinterpretationdifficult[35].

3. Developmentofnewantistaphylococcalagents

In a meta-analysis of 22 studies, vancomycin MICs were significantlyassociatedwithmortalityirrespectiveofthesourceof infection, although the effect was predominantly seen with bloodstreaminfections[oddsratio=1.58,95%confidenceinterval (CI) 1.06–2.37; P=0.03] [36]. Furthermore, the breakpoint for mortalitypredictionforMRSAinfectionsappearstobe1.5

m

g/mL (usingtheE-test),whichislowerthanthereducedClinicaland LaboratoryStandardsInstitute(CLSI)susceptibilitybreakpointof 2

m

g/mL(formerly4

m

g/mL).Withbloodstreaminfections,the effectonmortalitywasmorepronouncedininfectionswithstrains forwhichthevancomycinMICswere1.5

m

g/mL.HigherE-test MICs (which may remain in the CLSI susceptible range) may predicttreatment failurebecauseofpoorantimicrobialefficacy, particularlywhenthedruginquestionisvancomycin,givenitsPK/ PDproperties(e.g.theAUC:MICratioof>400isdifficulttoachieve at least in relation to strains with high MICs). However, it is possiblethattheelevatedE-testMICissimplyastrainmarkerfor changes ingenetic loci,suchas agrpolymorphisms, that affect organismmetabolismor virulencecharacteristics.Alternatively, hVISAstrainsmayhavebeenincludedinthemeta-analysisdata

yielding vancomycin E-test MICs 2

m

g/mL and this could potentiallyskewthedatainfavourofhighermortality.Whether thepresenceofhVISAstrainswasasignificantconfoundingfactor inthemeta-analysisisopen toquestion.Holmesetal.reported that while higher vancomycin MICs in MRSA strains were associated with treatment failure, the effect was also seen in MSSAstrainsforwhichtheE-testvancomycinMICswere1.5

m

g/ mL[7].Inotherwords,patientswithMSSAinfectionstreatedwith flucloxacillin had significantly worse outcomes if theinfecting MSSA strain gave a vancomycin E-test MIC result that was 1.5

m

g/mL[7].Despitethedrawbacksofthemeta-analysis[36]

and the fact that the use of vancomycin per se may not be associated withtreatment failure[7], thefindingsof the meta-analysis highlight concern with theuse of vancomycin for the treatmentofMRSAinfectionsinstrainsforwhichthevancomycin MICswereelevated(2

m

g/mLbyBMDor1.5

m

g/mLbyE-test). Thus,thereisagapintheclinicalmanagementofseriousMRSA infectionseventhoughitisnotalwayspossibletoidentify,with precision,patientswhowouldhaveanunfavourableoutcomewith vancomycin. Data on newer agents have made it possible to identifyareaswheretheseagentscouldbeusedwithsomebenefit. In the nextsectionwe discuss thedata on some ofthe newly licensedagentsactiveagainstMRSA.

4. NeweragentsforthetreatmentofMRSA

ThetrueefficacyoftheneweragentsagainstMRSAinfectionsin comparison with vancomycin is unclear. The small number of casesofvancomycin-resistantS.aureus(VRSA)infection,forwhich vancomycinisofnobenefit[37],isdwarfedbythenumberofVISA and hVISA cases reported. Several licensed and investigational agents appear to be effective for treating MRSA infections, although defining their precise use needs more study. In this section,wereviewsomeofthenewerantimicrobialsactiveagainst MRSA.

4.1. Oxazolidinones

4.1.1. Linezolidandtedizolid

Linezolidistheonlycurrentlylicensedoxazolidinoneinclinical practice.ItsfavourablePK/PDprofilesarewellknown.Linezolid wascomparedwithvancomycinina randomised,double-blind, multicentretrialinvolvinghospitalisedadultpatientswithMRSA pneumonia(hospital-acquiredorhealthcare-associated).Patients receivedlinezolid(600mgtwicedaily)orvancomycin(15mg/kg twicedaily)for7–14dayswithadjustmentofthevancomycindose basedon troughlevels.Clinical successattheend ofstudywas achievedin95(57.6%)of165patientsonlinezolidand81(46.6%) of174patientsinthevancomycingroup(per-protocolpopulation), adifferencethatwasstatisticallysignificant(95%CIfordifference, 0.5%to21.6%;P=0.042).Patientsonvancomycinweremorelikely toshowsignsofnephrotoxicitythanthoseonlinezolid(18.2%vs. 8.4%). The difference in clinical response was seen in various subgroup analyses. Thus, patients on mechanical ventilation receiving linezolid achieved a higher rate of clinical success (55.5% vs. 44.2%) as did patients with bacteraemia (44.4% vs. 31.6%).IntermsofvancomycinMIC,thedifferenceinresponsewas lessclearbecauseofseveralfactors.First,thenumberofpatients withinfectionscausedbystrainsforwhichthevancomycinMIC was>1

m

g/mLwasverysmall;second,theMICswereobtainedby theBMDmethodratherthanbytheE-testmethod.Nonetheless, thefactthatthedifferenceinclinicalresponsewassignificanteven whenavastmajorityofpatientshadMRSAinfectionwithstrains showinglowervancomycinMICs(1

m

g/mL)remains notewor-thy. Also, there was a correlation between microbiological responseandclinicalresponse,withpatientsonlinezolidshowing

a30%greaterclearanceofMRSA.However,therewasnostatistical differenceinmortality(Day60),incontrasttotheresultsofthe previous trials by the investigators. Thiswas due to improved survivalamongpatientstreatedwithvancomycin,whichmayhave beenduetogreaterattentionpaidtovancomycindosingduring thestudy periodorbecauseof theuseof salvagetherapy with linezolidinpatientsinthevancomycinarm.Thus,despitethelack ofademonstrablebenefitintermsofsurvival(andnotingthatthe study[38]wasnotaimedatdemonstratingsurvival),thechoiceof therapyforMRSAhospital-acquiredpneumoniamustbe consid-eredcautiously,particularlyduetoconcernofclinicalfailurewhen treatinginfections withstrainswithelevated vancomycin MICs butstillwithinthesusceptiblerange.Mostinternational guide-linesfallshortofrecommendinglinezolidasafirst-lineagentfor thetreatmentofMRSAhospital-acquiredpneumonia.Thesenew datamayimpactontheexistingrecommendations.

ThefirstdescriptionoflinezolidresistanceinS.aureusinvolved ribosomalmutationsinthe50Ssubunit.Anoutbreakoflinezolid resistancein12patientsinaSpanishICUwasdescribedin2010

[39].Strainsoflinezolid-resistantS.aureusisolatedfrompatients duringthisoutbreakharbouredtheplasmid-mediatedcfr (chlor-amphenicolflorfenicolresistance)generatherthantheG2675T ribosomal mutation observed in enterococci [40]. The cfr gene encodes a methyltransferase that catalyses the methylation of A2503inthe23SrRNAgeneofthelargeribosomalsubunit,thereby conferring resistance to five different groups of antimicrobial agents including pleuromutilins, chloramphenicol, florfenicol, oxazolidinones and clindamycin. Several congeners of linezolid [e.g.tedizolid (formerly torezolid)]demonstrateactivityagainst linezolid-resistantstrainsofstaphylococci.Approximately80%of MRSAstrainsareinhibitedbytedizolidat4

m

g/mL.Aninvivo MRSAmousepneumoniamodelcomparedtheefficacyoftedizolid to linezolid and vancomycin regimens. BALB/c mice were inoculatedwithMRSAand challengedwithtedizolid (20mg/kg once daily), linezolid (120mg/kg twice daily) or vancomycin (25mg/kgtwicedaily).Oncomparingthetreatmentgroupswith thecontrols,theinvestigatorsdemonstratedariseinbacterialload (1.1log)inthecontrolsandareductioninbacterialloadinallthe threetreatmentgroupsat24h,i.e.a1.2,1.6and0.1logreduction for tedizolid, linezolid and vancomycin, respectively, with no statisticallysignificantdifferencebetweenthetwooxazolidinones. Vancomycinwaslesseffectivethanbothoxazolidinones(survival of61.1%vs.94.7%inthetedizolidgroupand89.5%inthelinezolid group)[41].Similarly,amousethighinfectionmodel demonstrat-edcomparable efficacyfor both tedizolid and linezolid[42]. In studiesonhumanvolunteers,administrationoftedizolid(200mg oncedailyfor3days)ledtoconcentrationsintheepitheliallining fluidandalveolarmacrophagesthatwere,respectively,40and20 timeshigherthanmeanplasmafreedruglevels[43].

Arandomised,double-blind,phase2trialevaluated200,300 and400mgoforaltedizolid(oncedailyfor5–7days)inpatients withcomplicatedskinandskin-structureinfections(cSSSIs).MRSA isolates represented a large (76%) proportion of the bacteria recoveredfromthepatients.TedizolidMICswerelowercompared withlinezolid[MIC50(MICatwhich50%ofstrainsareinhibited) andMIC90valuesoftedizolidagainstS.aureus(MSSAandMRSA) wereboth0.25

m

g/mL,whilsttheMIC50and MIC90of linezolid wereof1

m

g/mLand2

m

g/mL,respectively].Theoverall microbi-ologicaleradicationratesandtheratesofclinicalcurewerehigh (both>95%forMSSAandMRSAinallthreedosagegroups)[44]. Thegreaterpotencyoftedizolid(basedontheMIC)couldturnout to be significant, particularly if linezolid resistance becomes widespread.Tedizolidwasactiveagainstlinezolid-resistantstrains forwhichthelinezolidMICsrangedfrom32

m

g/mLto>128

m

g/ mL.However,themajorityofstrainsinthisstudywere coagulase-negativestaphylococci(CoNS)[45].

4.2. Cephalosporins 4.2.1. Ceftaroline

Data from theCeftAroliNe Versus VAncomycinin Skin and Skin-StructureInfections(CANVAS)andtheFOCUStrialsarenow available[46–49].ThemeritsanddrawbacksoftheCANVAStrials were brieflydescribed in a previous consensuspaper [3].The FOCUStrialsdemonstratedthatceftarolineisaneffectiveagentin thetreatmentofcommunity-acquiredpneumonia,butMRSAis less of a concern in this diseasepopulation subset. Since the publication of theprevious consensusreports, several in vitro studies and caseseries have been completed focusing on the efficacy of ceftaroline against MRSA strains. Ho et al. [50]

investigated the outcome of ceftaroline for indications not coveredbyitscurrentlicensedindications,i.e.therapyofbacterial community-acquired pneumonia and acute bacterial skin and skin-structure infections [51]. Six cases of recurrent MRSA bacteraemia(whileonvancomycinordaptomycintherapy)and cases of endocarditis were reviewed by the authors [50]. CeftarolineledtoarapidclearanceofMRSAfromthebloodstream andsterilisation of heartvalves within2 weeksof ceftaroline therapy.Thesedataareencouraginggiventhehighfailureratefor S. aureus bacteraemia. Ceftaroline may fill two crucial unmet needs—bacteraemiaandendocarditis—givenitsfavourablePK/PD profile particularly at a higher frequency of administration (600mgthreetimesadayinsteadoftwicedaily).Ceftarolineis nowlicensedintheUSAandEurope.TheAssessingWorldwide AntimicrobialResistanceEvaluation(AWARE)Surveillance pro-gramme used the US Food and Drug Administration (FDA) susceptiblebreakpointof1

m

g/mLand98%ofS.aureusstrains hadaceftarolineMICatorbelowthiscut-offandnonehadMICs >2

m

g/mL[52].

4.3. Newerglycopeptides 4.3.1. Telavancin

Telavancinisalipoglycopeptidewithmultiplemechanismsof action.InacSSSIstudy,telavancinwasnon-inferiortovancomycin, achieving90%microbiologicaleradicationinpatientsinfectedwith MRSA[53].Rubinsteinetal.publishedthecombineddatafromthe Assessment of Telavancin for Treatment of Hospital-Acquired Pneumonia(ATTAIN)double-blind,phase3trials.Atotalof1503 patientswererandomisedtoreceivethestudymedications.Cure rates with telavancin in the all-treated population were 58.9% comparedwith59.5%forvancomycin(95%CIforthedifference, 5.6% to 4.3%) for the all-treated population. In the clinically evaluablepopulation (n=654),cure rateswithtelavancin were 82.4% compared with 80.7% with vancomycin (95% CI for the difference, 4.3%to7.7%).Inthesubsetanalysis,telavancinuse was associated with higher cure rates in patients with mono-microbialS.aureusinfectioncomparedwithvancomycin,butthe cureratesinpatientswithMRSAinfectionweresimilarforboth groups[54].Sinceitslicensingandavailability,therehavebeen furtherreportsontheclinicaluseoftelavancininspecificpatient groups. Stryjewski et al. published a post hoc analysis of the AssessmentofTeLAvancinincomplicatedSkinandskin-structure infections(ATLAS)trial,withatotalof1794patientsincludedin theirdataset.Patientswithmajorabscesses,infectivecellulitisand woundinfections, andthose withPanton–Valentine leukocidin-producing MRSA infections treatedwith telavancin had similar cureratescomparedwithpatientswhoreceivedvancomycin[55]. Thereareisolatedcasereportsclaimingsuccessfulclinicaluseof telavancininMRSAmitralvalveendocarditisfollowing daptomy-cin failure [56], in polymicrobial osteomyelitis in combination with rifampicin and meropenem [57] and in prosthetic joint infectioncausedbymeticillin-resistantCoNS[58].

4.3.2. Oritavancin

Oritavancinisa syntheticderivative of chloroeremomycin,a naturalglycopeptide.Likevancomycin,itinhibits transglycosyla-tionby binding totheterminal D-alanyl–D-alanine. Oritavancin

alsobindstothepentaglycylbridgeinthepeptidoglycanmoiety, whichexplainsitsactivityagainstvancomycin-resistantbacteria suchasvancomycin-resistantenterococci(VRE)andVRSA.Finally, oritavancin,liketelavancinbutunlikevancomycin,alsocausescell membranedisruption,resultingindepolarisationandcelldeath

[59].

Theinvitroactivityof oritavancinwasassessedagainst 866 Gram-positive isolates, confirming its potent activity against a widerangeofresistantMRSA,meticillin-resistantCoNSandVRE, includingthoseresistanttoneweragentssuchasdaptomycinand linezolid[60].

Withahalf-lifeof195h,oritavancinissuitableforonce-daily administration.Inaphase2multicentretrial,302adultpatients withcSSSIwererandomisedtothreegroupsthatreceivedadaily doseof200mgfor3–7days,asingledoseof1200mgoradoseof 800mg withan optional additional dose of 400mg on Day 5. ClinicalresponsewasassessedbetweenDays21and29.Thecure ratesintheevaluablepatientswere72.4%(55/76)inthedaily-dose group,81.5%(66/81)inthe1200mgsingle-dosegroupand77.5% (55/71)inthegroupwithinfrequentoptionaldosing.Inpatients withMRSAatbaseline,thecurerateswere78.3%(18/23),73.0% (27/37)and87.0%(20/23),respectively,althoughthestudydidnot have sufficient power to discriminate amongst the MRSA subgroup.There was no difference in thefrequency ofadverse effects in the three groups. Both single and infrequent dosing schedulesoforitavancinwereaseffectiveasonce-daily adminis-tration[61].TheFDA,however,didnotapproveoritavancinforthe treatmentofcSSSIasdatainrelationtoMRSAwerelacking.Since then,twostudies(SOLOIandSOLOII)havebeenregisteredwith ClinicalTrials.govandbothareexpectedtobeundertakensoon. 4.4. Lipopeptides

4.4.1. Daptomycin

Daptomycin is rapidly bactericidal against S. aureus and exhibitsconcentration-dependent killing in vitro. Its activity is dependent upon the availability of calcium ions. Calcium ions enhancetheactivityofdaptomycinintwoways:first,byinducing aconformationalchangeleadingtoacharge-dependent oligomer-isation and micelle formation; and second, by facilitating the binding of daptomycin with the acidic polysaccharide of the bacterial cell. Following this initial binding, the daptomycin molecule undergoes a structural alteration that allows it to penetratedeepintothemembrane layer.Ithasbeensuggested that the micelles dissociateand deliver individual daptomycin molecules to the cell surface, which subsequently oligomerise internally [62]. Resistance to daptomycin is associated with mutations in the phospholipid biosynthesis gene including cardiolipin synthase(cls2) and the CDP-diacylglycerol-glycerol-3-phosphate 3-phosphatidyltransferase (pgsA) gene. The mprF mutationpreviouslydescribedleadstothesynthesisoflysinated phosphatidylglycerol, thereby producing an overall positive surfacecharge thatthen causeselectrorepulsionof daptomycin

[63].In this context,availabledataon

b

-lactamantibioticsand daptomycincombinationtreatmentarerelevant.

b

-Lactamagents byreducingthepositivecellsurfacechargeareabletocounteract therepulsionofdaptomycin,thusfacilitatingthebindingofthe latter to the cell surface [64]. In vitro data lend support to daptomycin/

b

-lactam combinations: addition of oxacillin to a medium containing daptomycin delayed the emergence of daptomycin-resistant mutants in one such model [65]. Dhand etal.reporttreatingsevencasesofMRSAthatwererefractoryto

therapy withvancomycinordaptomycin withacombination of antistaphylococcal

b

-lactam agents and daptomycin. All seven cases had rapid clearance of bacteraemia, and the in vitro experiment showedenhancedbinding todaptomycin following exposure to nafcillin in one such strain. In addition, the investigatorsalsoconfirmedanetreductioninthesurfacecharge in the presence of oxacillin, and killing curves demonstrated enhancedkillingbytheantimicrobialcombination[66].Clinically, strainsexhibitingdaptomycin resistancearerarelyencountered among MRSA; however, emergence of daptomycin resistance amonghVISAstrainshasbeenreported inmultiplestudies.The genetic basisof resistance remains controversial. On theother hand,inotherstudiestheclinicaloutcomeofpatientstreatedwith daptomycindidnotappeartoberelatedtothevancomycinMIC

[67].Isolatesfrompatientswhoarelikelytoreceivedaptomycin therapyshouldbetestedforsusceptibilitytodaptomycinbyan MICmethodsuchasBMDorE-test.Novel strategieshavebeen used to treat patients with daptomycin-non-susceptible MRSA infections. Ina patientwithinfective endocarditis,combination therapywithdaptomycinandceftarolinewassuccessfullyusedto clear persistent bacteraemia [68]. High-dose daptomycin in combination with trimethoprim/sulfamethoxazole (TMP-SMX) hasalso beenusedto treatcomplicated infections with dapto-mycin-non-susceptible VISAstrains[69]. Inpatients treated for osteomyelitis, Moenster et al. reported significantly reduced recurrence rates with daptomycin compared with vancomycin (29% vs. 61.7%) [70]. Finally, salvage therapy with high dose (8mg/kg)daptomycinhasbeenevaluatedforthetreatmentof complicated bacteraemia,endocarditis,skinorwoundinfection, and bone and joint infection. Approximately 5% of patients developedbreakthroughinfectionwith daptomycin-non-suscep-tiblestrains[71].

5. Olderagents

Thedevelopmentandcommercialisationofnewantimicrobial agentsis complexandexpensive.Inthiscontext,several older agents have the potential to be clinically useful. A phase 2 randomised studycomparingloading (1500mg twicedailyon Day1followedby600mgtwicedaily)ornon-loading(600mg twicedaily)doseregimensoffusidicacidwithlinezolid(600mg twicedaily)wasrecentlyreported.Atotalof198patientswere enrolled. The high-dose fusidic acid regimen demonstrated comparable safety, tolerability and efficacy with linezolid for thetreatmentofacuteskinandskin-structureinfections.Inthe test-of-curegroup,thesuccessratesinthefusidicacid loading-dose group and the linezolid group in the intention-to-treat populationwere85.9%and94.8%,respectively[72].Schmitzetal. randomisedpatientswithuncomplicatedskinabscessesintotwo groups;eachgroupunderwentincisionanddrainagefollowedby eitherTMP-SMXorplacebo.TMP-SMXdidnotreducetreatment failure whencompared with placebo butwas associated with lower recurrence rates [73]. A retrospective investigation comparing TMP-SMX with vancomycin for the treatment of MRSAbacteraemiafoundsimilar30-daymortalitybetweenthe two groups (34.2% and40.8% respectively) anda numerically lowerrateofrelapseintheTMP-SMXgroup[74].Doxycyclineand chloramphenicolhaveundergonetrials,butinrestrictedsettings. The resurrection of older compounds,e.g.pleuromutilins, is a welcomedevelopment[75].Pleuromutilinswerediscoveredin 1951[76]andthefirstpleuromutilinforsystemicusewastested inaphase2trialin2011[77].Itisdifficulttopredictwhether someoftheseagentswouldbeofbenefitinthetreatmentofMRSA infections.Theirusemaydelaythespreadofresistancetothe neweragents.

6. Conclusions

Despite significant developments in the management and treatmentofMRSAinfections,therearestillimportantquestions thatremainunansweredregardingtheoptimaltherapyforthese infections.Even presumablyobjective assessments,suchas the determination of MICs for vancomycin, often show a lack of correlationbetweenvarioustestingmethods.Intheabsenceofa preciselaboratorymethodthatpredictstheefficacyofvancomycin (especiallyforhVISAstrains),theearlyuseofnewerantimicrobial agentsotherthanglycopeptidesmaybeamorereliableoption, particularlyforinvasiveinfections.Suchastrategyobviouslyhas drawbacks(e.g.cost)thatmustbebalancedagainstthebenefitof optimisedearlytherapy.Thechallengeistoavoidinappropriate empiricaltherapyforinvasiveMRSAinfectionsasthishasbeen showntobeassociatedwithhighermortality[4].

Funding None.

Competinginterests

AMBhasreceivedspeaker’shonorariafromPfizerandAstellas, hasparticipated in advisory boards of Pfizer, and has received educationalgrantsfromAstellas,PfizerandMSD.JGandIMGhave receivedresearchgrantsandspeaker’shonoraria/consultancyfees frommany manufacturersof MRSA-specificproducts. GRNis a memberoftheAustralianadvisoryboardsforWyeth,AstraZeneca andPfizer.ASisonthespeaker’sbureauofPfizerandNovartisand hasparticipatedinadvisoryboardsofPfizerandNovartis.FCTisan employeeandshareholderofCepheid.Allotherauthorsdeclareno competinginterests.

Ethicalapproval Notrequired. Acknowledgments

The authors acknowledge the supportprovided by Astellas, Becton Dickinson, Cepheid, Novartis and Pfizer towards the meetingheldbytheInternationalSocietyofChemotherapy,17– 18March2012,Naples,Italy.

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