Oralantibioticsarenotalwaysstraightforward

OPATRegionalWorkshop

1stMay2018

FionaRobb,AntimicrobialPharmacistNHSGreaterGlasgow&Clyde

Introduction

•  DescribeNHSGGC’sOralvsIVAntibiotics(OvIVA)trialexperience•  DescribetheoptimaloralantibioticchoiceforadministrationviaOPAT

•  SummarisethechallengesassociatedwiththechoiceoforalantibioticsforOPAT

WithinNHSeachyear:•  120,000joints&fractureprocedures(BJIs)

–  ~2000(2%)post-opinfection•  ~5000diabeticfootosteomyelitis/infections(DFIs)

–  Cost£20–40,000perpatient•  Current‘goldstandard’practice;4–6weeksIVtherapy•  Emergingevidence&Cochranereviewsupportoralantibiotics

fortreatmentoftheseinfectionsBUTsmalltrials

Studydesign•  Multi-centre,randomised,openlabel,non-inferioritytrial•  RandomisedwithinONEweekofdiagnosis/startingIVtherapy

OralvsIVAntibiotics(OvIVA)Trial

OralvsIVAntibiotics(OvIVA)Trial

Inclusioncriteria•  Bone&Jointinfection(nativeandprostheticjoint)•  Diabeticpatientswithsofttissue/boneinfections•  TraditionallyrequiredatleastSIXweeksofIVantibioticsExclusioncriteria•  Staphylococcusbacteraemia/endocarditis•  TB/Fungal/ParasiticinfectionsEndpoint•  Treatmentfailure(microbiology/histology/clinical)•  Seriousadversedrugreaction/intolerance•  Linecomplications

OralvsIVAntibiotics(OvIVA)Results

•  1054randomisedpatients(Samplesize>1050)–  Across26UKcentres–  RandomisedevenlybetweenIV/oralgroups

•  Non-inferiorityobservedbetweenIVandOraltreatmentgroups•  Representsmajorimplicationsforpractice

–  Choiceoforalantimicrobialagent–  Safemonitoringfortoxicity/efficacy–  Patientfollowup

NHSGGC’sOvIVAResults

•  Total 43 patients participated in OvIVA –  19 Randomised to ORAL therapy –  13 Male (6 Female) –  Median age 53 years (range 30 – 83) –  Median number of prior IV days; 6 (range 0 – 7)

•  3 patients received > 7 days IV therapy; wards failed to switch patient as planned

–  Median intended duration of therapy; 8 weeks (range 6 – 24 weeks)

•  1 patient remained on long-term antibiotics (18 months) –  17 patients reviewed at 14, 42, 120 & 365 days

•  1 patient re-admitted, 1 patient unable to contact at 365 days

NHSGGC’sOvIVAResults;RangeofOvIVAindications

0

5

10

15

20

25

30

35

40

45

Osteomyelitis PJI Infected1ststagejointrev

SSTI Discitis Septicarthrtitis

Percen

tageofp

atients(%)

NHSGGC’sOvIVAResults;Microbiologyidentified

Staphylococcusaureus37%

Nilpositive26%

Coagulasenegative

staphylococci21%

Mixedorganisms6%

Enterococcussp.5%

Proteus5%

NHSGGC’sOvIVAResults;Rangeofantibiotictherapy

48%

26%

6%

5%

5%

5% 5%

Ciprofloxacin+Rifampicin

Ciprofloxacin+Clindamycin

Ciprofloxacin+Sodiumfusidate

Ciprofloxacin

Linezolid

Pristinamycin+Rifampicin

Flucloxacillin+Rifampicin

NHSGGC’sOvIVAResults;Patientoutcomes

CompletedNILcomplications,68%

Adversedrugreactions,26%

FailedtoattendFU,5%Re-admitted(1patient)

Remainedoutpatient(4patients)

NHSGGC’sOvIVAResults;Additionaloralantibioticconsiderations

•  Twothirdsofpatients(63%)hadpotentialdruginteractions–  Quinolones+calcium/ironsupplements–  Rifampicin+analgesia/anti-diabetic/cardiovasculardrugs

•  1in2patients(53%)requiredadditional/increasedmonitoring

•  1in5patients(21%)requiredoutpatientECGs–  Quinolones+SSRIs/TCAs

•  Changestoregularmedication(1patient,5%)–  DevelopedAKI;loopdiuretic,ACEinhibitorandmetforminstopped

OptimalPharmaceuticalCareinOPAT?

OPATGoodPracticeRecommendations2012

PragmaticguidanceforaneffectiveOPATservice:•  Antimicrobialmanagementanddrugdelivery

–  Antibioticselectionshouldbebasedonappropriateprescribingprinciplesratherthanpurelydosingonconvenience

–  Antimicrobialchoiceshouldbesubjecttoreviewbythelocalantimicrobialstewardshipprogramme

•  MonitoringofthepatientduringOPAT–  Assessmentofclinicalresponsetoagreedtreatmentplan–  Regular/appropriatebloodmonitoring(U&Es,LFTs,FBC),therapeuticdrugmonitoringetc.

OPATservicesshouldprovidetreatmentthatis“atleastasequivalenttoinpatientcare”

AChapmanetal.JAC,2012;67:1053–1062.

OralAntimicrobialManagementChallenges

Patientfactors•  Allergy•  Renal/hepaticfunction•  PMHxandconcomittantdrugs•  Drug/foodinteractions•  Pregnancy/Breastfeeding

Antibioticfactors•  Spectrumofactivity•  Mechanismofaction•  Pharmacokinetics(PK)/

Pharmacodynamics(PD)•  Therapeuticdrugmonitoring•  Stability/storagerequirements•  Unlicenseddoses/preparations

https://aidsinfo.nih.gov/understanding-hiv-aids/fact-sheets/21/95/what-is-a-drug-interaction-

ExampleofapatientseeninGlasgow’sOPATservice

PatientExample•  34yroldfemale,osteomyelitisRdistalfemur•  Jointaspirate;MRSA

–  Resistanttorifampicin,clindamycin,doxycycline–  Sensitivetociprofloxacin,linezolid,sodiumfusidate,vancomycin,daptomycin

•  PMHx;focalepilepsysincechildhood•  DHx;Carbamazepine,Tramadol,Amitriptyline•  SocialHx;UKresident2years,limitedEnglish,livesathomewithhusbandand2children

•  CommencedonIVVancomycinasinpatient

PatientExample•  Erraticandsub-therapeuticvancomycinconcentrations

•  Arrangedinterpretertodiscussdesirabletreatmentoutcomes/optimalvancomycindosing–  Patientabsentfromward–  Nurseexpressed‘she’sdisconnectedherpumpagain!’

•  Treatmentoptionstocomplete12weekstherapy–  OptimiseIVVancomycinasinpatient–  DischargeviaOPATonsuitableantimicrobialregimen

MHRACarbamazepineadvice,2009

Serum (non-adjusted) calcium low, Vitamin D levels not checked.

PatientExample

•  OptionsviaOPATtocomplete12weekstherapy?–  IVDaptomycin+PoSodiumfusidate–  PoLinezoild+PoSodiumfusidate

•  Linezolid+carbamazepine

–  Liaisedwithneurologytochangeanti-epileptics•  Linezolid+tramadol+amitriptyline

–  Gradualwithdrawalandassessmentofanalgesia

•  Linezolidmonitoring–  FBC,lactate,peripheralneuropathy,eyesight,?TDM

GGCOPATLinezolidUsage,Q32015–Q22017

0

50

100

150

200

250

300

350

400

450

2015 Q3 2015 Q4 2016 Q1 2016 Q2 2016 Q3 2016 Q4 2017 Q1 2017 Q2

DD

Ds

Calendar Quarter

OvIVA

Addedlactatemonitoring,Mar2017

OralAntibiotics OralAntibiotic/Dose Drugmonitoring/CounsellingrequiredRifampicin

450mg12hrly

•  Neverprescribedasmonotherapy•  Numerousdruginteractions(CYP3A4)•  LFTs2–3timesweeklyasinpatient,2weekspostdischargethenmonthly(e.g.transaminitis)

•  Maycolourallbodilyfluidsorange/redcolourDoxycycline

100mg12hrly

•  Avoidconcomitantoralironsupplements•  SeparateadministrationfromCa2+,Mg2+,Al3+,somenutritionalsupplements

•  Riskofoesophageal/GIulceration;takewithalargeglassofwaterwhensitting/standing

•  Avoiddirectsunlight/wearsunscreenClindamycin

600mg8hrly

•  Stopimmediatelyifdiarrhoeaoccursduringtherapy

OralAntibiotics OralAntibiotic/Dose Drugmonitoring/CounsellingrequiredCiprofloxacin(orLevofloxacin*)

750mg12hrly(or500mg12hrly)

•  Numerousdruginteractions(CYP1A2,not*)•  SeparateadministrationfromCa2+(not*),Mg2+,Al3+,Fe2+,Zn2+,somenutritionalsupplements

•  Avoidinpatientwithhxofseizureactivity;canlowerseizurethreshold

•  IncreasedriskofprolongedQTcinterval•  Counselontendonitisesphighdose,elderlypts

Linezolid

600mg12hrly

•  SeeNHSGGCguidance(IPCprotocol)•  WeeklymonitoringincludingFBC,lactate•  Riskofserotoninsyndrome;SSRIs,TCAsetc•  Opticneuropathy;stopifchangesineyesight•  Peripheralneuropathy>28daysprescribepyridoxine10–25mgod

•  Licenseddurationtherapy28days

Oralantibioticclangers!

•  Rifampicin+Sodiumfusidate•  Rifampicin+Linezolid•  Rifampicin+Doxycycline•  Rifampicin+DOACs/Warfarin•  Doxycycline+oralironsupplements•  Linezolid+SSRIs/TCAs/MAOIs•  Quinolones+Seizurehistory•  Ciprofloxacin+Duloxetine

Summary•  OvIVATrial

–  Oralantimicrobialtherapynon-inferiortoIVtherapy–  Mustcontinuetooptimise&individualisepharmaceuticalcare–  Enablespatientstogohomeearly/Avoidsadmission

•  OPATserviceischanging–  GoldstandardcareforBJI/DFIinfectionsisbeingchallenged–  Opportunitytochangeandexpandservice

•  Oralantimicrobialtherapyisnotstraightforward–  Clinicalpharmacistinputisessentialtosupportthischangeinpractice(choiceoftherapy,monitoring&followup)

–  ConcernthatpatientsmaybedischargedwithoutOPATmonitoring/followup