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Oralantibioticsarenotalwaysstraightforward
OPATRegionalWorkshop
1stMay2018
FionaRobb,AntimicrobialPharmacistNHSGreaterGlasgow&Clyde
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Introduction
• DescribeNHSGGC’sOralvsIVAntibiotics(OvIVA)trialexperience• DescribetheoptimaloralantibioticchoiceforadministrationviaOPAT
• SummarisethechallengesassociatedwiththechoiceoforalantibioticsforOPAT
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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
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OralvsIVAntibiotics(OvIVA)Trial
Inclusioncriteria• Bone&Jointinfection(nativeandprostheticjoint)• Diabeticpatientswithsofttissue/boneinfections• TraditionallyrequiredatleastSIXweeksofIVantibioticsExclusioncriteria• Staphylococcusbacteraemia/endocarditis• TB/Fungal/ParasiticinfectionsEndpoint• Treatmentfailure(microbiology/histology/clinical)• Seriousadversedrugreaction/intolerance• Linecomplications
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OralvsIVAntibiotics(OvIVA)Results
• 1054randomisedpatients(Samplesize>1050)– Across26UKcentres– RandomisedevenlybetweenIV/oralgroups
• Non-inferiorityobservedbetweenIVandOraltreatmentgroups• Representsmajorimplicationsforpractice
– Choiceoforalantimicrobialagent– Safemonitoringfortoxicity/efficacy– Patientfollowup
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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
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NHSGGC’sOvIVAResults;RangeofOvIVAindications
0
5
10
15
20
25
30
35
40
45
Osteomyelitis PJI Infected1ststagejointrev
SSTI Discitis Septicarthrtitis
Percen
tageofp
atients(%)
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NHSGGC’sOvIVAResults;Microbiologyidentified
Staphylococcusaureus37%
Nilpositive26%
Coagulasenegative
staphylococci21%
Mixedorganisms6%
Enterococcussp.5%
Proteus5%
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NHSGGC’sOvIVAResults;Rangeofantibiotictherapy
48%
26%
6%
5%
5%
5% 5%
Ciprofloxacin+Rifampicin
Ciprofloxacin+Clindamycin
Ciprofloxacin+Sodiumfusidate
Ciprofloxacin
Linezolid
Pristinamycin+Rifampicin
Flucloxacillin+Rifampicin
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NHSGGC’sOvIVAResults;Patientoutcomes
CompletedNILcomplications,68%
Adversedrugreactions,26%
FailedtoattendFU,5%Re-admitted(1patient)
Remainedoutpatient(4patients)
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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
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OptimalPharmaceuticalCareinOPAT?
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OPATGoodPracticeRecommendations2012
PragmaticguidanceforaneffectiveOPATservice:• Antimicrobialmanagementanddrugdelivery
– Antibioticselectionshouldbebasedonappropriateprescribingprinciplesratherthanpurelydosingonconvenience
– Antimicrobialchoiceshouldbesubjecttoreviewbythelocalantimicrobialstewardshipprogramme
• MonitoringofthepatientduringOPAT– Assessmentofclinicalresponsetoagreedtreatmentplan– Regular/appropriatebloodmonitoring(U&Es,LFTs,FBC),therapeuticdrugmonitoringetc.
OPATservicesshouldprovidetreatmentthatis“atleastasequivalenttoinpatientcare”
AChapmanetal.JAC,2012;67:1053–1062.
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OralAntimicrobialManagementChallenges
Patientfactors• Allergy• Renal/hepaticfunction• PMHxandconcomittantdrugs• Drug/foodinteractions• Pregnancy/Breastfeeding
Antibioticfactors• Spectrumofactivity• Mechanismofaction• Pharmacokinetics(PK)/
Pharmacodynamics(PD)• Therapeuticdrugmonitoring• Stability/storagerequirements• Unlicenseddoses/preparations
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https://aidsinfo.nih.gov/understanding-hiv-aids/fact-sheets/21/95/what-is-a-drug-interaction-
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ExampleofapatientseeninGlasgow’sOPATservice
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PatientExample• 34yroldfemale,osteomyelitisRdistalfemur• Jointaspirate;MRSA
– Resistanttorifampicin,clindamycin,doxycycline– Sensitivetociprofloxacin,linezolid,sodiumfusidate,vancomycin,daptomycin
• PMHx;focalepilepsysincechildhood• DHx;Carbamazepine,Tramadol,Amitriptyline• SocialHx;UKresident2years,limitedEnglish,livesathomewithhusbandand2children
• CommencedonIVVancomycinasinpatient
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PatientExample• Erraticandsub-therapeuticvancomycinconcentrations
• Arrangedinterpretertodiscussdesirabletreatmentoutcomes/optimalvancomycindosing– Patientabsentfromward– Nurseexpressed‘she’sdisconnectedherpumpagain!’
• Treatmentoptionstocomplete12weekstherapy– OptimiseIVVancomycinasinpatient– DischargeviaOPATonsuitableantimicrobialregimen
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MHRACarbamazepineadvice,2009
Serum (non-adjusted) calcium low, Vitamin D levels not checked.
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PatientExample
• OptionsviaOPATtocomplete12weekstherapy?– IVDaptomycin+PoSodiumfusidate– PoLinezoild+PoSodiumfusidate
• Linezolid+carbamazepine
– Liaisedwithneurologytochangeanti-epileptics• Linezolid+tramadol+amitriptyline
– Gradualwithdrawalandassessmentofanalgesia
• Linezolidmonitoring– FBC,lactate,peripheralneuropathy,eyesight,?TDM
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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
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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
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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
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Oralantibioticclangers!
• Rifampicin+Sodiumfusidate• Rifampicin+Linezolid• Rifampicin+Doxycycline• Rifampicin+DOACs/Warfarin• Doxycycline+oralironsupplements• Linezolid+SSRIs/TCAs/MAOIs• Quinolones+Seizurehistory• Ciprofloxacin+Duloxetine
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Summary• OvIVATrial
– Oralantimicrobialtherapynon-inferiortoIVtherapy– Mustcontinuetooptimise&individualisepharmaceuticalcare– Enablespatientstogohomeearly/Avoidsadmission
• OPATserviceischanging– GoldstandardcareforBJI/DFIinfectionsisbeingchallenged– Opportunitytochangeandexpandservice
• Oralantimicrobialtherapyisnotstraightforward– Clinicalpharmacistinputisessentialtosupportthischangeinpractice(choiceoftherapy,monitoring&followup)
– ConcernthatpatientsmaybedischargedwithoutOPATmonitoring/followup