IVOST: Principles and Prac3ce in OPAT

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1 IVOST: Principles and Prac3ce in OPAT Andrew Seaton Infec&ous Diseases Consultant & Lead Doctor NHS GG&C An&microbial Management Team, Queen Elizabeth University Hospital, Glasgow

2 Disclosures Co- chair OPAT Standing CommiLee Honoraria and educa&onal grants received for presenta&ons, inves&gator ini&ated studies and advisory boards (EuMedica, Novar&s, Pfizer, Cubist, MSD, Astrazeneca and Astellas)

3 What is the role of OPAT in modern healthcare? To improve quality and efficiency of care and reduce risk of harm in pa3ents with infec3on who would otherwise be hospitalised for IV therapy Infec&on specialist influence in the broader pa&ent popula&on Essen&al component of the modern integrated, inter- disciplinary infec&on service More efficient and appropriate use of inpa&ent resource

4 What OPAT is not An alterna3ve to thoughful person- centred medical care An easy or cheap op3on Safer (than oral Rx) BeMer (than oral Rx all the 3me)

5 OPAT is part of an AMS Strategy Start SMART then FOCUS Review the clinical diagnosis + con&nuing need for an&bio&cs at 48*- 72 hours Document a clear plan of ac&on: Stop an&bio&cs if there is no evidence of infec&on Switch an&bio&cs from IV to oral Change an&bio&cs: narrower spectrum or broader if required Con&nue + document next review / stop date OPAT Start Smart - Then Focus An&microbial Stewardship Toolkit for English Hospitals, PHE, Updated March 2015

6 Propor&on of Pa&ents (n >3,500) Receiving An&bio&cs in NHS GGC Hospitals 40 % Receiving an An&bio&c SPSP and Sepsis 6 % IV Abx % All Abx NHS GGC Annual PPS

7 8 Mean Length of IV Rx 7 6 Average MEDIUM LARGE SMALL

8 Recording of Dx and proposed dura&on of Rx % Recording % Target 60% Below Target Indication Duration NHS GGC Annual PPS

9 Appropriateness of an&bio&c choice All 4C Alert % GAP NHS GGC Annual PPS

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13 CAREFUL ASSESSMENT OF REFERRALS

14 IV An&microbial IVOST or STOP SWITCH/ Narrow IV OPAT

15 OPAT ac&vity date Excluded Included

16 OPAT ac&vity date Excluded Included

17 OPAT ac3vity QEUH June October Resource Not appropriate Accepted FOCUS

18 Stewardship at the OPAT gate Is OPAT appropriate for this pa&ent? Correct diagnosis Correct interpreta&on of microbiology Proper source control Planned (or completed) an&bio&c Rx ARE THERE IVOST OPTIONS?

19 OPAT Gate- keeping 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% BELFAST ST GEORGES OTHER IVOST/STOP Accepted OPAT2016 posters: Hederwick and Peirse

20 When to IVOST - Criteria Pa3ent - Func&onal gastrointes&nal tract Infec3on - Absence of infec&on where few data support oral therapy (e.g. bacterial meningi&s, brain abscess, infec&ve endocardi&s, SAB). Clinical improvement Organism - Suscep&ble to oral agent(s) An3bio3c - Good oral bioavailability and penetra&on to infec&on site at appropriate concentra&ons, lack of DDIs, allergy and other CIs (QTc)

21 SAPG Good Prac3ce Recommenda3ons for Hospital AMS in Scotland An&microbial Guidelines should include/ take into account: Discharge Planning Support early hospital discharge in suitable pa&ents either through &mely IV to oral switch or, when the facility exists, in selected pa&ent groups through OPAT programmes Where OPAT programmes exist AMTs need to ensure that they are governed by na3onal standards and that the principles of AMS are adhered to so as to minimise the poten3al for inappropriate prac3ce or unintended harm. SAPG, December 2014

22 IVOST?

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24 IVOST in OPAT Minimise need for IVC Minimise device related infec&on Minimise complexity of pa&ent management Improve pa&ent life- style Reduc&on in Cost Nursing &me Drug cost Evidence in key areas BJI SSTI Need to embrace new data

25 OPAT Condi&ons and IVOST opportunity Celluli3s Wound infec3on GNB/MDR UTI Diabe3c Foot OM Prosthe3c joint infec3on Spinal infec3on CNS Infec3on Endocardi3s Planned IVOST

26 OPAT IVOST scenarios Scheduled/Fixed Dura&on IV An&cipated IVOST Unplanned IVOST e.g. Endocardi&s, CNS, BJI, GNB/ UTI e.g. Celluli&s, e.g. Toxicity or line infec3on

27 OPAT IVOST scenarios An&cipated Based on improvement in clinical signs e.g. Celluli&s, Wound infec&on

28 Good Prac3ce Recommenda3ons SSTI should be reviewed daily by the OPAT team to op&mize speed of intravenous to oral switch.

29 Skin and Soe Tissue Infec3on

30 OPAT Pa3ent Group Direc3on for SSTIs: empiric an3bio3c Rx History of MRSA or Beta-lactam allergy? Yes Teicoplanin Clindamycin* Review Daily To Op3mise IVOST *If Beta-lactam allergy or sensitive MRSA No Ceftriaxone Clindamycin or Flucloxacillin

31 IVOST criteria for SSTI in OPAT Regression of infec&on Reduc&on in heat, erythema, indura&on, extent No SIRS Oral route not compromised No malabsorp&on CRP should not determine IVOST

32 Nurse- led Mx for OPAT SSTIs Comparison of patients pre- and post-introduction of a nurse-led management protocol Protocol management was associated with reduced duration of outpatient i.v. therapy (from 4 to 3 days, P=0.02) Seaton RA et al. J Antimicrob Chemother 2005;55:

33 SSTI: Median duration of OPAT (days) Duration of OPAT (days) Linear time trend in log (OPAT days) Estmate ( ) p< Year Seaton RA et al, IJAA, 2011

34 Emergency Department OPAT for SSTI AMS criteria for OPAT SSTI Number % Inclusion/ Exclusion criteria % Assessed Daily for IVOST 97 55% IVOST guideline 79 44% Aware of GPR 23 11% Abx approved by ASP % Clinical Pharmacist 94 53% BSAC, CoEM, SAM Survey 2015

35 Appropriateness of Timing of IVOST for SSTI in OPAT Appropriateness of IVOST Daily IVOST 3 day IVOST 7 Day IVOST

36 OPAT IVOST scenarios Scheduled/ Fixed Dura&on IV Either exclusive IV Rx e.g. Endocardi&s, meningi&s or Planned switch (poorly evidence based) e.g. certain BJI

37 Scheduled / Fixed Dura3on IV Rx Pa&ent Considera&ons Clinical improvement (usual at &me of OPAT referral) Able to swallow (usual) An&microbial Considera&ons Absorbed and penetrates to site of infec&on Organism (if known) is sensi&ve Allergy Host and DDIs

38 Gram nega3ve infec3ons Minimal evidence base & limited oral op&ons in MDRGNB Pivmecillinam and Fosfomycin not recommended for uuti or bacteraemia and short dura&on Rx for Lower UTI limited OPAT use Opportuni&es for IVOST in liver abscess/ other intra- abdominal based on radiological & biochemical improvement (Quinolones, Co- amoxiclav, Metronidazole)

39 Common Oral An3bio3cs in BJI IVOST Oral An3bio3c MRSA CNS Bone Penetra3on Biofilm ac3vity QTc prolong Other DDIs Penicillins Clindamycin Linezolid Doxycycline Rifampicin Sodium fusidate Quinolones

40 Dura3on of OPAT in days (median, IQR) by year for non- SSTI cases by year of OPAT Spearman's coefficient of rank correlation = -0.17, p < Year SSTI = 0 Barr et al IJAA, 2012

41 Spinal Infec3on IV Dura3on

42 (Common) IVOST OPAT Barriers in BJI Enterococcal infec3on High dose Amox (bone penetra&on) Linezolid (DDIs + Toxicity) Staphylococcal infec3on Quinolones (QTc prolonga&on DDIs) Rifampicin (DDIs, co- admin with Linezolid) BH Streptococcal infec3on Clindamycin and doxycycline resistance Linezolid (DDIs + Toxicity)

43 An3bio3c Choice & Admin Route and Clostridium difficile (CDI) Risk in OPAT Despite higher use of IV cephalosporins in OPAT, UK OPAT cohort studies suggest much lower rates of Clostridium difficile (0.05 per 1000 OPAT days) compared to hospitalised pa&ents. Could more prolonged oral an&bio&c therapy (par&cularly Quinolones and Clindamycin) increase Clostridium difficile (CDI) risk? Duncan et al. Int J Clin Prac 2012 Jun;34(3):410-7 OPAT with cerriaxone, a review

44 Conclusions OPAT is an important arm of AMS programme OPAT pre- assessment is cri&cal must include opportuni&es for streamlining of Rx including IVOST + stop Daily review to op&mise IVOST opportunity in SSTI during OPAT Criteria for IVOST in BJI, Intra- abdominal infec&ons Probably no IVOST in CNS, Endocardi&s

45 Acknowledgements Mark Gilchrist Abi Jenkins Tracey Guise BSAC OPAT Standing commilee NHS GGC OPAT Team past and present: Lindsay Semple, Fiona Robb, Claire Vallance, Liz Collison, Lee Stewart, Beth White, Neil Ritchie

46 WELCOME 2016 NATIONAL OPAT CONFERENCE #OPAT16

47 Resurgence of older oral therapies in OPAT: options for OPAT sparing Dr Carolyn Hemsley Consultant in Infectious Disease and Microbiology, Guy s and St Thomas, London

48 Why do we intravenous therapy? Evidence that IV better than oral or belief that it is superior Endocarditis Staph aureus bacteraemia CNS infection Bone and joint No oral option because of resistance profile dictates IV (or allergy issues) Problems with enteral route and absorbance Ensure patient compliance or choice

49 Why do we give oral therapy or IV oral switch? Evidence that oral is equivalent to IV Evidence or experience that oral works Ease Patient choice IV not possible and many more reasons.

50 GSTT OPAT patient episodes ( ) n = 411 BJI (173) DFI (74) discitis (27) vasc graft infection (20) IE (17) MSSA Bacteraemia (9) Mycotic aneurysm (9) cbilary/liver (6) intrabdominal collection (6) CNS (4) MSSA empyema (14) NecOE (14) pyelo/cuti (12) prostatitis (3) CMV (4) cssi (9) other (10)

51 Could I have used orals instead? Excluded IE, mycotic AA, MSSA BSI, BJI, DFI, discitis, cssi, CNS, CMV, few others Remaining 61/411 (~14%) vasc graft infection (20) MSSA empyema (14) pyelo/cuti (12) intrabdominal collection (6) cbilary/liver (6) prostatitis (3) 0 Diagnosis Could we have IV to oral switched sooner? Could/should we have consider any older less commonly used agents?

52 In which areas might oral therapy be an option? cuti ESBLs (12) Prostatitis ESBL/cipro resistance (3) Biliary infection/liver abscess polymicrobial or ESBL harbouring organisms (12) Should we have considered any of the following? Fosfomycin Pivemecillinam Chloramphenicol

53 Fofosfomycin Licensed indications: treatment of acute lower uncomplicated urinary tract infections in adult and adolescent females. AND prophylaxis in diagnostic and surgical transurethral procedures. Phosponic acid derivative available Iv and oral preparations. Bactericidal inhibits bacterial cell wall synthesis Single 3g dose orally (~ 5 per sachet). NICE 2015 suggest 2 doses in men CMax >4000 mg/l (urine) 26-32mg/L (serum) Mean half life 5.6 hours Maintain urinary conc >128 mg/l for hours (compare to non-licensed suggested Rx dose 2-4g qds IV for systemic infections)

54 Fofosfomycin Clinical breakpoints BSAC : uncomplicated UTI E coli and Proteus only S< 32 R > 32 mg/l EUCAST : uncomplicated UTI Enterobacteriacae uncomplicated UTI S< 32 R > 32 CLSI :uncomplicated UTI Enterobacteriacae and Enterococcus faecalis S< 64 R > 256 Wider spectrum of activity in vitro Consider MCI data for multiple organisms

55 Spectrum of activity for fosfomycin

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57 Resistance rates to fosfomycin All urine E coli isolates at GSTT 2015 (S < 32mg/L) (28%) 2568 (98.4%) Sens 220 (1.6%) Res Oxford , 474 E coli and Kleb 3% resistance German study 2014 n=499 E coli 98% susceptible Chinese study 2012 E coli ESBL 6.2% resistance German study CREs 2014 n=107 enterobacteriacae 72% susceptible GSTT using fosfomycin routinely for uncomplicated MDR UTI for ~ 5 years and as step down oral therapy for bacteraemic UTI in not transplant population

58 Could we use Fosfo in place of OPAT erta/temocillin for lower urinary tract infection? Observational prospective - Fos vs carbapenem (27 vs 20). Clinical failure equivalent (21/27 vs 19/20) J Chem ;355) Retrospective cohort study - 89 each arm. 30 day revisit rate same 14.6% (FT) vs 13.% (erta).erta longer course 10 vs 6 days. J Int Antimicrob Agents. 2016;47:269

59 Other evidence for clinical efficacy for oral Fosfomycin + MDR pathogens/cuti Retrospective study Follow up on 58. (JAC 2016;71:2563) 30% had stents of structural abnormalities 33% CKD sage 3 or greater Clinical cure in fosfo susc orgs 63% CKD only predictor of failure Retrospective > 1 dose for culture pos UTI with symptoms n=57 only 28 evaluated ( Chemotherapy 2016;62;100) 77.2% complicated UTI and 63% MDR 96% cure Retrospective study > I dose with MDR pathogen. N=44. VRE, Pseud, CPEs, ESBL (AAC 2012;56:5744) Microbiological cure rate 60% Solid organ transplant associated with failure Urethral stents associated with failure

60 When should you IV to oral switch in cuti or pyelonephritis? Licensing trials for Ertapenem 89% clinical cure rate average 4 days IV before oral switch Trial of Erta vs Ceftriaxone for Pyelo average was 5.6 days before IV to oral switch Effectiveness of oral antibiotics for definitive therapy of Gram-Neg bloodstream infections (JAA 2016;48:498) Retrospective cohort study over 4 years 362 episodes. Mean of 4.7 days of IV therapy and 9.1 oral. Univariate cox proportional hazards regression model liver cirrhosis, immunocompromised host and bioavailability of definitive oral antibiotic was associated with treatment failure. (failure rate 2% vs 12% vs 14% in high, med, low bioavailability)

61 Prostatitis 1. FOS gets in to prostate 26 participants prostatic levels from Bx post oral 3g dose mg/l detectable up to 17 hours post dose (non inflammed prostate) (CID 2014;58:e101) 2. SUCCESSFUL in salvage therapy 2 cases successfully treated with pos fosfo post failure with IV erta. Showed plasma concentrations of 5.3 mg/l +1.3 in chronic prostatitis 3g po od (CID 2015;61:114). Daily 3g dose 15 cases with Chronic bacterial prostatitis failed alternative therapy. 3g alternate days. 47% cure rate (AAC 2016;60;1854) Probably need 3g od dose. Dose escalation limited by GI Side effects

62 Summary for Genitourinary infection Excreted in urine in active form in high doses Evidence for use to Rx cuti but no comparative trial data for pyelo It s distributed to the kidneys, bladder wall, prostate, and seminal vesicles BUT significantly lower doses to urine. Concentrated in prostate, seminal vesicles and testes serum level not representative of tissue concentrations BUT every 72 hours may be incorrect dose schedule. Questions raised What is correct dose for conditions other than uncomplicated UTI? Alternative to po cipro for pseudomonal UTI?

63 Pivmecillinam Licensed indications: treatment of acute lower uncomplicated urinary tract infections in adult Active agent is mecillinam. Bactericidal inhibition PBP2 DOSE - UTIs in adults is 400mg single dose followed by 200mg tds (3/7 total course length) CMax mg/l (urine) after 400mg dose /- 0.65mg/L Serum EUCAST/BSAC/CLSI clinical breakpoints BSAC : uncomplicated UTI E coli, Klebsiella and Proteus only S< 8 R > 8 mg/l EUCAST : Enterobacteriacae uncomplicated UTI S< 8 R > 8 mg/l CLSI : Enterobacteriacae S< 8 R > 16 mg/l

64 Resistance rates >20 years of clinical experience in Nordic countries 20-30% prescriptions for cystitis in Nordic countries are pivmecillinam UK study ESBL E coli 6.2% resistance to mecillinam (JAC 2010;65:79) >20,000 E coli isolates Sweden 4% resistance in E coli We ve only just started testing GSTT (not routinely) in context of NEW PHE guidance as empirical therapy for UTI

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66 Clinical efficacy for pivmecillinam - MDR pathogens/cuti Pubmed search Pivmecillinam 291 hits Pivmecillinam and ESBL OR MDR : 14 hits only 2 were clinical treatment studies as opposed to MIC data Swedish study prospective follow up of patients with ESBL E coli treated with pivmec n=39 84% clinical cure rate, 80% bacteriological cure rate (JAC 2014;69:769) N=8 clinical response 8/8 (Microb Drug Resist 2012;18:189) Case report use as salvage therapy in ESBL E coli pyelo post carbapenem failure (2 year of abx) (Scand J Infect Dis 2016) NO publications in pyelo

67 Summary for pivmecillinam Excreted in urine in active form in high doses Evidence for use to Rx uncomplicated UTI Questions raised wrt OPAT sparing Oral step down in complicated UTI? What is the bilary excretion and could it be of use in bilary infection? rabbit study showing good levels in bile after enteral administration

68 Chloramphenicol Discovered in 1947 use in typhoid, meningitis 80% bioavailability and excellent tissue penetration (CNS, pleura, lung, ascites, synovial fluid, bile) Not excreted in active form into urinary tract so not good for UTI WHO list of Essential Medicines meningitis, neonatal sepsis Wide spectrum activity EUCAST/BSAC/CLSI clinical breakpoints Enterobacteriacae Staphylococci Streptococci (beta haem, pneumo, viridans) Neisseria Anaerobes (gram po and neg) Haemophilus

69 Chloramphenicol 1980s - Do not use chloramphenicol if safer effective medicines can be used Why? Aplastic anaemia idiosynchratic and dose independent ~1 in 20,000 40,000 cases AND Only ~10% case reversible. Typically 3-12 weeks after initiation of therapy (can present as early as 5 days) Separate from chloramphenicol bone marrow suppression which is reversible

70 Safety data Efficacy and safety of chloramphenicol: systematic review and meta-analysis of randomised controlled trials (JAC 2015;70:979) 66 RCTs ( ) included (involving 9711 patients). RCTs meningitis,resp tract, enteric fever, mediterranean spotted fever NO statistically significant differences in adverse events between Chloramphenicol and other abx including all haematological events except for anaemia (RR 2.8, CI )

71 Should we use it more? Polymicrobial infection Anareobic infections MDR gram negatives Complicated Staphyloccocal/streptococcal infections as alternative agent VRE infections (linezolid alternative) Suppression/as alternative to palliative OPAT?

72 GSTT OPAT sparing vasc graft infection (20) MSSA empyema (14) pyelo/cuti (12) intrabdominal collection (6) cbilary/liver (6) prostatitis (3) 0 Diagnosis Umm Fosfomycin 2/3 Fosfomycin stepdown Chloramphenicol Pristinomycin, Chloramphenicol

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