The OVIVA study demonstrated noninferiority for managing bone and joint infections (BJIs) with oral antibiotics. We report that 79.7% of OPAT patients being treated for BJIs at our center would be eligible for oral antibiotics, saving a median (IQR) 19.5 IV-antibiotic days (8.5-37) and GBP 1234 (569-2594) per patient

Bell, Lucy CK

Jones, Imogen

Kranzer, Katharina

Logan, Sarah

Marks, Michael

Morris-Jones, Stephen

Pollara, Gabriele

Rampling, Tommy

LSHTM Research Online

LSHTM Research OnlineMarks, Michael; Bell, Lucy CK; Jones, Imogen; Rampling, Tommy; Kranzer, Katharina; Morris-Jones, Stephen; Logan, Sarah; Pollara, Gabriele; (2019) Clinical and economic impact of implementingOVIVA criteria on patients with bone and joint infections in OPAT. Clinical infectious diseases. ISSN1058-4838 DOI: https://doi.org/10.1093/cid/ciz991Downloaded from: http://researchonline.lshtm.ac.uk/id/eprint/4654859/DOI: https://doi.org/10.1093/cid/ciz991Usage Guidelines:Please refer to usage guidelines at https://researchonline.lshtm.ac.uk/policies.html or alternativelycontact researchonline@lshtm.ac.uk.Available under license: http://creativecommons.org/licenses/by/2.5/https://researchonline.lshtm.ac.uk © The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. Clinical and economic impact of implementing OVIVA criteria on patients with bone and joint infections in OPAT  Michael Marks1,2, Lucy CK Bell1, Imogen Jones1, Tommy Rampling1, Katharina Kranzer2,3, Stephen Morris-Jones3, Sarah Logan1, Gabriele Pollara1,4  1Division of Infection, University College London Hospitals, UK 2Clinical Research Department, London School of Hygiene and Tropical Medicine, United Kingdom 3Department of Clinical Microbiology, University College London Hospitals, UK 4Division of Infection & Immunity, University College London, UK  Corresponding author Dr Gabriele Pollara, Division of Infection & Immunity, University College London, Cruciform Building, Gower Street, London, WC1E 6BT, United Kingdom, g.pollara@ucl.ac.uk    Downloaded from https://academic.oup.com/cid/advance-article-abstract/doi/10.1093/cid/ciz991/5585680 by London School of Hygiene & Tropical Medicine user on 24 October 2019 2  Abstract The OVIVA study demonstrated non-inferiority for managing bone and joint infections (BJI) with oral antibiotics. We report that 79.7% of OPAT patients being treated for BJI at our centre would be eligible for oral antibiotics, saving median 19.5 IV antibiotic days (IQR 8.5-37) and GBP 1,234 (IQR 569-2,594) per patient.   Keywords OVIVA; OPAT; IV antibiotics   Downloaded from https://academic.oup.com/cid/advance-article-abstract/doi/10.1093/cid/ciz991/5585680 by London School of Hygiene & Tropical Medicine user on 24 October 2019 3  Introduction Bone and joint infections (BJI) are conventionally managed with up to six week courses of antibiotic therapy (1–3). Alongside appropriate surgical intervention, intravenous (IV) antibiotics are commonly recommended to maximise tissue penetration (1,2). Delivery of IV therapy is increasingly provided by outpatient parenteral antimicrobial therapy (OPAT) services enabling earlier discharge from hospital (4). Although OPAT is effective and popular (4), it still carries risks of adverse events due to requirements for IV catheters (5) as well as the IV antibiotics being administered (6). Therefore, there has been great interest in the potential role of oral antibiotics in managing BJI. A multi-centre, pragmatic randomised controlled trial (OVIVA study) revealed switching from IV to oral antibiotic therapy within 1 week of commencing treatment for BJI was non-inferior, with respect to treatment failure, after 1 year of follow up compared with 6 weeks of IV antibiotics to treat a wide range of BJI (7). The study extrapolated reductions in IV antibiotic use and cost savings (7). These findings are potentially paradigm shifting, but the impact of implementing such a change on real-world practice remains unknown. We used the OVIVA study criteria to infer eligibility of patients with BJI in our OPAT service for oral antibiotic regimens and assess possible cost savings (5,8).  Methods Patient cohort and data extraction We utilised data collected prospectively into the OPAT database at University College London Hospitals (UCLH) NHS Foundation Trust (5,8). We included all patients with a BJI treated via OPAT between January 2015 and October 2018. We did not include patients with BJI managed outside of OPAT. Microbiological results were extracted from the laboratory information system.  The study was approved by the Audit and Research Committee at the Hospital for Tropical Diseases, UCLH, which stated that, as this was a retrospective review of routine clinical data, formal ethical approval was not required.  Downloaded from https://academic.oup.com/cid/advance-article-abstract/doi/10.1093/cid/ciz991/5585680 by London School of Hygiene & Tropical Medicine user on 24 October 2019 4   Case review and analysis Suitability for an oral regimen was determined by a consultant microbiologist not involved with the OPAT service (KK). Clinical diagnosis, microbiological data and allergies were reviewed to ascertain if an effective oral antibiotic regimen was available to replace the IV regimen. In the absence of microbiological investigations, we constructed empirical oral antibiotic combinations that included clindamycin, ciprofloxacin or rifampicin, aiming to cover the most common syndrome-associated causative organisms (table S2). We closely mirrored enrolment into the OVIVA study, considering patients not to be suitable for an oral regimen if they met any of the stated trial exclusion criteria (7). We classified patients’ surgical interventions using the categories presented in the OVIVA trial (7). We considered ineligible a subset of patients with a coagulase negative staphylococcal infection (CoNS) where linezolid and/or chloramphenicol were the only oral options, based on toxicities related to prolonged use of these drugs.  Statistical analysis We estimated reduction in days of IV treatment and economic savings by following the OVIVA protocol of IV therapy being administered for 1 week prior to oral antibiotic switch. We deliver OPAT via community nursing services, attendance at hospital clinics or self-administration, depending on patient requirements. We considered the median cost of delivering these services, the cost of therapeutic drug monitoring and a one-off cost of IV catheter insertion (table S1). We did not include costs of other equipment, such as flushes, nor did we assign any costs when patients self-administered. Daily antibiotic costs were derived from our hospital pharmacy list pricing for both IV and oral antibiotics (table S1). We did not include the cost of a weekly outpatient review, as we assumed this would be indicated irrespective of whether the patient was on IV or oral antibiotics. As many patients in our service already receive <6 weeks of IV antibiotics, we also estimated hypothetical savings if patients had all in fact received 6 weeks IV therapy. Statistical analysis was performed using R v3.4.2.  Downloaded from https://academic.oup.com/cid/advance-article-abstract/doi/10.1093/cid/ciz991/5585680 by London School of Hygiene & Tropical Medicine user on 24 October 2019 5  Results We identified a total of 133 patients treated for BJI through our OPAT service, comprising approximately a quarter of all our OPAT patients (5). Non-vertebral, native osteomyelitis was the most common type of BJI, with a range of other native and prosthetic joint infections also being treated (Table 1). The majority of patients (74%) underwent a therapeutic or diagnostic surgical procedure (Table 1). Oral antibiotic treatment, in line with OVIVA, was considered appropriate for 106 (79.7%) patients. The most common reason patients were not eligible was the absence of a suitable oral agent on antibiotic susceptibility testing (n= 14, 10.5%), including for 8/18 (44.4%) CoNS infections in our cohort (Table 1).  Within the ‘oral therapy eligible’ group (n = 106), the two most commonly used IV drugs were ceftriaxone (n = 56, 52.9%) and teicoplanin (n = 53, 50%) whilst carbapenems were used in a minority (n = 10, 9.5%) (Table S2). Overall a significant proportion of these patients also received rifampicin (n = 43, 40.6%) or ciprofloxacin (n = 39, 36.8%). Of 106 ‘oral therapy eligible’ patients, 85 (80.2%) had microbiological data available to guide antibiotic choice and 21 (19.8%) did not. A variety of hypothetical oral regimens could be constructed; rifampicin and ciprofloxacin (n = 43) was the most common. In the ‘oral therapy eligible’ group, the median duration of IV therapy was 26.5 days (IQR 15.5-44) compared with patients who did not meet the criteria for oral therapy who received a median of 43 days (IQR 29.5-58, p = 0.02). Both groups received the majority of IV therapy through the OPAT service (table 1). In our 106 ‘oral therapy eligible’ patients, we estimated 2,589 days of IV treatment saved (median per patient 19.5, IQR 8.5-37). Total cost saved was estimated at GBP 185,788 (median GBP 1,234, IQR 569-2,594 per patient). If all patients had in fact received 6 weeks of IV therapy, rather than median 26.5 days, then the estimated median cost saving was GBP 2,950 (IQR 1,725 – 2,950). Discussion OVIVA provided strong evidence that BJI could be treated with appropriate oral antibiotic regimens, but most patients were recruited from two specialist bone and joint infection centres (7). Making use of a well-defined and prospectively recorded cohort of patients receiving OPAT (5,8), we provide the first real-world Downloaded from https://academic.oup.com/cid/advance-article-abstract/doi/10.1093/cid/ciz991/5585680 by London School of Hygiene & Tropical Medicine user on 24 October 2019 6  assessment that implementation of comparable criteria rendered the majority (80%) of our BJI cohort eligible for oral antibiotic treatment. We had elected not to participate in OVIVA as our practice at the time of recruitment was shorter than six weeks of IV therapy, reflected in median IV therapy duration of 29 days (IQR 18-45). In addition, inpatients discharged directly on oral antibiotics following short IV antibiotic courses were not included in this cohort as they were not referred to the OPAT service. Therefore, IV antibiotic and cost savings may be greater in centres routinely using longer courses of IV therapy. Our estimation suggests that centres routinely using 6 weeks of IV antibiotics might anticipate savings closer to GBP 2-3,000 per patient.  We estimated that increased use of oral antibiotics would result in significant reductions in IV antibiotic use, with ensuing reduced risks associated with IV catheters (5), as well as substantial cost savings. Nevertheless, we acknowledge that oral antibiotics still carry risks of adverse events that need monitoring (9). Indeed, our cost analysis excluded any reductions in visits to the outpatient department for patients receiving oral antibiotics for this reason. We previously demonstrated that both drug and IV catheter associated adverse events are uncommon in our cohort (5) and the OVIVA study did not demonstrate differences in the incidence of serious adverse events between the two arms (7). Therefore, we did not factor into our cost calculations savings associated with reductions in adverse events related to IV antibiotics. However, the frequency of adverse events related to IV antibiotics in other cohorts may be greater, and IV antibiotic use may be associated with other unrecorded costs, such as complications with IV drug administration in the community requiring hospital review. We acknowledge these factors may render our costings an underestimate of the true savings of oral antibiotic therapy. Our findings were derived from a single OPAT centre, although data were collected prospectively as part of routine clinical care and BJI made up a comparable proportion of OPAT cases as elsewhere (10). Despite independent review, decisions on oral regimens could not account for patient-specific factors, such as unanticipated drug intolerances, and clinician-specific opinions, such as the suitability of beta-lactams for BJI (11). We may have overestimated eligibility for oral regimens if a requirement for IV therapy was not recorded, such as drug interactions and oral drug intolerance. We considered patients eligible for oral Downloaded from https://academic.oup.com/cid/advance-article-abstract/doi/10.1093/cid/ciz991/5585680 by London School of Hygiene & Tropical Medicine user on 24 October 2019 7  therapy when there was no microbiological diagnosis on sampling (19.8% of our cohort), which was comparable to patients in the OVIVA study (20%) (7).   In conclusion, we present the first assessment of the potential impact of implementing the OVIVA findings in a real-world OPAT setting. The majority of patients could have been placed on an oral regimen with significant cost savings.  The challenge remains to identify the optimal oral antibiotic regimens and durations to effectively deliver excellent clinical outcomes in treatment of BJI (12).    Downloaded from https://academic.oup.com/cid/advance-article-abstract/doi/10.1093/cid/ciz991/5585680 by London School of Hygiene & Tropical Medicine user on 24 October 2019 8  Acknowledgement We thank our dedicated group of OPAT nurses who have compiled our prospective data over the duration of this study and beyond. Funding This work was supported by the Wellcome Trust (WT101766 to GP and WT102807 to MM). All authors were supported by the University College London Hospitals Comprehensive Biomedical Research Centre Infection Theme. The funding agencies had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.  Conflict of interest The authors have no conflicts of interest.   Downloaded from https://academic.oup.com/cid/advance-article-abstract/doi/10.1093/cid/ciz991/5585680 by London School of Hygiene & Tropical Medicine user on 24 October 2019 9  References 1.  Waldvogel FA, Medoff G, Swartz MN. Osteomyelitis: a review of clinical features, therapeutic considerations and unusual aspects. N Engl J Med. 1970 Jan 22;282(4):198–206.  2.  Osmon DR, Berbari EF, Berendt AR, Lew D, Zimmerli W, Steckelberg JM, et al. Diagnosis and management of prosthetic joint infection: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis. 2013 Jan;56(1):e1–e25.  3.  Bernard L, Dinh A, Ghout I, Simo D, Zeller V, Issartel B, et al. Antibiotic treatment for 6 weeks versus 12 weeks in patients with pyogenic vertebral osteomyelitis: an open-label, non-inferiority, randomised, controlled trial. The Lancet. 2015 Mar 7;385(9971):875–882.  4.  Mitchell ED, Czoski Murray C, Meads D, Minton J, Wright J, Twiddy M. Clinical and cost-effectiveness, safety and acceptability of community intravenous antibiotic service models: CIVAS systematic review. BMJ Open. 2017 Apr 20;7(4):e013560.  5.  Underwood J, Marks M, Collins S, Logan S, Pollara G. Intravenous catheter-related adverse events exceed drug-related adverse events in outpatient parenteral antimicrobial therapy. J Antimicrob Chemother. 2018 Nov 20;74(3):787–790.  6.  Keller SC, Williams D, Gavgani M, Hirsch D, Adamovich J, Hohl D, et al. Rates of and risk factors for adverse drug events in outpatient parenteral antimicrobial therapy. Clin Infect Dis. 2018 Jan 6;66(1):11–19.  7.  Li H-K, Rombach I, Zambellas R, Walker AS, McNally MA, Atkins BL, et al. Oral versus Intravenous Antibiotics for Bone and Joint Infection. N Engl J Med. 2019 Jan 31;380(5):425–436.  8.  Marks M, Pollara G, Miller D, Bhatt S, Reynolds C, Gant V, et al. elCID: An electronic Clinical Infection Database to support integrated clinical services and research in infectious diseases. J Infect. 2015 Sep;71(3):402–405.  Downloaded from https://academic.oup.com/cid/advance-article-abstract/doi/10.1093/cid/ciz991/5585680 by London School of Hygiene & Tropical Medicine user on 24 October 2019 10  9.  Seaton RA, Ritchie ND, Robb F, Stewart L, White B, Vallance C. From “OPAT” to “COpAT”: implications of the OVIVA study for ambulatory management of bone and joint infection. J Antimicrob Chemother. 2019 Apr 15;  10.  Hatcher J, Costelloe C, Cele R, Viljanen A, Samarasinghe D, Satta G, et al. Factors associated with successful completion of outpatient parenteral antibiotic therapy (OPAT): a 10-year review from a large West London service. Int J Antimicrob Agents. 2019 Apr 12;  11.  Spellberg B, Lipsky BA. Systemic antibiotic therapy for chronic osteomyelitis in adults. Clin Infect Dis. 2012 Feb 1;54(3):393–407.  12.  Gilchrist M, Seaton RA. Outpatient parenteral antimicrobial therapy and antimicrobial stewardship: challenges and checklists. J Antimicrob Chemother. 2015 Apr;70(4):965–970.    Downloaded from https://academic.oup.com/cid/advance-article-abstract/doi/10.1093/cid/ciz991/5585680 by London School of Hygiene & Tropical Medicine user on 24 October 2019 11  Table 1 Characteristics of all OPAT patients being treated for BJI, categorised according to eligibility for receiving treatment with oral antibiotic regimens. *The total duration of IV therapy considering both inpatient and OPAT IV therapy combined.  ^These estimates were derived from scenario of patients receiving a week of IV antibiotics prior to changing to an appropriate oral antibiotic regimen that matched the findings of their microbiological investigations. PJI = prosthetic joint infection, OPAT = Outpatient parenteral antimicrobial therapy.   Overall (n = 133) Eligible for oral antibiotics  (n = 106) Not eligible for oral antibiotics (n = 27) Male  92 (68.1%) 74 (69.8%) 18 (66.7%) Age in years (IQR) 62 (46 – 71) 62 (42.5-72) 63 (49 – 68) Diagnosis Discitis/Vertebral OM 25 23 4 Diabetic Foot 8 6 2 Osteomyelitis 52 37 13 PJI Knee 21 19 2 PJI Hip 20 16 4 PJI Other 7 5 2 Surgical interventions  Debridement, antibiotics and implant retention 13 (9.8%) 9 (8.5%) 4 (14.8%) No implant or device present; debridement of chronic osteomyelitis not performed 17 (12.8%) 14 (13.2%) 3 (11.1%) No implant or device present; debridement of chronic osteomyelitis performed 22 (16.5%) 17(16%) 5(18.5%) Prosthetic joint implant removed 14 (10.5%) 12 (11.3%) 2 (7.4%) Downloaded from https://academic.oup.com/cid/advance-article-abstract/doi/10.1093/cid/ciz991/5585680 by London School of Hygiene & Tropical Medicine user on 24 October 2019 12  Prosthetic joint implant, one-stage revision 27 (20.3%) 19 (17.9%) 8 (29.6%) Removal of orthopaedic device for infection 16 (12%) 15 (14.2%) 1 (3.7%) Surgery for discitis, spinal osteomyelitis, or epidural abscess; debridement not performed  22 (16.5%) 18 (17.0%) 4 (14.8%) Surgery for discitis, spinal osteomyelitis, or epidural abscess; debridement performed  2 (1.5%) 2 (2.2%) 0 (0%) Reasons could not receive oral agent Antibiogram of causative organism did not offer viable oral regimen N/A N/A 14 (51.9%)  Staphylococcus aureus bacteraemia within the preceding 30 days  N/A N/A 7 (25.9%)  Fungal BJI N/A N/A 4 (14.8%)  Allergy to the only oral antibiotic regimens possible N/A N/A  2 (7.4%) Duration Total IV Therapy (Median, IQR)* 29 (18-45)  26.5 (15.5-44)  43 (29.5-58.5)  Duration IV OPAT (Median, IQR) 20 (12-34) 17 (11-32)  26 (19-42.5) Extrapolated reduced length of IV antibiotic therapy per patient (median days, IQR) ^ N/A 19.5 (8.5-37) 0 Extrapolated cost saving per patient (median GBP, IQR) ^ N/A 1,234 (569-2,594) 0 Extrapolated daily cost saving per patient (median GBP, IQR) ^ N/A 63 (29 – 133) 0   Downloaded from https://academic.oup.com/cid/advance-article-abstract/doi/10.1093/cid/ciz991/5585680 by London School of Hygiene & Tropical Medicine user on 24 October 2019

Clinical and Economic Impact of Implementing OVIVA Criteria on Patients With Bone and Joint Infections in Outpatient Parenteral Antimicrobial Therapy.

The OVIVA study demonstrated noninferiority for managing bone and joint infections (BJIs) with oral antibiotics. We report that 79.7% of OPAT patients being treated for BJIs at our center would be eligible for oral antibiotics, saving a median (IQR) 19.5 IV-antibiotic days (8.5–37) and GBP 1234 (569–2594) per patient

Marks, M

Bell, LCK

Jones, I

Rampling, T

Kranzer, K

Morris-Jones, S

Logan, S

Pollara, G

UCL Discovery

English

Clinical and Economic Impact of Implementing OVIVA Criteria on Patients With Bone and Joint Infections in Outpatient Parenteral Antimicrobial Therapy

https://researchonline.lshtm.ac.uk/id/eprint/4654859/1/Clinical%20and%20economic%20impact%20of%20implementing%20OVIVA%20criteria%20on%20patients%20with%20bone%20and%20joint%20infections%20in%20OPAT.pdf

Clinical and Economic Impact of Implementing OVIVA Criteria on Patients With Bone and Joint Infections in Outpatient Parenteral Antimicrobial Therapy.

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