Gram-Positive Infections and OPAT:

Gram-Positive Infections and OPAT: Developments and Observations R. Andrew Seaton Gartnavel General Hospital Glasgow, Scotland, UK The views presented are the views of the speaker and not necessarily the views of Novartis

Disclosures Honoraria and educational grants received for presentations, investigator initiated studies and advisory boards (Novartis, Pfizer) Principle investigator (recent/current): DAP 002 (Cubist, Novartis) DAP-OST (Cubist) EU-CORE (Novartis)

The burden of inpatient i.v. antibiotic therapy 1/3 hospital admissions receive antibiotic treatment 1 1/10 receive i.v. antibiotics ~24,000 per million population/yr All specialties Integrated part of hospital care Necessitate hospital admission Prolong admission Some could be discharged if they do not require i.v. antibiotic therapy 2 Deep-seated 9% Infection types in acute admissions receiving i.v. antibiotics (n=381) 1 Unknown 9% Other 5% IAI 14% Not documented 4% SSTI 16% UTI 7% RTI 36% 1. Seaton RA et al. Int J Antimicrob Agents 2007;29:693 699 2. McLaughlin C et al. Q J Med 2005;98:745 752

Outpatient parenteral antimicrobial therapy (OPAT) Parenteral (i.v. or i.m.) antimicrobial administered on different days without an overnight hospital stay 12 1,2 If no oral agent available or appropriate Assures absorption, compliance and rapid achievement of therapeutic concentrations Proven effectiveness in: 1 Osteomyelitis SSTIs Endocarditis Meningitis 1. Tice AD et al. Clin Infect Dis 2004;38:1651 1672 2. Buxton ILO. In: Goodman & Gilman s The Pharmacological Basis of Therapeutics 11th edn. Brunton LL et al. (editors). 2006;1 39

OPAT: most common indications and pathogens Proportio on of all diagnos ses, % 25 20 15 10 5 0 OPAT outcomes registry 1996 2002 19.3 13.1 11.11 4.9 3.7 3.3 3.2 Pathog gens recov vered, % of total 25 20 15 10 5 0 22.2 5.9 50 5.0 49 4.9 42 4.2 38 3.8 2.3 2.1 Tice AD et al. Clin Infect Dis 2004;38:1651 1672

OPAT* in clinical trials: Complicated S. aureus bacteraemia 52% received OPAT (mean 14.9 days (1-49)) Proport ion of patients, % 100 80 60 40 20 0 36 MRSA 41 P<0.001 90 45 P=0.061 IE P<0.001 86 OPAT (n=103) IPAT (n=97) 56 54 47 P=0.001 19 19 18 9 4 Completed Successs Deaths Readmission SAE Rehm S et al. J Antimicrob Chemother 2009;63:1034 1042 ***Daptomycin or vancomycin or semi-synthetic penicillin

Phase IV studies: OPAT Daptomycin experience in CORE Clinical success rates for daptomycin OPAT or IPAT P=0.005 P<0.001 P<0.001 n=14 n=15 n=73 n=143 n=177 n=123 n=275 n=129 n=539 n=410 IE (n=29) Bacteraemia (n=216) cssti (n=300) Other (n=404) All (n=949) Martone W et al. Int J Clin Pract 2008;62:1183 1187 Cubicin Outcomes Registry and Experience (CORE ) a retrospective chart review of patients who have received daptomycin

Glasgow OPAT service Developed from 2000 onward ID led with team approach Clinical i l links Emergency department Diabetic clinic Orthopaedics i.v. admin: nurse or patient/carer Prospectively maintained database

Infections treated with OPAT in Glasgow Nu umber of patients Diagnoses for OPAT patients (n=2477) 350 Other 300 250 200 150 100 50 BJI SSTI 0 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010* Year *data to June Seaton RA. Unpublished data

Antibiotic agents used for OPAT Most frequently used antibiotic agents for OPAT (2279 episodes) 29% Ceftriaxone Teicoplanin Penicillin Daptomycin Ertapenem Amikacin Flucloxacillin Meropenem Pip-Taz Other 64% Seaton RA. Unpublished data

Teicoplanin in OPAT Indications 1 Resistant staphylococcal infections (CoNS or MRSA) Gram-positive infections with β-lactam allergy Failure with β-lactams Dosing regimen 2 Loading: 10-20 mg/kg for 3 days (inpatient or outpatient) Maintenance: 3 /week (butterfly) TDM at longest interval (72 hours) Target trough concentration for deep-seated infections: 20 30 μg/ml <20 μg/ml: increase dose or reduce interval (alt. days) >30 μg/ml: reduce dose or increase interval (2 or 1 /week) 1. Sanofi-aventis. Targocid (teicoplanin) Summary of Product Characteristics. 2010 2. Lamont E et al. J Antimicrob Chemother 2009;doi:10.1093/jac/dkp147

Skin and Soft Tissue Infection

Requires es IV Rx Surgery +/- HAI No Sepsis not Required Non-life Threatening Stable, Predictable Comorbidity Management Decisions i OPAT

OPAT treatment pathway for SSTIs: empiric antibiotic choice History of MRSA or Beta-lactam allergy? Yes Teicoplanin Clindamycin* *If Beta-lactam allergy or sensitive MRSA No Ceftriaxone Clindamycin or Flucloxacillin

Patient group direction for SSTIs Patient group : non-lifethreatening cellulitis amenable for home care and requiring i.v. therapy Uniform therapeutic management Suitable protocol in place Exclusions Prior physician review Indications for specialist review Indications for IVOST Trained, experienced staff Approved by ADTC IVOST, i.v. antibiotic oral switch therapy Seaton RA et al. J Antimicrob Chemother 2005;55:764 767

OPAT for cellulitis Propor rtion of pat tients, % Comparison of patients pre- and post-introduction of a nurse-led management protocol 100 80 60 40 20 0 Pre-intervention (n=230) Post-intervention (n=112) 99 100 97 6 7 4 7 0.4 19 2.6 5 4 Cure/ Re- Drug Surgery Medical improved admission reaction review Switch 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;55:764 767

Characteristics of 963 patients with OPAT managed SSTI Table 1. Patient baseline characteristics Median age in years (IQR ) 48 (37-64) Sex = female 396 41.1% Penicillin allergy 71 7.4% Referred from community (GP or Emergency department) 604 62.7% MRSA infection 47 4.9% Diabetes 85 88% 8.8% Vascular disease 30 3.1% Immunocompromised 49 5.1% Infection type: Cellulitis/ erysipelas Bursitis, with or without cellulitis Wound infection Infected ulcer Other 870 29 26 8 30 90.3% 3.0% 2.7% 0.8% 3.1% Managed via a nurse-led patient group direction 547 56.8% Seaton RA et al, P1333, 20th ECCMID 2010: Vienna, Austria.

Median duration of OPAT (days) OPAT (days) Duration of 14 13 12 11 Linear time trend in log (OPAT days) 10 Estmate 0.904 (0.886-0.922) p<0.0001 9 8 7 6 5 4 3 2 1 0 2001 2002 2003 2004 2005 2006 2007 2008 Year Seaton RA et al, P1333, 20th ECCMID 2010: Vienna, Austria.

Outcome of therapy by Primary OPAT Antibiotic Table 2. Outcome of therapy by primary OPAT antibiotic Outcome Ceftriaxone Teicoplanin All (n=811) (n=144) (n=963) Duration of OPAT in days 3 (2-4) 8 (3-12) 3 (2-5) (IQR*) Readmission 43 (5.3%) 15 (10.4%) 58 (6.0%) Significant adverse event 45 (5.5%) 21 (14.6%) 68 (7.1%) Progression of infection 21 (2.6%) 6 (4.2%) 27 (2.8%) OPAT failure* 85 (10.5%) 37 (25.7%) 124 (12.9%) *Switch of antibiotic, progression of infection or re-admission Seaton RA et al, P1333, 20th ECCMID 2010: Vienna, Austria.

Factors Associated with OPAT Failure (Switch of antibiotic, progression of infection or readmission) Univariate logistic regression Multiple logistic regression Variable OR (95% CI) P value OR (95% CI) P value Age (per additional 10 yrs) 1.13 (1.01, 1.25) 0.029 Gender = female 1.69 (1.15, 2.48) 0.0070 1.65 (1.10-2.47) 0.016 MRSA 3.63(1.90, 6.94) <0.00010001 Diabetes 2.26 (1.30, 3.92) 0.0045 2.02 (1.12-3.67) 0.020 Teicoplanin vs Ceftriaxone 2.95 (1.91, 4.57) <0.0001 1.87 (1.05-3.33) 0.033 Seaton RA et al, P1333, 20th ECCMID 2010: Vienna, Austria.

Factors Associated with increase in duration of OPAT Multiple linear regression Variable Estimate* (95% CI) P value Age (per additional 10 years) 1.03 (1.01-1.05) 0.0097 MRSA 1.47 (1.17-1.84) 0.0010 Vascular disease 1.29 (1.01-1.64) 0.041 Teicoplanin vs Ceftriaxone 1.32(1.16-1.50) 16-1 <0.00010001 Referred from community 0.91 (0.84-0.99) 0.021 Managed via PGD 0.71 (0.65-0.77) <0.0001 Infection type Bursitis vs cellulitis 1.81 (1.45-2.25) <0.0001 Wound infection vs cellulitis 1.74 (1.31-2.3) 0.0001 Other infection vs cellulitis 1.25 (1.00, 1.56) 0.0049 * Estimates: percentage change in number of days in OPAT: for example, an estimate of 1.10 means that, on average, a variable is associated with a 10% increase in the number of days of treatment. Seaton RA et al, P1333, 20th ECCMID 2010: Vienna, Austria.

Bone and joint Infection

OPAT for Bone and Joint Infections: Experience from a UK Teaching Hospital-based service 564 episodes Rx via OPAT 40 2001-2010 35 198 first patient episodes 2001-2005 84.3% positive microbiology 86% Gram +ve 51% Meticillin resistant Initial antibiotic therapy 30 PKI 25 20 15 71% Teicoplanin 5 26% Ceftriaxone 0 DFI OM PHI MWI 10 VOM Nature of Infection SA Mackintosh CL, White HA and Seaton RA, JAC (in press)

Definition of OPAT Failure in BJI When the prescribed OPAT course was not successful in eliciting either a cure or major improvement Continuation of IV Rx beyond the original course Unanticipated surgery Readmission or interruption of OPAT Rx Relapse or recurrence of infection Early Failure: within 4 weeks of discontinuation Late Failure: beyond 4 weeks or died during follow up Mackintosh CL, White HA and Seaton RA, JAC (in press)

Kaplan-Meier survival estimate of time to treatment failure for all patients per diagnosis.00 0.75 1. 0.50 0 0.25 0 MWI VOM SA PK/PH/OM DFI 0.00 0 20 40 60 80 100 analysis time (weeks) Mackintosh CL, White H.A, and Seaton R.A, JAC (in press)

Multivariate odds ratio of failing initial OPAT therapy Odds Ratio 95% C. I. P Diabetic foot infection 5.94 2.14-16.48 0.001 MRSA infection 3.30 1.15-9.46 0.026 CoNS/Diptheroids 4.53 1.18-17.47 0.028 80-89 89 yrs 5.32 1.41-20.11 0.014014 MRSA + mixed 4.55 0.84-24.78 0.079 Goodness of fit: log likelihood -66.5, r2 0.144 P=0.00040004 Mackintosh CL, White H.A, and Seaton R.A, JAC (in press)

Multivariate Cox regression model of significant factors from univariate analysis showing association with treatment failure over the follow-up period Hazard Ratio 95% C. I. P MRSA infection 2.23 1.05 3.29 0.009 Diabetic foot infection 3.77 2.17 6.56 <0.001 80-89 89 years 308 3.08 131 1.31 377 3.77 0003 0.003 Goodness of fit: log likelihood -280.44, X2 33.37, P<0.0001 Mackintosh CL, White H.A, and Seaton R.A, JAC (in press)

Endocarditis

OPAT Managed Endocarditis Results 63 episodes for 59 patients Median age 64 (54 72) 44% prosthetic ordevice relatedrelated 94% Left sided 49% home eadministered ed OPAT Mean OPAT days 35.5 2234bed days saved C. Duncan et al, FIS, Edinburgh 2010, Poster

Risk Factors for OPAT failure (P<0.05) Univariate Logistic regression Haemodialysis Nil Chronic renal failure CRP at beginning of OPAT OPAT via Hickman line C. Duncan et al, FIS, Edinburgh 2010, Poster

OPAT: future prospects and challenges Development potential depends on: Local economics and clinical needs Emergency medicine (SSTI, Hospital @ home) Oncology Cardiothoracic Minimizing i i i risks of HAI (CRBSI) (Endovascular) Alignment with other developing ambulatory care facilities Risk management and communication Cost-efficiency: logistics/funding, geography, politics and legal issues

Summary OPAT is safe and effective for a wide variety of Gram-positive infections in selected patients in UK Teicoplanin Rx is an independent risk factors for OPAT failure and prolongation of Rx in SSTI Female sex, diabetes, older age, vascular disease, diagnosis other than cellulitis, initial hospitalisation and MRSA infection associated with more complicated OPAT course in SSTI Reduced duration of therapy associated with management via PGD Independent risk factors for OPAT failure in BJI are Older age, MRSA infection and diabetic foot infection Early failure also in CNS/Diphtheroid infections Increasing utility of OPAT in management of Endocarditis

Conclusions As experience with OPAT grows in more complex patient groups, patient and infection- specific factors are emerging which may help predict success or failure of therapy Understanding of these factors may help guide patient selection (for OPAT) or refine treatment choices within OPAT http://www.e-opat.com/index.php

Acknowledgements Claire MacKintosh, Helena White, Chris Duncan,,,, Lindsay Semple, Emma Bell, Elspeth Lamont and Chris Weir

Infections treated with OPAT in Glasgow Nu umber of patients 100% Other 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Diagnoses for OPAT patients (n=2477) 80% SSTI 200101 200202 200303 200404 200505 200606 Year 200707 200808 200909 2010* BJI *data to June Seaton RA. Unpublished data