Key considerations choice of antimicrobial agents Dr Andrew Seaton

Transcription

1 Key considerations choice of antimicrobial agents Dr Andrew Seaton

2 Key Considerations choice of antimicrobial agents and managing the IV to oral switch R. Andrew Seaton NHS Greater Glasgow and Clyde, Scotland, UK

3 Disclosures Consultancy/ advisory or lectures for Novartis (Daptomycin), Pfizer (Linezolid), Astellas (Fidaxomycin), Astrazeneca (Ceftaroline) Principle Investigator: OVIVA study, EuCORE registry (Novartis sponsored) Council member British Society of Antimicrobial Chemotherapy, Co-Chair BSAC OPAT Standing Committee, Member Scottish Antimicrobial Prescribing Group, Chair Antimicrobial Utilisation Committee and Lead Antimicrobial Management Team, NHS GGC

4 The Dilemma of OPAT Potential conflict between the choice of the most effective and narrow spectrum agent and the need for convenience in dosing and administration. Antibiotic selection should be based on appropriate prescribing principles rather than purely dosing convenience Howden Grayson, Med J Aus 2002; 176: 440

5 OPAT Outcomes OPAT is different from traditional modes of Rx: community based oral therapy/ inpatient based IV therapy Outcome of both infection and process is important: the infection (cure, improvement, failure) the process (readmission, adverse events) Choice of antimicrobial agent may influence infection and process outcome HAI risk (probably) less Is it appropriate to transpose IP practice into OPAT setting? Complex dosing regimens may delay discharge

6

7 Good Practice Recommendations 3.2 The treatment plan is the responsibility of the OPAT infection specialist, following discussion with the referring clinician. It should include choice and dose, frequency and duration. Should take into account flexibility based on clinical response 3.3 Antimicrobial choice within OPAT should be subject to review by the local antimicrobial stewardship programme

8 Good Practice Recommendations 4.1 Patients with superficial skin and soft tissue infection should be reviewed daily by the OPAT team to optimize speed of intravenous to oral switch.

9 Antimicrobial Stewardship in OPAT: What is reasonable? Use narrowest spectrum agents within limitations of OPAT Don t use IV therapy when oral therapy would suffice SSTI ; Timely IVOST BJI; Trend towards shorter IV Rx, OVIVA study Avoid prolonged antibiotic therapy as an alternative to proper source control Engagement with local Antimicrobial Stewardship programme

10 Antimicrobial Considerations in OPAT Is there an evidence base for the use of the agent for the condition (in OPAT)? Are there any specific safety or monitoring requirements? Is there a convenient ambulatory dosing regimen? The ideal OPAT agent is one that optimises outcome, minimises adverse events and is patient focussed with minimal inconvenience

11 PK / PD Principles Acknowledgement: Fiona Robb

12 OPAT Evidence 2 RCTs of OPAT: 1999 (n=100, variety) and 2004 (n=200, SSTI). Mainly Cefazolin BD RCTs of new antimicrobials includes OPAT Rx pts Corwin et al BMJ doi /bmj EB; Board et al Aust N Z J Public Health 2000; 24:305

13 Proportion of patients, % OPAT* in clinical trials: Complicated S. aureus bacteraemia 52% received OPAT (mean 14.9 days (1-49)) 100 P< P< OPAT (n=103) IPAT (n=97) P=0.061 P= MRSA IE Completed Success Rehm S et al. J Antimicrob Chemother 2009;63: Deaths Readmission SAE ***Daptomycin or vancomycin or semi-synthetic penicillin

14 Distribution of patients within the Glasgow OPAT service ( ) a. OPAT patient episodes b. OPAT days Seaton and Barr, EJIM, 2013

15 Trends over 10 yrs Trend over time Referral from non-local hospital X 2 trend = Referral from secondary care X 2 trend = Co-morbidity X 2 trend = Non-SSTI infection X 2 trend = MRSA infections (as % of S. aureus) X 2 trend = G-ve infections (% of +ve cultures) X 2 trend = Self / carer antibiotic admin X 2 trend = p < p < p < p < p = p = p < Barr et al, IJAA 2012

16 Antibiotic agents used for OPAT Most frequently used antibiotic agents for OPAT (2279 episodes) Ceftriaxone Teicoplanin Other 29% 63%

17 Relative frequency of first line antimicrobial agent use in Glasgow OPAT service. 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% SSTI BJI CVS Bacterae mia CNS UTI Abdo. Abscess other ertapenem daptomycin teicoplanin ceftriaxone SSTI = skin and soft tissue infection; BJI = bone and joint infection; CVS = cardiovascular system infections including endocarditis and intra-cardiac device infections; CNS = cardiovascular system infections; UTI = urinary tract infections; Abdo. Abscess = Intra-abdominal abscess including liver abscess. Seaton and Barr, EJIM, 2013

18 Note: An ADR in an individual patient in some instances involved multiple drug reaction types (e.g. rash and fever); each ADR type is counted separately in frequency bars even where they stem from one ADR event. Relative frequency of adverse drug reaction (ADR) types, in all first OPAT episodes over 10 year study period. Rash Severe gastro-intestinal Chills or fever Leucopenia, thrombocytopenia Nephrotoxicity Hepatotoxicity Nature of ADR unrecorded Other Anaphylactoid Frequency of ADR type

19 % with ADR ADRs, Infection Type and AB Used Daptomycin Ceftriaxone Teicoplanin

20 Ceftriaxone in OPAT

21 Duncan et al, Int J Clin Pharm DOI /s z

22 Duncan et al, Int J Clin Pharm DOI /s z

23 Duncan et al, Int J Clin Pharm DOI /s z

24 Clostridium difficile and OPAT 4 per 3,356 UK OPAT episodes (0.1%) 2 per 2,233 Glasgow OPAT episodes (0.05 events per 1000 OPAT patient days) Chapman et al JAC 2009; 64:1316 Mathews et al JAC 2007; 60: 356 Seaton et al IJAA 2011; 38: 243 Barr et al IJAA 2012; 39: 407

25 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: 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: 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 Lamont E et al. J Antimicrob Chemother 2009;doi: /jac/dkp147

26 Lamont E et al. J Antimicrob Chemother 2009;doi: /jac/dkp147

27 Lamont E et al. J Antimicrob Chemother 2009;doi: /jac/dkp147

28 OPAT Outcomes and Antimicrobial Agent used Infection outcome Process (OPAT) outcome 3 main patient groups Skin and soft tissue infection Bone and joint infection Endocarditis

29 Skin and Soft Tissue Infection

30 Patient group direction for SSTIs Patient group : non-life-threatening 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:

31 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

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

34 Common OPAT Antibiotics in SSTI No. Duration (days) Progression (%) Readmission (%) Significant AE OPAT failure* Ceftriaxone (2-4) Teicoplanin (3-12) *Switch of antibiotic, progression of infection or readmission Seaton RA et al, IJAA 2011

35 Factors Associated with OPAT Failure* in SSTI (n=963) Multiple logistic Regression Variable OR (95% CI) P value Age (per + 10 yrs) NS Female 1.65 ( ) MRSA NS Diabetes 2.02 ( ) Teico vs Ceftriaxone 1.87 ( ) *Switch of antibiotic, progression of infection or readmission Seaton RA et al, IJAA 2011

36 OPAT SSTI: Factors Associated with increase in duration of OPAT Multiple linear regression Variable Estimate* (95% CI) P value Age (per additional 10 years) 1.03 ( ) MRSA 1.47 ( ) Vascular disease 1.29 ( ) Teicoplanin vs Ceftriaxone 1.32 ( ) < Referred from community 0.91 ( ) Managed via PGD 0.71 ( ) < Infection type Bursitis vs cellulitis 1.81 ( ) < Wound infection vs cellulitis 1.74 ( ) Other infection vs cellulitis 1.25 (1.00, 1.56) * 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, IJAA 2011

37 OPAT SSTI: Antibiotic therapy Nurse led IVOST effective and associated with reduced duration of IV Rx OPAT failure and Teicoplanin confounded by another variable? Teicoplanin less effective / more adverse events? Less subject to daily IVOST review therefore longer therapy? Alternative therapies when ceftriaxone contraindicated

38 Bone and joint Infection

39 Multivariate odds ratio of failing initial OPAT therapy Odds Ratio 95% C. I. P Diabetic foot infection MRSA infection CoNS/Diptheroids yrs Goodness of fit: log likelihood -66.5, r P= Mackintosh CL, White H.A, and Seaton R.A, JAC 2011

40 Kaplan-Meier survival estimate of time to treatment failure for all patients per diagnosis MWI VOM SA PK/PH/OM DFI analysis time (weeks) weeks Mackintosh CL, White H.A, and Seaton R.A, JAC 2011 number at

41 Hazard Ratio from Survival analysis (Cox regression) for the association of the initial IV Antibiotic with failure over the follow up period Initial IV Rx No. No. Failing Teicoplanin Hazard ratio Ceftriaxone Other 5 1 CI p

42 Endocarditis

43 OPAT Endocarditis Outcome Definitions OPAT failure (all OPAT episodes). Composite definition, any of: a) unplanned readmission or surgery during OPAT; b) adverse drug reaction leading to switch/readmission; and c) development of antibiotic resistance. Adverse Disease Outcome (ADO) (first OPAT episode). EXCLUDED: palliative intent cases; undetermined cause of death Definition of ADO: Endocarditis related death or suspected relapse at any time following OPAT completion / failure.

44 Baseline Characteristics: OPAT Endocarditis Characteristics of cohort 80 OPAT episodes (in 77 patients) Age in years, median (range) 60 (22 to 88) Male % Past medical history Previous episode of endocarditis % Adult congenital heart disease 7 8.8% Ischaemic heart disease % Cardiac failure % Chronic kidney disease % Immunosuppressive drugs % Current alcohol abuse 6 7.5% Site of infection Cardiac device related infection 4 5.0% Aortic valve % Prosthetic valve % Left sided % Septic emboli (pre-opat) %

45 Microbiology Microbiology N=80 % Viridans Streptococci % Oral Streptococci % Coagulase-negative Staphylococci % Methicillin sensitive S. aureus % No growth % Enterococcus 5 6.3% Mixed growth 3 3.8% MRSA 3 3.8% HACEK 2 2.5% Other 2 2.5% Unknown 1 1.3%

46 OPAT Antibiotics in Endocarditis Characteristics of OPAT procedures in cohort N = 80 Antimicrobial Ceftriaxone % Teicoplanin % Daptomycin % Flucloxacillin 4 5.0% Other 2 2.5%

47 Associations with OPAT failure Variable Failed n = 25 (31.3%) Completed n = 55 (68.7%) Multivariate analysis* OR CI P Cardiac failure or CKD 14 (63.6%) 8 (36.4%) Teicoplanin 12 (67.7%) 6 (33.3%) Specialist referral 17 (25.8%) 49 (74.2%) Also significant on univariate: Prosthetic valve, Median delay to IV start, per day (IQR), Glycopeptide-indicated organism, Implanted device, Streptococcal organism; ceftriaxone use. Not significant on univariate: Age; sex; other co-morbidities; S. aureus; left sided endocarditis; aortic valve endocarditis. *Logistic regression: stepwise backwards selection; factors retained in the model if P < 0.1. χ 2 = 30.3, full model 2 log likelihood = 63.6, P <

48 Reasons OPAT failure by antibiotic Endocarditis deterioration Other medical cause readmission Adverse drug reaction Venous catheter complication Antimicrobial resistance Unknown Teicoplanin (n=18) Ceftriaxone (n=45) Other (n=17)

49 Adverse Disease Outcome by prior OPAT failure Association of OPAT failure with subsequent Adverse Disease Outcome Hazard Ratio 4.78; p = (Log rank test)

50 OPAT and Endocarditis IE treated successfully in OPAT including some high risk features. History of cardiac or renal dysfunction may be unsuitable for OPAT, or require higher intensity monitoring. Increased risk of OPAT failure in Teicoplanin-treated patients, independent of microbiological aetiology and co-morbidity changed practice in Glasgow OPAT.

51 Frequency of first choice parenteral agent used in OPAT over 10 years (ceftriaxone and teicoplanin excluded). IM Penicillin preparation Daptomycin Ertapenem other combo Flucloxicillin Amikacin Non-antimicrobial Piperacillin-Tazobactam Meropenem or imipenem Amphoteracin B Anti-viral Amoxicillin or co-amoxiclav Gentamycin Vancomycin Ceftazadime Doxycycline Ben. Penicillin Colistin Frequency

52 Daptomycin in OPAT EuCORE study 550 (12%) of cohort Rx via OPAT over 5.5 yr period Prior AB Rx in 78% (48% prior Rx failure) SSTI, BJI, Prosthetic device-related and Endocarditis Concomitant Rx in 41%

53

54 28 days

55 Daptomycin-related adverse events in OPAT 15% AEs (86% mild/moderate) 9% ascribed to Daptomycin CPK increase in 1.5% Asthenia in 1.3% and Diarrhoea in 0.9% 3.1% discontinued CPK increase in 0.4% and Rhabdomyolysis in 0.4% 3.1% SAEs CPK/Rhabdomyolysis in 0.6% (all resolved) 2 deaths not related to Daptomycin

56 Ertapenem Carbapenem: Not Pseudomonas, Enterococci, Resistant G+ve infection ESBL infections Deep seated: First choice UTI: If no oral Rx possible (TMP, Nitrofurantoin, Pivmecillinam, Fosfomycin) Diabetic foot infection Intra-abdominal infection including liver abscess

57 Amikacin in OPAT Concentration dependent bactericidal activity Multi-drug resistant (MDR) mycobacterial infection inc. MDR-TB Alternative agent when drug toxicity or malabsorption Aminoglycoside of choice in NHS GGC Less susceptible to aminoglycoside inactivating bacterial enzymes Tuberculosis bacilli grow and multiply slowly Administer thrice weekly Therapeutic drug monitoring Adverse drug reactions Nephrotoxicity; monitor renal function weekly Ototoxicity; audiometry test every fortnight Acknowledgement: Fiona Robb

58 Current Amikacin Dosing Guidelines OPAT guidelines based on Peloquin et al 1,2 Outpatient 25 mg/kg three times weekly Amikacin concentration targets Outpatient Cmax mg/l Peloquin recommends 2 hr, 6 hr post dose and trough plasma concentrations In practice; weekly 1 hr post dose and trough plasma levels OPT; Pharmacokinetic parameter estimation programme MSc project has validated current practice 1. Peloquin C. Therapeutic Drug Monitoring in the Treatment of Tuberculosis. Drugs 2002; 62: Peloquin C. Using Therapeutic Drug Monitoring to Dose the Antimycobacterial Drugs. Clinics in Chest Med 1997; 18: Acknowledgement: Fiona Robb

59 Meropenem in OPAT Eliminated via kidneys Renal impairment ( dose) Drug interactions Sodium valproate levels Bactericidal Inhibit bacterial cell wall synthesis (PBPs) In vitro PK/ PD data Exhibits T > MIC Some concentration dependent killing Post antibiotic effect Acknowledgement: Fiona Robb

60 Meropenem in OPAT Bronchiectasis patients Persistent/progressive lung condition Intermittent infective exacerbations with increasingly resistant organisms e.g. pseudomonas spp Meropenem 3g IV once daily 1, 2 Ensure T > MIC at least 40% of dosing interval Cmax/MIC for SPC doses only 2.5 hrs PAE for gram -ve bacteria 1. Darley ESR. Use of meropenem 3g once daily for outpatient treatment of infective exacerbations of bronchiectasis. JAC 2000; 45: Bowker KE. Bactericidal activity, post antibiotic effect and modified controlled effective regrowth time of meropenem at high concentrations. JAC 1996; 38: Acknowledgement: Fiona Robb

61 Meropenem in OPAT MIC 0.5 mg/l correlates best with efficacy Acknowledgement: Fiona Robb

62 Independent Risk Factors for Line Complications during OPAT OR P value Line Infection Increasing duration of OPAT (44 vs 38 days) Other line events Flucloxacillin vs other Tunnelled Central line vs Midline PICC vs midline Barr, et al EJClinMicroID, 2012

63 Conclusions Antimicrobial Stewardship important in OPAT but possibly not entirely translatable from IP practice IVOST for SSTI important and will reduce unnecessary exposure to IV Rx Emerging evidence for other infections should be taken into account

64 Conclusions Ceftriaxone and Teicoplanin commonly used OPAT agents Teicoplanin associated with increase in OPAT failure in SSTI, Endocarditis and trend in BJI Daptomycin and Ertapenem emerging role in OPAT in variety of infections Increase in OPAT Rx G-ve infections will demand greater diversity of agents used eg Meropenem, Amikacin Role of infusion devices...

65 Acknowledgements OPAT Nurses: Lindsay Semple, Claire Vallance, Deepa Matthew, Emma Sharp Antimicrobial Pharmacist: Fiona Robb OPAT Medics past and present: David Barr, Chris Duncan, Claire Mackintosh

66 Current Practice: Gram Positive Infections INFECTION AGENT DOSE COMMENT Cellulitis/ SSTI Ceftriaxone Teicoplanin Daptomycin Ertapenem 1-2 g OD Variable dose 4-6mg/kg 1g OD Review daily: Oral switch Clinda/ fluclox/ Linezolid Bone/Joint infection Daptomycin 6-8mg/kg + Oral RIF or Sodium Teicoplanin 15-20mg/Kg 3 xs / fusidate or Doxy week Staph aureus bacteraemia Ceftriaxone 2g OD Daptomycin 6-8mg/Kg +/- RIF Ceftriaxone Endocarditis Daptomycin 8-10mg/kg +/- RIF Ceftriaxone 2g 2g OD

67 Current Practice: Gram Negative Infections INFECTION AGENT DOSE COMMENT UTI Ertapenem 1g OD Oral Rx: TMP, Nitrofurantoin, Amikacin 15mg/kg OD Pivmecillinam, Fosfomycin Enteric fever Ceftriaxone 2g OD Azithromycin Intra-abdominal Sepsis / Liver abscess Ertapenem 1g OD Mycobacterial Amikacin 25mg/kg 3xs/week (M)DRGNB Pip-Taz, Meropenem, Colistin, Amikacin, Meropenem In combination Rx