3/24/2014. Applying Principles of Antimicrobial Stewardship to Effective Patient Care

Transcription

1 Applying Principles of Antimicrobial Stewardship to Effective Patient Care David J. Feola, Pharm.D., Ph.D. Associate Professor, Pharmacy Practice and Science University of Kentucky College of Pharmacy CE Credit in Five Easy Steps! 1. Scan your badge as you enter each session. 2. Carry your Evaluation Packet to every session so you can add session evaluation forms to it. 3. Track your hours on the Statement of Session Attendance Form as you go. 4. At your last session, total the hours and sign both pages of your Statement of Session Attendance Form. Keep the PINK copy for your records. Put the YELLOW and WHITE copies in your Evaluation Packet. Make sure a completed Session Evaluation Form is in your Evaluation Packet for each session you attended. Missing one? Extras are in a file near Registration. 5. Complete the General Attendance Evaluation Form located in your Evaluation Packet and place it back in your envelope. Write your name on the outside of your Evaluation Packet envelope, seal it, and drop it in the box near Registration. Applying for Pharmacy CPE? If you have not yet registered for an NABP e Profile ID, please visit to do so before submitting your packet. You must enter your NABP e Profile ID in order to receive CE credit this year! 3/24/ Disclosure Slide The speaker declares no conflicts of interest or financial interest in any service or product mentioned in this program. Clinical trials and off label/investigational uses will not be discussed during this presentation. 3/24/

2 Learning Objectives 1. Describe current trends in antimicrobial resistance patterns among problem pathogens 2. Explain antimicrobial stewardship practices, their impact on the spread of resistance, and how they can be implemented in hospital out outpatient infusion settings 3. Discuss how emerging resistance problems impact treatment and therapeutic decision making 4. Describe methods of intervention to ensure optimization of antimicrobial therapy in the home setting Antimicrobial resistance: a crisis in medicine INTRODUCTION 5 Modern Healthcare, August 7, 2006, page 36 Protesting infections from MRSA 2

3 Why Stewardship is Needed Antimicrobial resistance results in Increased morbidity/mortality Increased healthcare costs Practices in antimicrobial use often inadequate, not routinely implemented Up to 50% antimicrobial prescribing inappropriate Causal relationship between antimicrobial use and emergence of resistance Sulfa, BL, AG TCN, MAC, Vanc, FQ No new classes. Modify existing agents. PCN-resistant S. aureus MRSA LZD DAP TIG VRE CTL VISA in 7 states MDR Gram (-), metallo-β-lactamases, carbapenemases A Disturbing Trend Half of companies END ID drug discovery LZD-R S. aureus VRSA Marketed Antibacterial Agents FDA 3

4 Bad Bugs, No Drugs, No ESKAPE ESKAPE pathogens Enterococcus Staphylococcus Klebsiella Acinetobacter Pseudomonas ESBL producers 2011 IDSA update Of the compounds active vs. resistant Gram negative bacteria in clinical development, NONE have activity against bacteria resistant to all currently available drugs No ongoing studies for the most life threatening Gram negative infections where > 20% of patients die Boucher HW et al. CID 2009; 48:1 12. The Critical Balance Importance of appropriate empiric therapy Mortality increases when initial therapy is inappropriate Effect of broad spectrum therapy on resistance Resistance increases when broad spectrum agents are needed; Resistance has a negative impact on outcomes Collateral damage A changing landscape TRENDS IN RESISTANCE 12 4

5 Antimicrobial Use and Resistance Changes in use parallel changes in resistance Patients with resistant infections more likely to have received prior antimicrobials Hospital areas of highest resistance associated with highest antimicrobial use Increased duration of therapy increases likeliness of colonization with resistant organisms Shales DM et al. CID 1997;25: Correlation: Use and Resistance Lepper PM et al. Antimicrob Agents Chemother 2002;46: Collateral Damage Oximinocephalosporins Cefotaxime, ceftazidime, ceftriaxone cause Extended spectrum beta lactamase production Selection of stably derepressed isolates in SPACE bacteria Selection of VRE Contribution to MRSA emergence Increased cases of Clostridium difficile associated diarrhea/colitis Dancer SJ. J Antimcirobial Chemother 2001; 48:

6 Perilous Cycle: KPC Example Resistant Pathogen ESBL producing E. coli, K. pneumo, SPACE KPC Antimicrobial Resistance ESBL production Carbapenemase development Infection Unknown pathogen ESBL producing bacteria KPC producing infection Antimicrobial Use Oximinocephalosporins Carbapenems????? TEM and SHV Lactamases Extended spectrum beta lactamases (ESBL) Mutants of classical enzymes Hydrolyze most extended spectrum cephalosporins and aztreonam Carbapenems are spared Inhibited by clavulanic acid Organisms that produce ESBLs Klebsiella, E. coli, other Enterobacteriaceae and non fermenting Gram negative bacteria Livermore DM. Clin Microbiol Inf. 2008;14:S3 10. Livermore DM et al. J Antimicrob Chemother. 2001;48(suppl): Molecular Basis of ESBLs Amino acid position Ceftazidime Enzyme MIC (μg/ml) TEM 1 <0.12 Glu Arg Glu TEM Glu Ser Glu TEM Glu Ser Lys TEM 26 >256 Lys Ser Glu Modified from Rice LB. Pharmacotherapy. 1999;19:120S 128S. 6

7 Chromosomal, Inducible AmpCs Produced by the SPACE Bacteria Serratia marcescens Pseudomonas aeruginosa Acinetobacter species Citrobacter species Enterobacter species β lactamase under the control of the ampc gene (turn on) and repressor gene (turn off) Mutation is loss of the repressor gene terminology is the isolate becomes stably de repressed Drugs of choice: carbapenems, cefepime Bush, K. Clin Infect Dis 2001; 32: Stable Derepression Selection During Therapy Resistant Strain Rare Resistant Strain Dominant Selection of stable derepressed mutants: susceptible when tested, then resistance 3 days later Carbapenemases Serine lactamases KPC All plasmid mediated Metallo lactamases (MBL) VIM, IMP, NDM Aztreonam retains activity Usually co expressed with other resistance mechanisms New carbapenem breakpoints in 2010 Combination studies in vitro, in vivo Suggest optimized PK with extended infusion Livermore DM, Woodford N. Trends Microbiol. 2006;14: Bonomo RA, Szabo D. Clin Infect Dis. 2006;43(suppl 2):S49 S56. 7

8 PCN Binding Proteins MRSA loss of the target site PBP2 which is replaced by PBP2a meca gene, associated with other resistance genes in the Staphylococcal chromosome cassette (SCCmec) PBP2a confers resistance to all beta lactams Streptococcus pneumoniae PCN resistance when mutations in 4 PBPs If PCN resistant, increased macrolide resistance, FQ resistance still low CA MRSA vs. HA MRSA Characteristic CA MRSA HA MRSA Susceptibility Chloramphenicol Usually susceptible Frequently resistant Clindamycin Usually susceptible Frequently resistant Erythromycin Usually resistant Usually resistant Fluoroquinolone Geographic variability Usually resistant TMP/SMZ Usually susceptible Usually susceptible SCC mec type IV II Lineage USA 300, USA 400 USA 100, USA 200 Toxins More Fewer PVL Common Rare Weber JT. CID 2005;41 Vancomycin Glycopeptide antimicrobial that inhibits transpeptidation reaction D ala D ala Mechanisms of resistance: change in bacterial target D ala D lac (VanA, VanB) D ala D ser (VanC) Enterococcus sp. E. faecium incidence of resistance higher that E. faecalis VanA gene is on a plasmid Am J Health Syst Pharm 2000;57:S4 9 Clin Pharmacokinet 2004;43: Clin Infect Dis 2006; 2006; 42:S35 9 8

9 S. pneumoniae Susceptibility Judicious use of antimicrobials can make an impact STEWARDSHIP PRACTICES 26 Definition: Antimicrobial Stewardship Infection control plus antimicrobial management Appropriate antimicrobial selection, dosing, route, and duration System selection of antimicrobials that cause the least collateral damage MRSA ESBLs Clostridium difficille Stable derepression Metallo beta lactamases and other carbapenemases VRE 9

10 Goals of Stewardship Primary goal Optimize clinical outcome/minimize unintended consequences of antimicrobial use Secondary goal Reduce healthcare costs without adversely impacting quality of care Core Members of the Team Infectious disease physician (Director or Codirector) Clinical pharmacist with infectious disease training (Co director or core member) Other members of the team Microbiologist Information system specialist Infection control professional Hospital epidemiologist Active Core Strategies Prospective audit with intervention and feedback to reduce inappropriate antimicrobial use Formulary restriction and pre authorization leading to reductions in antimicrobial use and cost NOTE neither of these strategies are mutually exclusive 10

11 Grams per 1000 Patient Days Formulary Restriction: Example Year Third Generation Cephalosporins Cefepime Ceftazidime Resistant K Pneumoniae % Ceftazidime Resistant K Pneumoniae Isolates After initiation of formulary restriction Third generation cephalosporins use decreased Cefepime use remained stable Rates of ceftazidime resistant Klebsiella pneumoniae decreased Martin CA et al. Am J Health Syst Pharm. 2005;62: Additional Strategies Streamlining or de escalation therapy Based on culture results, elimination of redundant therapy Decreases exposure and cost Dose optimization Based on PK/PD parameters Includes patient characteristics, causative organism, site of infection, characteristics of the drug Additional Strategies Educational programs, active intervention Provides foundation of knowledge Parenteral to oral conversion When the patient s condition allows Development of clinical criteria allowing conversion Guidelines and clinical pathways Seek multi disciplinary involvement and approval Incorporate local antimicrobial resistance patterns 11

12 Assessments Drug specific Antimicrobial consumption/cost Appropriate use Adverse events Resistance patterns/development Clinical outcomes measurements Cure vs. failure (clinical, microbiologic) Super infection rate Re infection rate Patel D et al. Exp Rev Anti Infect Ther 2008; 6: Fishman N. Am J Inf Contr 2006;34:S55 63 Limited Small Hospital Data Stewardship program in community hospital 535 bed, not university affiliated Prospective audit, targeted 8 antimicrobials Retrospective review of 510 antimicrobial orders, compared to order set before implementation 63% deemed appropriate,18% required de escalation, 5% required direct consultation Before After P value Death rate within 30 days 20.7% 16.0% 0.11 C. difficile infection rate 12.4% 5.8% <0.01 Total antimicrobial costs $1,503,748 $1,274,837 Antimicrobial cost per patient day $10.16 $8.81 Malani AN et al. Am J Inf Contr 2012 May 9 (Epub). Low Hanging Fruit Justified Targeting easily implemented interventions worthwhile 1234 bed, Ohio State University Wexner Medical Center Also reviewed literature from similar programs Focused on cost savings Method to establish program, justify costs to begin Intervention Annualized Cost Savings IV to PO conversion (linezolid, moxifloxacin, fluconazole) $242,713 Therapeutic substitution (IV vancomycin for oral use) $218,877 Batching IV antimicrobials (daptomycin) $83,991 Formulary restriction (doripenem, required pre auth) $61,000 Goff DA et al. CID 2012 Jun 7 (Epub). 12

13 How resistance impacts treatment THERAPEUTIC DECISION MAKING 37 MRSA Treatment Guidelines Clinical Practice Guidelines by the Infectious Diseases Society of America for the Treatment of Methicillin Resistant Staphylococcus aureus Infections in Adults and Children Liu C et al. CID 2011;52:1 38. Updated guideline was of critical need Landscape changing extremely rapidly due to CA MRSA emergence Updated practice recommendations for Focus on SSTI: decision making for covering MRSA, Strep, both Treatment of other infection types including pneumonia, bone and joint, CNS Management of recurrent MRSA SSTI: treatment and decolonization Drug dosing recommendations: focus on vancomycin Abscess Treatment Simple cutaneousabscess Incision and drainage alone likely adequate Can add topical antimicrobial treatment Abscesses that warrant systemic antibiotics Severe or extensive infection (deep or multiple sites) Rapid progression of associated cellulitis Systemic signs/symptoms Associated immunosuppression Lack of response to I and D Must cover MRSA; Strep coverage not necessary 13

14 CA MRSA Prescribing Trends KY Medicaid Database Beavers C. et al. Unpublished Staph vs. Strep Cutaneous abscess, purulent cellulitis CA MRSA coverage empirically Strep coverage not necessary Non purulent cellulitis Beta hemolytic Strep coverage empirically MRSA coverage not necessary unless patient does not respond To cover both Staph and Strep Clindamycin SMX TMP plus beta lactam Linezolid Vancomycin Resistance MRSA increasing MICs to vancomycin (1 2 mcg/ml) Still susceptible, but increase in treatment failures VISA mechanism: increased cell wall structural material VRSA mechanism: MRSA acquires the VanA gene Rare in the US VSSA VISA hvisa VRSA Vancomycin MIC 2 mcg/ml: susceptible 4 8 mcg/ml: intermediate 2 mcg/ml, subpopulation with MIC 4 8 mcg/ml 16 mcg/ml: resistant Clin Pharmacokinet 2004;43: Clin Infect Dis 2006; 2006; 42:S

15 Vancomycin Dosing mg/kg every 12 hours; obtain steady state trough concentration and adjust dose/interval if needed PD parameter that correlates to efficacy is AUC/MIC Target AUC/MIC is 400 based on available data To reach this, trough target mcg/ml Mean Trough Mean AUC Low dose (troughs < 15 µg/ml) 9.4 ± 3.2* 318 ± 111* High dose (troughs 15 µg/ml) 20.4 ± 3.2* 418 ± 152* However, MIC rules the situation: with high dose vancomycin, est probability of reaching AUC/MIC > 400 MIC Percent Jeffres MN et al. Chest 2006; 130: Vancomycin Toxicity Does renal toxicity limit our ability to optimize AUC/MIC? Nephrotoxicity percentage in 3 studies analyzing different vancomycin use scenarios Trough 15 mcg/ml Trough > 15 mcg/ml Nosocomial MRSA 0% 12% > 14 days of vanco 0% 15% MRSA HCAP 30.2% 58.8% Conclusion: if S. aureus MIC > 2 mcg/ml, use alternative agent (IDSA Guidelines) Lee Such SC et al ICAAC. Abstract L 1298 Hidayat LK et al. Arch Int Med. 2006;116: Jeffres MN et al. Clin Ther 2007;29(6): Susceptibilities of ESBL Producers Agent Nonsusceptibility (%) Piperacillin/tazobactam 0 53 Amoxicillin/clavulanate Gentamicin 9 67 Tobramycin Amikacin 5 27 Ciprofloxacin Sulfamethoxazole trimethoprim Nitrofurantoin 6 29 Fosfomycin 1 9 Tigecycline 0 1 Pitout JDD. Drugs 2010;70(3):

16 Treatment: ESBL Producers Carbapenems: current drugs of choice Cefepime: more stability but reports of treatment failures Little reported experience with trimethoprim/ sulfamethoxazole, aminoglycosides and fluoroquinolones Tigecycline may be an option Paterson DL, et al. CID 2004; 39: Treatment: AmpC Producers Retrospective cohort study John s Hopkins Hospital 96 cases, cefepime vs. meropenem, 32 matched pairs AmpC producing infections (Enterobacter, Serratia, Citrobacter) Had to be susceptible to agent used Cefepime shown to be equal to meropenem therapy No difference in 30 day mortality (31.2% vs. 34.3%) No difference in LOS 93% had source control Other antibiotics? Tamma PD et al. CID 2013 online Treatment: Carbapenemase Producers Multicenter, retrospective cohort study 3 teaching hospitals in Italy 125 patients with BSI with KPC producing organisms Therapy after Susceptibilities Known Nonsurvivors Survivors Mortality Rate P Value Monotherapy % 0.02 Combination % drug Combo % Tig+colistin+meropenem % Other 3 drug combo % 0.47 Tumbarello M et al. CID 2012;55(7):

17 Treatment: Carbapenemase Producers Multicenter, retrospective cohort study Outcomes stratified based upon meropenem MIC 36 BSI treated with meropenem in combination Meropenem MIC Total Nonsurvivors Survivors Mort (%) (mg/l) Total Tumbarello M et al. CID 2012;55(7): Treatment: Carbapenemase Producers Multicenter, retrospective cohort study Combination therapy impacted 30 day mortality rate (p=0.002) Multivariate analysis 4 independent RF for mortality Presentation with shock P=0.008 Inadequate initial treatment P=0.003 High APACHE III score P<0.001 Therapy with tig+col+mero P=0.01 Patients that received combination therapy had Increased acuity High MIC s to tigecycline and colistin Meropenem given over extended infusion Tumbarello M et al. CID 2012;55(7): Issues for the home infusion clinician OPTIMIZATION IN THE HOME 51 17

18 Resistance and OPAT Risk factors for infection with resistant organisms Severity of illness Previous exposure to antimicrobial agents Underlying disease conditions Chronic renal disease, DM, PVD, skin lesions Invasive procedures Dialysis, invasive devices, urinary catheterization Repeated contact with healthcare system Previous colonization with drug resistant organisms Advanced age CDC. Multidrug Resistant Organisms in Non Hospital Healthcare Settings. Resistance and OPAT Home precautions Wash hands with soap and water after physical contact with infected person, and before leaving the home Wash towels after each use Wear disposable gloves for contact of body fluids, and wash hands after glove removal Change linens on a routine basis Clean patient environment regularly Notify all who provide care that the patient is colonized/infected with a multidrug resistant pathogen CDC. Multidrug Resistant Organisms in Non Hospital Healthcare Settings. Treatment Duration CDC Get Smart Website Complete the prescribed course of treatment, even if you are feeling better. Example: CAP Guidelines 2000: We are not aware of any controlled trials that have specifically addressed the question of how long pneumonia should be treated 2007: Patients with CAP should be treated for a minimum of 5 days, should be afebrile for 48 72h, and should have no more than 1 sign of CAP associated clinical instability before discontinuation of therapy. Rice LB. CID 2008;46: (accessed Mar 29, 2011) Mandel LA et al. CID 2007;44(Suppl 2):S

19 The Issue with Infectious Diseases Research an example Animation of Tables from a meta analysis of treatment of osteomyelitis Highlights the issues with clinical trial data on which we base infectious diseases treatment decisions Limited to case series and studies with extremely small sample sizes Lazzarini L et al. Int J Inf Dis 2005;9: PK/PD Challenges in OPAT Must balance optimum dosing and convenience Continuous infusion of beta lactams increasingly studied Intricate communication required for therapeutic drug monitoring and dosage adjustment in home Adequate dosing must minimize collateral damage Treatment duration with antimicrobials an issue on the horizon Tice AD et al. CID 2004;38: Conclusions Solid understanding by home infusion clinicians of treatment issues involving Gram positive organisms can enhance care Epidemiology Resistance mechanisms Drug utilization Decolonization and hygiene measures Optimal antimicrobial use impacted greatly by OPAT Opportunities for future advancements Opportunities for individual patient interventions 57 19

20 Summary and Conclusions Antimicrobial Stewardship programs show great promise and offer new opportunities for patient care and cost impact Recommendation by both IDSA/ASHP and the CDC offer firm foundations to obtain support and funding for antimicrobial stewardship programs Optimal antimicrobial use impacted greatly by OPAT Opportunities for future advancements Opportunities for individual patient interventions 20