Antibiotic Stewardship or Reinventing the Wheel Ellie JC Goldstein MD Director, R M Alden Research Laboratory Clinical Professor of Medicine, UCLA Survival of the Fittest vs. Solution Darwin 1984
The Evolution of Cooperation When should a person co-operate and when should a person be selfish? should a friend keep providing favors to another friend who never reciprocates?... Under what conditions will co-operation emerge in a world of egoists? Success in an evolutionary "game correlated with Be nice: cooperate, never be the first to defect. Be provocable: return defection for defection, cooperation for cooperation. Don't be envious: be fair with your partner. Don't be too clever: or, don't try to be tricky. Resistant Organisms 2011: When One is Targeted, What is the Effect on the Non-Targets? Current Issues MRSA Vancomycin MIC creep VRE ESBL Increasing prevalence P. aeruginosa Pan-resistance Acinetobacter Pan-resistance E. coli (NDM1) Integrons K. pneumoniae carbapenemase (KPC) Future? What Next?
Impact of Antibacterial Resistance 100,000 people 1. Klevens RM, et al. Public Health Rep. 2007;122:160-166. 2. Stone PW, et al. Am J Infect Control. 2005;33:542-547. ~1.7 million patients in US hospitals acquire an infection resulting in 100,000 deaths ANNUALLY 1 This results in an additional $6.5 billion in health care expenditures 2 On October 1, 2008, CMS limited reimbursement for hospital-acquired acquired conditions deemed preventable Catheter-associated associated urinary tract infections Vascular catheter-associated associated infections Mediastinitis after coronary artery bypass graft surgery Surgical site infections D Goff 11-09 DEALING WITH ANTIBIOTIC RESISTANCE & NEW DRUG DEVELOPMENT ENTITY WHO WHAT White House President Obama TransAtlantic TF on Abx Resist. TATFAR Congress House (6331) Generating Abx Incentives(GAIN) Senate (2313) STARR PAMITA FDA M. Hamberg, et al Agency priority NIH T. Fauci Clinical Trials Network HHS Sebelius Public Health Emergencies CDC Srinivasan Surveillance; Get Smart Media Extensive Societies 21 Endorsed (J Bartlett 2011)
Microbiology ID Physician Epidemiology Why Have Antimicrobial Stewardship? ASP ID Pharmacist Information Services Infection Control Antibiotics are unlike any other drugs Anyone can prescribe antibiotics despite a lack of specialized training Antimicrobials benefit the prescribed patient but can impact countless others Resistant microorganisms can be spread to patients who have never received an antibiotic D Goff 11-09 CA Senate Bill No. 739 Approved by Governor September 28, 2006 1288.8 (a) By January 1, 2008, the department shall take all of the following actions to protect against health care associated infections (HAI) in general acute care hospitals statewide: (4) Require that general acute care hospitals develop a process for evaluating the judicious use of antibiotics, the results of which shall be monitored jointly by appropriate representatives and committees involved in quality improvement activities. 8 http://www.dhcs.ca.gov/provgovpart/initiatives/nqi/documents/sb739.pdf
CA SB 739: What Does this Mean? By January 1, 2008 each CA acute care hospital: Monitor and evaluate antimicrobial use Assemble a quality improvement committee to oversee antimicrobial use Each hospital left to comply on its own CDPH HAI Program interpretation: each CA acute care hospital should have an ASP Meeting February 17, 2011 Formal education course for ASP physician and pharmacist 9 Healthcare Associated Infections Advisory Committee Meeting February 17, 2011 ASP should monitor process and outcome measures: Risk assessment including scope of practice Usage patterns for broad-spectrum antimicrobials Defined Daily Dose (DDD) or Days of Therapy (DOT) Examined for appropriateness Multidrug-resistant organism trends Medical Use Evaluations Antibiogram prepared according to CLSI standards and distributed to clinical staff 10 http://www.cdph.ca.gov/services/boards/documents/abssummary2-4-11haiac.pdf
Antimicrobial Stewardship Team Stakeholder Involvement: Ideal versus Reality Clinical Pharmacist ID Physician Clinical Pharmacist Infection Control Professional Patient Clinical Microbiologist Patient ID Physician Hospital Epidemiologist Information System Specialist Each Member needs a defined role Optimal Team Members (A-III) 1 Core Team Members (A-III) 1 1. Dellit TH, et al. Clin Infect Dis. 2007;44:159-177. 2. Drew RH. J Manag Care Pharm. 2009;15:S18-23. D Goff 11-09 Appropriate Antimicrobial Therapy Matches antibiotic sensitivities of the organism to the antibiotic used Improved Outcomes = Reductions In: Hospital and infection-related mortality Infection-related morbidity Length of hospital stay Days of antimicrobial therapy Cost of hospitalization 1. Pelz RK, et al. Intensive Care Med.. 2002;28:692-7. 3. Engemann JJ, et al. Clin Infect Dis.. 2003;36:592-8. 5. Kollef M, et al. Chest.. 1999;115:462-74. 2. Lodise TP, et al. Clin Infect Dis.. 2002;34:922-9. 9. 4. Song X, et al.. Infect Control Hosp Epidemiol.. 2003;24:251-6. 6. Toubes E, et al. Clin Infect Dis. 2003;36 36 724 30
Antibiotics as Percentage of Total Healthcare Costs CAP 1 HAP 2 Abdominal trauma 3 Diabetic foot 4 Burn 5 0 10 20 30 40 50 60 70 80 90 100 Total Costs (%) Antibiotic cost Healthcare cost 1. Dresser LD, et al. Chest. 2001;119:1439-48. 4. McKinnon PS, et al. Clin Infect Dis. 1997;24:57-63. 2. Paladino JA & Fell RE. Ann Pharmacother. 1994;28:384-9. 5. Nicolau DP, et al. J Burn Care Rehabil. 1994;15:244-50. 3. Friedrich LV, et al. Am J Hosp Pharm. 1992;49:590-4. Balancing Effective Therapy With Concerns About Resistance Dilemma: Use broad-spectrum agents or regimens sparingly, yet promptly When does the need to treat outweigh waiting for culture results? Critically ill, febrile patients Prior antibiotic use Prolonged mechanical ventilation / recent surgery Prolonged hospital stay; healthcare associated inf. Weber DJ. Int J Infect Dis. 2006;10:S17-24.
Hospital and Societal Costs of Antimicrobial-Resistant Infections Projected cost savings if antimicrobial-resistant resistant infection (ARI) rates were reduced from 13.5% to 10.0% Current ARI rate: 13.5% Reduced ARI rate: 10.0% Cost $12,000,000 $10,688,004 $10,000,000 $8,000,000 $7,978,299 } $6,000,000 $4,000,000 $3,494,544 $2,583,732 $2,000,000 $0 13.5% ARI proportion 10.0% Medical Cost Roberts RR, et al. Clin Infect Dis.. 2009;49:1175-1184. 1184. Societal Cost Savings for 1391 patients: $2.7 million total $1,948 per patient Inappropriate Therapy Often Due to Antibiotic Resistance Inappropriate therapy more likely if antibiotic resistance is present Antibiotic-resistant organisms are more commonly associated with inappropriate therapy 40 Inappropriate treatment (%) 30 20 10 0 Pseudomonas aeruginosa Kollef MH. Clin Infect Dis. 2000;3:S131 138. 138. S. aureus Acinetobacter Other Klebsiella spp. pneumoniae
The Association between Antibiotic Use and Resistance Decreasing susceptibility trends over time were not statistically associated with the primary drug (e.g., organism susceptibility rate to imipenem with imipenem usage). However, secondary drug use was associated with susceptibility rates (e.g., susceptibility of E. cloacae to cefepime with piperacillin/tazobactam usage). Conclusions: These results suggest that antibiotic use - resistance relationships are influenced by the use of secondary antibiotics. Thus, a resistance problem may not be adequately addressed by simply altering the utilization of the primary antibiotic. Bosso et al. Joint meeting ICAAC/IDSA 2008 Getting it Right Upfront and Finishing Strong: De-escalation escalation & Short Courses Early, broad-spectrum empiric therapy Select antimicrobial based on local antibiogram Optimize antimicrobial exposures (i.e., make use of pharmacodynamic dosing strategies) Ensures early & maximally effective therapy To maintain efficacy and decrease risk of resistance Consider patient status & culture results early in therapy CHANGE (de-escalate) or STOP antibiotics as appropriate Employ short course therapy when possible Costs saved by avoiding treatment failure greater than costs spent on antimicrobial therapy 1. Niederman MS. Semin Respir Crit Care Med. 2006:27:45-50. 2. Nicolau DP. Critical Care 2008;12:S1-5.
Outcomes of Bacteremia Due to P. aeruginosa Based on the Susceptibility of Piperacillin/Tazobactam 30-Day Mortality Rate (%) 100 90 80 70 60 50 40 30 20 10 0 Pip/Tazo Control MIC, 32 or 64 mg/l MIC, 16 mg/l All = Susceptible Tam VH, et al. Clin Infect Dis. 2008;46:862-7. Nicolau Stewardship: Supplemental Strategies (I) Education is essential for any program Guidelines and clinical pathways can improve antimicrobial utilization Antimicrobial cycling insufficient data to recommend routine use Antimicrobial order forms can be an effective component of stewardship Guidelines for Developing an Institutional Program to Enhance Antimicrobial Stewardship. Clin Infect Dis. 2007;44:159-77.
Economics of the VAP Pathway Variable Control (n=73) Pathway (n=93) P-value LOTVAP 27.1±18.5 18.5 12.7±8.1 <0.001 LOS 35.0±22.0 28.9±17.3 0.076* COSTVAP $75K $35K <0.001 COST after $95K $76K 0.077* Antibiotic Cost $934±1533 $766±755 755 0.45 Hospital costs similar for pathway ($24,501) and control ($28,13,817) over first week of VAP, but significantly lower for clinical pathway during week 2 ($12,231 vs $20,947, P<0.001). * Treatment on Clinical Pathway was independently associated with lower total LOS after VAP (P=0.012) and lower total hospital costs after VAP (P=0.033) in multivariable models. LOTVAP = length of VAP treatment; LOS = total length of hospital stay after identification of VAP; COSTVAP = hospital costs (2007$) of treating VAP; COST after = total hospital costs s (2007$) of treating VAP after VAP identification; Antibiotic Cost = acquisition cost of antibiotics used to treat VAP Nicasio AM, et al. Pharmacotherapy 2010; in press. Nicolau Stewardship: Supplemental Strategies (II) Combination therapy insufficient data to recommend routine use...to prevent resistance Streamlining or de-escalation can decrease antimicrobial exposure and save costs Dose optimization an important part of stewardship IV-to-PO switch can decrease LOS and health care costs LOS = Length of stay Guidelines for Developing an Institutional Program to Enhance Antimicrobial Stewardship. Clin Infect Dis. 2007;44:159-77.
Optimizing β-lactam Therapy: Maximizing Percent T>MIC Increased duration of infusion Prolonged infusion 32 16 Same dose and dosing interval, 100-250ml, however, change duration of infusion (0.5 hr 3-4hr) Concentration (mg/l) 8 4 2 MIC 1 0 2 4 6 8 10 12 Time Since Start of Infusion (h) Nicolau What is Collateral Damage? A Movie? Resistant fecal flora? C. difficile infection? Resistant isolates? Gram positive? Gram negative? Industry spin? Whatever you want it to be?
Potential collateral damage from use of cephalosporins and quinolones Class of agent, pathogen(s) ) selected for: Third generation cephalosporins VRE ESBL Klebsiella sp. C difficile Quinolones MRSA Quinolone-resistant GNRs,, including P. aeruginosa DL Patterson Clin Infect Dis 2004; 38 (Suppl 4): S 341 ASP Management of S. aureus Bacteremia Using a Rapid PCR Test* Suspect SA Blood cultures drawn Start Vancomycin Growth in blood culture Gram stain: gm+cocci groups Results called to MD or RN Pre Xpert SA/MRSA BC Post Xpert SA/MRSA BC Suspect SA Blood cultures drawn Start Vancomycin Growth in blood culture Gram stain: gm+cocci groups Xpert SA/MRSA done in 1 hour Results called to MD or RN and PharmD Vanco continued Final report 2-4 days Vanco usually continued ID PharmD calls MD with antibiotic recommendation MSSA: Vanco switched to nafcillin or cefazolin MRSA: Vanco continued or switched to dapto * Real-time PCR rapid detection of MRSA/SA BC; GeneXpert MRSA/SA BC Bauer K, Goff D, et al. Clin Inf Dis 2010; 51:1074
Economic Impact of rapid PCR for SAB LOS decreased 6.2 Days mean days 25 20 15 10 5 0 21.5 LOS 15.3 US dollars Mean Hospital costs decreased $21,287 (P=0.02) ICU costs decreased $9,930 (P=0.03) 80000 70000 60000 50000 40000 30000 20000 10000 0 69737 48350 pre post pre-pcr post-pcr The TWO Carbapenem Formulary Reduces selective pressure on P. aeruginosa: : Effect of Ertapenem Basic Science Livermore, J Antimicrob Chemother. 2005;55:306-311. 311. Collateral Damage OASIS 1 and OASIS 2, Eur J Clin Micro Infect Dis. 2005;24:443-449. 449. STITCH, Surg Infect. 2007;8:15-28. 28. Clinical Studies Crank, 44th IDSA Annual meeting, Toronto, 2006. Abstract 285. Goff, J Infection. 2008;57:123-126. 126. Goldstein, AAC. 2009;53:5122-5126. 5126. Carmeli,, 47th ICAAC, Chicago, 2007. K-396K Eagye KJ, & Nicolau DP ICHE 2010 31:485 ICHE May Conclusions Use of ertapenem did not decrease susceptibilities of Pseudomonas aeruginosa to carbapenems.
Anti-Pseudomal Carbapenem Stewardship (LA Hospital X/Y) Carbapenem Ertapenem Doripenem Imipenem Meropenem Cost per Dose $51-$54 $18-$27 (500 mg) $13-$14 (500 mg) $14 (1 gm) Cost per Day $51-$54 $54-$71 $39/42-$52/56 $42 Univariate ARIMA Model Fitted to the Usage Series Mont h Susceptibility P. aeruginosa Imipenem (%) Min Max Mean Median Standard Error Before Ertapenem added After Ertapenem was added, Before the substitution 0-9 60.00 81.00 70.00 69.0 2.69 10-20 63.00 91.00 77.00 77.00 2.90 After the substitution 21-48 67.00 100.00 87.86 89.0 1.62 Goldstein EJ, et al. Antimicrob Agents Chemother.. 2009;53:5122-5126. 5126.
25 OASIS II Therapy Resistant Enterobacteriaceae Subanalysis Ertapenem Ceftriaxone/Metronidazole 22.4 20 17.1 17.2 Percent 15 10 9.3 5 0 n= 4.0 0.5 0.5 0 0 2.2 2.6 201 196 182 201 196 182 195 193 174 195 193 174 Resistant ESBL Producers Resistant ESBL Producers 2.1 Baseline End of Therapy 2 Weeks Post Therapy Adapted from DiNubile MJ, et al. Eur J Clin Microbiol Infect Dis 2005;24:443 449. Current Pathogenesis Model for C. difficile Infection (CDI) C. difficile acquisition Antimicrobial(s) C. difficile acquisition Asymptomati c C. difficile colonization Hospitalization CDI Acquisition of a toxigenic strain of C. difficile and failure to mount an anamnestic Toxin A IgG antibody response results in CDI. Courtesy of Dale Gerding, MD
Vanco vs OPT-80 Acquisition of VRE colonization during CDI treatment 35 30 25 20 Percent 15 10 5 0 T Louie et al AAC 2009 Vancomycin Fidaxomicin 41/133 8/115 P <0.001 Clostridium difficile Diagnostic Testing (LA Hospital Y) Test Cost/Test #Test/Month Cost EIA $3 70 $210 QC Test $3 50 $180 Average 2 test/patient/week 50 $300 Added QC 50 $180 Total LAMP Assay No QC $28 50 $480 or $9.60 per patient $1395 Change Policy for frequency of testing due to high sensitivity no duplicate tests
Difference between EIA & LAMP for Detection of C.difficile Difference $915/month or $10,980/year Less empirical drug use Better diagnostics Less isolation costs More specific therapy Equivalent cost but better quality of care CANDIDA (blood culture) Identification and Therapy
Yeast Traffic Light PNA FISH PN1870A Fluconzaole vs Echinocandin Agent Cost/day Days of Rx Total Cost 70% Fluconazole $5 10 $6,510 30% Echinocandin $76 10 $41,268 If no rapid ID - empirical Echinocandin for all for ~ 5 days, adds an extra $42,221 to costs Cost of FISH test ~$60 x 186 = $11,160 Cost savings, but it is also a quality of care issue
ASP in a Community Hospital Focused on 3 items IV to Oral ( low-hanging fruit ) Pre-op prophylaxis Selected drugs ID consult after 48 hours Antimicrobial cost per patient-day $14 $12 $10 $8 $6 $4 $2 $0 2000 2001 2002 2003 Cost/Census Day Cost Savings for 2001 = $399,238 Cost Savings for 2002 = $659,812 Cost Savings for 2003 = $782,153 Total Cost Savings = $1,841,203 Philmon C, et al. Infect Control Hosp Epidemiol. 2006;27:239-244. 244. Abx Stewardship Strategies 522/1044 (50%) ID respondents Strategy Current ASP Planned ASP Primary 264 (100%) 41 (100%) Single 63 (24%) 14 (34%) Formulary restriction 17 (6%) 8 (19%) Preauthorization 5 (2%) 0 PostRx review-feedback 41 (16%) 6 (15%) Combinations 194 (73%) 23 (56%) Restriction & Pre-auth 57 (22%) 3 (7%) Restriction & Post RX 33 (12%) 8 (19%) All three 83 (31%) 12 (29%) No Primary Strategy 8 (3%) 4 (10%) Johannsson et al ICHE 2011; 32:367
Abx Stewardship Supplemental Strategies None 11 (4%) Education 212 (80%) Guidelines/Pathways 187 (71%) IV po conversion 161 (61%) Dose optimization 147 (55%) De-escalation/Streamlining 132 (50%) Automatic Stop orders 110 (42%) Abx order forms 75 (28%) Cycling 6 (2%) Johannsson et al ICHE 2011; 32:377 ASP Criteria for Abx Review High Cost 215 (87%) Potential misuse 166 (67%) Broad spectrum 141 (57%) Potential IV po 130 (52%) Resistance profile(eg MRSA) 130 (52%) Novel agents 128 (52%) High Use agents 114 (46%) High Adverse Rxn 98 (40%) Overlapping spectrum 70 (28%) Site of infection (eg Blood) 44 (18%) Johannsson et al ICHE 2011: 32:367
Outcomes data useful to support ASP Johannsson et al ICHE 2011 32:367 Administration Views Be Prepared Who is the decision maker? CEO, COO, other Who is the best proponent Track record Educate the decision maker Not too much detail on 1 st meeting- set the stage ROI Quality and Economic Aspects Have a Timeline Identify who needs to get the message
Administration Views Undersell and Over deliver Be committed to the Program Prioritize existing resources Don t join BMW club Bitch, moan and whine Identify who is doing it already- success and value Legislation & Regulation Do it for the right reason Thank you