Therapeutic Strategies for Gram Negative Multi- Bacterial Infections Debra A. Goff, Pharm.D., FCCP Clinical Associate Professor Infectious Diseases Specialist The Ohio State University Medical Center Columbus, drug resistant Ohio
Columbus, Ohio USA
The Ohio State University Medical Center James Cancer Center bone marrow transplants & oncology Ross Heart Hospital Heart and lung transplants, cardiac The Ohio State University Hospital solid organ transplant, General Medicine Surgery, SICU, MICU, NICU, Burn unit 165 beds 130 beds 850 beds
The Ohio State University Football Stadium Capacity up to 105,000 people Imagine the stadiums filled with people
Impact of Antibacterial Resistance 100,000 people Each year an estimated 1.7 million patients in U.S. hospitals acquire an infection resulting in 100,000 deaths 1 This results in an additional $6.5 billion in health care expenditures 2 On October 1, 2008, Centers for Medicare Services in USA limited reimbursement for hospital-acquired conditions deemed preventable - catheter-associated urinary infections - vascular catheter-associated infections - mediastinitis after coronary artery bypass graft (CABG) surgery - surgical site infections. Klevens et al. Public Health Rep. 2007;122(2):160-166. 2. Stone et al. Am J Inf Control. 2005;33(9);542-547.
ESCAPE Pathogens ESKAPE: Describes the most critica al drug resistant pathogens: E = Enterococcus faecium S = Staphylococcus aureus C = Clostridium difficile A = Acinetobacter baumannii P = Pseudomonas aeruginosa E = Enterobacteriaceae (E. coli in nfection more numerous than Klebsiella and Enterobacter comb bined) Peterson, LR. Clin Inf Dis. 2009;49;992.
Surrogate for Serious Infections Caused by Multidrug-Resistant (MDR) Gram-Negative Bacilli Colistin Use at OSUMC Year Cost 2003-2004 $2,375 2007-2008 2008-2009 $23,309 $48,324 Colistin is only prescribed for MDR options. organisms when there are no other
cute MI STEMI alert Minutes mean uscle Multidrug resistant gram negative organisms BAD BUGS We NEED DRUGS Antibiotics are unique in that they become LESS effective the more they are used Antibiotics are unlike any other drugs in that use of antibiotics in one patient can compromise efficacy in another. Resistant microorganisms received an antibiotic. can be spread to patients who have never You can t catch cancer from the patient next to you. You CAN catch Acinetobacter or many other drug- resistant microorganisms!
Hospital and Societal Costs of Antimicrobial-Resistant Infections 1 All patients Patients with ARI Patients without ARI n (%) 1391 APACHE III score 42.1 Duration of stay(days) 10.2 HAI (n) 260 Cost per day (US$) 1651 Total cost (US$) 19,267 Death [n (%)] 70 188 (13.5) 1203 (86.5) 54.8 40.1 24.2 8.0 135 125 2098 1581 58,029 13,210 34 (18.1) 36 (3.0) Mean values shown in table. HAI: health care acquired infection 1. Roberts RR et al. Clin Infect Dis. 2009 vol49(8) p1175-84.
Hospital and Societal Costs of Antimicrobial-Resistant Infections organism Mean cost (USD) per patients N=1391 E VRE $66,,416 $73,481 S MRSA $46,,236 $60,984 A Acinetobacter E resistant to amikacin or imipenem Klebsiella or Ecoli resistant to quinolones or 3GC Multiple ARIs $157,835 Mean cost (USD) per patients Health-care acquired $97,,444 $111,062 $26,,549 $39,403 Roberts et al Clin Inf Dis 2009;49:1175-84.
Hospital and Societal Costs of Antimicrobial-Resistant Infections Roberts RR et al.clin Inf Dis.2009;49:1175-84.
Hospital and Societal Costs of Antimicrobial-Resistant Infections Roberts et al Clin Inf Dis 2009;49:1175-84.
Hospital and Societal Costs of Antimicrobial-Resistant Infections The attributable medical and societal costs of ARIs are considerable. The lowest estimate using sensitivity analysis resulted in a cost of $13.35 million in 2008 dollars in this patient cohort. This detailed analysis of the cost of antibiotic resistance in a single large teaching hospital gives an indication of the magnitude of the burden imposed by resistance. Efforts must be increased to control antibiotic resistance. Roberts RR et al. Clin Infect Dis. 2009; 49:1175-84.
Strategy #1 Antimicrobial Stewardsh hip Team Clinical Pharmacist ID Physician Infection Control Professional Patient Clinical Microbiologist ASP: there s no such thing as too much Dr Pagani Bolzano Italy Hospital Epidemiologist Information System Specialist Optimal Team Members (A-III) 1. Dellit TH et al. Clin Infect Dis 2007;44(2):159-77. 2. Drew RH. J Manag Care Pharm. 2009;15(2 Suppl):S18-23.
OSU Antimicrobial Stewardship Program SP is a corporate commitment!
Are Guidelines Focused and Easy to Follow?
Strategy #2 Develop Specific Antibiograms Consensus Guideline from Clinical and Laboratory Standards Institute (CLSI) Monitoring of drug resistance at the local level is crucial to support clinical decision making. Algorithms for handling repeat isolates - patient-based - episode-based - resistance phenotype-based Combination Antibiograms useful in ICU with high gram-negative resistance Hindler JF et al. Clin Infect Dis. 2007; 44:867-73. Kuper KM et al. Pharmacotherapy. 2009; 29:1326-43.
Do MD s Use Hospital Antibiograms? Online survey of 545 residents at a University Teaching Hospital 1%3% 32% How data is communicated to the medical staff is critical 64% always frequently occasionally never Mermel et al. Clin Inf Dis. 2008:46;1789.
Antibiograms Should be produced annually ICU specific is necessary in era of escalating resistance ED specific skin/skin st tructure antibiogram Developed in response to escalating prevalence of CA-MRSA Combination Antibiograms Useful in ICU with high gram-negative resistance Use this data to guide/change prescribing It s based on evidence/data from your own hospital CA-MRSA = community-acquired methicillin-resistant Staph. aureus
Example: Hospital-wide Antibiogram Pip/tazo Cefepime K. pneumoniae (9 54) 91 95 E. cloacae (2 87) 79 95 E. coli (1 971) 96 99 P. aerugin osa (1 039) 87 70 A. bauma nn ii (1 21) 91 80 Imipenem Cipro Tobramycin 99 88 92 95 92 91 99 89 98 81 70 89 100 70 85
Example:ICU Antibiogram First isolates only Pip/tazo Cefepime K. pneumoniae (3 2) 66 71 E. cloacae (1 3) 77 77 E. coli (1 6) 94 94 P. aerug ino sa (3 7) 81 59 A. bauma nn ii (2 1) 86 14 Imipenem Cipro Tobramycin 100 63 63 92 77 69 94 89 94 70 78 95 86 52 19
Targeted Empiric Coverage Ertapenem Ampicillin/sulbactam Piperacillin/tazobactam Imipenem Non-Pseudomonas gram-negatives Anaerobes Gram-positives Resistant ESBL s Pseudomonas aeruginosa Empiric coverage
ASP initiative in the Management of complicated intra-abdominal Infection Example: Surgical ICU and Hospital Antibiogram Organism Ampicillin/ sulbactam Ertapenem SICU hospital SICU hospital E. coli 42% E. coli 0% ESBL-producing K. pneumoniae 75% K. pneumoniae ESBL-producing 0% Anaerobes + Enterococcus + 45% 100% 0% 100% 78% 100% 0% 100% + + + - Neither ampicillin-sulbactam nor ertapenem covers P. aeruginosa
Antibiotic By Site of Infection Computer order entry
Strategy # 3 Evaluate the impact of your recommendations Ertapenem: No Effect on Imipenem Susuceptibility to Gram-Negative Pathogens 5 Years after Formulary Addition Carbapenem Use and P. aeruginosa Susceptibility 40 100 DDD/1000 0PD 35 30 25 20 15 10 5 90 80 70 60 50 40 30 20 10 Imipenem susc ceptible P. aerugino osa 0 2002 2003 2004 2005 2006 2007 0 imipenem ertapenem imipenem % susceptible Goff D, Mangino J. 2008 J. Infection 57(2 2);123-127
Consensus Guideline from Clinical and Laboratory Standards Institute: Antibiograms Monitoring of drug resistance at the local level is crucial to support clinical decision making. Algorithms for handling repeat isolates - patient-based - episode-based - resistance phenotype-based Hindler JF et al. Clin Infect Dis. 2007; 44:867-73. Kuper KM et al. Pharmacotherapy. 2009; 29:1326-43.
Examples of How Different Methods Yield Different % Susceptibility Hindler JF et al. Clin Infect Dis. 2007; 44:867-73.
Combination Antibiogram:SICU Empiric antibiotics: pip/tazo + amikacin Pip/tazo Cefepime P.. aeruginosa (116) 84% 67% Imipenem Cipro Amikacin 69% 65% 89% For all pip/tazo resistant P. aeruginosa what is the most effective 2 nd agent? P. aerug ino sa (19 ) pip/tazo R 0 9 39 33 89 17/19 pip/tazo resistant isolates are covered (susceptible) by amikacin The additional of empiric amikacin benefits only 14.6% (17/116) of all patients.
Utilize current data to support change in therapy CLSI (EUCAST in Europe) will be adjusting the MIC break points for susceptibility of P. aeruginosa to piperacillin- tazobactam. Currently an MIC of 64 mg/l is considered susceptible. This will be considered resistant based on published PK/PD data. Evaluate your own hospital isolates to determine what % have MIC=64 mg/l. When evaluating patients, if the MIC is 64 mg/l, recommend alternative therapy. CLSI = Clinical and Laboratory Standards Institute MIC = minimum inhibitory concentration
Who is Your Audience? ID MDs Residents and Fellows RNs Pharmacists in your department! Critical Care Hospitalists Emergency room MDs Surgeons
Strategy #4 Take old Implement Continuous/Extended Infusion pip/tazo Why do this? Have knowledge of the literature How do I do this? drugs and maximize the PK/PD Talk with the IV room pharmacists, discuss logistics and work load, discuss infusion pump-related issues Think about who might object to the idea? The person who is inconvenienced most is the RN Need to worry about drug incompatibility Ties up the line
Pharmacodynamic Dose Optimization Extended infusion pip/tazo, Purpose: optimize current antimicrobials Maximize dosing to treat resistant or high MIC organisms Efficacy of pip/tazo extended infusion reduced mortality compared with intermittent infusion in patients with P. aeruginosa infection and APACHE II scores 17 APACHE II = Acute Physiological and Chronic Health Evaluation-II Lodise TP Jr et al. Clin Infect Dis. 2007; 44:357-63.
Extended-Infusionn Dosing Strategy Slide used at OSUMC to Educate RNs Lodise TP Jr et al. Clin Infect Dis. 2007; 44:357-63.
Strategy #5 Checklist of Interventions to Decrease Healthcare-Associated C. difficile Infection Bundled approach: antimicrobial use, infection control, and proper environmental cleaning antibiotic Infection control housekeeping
Checklist of Interventions to Decrease HCA-C. difficile Infection Bundled approach: antimicrobial us se, infection control, and proper environmental cleaning antibiotic Infection control housekeeping Abbett SK et al. Infect Control Hosp Epidemiol. 2009; 30:1062-9. Owens RC Jr et al. Clin Infect Dis. 2006; 42(Suppl 4):S173-81.
Hospital-wide impact of a standardized order set for the management of bacteremic severe sepsis Order sets weree derived from the Surviving Sepsis Campaign A retrospective before after study design of 400 patients Patients had have a diagnosis of severe sepsis & + blood culture Patients in the after group received more IV fluids in the 1 st 12 hours after hypotension more likely to receive appropriate initial antibiotics lower in-house mortality (55% vs 39.5%, p<0.01) Order sets improved the management of severe sepsis and improved survival. Ref: Thiel Crit Care Med 2009;37: :819-824.
Strategy #6 New diagnostic tests Multiplex PCR detection enhancement of bacteremia and fungemia Objective: test a multiplex RT-PCR method for simultaneous detection of multiple organisms in bloodstream infections Methods: Prospective observational study of 200 patients at risk of BSI with signs of SIRS. Louie R. et al 2008 CCM :36(5);1487-1492. Tsalik E et al 2010 JCM 48(1); 26-33.
Organisms detectedd by multiplex PCR Louie R. et al CCM 2008:36(5);1487-1492.
Results PCR detected bacteria/fungi in 45 cases vs 37 by blood culture. PCR detected meca in all 3 culture confirmed MRSA PCR did not detect E. faecalis in 5 BC confirmed cases 7 samples could be tested simultaneously in 6.54 hours ouie R. et al CCM 2008:36(5);1487-1492.
Conclusion Despite limitations of both blood culture and RT multiplex PCR methods 1.PCR could be an adjunct to BC 2. PCR can facilitate early detection 3. Early detection can facilitate evidence- based treatment decisions Louie R. et al 2008 CCM 36(5);1487-1492. Tsalik E et al 2010 JCM 48(1); 26-33.
Use of procalcitonin to reduce patients exposure to antibiotics in ICU (PRORATA trial) A randomized multicenter effectiveness trial to assess the benefit of procalcitonin to help MD start,continue, or stop antibiotics for patients in ICU with suspected bacterial infections Results: Procalcitonin guided antibiotic treatment Lowers antibiotic exposure by 2.7 days and is Non-inferior to standard care with respect to outcomes. Ref; Bouadma et al Lancet 2010;375:463-474
Strategy # 7 New technology ere's how it works.. The hospital workers squirt sanitizer gel or wash wit th soap before passing their hands under a wall-mounted sensor.. A wireless signal from a badge the worker is wearing activates a green light on the handwashing sensor.. When the worker approaches the patient's bedside, a monitor detects the status of the badge. Clean hands get a green light.. If the person has not washed, or if too much time has passed since washing up, the badge will vibrate as a reminder to wash their hands again.
Infectious Diseasee resources for the iphone 50 million users Leading handheld platform for medical personnel Over 100,000 apps Outbreaks near me app Swine flu tracker map app In 2008 Apple created a medical community OSU is developing a STAB-IT app for internal use Ref: Oehler et al CID 2010;50:9