MDR AGENTS: RISK FACTORS AND THERAPEUTIC STRATEGIES 1 Marin H. Kollef, MD Professor of Medicine Virginia E. and Sam J. Golman Chair in Respiratory Intensive Care Medicine Washington University School of Medicine St. Louis, Missouri
Merck Actavis Arsanis Cubist Cardeas 2 Conflicts of Interest Medimmune Astrazeneca Accelerate Academy for Infection Management Barnes-Jewish Hospital Foundation
First Understand your local problem with MDR/XDR! 3
Top 3 pathogens causing HAIs: diversity in different countries E. coli (17%) S. aureus (15%) C. difficile (12%) E. coli (18%) Enterococcus (15%) S. aureus (13%) E. coli (27%) S. aureus (14%) Enterococcus (10%) E. coli (15%) Klebsiella (12%) P. aeruginosa (11%) E. coli (17%) Enterococcus (12%) S. aureus (11%) Klebsiella (18%) P. aeruginosa (17%) Acinetobacter (17%) 4 Klebsiella (13%) E. coli (13%) P. aeruginosa (11%) European Centre for Disease Prevention and Control. Point prevalence survey of healthcare-associated infections and antimicrobial use in European acute care hospitals. Stockholm: ECDC; 2013
Antibiotic Use Counterintuitive Antibiotic Resistance (MDR/XDR) 5 Inappropriate Therapy
Risk Factors for VAP Variable AOR 95% CI P Value OSFI >3 10.2 4.5-23 < 0.001 Age > 60 5.1 1.9 14.1 0.002 Supine* 2.9 1.3 6.8 0.013 Prior Antibiotics 3.1 1.4 6.9 0.004 6 Kollef MH. JAMA 1993;270:1965-1970 *First 24 hours of mechanical ventilation.
7 2 Martin-Loeches I, et al. Curr Opin Crit Care 2014; 20:516-524.
Risk Factors for Resistant Organisms Previous antibiotic treatment Previous hospital admission Nursing home Comorbidities CAD, HIV, COPD, kidney disease Hemodialysis Home wound care (past 30 days) Family member with resistant organism Herrero FS, 8 et al. Semin Respir Crit Care Med. 2012;33;220-231.
Criteria for Health Care Associated Pneumonia 9 Wunderink RG, et al. N Engl J Med 2014;370:543-551.
HCAP Criteria Hospitalized in the previous 90 days Nursing home resident Home infusion therapy Chronic dialysis or home wound care Family member with resistant bacteria St. Louis, Missouri Hospitalized in the previous 90 days Criteria Nursing home resident Chronic dialysis ICU admission Milan, Italy Comorbid conditions (CVA, DM, COPD) Criteria Antibiotics in prior 90 days Immunosuppression/Chronic renal failure Home wound care or infusion therapy Nursing home resident Hospitalized in prior 90 days Joint Japanese- ICU admission U.S. Criteria Immunosuppression Hospitalized in prior 90 days Antibiotics in prior 6 months Poor functional status 10 Vazquez-Guillamet C, Kollef MH. ICM (In press). A risk factor approach for MDR syndromes (pneumonia)
Nagoya, Japan Hospitalized in prior 90 days Criteria Immunosuppression Antibiotics in prior 90 days Gastric acid suppression medication Tube feeding Nonambulatory status Rome, Italy Criteria One risk factor for HCAP Bilateral infiltrates Pleural effusion pao2/ FiO2 ratio <300 Spanish Criteria Hospitalization in previous 90 days HCAP Residence in a nursing home or extended care facility Home infusion of antibiotics Chronic hemodialysis Home wound care Family member colonized with MDR isolate Spanish Criteria ICP 11 Vazquez-Guillamet C, Kollef MH. ICM (In press). A risk factor approach for MDR syndromes (pneumonia) HIV Organ transplant Chemotherapy, steroids, other immunosuppressive therapy for at least four weeks prior to the diagnosis of pneumonia
ATS/IDSA. (2005) AJRCCM 171:388-416 Shorr AF, et al. (2012) Clin Infect Dis 54:193-198. Aliberti S, et al. (2012) Clin Infect Dis 54:470-478. Maruyama T, et al. (2013) Clin Infect Dis 57:1373-1383. Shindo Y, et al. (2013) AJRCCM 188:985-995. Falcone M, et al. (2015) PLoS One. 10(4):e0119528. Vallés J, et al. (2014) Intensive Care Med 40(4):572-581. 12
HCAP Requires Broad Spectrum Empiric Therapy Agent 1 + Agent 2 + Agent 3 13 ATS/IDSA. Am J Resp Crit Care Med. 2005;171:388.
MDR Risk Factors in Pneumonia Coming From the Community Logit in 170 patients with pathogen isolated Variable OR 95% CI P Value Prior Hospitalization 4.87 1.90-12.4 0.001 Nursing Home 3.55 1.12-11.24 0.031 14 Aliberti S, et al. Clin Infect Dis 2012; 54:470-478.
0 0.5 3 12.5 Variable Score *CVA, DM, COPD, antibiotics in preceeding 90 days, home wound care, home infusion therapy Aliberti S, et 15 al. Clin Infect Dis 2012; 54:470-478. None 0 Co-morbidites* 0.5 Nursing home 3 Prior hospitalization 4 Chronic renal failure 5
Validation of Risk Score for MDR in Pneumonia From the Community Variable Score Recent hospitalization 4 Nursing home 3 Chronic renal failure 2 ICU admission 1 HCAP Definition Risk Score > 0 Sens Spec PPV NPV Accuracy 91.0% 34.3% 54.8% 81.3% 60.7% 88.6% 54.5% 63.0% 84.5% 70.4% 16 Shorr AF, et al. Clin Infect Dis 2012; 54:193-198.
% of Patients Validation of Risk Score for MDR in Pneumonia From the Community Prevalence of Resistant Pathogens as Function of Score Figure 1. Receiver Operating Curve Figure 2. 100 80 60 p<0.0001 n=456 n=185 40 20 0 n=336 0 1-5 6-10 Total Score 17 Shorr AF, et al. Clin Infect Dis 2012; 54:193-198. N = 977 Resistant pathogen = 456 (46.7%)
Proposed Algorithm for HCAP Therapy HCAP Is Present (from a nursing home, home infusion therapy, home wound care, dialysis center, hospitalized in past 90 days) Assess Severity of Illness (ICU or mechanical ventilation) and MDR Risks (recent antibiotic therapy, poor functional status, recent hospitalization, immune supression) Severe Illness NO YES 0 1 MDR Risks: Treat for common CAP pathogens (consider oral Rx) Quinolone, β-lactam/macrolide 18 > 2 MDR Risks: Consider hospital admit Treat for MDR pathogens with HAP recommendations 0 MDR Risks: Consider IV therapy with β-lactam PLUS Macrolide or Quinolone Brito V, Niederman MS. Current Opinion in Infectious Diseases 2009; 22:319-325. > 1 MDR Risks: Treat for MDR pathogens with HAP recommendations Need 3 drugs
Thirty-day mortality in CAP and HCAP, with each HCAP stratified by the number of (MDR) risk factors 19 Maruyama T et al. Clin Infect Dis. 2013;57:1373-1383
Comparison of Clinical Prediction Models for Resistant Bacteria in CAP ROC AUC was similar for each of the six algorithms, ranging from 0.63 to 0.6 20 Self WH, et al. Acad Emerg Med 2015;22:730-740.
Local Prevalence of MDR/XDR is Key! 21 Martin-Loeches I, et al. Curr Opin Crit Care 2014; 20:516-524.
Clinical Features Suggesting Community- Acquired MRSA Pneumonia 22 Wunderink RG, et al. N Engl J Med 2014;370:543-551.
In the Critically ill Patient Hit Hard and Fast 23
Probability of Adequate Empiric Therapy in Patients with K. pneumoniae Bacteremia 24 Girometti, et al. Medicine 2014;93: 298 308.
BJH/WU St. Louis 1250-Beds (+ 350 beds): Medical ICU 44 beds Surgical/Trauma ICU 24 beds Neuro ICU - 24 beds Coronary Care Unit - 18 beds Cardiothoracic ICU - 24 beds 25 PACU 80 beds Specialty Surgery ICU 12 beds LVAD/ECMO ICU 9 beds LTAC 12 beds New Wing 24 beds 271 ICU Beds
26 Vazquez-Grande G, et al. Semin Respir Crit Care Med. 2015 Feb;36(1):154-166.
Combination Therapy Gram-negative Bacteremia Complicated by Severe Sepsis (N = 760) Pathogen, N (%) Community Acquired N = 72 Healthcare-associated Community onset N = 269 Hospital - onset N = 419 P. aeruginosa (n = 132) 6 (4.5) 44 (33.3) 82 (62.1) Acinetobacter sp. (n = 63) 3 (4.8) 16 (25.4) 44 (69.8) Other NFGNR (n = 32) 0 (0) 2 (6.3) 30 (93.7) E. coli (n = 232) 43 (18.5) 102 (44.0) 87 (37.5) Klebsiella sp. (n = 188) 10 (5.3) 61 (32.4) 117 (62.2) Enterobacter sp. (n = 76) 5 (6.5) 24 (31.6) 47 (61.8) Other enterobacteriaceae (n = 98) 10 (10.2) 43 (43.9) 45 (45.9) 27 Micek ST, et al. AAC 2010;54:1742.
Sepsis Due to GNB in the Hospital Setting 28 Micek ST, et al. AAC 2010;54:1742-1748.
Antimicrobial Resistance 29 Micek ST, et al. AAC 2010;54:1742.
Resistance (%) The Impact of Combination Therapy: Hospital-Onset or Healthcare-Associated Alone Plus Ciprofloxacin Plus Gentamicin 30 25 20 15 10 23.6 19.6 15.5 15.8 11.2 8.8 26.3 18 12.9 5 0 Cefepime Imipenem or Meropenem Piperacillintazobactam 30 Micek ST, et al. AAC 2010;54:1742.
De-Escalation and Outcome In Severe Sepsis/Septic Shock N = 628 31 Garnacho-Montero J, et al. Intensive Care Med 2014;40:32-40.
New Paradigm - Pathogen directed therapies have arrived! 32
Empiric Gram-Negative Regimen Recommendation + MRSA + MRSA 33 UptoDate 2015
Conclusions Understand your local epidemiology Appropriate drug selection and Adequate dosing/duration/infusion/timing Use microbiology results to de-escalate Insure compliance w/ ASP Employ new agents/technology as available 34
35 Thank you!