Rise of Resistance: From MRSA to CRE Paul D. Holtom, MD Professor of Medicine and Orthopaedics USC Keck School of Medicine SUPERBUGS (AKA MDROs) MRSA Methicillin-resistant S. aureus
Evolution of Drug Resistance in S. aureus Penicillin Methicillin Methicillinresistant S. aureus Penicillin-resistant [1950s] [1960s] S. aureus S. aureus (MRSA) MRSA Trend (HA + CA) in US TSN Database USA (1993-2003) % of MRSA among S. aureus Isolates 45 40 35 30 25 20 15 10 48.5 42.5 36.0 29.1 25.1 26.2 1993 1995 1997 1999 2001 2003 Year MDR = multidrug resistant, CA = community-acquired. TSN Database, USA, Focus Technologies. Data on file, Ortho-McNeil Pharmaceutical, Inc. METHICILLIN RESISTANT STAPHYLOCOCCUS AUREUS Contains meca gene for PBP-2a PBP-2a has low affinity for all β lactams: Penicillins Cephalosporins (except ceftaroline (Teflaro)) Carbapenems meca gene located on mobile element integrates into specific site of chromosome
Evolution of Drug Resistance in S. aureus Penicillin Methicillin [1997] Vancomycin Methicillinresistant S. aureus Penicillin-resistant [1950s] [1960s] S. aureus S. aureus (MRSA) Vancomycinresistant S. aureus Vancomycin intermediateresistant S. aureus (VISA) [1990s] Vancomycin-resistant enterococci (VRE) Risk Factors for MRSA Setting Risk Factors for Infection and Colonization n Previous hospital stay 1,2 n Prolonged length of stay prior to infection 1 Hospitals n Surgical procedure(s) 1 n Enteral feeding 1 n Levofloxacin use 1 n Presence of decubitus ulcer Long-Term Care Facilities 3 n Presence of wounds 3 Prior Antibiotic Exposure 4,5 n Third-generation cephalosporins 6 n Fluoroquinolones 1,7,8 1.Graffunder EM, Venezia RA. J Antimicrob Chemother. 2002;49:999-1005. 5.Law MR et al. Epidemiol Infect. 1988;101:623-629. 2.Asensio A et al. Infect Control Hosp Epidemiol. 1996;17:20-28. 6. Peacock JE et al. Ann Intern Med. 1980;93:526-532. 3.Terpenning MS, et al. J Am Geriatr Soc. 1994;42:1062-1069. 7. Evans ME et al. J Antimicrob Chemother. 1998;41:285-288. 4.Hershow RC et al. Infect Control Hosp Epidemiol. 1992;13:587-593. 8.Harbarth S et al. Clin Infect Dis. 2000;31:1380-1385. Risk Factors Associated Independently with MRSA Infection Risk Factor OR 95% CIs P Value Levofloxacin use 8.01 3.15, 20.3 <0.001 Enteral feeding 2.55 1.37, 4.72 0.003 Surgery 2.24 1.19, 4.22 0.01 Previous hospitalization Length of stay before culture 1.95 1.02, 3.76 0.04 1.03 1.0, 1.07 0.05 Graffunder EM, Venezia RA. J Antimicrob Chemother. 2002;49:999-1005.
Mortality Associated with Bacteremia Due to MRSA vs. MSSA Outcome MRSA-infected Patients MSSA-infected Patients Recovered 70.4% 86.4% Died of other causes 17.8% 8.5% Died of infection* 11.8% 5.1% *P<0.001 Melzer M, et al. Clin Infect Dis. 2003;37:1453-1460. S. aureus Surgical Site Infections : Impact of Methicillin Resistance on Outcomes All-cause 90-day mortality, unadjusted (%) 30 20 10 0 25/121 Independent effect of MRSA: OR 3.4 (95% CI 1.5-7.2, P = 0.003) After adjusting for age, ASA score, duration of surgery 11/165 4/193 MRSA MSSA Controls ASA Score: American Society of Anesthesiologists score of pre-operative physical fitness Engemann JJ, Carmeli Y, Cosgrove SE, et al. 2003 Clin Infect Dis. 36:592-598. MRSA Increasing prevalence >60%-70% of S. aureus in ICUs? Increasing virulence CA-MRSA and PVL?? Optimal therapy
VANCOMYCIN IN MSSA PNEUMONIA Mortality 50 45 40 35 30 25 20 15 10 5 0 Cloxacillin (0/10) Vancomycin (8/17) Gonzalez C. CID 29:1171-7, 1999 VANCOMYCIN IN MSSA BACTEREMIA 25 20 21 19 % patients 15 10 6 11 7 Nafcillin Vancomycin 5 0 Persistent >3 d 0 0 0 Persistent Relapse Failure >7 d Chang FY, et al. Medicine. 82:333-339, 2003. VANCOMYCIN Current challenges Reported cases of failure with vanco Rising MICs and reports of resistance Heteroresistance Choosing doses: what level is best? What about continuous infusion? Toxicities
MRSA?? Optimal therapy Vancomycin Quinopristin/dalfopristin (Synercid) Linezolid (Zyvox) Daptomycin (Cubicin) Ceftaroline (Teflaro) [Tigecycline (Tygacil)] [Telavancin (Vibatif)] SUPERBUGS (AKA MDROs) MRSA Methicillin-resistant S. aureus VRSA or GRSA Vancomycin resistant S. aureus VISA/GISA Vancomycin (Glycopeptide) Intermediate resistant S. aureus First identified 1996 in Japan Reported in US, UK, France, Brazil, Asia Have thickened cell wall Vancomycin MIC is 8-16 µg/ml
VRSA Due to VRE gene (VanA) Vancomycin MIC is >32 µg/ml Only 10 cases reported so far Optimal treatment unknown Prevention is the key SUPERBUGS (AKA MDROs) MRSA Methicillin-resistant S. aureus VRSA or GRSA Vancomycin resistant S. aureus VRE Vancomycin resistant Enterococcus VANCOMYCIN RESISTANT ENTEROCOCCI First seen in Europe in 1986 US in 1989 Usually in Enterococcus faecium Resistance due to change in binding site for vancomycin
VANCOMYCIN RESISTANT ENTEROCOCCI Usually a hospital-acquired infection Between 20,000 and 85,000 cases of VRE each year in U.S. hospitals Rate continues to increase VRE is now endemic in many ICUs Persists in environment for months VANCOMYCIN RESISTANT ENTEROCOCCI Infections: Urine Bloodstream Wounds Associated with significant excess morbidity, mortality, and cost MRSA VRSA or GRSA VRE SUPERBUGS (AKA MDROs) ESBLs Extended spectrum beta-lactamases
MDRO Gram-Negative Rods Extended-spectrum beta-lactamase Resistance to all penicillins and cephalosporins E. coli, Klebsiella pneumoniae, Enterobacter spp Increasing prevalence Classification of Beta-Lactam Hydrolyzing Enzymes Beta - Lactamases Serine Serine acylation Metallo(Zn) Zinc-facilitated hydrolysis Group 1 Group 2be Group 2d Group 3 Group 4 Class C AmpC Clav-R Class A TEM/SHV CTX- M ESBLs Clav-S Single point mutations in TEM-1 create CTX-Ms Class D OXA Clav-R/S Chromosomal and plasmid Class B IMP/VIM Clav-R EDTA-S Plasmid-mediated transfer Not wellcharacterized Global Issues with ESBL- Producing Enterobacteriaceae More frequent outside USA Asia, 9-30% Latin America and parts of Europe, 60% In USA, ESBL-E.coli and K. pneumoniae rates: 5%-10% Higher in Mid-Atlantic states (ESBL-producing K.pneumoniae, ~20%) Brooklyn, NY 34% K. pneumoniae produce ESBL ICUs have higher rates of ESBLs Rising incidence in LTCFs
Adverse Clinical Impact of ESBL- Producing Enterobacteriaceae Inadequate initial antimicrobial therapy associated with higher mortality in non-urinary infections due to ESBL-producing Enterobacteriaceae (OR=2.28) Delay in time to institution of effective antimicrobial therapy was associated with increasing mortality The rate of treatment success for patients infected with ESBL-producing E. coli and Klebsiella spp. whose initial treatment involved non-carbapenems was lower than controls (39% vs 83%; P=0.013) 1 Hyle EP et al. Arch Intern Med. 2005;163:1375-80. 2 Lee SY et al. Infect Cont Hosp Epidemiol. 2006;27:1226-32. SUPERBUGS (AKA MDROs) ESBLs Extended spectrum beta-lactamases CREs Carbapenemase producers CREs Carbapenem-resistant Enterobacteriaceae Klebsiella, Enterobacter, E. coli Produce enzymes that destroy carbapenems (imipenem, meropenem, doripenem and ertapenem) KPC, NDM-1,VIM, IMP Resistance to all beta-lactams
CREs First detected in a North Carolina hospital in 2001 Primarily a hospital acquired infection Increasing prevalence One in 25 acute-care facilities reported at least one case of hospital-acquired CRE last year CRE in the United States CREs Increasing prevalence 3% of patients in Chicago-area ICUs carried CRE 30% colonization rate in long-term care facilities In first half of 2012, almost 200 hospitals and long-term acute care facilities treated at least one patient
CRE Outbreak in Denver in 2012 Largest US outbreak of NDM 8 patients; all isolates highly related CREs Associated with higher mortality Mortality from bacteremia is 50% Optimal therapy is undefined Colistin is often used COLISTIN Discovered in 1949 Released in 1952 Polymyxin antibiotic Acts by destroying bacterial cell membrane Optimal dosing unknown Must be dose adjusted in renal failure
FUTURE DIRECTIONS New antibiotics Very few in development at this point ANTIBACTERIAL AGENTS APPROVED 1983-2011 16 No. of New Antibacterial Agents 14 12 10 8 6 4 2 0 1983-87 1988-92 1993-97 1998-2002 2003-7 2008-11 Period Clin Infect Dis. 2011;52:S397-S428. A SHORT HISTORY OF MEDICINE 2000 BC: Here, eat this root 1000 AD: That root is superstitious. Here, say this prayer. 1700 AD: That prayer is superstitious. Here, take this potion. 1900 AD: That potion is ineffective. Here, take this pill. 1950 AD: That pill is ineffective. Here, take this antibiotic.
A SHORT HISTORY OF MEDICINE 2000 AD: That antibiotic is ineffective. Here, eat this root. FUTURE DIRECTIONS New antibiotics Antibiotic stewardship De-escalation of therapy Culture directed, narrow spectrum The Cycle of Antimicrobial Use and Resistance Resistance Houghton, D. AACN Clin Issues. 2002;13:410-420.
FUTURE DIRECTIONS New antibiotics Antibiotic stewardship Prevention PREVENTION Hand hygiene
PREVENTION Environmental measures Adequate cleaning of all surfaces? Daily chlorhexidine baths PREVENTION Isolation precautions Spread by contact and fomites Should we screen? Who? When to put patients in? When to take patients out? Human destiny is bound to remain a gamble, because at some unpredictable time and in some unforeseeable manner, nature will strike back. Mirage of Health, Rene Dubos, 1959
THANK YOU