Current issues in Antibiotic Use: the Continued Evolution of Antimicrobial Resistance

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1 Current issues in Antibiotic Use: the Continued Evolution of Antimicrobial Resistance Bert K. Lopansri, MD Division of Infectious Diseases and Clinical Epidemiology Associate Professor, University of Utah Medical Director, Intermountain Central Laboratory DISCLOSURES Research support from: Nanosphere, Inc. Ansell, Inc. Catheter Connections, Inc. 1

2 Objectives Discuss emerging emerging antimicrobial resistant organisms Discuss methods to control antimicrobial resistance Encourage healthcare workers to think about how antibiotics are used 2

3 Fleming in reference to Penicillin The public will demand [the drug and] then will begin an era of abuses. The microbes are educated to resist penicillin and a host of penicillin fast organisms is bred out which can be passed to other individuals In such a case the thoughtless person playing with penicillin treatment is morally responsible for the death of the man who finally succumbs to infection with penicillin resistant organism. I hope the evil can be averted. Fleming A. Penicillin s finder assays its future. New York Times. 1945; 21 Trends in outpatient antibiotic use in U.S. (per 1000 persons) AGENT % Change 2010 (UT) ALL CLASSES Penicillins Macrolides NC 176 Cephalosporins Fluoroquinolones Tetracyclines TMP/Sulfa Other (vanco, linezolid, dapto, polymyxins, carbapenems) Data from (Center for Disease Dynamics, Economics & Policy) 3

4 Outpatient antibiotic prescriptions per 1000 Persons, 2010 LA Hicks. NEJM. 368;15. April 11, 2013 Outpatient ABX Use: US vs. Sweden U.S. (2010) SWEDEN (2012) ABX/1000 persons Top Antibiotics Azithromycin Penicillins PCN VK Doxycycline Floxacillin Pivmecillinam Nitrofurantoin LA Hicks. NEJM. 368;15. April 11, 2013 A Ternhag. NEJM. 369;12. Sept 19,

5 materials/week/images/antibiotic use.jpg CASE 79 y/o woman with HPV, cirrhosis, DM admitted with fever and diarrhea. Multiple episodes of daily, non bloody diarrhea and abdominal pain x1 month. 1 week PTA, developed regular fevers to 101 o F +urinary frequency without dysuria or urgency. Recently returned from a 3 month stay in India 5

6 PMHX Breast CA s/p lumpectomy 5 months earlier DM HTN Hep B with cirrhosis Choledocholithiasis PSHX Lumpectomy Cholecystectomy R TKA CASE EXAM: Temp 38.4, RR 25, HR 120, BP 138/71 Non toxic ABD distended with diffuse tenderness. Liver and spleen unable to be palpated LABS: WBC 13.0 (PMN 81.4%), HGB 8.2, PLT 275 BUN 36, Cr 3.17 Urine: Cloudy, + Nitrite, Large Leuk Esterase, >30 WBC Question #1 Patient was diagnosed with urosepsis. What antibiotic regimen would you start? a) Cefepime b) Ceftriaxone c) Imipenem/meropenem d) Ertapenem e) Ciprofloxacin f) Piperacillin/Tazobactam 6

7 Question #2 Carbapenem resistant Enterobacteriaceae (CRE) is: a) An overhyped, story that is unlikely to be a significant problem where I practice medicine. b) A global problem c) A U.S. problem d) A problem only in certain parts of the world e) Europe s fault f) What in the world is a CRE? Emerging Antibiotic Resistant Organisms 7

8 VRE MRSA Penicillin resistant Staph aureus PCN Res Strep pneumo CRE ESBL FQR CRAB E. coli FQR FQR Campy NG Ceftriaxone Resistant NG MDRO P. aerug FQR= fluoroquinolone resistant MDRO=multidrug resistant MRSA=methicillin resistant Staph aureus NG=Neiserria gonorrhea PCN=penicillin CRAB=carbapenem resistant Acinetobacter baumanii CRE=carbapenem resistant Enterobacteriaceae ESBL=extended spectrum β lactamase VRE=vancomycin resistant Enterococcus Number of β-lactamase enzymes described during age of antibiotics 900 Number of Unique Enzymes Julian Davies. Micro biol and Molecular Bio Rev. Sept. 2010, p

9 Enzymes that mediate resistance to extendedspectrum cephalosporins (third generation) and monobactams but do not affect cephamycins (cefoxitin/cefotetan) or carbapenems. Activity is reversed by clavulanic acid Antibiotic Resistance Threats in the U.S., CDC Common ESBLs TEM/SHV CTX M Epidemiology Associated with HAIs Community associated infections Preferential Ceftazidime Cefotaxime targets Number of types >100 >50 Distribution Global Global 9

10 Emergence of CTX-M in a Single Health Care System 88 proven ESBL isolates CTX M = 59% SHV = 47% Most common sources: Urine (60%) Blood (21%) Respiratory (10%) TOTAL ESBL CTX M SHV TEM CTX M + SHV 2006 JS Lewis II, and others. AAC. Nov (11):4015 CTX-M E. coli is Resistant to Multiple Classes of Antibiotics (% Resistant) CTX-M (n=319) Non-CTX-M (n=58) Ciprofloxacin 95% 60% <0.001 Tobramycin 65% 31% <0.001 Gentamicin 51% 24% <0.001 TMP/SMX 62% 41% 0.06 Tetracycline 63% 41% Nitrofurantoin 13% 19% Pip/Taz 10% 12% 0.63 Cefepime 93% 36% <0.001 K. Hayakawa. AAC. August Vol 57(8): P 10

11 Risk Factors for ESBL Infections Length of hospital stay Severity of illness Time in ICU Mechanical ventilation Urinary catheterization Previous antibiotic exposure Bradford PA. Clin Microbiol Rev. 2001;14: CASE Started on empirically Ciprofloxacin and ceftriaxone Blood + urine cultures: for E. coli ABX changed to MEROEPNEM E coli susceptibilities Susceptible Carbapenems Nitrofurantoin Resistant All cephalosporins Pip/Tazobactam Cipro/levaquin Amox/Clav Ampicillin Tobramycin Gentamicin Bactrim 11

12 M. McKenna. Nature. Vol July 2013 MECHANISMS OF CARBAPENEM RESISTANCE ESBL or AmpC with porin loss Efflux pump Carbapenemase Common organisms Pseudomonas aeruginosa Acinetobacter spp. Enterobacteriaceae (Klebsiella pneumoniae, E coli) 12

13 CRE = Enterobacteriaceae resistant to one of the carbepenems (Doripenem, imipenem or meropenem) and third generation cephalosporins (ceftriaxone, cefotaxime, ceftazidime) Guidance for Control of Carbapenem resistant Enterobacteriaceae 2012 CRE Toolkit, CDC. Antibiotic Resistance Threats in the U.S., CDC Carbapenemases Ambler Classification Class A Class B (metallo βlactamase) Enzyme KPC, SME, IMI, NMC, GES NDM 1, IMP, VIM Organisms Enterobacteriaceae Enterobacteriaceae, Acinetobacter sp, P. aeruginosa Class D OXA Acinetobacter sp 13

14 Emergence of CRE M. McKenna. Nature. Vol July 2013 Global Distribution of Klebsiella pneumoniae carbapenemase (KPC) LS Munoz Price. LANCET INFECT DISEASES. Vol 13:785. Sept

15 KPC in U.S. Regional spread of KPC CRE 1. DELAYED RECOGNITION OF KPC 2. AMPLIFICATION IN LTACHS AND NH 3. DESPITE INVOLVEMENT OF A SINGLE LTACH, KPC QUICKLY BECAME A REGIONAL PROBLEM 4. COORDINATED, REGIONAL EFFORTS AMONG HOSPITALS, LTACHS, AND PUBLIC HEALTH DEPT S.Y. Won. CID. 2011;53(6):

16 From Emergence of CRE M. McKenna. Nature. Vol July

17 Why are CREs clinically important? KPC NDM 1 Gene Location Treatment options Outcomes Organisms Highly transferable plasmids Limited Infections associated with high mortality K. pneumoniae, E. coli (other Enterobacteriaceae) Outbreaks Mostly clonal Mostly polyclonal Asymptomatic carriage plays a key role in transmission RISK FACTORS FOR CRE AQUISITION Exposure to healthcare Recent organ or stem cell transplantation Mechanical ventilation Longer length of stay Poor functional status Receipt of multiple classes of antibiotics Carbapenems Cephalosporins Fluoroquinolones Vancomycin Neil Gupta. CID. 2011:53. (July 1) 17

18 Antibiotic Susceptibilities for NDM-1 UK (n=37) Chennai (n=44) Haryana (n=26) Imipenem 0% 0% 0% Meropenem 3% 3% 3% Piperacillin tazobactam 0% 0% 0% Cefotaxime 0% 0% 0% Ceftazidime 0% 0% 0% Cefpirome 0% 0% 0% Aztreonam 11% 0% 8% Ciprofloxacin 8% 8% 8% Gentamicin 3% 3% 3% Tobramycin 0% 0% 0% Amikacin 0% 0% 0% Minocycline 0% 0% 0% Tigecycline 64% 56% 67% Colistin 89% 94% 100% KK Kumarasamy. Lancet ID. Vol 10. September 2010 Outbreak of NDM-1 K. pneumoniae in Denver, CO 8 cases between Jan Oct 2012 at acute care hospital 3 infections 5 identified by active surveillance K pneumoniae Susceptible to tigecycline with colisitin MIC 2 μg/ml Highly related by PFGE Multiple transmission events in 3 units Not all patients overlapped Source not identified MMWR. Feb. 15, (06);108 18

19 KPC Treatment Failure: Monotherapy vs. Combination Mono (%) Combo (%) P OVERALL 24/49 (49) 14/56 (25) 0.01 Source Blood 12/24 (50) 9/32 (28) 0.09 Pulmonary 10/15 (67) 5/17 (29) 0.03 Urine 1/8 (13) 0/3 (0) 0.4 Polymyxin failure 8/11 (73) 10/34 (29) 0.03 Carbapenem 12/20 (60) 5/19 (26) 0.03 Tigecycline 2/7 (29) 7/19 (37) 0.4 Aminoglycoside 0/6 (0) 4/24 (17) 0.6 GC Lee and DS Burgess. Annals of Clin Micro and Antimicrobials. 2012, 11:32 Monotherapy with Polymyxin B May Select for Resistance Monotherapy (n=12) + Tigecycline (n=4) Increased MIC 3/12 (25%) 0 CASE μg/ml CASE μg/ml CASE μg/ml Jooyun Lee. J Clin Micro. May Vol 47(5):

20 Seven Ways to Preserve Antibiotics US database for antibiotic use and resistance Restrict use of antibiotics in agriculture Prevent selected nosocomial infections Practice antimicrobial stewardship Promote use of new diagnostic tests (POC) Reduce FDA antibiotic barrier Facilitate public private partnerships for antibiotic development Bartlett, JG. CID. 2013:56 (15 May) Mechanism of Resistance: Horizontal Gene Transfer 20

21 PREVENT SPREAD OF CRE Awareness Hand hygiene Contact Isolation Gloves + Gowns Equipment dedicated to room Disinfect personal equipment used in room Limit HCW exposure COMMUNICATE!!! 21

22 Antibiotic Pipeline PRODUCT STATUS WT P aerug ESBL KPC NDM 1 Ceftolozane/taxobactam a Phase 3 Y Y N N Ceftazidime avibactam a Phase 3 Y Y Y N Ceftaroline avibactam a Phase 2 N Y Y N Imipenem/MK 7655 a Phase 2 Y Y Y N Plazomicin b Phase 2 N Y Y? Eravacycline c Phase 2 N Y Y? Brilacidin d Phase 3? Y?? a. Β lactamase inhibitor b. Aminoglycoside c. Fluorocycline (targets ribosome) d. Peptide defense protein mimetic WT=wild type ESBL=Extended spectrum beta lactamase KPC=Klebsiella pneumoniae carbapenemase NDM 1=New Delhi metallo β lactamase HW Boucher. CID. 2013;56(12): FDA approved rapid pathogen identification platforms: blood cultures METHOD ADVANTAGES DISADVANTAGES PNA FISH Quick FISH (AdvanDX) Xpert (Cepheid) Verigene BC GP (Nanosphere, Inc.) Verigene BC GN Film Array BCID panel (Biofire/bioMe rieux) Nucleic acid hybridization PCR Microarray based nucleic acid hybridization Multiplex PCR Rapid speciation of Staphylococcus sp, Enterococcus sp, GNR, Candida sp Rapid detection of MRSA/MSSA Rapid speciation of most common gram positive cocci and resistance markers (meca, Van A/Van B) Drug resistance markers (NDM 1, KPC, CTX M) Gram positive, gram negative, yeast, resistance markers (meca, VanA/Van B) No resistance markers Limited number of pathogens Gram negative rods pending FDA approval No Candida sp Pending FDA approval No gram negative resistance markers 22

23 Impact of rapid identification of MRSA/MSSA (Xpert MRSA kit) combined with antimicrobial stewardship Pre-PCR (n=74) Post-PCR (n=82) Mean (SD) LOS, days 21.5 ± ± Mean (SD) Total hospital cost, USD $69,737 ± $96,050 $48,350 ± $55,196 P 0.03 ICU 66% 67% NS Time to optimal therapy (MSSA) Number of vanc to cefazolin/naf changes 8 27 KA Bauer, and others. CID. 2010;51(9): SUMMARY Antibiotic resistance in gram negative organisms is increasing rapidly Preventing spread of organisms in healthcare settings is critical We need to be wiser about how we use antibiotics New antibiotics are essential however are not the solution for combating antibiotic resistance 23

24 THANK YOU! 24