Current issues in Antibiotic Use - Internal Medicine | ACP

Current issues in Antibiotic Use - Internal Medicine | ACP

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. Objectives Discuss emerging issues related to antimicrobial resistance Discuss methods to control antimicrobial resistance

Encourage healthcare workers to think about how antibiotics are used 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 penicillinfast organisms is bred out which can be passed to other individualsIn 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. Penicillins finder assays its future. New York Times. 1945; 21 Outpatient antibiotic prescriptions per 1000 Persons, 2010 LA Hicks. NEJM. 368;15. April 11, 2013

Trends in outpatient antibiotic use in U.S. (per 1000 persons) AGENT ALL CLASSES Penicillins Macrolides Cephalosporins Fluoroquinolones Tetracyclines TMP/Sulfa Other (vanco, linezolid, dapto, polymyxins, carbapenems) 1999 966 352 209 117

83 71 74 0.33 2010 801 248 211 114 94 67 66 1.0 % Change -17 -30 NC

-35 +14 +200 2010 (UT) 791 293 176 129 69 73 51 0.7 Data from www.cddep.org (Center for Disease Dynamics, Economics & Policy) Outpatient ABX Use: US vs. Sweden U.S.

(2010) ABX/1000 persons 833 TOP ANTIBIOTICS AZITHROMYCIN PENICILLINS SWEDEN (2012) 388 PCN VK DOXYCYCLINE FLOXACILLIN PIVMECILLINAM NITROFURANTOIN LA Hicks. NEJM. 368;15. April 11, 2013 A Ternhag. NEJM. 369;12. Sept 19, 2013 CASE #1

76 y/o man presented to ED with abrupt onset of chills, nausea, vomiting, dysuria and difficulty urinating. In usual state of health prior to admission. Other than constipation, ROS negative No hospitalizations in past 12 months CASE #1 PMHx: DM Recurrent DVT HTN Factor V Leiden Deficiency MEDICATIONS (HOME): Glipizide Metformin Lipitor Coumadin

Lisinopril/HCTZ Diltiazem SOCIAL HISTORY: Retired landscaper No ETOH, Illicits, Tobacco Exercises weekly CASE #1 VITALS: Temp 39.2, HR 108, BP 111/52, Sat 92% ABDOMEN: Soft/slightly distended/ non-tender BACK: No CVA tenderness LABS:

Cr 1.41 (Baseline 1.25) WBC 3.7, HGB 14.2, PLT 85 Urinalysis: Cloudy, Large Leuk Esterase, >30 WBC Question #1 Patient was diagnosed with urosepsis. What antibiotic regimen would you start? a) b) c) d) e) f) Cefepime

Ceftriaxone Imipenem or meropenem Ertapenem Ciprofloxacin Piperacillin/Tazobactam CASE #2 79 y/o woman with HPV, cirrhosis, DM admitted with fever and diarrhea. Multiple episodes of daily, non-bloody diarrhea and abdominal pain x 1 month. 1 week PTA, developed regular fevers to 101 +urinary frequency without dysuria or urgency. Recently returned from a 3 month stay in India CASE #2 PMHX Breast CA s/p lumpectomy

4/2013. On tamoxifen. DM HTN Hep B with cirrhosis Choledocholithiasis PSHX Lumpectomy Cholecystectomy R TKA 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 #2 Patient was diagnosed with urosepsis. What antibiotic regimen would you start? a) b) c) d) e) f) Cefepime Ceftriaxone

Imipenem/meropenem Ertapenem Ciprofloxacin Piperacillin/Tazobactam Hospital Course Blood + urine cultures: for ESBL E. coli Case #1 Started on Cefepime Switched to MEROPENEM on Day #3 of hospitalization Case #2 Started on Ciprofloxacin and ceftriaxone Switched to MEROPENEM on Day #3

E coli susceptibilities: CASE #1 AND #2 Susceptible Carbepenems Nitrofurantoin Resistant All cephalosporins Pip/Tazobactam Cipro/levaquin Amox/Clav Ampicillin Tobramycin Gentamicin Bactrim QUESTION #3 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) Europes fault f) What in the world is a CRE? Emerging Antibiotic Resistant Organisms PCN Res Strep pneumo VRE MRSA Penicillin resistant Staph

aureus CRE MDRO P. aerug FQR CRAB ESBL E. coli FQR FQR Ceftriaxone Campy Resistant NG NG 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 -lactamase VRE=vancomycin resistant Enterococcus http://wellcommons.com/users/jestevens/photos/2011/apr/10/211822/ Fluorquinolone-resistant E. coli (%) RESISTANT (2009) Iceland UK US Mountain Region=18% United States

Germany Spain Turkey 0% 10% 20% 30% 40% 50% 60% http://www.cddep.org/ResistanceMap/bugdrug/EC-FQ#.Ui0G-Ra3CRI

Mechanisms of FQ Resistance Alterations in target enzymes DNA gyrase (GyrA and GyrB) Topoisomerase IV (ParC and ParE) Alterations in permeation of drug to reach target Porin reduction Eflux pumps Plasmid Mediated FQ Resistance Discovered in 1994 Plasmid = pMG252 Encodes QnrA protein Carries multiple resistance determinants Binds to DNA gyrase and Topoisomerase IV May be carried with other resistance genes

Risk Factors for Acquisition of FQ Resistance in LTCF Prospective, cohort study 47.5% LTCF residents became colonized Time to colonization=57 days Fecal Incontinence Receipt of amox/clavulanate Presence of urinary catheter HR 1.78 6.48 3.81 95% CI 1.04, 3.06 1.43, 29.4 1.06, 13.8

JH Han, JID. 2013 Aug 28 Risk Factors for Acquisition of Community-Acquired FQREC Nested case-control study FQREC=51, Controls=369 Resistance to multiple antibiotics present Hospitalization within previous 6 months Receipt of FQ Presence of urinary catheter HR 2.03 95% CI

0.96-4.31 17.5 3.14 6.0-50.7 0.85-11.6 WE van der Starre. JAC. 2011;66 650-656 Number of -lactamase enzymes described during age of antibiotics Number of Unique Enzymes 900 1973

2013 Julian Davies. Micro biol and Molecular Bio Rev. Sept. 2010, p. 417-433 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., 2013. CDC Location of gene Inhibited by clavulanic acid Cefepime useful Cephamycin resistant Pathogens ESBL (CLASS A)

AmpC (CLASS C) Plasmid YES Chromosomal NO NO NO YES YES Klebsiella pneumoniae Escherichia coli Proteus mirabilis Enterobacter cloacae

Salmonella E. cloacae S. marcescens C. freundii M. Morgagnii P. Aeruginosa Y. Enterocolitica Hafnia alvei Common ESBLs blaTEM/blaSHV Epidemiology Preferential targets Number of types Distribution

blaCTX-M Associated with HAIs Community-associated infections Ceftazidime Cefotaxime >100 >50 Global Global 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;14:933-951 M. McKenna. Nature. Vol 499. 25 July 2013 MECHANISMS OF CARBAPENEM RESISTANCE

ESBL or AmpC with porin loss Efflux pump Carbapenemase Common organisms Pseudomonas aeruginosa Acinetobacter spp. Enterobacteriaceae 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., 2013. CDC Carbapenemases

Ambler Classification Class A Enzyme KPC, SME, IMI, Organisms Enterobacteriaceae NMC, GES Class B (metallo-lactamase) NDM-1, IMP, VIM Class D

OXA Enterobacteriaceae, Acinetobacter sp, P. aeruginosa Acinetobacter sp Emergence of carbapenem resistant Enterobacteriaceae M. McKenna. Nature. Vol 499. 25 July 2013 Global Distribution of Klebsiella pneumoniae carbapenemase LS Munoz-Price. LANCET INFECT DISEASES. Vol 13:785. Sept 2013. 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):532-540 From www.medicaltourismmag.com Outbreak of NDM-1 K. pneumo 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 MIC2 g/mLg/mL Highly related by PFGE Multiple transmission events in 3 units Not all patients overlapped Source not identified MMWR. Feb. 15, 2013. 62(06);108 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 Why are CREs clinically important? KPC Gene Location

NDM-1 Highly transferable plasmids Treatment options Outcomes Limited Infections associated with high mortality Reporting required in Utah Outbreaks Mostly clonal Mostly polyclonal Asymptomatic carriage plays an key role in transmission

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) CDCs Four Core Actions Prevent infections, prevent spread Track resistance patterns Improve use of antibiotics Develop new antibiotics and diagnostic tests Antibiotic Resistance Threats in the U.S., 2013. CDC Mechanism of Resistance: Horizontal Gene Transfer INFECTION CONTROL MEASURES TO

PREVENT SPREAD OF CRE Awareness HAND HYGIENE Use glove and gowns for every encounter Use equipment dedicated Communicate with facilities for transfers Limit HCW exposure Emerging Antibiotics Antibiotic Pipeline PRODUCT STATUS WT P aerug

ESBL KPC NDM-1 Ceftolozane/taxobactama Ceftazidime-avibactama Phase 3 Phase 3 Y Y Y Y

N Y N N Ceftaroline-avibactama Phase 2 N Y Y N Imipenem/MK-7655a

Phase 2 Y Y Y N Plazomicinb Phase 2 N Y

Y ? Eravacyclinec Phase 2 N Y Y ? Brilacidind Phase 3

? Y ? ? a. b. c. d. -lactamase inhibitor Aminoglycoside Fluorocycline (targets ribosome) Peptide defense protein mimetic

WT=wild type ESBL=Extended spectrum beta lactamase KPC=Klebsiella pneumoniae carbapenemase NDM-1=New Delhi metallo--lactamase HW Boucher. CID. 2013;56(12):1685-94 FDA approved rapid diagnostic platforms MALDI-TOF Method Mass spectrometry ADVANTAGES Rapid speciation of microorganisms PNA FISH Quick FISH Nucleic acid

hybridization Rapid speciation of Staphylococcus sp, Enterococcus sp, GNR, Candida sp directly out of blood culture Rapid speciation of most common gram positive cocci and resistance markers (mecA, Van A, Van B) directly out of blood culture Gram positive, gram negative, yeast, resistance markers (VanA, Van B, mecA) directly out of blood culture Verigene BCGP Film Array

BCID panel Microarray-based nucleic acid hybridization Multiplex PCR DISADVANTAGES Requires growth in solid media No resistance markers No resistance markers No gram negatives rods or Candida sp yet No gram negative resistance markers

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 While essential, waiting for new antibiotics is not the solution for combating antibiotic resistance THANK YOU FOR YOUR ATTENTION!

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