CARBAPENEM-RESISTANT ENTEROBACTERIACEAE (CRE): STRATEGIES IN TREATMENT

Prepared by: Diana Nicole Nowicki, PharmD Candidate 2017

Objectives

¨ Define Carbapenem-Resistant Enterobacteriaceae (CRE) and mechanisms of resistance

¨ Assess clinical significance of CRE nationally, statewide, and institutionally

¨ Review traditional agents used for CRE ¨ Discuss recent literature evaluating

ceftazidime/avibactam (CTZ-AVI) in severe CRE infections and role in current practice

¨ Highlight potential future agents and concerns

Carbapenem-Resistant Enterobacteriaceae (CRE)1,2

¨ Enterobacteriaceae include more than 70 different genera and many different mechanisms can lead to carbapenem resistance.

¨ These gram negative rod bacteria have become resistant to most available antibiotics

¨ Carbapenemase-producing CRE (CP-CRE) are currently believed to be primarily responsible for the increasing spread of CRE in the United States (e.g. Klebsiella pneumoniae carbapenemases(KPC)).

¨ Implicated in a variety of infections, including bacteremia, ventilator-associated pneumonia (VAP), urinary tract infection (UTI), and central venous catheter infection, intra-abdominal infection (IAI).

¨ Generally of concern in severely ill patients in hospital-acquired infections.

¨ Approximately 50% mortality rate with bloodstream infections (BSI) from CRE.

CDC’s CRE definition1

¨ Previous definition (Prior to 1/2015):¤ Nonsusceptible to imipenem, meropenem, or

doripenem, AND resistant to all third generation cephalosporins tested (ceftriaxone, cefotaxime, and ceftazidime).

¨ Current definition¤ Resistant to imipenem, meropenem, doripenem, or

ertapenem OR documentation that the isolate possess a carbapenemase

The True Enemy: Carbapenemases3

¨ Carbapenem-hydrolyzing β-lactamases that confer resistance to a broad spectrum of beta-lactam substrates, including carbapenems.

¨ Ambler Classification: ¤ Class A – KPC , SME, IMI, NMC, GES¤ Class B – NDM, VIM, IMP (Metallo-enzymes)¤ Class C – CMY-10¤ Class D – OXA

Klebsiella Pneumoniae Carbapenemase (KPC)3

¨ Confers resistance to all β-lactams including extended-spectrum cephalosporins and carbapenems

¨ Occurs in Enterobacteriaceae¤ Commonly in Klebsiella pneumoniae¤ Can occur in:

n Other Enterobacteriaceae: E. Coli, Citrobacter, Enterobacter, Salmonella, Serratia spp.

n Non-Enterobacteriaceae: Pseudomonas, Acinetobacter spp.

¨ Identification¤ C&S: Ertapenem resistance (better indicator than other

carbapenems which can be misreported as susceptible)¤ Carbapenemases: Modified Hodge Test¤ PCR: primarily for epidemiological purposes

Why should we be concerned?4

Illinois CRE Surveillance Report, 20145

¨ Started 11/2013, XDRO registry and CRE reporting from Illinois HC facilities and labs

¨ Predominant organism: Klebsiella pneumoniae (85%)¨ Resistance mechanism identified in only 26% total

¤ Of these isolates, 91% KPC¤ Others: OXA-48-like, IMP

¨ 80% identified by following cultures: urine>>sputum>wound

¨ 19% specimen sources were rectal screening cultures (>99% from Chicago and West Chicago)

4

Jesse Brown VA: Example C&S

Jesse Brown VA

MDRO 2010a 2011a 2012a 2013 2014 2015 2016

Klebsiella sp. 2 12 18 6 7 9 3

Carbapenem-Resistant Acinetobacter baumannii

3

Acinetobacter baumannii 2 1

Serratia marcescens 1

Enterobacter sp. 3 1

Citrobacter koseri 1

Total per year 2 12 18 9 10 11 7a Only Klebsiella sp. tracked in 2010-2012

Risk Factors for CP-MDROs3

¨ Use of broad spectrum cephalosporins and/or carbapenems, especially long-duration

¨ Trauma ¨ Malignancy¨ Organ transplantation¨ Mechanical ventilation¨ Indwelling urinary or venous catheters¨ Overall poor functional status or severe illness

Patient Screening & Infection Control3

¨ Transfers¤ Review patient history and colonization/surveillance cultures of MDRO¤ Stay up-to-date on local and institutional outbreaks

¨ Rectal CRE screening culture considerations¤ Hospitalized outside U.S. in past 6 months?¤ Indwelling devices (urinary catheters, tracheostomy, peg tube, ostomy, bile

drainage tube, venous access device)?¤ History of transfers especially from high risk health-care facilities (e.g.

LTACHs, SNFs)?¨ New patient identified

¤ Consult with infection controln Patient exposure if shared room & surveillance cultures n Contact precautions and PPEn Enhanced environmental cleaning

¤ Antimicrobial stewardship

Traditional Agents for CRE6

¨ Refer to C&S¨ Uncomplicated UTI: Aminoglycosides, Fosfomycin¨ Severe Infections (Bacteremia/Lung): Combination*

¤ Dual carbapenem treatment (ertapenem + doripenem or meropenem)

¤ High-dose extended infusion carbapenems (doripenem or meropenem)

¤ A polymyxin¤ Aminoglycosides¤ Glycylcyclines

* Combinations are not well studied and controversial

Ceftazidime-avibactam (CTZ-AVI)7-10

¨ β-lactam (cephalosporin)/β-lactamase inhibitor ¨ Inhibits ESBLs, Ambler class A, C, & D β-lactamases¨ Avibactam prevents and reduces ceftazidime

hydrolysis allowing ceftazidime to remain active against CP/ESBL-Enterobacteriaceae, Pseudomonas

¨ FDA approved 2/2015 for cIAI (+ metronidazole) and cUTI

¨ Currently being studied in more severe infections¤ BSI & Nosocomial Pneumonia (HAP/VAP)

cIAI: complicated intraabdominal infection; cUTI: complicated urinary tract infection

In Vitro Activity11

¨ 2015: Shields et al. examined 72 K. pneumoniae strains, KPC-2 and KPC-3, from 68 UPMC pts and 4 UFH-SH

¨ These strains also haven for other MDR mechanisms (+ESBLs, ompK36)

¨ Results show that avibactam enhances ceftazidime activity, resulting in MICs that are at or below the CLSI ceftazidime susceptibility breakpoint (4 g/ml)¤ However, 24% of the strains exhibited MICs within two 2-

fold dilutions of the CLSI breakpoint (classified as ceftazidime nonsusceptible by EUCAST criteria = susceptible MIC, 1 g/ml)

In Vitro Activity12

¨ JMI Laboratories - Iowa, USA¤ 2012 – 73 medical centers representing all 9 US regions

submitted isolatesn GN isolates from BSI (n=1466) and pneumonia (n=3245)n Susceptibilities of CTZ-AVI, Cefepime, Ceftazidime, Ceftriaxone,

Zosyn, Meropenem, Levofloxacin, Gentamicin, Tigecycline.n CTZ-AVI

n 99.8% of all Enterobacteriaceae exhibited MIC ≤ 4 mg/Ln 96.3% of P. aeruginosa exhibited MIC ≤ 8 mg/Ln 79% showed activity against non-susceptible P. aeruginosa

In Vitro Activity13

¨ JMI Laboratories Surveillance Studies- Iowa, USA¤ 2012-2013 – 71 medical centers provided :

n ICU (n=4381) (including VAP, n=435) n Non-ICU isolates (n=14,483)n Susceptibilities of CTZ-AVI, Cefepime, Ceftazidime, Ceftriaxone,

Zosyn, Meropenem, Levofloxacin, Gentamicin, Colistin.n CTZ-AVI

n 99% activity against all Enterobacteriaceae and MDR strainsn 96.5% activity against XDR strainsn 98% activity against meropenem-non-susceptible strainsn 95.6/97.5/97.3% activity against Pseudomonas of ICU/non-ICU/VAP

n Showed overall poor to no activity for most agents in A. bamanniiisolates

Strengths/Limitations12,13

¨ Studies conducted in vitro with isolates prior >5y ago

¨ Breakpoints used are controversial and

¨ “Clinically Significant” bacterial isolates not define in study protocol but based on local institutions reporting algorithms à influence sample set

¨ Phenotypic testing only

¨ Difficult to evaluate if diverse sample set and assess resistance mechanism

¨ Not all isolates had reported sensitivities

¨ Specified UTI, IAI, pneumonia, and BSI

¨ Sponsorship by makers of CTZ-AVI

CTZ-AVI in Bacteremia10

¨ In July 2016, Wu et al. published case series on 3 patients with CRE bacteremia treated with CTZ-AVI at NY Methodist Hospital, Brooklyn, NY.

¨ In all cases, empiric therapy was started and CTZ-AVI was initiated once pathogen identified but before C&S results were available.

CTZ-AVI in Bacteremia10

77yo F with PMHx DM, CAD, CHF, CKD, dementia presented with

¤ Prior Abx exposure: Cefepime, Cipro, Tobramycin, Gentamicin, Vancomycin, Metronidazole

¤ Organism: Enterobacter aerogenes¤ C&S

n Imipenem (≥ 4)n Ertapenem (≥ 2)n Polymyxin B (6)n Tigecycline (0.5)n CTZ-AVI (1.5)

¤ Treated for 15d with eradication and clinical cure.

¤ Pt d/c to SNF.

72yo F with PMHx of DM and UTI.¤ Prior Abx exposure: meropenem,

polymyxin, tigecycline¤ Organism: Klebsiella Pneumoniae¤ C&S

n Imipenem (≥ 4)n Ertapenem (≥ 2)n Polymyxin B (48)n Tigecycline (1)n CTZ-AVI (0.5)

¤ Treated for 10d with eradication and clinical cure.

¤ D/c home.

Pt 1: Septic shock suspected 2/2 UTI. Pt 2: Bacteremia 2/2 UTI

CTZ-AVI in Bacteremia10

¨ Pt 3: Suspected CRE endocarditis w/ persistent +BCx and new mitral valve vegetation on TTE¤ 89yo F with PMHx UTI, chronic respiratory failure, aortic valve

replacement, mitral valve repair, DM, CKD. ¤ Prior Abx exposure: Meropenem, Gentamicin, Polymyxin, Ceftriaxone¤ Organism: Klebsiella pneumoniae¤ C&S

n Imipenem (≥ 4)n Ertapenem (≥ 2)n Polymyxin B (1.5)n Tigecycline (1.5)n CTZ-AVI (1.5)

¤ Treated for 42d (received treatment x16d in hospital)¤ D/c with remainder of therapy to SNF with eradication and clinical

improvement.

Strengths & Limitations10

¨ Case series Vs. RCT¨ Not clear if CTZ-AVI was the sole agent. Suspect that it may have been used in

combination, especially in the endocarditis case.¨ Not clear if prior agents were during acute stay or recent exposure.¨ All patients either were “assumed” non-responders to previous Abx exposure that

included other studied medications for CRE (e.g. a polymyxin, tigecycline, meropenem). However, dosing regimens not included.

¨ 2/3 patients received CKD dosing based on PI but not clear what dose adjustments were made

¨ Phenotyping but not genotyping of isolates, although this is common in practice (e.g. JBVA). However, NYC hospitals have evaluated that CRE primarily d/t KPC and carriers from OSH transfers.14

¨ Follow up limited to 30 days and only state no “extremely resistant pathogen” infection. Other infection present? Definition not clear.

¨ In endocarditis case, described as microbiological outcome success with eradication. However, clinical improvement not clinical cure and not clarified.

¨ Small subset not evaluating occurrence of non-susceptibility of CTZ-AVI at institution.¨ Break points

CTZ-AVI in Bacteremia15

¨ June 2016, Jacobs et al. published case of CTZ-AVI used in bacteremia 2/2 abdominal abscess at a NY teaching hospital.¤ 47yo F with PMHx kidney transplant. Underwent pancreas

transplant and admitted to ICU for post-surg care. Hours later, pt became hemodynamically unstable and was returned to OR to find iliac artery bleed which was sutured and femoral line placed.

¤ Day 2 post-op, pt seem improved but spiked fever¤ Following days: Tmax: 38.3, WBC 15.8, SCr 1.6, anuria,

2/2 BCx taken.¤ CRRT started d/t AKI 2/2 sepsis¤ Meropenem and amikacin started

CTZ-AVI in Bacteremia15

¨ Day 6 post-op: Culture Results Reported¤ 2/2 BCx (+) KPC-3

producing/CR-K. pneumoniae¤ Abdominal Cx (+) Gram-

negative bacilli¤ C&S:

n Amikacin (32) – [I]n CTZ-AVI (0.5) – [S]n Colistin (0.25) – [S]n Gentamicin (8) – [I]n Polymyxin B (1) – [S]n Tigecycline (2) – [S]n All others resistant

¤ Changed Abx to meropenem + tigecycline +colistin

¤ Changed again to CTZ-AVI + tigecycline +colistin

¨ BCx persistently (+) x 48h¨ Femoral line exchanged¨ Tigecycline d/c day 23¨ Colistin d/c day 28¨ CTZ-AVI d/c day 32¨ On day 37, Pt desaturated and went

into cardiopulmonary arrest.Transferred to unit and soon later expired.

CTZ-AVI in Bacteremia15

¨ Multiple co-morbidities¨ No clear indication of microbiological/clinical

improvement of infection¨ 400mg Colistin/day (Pt wt? 2-3mg/kg/d

recommended for GNIs¤ Pulmonary toxicity? Anuria?

¨ Concomitant therapies and toxicities¨ Not clear on decision-making antibiotics

HAP/VAP

¨ Seen shift to piperacillin/tazobactam for broad-spectrum empiric treatment for both HAP/VAP pneumonia16

¤ Cheaper/generic alternative ¤ GP/GN coverage (MSSA/Strep, H. Influenzae,

Pseudomonas, ¤ Generally well tolerated

¨ 2016 ATS/IDSA HAP/VAP Guidelines17

¨ In-progress per ClinicalTrials.gov for CTZ-AVI ¤ NCT02168946, NCT01395420, NCT02822950,

NCT01808092

CTZ-AVI: Current Role In Antimicrobial Stewardship

¨ Based on current literature that is primarily limited to in vitro data and case studies in bacteremia and nosocomial pneumonias, CTZ-AVI should continue to be a last line treatment option in MDR gram negative infections.

¨ Consider in:¤ Combination, directed therapy in CRE infections, especially

if carbapenemase/KPC have been identified.¨ DO NOT recommend in empiric therapy due to

coverage gaps (e.g. anaerobic and gram-positive pathogens, Acinetobacter sp., )

The Future Agents of CRE?6,18,19

¨ Other medications in the pipeline¤ IV Fosfomycin coming to the U.S.A¤ Plazomicin¤ Eravacycline¤ Carbapenem/BLI combinations

n Meropenem/vaborbactamn Imipenem-relebactam

¤ Avibactam/aztreonam

The Future of CRE20

¨ Greater utilization of new commercially available FDA approved real-time PCR assay targeting the five most common carbapenemases genes (KPC, VIM, IMP, NDM-1, OXA-48) à targeted treatment selection changes?

¨ NDM threat in the United States on the horizon? ¨ Agents for Acinetobacter in the presence of polymyxin

resistance and toxicity¨ Continuation of shift to B-lactam/B-lactam inhibitors

rather than carbapenems to reduce over exposure of class

¨ Generic and cost considerations¨ Agents with reduced toxicity?

NDM: New Delhi metallo-beta-lactamase

CRE Toolkit – Updated 11/2015

¨ Guidance in CRE prevention and infection control¤ E.g. isolation recommendations, patient flagging, etc.

References

1. Healthcare-associated Infections. Centers for Disease Control and Prevention website http://www.cdc.gov/hai/organisms/cre/definition.html. Updated June 29, 2015. Accessed July 31, 2016.

2. Antibiotic resistance threats in the United States . Centers for Disease Control and Prevention. PDF available at http://www.cdc.gov/drugresistance/pdf/ar-threats-2013-508.pdf. Updated 2013. Accessed July 31, 2016.

3. Quale, J, Spelman, D. Overview of carbapenemase producing gram-negative bacilli. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. Updated November 13, 2015. Accessed on August 2, 2016.

4. Ray MJ, Lin MY, Weinstein RA, Trick WE. Spread of Carbapenem-Resistant Enterobacteriaceae Among Illinois Healthcare Facilities: The Role of Patient Sharing. Clin Infect Dis. 2016 Aug 2.

5. Illinois Carbapenem-Resistant Enterobacteriaceae (CRE) Surveillance Report, 2014. Illinois Department of Public Health. PDF available at http://www.healthcarereportcard.illinois.gov/files/pdf/CRE_surveillance_report_2014_Final.pdf. Published November 2015.

6. Thaden JT, Pogue JM, Kaye KS. Role of newer and re-emerging older agents in the treatment of infections caused by carbapenem-resistant Enterobacteriaceae. Virulence. 2016 Jul 6:1-14.

7. Ceftazidime/avibactam. Drug Facts and Comparisons. Facts & Comparisons [database online]. St. Louis, MO: Wolters Kluwer Health, Inc; March 2016. Accessed July 30, 2016.

8. Avycaz ceftazidime/avibactam [PI]. Cincinnati, OH: Forest Pharmaceuticals; June 2016.

9. Ceftazidime and Avibactam. Lexi-Interact. Lexicomp Online. Hudson, OH: Wolters Kluwer Clinical Drug Information Inc.. Accessed July 30, 2015.

10. Wu G, Abraham T, Lee S. Ceftazidime-avibactam for treatment of carbapenem-resistant Enterobacteriaceae bacteremia. Clin Infect Dis. 2016 Jul 17. pii: ciw491.

11. Shields RK, Clancy CJ, Hao B, Chen L, Press EG, Iovine NM, Kreiswirth BN, Nguyen MH. Effects of Klebsiella pneumoniae carbapenemase subtypes, extended-spectrum β-lactamases, and porin mutations on the in vitro activity of ceftazidime-avibactam against carbapenem-resistant K. pneumoniae. Antimicrob Agents Chemother. 2015 Sep;59(9):5793-7. Epub 2015 Jul 13.

References ctd.

12. Flamm RK, Farrell DJ, Sader HS, Jones RN. Ceftazidime/avibactam activity tested against Gram-negative bacteria isolated from bloodstream, pneumonia, intra-abdominal and urinary tract infections in US medical centres (2012). J Antimicrob Chemother. 2014 Jun;69(6):1589-98.

13. Sader HS, Castanheira M, Flamm RK, Mendes RE, Farrell DJ, Jones RN. Ceftazidime/avibactam tested against Gram-negative bacteria from intensive care unit (ICU) and non-ICU patients, including those with ventilator-associated pneumonia. Int J Antimicrob Agents. 2015 Jul;46(1):53-9.

14. Currie,B. New York Hospital Virtually Eliminates CRE Transmission in ICU Settings. Centers for Disease Control and Prevention website http://blogs.cdc.gov/safehealthcare/new-york-hospital-virtually-eliminates-cre-transmission-in-icu-settings/. Published March 7, 2013. August 2, 2016.

15. Jacobs DM, DiTursi S, Ruh C, Sharma R, Claus J, Banjade R, Rao GG. Combination treatment with extended-infusion ceftazidime/avibactam for a KPC-3-producing Klebsiella pneumoniae bacteraemia in a kidney and pancreas transplant patient. Int J Antimicrob Agents. 2016 Aug;48(2):225-7. Epub 2016 Jun 23.

16. Jones BE, Jones MM, Huttner B, Stoddard G, Brown KA, Stevens VW, Greene T, Sauer B, Madaras-Kelly K, Rubin M, Goetz MB, Samore M. Trends in Antibiotic Use and Nosocomial Pathogens in Hospitalized Veterans With Pneumonia at 128 Medical Centers, 2006-2010. Clin Infect Dis. 2015 Nov 1;61(9):1403-10.

17. Kalil AC, Metersky ML, Klompas M, Muscedere J, Sweeney DA, Palmer LB, Napolitano LM, O'Grady NP, Bartlett JG, Carratalà J, El Solh AA, EwigS, Fey PD, File TM Jr, Restrepo MI, Roberts JA, Waterer GW, Cruse P, Knight SL, Brozek JL. Management of Adults With Hospital-acquired and Ventilator-associated Pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis. 2016 Jul 14. pii: ciw353.

18. Rodríguez-Avial I, Pena I, Picazo JJ, Rodríguez-Avial C, Culebras E. In vitro activity of the next-generation aminoglycoside plazomicin alone and in combination with colistin, meropenem, fosfomycin or tigecycline against carbapenemase-producing Enterobacteriaceae strains. Int J AntimicrobAgents. 2015 Dec;46(6):616-21.

19. García-Salguero C, Rodríguez-Avial I, Picazo JJ, Culebras E. Can Plazomicin Alone or in Combination Be a Therapeutic Option against Carbapenem-Resistant Acinetobacter baumannii? Antimicrob Agents Chemother. 2015 Oct;59(10):5959-66.

20. Gomez CA, Deresinski S. Treatment of HAP/VAP due to CRE: Leveraging Molecular Resistance Testing and Combination Therapy to Improve Outcomes. Clin Infect Dis. 2016 Aug 9. pii: ciw555.

-End-

Thank You

Reporting CRE in Illinois

¨ Reporting Requirements¤ As of November 1, 2013, the first CRE-positive culture

per patient stay must be reported to the XDRO registry (77 Ill. Adm. Code Part 690 Control of Communicable Diseases Code). Hospitals, hospital-affiliated clinical laboratories, independent or free-standing laboratories, longer-term care facilities, and long-term acute care hospitals in Illinois are required to report CRE isolates that meet surveillance criteria.

http://dph.illinois.gov/topics-services/prevention-wellness/patient-safety-quality/cre/reporting

Illinois’s CRE surveillance criteria

¨ CRE surveillance criteria¤ Enterobacteriaceae (e.g., E. coli, Klebsiella species, Enterobacter

species, Proteus species, Citrobacter species, Serratia species, Morganella species or Providentia species) with one of the following laboratory test results:n Molecular test (e.g., polymerase chain reaction [PCR]) specific for

carbapenemase.n Phenotypic test (e.g., Modified Hodge) specific for carbapenemase

production.n Susceptibility test (for E. coli and Klebsiella species only): non-

susceptible (intermediate or resistant) to ONE of the following carbapenems (doripenem, meropenem or imipenem) AND resistant to ALL of the following third generation cephalosporins tested (ceftriaxone, cefotaxime and ceftazidime). Note: ignore ertapenem for this definition.

http://dph.illinois.gov/topics-services/prevention-wellness/patient-safety-quality/cre/reporting