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Carbapenem-Resistant Enterobacteriaceae (CRE): Where Are We Now and Where Are We Going?

Thursday, December 21, 2017  
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Student Submission By: Brendan Mangan, Pharm.D. Candidate 2018, Stacy Pasciolla, Pharm.D. Candidate 2018, Jason Gallagher, Pham.D., BCPS


Antibiotic resistance has been a continuous challenge of infectious disease. Antibiotics are effective agents used to treat bacterial infections, but are commonly overused. Society’s use of antibiotics has given rise to microorganisms that are increasing difficult to treat. The increase in resistance coupled with decreased antibiotic development has led to less treatment options available for these infections. There are multiple problematic microorganisms that have arisen, with one of the most problematic being carbapenem-resistant Enterobacteriaceae (CRE). Enterobacteriaceae is a large family of gram-negative bacilli (such as Escherichia coli, Klebsiella, Enterobacter, Proteus, and Serratia) that are a part of the human gastrointestinal flora.1,2 Traditionally, infections caused by these organisms have been susceptible to current antibiotics, including carbapenems, but over the past fifteen years this has changed. Since carbapenem antibiotics are some of the broadest spectrum, resistance to them poses great concern.


In the early 2000s, CRE was rare in North America. However, breakouts in the Northeast caused spread throughout the United States.1 By 2013, the Centers for Disease Control and Prevention (CDC) revealed that CRE had been found in at least 42 states, and the proportion of Enterobacteriaceae that are carbapenem-resistant had increased four-fold in the past 10 years.1,2 The first enzyme was identified in Klebsiella pneumoniae in 1996, and was designated Klebsiella pneumoniae carbapenemase (KPC). Strains of KPC producing CRE remain the most common isolates in America.2 Multiple enzymes have been isolated as carbapenemases, such as KPC, oxacillinase (OXA-48), verona integron-encoded metallo-beta-lactamase (VIM), imipenemase metallo-beta-lactamase (IMP), Serratia marcescens enzyme (SME), and most recently New Delhi metallo-beta-lactamase (NDM).2 Infections caused by Enterobacteriaceae are mostly healthcare-associated. Historically, CRE has been primarily isolated in the elderly and those with multiple comorbidities, such as diabetes mellitus and the immunosuppressed population.3 More recent data has shown CRE is now being found in other populations, such as critically-ill children, cancer, and burn patients. This has led to the CDC recognizing CRE as a public health threat, requiring immediate and aggressive action.3

Current Treatment Options

Outcomes of CRE infections are generally poor, and mortality rates are between 40-50%.1 Since species of Enterobacteriaceae that are CRE have resistance to other antibiotics such as aztreonam, all of the cephalosporins, and beta-lactamase inhibitors (such as clavulanic acid and tazobactam), there are not many options for the treatment of these infections.2 This has necessitated the use of older antibiotics such as colistin, polymyxin B, and aminoglycosides. These older antibiotics have a high risk of toxicity and are not always effective. Aminoglycosides possess concentration-dependent killing and are active against CRE, but nephrotoxicity and irreversible ototoxicity limit their utility in treatment.4 Colistin has a high degree of nephrotoxicity and unfavorable pharmacokinetics, as it is administered as the prodrug colistimethate sodium (CMS).5   By contrast, polymyxin B is administered as an active drug, and can reach desired plasma concentrations must faster than CMS, but is also nephrotoxic.6 When polymyxin therapy is warranted due to sensitivity results, polymyxin B has a more predictable pharmacokinetic profile and lower incidence of nephrotoxicity.7-8 In 2015, ceftazidime-avibactam was introduced, which has activity against KPC producing CRE strains. A retrospective study has even shown that ceftazidime-avibactam has had superior outcomes in treating KPC producing CRE compared to other therapies like aminoglycosides, carbapenems, and colistin.9 In this study, patients who received ceftazidime-avibactam achieved clinical success more frequently (p=0.006) as well as had higher survival rates (90%).9 The incidence of

Treatment Options for CRE12


FDA Indication



infections due to gram-negative bacteria (such as P. aeruginosa, Enterobactor aerogenes, E. coli, and K. penumoniae)



Infections due to susceptible strains of P. aeruginosa, Proteus spp., E. coli, Klebsiella-Enterobacter-Serratia spp., Citrobacter spp., and Staphylococcus spp.

Nephrotoxic, neurotoxicity, and ototoxicity


Community-acquired pneumonia, complicated skin/skin structure infection, complicated intra-abdominal infection

Increased risk of mortality


Intraabdominal infections and UTI

Effectiveness unknown against other strains of CRE



Complicated urinary tract infections including pyelonephritis


Limited data for other indications and with other strands of CRE


acute kidney injury in patients treated with a beta-lactam/beta-lactamase inhibitor are also lower compared to the aminoglycosides and polymyxins used in these infections.10 Although ceftazidime-avibactam is an effective alternative with less toxicity, its effectiveness has not been shown against other strains of CRE.10,11

New Treatments in the Pipeline

With the prevalence of CRE strains continuously increasing, the development of new antibiotics to combat the growth of these strains is necessary. Meropenem-vaborbactam is a carbapenem/beta-lactamase inhibitor combination that was currently granted approval after it was shown to have improved clinical cure rates against CRE infections. In addition to this, it has also shown less renal toxicity compared to the best available therapies.14 Plazomicin, an aminoglycoside antibiotic, is currently in phase III studies with encouraging results when compared to colistin in CRE infections.15 Two other antibiotics, cefiderocol and imipenem/cilastatin-relebactam, are currently also in phase III studies against CRE with efficacy data still pending.16 With new antibiotic choices recently out, and more in the pipeline, the treatment outcomes for CRE infections may be soon changing.  




1.    Centers for Disease Control and Prevention (CDC), 2013. Vital Signs: Carbapenem-Resistant-Enterobacteriaceae MMWR. Morbidity and Mortality Weekly Reports 2013;62(9):165

2.    Perez, F, Duin, DV. Carbapenem-resistant enterobacteriaceae: a menace to our most vulnerable patients. Clin J Med. 2013 April 80(4): 225-233.

3.    Bowers, D, Huang, V. Emerging Issues and Treatment Strategies in Carbapenem-Resistant Enterobacteriaceae (CRE). Curr Infect Dis Rep. 6 Dec 2016; 18 (48).

4.    Duin DV, Kaye KS, Neuner EA, Bonomo RA. Carbapenem-resistant Enterobacteriaceae: a review of treatment and outcomes. Diagn Microbiol and Infect Dis 2013;75(2):115-120.

5.    Nation RL, Velkov T, Li J. Colistin and Polymyxin B: Peas in a Pod, or Chalk and Cheese? Clin Infect Dis. 2014 Jul 1; 59(1):88-94.

6.    Lexi-Comp Online, Lexi-Comp Online, Hudson, Ohio: Lexi-Comp Inc.: Accessed November 17, 2016.

7.    Phe K, Lee Y, McDaneld P, In Vitro Assessment and Multicenter Cohort Study of Comparative Nephrotoxicity Rates Associated with Colistimethate versus Polymyxin B Therapy. Antimicrob Agents and Chemother. 2014; 58(5): 2740-2746. 

8.    Akajagbor DS, Wislon S, Shere-Wolfe K, et. al. Higher Incidence of Acute Kidney Injury With Intravenous Colistimethate Sodium Compared With Polymyxin B in Critically Ill Patients at a Tertiary Care Medical Center. Clin Infect Dis. 2013: 57(9); 1300-1303.

9.    Shields RK, Nguyen MH, Chen L,et al.. 2017. Ceftazidime-avibactam is superior to other treatment regimens against carbapenem-resistant Klebsiella pneumoniae bacteremia. Antimicrob Agents Chemother 61: e00883-17.

10.  Shields RK, Potoski BA, Haidar G, et al. Clinical Outcomes, Drug Toxicity, and Emergence of Ceftazidime-Avibactam Resistance Among Patients Treated for Carbapenem-Resistant Enterobacteriaceae Infections. Clin Infect Dis. 2016;63(12):1615-1618.

11.  Spellburg, B., Bonomo, R. Ceftazidime-avibactam and carbapenem-resistant enterobacteriaceae:”we’re gonna need a bigger boat”. Clin Infect Dis. 2016 Dec 15;63(12):1619-1621.

12.  Martirosov D, Lodise TP. Emerging trends in epidemiology and management of infections caused by carbepenem-resistant Enterobacteriaceae. Diagn Micro and Inf Dis. 14 Oct 2015; 85(2016); 266-275.

13.  Vabomere [package insert]. Parsippany, NJ: The Medicine Company; 2017.

14. Accessed September 6, 2017.

15.  Ian Friedland. Development of Antibacterial Drug for Patients with Unmet Needs: Experience and Recommendations. FDA. Accessed February 27, 2017.

16.  "Antibiotics Currently In Clinical Development". N.p., 2017. Web. 10 Mar. 2017.


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