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How to Tackle ESBL-related Infections: A Page from the Infectious Diseases Playbook


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Joanna Schaenman, MD, PhD
David Geffen School of Medicine at UCLA
Los Angeles, CA, United States
JSchaenman@mednet.ucla.edu



Your patient, Mr. E., is a 68-year-old man with ischemic cardiomyopathy who underwent mechanical circulatory support device (MCSD) implantation and was doing well until fever and leukocytosis developed on post-op day 3. Prior to surgery he had been hospitalized for several weeks in an attempt at medical stabilization, complicated by a catheter-associated urinary tract infection requiring antibiotic treatment. After obtaining blood cultures, you begin to administer empiric vancomycin and piperacillin-tazobactam. On post-op day 5 the nurse notifies you that the microbiology lab called to report identification of an "ESBL-producing organism." What should you do now, and could you have predicted this development?

"Extended Spectrum Beta-Lactamase" or "ESBL" is an enzyme produced by some Gram-negative bacilli and that confers resistance to many commonly used antibiotics [1]. The Gram-negative organisms that can commonly develop this drug resistance are Klebsiella pneumoniae, Klebsiella oxytoca, and Eschericia coli; however, there have been cases reported involving other Enterobacteriaceae, including Enterobacter, Morganella, and Proteus [2].

The rise of ESBL-producing organisms is generally attributed to the increased use of third-generation cephalosporins during the 1980's in an attempt to attack resistant Gram-negative bacteria expressing the more narrow-spectrum beta-lactamases prevalent at that time [1]. Widespread use of these antibiotics led to the evolution of "extended" beta-lactamase resistance such as SHV, CTX-M, and OXA. These extended spectrum enzymes are generally defined as beta-lactamases and confer bacterial resistance to penicillins, first-, second-, and third-generation cephalosporins and to aztreonam, but not the carbapenems [1]. These resistance genes are present on transmissible plasmids, which can be easily shared amongst bacteria. There are over 200 known ESBL enzymes, a list of which is maintained in an online database by the Lahey Medical Group [3].

Risk factors for development of infections due to ESBL-producing-organisms include increased patient age, hospitalization or residence in a long-term care facility, and previous antibiotic use [4]. Studies in kidney transplant recipients have also identified positive status for hepatitis C and the need for post-transplant surgery as potential risk factors [5]. Although ICU-related outbreaks are well-described, one study suggests that patients infected with ESBL-expressing organisms can lead to infection in subsequent occupants of the same room [6]. It is now also apparent that ESBL-producing Gram negative bacteria are a problem in thoracic organ transplant and MCSD recipients [7-9]. Significantly, these resistant bacteria are associated with increased mortality compared to non-ESBL organisms, with a relative risk of 1.85 for mortality in a meta-analysis of patients with bacteremia [10]. The main driver of this increased mortality is likely due to delay in administration of effective antibiotic therapy.

Although quinolones may be used to treat simple urinary tract infections caused by ESBL-producing organisms, the mainstay of antibiotic therapy is the carbapenem class of drugs including meropenem, imipenem, and the relatively new antibiotic doripenem. Although beta-lactam/beta-lactamase combinations, such as piperacillin-tazobactam, may exhibit in vitro activity against these bacteria, it is hypothesized that with the increasing bacterial concentrations likely to be present in a naturally occurring infection, a rise in the MIC will make these drugs ineffective and they are therefore not recommended [1]. Ertapenem is a carbapenem with in vitro activity against most ESBL-producing organism and the convenience of once-daily administration; however, the lack of clinical data for use of this drug makes it suitable only for outpatient use in the setting of a clinically mild infection.

In a review of 1065 patients at the UCLA Medical Center who had undergone heart or lung transplantation, or MCSD implantation between 1996 and 2010, the incidence of ESBL-related infections in these groups was observed to be 2.2%, 5.5% and 10.7% of patients, respectively, with a mortality rate of 8.3% [9]. Surprisingly, the majority of these infections were due to E. coli, rather than Klebsiella pneumoniae as has been commonly described in the non-transplant literature, and many infections were recurrent, especially in the setting of pneumonia in lung transplant recipients. Risk factors for ESBL-related infection included increased duration of ICU stay, presence of nasogastric tubes and arterial lines, and recent surgery [9].

In conclusion, our patient Mr. E. was at increased risk of ESBL-related infection due to his age, hospitalization, and previous receipt of antibiotics. In order to combat these risks he should be switched to a carbapenem without delay, and catheters should be changed as possible. Defensive measures should be taken, in addition to the offensive measures to decrease the time to start of effective treatment, in an effort to prevent hospital outbreaks. The adoption of increased vigilance in patients with risk factors for infection is also suggested as a means of decreasing the clinical effect of these bacteria.

Although much attention has focused on resistant Gram-positive species, it is now also recognized that resistant Gram-negative bacteria pose a significant threat to survival in thoracic organ transplant recipients and after MCSD implantation. Future challenges will include facing the growing scourge of these ESBL-producing organisms, as well as other highly resistant bacteria such as Acinetobacter and the carbapenem-resistant Klebsiella pneumoniae. ■

Disclosure Statement: the author has no conflicts of interest to report.


References:

  1. Paterson DL, Bonomo RA. Extended-Spectrum-Lactamases: a Clinical Update. Clinical Microbiology Reviews 2005; 18:657-686.
  2. Bradford PA. Extended-spectrum beta-lactamases in the 21st century: characterization, epidemiology, and detection of this important resistance threat. Clinical Microbiology Reviews 2001; 14:933-51- table of contents.
  3. Beta-Lactamase Classification and Amino Acid Sequences for TEM, SHV and OXA Extended-Spectrum and Inhibitor Resistant Enzymes. Lahey Hospital and Medical Center, Available at: http://www.lahey.org/Studies/. Accessed 23 June 2014.
  4. Ben Ami R, Rodríguez Baño J, Arslan H, et al. A Multinational Survey of Risk Factors for Infection with Extended-Spectrum βLactamase-Producing Enterobacteriaceae in Nonhospitalized Patients. CLIN INFECT DIS 2009; 49:682-690.
  5. Linares L, Cervera C, Cofán F, et al. Epidemiology and Outcomes of Multiple Antibiotic-Resistant Bacterial Infection in Renal Transplantation. Transplantation Proceedings 2007; 39:2222-2224.
  6. Ajao AO, Johnson JK, Harris AD, et al. Risk of Acquiring Extended-Spectrum β-Lactamase-Producing Klebsiella Species and Escherichia colifrom Prior Room Occupants in the Intensive Care Unit. Infection Control and Hospital Epidemiology 2013; 34:453-458.
  7. van Delden C, Blumberg EA, the AST Infectious Diseases Community of Practice. Multidrug Resistant Gram-Negative Bacteria in Solid Organ Transplant Recipients. American Journal of Transplantation 2009; 9:S27-S34.
  8. Linares L, Cervera C, Hoyo I, et al. Klebsiella pneumoniae infection in solid organ transplant recipients: epidemiology and antibiotic resistance. Transplantation Proceedings 2010; 42:2941-2943.
  9. Bui KT, Mehta S, Khuu TH, et al. Extended Spectrum β-Lactamase-Producing Enterobacteriaceae Infection in Heart and Lung Transplant Recipients and in Mechanical Circulatory Support Recipients. Transplantation 2013;:1.
  10. Schwaber MJ, Carmeli Y. Mortality and delay in effective therapy associated with extended-spectrum-lactamase production in Enterobacteriaceae bacteraemia: a systematic review and meta-analysis. Journal of Antimicrobial Chemotherapy 2007; 60:913-920.



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