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Journal of the American Academy of Physician Assistants:
doi: 10.1097/01.JAA.0000443810.42907.ec
Pharmacology Consult

What are extended-spectrum beta-lactamases?

Sutton, S. Scott PharmD, BCPS

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Author Information

S. Scott Sutton is an associate professor at the University of South Carolina's College of Pharmacy, and a clinical pharmacist in medicine, infectious diseases, and research at Dorn VA Medical Center, both in Columbia, S.C. The author has disclosed no potential conflicts of interest, financial or otherwise.

Mary Lou Brubaker, PharmD, PA-C, department editor

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Abstract

ABSTRACT: The emergence and spread of extended-spectrum beta-lactamases (ESBLs) in Gram-negative bacteria pose important challenges for clinicians, as management options for these organisms are limited. The emergence of ESBL-producing Gram-negative bacteria is one of the most significant epidemiologic changes in infectious diseases during recent years. Failure to treat with an antibiotic active against ESBL-producing organisms is associated with increased patient morbidity and mortality. Carbapenems are considered the primary antibacterials for infections caused by ESBL-producing organisms but their overuse poses significant cause for concern.

Production of beta-lactamase is the major mechanism of resistance to beta-lactam antibiotics. Beta-lactamases are enzymes that open the beta-lactam ring and inactivate a beta-lactam antibiotic. Their production may be chromosome- or plasmid-mediated. Plasmid-mediated beta-lactamases of Gram-negative bacteria (such as TEM-1, TEM-2, and SHV-1) hydrolyze penicillins and narrow-spectrum first-generation cephalosporins such as cephalothin and cefazolin. They do not hydrolyze higher-generation cephalosporins with an oxyimino side chain (for example, third- and fourth-generations cephalosporins such as cefotaxime, ceftazidime, ceftriaxone, or cefepime).

Extended-spectrum beta-lactamases (ESBLs) confer resistance to penicillins, cephalosporins (including oxyimino), and aztreonam. Because higher-generation cephalosporins are affected, this type of beta-lactamase is conferred as extended spectrum.1,2

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ESBL EPIDEMIOLOGY AND DETECTION

ESBLs are found predominantly in Enterobacteraciae (primarily Klebsiella species and Escherichia coli) but may also be found in Acinetobacter, Pseudomonas, and other Gram-negative bacteria. They are detected based on the resistance they confer to oxyimino-beta-lactam substrates (cefotaxime, ceftazidime, ceftriaxone, or cefepime) and to the ability of a beta-lactamase inhibitor such as clavulanic acid to attenuate this resistance on an in-vitro basis. Other beta-lactamase enzymes have different features that can be misleading in the laboratory. For example, AmpC beta-lactamases also confer oxyimino-beta-lactam resistance but are resistant to inhibition by clavulanate and usually confer resistance to cephamycins such as cefoxitin and cefotetan. ESBLs do not confer in-vitro resistance to cephamycins.

Unfortunately, ESBLs can be difficult to detect because they have different levels of activity against various cephalosporins. Thus, the choice of which antimicrobial agents to test is critical. Some ESBLs are best detected with ceftazidime and others with cefotaxime. Consequently, susceptibility to several oxyimino-beta-lactams must be tested. If an ESBL is detected, all penicillins, cephalosporins, and aztreonam should be reported as resistant, even if in-vitro test results indicate susceptibility.3–5

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TREATMENT

ESBLs vary in activity against different oxyimino-beta-lactam substrates but cannot hydrolyze or inactivate the cephamycins (cefoxitin, cefotetan) or the carbapenems (imipenem, meropenem, doripenem, and ertapenem). They are also generally susceptible to beta-lactamase inhibitors, such as clavulanic acid, sulbactam, and tazobactam. Besides resistance to penicillin, cephalosporin, and aztreonam, ESBL-producing isolates often exhibit resistance to other antibiotics including aminoglycosides, sulfamethoxazole-trimethoprim, and fluoroquinolones.

No randomized controlled trials have studied ESBL infections and most published literature describes in-vitro analysis or a small number of cases. The choice of an appropriate antibiotic is crucial because failure to treat with an antibiotic active against ESBL-producing organisms is associated with increased patient morbidity and mortality.6,7

For empiric therapy targeted at an expected ESBL, refer to local area antibiogram data or infectious diseases specialists for guidance. Individualized therapy should be guided by culture and susceptibility reports, with potential consultation of an infectious diseases specialist, especially for complicated or invasive ESBL-infections. Remember, ESBL detection may be difficult, so expertise in interpreting a culture and susceptibility report may be needed.6,7

Carbapenems These antibiotics are recommended for treatment of infections caused by ESBL-producing organisms and have produced the best outcomes in terms of survival and bacteriologic clearance.6 No clear differences in efficacy against ESBL exist between the various carbapenem drugs. Ertapenem may be used as outpatient parenteral antimicrobial therapy for ESBL urinary tract infections because of its once-daily dosing.

Cefepime This drug may be effective against ESBL-producing organisms if administered in high doses (2 g every 8 hours) rather than standard doses (1 to 2 g every 12 hours). Treatment of infections due to ESBL-producing organisms with an oxyimino-beta-lactam such as cefepime may result in treatment failure, even if the organism demonstrates in-vitro susceptibility.6–9 Most clinicians do not recommend cefepime for ESBL-producing pathogens.10

Cephamycins Although ESBL-producing bacteria often test susceptible to cephamycins, they can develop resistance due to loss of porin channels for cephamycin entry.2 Clinical experience to demonstrate their effectiveness is limited.

Beta-lactam/beta-lactamase inhibitor combinations Piperacillin-tazobactam may be effective for ESBL isolates with minimal inhibitory concentrations of 16 mcg/mL or less, and for urinary tract infections, regardless of susceptibility because of higher drug concentrations in urine compared to plasma.11 Piperacillin-tazobactam and amoxicillin-clavulanic acid may be alternatives for select patients with E. coli ESBL infections.12 Treatment failures have been described with piperacillin-tazobactam in ESBL infections and resistance may develop during therapy.13

Fosfomycin Initial clinical data support the use of fosfomycin for treating ESBL urinary tract infections, although further research is needed. Oral treatment with fosfomycin-trometamol was demonstrated clinically effective against complicated or uncomplicated lower urinary tract infections caused by ESBL-producing E. coli.14

Tigecycline This drug is active against most ESBL E. coli and Klebsiella species isolates.15 Further evaluation of its clinical utility against ESBL Enterobacteriaceae is warranted before the drug is used for treatment, so tigecycline would be a last-line option.

Colistin This drug has resurfaced as a last-line treatment option for multidrug-resistant organisms including ESBLs.16 Colistin is a last-line agent because of its associated renal toxicity.

Miscellaneous The plasmids bearing the genes encoding ESBLs frequently carry genes encoding resistance to aminoglycosides.6 Plasmid-encoded decreases in susceptibility to quinolones also have been reported. These reports document nonresponse to ciprofloxacin in patients with an ESBL infection, although the organism was sensitive to ciprofloxacin on culture and susceptibility reports.17 However, quinolones and sulfamethoxazole/trimethoprim may be used to treat select ESBL infections, in particular, urinary tract infections.

Antibiotic overuse Overuse of antibiotics is a risk factor for the development of bacterial resistance.18 Because of the limited treatment options for ESBL and other multidrug-resistant infections, overuse of the above antibiotics, especially carbapenems, is a major concern. If an antibiotic is needed for treatment, de-escalation to a narrow-spectrum antibiotic is a critical component to minimize antibiotic overuse.

Infection control The main strategy for controlling the spread of multidrug-resistant bacterial infections is infection control, especially through hand hygiene. Other strategies to control ESBL outbreaks include barrier protection of infected or colonized patients and restricted use of beta-lactam antibiotics.

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CONCLUSION

The emergence and spread of ESBLs are important challenges for clinicians, as management options for these organisms are limited. These infections can be difficult to detect because they have different levels of activity against various cephalosporins, and the epidemiology is highly complex. No randomized controlled trials have studied ESBL infections, and empiric therapy should be guided by a local area antibiogram or infectious diseases specialist. Carbapenems are considered the primary antibacterials for infections caused by ESBL-producing organisms, but their overuse poses significant cause for concern.

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REFERENCES

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1. Bradford PA. Extended spectrum beta-lactamases in the 21st century: characterization, epidemiology, and detection of this important resistance threat. Clin Microbiol Rev. 2001;14(4):933–951.

2. Paterson DL, Bonomo RA. Extended-spectrum beta-lactamases: a clinical update. Clin Microbiol Rev. 2005;18(4):657–686.

3. Gupta K, Hooton TM, Naber KG, et al. International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: a 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases. Clin Infect Dis. 2011;52(5):e103–e120.

4. Rodríguez-Baño J, Navarro MD, Romero L, et al. Epidemiology and clinical features of infections caused by extended-spectrum beta-lactamase producing Escherichia coli in nonhospitalized patients. J Clin Microbiol. 2004;42(3):1089–1094.

5. Centers for Disease Control. Laboratory detection of extended-spectrum beta-lactamases (ESBLs). http://www.cdc.gov/hai/settings/lab/lab_esbl.html. Accessed October 7, 2013.

6. Paterson DL, Ko WC, Von Gottberg A, et al.. Antibiotic therapy for Klebsiella pneumonia bacteremia: implications of production of extended-spectrum beta-lactamases. Clin Infect Dis. 2004;39(1):31–37.

7. Paterson DL, Ko WC, Von Gottberg A, et al. Outcome of cephalosporin treatment for serious infections due to apparently susceptible organisms producing extended-spectrum beta-lactamases: implications for the clinical microbiology laboratory. J Clin Microbiol. 2001;39(6):2206–2212.

8. Lee NY, Lee CC, Huang WH, et al. Cefepime therapy for monomicrobial bacteremia caused by cefepime-susceptible extended-spectrum beta-lactamase-producing Enterobacteriaceae: MIC matters. Clin Infect Dis. 2013;56(4):488–495.

9. Goethaert K, Van Looveren M, Lammens C, et al. High-dose cefepime as an alternative treatment for infections caused by TEM-24 ESBL-producing Enterobacter aerogenes in severely-ill patients. Clin Microbiol Infect. 2006;12(1):56–62.

10. Chopra T, Marchaim D, Veltman J, et al. Impact of cefepime therapy on mortality among patients with bloodstream infections caused by extended-spectrum beta-lactamase-producing Klebsiella pneumonia and Escherichia coli. Antimicrob Agents Chemother. 2012:56(7):3936–3942.

11. Gavin PJ, Suseno MT, Thomson RB Jr, et al.. Clinical correlation of the CLSI susceptibility breakpoint for piperacillin-tazobactam against extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella species. Antimicrob Agents Chemother. 2006;50(6):2244–2247.

12. Rodríguez-Baño J, Navarro MD, Retamar P, et al. β-Lactam/β-lactam inhibitor combinations for the treatment of bacteremia due to extended-spectrum β-lactamase-producing Escherichia coli: a post hoc analysis of prospective cohorts. Clin Infect Dis. 2012;54(2):167–174.

13. Zimhony O, Chmelnitsky I, Bardenstein R, et al. Endocarditis caused by extended-spectrum-beta-lactamase-producing Klebsiella pneumonia: emergence of resistance to ciprofloxacin and piperacillin-tazobactam during treatment despite initial susceptibility. Antimicrob Agents Chemother. 2006;50(9):3179–3182.

14. Falagas ME, Kastoris AC, Kapaskelis AM, et al. Fosfomycin for the treatment of multidrug-resistant, including extended-spectrum beta-lactamase producing, Enterobacteriaceae infections: a systematic review. Lancet Infect Dis. 2010;10(1):43–50.

15. Hope R, Warner M, Potz NA, et al. Activity of tigecycline against ESBL-producing and AmpC-hyperproducing Enterobacteriaceae from south-east England. J Antimicrob Chemother. 2006;58(6):1312–1314.

16. Paolino K, Erwin D, Padharia V, et al. In vitro activity of colistin against multidrug-resistant gram-negative bacteria isolated at a major army hospital during the military campaigns in Iraq and Afghanistan. Clin Infect Dis. 2007;45(1):140–141.

17. Endimiani A, Luzzaro F, Perilli M, et al. Bacteremia due to Klebsiella pneumoniae isolates producing the TEM-52 extended-spectrum beta-lactamase: treatment outcome of patients receiving imipenem or ciprofloxacin. Clin Infect Dis. 2004;38(2):243–251.

18. Centers for Disease Control. Mission critical: preventing antibiotic resistance. http://www.cdc.gov/features/antibioticresistance. Accessed October 7, 2013.

Keywords:

extended-spectrum beta-lactamases; Gram-negative bacteria; antibiotics; carbapenems; overuse; tigecycline

© 2014 American Academy of Physician Assistants.

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