Discussing the causing factors of evolving bacteria through the history, and the current treatment modalities of treating such infections.

1. ESBL-producing
G- organisms
Pharmacy intern, Bader Awlaqi
CoP
, KSAU-HS
NGHA

2. Objectives
 History and Epidemiology
 What is ESBL?
 Underlying Factors That Gave it Rise
 Common Organisms
 Spectrum of Resistance
 Modes of Resistance
 Mode of Resistance in ESBL
 Genes Responsible for Producing it
 Detection Methods
 Treatment
 Conclusion

3. History and Epidemiology
 The first ESBL was identified in Germany in 1983.
 The number of such cases increased by 100% from 2008 to 2011 according to the
Swedish Institute for Infectious Disease Control.
 Antimicrobial resistant pathogens caused more than 2.8 million infections, and it
caused over 35,000 deaths annually in the United States from 2012 through 2017.
 They were used to be found mostly in hospitals. Today, they are not uncommon in
outpatient setting.

4. What is ESBL?
 Extended Spectrum Beta-Lactamases (ESBLs) is one type of antimicrobial
resistance (AMR).
 They are enzymes produced by certain types of bacteria that grew as a
defensive mechanism by genetic modifications.
 It is continually growing problem since the persistent exposure of b-lactams
induce continuous production and mutation of b-lactamases in these bacteria.

5. Underlying Factors That Gave it Rise
 Insufficient controls on drug prescribing.
 Inadequate compliance with treatment regimens.
 Poor dosing.
 The heightened use and misuse of antibiotics in agriculture and veterinary.
 Insufficient incentives for patients, physicians, or even governments to care
about increasing resistance.
 Increased frequency and speed of travel.

6. Most Common Organisms
 Escherichia coli (E. coli)
 Klebsiella pneumoniae.
 Pseudomonas aeruginosa.
 K. oxytoca.
 Proteus mirabilis.
 Salmonella enterica.
 Neisseria gonorrhoeae.
 Haemophilus influenzae.

7. Spectrum of Resistance
 Extended-spectrum β-lactamases (ESBLs) mediate resistance to most available
b-lactam antibiotics including:
-All Penicillins even if it is in combination with beta-lactamase inhibitors. Ex.
Piperacillin/Tazobactam.
-All Cephalosporins with G- coverage, especially third-gen. Ex. ceftazidime,
cefotaxime, and ceftriaxone.
-Monobactam narrowly active against Gram-negative organisms. Aztreonam.
What about Carbapenem?
B-lactams
ESBL-E

8. Modes of
Resistance
 There are two types of
resistance.
 Intrinsic such as Aztreonam to
all G+ organisms, and Listeria
monocytogenes to
Cephalosporins.
 Acquired such as mutations of
the sequences of genes
encoding targeting certain
antibiotics including:
-Reduce expression of pores that
uptake antibiotic.
-Efflux systems.
-Inactivating enzymes.
-Target alteration.

9. ESBL Mode of Resistance
 Many b-lactams have hydrogen and amide bonds which are hydrolytically
susceptible, so the main mode of resistance among all different enzymes
produced by all the upcoming genes is by hydrolysis.
 ESBL inactivates b-lactams by targeting and cleaving these bonds.

10. Genes Responsible for its Production
 CTX-M group 1, 2, 8, 9, and 25.
 Found first in Salmonella enterica, Typhimurium, and E. coli.
 Confer resistance initially against Cefotaxime. This is where it gained its name.
 With time, we got the strain CTX-M-15 that confers resistance to Amoxicillin,
Augmentin, Cefuroxime, Cefotaxime, Ceftazidime, Cefepime, Gentamicin,
Tobramycin, Bactrim, ciprofloxacin, norfloxacin, and is susceptible to
Imipenem, Polymyxin B, Cefoxitin, and Meropenem.

11. Genes Responsible for its Production
cont.
 SHV family of b-lactamases.
 Appears to be derived from Klebsiella spp.
 SHV-1 b-lactamase evolved as a chromosomal gene in K. Pneumonia.
 LEN-1 is thought to be the precursor chromosome.
 Confers resistance to broad-spectrum Penicillins such as Ampicillin, and
Piperacillin, but susceptible the oxyimino substituted cephalosporin
Ceftaroline.

12. Genes Responsible for its Production
cont.
 TEM group include, TEM-1, TEM-3, and TEM-12.
 TEM-1 first reported from an E. coli isolate that confers resistance against
penicillins and first generation cephalosporins.
 TEM-3 producing enzyme was first seen in K. Oxytoca and has an increased
activity against extended spectrum cephalosporins.
 TEM-12 producing enzyme was first seen in K. Oxytoca carries a gene
encoding ceftazidime resistance.

13. Genes Responsible for its Production
cont.
 OXA-type group b-lactamases, include: OXA-1, OXA-10, OXA-18.
 The OXA-type ESBLs were originally discovered in P. aeruginosa isolates from a
single hospital in Ankara, Turkey.
 These b-lactamases are characterized by hydrolysis rates for Cloxacillin and
Oxacillin. It gained its name due to that reason.
 The evolution of ESBL OXA-type b-lactamases has many parallels with the
evolution of SHV- and TEMtype ESBLs which leads us to a conclusion that they
exchange their encoded genes among other bacteria.

14. Detection Methods
 Phenotypic tests such as double-disk synergy test, ETEST®, automated
susceptibility platform algorithms, work to exclude the possibility of ESBL
production by clinical isolates.
 There is no clinical and laboratory standards endorsed phenotypic method for
confirmatory ESBL testing.
 Non-susceptibility to ceftriaxone (i.e., ceftriaxone minimum inhibitory
concentrations [MICs] > 2 mcg/mL) is being used as a proxy for ESBL
production.

15. Treatment
 The treatment is guided by the location of the infection.
 The latest IDSA guideline provided the treatment in 3 categories:
-Uncomplicated cystitis.
-cUTI or Pyelonephritis.
-Infection outside the urinary tract.
 If an infections located in an unmentioned location, like SSTI, the
recommendations provided shall be extrapolated.
 The guidelines neither provided empirical therapy options nor recommended
duration of therapy recommendations.

16. Treatment cont.
 Empirical antibiotic should be guided by:
-Local susceptibility data.
-Antibiotic exposures in the past 30 days.
-Based on the severity of illness.(Cystitis vs. VAP).
 Duration of therapy should be guided by:
-Knowing that prolonged treatment courses are not necessary against
infections by antimicrobial resistant pathogens.
-Repeated cultures to change or extend the antibiotic regimen.
- host factors related to immune status, and the response to the treatment.
-The ability to attain source control.

17. Treatment cont.
 Uncomplicated Cystitis:
-Nitrofurantoin
-Bactrim
 Why?
-Nitrofurantoin and trimethoprim-sulfamethoxazole have been shown to be
safe and effective options for cystitis.
-Amoxicillin-clavulanate, single-dose aminoglycosides, and oral fosfomycin
are alternative options for ESBL-E cystitis.
-Other bigger guns like Quinolones or Carbapenems were preserved for more
severe infx.

18. Treatment cont.
 Pyelonephritis and Complicated Urinary Tract Infections (cUTIs):
-Carbapenems (Mero, Erta, Imi-Cila).
-Quinolines (Cipro, Levo).
-Bactrim.
 Why?
-based on clinical experience and the ability of these agents to achieve high
concentrations in the urine.
 If a carbapenem is initiated and susceptibility to one of the other mentioned
options is demonstrated, transitioning to these agents is preferred.

19. Treatment cont.
 Infections outside of the urinary tract:
-A carbapenem is preferred for the treatment of infections outside of the
urinary tract.
 Why?
-Based largely on data from a multicenter randomized controlled MERINO
trial. 30-day mortality was reduced for patients with ESBL-E bloodstream
infections treated with meropenem compared to piperacillin-tazobactam.

20. Treatment cont.
 Infection outside of the urinary tract cont.
 Oral step-down therapy: Shown to be a reasonable treatment consideration
for Enterobacterales bloodstream infections.
 When?
-Susceptibility to the oral agent is demonstrated.
-Patients are afebrile and hemodynamically stable.
-Appropriate source control is achieved.
-There are no issues with intestinal absorption.

21. Treatment cont.
 Is there a role for Piperacillin-Tazobactam or Cefepime in the treatment of
infections caused by ESBL-E when in vitro susceptibility to piperacillin-
tazobactam is demonstrated?
-Their use should be avoided even if susceptibility to Piperacillin-
Tazobactam or Cefepime is demonstrated.
-If one of which was initiated as empiric therapy for cystitis caused by and
clinical improvement occured, no change or extension of antibiotic therapy
is necessary.

22. Conclusion
 ESBL-E infections is one of the highest priority concern in the medical field
due to its continuous growth as new antibiotics rise.
 Medical team should always try to preserve bigger guns for the more severe
infections.
 Oral step-down therapy should be implemented not only in ESBL-E infection if
susceptibility is granted.
 Practical phenotypic testing method with high sensitivity and specificity
should be endorsed in the future due to unreliability on non-susceptibility
test.

23. References
 Idsociety.org. 2020. [online] Available at:
<https://www.idsociety.org/globalassets/idsa/practice-guidelines/amr-
guidance/idsa-amr-guidance.pdf> [Accessed 21 September 2020].
 Shaikh S, Fatima J, Shakil S, Rizvi SM, Kamal MA. Antibiotic resistance and
extended spectrum beta-lactamases: Types, epidemiology and treatment. Saudi J
Biol Sci. 2015;22(1):90-101. doi:10.1016/j.sjbs.2014.08.002
 Robberts FJ, Kohner PC, Patel R. Unreliable extended-spectrum beta-lactamase
detection in the presence of plasmid-mediated AmpC in Escherichia coli clinical
isolates. J Clin Microbiol. 2009;47(2):358-361. doi:10.1128/JCM.01687-08
 Laxminarayan R, Bhutta Z, Duse A, et al. Drug Resistance. In: Jamison DT, Breman
JG, Measham AR, et al., editors. Disease Control Priorities in Developing Countries.
2nd edition. Washington (DC): The International Bank for Reconstruction and
Development / The World Bank; 2006. Chapter 55. Available from:
https://www.ncbi.nlm.nih.gov/books/NBK11774/ Co-published by Oxford
University Press, New York.

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