ESBLs

Kamal Prakash Saud

Int Medicine
 Outline
• Introduction
• Classification
• Mechanism of resistance
• Epidemiology
• Clinical features
• Treatment
• Prognosis
• Prevention
Antibiotics
Antibiotics
 ESBLs
• ESBL are family of enzymes that hydrolyses the B-lactams and confer
resistance to newer B-lactam antibiotics including third generation
cephalosporins.
• Confer resistance to penicillin, oxyimino-cephalosporins and
monobactams.
• Don’t hydrolyze cephamycins and carbapenams.
• Can usually be inhibited by b-lactamase inhibitors.
• Coding genes are usually acquired via mobile genetic elements such
as plasmids.
 Bacteriology of ESBL
• Enterobacteriaceae
 E. coli
 Klebsiella pneumoniae
 Klebsiella oxytoca
 Citrobacter sp.
 Enterobacter sp.
 Salmonella sp.
 Serratia sp.
• Pseudomonas
• Acinetobacter

.
1 Jacoby, George A, and Luisa Silvia Munoz-Price. “The new beta-lactamases.” The New England journal of medicine vol. 352,4 (2005)
2. El Salabi, Allaaeddin et al. “Extended spectrum β-lactamases, carbapenemases and mobile genetic elements responsible for antibiotics resistance in
Gram-negative bacteria.” Critical reviews in microbiology vol. 39,2 (2013)
 Classes/Mechanism of resistance in ESBL
1. TEM enzymes
• Hydrolyse penicillins and early generation cephalosporins
• Greater hydrolysis towards cetazidime and aztreonam than cefotaxme
2. SHV enzymes
• Hydrolyse penicillins and early generation cephalosporins
• Associated resistance to ceftazidime, aztreonam and cefotaxime.
3. CTX-M enzymes
• Beta-lactamases from Kluyvera species(enterobactericeae).
• Hydrolyses more of cefotaxime than ceftazidime and may also hydrolyse
cefepime.

.
1 Jacoby, George A, and Luisa Silvia Munoz-Price. “The new beta-lactamases.” The New England journal of medicine vol. 352,4 (2005)
2. El Salabi, Allaaeddin et al. “Extended spectrum β-lactamases, carbapenemases and mobile genetic elements responsible for antibiotics resistance in
Gram-negative bacteria.” Critical reviews in microbiology vol. 39,2 (2013)
 Classes/Mechanism of resistance in ESBL
4. OXA enzymes
• Hydrolyse cloxacillin, oxacillin, cefepime and carbapenams
• Most found in pseudomonas and Acinetobacter.

AmpC B-lactamases
• Confer resistance to antbiotics as ESBL but belong to different class.
• Encoded by chromosome and inducible by B- lactam misuse.
• Cefepime has poor affinity towards them.
• Not amenable to inhibition by B-lactamase inhibitors

.
1 Jacoby, George A, and Luisa Silvia Munoz-Price. “The new beta-lactamases.” The New England journal of medicine vol. 352,4 (2005)
2. El Salabi, Allaaeddin et al. “Extended spectrum β-lactamases, carbapenemases and mobile genetic elements responsible for antibiotics resistance in
Gram-negative bacteria.” Critical reviews in microbiology vol. 39,2 (2013)
 Classes/Mechanism of resistance in ESBL

Jacoby, George A, and Luisa Silvia Munoz-Price. “The new beta-lactamases.” The New England journal of medicine vol. 352,4 (2005)
 Classes/Mechanism of resistance in ESBL

Jacoby, George A, and Luisa Silvia Munoz-Price. “The new beta-lactamases.” The New England journal of medicine vol. 352,4 (2005)
 Pattern of resistance in ESBL
Resistant to May be resistant to
 Penicillins  Sulfonamides
 Monobactams  Cotrimoxazole
 Oxyamino cephalosporins like  Tetracyclines
cefotaxime, ceftazidime,  Aminoglycosides
ceftriaxone, cefiroxime and  Carbapenams (less frequently)
cefepime

.
1 Jacoby, George A, and Luisa Silvia Munoz-Price. “The new beta-lactamases.” The New England journal of medicine vol. 352,4 (2005)
2. El Salabi, Allaaeddin et al. “Extended spectrum β-lactamases, carbapenemases and mobile genetic elements responsible for antibiotics resistance in
Gram-negative bacteria.” Critical reviews in microbiology vol. 39,2 (2013)
 CLSI

Dudley, Michael N et al. “Background and rationale for revised clinical and laboratory standards institute interpretive criteria (Breakpoints) for Enterobacteriaceae and Pseudomonas
aeruginosa: I. Cephalosporins and Aztreonam.” Clinical infectious diseases : an official publication of the Infectious Diseases Society of America vol. 56,9 (2013): 1301-9.
doi:10.1093/cid/cit017
 EUCAST

Dudley, Michael N et al. “Background and rationale for revised clinical and laboratory standards institute interpretive criteria (Breakpoints) for Enterobacteriaceae and Pseudomonas
aeruginosa: I. Cephalosporins and Aztreonam.” Clinical infectious diseases : an official publication of the Infectious Diseases Society of America vol. 56,9 (2013): 1301-9.
doi:10.1093/cid/cit017
 Epidemiology
• ESBL producing Enterobacteriaceae reported worldwide
 Initially health care associated
 Community acquired infections rising
 Considered as global epidemic in resource rich as well as
limited nations
 E. Coli producing CTX-M beta lactamases have been global
problem.

Lynch, Joseph P 3rd et al. “Evolution of antimicrobial resistance among Enterobacteriaceae (focus on extended spectrum β-lactamases and
carbapenemases).” Expert opinion on pharmacotherapy vol. 14,2 (2013)
Epidemiology
Epidemiology
 Clinical picture: Risk Factors
Community onset Hospital onset
 Recurrent UTI  Longer length of hospital stay
 Exposure to antibiotics esp.  Increased severity of illness
cephalosporins and  Longer time in the ICU
fluoroquinolones  Mechanical ventilation
 Previous hospitalization  Urinary/ arterial catheterization
 Nursing home residents.  Previous antibiotic exposure
 Older age
 Diabetes mellitus
 Underlying liver or renal
pathology
 International travel esp. to Asia
and Northern Africa

Pitout, Johann D D, and Kevin B Laupland. “Extended-spectrum beta-lactamase-producing Enterobacteriaceae: an emerging public-health concern.” The Lancet.
Infectious diseases vol. 8,3 (2008)
 Clinical picture
• ESBL are related to wide variety of nosocomial and community
acquired infections
 UTI
 Bacteremia
 Wound infections
 Prostatitis
 Pneumonia
 Osteomyelitis
 Spontaneous bacterial peritonitis
 Pyomyositis in hematological malignancies

1.Oteo, Jesús et al. “Extended-spectrum [beta]-lactamase producing Escherichia coli: changing epidemiology and clinical impact.” Current opinion in infectious
diseases vol. 23,4 (2010): 320-6.
2. Lynch, Joseph P 3rd et al. “Evolution of antimicrobial resistance among Enterobacteriaceae (focus on extended spectrum β-lactamases and carbapenemases).”
Expert opinion on pharmacotherapy vol. 14,2 (2013)
 Clinical picture: Risk Factors

Kassakian, Steven Z, and Leonard A Mermel. “Changing epidemiology of infections due to extended spectrum beta-lactamase producing bacteria.” Antimicrobial resistance and
infection control vol. 3,1 9. 25 Mar. 2014
 Treatment: Carbapenams
• DOC for severe infections caused by ESBL producing organisms.
• Efficacy of data available treatments is less.
• Bactericidal and highly stable against hydrolysis by ESBL
• High body tissue concentrations
• Empiric therapy with them have mortality benefit.
• Carbapenamase producers are arising.

Pitout, Johann D D, and Kevin B Laupland. “Extended-spectrum beta-lactamase-producing Enterobacteriaceae: an emerging public-health concern.” The Lancet.
Infectious diseases vol. 8,3 (2008)
 Treatment: other
• Fluoroquinolones: not superior to carbapenams
• Aminoglycosides:
 Gentamicin, amikacin, tobramycin
 Bactericidal
 Susceptibilty is variable
 Not used as monotherapy but can be used in combination with carbapenems.
• Cefepime
 4th generation cephalosporin with cidal activity.
 May be useful in clinical settings where resistance is to 3rd generation
cephalosporins.
 Dose dependent susceptibility demonstrated in in-vitro studies
 Treatment: b-lactam+b-lactamase inhibitors

Combinations Comments
• Piperacillin/tazobatam • In-vitro activity against ESBL has been seen
• Ampicillin/sulbactam • Specific population in which they have better
• Ceftazidime/avibactam efficacy hasn’t been clearly defined
• Ceftolozone/tazobactam
• Meropenam/varbobactam
• Imipenam/relebactam

Ceftolazone/tazobactam • Combination+metronidazole is as effective as

ASPECT-cIAI /ASPECT-cUTI meropenem for cIAI
• Combination is as effective as levofloxacin for cUTI
Ceftazidime/avibactum • Indicated for complicated UTI and complicated IAI
(2 phase 2 trials)

Meropenam/avibactum • Adverse reactions more than benefits

 Treatment: fosfomycin
• Fosfomycin improve symptoms of lower UTI caused by ESBL.

Falagas, Matthew E et al. “Fosfomycin for the treatment of multidrug-resistant, including extended-spectrum beta-lactamase producing, Enterobacteriaceae infections: a
systematic review.” The Lancet. Infectious diseases vol. 10,1 (2010)
 Treatment: Nitrofurantaoin
• Nitrofurantoin improves symptoms of lower UTI caused by ESBL.

Tasbakan, Meltem Isikgoz et al. “Nitrofurantoin in the treatment of extended-spectrum β-lactamase-producing Escherichia coli-related lower urinary tract infection.”
International journal of antimicrobial agents vol. 40,6 (2012)
 Treatment: Tigecycline
• Tigecycline is useful in ESBL in complicated IAI.

Oliva, María E et al. “A multicenter trial of the efficacy and safety of tigecycline versus imipenem/cilastatin in patients with complicated intra-abdominal infections [Study
ID Numbers: 3074A1-301-WW; ClinicalTrials.gov Identifier: NCT00081744].” BMC infectious diseases vol. 5 88. 19 Oct. 2005
 IDSA
• Empiric therapy is not ideal. But understanding of previous
organism/antibiotics and local resistance pattern can help.
• Duration, not fixed; clinical scenario guides it. And usually like the
susceptible organisms.
• Uncomplicated cystitis use cotrimoxazole and nitrofurantoin.
• Pyelonephritis and cUTI : carbapenams, fluoroquinolones and
cotrimoxazole
• Other than UTI cases: carbapenems are preferrable.
• Cefepime and cephamycin (cefoxitin and cefotetan) are never
effective.

Tamma PD, Aitken SL, Bonomo RA, Mathers AJ, van Duin D, Clancy CJ. Infectious Diseases Society of America Antimicrobial-Resistant Treatment Guidance: Gram-
Negative Bacterial Infections. Infectious Diseases Society of America 2022
 Prognosis

• Severe ESBL infections are associated with

 Longer hospital stay

 Higher rates of treatment failure

 Increased rates of mortality

 Especially when carbapenems are not used or when there is inadequate

empiric antimicrobial therapy
 Prevention

Acquisition Strategy

• Food • Antimicrobial stewardship

• Person to person from fecal carriers
• Environment and sewage
• Domestic and wild animals
• Long term care facilities and nursing
homes
• Active surveillance and isolation
• Bundles of staff education
• Contact precaution
• Isolation and cohorting of colonized
patients
 Take home
• ESBLs are emerging as global epidemic.
• Can hydrolyze the B-lactam rings.
• They might not be limited among B-Lactam anti-biotics only
pertaining to their resistance.
• Antibiotic misuse, old age, comorbidities, health care contacts remain
the risk factors.
• Complicated UTI and complicated IAI are the main clinical scenarios.
• Uncomplicated UTI: nitrofurantoin and cotrimoxazole
• Complicated UTI and others : carbapenams
• Prevention is better than cure.
 Take home

Thank you ……have a good day