ESBL (Extended Spectrum Beta-Lactamase)- Introduction, List

Introduction

Table of Contents

Extended Spectrum Beta-Lactamase (ESBL) is a term that encompasses a group of enzymes produced by certain bacteria. These enzymes impart resistance to a wide range of beta-lactam antibiotics, which are frequently used in clinical medicine. Here’s an introduction to ESBL:

Origin and Mechanism:

Definition: ESBLs are enzymes that confer resistance to most penicillin derivatives, cephalosporins (especially the third-generation ones), and aztreonam (a monobactam). They are thus termed “extended spectrum” because of their capability to hydrolyze a broader spectrum of beta-lactam antibiotics compared to older beta-lactamases.
Mechanism: The ESBL enzymes act by breaking the beta-lactam ring of the antibiotic, rendering it ineffective. Their activity can usually be inhibited by substances like clavulanic acid, sulbactam, or tazobactam.

Clinical Implications:

Bacterial Strains: The most common bacteria that produce ESBL enzymes are Escherichia coli and Klebsiella pneumoniae. However, other bacteria can also produce these enzymes.
Treatment Challenges: Bacterial strains that produce ESBL are resistant to many of the usual first-line antibiotics. This makes infections caused by these bacteria harder to treat, leading to prolonged illness, higher healthcare expenses, and increased mortality.
Healthcare Settings: Initially, ESBL-producing organisms were mainly found in hospitals, especially among patients in intensive care units or those who had been on prolonged antibiotic treatment. However, over time, community-acquired infections with these bacteria have also been reported.

Epidemiology:

Spread: ESBL-producing bacteria have become widespread worldwide. Their spread is driven by the excessive and inappropriate use of antibiotics both in healthcare settings and in the community.
Gene Transfer: The genes coding for ESBL enzymes are often located on plasmids, which are mobile genetic elements. This allows for easy transfer of resistance genes between different bacteria, further complicating control measures.

Detection and Management:

Identification: Special laboratory tests are required to detect ESBL production in bacterial strains. The detection is crucial for guiding appropriate antibiotic therapy.
Treatment: Carbapenems are often used as the drug of choice for severe infections with ESBL-producing bacteria. However, with emerging resistance to even these antibiotics, it’s crucial to choose treatments based on susceptibility testing. Newer drugs and combinations have been developed over the years to counter ESBL-producing bacteria.
Prevention: Effective infection control measures, judicious use of antibiotics, and regular surveillance are crucial in controlling the spread of ESBL-producing organisms.

List of Bacteria

Extended Spectrum Beta-Lactamase (ESBL) enzymes are most commonly produced by Gram-negative bacteria. Here is a list of some of the bacteria that have been identified to produce ESBLs:

Escherichia coli (E. coli): A common inhabitant of the human intestine, some strains of which can cause urinary tract infections, sepsis, and other infections.
Klebsiella pneumoniae: Known to cause pneumonia, bloodstream infections, wound infections, and urinary tract infections.
Klebsiella oxytoca: Less common than K. pneumoniae, but can also cause a variety of infections.
Proteus mirabilis: Primarily associated with urinary tract infections.
Proteus vulgaris: Another species of the genus Proteus known to produce ESBLs.
Salmonella species: Certain strains can produce ESBLs, making infections harder to treat.
Shigella species: Some strains have been identified to produce ESBLs, leading to concerns about treatment of dysentery and related conditions.
Enterobacter species, such as:
- Enterobacter aerogenes
- Enterobacter cloacae
Citrobacter species, including:
- Citrobacter freundii
- Citrobacter koseri
Morganella morganii: While not as common, some strains can produce ESBLs.
Serratia marcescens: Known to cause a range of infections, especially in hospitalized patients.
Pseudomonas aeruginosa: Though not as common, some strains have been reported to produce ESBLs.
Acinetobacter species: Some strains, especially Acinetobacter baumannii, can produce ESBLs, though carbapenemase production is more common in this genus.

While the above list covers several of the known ESBL producers, it’s worth noting that the ability to produce ESBLs can be transferred between bacteria due to the mobile nature of the genes encoding these enzymes (often located on plasmids). This means that new ESBL-producing strains or species can emerge. Thus, ongoing surveillance and research are crucial in understanding the evolving landscape of antibiotic resistance.

Pathogenicity

The pathogenicity of ESBL-producing bacteria refers to their ability to cause disease in humans or animals. The presence of Extended Spectrum Beta-Lactamase (ESBL) enzymes in these bacteria does not directly contribute to their ability to cause disease; rather, ESBLs give these bacteria resistance to many commonly used antibiotics, which complicates treatment. However, the pathogenic potential of these bacteria arises from a combination of their intrinsic virulence factors and the added challenge posed by their drug resistance.

Here’s a closer look at the pathogenicity of ESBL producers:

Complicated Treatment: As mentioned, ESBL-producing bacteria can resist many of the first-line antibiotics used to treat infections. This resistance can lead to delays in effective treatment, which in turn can worsen the disease outcome, prolong hospital stays, and increase the risk of complications.
Infections in Vulnerable Populations: ESBL-producing bacteria can cause infections in patients with weakened immune systems, including those in hospitals, especially in intensive care units. Such patients are more susceptible to infections and can experience more severe disease outcomes.
Range of Infections: ESBL-producing strains of bacteria like E. coli and Klebsiella pneumoniae can cause a wide range of infections, including urinary tract infections, bloodstream infections, pneumonia, intra-abdominal infections, and more.
Virulence Factors: Many ESBL-producing bacteria possess additional virulence factors that enhance their ability to cause disease. For example, some strains might have toxins, adhesion factors, or secretion systems that enable them to invade host tissues, evade the immune system, or cause cellular damage.
Outbreaks: Hospitals and long-term care facilities have seen outbreaks caused by ESBL-producing bacteria. These outbreaks can be challenging to control due to the limited treatment options and the need for stringent infection prevention measures.
Community-Acquired Infections: While initially seen mainly in healthcare settings, ESBL-producing bacteria are now also causing community-acquired infections. This means that individuals without prior hospitalization or typical healthcare-associated risk factors are also at risk.
Co-resistance: Many ESBL-producing bacteria are also resistant to other classes of antibiotics due to the coexistence of multiple resistance genes. This multidrug resistance further narrows the treatment options and complicates therapy.

Symptoms

The symptoms of an infection caused by ESBL-producing bacteria depend on the site of the infection. Extended Spectrum Beta-Lactamase (ESBL) production in itself doesn’t cause specific symptoms; instead, it denotes antibiotic resistance in the bacterial pathogen. Here are the common types of infections caused by ESBL-producing bacteria and their associated symptoms:

Urinary Tract Infections (UTIs):
- Burning sensation during urination
- Frequent urination
- Cloudy or bloody urine
- Pain or discomfort in the lower abdomen
- Fever or chills (indicating a possible spread to the kidneys)
Bloodstream Infections (Sepsis or Bacteremia):
- Fever and chills
- Rapid heart rate and rapid breathing
- Low blood pressure
- Fatigue or lethargy
- Confusion or altered mental state
Pneumonia:
- Fever and chills
- Cough (can be with yellow/green or bloody mucus)
- Shortness of breath or difficulty breathing
- Chest pain that worsens with breathing or coughing
- Fatigue
Intra-abdominal Infections:
- Abdominal pain or discomfort
- Nausea or vomiting
- Diarrhea or constipation
- Fever
Skin and Soft Tissue Infections:
- Redness, warmth, and swelling of the affected area
- Pain or tenderness
- Discharge or pus from the wound or affected area
- Fever
Meningitis (less common with ESBL producers, but possible):
- Severe headache
- Neck stiffness
- Fever and chills
- Sensitivity to light
- Altered mental state or confusion
- Nausea and vomiting
Others: ESBL-producing bacteria can potentially infect other body sites, leading to symptoms corresponding to that specific site.

It’s essential to understand that ESBL-producing bacteria can cause the same range of infections as their non-ESBL-producing counterparts. The key concern with ESBL producers is that they are resistant to a wide range of commonly used antibiotics, which makes treatment more challenging.

Lab Diagnosis

Laboratory diagnosis of Extended Spectrum Beta-Lactamase (ESBL) producers is crucial for selecting the right antibiotic treatment and controlling the spread of these resistant bacteria. The diagnosis can be approached through phenotypic tests (based on observable traits and behaviors of the bacteria) and genotypic methods (based on genetic material).

Phenotypic Tests:

ESBL (Extended Spectrum Beta-Lactamase)- Introduction, List of Bacteria, Pathogenicity, Symptoms, Lab Diagnosis, Treatment, Prevention, and Keynotes — Fig. ESBL (Extended Spectrum Beta-Lactamase) Phenotypic Test- Double Disk Synergy Test (DDST)

Disk Diffusion Methods:
- Double Disk Synergy Test (DDST): This involves placing cephalosporin disks and a disk containing clavulanic acid (a beta-lactamase inhibitor) on an agar plate inoculated with the test organism. Enhancement of the inhibition zone around the cephalosporin in the direction of the clavulanic acid disk suggests ESBL production.
- Combined Disk Test: This uses disks containing a cephalosporin alone and the same cephalosporin combined with clavulanic acid. A significant increase in the zone diameter for the combination disk compared to the cephalosporin alone disk indicates ESBL production.
ESBL E-test: A strip containing a gradient of antibiotic concentration is placed on an agar plate inoculated with the test organism. One side of the strip contains a cephalosporin alone, and the other side contains the cephalosporin with clavulanic acid. A significant reduction in the minimum inhibitory concentration (MIC) in the presence of clavulanic acid is indicative of ESBL production.
Automated Systems: Automated systems like Vitek 2 (bioMérieux) and Phoenix (BD) are often equipped to detect ESBL production. They typically use microbroth dilution methods comparing cephalosporins alone and in combination with clavulanic acid.

Genotypic Methods:

Polymerase Chain Reaction (PCR): PCR can detect genes responsible for ESBL production, such as bla_TEM, bla_SHV, and bla_CTX-M. This method identifies the presence of ESBL genes in the bacterial genome.
Real-time PCR: This allows for faster detection and, in some cases, quantification of specific ESBL genes.
DNA Sequencing: After PCR amplification, sequencing of the amplified product can identify specific ESBL types and variants.
Whole Genome Sequencing (WGS): WGS provides comprehensive information about all resistance mechanisms, including ESBL genes.
Microarrays: These platforms can detect multiple resistance genes, including ESBL genes, in one assay.

Confirmatory Tests:

It’s essential to use appropriate control strains, both ESBL-positive and ESBL-negative, when performing tests to confirm the presence of ESBLs. This ensures accuracy and helps differentiate true ESBL production from other resistance mechanisms.

Treatment

The treatment of infections caused by Extended Spectrum Beta-Lactamase (ESBL) producing bacteria can be challenging due to their resistance to a wide range of commonly used antibiotics. However, there are still treatment options available:

Carbapenems: These are often the drugs of choice for serious infections caused by ESBL-producing organisms.
- Examples: Imipenem, meropenem, ertapenem, and doripenem.
Beta-lactam/Beta-lactamase Inhibitor Combinations: Some newer combinations have shown activity against certain ESBL-producing bacteria.
- Examples: Ceftazidime/avibactam and ceftolozane/tazobactam.
Quinolones: In regions where resistance isn’t prevalent, fluoroquinolones might be effective. However, resistance to quinolones is increasing in many areas.
- Examples: Ciprofloxacin and levofloxacin.
Aminoglycosides: They can be effective against some ESBL-producing organisms but are often used in combination with other drugs.
- Examples: Gentamicin, tobramycin, and amikacin.
Piperacillin/Tazobactam: Some ESBL-producing organisms might be susceptible to this combination, especially in urinary tract infections. However, its efficacy for bloodstream infections or other severe infections is debated.
Fosfomycin: For uncomplicated lower urinary tract infections caused by ESBL-producing E. coli, fosfomycin might be an option.
Nitrofurantoin: This can be used for uncomplicated UTIs caused by ESBL-producing E. coli, but it is not effective for more severe infections or infections outside the urinary tract.
Colistin (polymyxin E): This is considered a last-resort antibiotic for multidrug-resistant gram-negative infections. It’s active against some ESBL producers, but its use is limited due to potential nephrotoxicity and neurotoxicity.
Tigecycline: This is a glycylcycline antibiotic that has activity against many multidrug-resistant bacteria, including some ESBL producers. However, it’s not the first choice due to its pharmacokinetic profile and concerns about increased mortality in some situations.
Cefiderocol: A newer siderophore cephalosporin with activity against a broad range of gram-negative bacteria, including some ESBL producers.

Prevention

Preventing the spread and emergence of Extended Spectrum Beta-Lactamase (ESBL) producing bacteria is crucial given their resistance to multiple antibiotics. Here are several strategies and measures that can help in this endeavor:

Infection Control in Healthcare Settings:
- Hand Hygiene: Ensure that healthcare workers practice proper hand hygiene, particularly before and after patient contact. This is one of the most effective measures to prevent the spread.
- Isolation Precautions: Patients known to be infected or colonized with ESBL-producing bacteria may need to be placed in isolation to prevent transmission to other patients.
- Cleaning and Disinfection: Regular cleaning and disinfection of patient care areas and equipment.
- Protective Equipment: Use of personal protective equipment (PPE) like gowns and gloves, especially when handling body fluids or when in contact with patients known to be infected or colonized.
- Education: Training healthcare workers about ESBLs and the risks associated with them.
Antibiotic Stewardship:
- Prudent Use: Only use antibiotics when necessary, and select the most appropriate antibiotic for the infection.
- Avoid Prolonged Use: Limit the duration of antibiotic treatment to what’s necessary.
- Review and De-escalate: Start with broad-spectrum antibiotics if needed, but once culture and sensitivity results are available, switch to narrower-spectrum antibiotics.
- Regular Audits: Periodic reviews of antibiotic prescription practices in healthcare institutions.
Surveillance:
- Monitoring: Regularly monitor for the emergence of ESBL-producing bacteria in clinical settings.
- Reporting: Share data about ESBL prevalence with regional and national health bodies to understand and respond to trends.
Patient Education:
- Completion of Course: Educate patients to complete the entire prescribed course of antibiotics, even if they feel better.
- No Self-Prescription: Advise against using antibiotics without a prescription.
- Understanding Risks: Make patients aware of the risks of antibiotic resistance and the importance of prevention.
Limit Use in Agriculture:
- Antibiotics, especially those critical for human medicine, should not be used in agriculture for growth promotion. Their use should be limited to treating diagnosed infections in animals.
Travel Precautions:
- Travelers to regions with a high prevalence of ESBL-producing bacteria should be cautious about consuming uncooked food, drinking untreated water, and ensure they practice good hand hygiene.
Community Level Prevention:
- Encourage good hygiene practices, including proper handwashing.
- Advocate for the judicious use of antibiotics even in outpatient settings.

Keynotes

Here are the keynotes on Extended Spectrum Beta-Lactamase (ESBL):

Definition: ESBLs are enzymes produced by certain bacteria that provide resistance to a wide range of beta-lactam antibiotics, particularly penicillins and cephalosporins.
Origin: First identified in the 1980s, their prevalence has been increasing worldwide.
Common Producers: The most frequent ESBL-producing bacteria include Escherichia coli (E. coli) and Klebsiella pneumoniae.
Mechanism: ESBLs break down and inactivate the beta-lactam ring of antibiotics, rendering them ineffective.
Clinical Implication: ESBL-producing bacteria can cause various infections, including urinary tract infections, bloodstream infections, and respiratory infections. Treatment becomes challenging due to their resistance profile.
Spread: Initially more common in healthcare settings, community-acquired ESBL infections are now increasing.
Detection: Phenotypic tests, like the Double Disk Synergy Test (DDST) and Combined Disk Test, are commonly used. Molecular methods, such as PCR, can identify specific ESBL genes.
Treatment: Carbapenems are often the drugs of choice for severe ESBL infections. Other alternatives include certain beta-lactam/beta-lactamase inhibitor combinations, and newer agents like ceftazidime/avibactam.
Resistance Concern: Overuse of carbapenems to treat ESBL infections can lead to carbapenem-resistant organisms, which pose an even greater therapeutic challenge.
Prevention: Infection control in healthcare settings, antibiotic stewardship, patient education, and surveillance are key strategies to prevent the spread of ESBL-producing bacteria.
Global Concern: The spread of ESBL-producing bacteria is a significant public health concern due to the limited treatment options, potential for outbreaks, and associated morbidity and mortality.

ESBL (Extended Spectrum Beta-Lactamase)- Introduction, List of Bacteria, Pathogenicity, Symptoms, Lab Diagnosis, Treatment, Prevention, and Keynotes