ESBL Bacterial Infections: Causes, Detection, and Treatment of UTI, E. coli & Klebsiella

Table of Contents

• What is ESBL?
• Classification of ESBLs
• Evolution of ESBLs
• How Are ESBL-Producing Bacteria Spread?
• Transmission of ESBLs
• Prevalence of ESBL-Producing Bacteria
• Colonization vs. Infection
• Where Are ESBLs Commonly Spread?
• Symptoms of ESBL Infection
• Causes and Risk Factors
• Who Is at Risk?
• Can ESBL Infections Be Treated?
• Prevention and Control
• Future Threats of ESBL in South Asian Developing Countries
• References

What is ESBL?

• ESBL stands for Extended Spectrum Beta-Lactamase.
• These are enzymes produced by certain Gram-negative bacteria that can break down and inactivate a wide range of beta-lactam antibiotics.
• The antibiotics affected include penicillins, third-generation cephalosporins, and aztreonam.
• ESBLs render these antibiotics ineffective, making infections harder to treat.
• The most common ESBL-producing bacteria are from the Enterobacteriaceae family, including Escherichia coli, Klebsiella pneumoniae, and Proteus species.
• These bacteria often live harmlessly in the human intestinal tract as part of the normal gut flora.
• Problems arise when ESBL-producing bacteria move to sterile body sites like the bladder, lungs, or bloodstream, causing infections.
• People with weakened immune systems, recent hospital stays, or those on prolonged antibiotic treatment are more likely to become infected.
• Infections may include urinary tract infections (UTIs), bloodstream infections, wound infections, or hospital-acquired pneumonia.
• Carriers of ESBL-producing bacteria may have no symptoms but can still spread the bacteria to others.
• These enzymes are a growing global health concern, as the infections they cause often require treatment with stronger antibiotics like carbapenems, which should be preserved for severe infections.
• ESBL-producing bacteria are resistant to multiple drugs, leaving fewer options for effective therapy.
• The World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC) have listed ESBLs among the top threats of antibiotic resistance globally.

Classification of ESBLs

• Molecular Class: ESBLs (Extended-Spectrum β-Lactamases) are serine β-lactamases and fall under Ambler class A, based on their molecular structure (JAC-AMR, 2021).
• Biochemical Properties: These enzymes hydrolyze expanded-spectrum β-lactam antibiotics such as third-generation cephalosporins and are inhibited by β-lactamase inhibitors like clavulanate (JAC-AMR, 2021).

Major ESBL Families and Their Characteristics:

• TEM
• Named after the first patient "Temoneira".
• Evolved through point mutations from TEM-1 or TEM-2.
• Found mostly in Escherichia coli and Klebsiella pneumoniae (PMC89009; MicrobeOnline).
• SHV
• Stands for Sulfhydryl Variable.
• Derived from SHV-1 by point mutations.
• Common in E. coli and K. pneumoniae (PMC89009; MicrobeOnline).
• CTX-M
• Stands for "cefotaxime-hydrolyzing, Munich origin".
• Derived from Kluyvera spp. chromosomal β-lactamases.
• Highly diverse; now the most prevalent ESBLs globally (JAC-AMR, 2021; Nature, 2024).
• GES
• Guiana-Extended Spectrum β-lactamases.
• Seen more frequently in Pseudomonas aeruginosa.
• Some variants can also hydrolyze carbapenems (Frontiers in Microbiology, 2016).
• PER
• Pseudomonas Extended Resistant.
• Prevalent in P. aeruginosa and Acinetobacter baumannii (PubMed 18154525).
• VEB
• Vietnam ESBLs.
• Prefer hydrolyzing ceftazidime and aztreonam.
• BEL, TLA, SFO, OXY
• Less common, have unique hydrolysis profiles.
• Some are chromosomally encoded and regionally important (JAC-AMR, 2021).
• Other Enzymes
• OXA-type β-lactamases, though mostly oxacillinases, include some ESBL variants (PMC89009).

Evolution of ESBLs

• Origin: Most ESBLs originated from broad-spectrum β-lactamases like TEM-1, TEM-2, and SHV-1 via point mutations that expanded their activity to include third-generation cephalosporins (PubMed 18154525; PMC89009).
• Mechanisms of Evolution:
• Point Mutations: Amino acid substitutions (e.g., TEM-1 to TEM-3) change enzyme activity (PMC89009).
• Gene Mobilization: Plasmid-mediated horizontal gene transfer allows rapid spread between bacteria (PubMed 18154525).
• Recombination: DNA recombination adds to the diversity of ESBL genes (Orbit DTU, 2019).
• Selective Pressure: Overuse of β-lactam antibiotics in both hospitals and communities accelerates the emergence and spread of ESBLs (PubMed 18154525; Microbenotes).

How Are ESBL-Producing Bacteria Spread?

• ESBL-producing bacteria are primarily spread through contact transmission, especially in healthcare environments such as hospitals and nursing homes.
• The most common route of transmission is via contaminated hands, medical equipment, or surfaces that come into contact with infected or colonized individuals.
• Both patients and healthcare workers can unknowingly transfer the bacteria from one person or surface to another.
• Inadequate hand hygiene is the leading factor contributing to the spread of ESBL-producing bacteria.
• The risk of spreading ESBL is significantly higher in individuals with:
• Diarrhoea, which increases fecal shedding of bacteria
• Urinary catheters, which provide a direct path for bacteria to enter the body
• Wound drainage tubes or open wounds, which allow bacteria to escape and contaminate external surfaces
• ESBL bacteria can survive on hospital surfaces, such as bed rails, doorknobs, medical devices, or even charts, for extended periods.
• Improper cleaning or disinfection of reusable equipment can also lead to spread among patients.
• Visitors and family members who fail to practice good hand hygiene can also carry ESBL bacteria between patients.
• Outside healthcare settings, ESBL bacteria can be acquired from contaminated water, soil, or contact with animals carrying the bacteria.
• Touching contaminated fecal matter or improperly cooked meat can also result in colonization or infection.
• ESBLs can also be transmitted through international travel, especially to regions where antibiotic resistance is widespread.

Transmission of ESBLs

• ESBL-producing bacteria can be transmitted through various environmental and interpersonal pathways, both in healthcare settings and the community.

Environmental sources play a significant role in community-acquired ESBL colonization or infection:

• Contact with water or soil contaminated with human or animal feces can result in exposure.
• Poor sanitation and inadequate sewage disposal increase the risk of environmental transmission.
• Agricultural runoff containing animal waste may contaminate rivers, lakes, or crops with resistant bacteria.

Direct and indirect contact is a common route of spread:

• Touching infected or colonized individuals (even without symptoms) can lead to transmission.
• Contact with animals (especially livestock or pets treated with antibiotics) may also be a source.
• Handling contaminated objects like razors, thermometers, bedpans, or medical instruments facilitates bacterial transfer.
• Bacteria may also be spread via clothing, towels, or shared surfaces.

Airborne or droplet spread, though less common, may occur:

• Close contact activities like sneezing, coughing, or heavy breathing can release microdroplets carrying bacteria.
• This mode is more likely in high-density healthcare settings or areas with poor ventilation.

Foodborne transmission is also possible:

• Consuming undercooked or contaminated meat, especially poultry and beef, may introduce ESBL-producing bacteria into the gut.
• Cross-contamination during food preparation can transfer bacteria to other surfaces or foods.

Travel-related transmission:

• Travelers to regions with high antibiotic resistance or poor hygiene infrastructure are at increased risk.
• In some studies, up to 70% of international travelers return home colonized with ESBL bacteria after visiting endemic areas.
• Once a person is colonized, they may unknowingly spread bacteria to others, even in the absence of illness.

Prevalence of ESBL-Producing Bacteria

• The global pooled prevalence of ESBL-producing Escherichia coli in healthcare and community settings is approximately 25.4% (95% CI: 19.7%–31.2%), according to studies by JAC-AMR (2023) and PubMed (39866328).
• The highest prevalence is reported in Southeast Asia, Western Pacific, and Eastern Mediterranean regions, as highlighted by JAC-AMR (2023) and Infectiology Journal (2023).
• The European Region has the lowest reported prevalence, likely due to stringent antimicrobial stewardship and infection control (JAC-AMR, 2023).
• In healthcare settings, including hospitals and long-term care facilities, prevalence reaches 27.7%, while in community settings, it is around 23.4% (JAC-AMR, 2023; PubMed 39866328).
• Among all ESBL-producing bacterial isolates:
• Escherichia coli accounts for 38%–64.6% of cases (PMC7821812; PMC6708561; JIDC).
• Klebsiella pneumoniae makes up about 27%–34% of isolates (PMC7821812; PMC6708561; JIDC).
• The most common genetic markers for ESBL resistance include:
• blaTEM (86%), blaCTX-M (78%), and blaSHV (28%), with frequent co-occurrence of multiple genes (PMC7821812).
• Risk factors for colonization and infection are multifactorial:
• Use of indwelling devices such as urinary catheters, or recent ICU stay (JIDC).
• Inappropriate use of antibiotics, especially cephalosporins and fluoroquinolones (Infectiology Journal, 2023).
• Travel to high-risk regions, where antimicrobial resistance is more prevalent (Infectiology Journal, 2023).
• ESBL-producing bacteria demonstrate high levels of resistance to common antibiotics:
• Resistance to ciprofloxacin (72%), ofloxacin (73%), and amoxicillin (95.7%) is widespread (PMC7821812; JIDC).
• Resistance to fosfomycin is relatively low (15.2%), making it a useful option for treating UTIs (JIDC).
• The rise of ESBLs carries critical public health implications:
• There is an urgent need for regional surveillance and global data sharing to track resistance patterns (JAC-AMR, 2023).
• Antimicrobial stewardship must be reinforced, especially following the overuse of antibiotics during the COVID-19 pandemic (JAC-AMR, 2023; Infectiology Journal, 2023).
• Infection control protocols in healthcare facilities should be strengthened to reduce nosocomial transmission (JIDC).

Colonization vs. Infection

Colonization and infection are two different stages of interaction between the body and ESBL-producing bacteria.

Colonization:

• Occurs when ESBL-producing bacteria are present in or on the body (typically in the intestines, skin, or mucous membranes) without causing symptoms of illness.
• The gastrointestinal tract, especially the colon, is the most common site of colonization.
• Individuals may carry these bacteria for weeks, months, or even years without developing an infection.
• Colonized individuals are often unaware of their carrier status unless tested during hospital screenings or outbreak investigations.
• No antibiotic treatment is required for colonization, as it does not involve tissue invasion or clinical symptoms.
• However, colonized individuals can still transmit ESBL bacteria to others, particularly through:
• Poor hand hygiene
• Contact with shared items or medical equipment
• Use of catheters or other invasive devices
• Colonization can serve as a reservoir for future infection, especially if the immune system becomes compromised.

Infection:

• Occurs when ESBL-producing bacteria invade normally sterile areas of the body, such as:
• Bloodstream
• Urinary tract
• Lungs
• Surgical wounds
• Infection leads to clinical signs and symptoms, such as:
• Fever, chills
• Pain or inflammation at the infection site
• Fatigue or confusion (especially in older adults)
• Infections can be mild to life-threatening, depending on the site and the patient’s health condition.
• Antibiotic treatment is required, and choices are often limited due to resistance.
• Infections are more common in hospitalized or immunocompromised patients, particularly those with:
• Indwelling catheters or IV lines
• Recent surgery
• Prolonged antibiotic use

Where Are ESBLs Commonly Spread?

• Hospitals and healthcare settings are the most common sources of ESBL-producing bacteria transmission.
• ESBLs are frequently encountered in patients who are critically ill, immunocompromised, or undergoing invasive medical procedures.
• Long-term care facilities, such as nursing homes or rehabilitation centers, pose a high risk due to:
• Prolonged stays
• Presence of indwelling devices (e.g., urinary catheters, feeding tubes)
• Frequent use of broad-spectrum antibiotics
• Shared medical equipment or poor infection control practices in healthcare settings increase the likelihood of cross-transmission.
• Environments contaminated with fecal matter also serve as significant reservoirs for ESBL bacteria, including:
• Poorly sanitized public toilets, which may harbor bacteria on surfaces such as toilet seats, handles, and sinks
• Contaminated soil and water, especially in regions with inadequate sewage systems or heavy agricultural runoff
• Community sources where human or animal feces contaminate public spaces
• Contact with animals can also spread ESBLs:
• Livestock, especially those exposed to antibiotics in farming, may carry resistant strains
• Domestic pets can become carriers of ESBL bacteria through environmental exposure or contaminated food
• People working in animal care, agriculture, or veterinary settings are at increased risk
• International travel, especially to areas with high antibiotic resistance, is associated with increased colonization risk.
• Household transmission can occur, particularly if:
• A family member is colonized or infected
• There is poor hand hygiene or shared personal items

Symptoms of ESBL Infection

• Symptoms of infections caused by ESBL-producing bacteria are often non-specific and resemble those of other bacterial infections, but can vary based on the site of infection.
• Infections may range from mild to severe, and can affect different organs, especially in hospitalized or immunocompromised individuals.
• General symptoms may include:
• High fever, often persistent and difficult to control
• Chills and shivering, indicating systemic infection
• Muscle aches and body pain, due to inflammatory response
• Fatigue, weakness, or malaise
• Confusion or disorientation, especially common in the elderly or those with bloodstream infections
• Urinary tract infection (UTI)-related symptoms caused by ESBL-producing E. coli or Klebsiella may include:
• Burning sensation or pain during urination
• Frequent urge to urinate, even when the bladder is empty
• Cloudy or foul-smelling urine
• Lower abdominal or pelvic pain
• Back or flank pain, suggesting kidney involvement (pyelonephritis)
• Abdominal pain or tenderness, especially if the infection has spread from the gut or is related to post-surgical complications
• Wound infections may show:
• Redness, swelling, or warmth around the wound site
• Pus or discharge
• Delayed healing
• Respiratory symptoms in case of pneumonia or ventilator-associated infections may include:
• Cough with sputum
• Difficulty breathing
• Chest discomfort
• Bloodstream infections (sepsis) can result in:
• Drop in blood pressure
• Rapid heart rate
• Organ dysfunction
• These infections can be life-threatening without prompt treatment

Causes and Risk Factors

ESBL-producing bacteria are more likely to cause infection in individuals with weakened immune systems or those exposed to healthcare environments.
Risk significantly increases in people who are already ill or undergoing invasive medical interventions, particularly in hospitals or long-term care facilities.
Common causes and risk-enhancing conditions include:

• Major surgeries:
• Surgical procedures can introduce bacteria into sterile body areas.
• Post-operative wounds and surgical drains increase vulnerability.
• Chemotherapy or cancer treatments:
• These treatments suppress the immune system, reducing the body’s ability to fight infections.
• Prolonged ICU stays:
• ICU patients often require ventilators, central lines, or urinary catheters, all of which raise the risk of bacterial invasion.
• Frequent contact with healthcare workers and shared equipment further increases exposure.
• Use of invasive medical devices:
• Urinary catheters, central venous catheters, feeding tubes, and endotracheal tubes can serve as entry points for bacteria.
• Prolonged use or improper handling of these devices increases infection risk.
• Repeated or improper antibiotic use:
• Overuse of broad-spectrum antibiotics promotes the survival of resistant bacteria like ESBL-producers.
• Self-medication or use of antibiotics without prescription accelerates resistance.
• Failure to complete prescribed antibiotic courses can leave behind resistant strains that multiply and spread.
• Misuse disrupts the normal gut flora, allowing ESBL-producing bacteria to colonize and dominate.
• Previous hospitalizations or residence in healthcare facilities:
• Prior exposure increases the chance of colonization or re-infection with resistant bacteria.
• Advanced age and chronic diseases (e.g., diabetes, kidney disease) also impair immune defense and increase susceptibility.

Who Is at Risk?

• Anyone can acquire an ESBL-producing bacterial infection, regardless of age or health status, especially if exposed to contaminated environments or individuals.
• However, certain groups face a significantly higher risk of colonization and infection due to compromised immunity or increased exposure.
• Hospitalized patients, particularly those in intensive care units (ICUs), are at high risk due to:
• Frequent contact with healthcare workers and equipment
• Use of invasive devices like catheters, IV lines, or ventilators
• Longer hospital stays, which increase the chance of exposure
• Elderly individuals are more vulnerable due to:
• Natural weakening of the immune system with age
• Higher likelihood of underlying chronic conditions
• Increased need for hospitalization or care home residency
• Immunosuppressed patients, such as those undergoing chemotherapy, organ transplantation, or treatment for autoimmune diseases, have:
• Reduced ability to fight infections
• Higher risk of developing serious complications from ESBL bacteria
• Individuals with urinary catheters, surgical wounds, or drainage tubes are more likely to develop infections because:
• These devices provide direct entry routes for bacteria
• Wound sites and mucous membranes can be colonized quickly in compromised settings
• Close contacts of ESBL-infected or colonized individuals, especially within households or care facilities, may contract the bacteria through:
• Shared items like towels, razors, or bedding
• Inadequate hand hygiene after contact
• People who travel to regions with high antibiotic resistance rates, particularly in parts of Asia, the Middle East, Africa, and South America, are at risk due to:
• Exposure to contaminated food, water, or medical care
• Limited infection control practices in some areas
• Studies have shown up to 70% of travelers to high-risk regions return colonized with resistant bacteria
• Patients with recent or repeated use of antibiotics, especially broad-spectrum drugs, are more susceptible due to:
• Disruption of normal gut microbiota, which allows ESBL-producing organisms to flourish
• Selective pressure that favors the survival of resistant strains

Can ESBL Infections Be Treated?

• ESBL infections can be treated, but they are resistant to many commonly used antibiotics, such as penicillins and cephalosporins.
• Treatment requires carefully selected antibiotics based on laboratory sensitivity testing (antibiotic susceptibility tests).
• Effective antibiotics for ESBL-producing bacteria may include:
• Carbapenems (e.g., meropenem, imipenem): Considered the drugs of choice for serious ESBL infections, especially in the bloodstream, lungs, or urinary tract
• Fosfomycin: Often used for uncomplicated urinary tract infections (UTIs) caused by ESBL-producing organisms
• Colistin (Polymyxin E): Used in life-threatening infections when no other options are available; however, it carries a risk of kidney toxicity (nephrotoxicity) and must be used cautiously
• Other potential options (depending on resistance patterns): Amikacin, tigecycline, ceftazidime-avibactam, or newer β-lactamase inhibitor combinations
• Treatment depends on the severity and location of the infection:
• Mild infections, such as minor UTIs, may be treated at home with oral antibiotics under close medical supervision
• Severe infections, such as sepsis or pneumonia, require hospitalization and administration of intravenous (IV) antibiotics
• Patients may require additional supportive care, such as fluids or oxygen therapy, in intensive settings
• Individuals who are colonized (carriers) but not actively infected:
• Do not need antibiotic treatment
• Should follow strict hygiene practices (e.g., handwashing, personal hygiene) to prevent transmission to others
• May still be monitored during hospital admissions or before surgeries to prevent possible complications
• Antibiotics should be used responsibly:
• Only take antibiotics prescribed by a qualified healthcare professional
• Complete the full course of treatment, even if symptoms improve
• Avoid self-medication or stopping antibiotics early, as this increases resistance risk
• Antibiotic stewardship programs in hospitals are critical to control the spread of ESBLs and preserve the effectiveness of last-line treatments.

Prevention and Control

• Wash hands frequently with soap and water, especially after using the toilet, before eating, and after handling raw meat or pets.
• Avoid sharing personal hygiene items such as razors, towels, toothbrushes, or nail clippers to reduce the risk of transmitting bacteria.
• Keep kitchen surfaces, utensils, and cutting boards clean, especially when preparing raw meat, to prevent bacterial contamination and cross-infection.
• Thoroughly cook food, particularly meat, to kill any harmful bacteria that may be present.
• In healthcare settings, use personal protective equipment (PPE) such as gloves and gowns when caring for infected or colonized individuals.
• Follow strict hand hygiene practices using alcohol-based sanitizers or soap before and after contact with patients or bodily fluids.
• Infected or colonized patients may need to be isolated in hospitals to prevent the spread of ESBL-producing bacteria to others.
• Reusable medical equipment must be cleaned and sterilized properly between patients to prevent cross-contamination.
• Healthcare professionals and visitors should be educated about infection control measures and hygiene practices.
• Avoid unnecessary use of antibiotics, as misuse contributes to the development and spread of antibiotic-resistant bacteria.
• Always take antibiotics exactly as prescribed by a healthcare professional and complete the full course, even if symptoms improve.
• Do not self-prescribe or use leftover antibiotics, as this can worsen resistance and reduce treatment options.
• Inform healthcare providers about any previous infections or colonization with resistant bacteria before surgeries or hospital admissions to ensure appropriate precautions are taken.

Future Threats of ESBL in South Asian Developing Countries

1. Emergence of Pan-Resistant Superbugs

• Carbapenem resistance: Variants of New Delhi Metallo-β-lactamase (NDM), such as NDM-1, NDM-17, and NDM-20, are increasingly reported in Enterobacteriaceae from both clinical and livestock sources, including pigs and chickens. These enzymes neutralize carbapenems, severely limiting treatment options (Kumar et al., 2024; Zhang et al., 2023).
• Colistin resistance: The mcr-1 gene, responsible for resistance to colistin (a last-line antibiotic), has been found in E. coli from farm animals. Its presence is linked to historical use of colistin as a growth promoter in agriculture, raising concerns of zoonotic spread (Zhang et al., 2023; Subramaniam et al., 2021).

2. Environmental Contamination and Gene Spread

• Antibiotic residues: Discharge from hospitals, farms, and pharmaceutical industries introduces antimicrobials into water bodies and soil, selecting for resistant organisms and facilitating gene exchange (BMJ AMR, 2024).
• Co-transmission of resistance genes: Mobile genetic elements like plasmids carrying ESBL genes (e.g., blaCTX-M-15) can be transferred between environmental, animal, and human microbiota, amplifying resistance across ecosystems (Kumar et al., 2024; Zhang et al., 2023).

3. Weak Surveillance and Diagnostic Gaps

• Underreporting: Many South Asian countries lack robust surveillance systems for antimicrobial resistance (AMR), especially in animal health. Inadequate lab infrastructure often delays or prevents the detection of emerging resistant strains (WHO, 2021; Chaudhary et al., 2023).
• Diagnostic limitations: Rapid molecular diagnostics for ESBL and carbapenemase producers remain largely inaccessible in rural and secondary care settings, encouraging inappropriate antibiotic use (Zhang et al., 2023).

4. Socioeconomic Drivers of Resistance

Antibiotic overuse:

• In humans, resistance is driven by unregulated antibiotic sales, self-medication, and incomplete dosing (Kumar et al., 2024; Zhang et al., 2023).
• In agriculture, routine prophylactic use of antibiotics in livestock promotes the evolution and spread of ESBLs and mcr-type genes (Subramaniam et al., 2021; Sharma et al., 2023).
• Healthcare infrastructure: Overcrowded public hospitals with limited infection control, particularly in peri-urban and rural zones, serve as hotspots for nosocomial spread of ESBL-producers (Saha et al., 2021).

5. Regional and Global Spread

• Travel and trade: International mobility and food exports from South Asia have been identified as conduits for global distribution of ESBL-positive bacteria and resistance genes (Kumar et al., 2024; Zhang et al., 2023).
• Climate factors: Seasonal flooding, poor sanitation, and population density facilitate contamination of drinking water sources and increase risk of horizontal gene transfer among bacterial populations (BMJ AMR, 2024).

Projected Impact Without Intervention

• Mortality burden: Without effective treatments, multidrug-resistant infections could reverse decades of progress in treating neonatal sepsis, surgical infections, and chronic comorbidities (Kumar et al., 2024; Zhang et al., 2023).
• Economic strain: The rise of pan-resistant strains may lead to longer hospitalizations, increased healthcare costs, and loss of productivity—especially harmful in resource-limited settings (BMJ AMR, 2024; Subramaniam et al., 2021).

Urgent Interventions Needed

• One Health integration: Coordinated surveillance across human, animal, and environmental sectors is essential for controlling ESBL transmission (BMJ AMR, 2024; Kumar et al., 2024).
• Antibiotic stewardship: Tighter regulations on over-the-counter antibiotic sales and veterinary antibiotic usage, paired with promotion of alternatives such as bacteriophage therapy, are crucial (Zhang et al., 2023).
• Diagnostic accessibility: Investment in affordable, rapid diagnostic tools, especially in rural healthcare settings, can improve treatment outcomes and reduce misuse (Subramaniam et al., 2021).
• Public education: Community-driven educational campaigns are essential to correct misconceptions about antibiotics and prevent self-medication (BMJ AMR, 2024).

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