Enterobacteriaceae are the most important pathogens in clinical bacterial infectious diseases, and the primary mechanism of antibiotic resistance among these bacteria is the production of extended-spectrum β-lactamases (ESBLs).

ESBLs are a class of β-lactamases mediated by plasmids that can hydrolyze penicillins, oximino-cephalosporins (including third- and fourth-generation cephalosporins), and the monobactam amikacin, and are inhibited by β-lactamase inhibitors.

The diagnosis and early, appropriate treatment of infections caused by ESBL‑producing Enterobacteriaceae have become critical issues urgently requiring resolution in clinical practice. Therefore, the development of consensus guidelines that offer clinicians actionable, evidence‑based recommendations is of significant practical importance for standardizing and enhancing the diagnosis, treatment, and prevention of such infections in China.

1. Epidemiological Overview of ESBL-Producing Enterobacteriaceae

Enterobacteriaceae producing ESBLs are most commonly represented by Escherichia coli and Klebsiella pneumoniae; other frequently encountered species include Proteus and Enterobacter[1]. The prevalence of ESBL-producing Enterobacteriaceae varies considerably across countries and regions. In countries such as Japan and the Netherlands, the incidence is very low, whereas in nations like India and Russia, more than 50% of Klebsiella spp. produce ESBLs[2–3].

In mainland China, the detection rates of ESBL-producing Escherichia coli and Klebsiella pneumoniae are high and have been increasing year by year. According to the CHINET bacterial resistance surveillance program, among hospitalized patients from 2005 to 2010, the ESBL-positive rates rose from 38.9% to 56.2% for E. coli and from 39.1% to 43.6% for Klebsiella species; the rate for Proteus mirabilis also increased from 6% to 16% [4–9]. In 2012, the ESBL-positive rates were 55.3% for E. coli and 33.9% for Klebsiella species [10].

Epidemiological surveys conducted from 2008 to 2010 revealed that, among the pathogens responsible for hospital-acquired pneumonia (HAP) in China, Klebsiella pneumoniae and Escherichia coli accounted for 9.67% and 3.68%, respectively, ranking third and fourth among Gram-negative bacteria. The resistance rates of Enterobacteriaceae were 66.7% to cefotaxime and 35.4% to ceftazidime [11]. Furthermore, Enterobacteriaceae are among the major causative agents of acute exacerbations of chronic obstructive pulmonary disease (COPD), acute exacerbations of bronchiectasis, empyema, and mediastinitis.

In 2010, CHINET surveillance reported that Escherichia coli and Klebsiella pneumoniae accounted for 15% and 6.0%, respectively, of isolates from blood cultures, ranking first and second among Gram-negative pathogens [9]. Among these, the proportions of ESBL-producing strains were 50.7% and 38.5%, respectively [12]. In urinary tract infections, E. coli was the most frequently isolated pathogen, with a detection rate of 65.0%, followed by K. pneumoniae at 5.3% and Proteus mirabilis at 4.7% [13]. The corresponding proportions of ESBL-producing strains ranged from 52.3% to 68.8%, 43.8% to 49.1%, and 14.3%, respectively [13–14].

Enterobacteriaceae are also the most common pathogens causing intra-abdominal infections, particularly Escherichia coli and Klebsiella pneumoniae, which are frequently isolated from bile and peritoneal fluid in patients with intra-abdominal infections. Intra‑cranial infections caused by Enterobacteriaceae account for approximately 5.2% of all bacterial intracranial infections, most of which occur following trauma or surgery. Among these, Klebsiella pneumoniae and Escherichia coli comprise 32.6% and 23.9%, respectively, making them the most prevalent species within this family [15].

At present, reports of intracranial infections caused by ESBL-producing Enterobacteriaceae are relatively rare; approximately 10.9% of Enterobacteriaceae produce ESBLs, with the majority (around 60%) belonging to the CTX-M group [16].

An increasing proportion of Enterobacteriaceae isolates from community-acquired infections producing ESBLs represents a new epidemiological feature. Recent surveys in the United States have shown that 10.9% of community‑derived Escherichia coli strains produce ESBLs, and these strains have become the predominant pathogens responsible for community‑acquired bloodstream and urinary tract infections [17].

Community-onset bloodstream infections (COBSI) caused by ESBL-producing Escherichia coli and Klebsiella pneumoniae have been reported worldwide [18–19], though their incidence is lower than that of hospital-acquired bloodstream infections. In 2010, Spain reported that COBSI due to ESBL-producing E. coli accounted for 7.3% of cases [20], while in 2011, South Korea found that among COBSI caused by K. pneumoniae, only 7.6% were attributable to ESBL-producing strains [21].

China has limited epidemiological data on COBSI. A 2002 survey of seven Chinese cities reported that among adults with community-acquired infections, the proportions of Escherichia coli and Klebsiella pneumoniae producing ESBLs were 16% and 17%, respectively [22]. In 2007, a study of complicated intra-abdominal infections (the SMART study) found that the detection rates of ESBL-producing E. coli and K. pneumoniae in the community were 36% and 15.2%, respectively [23].

Two additional studies reported that among adults with community-acquired respiratory tract infections, the prevalence of ESBL-producing Klebsiella pneumoniae was 38.8% [24], while in community-acquired urinary tract infections, the detection rate of ESBL-producing Escherichia coli was 13.5% [25]. Appropriate measures are needed to manage infections caused by community-acquired ESBL-producing strains.

In recent years, the genotypes of ESBLs have undergone substantial changes. CTX-M–type ESBLs have replaced TEM- and SHV-type ESBLs as the predominant genotypes. Over the past decade in China, CTX-M–type ESBLs have accounted for more than 70% of all ESBL genotypes [24–25]. A U.S. survey conducted from 2010 to 2011 revealed that CTX-M–type ESBLs comprised 85.4% of ESBL-producing Escherichia coli isolates, with CTX-M‑15 accounting for 75.4% of the CTX-M–type ESBLs [17].

The proportion of CTX-M-15–type ESBLs has increased significantly [17, 26–29]. Because CTX-M-15–type ESBLs exhibit stronger hydrolytic activity against cephalothin and other oximino‑β‑lactam antibiotics, ESBL‑producing strains retain high susceptibility only to carbapenems, cefoperazone/sulbactam, piperacillin/tazobactam, and similar agents [28–29].

2. Laboratory detection of ESBL-producing Enterobacteriaceae

Based on the characteristics of ESBLs, several phenotypic detection methods are currently available, including the ESBL screening and confirmatory tests recommended by the Clinical and Laboratory Standards Institute (CLSI), the double-disc synergy test, the E-test, and the three-dimensional test, among others.

For all confirmed ESBL-producing strains, the CLSI previously recommended that clinical microbiology laboratories report resistance to all penicillins, cephalosporins, and aztreonam [30], whereas the European Committee on Antimicrobial Susceptibility Testing (EUCAST) advises classifying susceptibility as “intermediate” and intermediate as “resistant” [31].

Recently, both CLSI and EUCAST have revised the breakpoints for certain cephalosporins against Enterobacteriaceae. At the same time, they recommend that clinical microbiology laboratories no longer perform ESBL testing for the purpose of patient treatment; ESBL testing should be reserved solely for epidemiological investigations [32–33].

This is primarily because current phenotypic ESBL detection methods fail to comprehensively reflect the cephalosporin resistance of Enterobacteriaceae, and other resistance mechanisms—such as AmpC enzyme production, carbapenemase activity, and loss of outer membrane porins—can also interfere with ESBL assay results. Data from animal infection models, pharmacokinetic studies, and certain clinical case reports further indicate that bacterial minimum inhibitory concentrations (MICs), rather than specific resistance mechanisms, are more closely associated with clinical efficacy [34–36].

However, it should be noted that the CLSI’s new breakpoints for cephalosporins differ significantly from those of EUCAST, and many of these new breakpoints remain uncertain. Moreover, due to equipment limitations, numerous clinical microbiology laboratories in China are currently unable to implement the new breakpoints. In addition, there is currently insufficient clinical data to demonstrate that these new breakpoints reliably predict clinical outcomes [37]. Therefore, it is recommended that clinical microbiology laboratories in China continue to routinely test for and report ESBLs.

3. Treatment of infections caused by ESBL-producing Enterobacteriaceae

3.1 Therapeutic agents for infections caused by ESBL-producing Enterobacteriaceae

Based on in vitro antimicrobial susceptibility testing and the pharmacological characteristics of these agents, the main antibacterial drugs that can be used to treat infections caused by ESBL-producing strains include the following.

Carbapenems: These antibiotics exhibit high antibacterial activity against ESBL-producing strains and are currently the most effective and reliable agents for treating various infections caused by ESBL-producing Enterobacteriaceae. For patients with severe sepsis or septic shock due to ESBL-producing strains, carbapenems may be selected as first-line therapy.

Currently, the clinically available agents include ertapenem, imipenem, meropenem, panipenem, and biapenem. The usual dose of ertapenem is 1.0 g once daily, while imipenem, meropenem, and panipenem are typically administered at 0.5 g every 8 hours or every 6 hours via intravenous infusion. The dose of biapenem is 0.3 to 0.6 g every 8 hours. For the treatment of central nervous system infections, the dose of meropenem may be increased to 1.0 to 2.0 g every 8 hours.

β-Lactam/β-lactamase inhibitor combinations: In vitro susceptibility testing indicates substantial variability in the susceptibility of ESBL-producing strains to different combination agents; rates of susceptibility exceed 80% for cefoperazone/sulbactam and piperacillin/tazobactam, whereas susceptibility is lower for amoxicillin/clavulanate, ampicillin/sulbactam, and ticarcillin/clavulanate.

Therefore, at present, the β-lactam/β-lactamase inhibitor combinations that demonstrate favorable clinical efficacy in treating infections caused by ESBL-producing strains are cefoperazone/sulbactam and piperacillin/tazobactam; however, these agents are primarily indicated for patients with mild to moderate infections and require appropriate increases in both the dose and frequency of administration.

Cefoperazone/sulbactam is available in 2:1 and 1:1 ratios; the usual dosing is 3.0 g every 8 hours (2:1 ratio) or 2.0 g every 6 hours (1:1 ratio). Piperacillin/tazobactam is typically administered at 4.5 g every 6 hours. For lower urinary tract infections caused by susceptible pathogens, some patients may be treated orally with amoxicillin/clavulanate.

Cephamycins: Cephamycins are stable against ESBLs and exhibit good antibacterial activity against ESBL-producing Escherichia coli and Klebsiella pneumoniae; however, their resistance rates are significantly higher than those of carbapenems, cefoperazone/sulbactam, and piperacillin/tazobactam, which may be related to the concurrent presence of other resistance mechanisms in bacteria, such as the loss of outer membrane porins.

Therefore, cephamycins can be used to treat patients with mild to moderate infections caused by ESBL‑sensitive strains and are primarily employed in de-escalation therapy for infections due to ESBL‑producing organisms. Commonly used agents include cefmetazole, cefoxitin, and cefminox. The typical dosage is 2.0 g administered once every 12 hours.

Oxacephems: Oxacephem antibiotics are stable against ESBLs, and in vitro studies have demonstrated high susceptibility to ESBL-producing Escherichia coli and Klebsiella pneumoniae. However, their in vivo antibacterial activity is inferior to that of carbapenems and β-lactam/β-lactamase inhibitor combinations (such as cefoperazone/sulbactam and piperacillin/tazobactam). Consequently, there are relatively few clinical reports of their use for treating infections caused by ESBL-producing organisms.

Currently, these agents are recommended for mild infections caused by ESBL-producing strains or as part of de-escalation therapy. The main clinical options are latamoxef and flomoxef, with a typical dosage of 1–2 g administered once every 12 hours.

Fluoroquinolones: Strains producing ESBLs are typically resistant to fluoroquinolones. CHINET data indicate that ESBL-producing Escherichia coli and Klebsiella pneumoniae exhibit resistance rates of 70% and over 30%, respectively, to ciprofloxacin. Therefore, fluoroquinolone antibiotics are not indicated for empirical therapy in ESBL-producing strains. However, if in vitro susceptibility testing demonstrates susceptibility, these agents may be used to treat urinary tract infections caused by ESBL-producing strains and may also serve as part of combination therapy for severe infections due to such strains.

Aminoglycosides: Although ESBL-producing strains typically harbor aminoglycoside resistance genes, overall resistance rates to this class of agents remain relatively low (approximately 10%), particularly for amikacin and isepamicin. However, these drugs are associated with ototoxicity and nephrotoxicity, and their tissue distribution is suboptimal. Clinically, aminoglycosides are used only as part of combination therapy for patients with severe infections caused by ESBL-producing organisms.

Colistin and polymyxin B: ESBL-producing strains are typically susceptible to carbapenems, cefoperazone/sulbactam, and piperacillin/tazobactam. However, in a small subset of ESBL-producing isolates that also exhibit loss of outer membrane porins, carbapenem resistance may develop; such strains can still be treated with these agents.

Due to their nephrotoxicity and neurotoxicity, as well as significant heterogenous resistance, these agents are generally reserved for the treatment of infections caused by carbapenem‑resistant strains. Although they exhibit high activity against ESBL‑producing organisms, they are not routinely used for treating infections caused by such strains.

Glycylcyclines: Currently, the only approved member of this class is tigecycline. Strains producing ESBLs, including carbapenem‑resistant isolates, exhibit high susceptibility to this agent. The approved clinical indications include intra-abdominal infections, skin and soft‑tissue infections, and community‑acquired pneumonia (CAP).

This drug has been recommended for the treatment of infections caused by ESBL-producing strains, but clinical experience is limited and further clinical trials are needed to confirm its efficacy. The drug achieves only low concentrations in urine and is therefore not indicated for the treatment of urinary tract infections; at standard doses, plasma concentrations are insufficient, making it unsuitable for the management of bloodstream infections.

Fosfomycin: In vitro susceptibility testing demonstrates that it exhibits potent antibacterial activity against ESBL-producing Escherichia coli and Klebsiella pneumoniae. Fosfomycin achieves high urinary concentrations, and internationally it is primarily recommended as a therapeutic agent for uncomplicated urinary tract infections. Two open-label studies have shown an efficacy rate of over 90% in the treatment of lower urinary tract infections. For lower urinary tract infections, in addition to intravenous formulations, the oral formulation fosfomycin trometamol may also be used.

Fosfomycin also exhibits some efficacy against infections caused by ESBL-producing strains in other systems, but it is not considered the drug of first choice.

Nitrofurantoin: It exhibits high activity against ESBL-producing Escherichia coli. However, this drug achieves effective concentrations only in urine; therefore, it is indicated solely for the treatment of uncomplicated urinary tract infections, as part of sequential or maintenance therapy, and for the prophylaxis of recurrent urinary tract infections, although its tolerability is suboptimal.

Cephalosporins: Third- and fourth-generation cephalosporins exhibit a pronounced inoculum effect against ESBL-producing strains; accordingly, the CLSI has stipulated that all ESBL-producing isolates are considered resistant to all cephalosporins, and even if in vitro susceptibility is demonstrated, these agents are not recommended for clinical use. Recent studies have shown that, for ESBL-producing strains, the clinical efficacy of cephalosporin therapy correlates more closely with the bacterial MIC values than with ESBL production per se.

In 2010, CLSI revised the interpretive criteria for cephalosporin susceptibility in Enterobacteriaceae, lowering the susceptible breakpoints. Currently, there is limited clinical evidence regarding the use of cephalosporins to treat infections caused by ESBL-producing organisms that are reported as susceptible on in vitro susceptibility testing. To ensure clinical efficacy, it is recommended to obtain definitive susceptibility data and reserve the use of the appropriate cephalosporin only when high-level susceptibility (MIC ≤ 2 μg/mL) is demonstrated. At a minimum, cephalosporins should not be used to treat severe infections caused by ESBL-producing bacteria.

3.2 Assessment of Risk Factors for ESBL Production by Enterobacteriaceae

Antimicrobial therapy for Enterobacteriaceae infections must be tailored to the bacterial resistance profile, with extended-spectrum β-lactamase (ESBL) production being the most common and clinically significant resistance mechanism. Therefore, when initiating empirical treatment for Enterobacteriaceae infections, it is essential to carefully assess risk factors for ESBL production and, in conjunction with the severity of the illness, select an appropriate antimicrobial agent.

The major risk factors for ESBL-producing bacterial infections include repeated use of antimicrobial agents, the presence of indwelling medical devices (such as central venous or arterial catheters, percutaneous gastrostomy or jejunostomy tubes, and urinary catheters), calculi or obstructions (e.g., in the biliary or urinary tracts), a prior history of ESBL-producing bacterial infection, frequent hospitalizations (including stays in nursing homes), previous admission to the intensive care unit (ICU), advanced age, underlying comorbidities (such as diabetes or immunosuppression), and mechanical ventilation [20, 38–40]. If a patient lacks these risk factors, common infections caused by Enterobacteriaceae typically do not require coverage against ESBLs.

3.3 Assessment of Disease Severity in Infected Patients

The severity of infection in a patient is one of the key factors guiding the selection of antimicrobial agents; therefore, when determining an antimicrobial treatment regimen for each infected patient, it is essential to assess both the causative pathogen and its resistance profile, as well as the severity of the infection. Severe infections refer to patients who develop severe sepsis or septic shock secondary to infection.

Currently, the assessment of infection severity is primarily based on the 2012 International Guidelines for Sepsis [41]. According to these guidelines, infections are classified into sepsis, severe sepsis, and septic shock, depending on the patient’s clinical condition.

Sepsis: In the presence of a confirmed or suspected infection, plus the following criteria:

General condition: fever (>38.3°C) or hypothermia (<36°C); tachycardia (>90 beats/min) or a heart rate more than 2 standard deviations above the age‑adjusted normal; tachypnea; altered mental status; significant edema or a positive fluid balance >20 mL/kg lasting for more than 24 hours; hyperglycemia (blood glucose >140 mg/dL or >7.7 mmol/L) in the absence of a prior history of diabetes.

Inflammatory markers: leukocytosis (>12 × 10^9/L) or leukopenia (<4 × 10^9/L); neutrophil percentage >10%; plasma C-reactive protein >2 standard deviations above the upper limit of normal; plasma procalcitonin >2 standard deviations above the upper limit of normal.

Hemodynamic parameters: hypotension (systolic blood pressure < 90 mmHg, mean arterial pressure < 70 mmHg, or below the age‑adjusted normal value by 2 standard deviations) (1 mmHg = 0.133 kPa).

Organ dysfunction criteria: oxygenation index (PaO2/FiO2) < 300; acute oliguria (urine output < 0.5 mL/kg/h despite adequate fluid resuscitation); serum creatinine > 1.5 mg/dL or 44.2 μmol/L; coagulopathy (international normalized ratio > 1.5 or activated partial thromboplastin time > 60 s); intestinal paralysis (absent bowel sounds); thrombocytopenia (platelet count < 100 × 10^9/L); hyperbilirubinemia (total plasma bilirubin > 4 mg/dL or 70 μmol/L).

Organ perfusion indicators: hyperlactatemia (>1 mmol/L); prolonged capillary refill time or mottled skin.

Severe sepsis: Sepsis that results in inadequate tissue perfusion or organ dysfunction; sepsis‑induced hypotension; a blood lactate level exceeding the upper limit of normal; urine output <0.5 mL·kg⁻¹·h⁻¹ persisting for more than 2 hours despite adequate fluid resuscitation; acute lung injury due to pulmonary infection, with a PaO₂/FiO₂ ratio <200; acute lung injury not attributable to pulmonary infection, with a PaO₂/FiO₂ ratio <250; serum creatinine >2.0 mg/dL or 176.8 μmol/L; bilirubin >2 mg/dL or 34.2 μmol/L; platelet count <100×10⁹/L.

Septic shock: persistent hypotension that does not improve despite fluid resuscitation in severe sepsis.

3.4 Principles of Antimicrobial Therapy for Infections Caused by ESBL-Producing Enterobacteriaceae

A comprehensive assessment should be made, taking into account the antibiotic resistance of the Enterobacteriaceae involved, the site and severity of the infection, the patient’s pathophysiological status, and the pharmacokinetic and pharmacodynamic properties of the antimicrobial agents. The key principles are:

In the early stages, perform standardized bacterial cultures and antimicrobial susceptibility testing to determine whether the patient has an infection caused by ESBL-producing bacteria.

Initiate empirical therapy promptly: Before the results of bacterial culture are available, empirical antimicrobial therapy should comprehensively consider the local prevalence of ESBL-producing organisms, the source of infection (hospital‑acquired or community‑acquired), and relevant risk factors for ESBLs, to assess the likelihood of an ESBL‑producing Enterobacteriaceae pathogen. The choice of antimicrobial agent should then be guided by the severity of the infection.

Select antimicrobial agents according to the severity of infection: For severe infections, such as bloodstream infections caused by ESBL-producing bacteria or complicated intra-abdominal and urinary tract infections that progress to severe sepsis or septic shock, carbapenems should be首选 [42–43]. For mild to moderate infections caused by ESBL-producing bacteria—including urinary tract infections, liver abscesses, biliary tract infections, peritonitis, and hospital-acquired pneumonia—choose cephalosporins with β-lactamase inhibitors (e.g., cefoperazone/sulbactam, piperacillin/tazobactam) or cephamycins, based on local susceptibility patterns or results; if efficacy is suboptimal, consider switching to a carbapenem.

Based on the patient’s pathophysiological status and the pharmacokinetic/pharmacodynamic (PK/PD) characteristics of the antimicrobial agents, the optimal dosing regimen should be determined, including the dose, dosing interval, and appropriate duration of therapy. For cefoperazone/sulbactam and piperacillin/tazobactam, the dose and frequency of administration should be appropriately increased.

Use combination therapy when necessary: In the vast majority of infections caused by ESBL‑producing bacteria, monotherapy is sufficient; only a small subset of patients with severe infections—particularly those with risk factors for co‑infection by non‑fermenting Gram‑negative bacilli—may require combination regimens, such as carbapenems, cefoperazone/sulbactam, or piperacillin/tazobactam in combination with quinolones or aminoglycosides. A clinical decision‑making flowchart for infections caused by ESBL‑producing Enterobacteriaceae is shown in Figure 1.

3.5 Treatment of Infections Caused by ESBL-Producing Enterobacteriaceae

Bloodstream Infections: Bloodstream infections encompass both hospital-acquired and community-acquired cases; delayed or inadequate management significantly increases mortality. Treatment should first identify the source of infection. For secondary bloodstream infections, the primary focus should be on addressing the underlying source. In cases of catheter-related bloodstream infections, the catheter should be removed, accompanied by appropriate antimicrobial therapy. If disseminated infection occurs, surgical intervention may be indicated when necessary.

As for the selection of antimicrobial agents, it should be based on a comprehensive assessment that takes into account local epidemiological data, the patient’s prior medication history, bacterial susceptibility test results, and the severity of the patient’s condition.

A recently published meta-analysis by Vardakas [44] comparing carbapenem antibiotics with other agents for the treatment of ESBL-producing bacteremia concluded that, in both targeted and empirical settings, carbapenems were associated with significantly lower mortality compared with non–β-lactam agents or β-lactamase inhibitor combinations.

Compared with β-lactam/β-lactamase inhibitor combinations, carbapenem antibiotics show no significant differences in treatment outcomes. The analysis suggests that carbapenems are the preferred choice for empirical therapy; in regions with low rates of resistance, β-lactam/β-lactamase inhibitor combinations may also be considered.

Intracranial Infection: When acute bacterial intracranial infection is suspected, blood cultures should be obtained promptly, and cerebrospinal fluid (CSF) analysis—including routine examination, biochemical testing, and culture—should be performed; cranial CT imaging may also be indicated. In addition, empirical antimicrobial therapy should be initiated without delay.

For intracranial infections caused by ESBL-producing Escherichia coli and other Enterobacteriaceae, the use of third-generation cephalosporins often leads to treatment failure. According to the literature, more than half of cases are currently treated with carbapenem antibiotics that readily cross the blood–brain barrier, with favorable outcomes [45]. Furthermore, in refractory intracranial infections associated with ESBL-producing bacteria, there have also been successful reports of treatment with tigecycline [46].

Respiratory system and thoracic–mediastinal infections: Enterobacteriaceae can cause respiratory tract infections, including pulmonary parenchymal and airway infections, as well as thoracic infections such as empyema and mediastinitis. Enterobacteriaceae are the predominant pathogens isolated from lower respiratory tract specimens; sputum samples are prone to contamination by oropharyngeal flora, necessitating differentiation among contamination, colonization, and infection. Whether in community-acquired pneumonia (CAP) or hospital-acquired pneumonia (HAP), clinical features alone are insufficient to diagnose an infection caused by Enterobacteriaceae.

Typically, elderly patients with community-acquired pneumonia (CAP) who have underlying cardiopulmonary disease but do not require ICU admission, as well as those with acute exacerbations of chronic obstructive pulmonary disease (COPD) that necessitate hospitalization but not ICU care, and early-onset hospital-acquired pneumonia (HAP), are recommended by both domestic and international guidelines to receive initial empirical therapy covering Enterobacteriaceae. However, coverage of ESBL-producing Enterobacteriaceae is generally not required. In cases of severe CAP and late-onset HAP where nonfermenting Gram-negative bacilli such as Pseudomonas aeruginosa need to be targeted, carbapenems or β‑lactam/β‑lactamase inhibitor combinations—such as cefoperazone/sulbactam or piperacillin/tazobactam—are often preferred; these regimens effectively also cover ESBL-producing Enterobacteriaceae.

Currently, neither domestic nor international guidelines for lower respiratory tract infections provide stratification specifically addressing ESBL-producing Enterobacteriaceae. Therefore, when considering the possibility of an Enterobacteriaceae infection, it is necessary to assess the risk of ESBL production. Enterobacteriaceae are readily isolated from the lower respiratory tract, and persistent negative cultures often indicate a low likelihood that these organisms are the causative pathogen; accordingly, the treatment regimen should be adjusted.

Intra-abdominal infections: Based on the site of onset, intra-abdominal infections can be classified as community-acquired or hospital-acquired; based on the affected anatomical location, they include peritonitis, cholecystitis, cholangitis, appendicitis, and hepatic or splenic abscesses, among others. For mild to moderate intra-abdominal infections caused by ESBL-producing Enterobacteriaceae, cefoperazone/sulbactam, piperacillin/tazobactam, or cephamycins may be selected.

Patients with intra-abdominal infections who develop severe sepsis or septic shock should be treated with carbapenem antibiotics. Debridement and drainage of the infectious focus are critically important; patients requiring surgical intervention for the infected site should undergo timely surgical management.

Urinary Tract Infection: Urinary tract infection, also known as a urinary system infection, encompasses both uncomplicated and complicated forms. Complicated urinary tract infections are often associated with underlying urological conditions, such as anatomical abnormalities or functional disorders.

For acute uncomplicated lower urinary tract infections caused by ESBL-producing Enterobacteriaceae, oral therapy with nitrofurantoin or fosfomycin trometamol may be selected [47]. In cases of complicated urinary tract infections with risk factors for resistance to ESBL-producing organisms, β‑lactam/β‑lactamase inhibitor combinations, cephamycins, nitrofurantoin, or fosfomycin may be considered. Patients who develop severe sepsis or septic shock should be treated directly with carbapenems.

Neutropenia with fever: Neutropenia is defined as an absolute neutrophil count (ANC) <0.5×10^9/L, or an anticipated ANC decrease to <0.5×10^9/L within 48 hours; severe neutropenia is defined as an ANC <0.1×10^9/L. Neutropenia with fever is diagnosed when a patient with neutropenia has a single oral temperature measurement ≥38.3°C, or a temperature ≥38.0°C lasting for more than 1 hour.

However, in patients with generally poor clinical status—particularly elderly patients—it is important to recognize that fever may be absent or even paradoxically low during infection. Between 10% and 50% of patients with solid tumors, and more than 80% of those with hematologic malignancies, develop chemotherapy‑related febrile neutropenia after at least one cycle of chemotherapy.

Under domestic medical conditions, the incidence of infection in patients with neutropenia may range from 95.3% to 98.1%; among hematologic malignancy patients who develop neutropenia complicated by infection, the rates of ESBL positivity in Escherichia coli and Klebsiella spp. are 50%–60% and 40%–50%, respectively, with a mortality rate as high as 11.0% [48].

When selecting antimicrobial agents, patients with neutropenia and fever should be stratified according to risk level for treatment in accordance with the “Clinical Practice Guidelines for the Use of Antimicrobial Agents in Patients with Neutropenia and Fever in China” [48].

High-risk patients: Patients meeting any of the following criteria are considered high-risk and should, as a first choice, receive inpatient empirical intravenous antimicrobial therapy.

Severe neutropenia (ANC < 0.1 × 10^9/L) for ≥7 days.

The presence of any one of the following medical comorbidities, including but not limited to:

Hemodynamic instability;

Mucositis of the oral cavity or gastrointestinal tract, dysphagia, or severe diarrhea;

Gastrointestinal symptoms, including abdominal pain, nausea, and vomiting or diarrhea;

Newly onset neurological changes or altered mental status;

Intravascular catheter infections, particularly catheter tunnel infections;

Newly developed pulmonary infiltrates or hypoxemia, or underlying chronic lung disease.

Hepatic insufficiency (defined as transaminase levels >5 times the upper limit of normal) or renal insufficiency (defined as a creatinine clearance <30 mL/min).

Low-risk patients are defined as those in whom neutropenia is expected to resolve within 7 days, who have no active comorbidities, and whose hepatic and renal functions are stable. Any patient who does not meet the strict low-risk criteria should be managed according to the high-risk patient guidelines.

For high-risk patients with ESBL-producing bacterial infections, carbapenems combined with aminoglycosides (including amikacin and tobramycin) are recommended. For patients classified as low-risk, treatment may be initiated with a β-lactam/β-lactamase inhibitor combination (such as cefoperazone/sulbactam or piperacillin/tazobactam) or with cephamycins (cefmetazole, cefoxitin, or cefminox) in combination with an aminoglycoside.

The anti-infective regimen selected in accordance with the aforementioned treatment principles should be continued for at least the entire duration of neutropenia (until the ANC reaches ≥0.5 × 10^9/L). For patients with any of the following conditions—such as severe pulmonary infection, catheter‑related bloodstream infection, or a prior episode of hemodynamic instability—the duration of therapy may be further extended, with the specific length of treatment determined on an individual basis.

For patients with both clinical and microbiological evidence of infection, the duration of therapy depends on the specific pathogen and the site of infection. In neutropenic patients with persistent fever of unknown origin and hemodynamic instability, if empirical therapy targeting ESBL-producing Enterobacteriaceae proves ineffective, the antimicrobial regimen should be broadened to ensure adequate coverage of Gram-negative and Gram-positive cocci that may harbor additional resistance mechanisms, as well as anaerobes and fungi.

4. Management of Infections Caused by ESBL-Producing Enterobacteriaceae

4.1 Clinical management and control of antibiotics to reduce the emergence of ESBL-producing Enterobacteriaceae

Antibiotic stewardship refers to the ongoing efforts of healthcare institutions to optimize the clinical use of antibiotics, thereby improving patient outcomes and ensuring cost-effective treatment while minimizing adverse events, including the emergence of bacterial resistance. Research has demonstrated that effective antibiotic stewardship plays a critical role in controlling bacterial resistance. The primary antibiotic stewardship strategies for addressing the spread of ESBL-producing Enterobacteriaceae are as follows.

Strengthen education on the rational use of antimicrobial agents: Continuously implement educational and continuing‑education programs on the appropriate use of antimicrobials to reduce overall antibiotic consumption and improve the level of rational antibiotic prescribing.

Accurate diagnosis is the prerequisite for effective treatment: the clinical diversity and complexity of infectious diseases make accurate diagnosis far from straightforward, and diagnostic capabilities should be continuously improved.

Striving to integrate empirical and targeted therapies: In infectious diseases, empirical treatment plays a crucial role; however, clinicians must create the conditions necessary for transitioning from empirical to targeted therapy. Prior to initiating empirical therapy, high-quality specimens must be provided to the microbiology laboratory.

Strive for individualized empirical anti-infective therapy in the context of antimicrobial resistance: Clinicians should endeavor to develop the ability to “assess the pathogen” and “assess antimicrobial resistance.” “Estimating the pathogen” requires, on the basis of a thorough understanding of the epidemiology of pathogens at the site of infection, consideration of the patient’s specific modifying factors. The physician conducts an individualized assessment of the etiology and, on this basis, strives to develop the ability to understand infectious diseases from an etiological perspective, endeavoring to avoid the awkwardness of indiscriminately covering “all pathogens.”

“Assessing antibiotic resistance” requires understanding the epidemiological findings from local bacterial resistance surveillance and, on this basis, conducting a stratified analysis of risk factors for infections caused by resistant pathogens.

In the context of a high prevalence of ESBL-producing Enterobacteriaceae, guiding the rational clinical use of cephalosporins, particularly third-generation cephalosporins:

Third-generation cephalosporins should be used selectively to treat infections caused by non-ESBL‑mediated multidrug‑resistant organisms. Whether the infection is community‑acquired or hospital‑acquired, patients with well‑defined risk factors for multidrug‑resistant organism (MDRO) infection should have antimicrobial agents selected to cover MDROs based on an assessment of these risk factors.

It is worth noting that these predictors exhibit low positive predictive values for MDRO infection risk factors, while their negative predictive values are relatively high. Consequently, leveraging the high negative predictive value can be highly beneficial in guiding the use of third-generation cephalosporins for treating non‑MDRO infections.

The use of third-generation cephalosporins for perioperative prophylaxis should be restricted. Studies have shown that ceftriaxone is superior to other third-generation cephalosporins in contaminated surgeries, whereas no significant differences were observed in other types of surgery [49]. Therefore, third-generation cephalosporins, including ceftriaxone, should be reserved exclusively for prophylactic use in contaminated procedures.

Strive to achieve diversity in the treatment of infections caused by ESBL-producing bacteria. Carbapenem antibiotics occupy a central role in the management of severe infections due to ESBL‑mediated multidrug‑resistant Enterobacteriaceae. However, several studies have demonstrated that β‑lactam/β‑lactamase inhibitor combinations also confer clinical benefits [43, 50–51].

This provides a range of options for empirical therapy in suspected or confirmed ESBL‑positive bacterial infections, as well as for targeted treatment of such infections. Overseas studies have largely focused on piperacillin/tazobactam, whereas domestically, cefoperazone/sulbactam exhibits in vitro antibacterial activity against Enterobacteriaceae that is comparable to that of piperacillin/tazobactam; whether it can deliver similar clinical efficacy warrants further investigation.

Therapeutic substitution for outbreaks of ESBL-producing organisms: Therapeutic substitution refers to the strategic replacement of the original antimicrobial regimen in response to a localized outbreak of resistant bacteria, with the aim of treating infections caused by these pathogens and containing the spread of resistance.

Numerous studies on antibiotic substitution have been conducted to address the outbreak of third-generation cephalosporin‑resistant Gram‑negative bacilli, indicating that β‑lactam/β‑lactamase inhibitor combinations may be a particularly promising option for therapeutic replacement [52–55]. Although this substitution strategy cannot fully resolve the issue of resistance, given the high prevalence of ESBLs in China, such an approach warrants careful consideration.

4.2 Strictly adhere to aseptic techniques and infection control protocols.

Healthcare personnel should strictly adhere to aseptic technique during all invasive procedures to prevent contamination and minimize risk factors for infection. For indwelling medical devices, it is essential to rigorously implement the evidence-based “comprehensive” strategies outlined in infection control guidelines.

4.3 Blocking the transmission routes of ESBL-producing strains

Enhance hand hygiene: Healthcare workers and ward staff must strictly adhere to the “Hand Hygiene Guidelines for Healthcare Personnel in Medical Institutions,” issued by the National Health Commission in April 2009. Rigorous implementation of hand hygiene is essential for reducing the transmission and incidence of infections, encompassing the provision of appropriate hand‑hygiene facilities, the promotion of alcohol‑based quick‑drying hand rubs, and the improvement of hand‑hygiene compliance.

Implement contact isolation: In accordance with the “Hospital Isolation Technical Specifications” issued by the National Health Ministry in April 2009, patients who test positive for ESBL-producing bacteria must be clearly identified and subjected to standardized contact‑precaution measures.

Enhance environmental cleaning and disinfection: In accordance with the “Technical Specifications for Disinfection in Medical Institutions” issued by the National Health Commission in April 2012, effective cleaning and disinfection of environments and medical equipment can help reduce the risk of transmission of multidrug-resistant organisms.

Article excerpted from: Chinese Medical Journal, June 2014, Vol. 94, No. 24, pp. 1847–1856.

Authors of the article: Zhou Hua, Li Guanghui, Chen Baiyi, Zhuo Chao, Cao Bin, Yang Yi, Zhang Jing, Wang Hui, He Lixian, Hu Bijie, Huang Xiaojun, Lü Xiaoju, Shao Zonghong, Sun Zimin, Liu Youning, Ni Yuxing, Qiu Haibo, Shi Yi, Wang Minggui, Xie Canmao, Zhou Jianying, Zhou Zhihui, Liu Zhengyin, Yu Yunsong.