Antibiotic Resistance in Enterobacteriaceae

Introduction to Antibiotic Resistance

• Antibiotic resistance in Enterobacteriaceae is a growing concern, with various mechanisms of resistance transfer, including plásmidos, vesículas de membrana externa (OMVs), and elementos genéticos móviles, facilitating the dissemination of carbapenem resistance among different bacterial species 1

Mechanisms of Resistance and Classification

• Beta-lactamases are classified into four main classes according to the Ambler system:

  Class	Description	Examples
  Class A	serine-beta-lactamases	KPC
  Class B	metallo-beta-lactamases	NDM, VIM, IMP
  Class C	AmpC beta-lactamases
  Class D	OXA-48 and similar	OXA-48

  2

• OXA-type β-lactamases (Class D carbapenemases) demonstrate variable activity against different carbapenems due to several factors, including enzyme-specific hydrolytic profiles, with many showing preferential hydrolysis of ertapenem over meropenem, as reported by the International Journal of Antimicrobial Agents 2

Infection Control Measures

• The American Thoracic Society recommends reinforcing standard and contact precautions to prevent the transmission of carbapenem-resistant enterobacterias among patients, with a strength of evidence considered high 1
• Implementing programs of vigilancia activa to detect the presence of NDM-producing enterobacterias early is crucial to limit the dissemination of resistance 1
• Limiting the use of carbapenémicos and other broad-spectrum antibiotics can reduce the selective pressure, according to the Centers for Disease Control and Prevention guidelines 1

Treatment Options

• For infections caused by NDM-producing enterobacterias, treatment options are limited, and the use of new combinations of antibiotics, such as ceftazidima-avibactam, may be considered, although their efficacy against NDM producers is variable 1
• The use of terapias combinadas, including colistina, tigeciclina, or aminoglucósidos, may be necessary in severe infections 1
• Cefiderocol, a new sideróforo antibiotic, may be an option, although resistance development during treatment has been reported in NDM-producing bacteria 1
• For infections caused by ESBL-producing bacteria, the first-line treatment option is carbapenems, such as ertapenem, meropenem, and imipenem 3
• Alternative treatment options include piperacillin/tazobactam for less severe infections, and ceftazidime/avibactam or ceftolozane/tazobactam for more severe infections 4, 5
• For infections caused by KPC-producing bacteria (Class A), new beta-lactam agents like ceftazidime/avibactam and meropenem/vaborbactam are recommended as first-line options 2
• For infections caused by metallo-beta-lactamase-producing bacteria (Class B), options are limited, but aztreonam and combinations like aztreonam-avibactam may be considered 2
• For infections caused by OXA-48-producing bacteria (Class D), ceftazidime/avibactam is active against certain Class D carbapenemases 3

Prevention and Surveillance

• The International Society for Antimicrobial Chemotherapy recommends rapid testing to identify specific carbapenemase families, as each enzyme confers variable susceptibility profiles requiring different treatment strategies 2
• The Infectious Diseases Society of America recommends considering alternative treatment options, such as newer β-lactam/β-lactamase inhibitor combinations like ceftazidime-avibactam, for certain OXA variants, with a moderate strength of evidence 2
• The European Society of Clinical Microbiology and Infectious Diseases advises that combination therapy may be necessary in some cases, with a low strength of evidence 2
• The use of third-generation cephalosporins and fluoroquinolones should be limited to reduce selective pressure and prevent the emergence of resistance 4
• In areas with high prevalence of ESBL or AmpC producers, carbapenems should be considered as initial empirical therapy for severe infections 3
• Therapy should be de-escalated based on microbiological results to reduce selective pressure and prevent the emergence of resistance 4
• Patients receiving antibiotics that induce AmpC production should be closely monitored for therapeutic failures 5
• Frequent cultures during treatment are crucial for detecting the development of resistance, and the American College of Clinical Microbiology recommends monitoring for resistance in patients with infections caused by beta-lactamase-producing bacteria 3
• The WSES guidelines recommend that, in environments with high incidence of ESBL-producing Enterobacteriaceae, the use of cephalosporins should be discouraged and therapy should be targeted to the specific pathogen due to the selective pressure that results in the emergence of resistance 4
• The American College of Clinical Microbiology recommends using carbapenemics, such as meropenem, as first-line treatment for suspected AmpC resistance when cefoxitin is not available, especially in severe infections 6
• Combination therapies, such as aztreonam-avibactam, and new agents like cefiderocol, have shown promising results, while combinations including colistin, tigecycline, or aminoglycosides may be necessary in some cases 7