What are the treatment options for gram-negative Extended-Spectrum Beta-Lactamase (ESBL)-producing bacteria?

From the Guidelines

Carbapenems, such as meropenem, imipenem, and ertapenem, are the primary treatment options for ESBL-producing gram-negative bacteria, with alternative options including ceftazidime-avibactam, piperacillin-tazobactam, and cefepime, as well as fosfomycin and nitrofurantoin for urinary tract infections, and aminoglycosides and polymyxins for multidrug-resistant strains 1.

Treatment Options

The treatment of ESBL-producing gram-negative bacteria requires careful consideration of the severity of the infection, the site of infection, and the local resistance epidemiology.

• For serious infections, meropenem 1g IV every 8 hours or imipenem 500mg IV every 6 hours is typically recommended for 7-14 days, depending on the infection site and severity.
• Ertapenem 1g IV daily may be used for less severe infections.
• Alternative options include ceftazidime-avibactam, which combines a cephalosporin with a beta-lactamase inhibitor, typically dosed at 2.5g IV every 8 hours.
• Piperacillin-tazobactam and cefepime may be effective for some ESBL infections with lower minimum inhibitory concentrations, though they carry higher failure rates.

Specific Considerations

• For urinary tract infections specifically, fosfomycin (3g oral single dose) or nitrofurantoin (100mg oral twice daily for 5-7 days) may be effective.
• Aminoglycosides like amikacin or gentamicin, and polymyxins (colistin or polymyxin B) can be used as part of combination therapy for multidrug-resistant strains.
• The use of carbapenems should be limited to preserve their activity, and alternative options should be considered when possible, as recommended by the 2017 WSES guidelines for management of intra-abdominal infections 1.

Key Recommendations

• The choice of empiric antibiotic regimens should be based on the clinical condition of the patients, the individual risk for infection by resistant pathogens, and the local resistance epidemiology 1.
• In patients at risk for infection with community-acquired ESBL-producing Enterobacteriaceae, ertapenem 1g 24 hourly or tigecycline 100mg initial dose, then 50mg 12-hourly may be considered 1.

From the FDA Drug Label

AVYCAZ demonstrated in vitro activity against Enterobacteriaceae in the presence of some beta-lactamases and extended-spectrum beta-lactamases (ESBLs) of the following groups: TEM, SHV, CTX-M, Klebsiella pneumoniae carbapenemase (KPCs), AmpC, and certain oxacillinases (OXA). AVYCAZ has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections [see Indications and Usage (1.1), (1.2) and (1. 3)] Among Gram-negative uropathogens from both arms of Trial 2, genotypic testing identified certain ESBL groups (e.g., TEM-1, SHV-12, CTX-M-15, CTX-M-27, KPC-2, KPC-3, OXA-48) and AmpC beta-lactamases expected to be inhibited by avibactam in isolates from 273/281 (97. 2%) patients in the mMITT population.

Treatment options for gram-negative ESBL-producing bacteria include:

• Avibactam in combination with ceftazidime (2)
• Carbapenem antibacterial drugs, such as meropenem, imipenem, and doripenem (2)
• Colistin (2)

Note: The use of these treatments should be guided by susceptibility testing and clinical judgment.

From the Research

Treatment Options for Gram-Negative ESBL-Producing Bacteria

The treatment of gram-negative Extended-Spectrum Beta-Lactamase (ESBL)-producing bacteria can be challenging due to their resistance to many antibiotics. However, several treatment options are available:

• Oral options for UTIs due to ESBLs-E coli include nitrofurantoin, fosfomycin, pivmecillinam, amoxicillin-clavulanate, finafloxacin, and sitafloxacin 3
• Parenteral treatment options for UTIs due to ESBLs-producing Enterobacteriales include piperacillin-tazobactam (for ESBL-E coli only), carbapenems including meropenem/vaborbactam, imipenem/cilastatin-relebactam, and sulopenem, ceftazidime-avibactam, ceftolozane-tazobactam, aminoglycosides including plazomicin, cefiderocol, fosfomycin, sitafloxacin, and finafloxacin 3
• Carbapenem-sparing alternatives, such as beta-lactam/beta-lactamase inhibitor combinations, cefepime, cephamycins, fluoroquinolones, aminoglycosides, fosfomycin, pivmecillinam, temocillin, and various oral alternative agents, can be considered for milder infections, particularly urinary tract infections 4
• Ertapenem, a carbapenem, has been shown to be effective as a first-line treatment option for infections caused by ESBL-producing gram-negative bacteria, with clinical response and microbiologic cure rates similar to those achieved with other carbapenems 5, 6

Carbapenem-Sparing Regimens

Carbapenem-sparing regimens, such as beta-lactam/beta-lactamase inhibitor combinations and cefepime, can be effective alternatives to carbapenems for the treatment of ESBL-producing Enterobacteriaceae:

• Piperacillin-tazobactam and cefepime may be effective in certain infections and patient characteristics, but their use cannot be widely recommended 7
• Cefepime has been shown to be a clinically useful carbapenem-sparing alternative for the treatment of infections caused by AmpC-producing Enterobacteriaceae 7