What is the recommended first‑line therapy for serious infections caused by CTX‑M‑producing extended‑spectrum β‑lactamase organisms?

Treatment of CTX-M-Producing ESBL Infections

First-Line Therapy Recommendation

For serious infections caused by CTX-M-producing extended-spectrum β-lactamase organisms, carbapenems (ertapenem, meropenem, or imipenem) remain the definitive first-line therapy. 1

Understanding CTX-M Resistance

CTX-M enzymes are the most prevalent ESBL type worldwide, with CTX-M-15 dominating globally, followed by CTX-M-14 and the emerging CTX-M-27. 2 These enzymes:

• Hydrolyze cefotaxime, ceftriaxone, and aztreonam efficiently but are inhibited by clavulanate, tazobactam, and sulbactam 3, 4
• Typically show higher MICs to cefotaxime than ceftazidime, distinguishing them from other ESBLs 3, 5
• Are frequently co-resistant to fluoroquinolones, with 60-93% of CTX-M-positive E. coli showing quinolone resistance in major geographic regions 1

Treatment Algorithm by Clinical Context

For Community-Acquired Infections with ESBL Risk Factors

Risk factors for CTX-M-producing organisms include: 1

• Recent antibiotic exposure (especially third-generation cephalosporins or fluoroquinolones) within 90 days
• Known colonization with ESBL-producing Enterobacteriaceae
• Travel to high-prevalence regions (Western Pacific, Eastern Mediterranean, Southeast Asia)
• Poor access to clean water or high population density areas

Empiric therapy should include carbapenem coverage immediately when these risk factors are present. 1

For Healthcare-Associated Infections

Broader spectrum regimens are mandatory, as hospital-acquired CTX-M infections often carry additional resistance mechanisms. 1

For Multidrug-Resistant Gram-Negative Infections

When CTX-M is suspected alongside other resistance genes (particularly carbapenemases):

• If NDM (metallo-β-lactamase) is co-produced: Use ceftazidime-avibactam 2.5g IV every 8 hours PLUS aztreonam 2g IV every 8 hours 6, 1
• If OXA-48 is co-produced with NDM: The same combination (ceftazidime-avibactam plus aztreonam) is required, as ceftazidime-avibactam neutralizes both OXA-48 and CTX-M while aztreonam remains stable against NDM 6
• If KPC is co-produced: Ceftazidime-avibactam or meropenem-vaborbactam monotherapy is appropriate 7

Critical Pitfalls to Avoid

Do not use third-generation cephalosporins or piperacillin-tazobactam for serious CTX-M infections, even if in vitro susceptibility suggests otherwise—clinical outcomes are significantly worse compared to carbapenems. 1 This is particularly true for bloodstream infections and critically ill patients.

Do not delay carbapenem therapy while awaiting susceptibility results in patients with sepsis or severe infection and ESBL risk factors. 1

Avoid fluoroquinolones as empiric therapy, given the 60-93% co-resistance rates in CTX-M-producing organisms. 1

Never use aztreonam monotherapy if NDM co-production is suspected—the CTX-M enzyme will inactivate aztreonam, leading to treatment failure. 6

Special Considerations for Catheter-Related Infections

For CTX-M-producing gram-negative catheter-related bloodstream infections: 1

• Remove short-term catheters immediately
• Initiate two antimicrobial agents of different classes with gram-negative activity as initial therapy
• De-escalate to carbapenem monotherapy once culture confirms CTX-M without carbapenemase co-production
• Treat for 7-14 days after catheter removal, extending duration if endovascular infection or metastatic foci are identified

Duration and Monitoring

• Minimum 7-14 days for most serious infections after source control 1
• Obtain follow-up cultures to document pathogen eradication, particularly in bloodstream infections 1
• Extend therapy beyond 14 days if persistent bacteremia, inadequate source control, or metastatic complications occur 1