Should aztreonam be added to a patient already receiving Zerbaxa (ceftolozane/tazobactam) after a multidrug‑resistant organism is identified, or should Zerbaxa be discontinued?

Should You Add Aztreonam to Zerbaxa After Identifying an MDRO?

The answer depends critically on whether the MDRO produces a metallo-β-lactamase (MBL): if MBL is present, switch to ceftazidime-avibactam plus aztreonam; if no MBL is detected, discontinue Zerbaxa and switch to an appropriate alternative based on susceptibility testing.

Critical First Step: Identify the Resistance Mechanism

Before making any treatment decision, you must determine:

• The specific organism (CRE vs. carbapenem-resistant Pseudomonas vs. other)
• Whether metallo-β-lactamases are present (NDM, VIM, IMP)
• The complete susceptibility pattern

This distinction is essential because it fundamentally changes your treatment approach 1.

If MBL-Producing CRE is Identified

Discontinue Zerbaxa (ceftolozane-tazobactam) and switch to ceftazidime-avibactam plus aztreonam for severe infections 1. This combination has moderate-quality evidence showing:

• Reduced 30-day mortality (HR 0.37,95% CI 0.13-0.74) compared to other active therapies
• Lower clinical failure rates (HR 0.30,95% CI 0.14-0.65)
• Shorter hospital stays in patients with MBL-producing CRE bloodstream infections 1, 2

The rationale: Aztreonam is not hydrolyzed by metallo-β-lactamases, while ceftazidime-avibactam protects aztreonam from other β-lactamases (ESBLs, AmpC) that these organisms typically co-produce 1, 2. Zerbaxa (ceftolozane-tazobactam) has no activity against MBL producers and continuing it would be futile.

Important Caveats for MBL Treatment:

• There are no standardized susceptibility testing methods or clinical breakpoints for the aztreonam-ceftazidime-avibactam combination 1
• The combination must be given with overlapping infusion times to ensure simultaneous drug exposure 3
• Consider cefiderocol as an alternative if the combination is unavailable or the organism is resistant 1

If Non-MBL CRE (e.g., KPC, OXA-48) is Identified

Discontinue Zerbaxa and switch to monotherapy with ceftazidime-avibactam, meropenem-vaborbactam, or imipenem-relebactam based on susceptibility 1. The guidelines explicitly state:

• Do NOT use combination therapy for CRE susceptible to these newer agents (strong recommendation, low-quality evidence) 1
• Multiple retrospective studies with 824 patients showed no mortality benefit from adding a second agent to ceftazidime-avibactam for KPC/OXA-48 producers 1

Zerbaxa is not the preferred agent for CRE—it should be reserved for difficult-to-treat resistant Pseudomonas aeruginosa 1.

If Carbapenem-Resistant Pseudomonas aeruginosa (CRPA) is Identified

Continue Zerbaxa (ceftolozane-tazobactam) if the organism is susceptible in vitro 1, 4. This is actually the primary indication for Zerbaxa—it is the most active antipseudomonal agent available, including against multidrug-resistant strains 4.

Key Points for CRPA:

• Ceftolozane-tazobactam is conditionally recommended for severe CRPA infections when active in vitro 1
• There is insufficient evidence to recommend for or against adding a second agent 1
• Do not add aztreonam—there is no established benefit and it adds unnecessary cost and toxicity risk

Antibiotic Stewardship Considerations

The guidelines emphasize that newer β-lactam/β-lactamase inhibitor combinations like Zerbaxa should be reserved for extensively resistant bacteria 1. If your MDRO is susceptible to older agents (fluoroquinolones, aminoglycosides, trimethoprim-sulfamethoxazole), consider de-escalating to these options, especially for non-severe infections 1.

Common Pitfalls to Avoid

1. Don't continue Zerbaxa for MBL producers—it has no activity and delays appropriate therapy
2. Don't add aztreonam empirically—only use it in the specific context of MBL-producing CRE with ceftazidime-avibactam
3. Don't use combination therapy for non-MBL CRE susceptible to newer agents—it doesn't improve outcomes 1
4. Don't forget to adjust for renal function—Zerbaxa has reduced efficacy in patients with CrCl 30-50 mL/min 5

Practical Algorithm

1. Obtain MBL testing immediately (PCR or phenotypic methods)
2. If MBL positive: Switch to ceftazidime-avibactam + aztreonam
3. If MBL negative but CRE: Switch to ceftazidime-avibactam, meropenem-vaborbactam, or imipenem-relebactam (monotherapy)
4. If CRPA: Continue Zerbaxa if susceptible; consider alternatives if resistant
5. Monitor clinical response and adjust based on final susceptibility results

The bottom line: Adding aztreonam to Zerbaxa is not a standard approach—you need to switch regimens based on the specific resistance mechanism identified 1, 2.