Ceftazidime-avibactam use selects multidrug-resistance and prevents designing collateral sensitivity-based therapies...

Area of Science:

• Microbiology
• Evolutionary Biology
• Pharmacology

Background:

• Ceftazidime-avibactam treats multidrug-resistant Pseudomonas aeruginosa infections.
• Exploiting collateral sensitivity (CS) for evolution-based strategies is promising but requires robust emergence in clinical isolates.
• Previous CS studies primarily used model strains, not clinically relevant resistant mutants.

Purpose of the Study:

• To analyze the robustness of collateral sensitivity (CS) to ceftazidime-avibactam in clinical isolates of Pseudomonas aeruginosa.
• To determine if ceftazidime-avibactam use can inform new evolution-based treatment strategies.
• To assess the clinical applicability of CS in pre-existing resistant mutants.

Main Methods:

• Evolved 15 clinical isolates of Pseudomonas aeruginosa on ceftazidime-avibactam and without the inhibitor.
• Assessed the emergence of collateral sensitivity (CS) patterns in evolved strains.
• Investigated cross-resistance and the feasibility of applying existing CS-based strategies.

Main Results:

• No robust or exploitable collateral sensitivity (CS) pattern was observed in evolved clinical isolates.
• Cross-resistance was selected during evolution experiments.
• Previously described CS-based strategies were not applicable due to the lack of robust CS.

Conclusions:

• The lack of robust collateral sensitivity (CS) suggests ceftazidime-avibactam should be restricted to treating specific genotypes of Pseudomonas aeruginosa.
• Evolution-based treatment strategies exploiting CS are not reliably supported by this last-resort drug.
• Further research into genotype-specific antibiotic use is warranted.