Pharmacodynamic insights to support pneumonia treatment in a patient co-infected with two carbapenem-resistant bacteria

Identifying optimal antibiotic therapy for patients infected with extensively resistant bacteria is challenging, particularly when there are multiple organisms at the infection site. Personalized time-kill assays (TKAs) can be used to test the pharmacodynamic activity of clinically relevant antibiotic combinations to help select appropriate therapy for these difficult-to-treat infections. We report a case of ventilator-associated pneumonia due to Pseudomonas aeruginosa and Providencia stuartii that were each carbapenem resistant. Due to the complex resistance phenotypes, the isolates were analysed via TKAs during the patient's hospitalization to evaluate the activity of relevant antibiotic combinations. Using the patient's isolates, the TKAs showed that a combination of ceftazidime/avibactam and a polymyxin was synergistic against the P. aeruginosa whereas ceftazidime/avibactam plus aztreonam was slightly more active than ceftazidime/avibactam alone against the P. stuartii. The results of the TKAs helped to validate the patient's treatment regimen of aztreonam, ceftazidime/avibactam, and colistin (inhaled), which successfully treated the infection. Whole genome sequencing later revealed that the P. stuartii harbored a bla_OXA-48 carbapenemase while the mechanism of carbapenem resistance in the P. aeruginosa was likely due to OprD loss combined with extended-spectrum β-lactamase expression. The putative mechanism of cefiderocol resistance in the P. stuartii isolate was identified as a premature stop codon in the cirA-like gene combined with the presence of β-lactamases. The patient's carbapenem-resistant coinfection was successfully treated with agents that were validated in real time using personalized TKAs. TKAs may be useful to optimize combination antibiotic therapy for patients infected with extensively resistant bacteria.