Ceftazidime–Avibactam Resistance in CRKP Bacteremia Linked to Prolonged Hospitalization and Comorbidity

A single-center retrospective study from Turkey has reported a high prevalence of ceftazidime–avibactam (CAZ-AVI) resistance among patients with carbapenem-resistant Klebsiella pneumoniae (CRKP) bloodstream infections, highlighting several clinical factors associated with its emergence. The findings underscore the complexity of treating CRKP bacteremia and suggest that host characteristics and hospital exposure may play a more decisive role in clinical outcomes than resistance status alone.

Among 154 adult patients with hospital-acquired CRKP bacteremia treated between 2021 and 2024, 42.8% were infected with CAZ-AVI-resistant strains. The median patient age was 73 years, and just over half were male. CAZ-AVI resistance was significantly associated with two factors: a longer hospital stay prior to infection and a higher Charlson Comorbidity Index (CCI). Multivariate analysis confirmed both as independent predictors. A one-day increase in hospital stay was associated with a 1.1% rise in the odds of resistance, while each additional point in the CCI score increased the odds by 27%.

The analysis also found that prior use of fluoroquinolones or fosfomycin was more common among patients with resistant infections. Although these variables did not remain statistically significant in multivariate modeling, their frequent appearance in the resistant group suggests that previous antibiotic exposure may contribute to resistance development. Conversely, patients with concomitant intra-abdominal infections—many of whom had undergone procedures like endoscopic retrograde cholangiopancreatography—showed a significantly lower rate of CAZ-AVI resistance. These patients also tended to have fewer comorbidities and shorter hospital stays.

Despite the high rate of resistance, CAZ-AVI-resistant infections were not associated with an increased 30-day mortality compared to susceptible cases. Overall 30-day mortality in the cohort was 57%, with minimal difference between the resistant and susceptible groups. This observation aligns with prior studies suggesting that resistance to CAZ-AVI may not directly impact mortality when alternative treatments are used effectively.

However, the study did identify two independent predictors of 30-day mortality: elevated creatinine levels and higher Pitt bacteremia scores at infection onset. Patients with serum creatinine levels ≥1.01 mg/dL or Pitt scores ≥4.5 had significantly higher mortality rates. The Pitt score, which incorporates clinical indicators of severe sepsis, demonstrated high sensitivity in predicting fatal outcomes. Similarly, elevated creatinine likely reflected renal dysfunction, a marker of both disease severity and therapeutic challenge, especially in patients requiring dose adjustments.

Notably, inappropriate empirical therapy—defined as use of antibiotics with no documented in vitro activity against the pathogen—was frequent in both resistant and susceptible groups. This is likely attributable to national prescribing guidelines in Turkey, which restrict use of CAZ-AVI until susceptibility is confirmed, potentially delaying targeted treatment in critically ill patients.

While this study provides detailed insight into the risk profile of CAZ-AVI resistance in CRKP bacteremia, its findings may be shaped by local epidemiology. In Turkey, OXA-48 and NDM carbapenemases are prevalent, and previous use of CAZ-AVI is uncommon due to stewardship policies. As a result, resistance may arise through alternative mechanisms, including clonal spread or selective pressure from other antibiotics. The authors note that molecular characterization of resistance pathways was not performed, which limits conclusions about specific genetic drivers.

These findings emphasize the importance of early identification of high-risk patients and individualized treatment planning. The presence of CAZ-AVI resistance complicates therapeutic decision-making but does not independently predict poor outcomes when managed with appropriate alternatives. Ongoing surveillance and broader multicenter studies are warranted to inform antimicrobial stewardship and optimize treatment strategies in the context of rising resistance.