Phd in ADVANCES IN INFECTIOUS DISEASES, MICROBIOLOGY, LEGAL
MEDICINE AND PUBLIC HEALTH SCIENCES

Thesis title: Risk factors and outcomes of infections by ceftazidime/avibactam resistant, KPC-producing Klebsiella pneumoniae: results from a retrospective study.

Introduction. The KPC carbapenemase is the most widespread mechanism of resistance to carbapenems and has the greatest clinical impact. The availability of ceftazidime/avibactam (CZA) has represented a real breakthrough in treating infections caused by KPC-producing pathogens, primarily Klebsiella pneumoniae (Kp). However, KPC variants with acquired resistance to CZA (CZA-R) emerged soon and spread with increasing frequency, often displaying a paradoxical recovery of susceptibility to meropenem (MEM). In very recent years, new therapeutic options with activity against CZA-R KPC variants have become available, including cefiderocol (CFDC), imipenem/relebactam (IMR) and meropenem/vaborbactam (MVB), the latter being the regimen with the widest clinical use. Nevertheless, practical experience and official guideline recommendations are still limited about the treatment of CZA-R KPC-Kp. Objective. The aim of this study is to analyse from a clinical point of view a population of patients infected with CZA-R KPC-Kp and to compare the different treatment regimens in real life scenarios. The study also aims to investigate the impact of meropenem resistance reversal and to examine the characteristics and outcomes of patients treated with MVB compared to those receiving treatment based on older-generation drugs. Results. We studied 137 patients with a microbiologically confirmed and treated CZA-R KPC-Kp infection. These patients have multiple comorbidities, with long hospital stays, and have often already been heavily exposed to CZA. The CZA-R KPC-Kp infections were categorised as BSI (44.5%), LRTI (34.3%), UTI (12.4%), IAI (2.9%), and other (5.8%). Over 51% of the pathogens showed an MEM-S phenotype and this population exhibited different clinical characteristics compared those with MEM resistant infections. The regimens used were MVB (44.5%), MEM-containing (32.8%), older-generation antibiotics (excluding MEM) in 20 patients (14.6%), CFDC-containing (4.4%), and IMR-containing (3.6%). The overall 30-day mortality rate was 18.2% and was associated with therapeutic appropriateness, source control, and increment-CPE score. Patients treated with MVB display a survival advantage in the VAP subgroups and in those starting therapy early. Besides, MVB was associated with fewer secondary candidemias. Conclusions. This study attempts to shed light on the characteristics of CZA-R KPC-Kp infections. Treatment with MVB appears to offer some advantages in terms of outcome.