Carbapenems, often regarded as the last line of defense in treatment of urinary tract infections and urosepsis caused by Escherichia coli, are under pressure from emerging resistance. Thus, it is necessary to investigate carbapenem-sparing agents to mitigate the dissemination of carbapenem resistance. In this study, we aimed to evaluate the efficacy of ceftazidime/avibactam plus amikacin combination therapy against two ceftazidime/avibactam-resistant E. coli clinical isolates harboring IMP-4 carbapenemase (CTAP #226 and CTAP #233). To achieve this, we used a hollow fiber infection model (HFIM) with clinically relevant regimens of amikacin (15 mg/kg q24h) and ceftazidime/avibactam (2 g ceftazidime/0.5 g avibactam q8h), which were administered to the HFIM either alone or in combination over a 7-day treatment course. Initial inoculum was ~1 × 10[7] CFU/mL. Both amikacin and ceftazidime/avibactam monotherapies resulted in bacterial killing (~4 log10 and ~3 log10, respectively) within the first 8 h; however, regrowth surpassing the baseline was observed over the following 7 days. Conversely, combination therapy resulted in bacterial killing to <the limit of quantification (10[2] CFU/mL) within the first 48 h, which was sustained for the entirety of the experiment. This study showed that the combination of amikacin and ceftazidime/avibactam was superior to both monotherapies and therefore presents a promising carbapenem-sparing option for the treatment of ceftazidime/avibactam-resistant E. coli. Further clinical studies are required to assess the suitability for use in vivo.

Candiduria, defined as the presence of Candida spp. in urine, is more common among hospitalized patients, particularly those admitted to intensive care units (ICUs). This study aimed to determine the epidemiology, associated risk factors, clinical symptoms, ultrasound findings, and outcomes of empirical antifungal therapy in neonates, infants, and pediatric patients with symptomatic candiduria admitted to neonatal ICU (NICU) and pediatric ICU (PICU) in southern Iran. In this retrospective cross-sectional study, medical records of neonates, infants, and pediatric patients with candiduria admitted to the NICU and PICU of two tertiary-care hospitals in Shiraz, Iran, between March 2012 and March 2022 were reviewed. Data were extracted from the hospital information system. Among 19,900 ICU admissions (3,471 neonates; 4,810 infants; and 11,619 pediatric patients), 400 patients (2.01%) were diagnosed with candiduria. The prevalence was 2.18% (n = 76) in neonates, 1.58% (n = 76) in infants, and 2.13% (n = 248) in pediatric patients. Prematurity was the most common risk factor among neonates (29, 38.15%), whereas urinary catheterization was predominant in infants (41, 53.94%) and history of bacterial urinary tract infection in pediatric patients (165, 66.53%). Hydronephrosis (176, 44%) was the most frequent ultrasound finding. Most patients had an ICU stay of 1-5 days (335, 83.75%), and candiduria was typically diagnosed within the first three days of ICU admission. Fluconazole was the primary empirical antifungal agent, while amphotericin B was administered in selected cases. All patients achieved complete clinical and microbiological resolution following treatment. Our findings indicate that history of bacterial urinary tract infection, urinary catheterization, antibiotic exposure, poor feeding, and hydronephrosis are important predisposing factors for candiduria in critically ill neonates, infants, and pediatric patients. Fluconazole appears to be an effective first-line empirical therapy in this population.