666. Efficacy and Safety of Cefiderocol According to Renal Impairment in Patients With Complicated Urinary Tract Infection (cUTI) in a Phase 2 Study

Background Cefiderocol, a novel siderophore cephalosporin with broad activity against Gram-negative bacteria, requires dose adjustment in patients with renal impairment or augmented renal clearance, similarly to other β-lactams. The efficacy and safety of cefiderocol were assessed according to degree of renal impairment as part of a pivotal study vs. imipenem–cilastatin (IPM/CS) in patients with cUTI (NCT02321800). Methods A total of 448 randomized adults with cUTI received cefiderocol (2 g) or IPM/CS (1 g / 1 g), IV, q8h, for 7–14 days (safety population), with 371 patients in the microbiological intent-to-treat (Micro-ITT) population. Dose adjustments were made based on body weight (to enable IPM/CS blinding) and creatinine clearance (CrCL). The composite (clinical and microbiological) outcome at a test of cure (TOC; 7 days after treatment cessation) was analyzed by CrCL subgroup. Adverse events (AEs) according to renal subgroup were monitored throughout the study. Results A treatment difference in the composite outcome at TOC in favor of cefiderocol vs. IPM/CS was observed across renal subgroups (table), with greater differences in moderate and severe groups, consistent with that observed in the overall population (n = 371; 18.0%, 95% confidence interval: 7.5; 28.5). The incidence of AEs in the cefiderocol group was comparable across all renal subgroups. Conversely, AE incidence increased with the degree of impairment in the IPM/CS group (table). Conclusion In contrast to IPM/CS, the efficacy of cefiderocol was maintained across all renal function subgroups with no increase in the rate of AEs. These findings underscore the efficacy and safety of cefiderocol in patients with renal impairment and support the adequacy of the dose adjustment. Disclosures All authors: No reported disclosures.

Inhalation with intravenous loading dose of colistin in critically ill patients with pneumonia caused by carbapenem-resistant gram-negative bacteria

Background: Despite the increasing use of colistin in clinical practice, the optimal dosing, and administration route have not been established. This study aimed to evaluate the clinical outcome and safety of intravenous (IV) colistin with a loading dose (LD) and adjunctive aerosolized (AS) colistin administration in critically ill patients with hospital-acquired pneumonia (HAP) or ventilator-associated pneumonia (VAP) caused by carbapenem-resistant gram-negative bacteria (CRGNB). Methods: We retrospectively reviewed 191 critically ill patients who received colistin for the treatment of HAP or VAP caused by CRGNB. Patients were divided into three groups: non-LD IV (patients received only IV colistin without LD), LD IV (patients received only IV colistin with LD), and AS–LD (patients received IV colistin with LD and adjunctive AS colistin). Results: There was no difference in clinical response between the three groups. However, the rate of microbiological eradication was significantly higher in the AS–LD group (60%) than in the non-LD IV (31%), and LD IV (33%) groups ( p = 0.010). Patients treated with adjunctive AS colistin in combination with LD IV had significantly lower 30-day mortality rates than patients treated with IV colistin alone ( p = 0.027). After adjusting for potential confounding factors, adjunctive AS colistin was still significantly associated with lower mortality (adjusted OR 0.338, CI 95% 0.132–0.864, p = 0.024). However, nephrotoxicity did not change according to the use of LD regimen and AS colistin administration ( p = 0.100). Conclusions: Adjunctive AS colistin in combination with IV colistin with LD was related to an improved 30-day mortality and microbiological outcome without an increase in nephrotoxicity in critically ill patients with HAP and VAP caused by CRGNB. The reviews of this paper are available via the supplemental material section.

Influence of Different Peritoneal Dialysis Fluids on theIn VitroActivity of Cefepime, Ciprofloxacin, Ertapenem, Meropenem and Tobramycin againstEscherichia Coli

BackgroundPeritonitis is a major problem among patients on peritoneal dialysis (PD). The influence of diverse PD fluids on the activity of frequently used antibiotics has been insufficiently investigated. Thus, the present study set out to investigate the impact of different PD fluids on the activity of cefepime, ciprofloxacin, ertapenem, meropenem, and tobramycin against Escherichia coli.MethodsTime-kill curves in 4 different PD fluids (Dianeal PDG4, Extraneal, Nutrineal PD4 and Physioneal 40, all Baxter Healthcare Corp., Deerfield, IL, USA) were performed over 24 hours with 4 different concentrations (1 x minimum inhibitory concentration [MIC], 4 x MIC, 8 x MIC, 30 x MIC) of each antibiotic evaluated and without antibiotics as control. Cation-adjusted Mueller Hinton broth (CA-MHB) was used as comparator solution.ResultsIn all PD fluids investigated, bacterial growth and antimicrobial activity of all antibiotics tested was significantly reduced compared with the CA-MHB comparator solution. Except at high concentrations of 30 x MIC, cefepime, ertapenem and meropenem demonstrated a strongly reduced activity in all PD fluids investigated. Ciprofloxacin and tobramycin were highly active and bactericidal in all PD fluids and demonstrated dose-dependent activity.ConclusionThe antimicrobial activity of cefepime, ertapenem and meropenem is limited or even nullified in certain PD fluids in vitro, whereas ciprofloxacin and tobramycin show excellent activity. The choice of PD fluids can impact the activity of antimicrobial agents and might influence microbiological outcome. Further studies are required to verify the clinical relevance of our findings.

Sonication of Intramedullary Nails: Clinically-Related Infection and Contamination

Background and Aim: Sonication is currently considered the best procedure for microbiological diagnosis of implant-related osteoarticular infection, but studies in nail-related infections are lacking. The study aim was to evaluate implant sonication after intramedullary nail explantation, and relate it to microbiological cultures and clinical outcome. Patients and Methods: A study was performed in two University Hospitals from the same city. Thirty-one patients with implanted nails were prospectively included, whether with clinical infection (8 cases) or without (23 cases). Retrieved nails underwent sonication according a previously published protocol. The clinical and microbiological outcome patient was related to the presence of microorganisms in the retrieved implant. Results: Positive results appeared in 15/31 patients (9 with polymicrobial infections) almost doubling those clinically infected cases. The most commonly isolated organisms were Staphylococcus epidermidis (19.2 %) and Staphylococcus aureus (15.4 %). A significant relationship was found between the presence of positive cultures and previous local superficial infection (p=0.019). The presence of usual pathogens was significantly related to clinical infection (p=0.005) or local superficial infection (p=0.032). All patients with positive cultures showed pain diminution or absence of pain after nail removal (15/15), but this only occurred in 8 (out of 16) patients with negative cultures. Conclusions: In patients with previously diagnosed infection or local superficial infection, study of the hardware is mandatory. In cases where pain or patient discomfort is observed, nail sonication can help diagnose the implant colonization with potential pathogens that might require specific treatment to improve the final outcome.