Pharmacokinetics and Efficacy of Ceftazidime-Avibactam in the Treatment of Experimental Pneumonia Caused by Klebsiella pneumoniae Carbapenemase-Producing K. pneumoniae in Persistently Neutropenic Rabbits.

Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae (KPC-Kp) is an emerging global public health threat that causes life-threatening pneumonia and bacteremia. Ceftazidime-avibactam (CZA) represents a promising advance for the treatment of serious infections caused by KPC-Kp We investigated the pharmacokinetics and efficacy of ceftazidime-avibactam in the treatment of experimental KPC-Kp pneumonia in persistently neutropenic rabbits. For single-dose and multidose (administration every 8 h) pharmacokinetics, rabbits received ceftazidime-avibactam intravenous infusions at 60/15, 90/22.5, and 120/30 mg/kg of body weight. Ceftazidime mean area under the concentration-time curves (AUCs) ranged from 287 to 608 µg·h/ml for a single dose and from 300 to 781 µg·h/ml for multiple doses. Avibactam AUCs ranged from 21 to 48 µg·h/ml for a single dose and from 26 to 48 µg·h/ml for multiple doses. KPC-Kp pneumonia was established by direct endotracheal inoculation. Treatments consisted of ceftazidime-avibactam at 120/30 mg/kg every 6 h, a polymyxin B (PMB) loading dose of 2.5 mg/kg followed by 1.5 mg/kg every 12 h q12h, or no treatment (untreated controls [UC]). There were significant reductions in the residual bacterial burden, lung weights, and pulmonary hemorrhage scores in CZA- and PMB-treated rabbits for a 7-day or a 14-day (P ≤ 0.01) course in comparison with those in the UC. These results corresponded to significant decreases in the bacterial burden in bronchoalveolar lavage fluid after a 7-day or a 14-day treatment (P ≤ 0.01). The outcomes demonstrated an improved response at 14 days versus that at 7 days. There was significantly prolonged survival in rabbits treated with CZA for 14 days in comparison with that in the PMB-treated or UC rabbits (P ≤ 0.05). This study demonstrates that ceftazidime-avibactam displays linear dose-proportional exposures simulating those seen from human plasma pharmacokinetic profiles, is active for the treatment of experimental KPC-Kp pneumonia in persistently neutropenic rabbits, and provides an experimental foundation for the treatment of severely immunocompromised patients with this life-threatening infection.

Pharmacokinetics and Comprehensive Analysis of the Tissue Distribution of Eravacycline in Rabbits.

Eravacycline (7-fluoro-9-pyrrolidinoacetamido-6-demethyl-6-deoxytetracycline or TP-434) is a novel, fully synthetic broad-spectrum fluorocycline with potent activity against Gram-positive bacteria, anaerobes, and multidrug-resistant Enterobacteriaceae We characterized the plasma pharmacokinetics of eravacycline and conducted a comprehensive analysis of the eravacycline tissue distribution in rabbits after multiple-day dosing. For single-dose pharmacokinetic analysis, eravacycline was administered to New Zealand White (NZW) rabbits at 1, 2, 4, 8, and 10 mg/kg of body weight intravenously (i.v.) once a day (QD) (n = 20). For multidose pharmacokinetic analysis, eravacycline was administered at 0.5, 1, 2, and 4 mg/kg i.v. QD (n = 20) for 6 days. Eravacycline concentrations in plasma and tissues were analyzed by a liquid chromatography-tandem mass spectrometry assay. Mean areas under the concentration-time curves (AUCs) following a single eravacycline dose ranged from 5.39 µg · h/ml to 183.53 µg · h/ml. Within the multidose study, mean AUCs ranged from 2.53 µg · h/ml to 29.89 µg · h/ml. AUCs correlated linearly within the dosage range (r = 0.97; P = 0.0001). In the cardiopulmonary system, the concentrations were the highest in the lung, followed by the heart > pulmonary alveolar macrophages > bronchoalveolar lavage fluid; for the intra-abdominal system, the concentrations were the highest in bile, followed by the liver > gallbladder > spleen > pancreas; for the renal system, the concentrations were the highest in urine, followed by those in the renal cortex > renal medulla; for the musculoskeletal tissues, the concentrations were the highest in muscle psoas, followed by those in the bone marrow > adipose tissue; for the central nervous system, the concentrations were the highest in cerebrum, followed by those in the aqueous humor > cerebrospinal fluid > choroid > vitreous. The prostate and seminal vesicles demonstrated relatively high mean concentrations. The plasma pharmacokinetic profile of 0.5 to 4 mg/kg in NZW rabbits yields an exposure comparable to that in humans (1 or 2 mg/kg every 12 h) and demonstrates target tissue concentrations in most sites.

Factors Impacting the Occurrence of Local, Distant and Atypical Recurrences after Robot-Assisted Radical Cystectomy: A Detailed Analysis of 310 Patients.

PURPOSE: Peritoneal carcinomatosis and extrapelvic lymph node metastases can be seen following robot-assisted radical cystectomy. In an attempt to identify predictors of these atypical metastases we report a detailed analysis of patients treated with robot-assisted radical cystectomy in whom recurrences developed. MATERIALS AND METHODS: A total of 310 patients underwent robot-assisted radical cystectomy for bladder cancer from 2001 to 2015. Descriptive statistics were used to compare baseline variables between patients without recurrence and those with local, distant or atypical recurrence. Univariate and multivariable regression models were used to assess the effect of variables on oncologic outcomes including recurrence location. RESULTS: At a median followup of 24 months (IQR 14-51) 81 patients had recurrence. On multivariable analysis tumor classification, lymphovascular invasion, estimated glomerular filtration rate less than 60 ml/minute/1.73 m2 and perioperative blood transfusion were significantly associated with any recurrence. Specific analyses showed that tumor and nodal classification, lymphovascular invasion and positive surgical margins were associated with all 3 recurrence locations (all p <0.05). Previous abdominal surgery was protective against atypical recurrences (HR 0.36, 95% CI 0.13-0.95, p = 0.04). Estimated glomerular filtration rate less than 60 ml/minute/1.73 m2 and perioperative blood transfusion conferred a higher risk of distant or atypical recurrence but not of local recurrence (all p <0.05). Operative time and previous pelvic radiotherapy were not associated with any recurrence locations. CONCLUSIONS: Predictors of distant recurrences, peritoneal carcinomatosis and extrapelvic lymph node metastases after robot-assisted radical cystectomy did not significantly differ and were mainly dictated by pathological tumor characteristics. Results suggest that the risk of atypical recurrence is chiefly influenced by tumor biology rather than surgical aspects.

The safety of robot-assisted cystectomy in patients with previous history of pelvic irradiation.

OBJECTIVE: To determine the safety of robot-assisted cystectomy (RAC) in patients with an irradiated pelvis, by comparing perioperative complication outcomes after RAC in patients with and without a history of pelvic irradiation. PATIENTS AND METHODS: In all, 252 consecutive patients underwent RAC at a tertiary referral centre from 2002 to 2013. Of all patients, 46 (18%) had a history of pelvic irradiation. Complications occurring at ≤30 days and ≤90 days of RAC were graded using the modified Clavien-Dindo classification system and additionally categorised by organ system. Baseline variables and outcomes of irradiated and non-irradiated patients were compared using descriptive statistics. Multivariable logistic regression models were generated to test the effect of previous pelvic irradiation on complications. RESULTS: The indications for RAC in patients with a history of pelvic irradiation were: bladder cancer (30 patients, 65%), prostate cancer (two, 4%), fistulae (five, 11%), and intractable symptoms from radiation cystitis (nine, 20%). In all, 25 (54%) irradiated and 112 (54%) non-irradiated patients had complications at ≤90 days (P > 0.9), of which 11 (24%) and 43 (21%) respectively had major complications (P = 0.7). One (2%) patient with and two (1%) patients without a history of irradiation died from surgical complications (P = 0.5). Infectious, bleeding, and gastrointestinal complications were the most common events in both groups. In multivariable analyses, a history of pelvic irradiation was not associated with a higher risk of complications. CONCLUSION: RAC performed by an experienced surgeon is a reasonable option in selected patients with a history of pelvic irradiation, as complication rates do not significantly differ compared with non-irradiated patients.