A doripenem population pharmacokinetic model and Monte Carlo simulations were utilized for dose regimen decision support for future clinical development. Simulation results predict that 500 mg of doripenem administered over 1 h every 8 h would be effective against bacterial strains with MICs less than 2 microg/ml and that less susceptible strains could be treated with prolonged infusions.
Meropenem-vaborbactam is a fixed-dose beta-lactam/beta-lactamase inhibitor with potent in vitro and in vivo activity against Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacterales. Pharmacokinetic-pharmacodynamic (PK-PD) target attainment analyses were undertaken using population pharmacokinetic models, nonclinical PK-PD targets for efficacy, in vitro surveillance data, and simulation to provide support for 2 g meropenem-2 g vaborbactam every 8 h (q8h) administered as a 3-h intravenous (i.v.) infusion, and dosing regimens adjusted for patients with renal impairment. Simulated patients varying by renal function measure (estimated glomerular filtration rate [eGFR], mL/min/1.73 m2 and absolute eGFR, mL/min) and resembling the clinical trial population (complicated urinary tract infection, including acute pyelonephritis) were generated. The PK-PD targets for meropenem, the percentage of time on day 1 that free-drug plasma concentrations were above the MIC (%T>MIC), and vaborbactam, the ratio of free-drug plasma area under the concentration-time curve (AUC) on day 1 to the MIC (AUC:MIC ratio), were calculated. Percent probabilities of achieving meropenem free-drug plasma %T>MIC and vaborbactam free-drug plasma AUC:MIC ratio targets were assessed. MIC distributions for Enterobacterales, KPC-producing Enterobacterales, and Pseudomonas aeruginosa were considered as part of an algorithm to assess PK-PD target attainment. For assessments of free-drug plasma PK-PD targets associated with a 1-log10 CFU reduction from baseline, percent probabilities of PK-PD target attainment ranged from 81.3 to 100% at meropenem-vaborbactam MIC values of 4 or 8 μg/mL among simulated patients. The results of these PK-PD target attainment analyses provide support for a dosing regimen of 2 g meropenem-2 g vaborbactam q8h administered as a 3-h i.v. infusion, with dosing regimens adjusted for patients with renal impairment and a meropenem-vaborbactam susceptibility breakpoint of ≤8 μg/mL (tested with a fixed vaborbactam concentration of 8 μg/mL) for Enterobacterales and P. aeruginosa based on these dosing regimens.
In Brief OBJECTIVE: To compare tubal anastomosis by robotic system compared with outpatient minilaparotomy. METHODS: In this retrospective case–control study, women were identified by current procedural terminology code for tubal anastomosis. We included all cases of tubal anastomosis for reversal of a prior tubal ligation by either outpatient minilaparotomy or robotic system technique. Cases performed by laparoscopy without aid of the robot were excluded. Comparisons were based on Fisher's exact, χ2, and Wilcoxon rank sum tests. RESULTS: There were 26 cases of tubal anastomosis performed with the robot and 41 cases performed by outpatient minilaparotomy. The two groups were comparable in age, body mass index, and parity. Anesthesia time for the robotic technique (median with interquartile range) was 283 (267–290) minutes compared with 205 (170–230) minutes with outpatient minilaparotomy (P<.001). Surgical times for the robot and minilaparotomy were 229 (205–252) minutes and 181 (154–202) minutes respectively (P=.001). Hospitalization times, pregnancy, and ectopic pregnancy rates were not significantly different. The robotic technique was more costly. The median difference in costs of the procedures was $1,446 (95% confidence interval $1,112–1,812) (P<.001). The time to return to work was significantly shorter in the robotic system group by approximately 1 week (P=.013). CONCLUSION: Robotic surgery for tubal anastomosis was successfully accomplished without conversion to laparotomy. The robotic technique for tubal anastomosis required significantly prolonged surgical and anesthesia times over outpatient minilaparotomy (P≤.001). Costs were higher with the robotic technique. Return to normal activity was shorter with the robotic technique. LEVEL OF EVIDENCE: II Robotic surgery for tubal anastomosis requires significantly prolonged surgical and anesthesia times compared with outpatient minilaparotomy.
Tuberculous meningitis (TBM) is the most lethal form of tuberculosis, and new treatments that improve outcomes are required. We randomly assigned adults with TBM to treatment with standard antituberculosis treatment alone or in combination with ciprofloxacin (750 mg/12 h), levofloxacin (500 mg/12 h), or gatifloxacin (400 mg/24 h) for the first 60 days of therapy. Fluoroquinolone concentrations were measured with plasma and cerebrospinal fluid (CSF) specimens taken at predetermined, randomly assigned times throughout treatment. We aimed to describe the pharmacokinetics of each fluoroquinolone during TBM treatment and evaluate the relationship between drug exposure and clinical response over 270 days of therapy (Controlled Trials number ISRCTN07062956). Sixty-one patients with TBM were randomly assigned to treatment with no fluoroquinolone (n = 15), ciprofloxacin (n = 16), levofloxacin (n = 15), or gatifloxacin (n = 15). Cerebrospinal fluid penetration, measured by the ratio of the plasma area under the concentration-time curve from 0 to 24 h (AUC(0-24)) to the cerebrospinal fluid AUC(0-24), was greater for levofloxacin (median, 0.74; range, 0.58 to 1.03) than for gatifloxacin (median, 0.48; range, 0.47 to 0.50) or ciprofloxacin (median, 0.26; range, 0.11 to 0.77). Univariable and multivariable analyses of fluoroquinolone exposure against a range of different treatment responses revealed worse outcomes among patients with lower and higher plasma and CSF exposures than for patients with intermediate exposures (a U-shaped exposure-response). TBM patients most likely to benefit from fluoroquinolone therapy were identified, along with exposure-response relationships associated with improved outcomes. Fluoroquinolones add antituberculosis activity to the standard treatment regimen, but to improve outcomes of TBM, they must be started early, before the onset of coma.
Growth factor profiles could be influenced by the utilization of exogenous insulin. The data presented shows the relationship between pre-existing use of injectable insulin in women diagnosed with breast cancer and type 2 diabetes mellitus, the growth factor profiles at the time of breast cancer diagnosis, and subsequent cancer outcomes. A Pearson correlation analysis evaluating the relationship between growth factors stratified by of insulin use and controls is also provided.
ABSTRACT Ceftaroline is a cephalosporin with broad-spectrum in vitro activity against pathogens commonly associated with acute bacterial skin and skin structure infections (ABSSSI), including methicillin-resistant Staphylococcus aureus . Ceftaroline fosamil, the prodrug of ceftaroline, is approved for the treatment of patients with ABSSSI. Using data from the microbiologically evaluable population from two phase 2 and two phase 3 randomized, multicenter, double-blind studies of patients with ABSSSI, an analysis examining the relationship between drug exposure, as measured by the percentage of time during the dosing interval that free-drug steady-state concentrations remain above the MIC ( f % T >MIC), and clinical and microbiological responses was undertaken. The analysis population included 526 patients, of whom 423 had infections associated with S. aureus . Clinical and microbiological success percentages were 94.7 and 94.5%, respectively, among all of the patients and 95.3 and 95.7%, respectively, among those with S. aureus infections. Univariable analysis based on data from all of the patients and those with S. aureus infections demonstrated significant relationships between f % T >MIC and microbiological response ( P < 0.001 and P = 0.026, respectively). Multivariable logistic regression analyses demonstrated other patient factors in addition to f % T >MIC to be significant predictors of microbiological response, including age and infection type for all of the patients evaluated and age, infection type, and the presence of diabetes mellitus for patients with S. aureus infections. Results of these analyses confirm that a ceftaroline fosamil dosing regimen of 600 mg every 12 h provides exposures associated with the upper plateau of the pharmacokinetic-pharmacodynamic relationship for efficacy.
BackgroundThe association between primary sclerosing cholangitis (PSC) and underlying inflammatory bowel disease (IBD) is well established. There are scant data on the association between non-IBD immunological diseases (NID) and PSC outcomes. Our objective was to investigate the impact of NID on the clinical outcomes in patients with PSC.
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