Colorectal Cancer Stage at Diagnosis Before vs During the COVID-19 Pandemic in Italy

IMPORTANCE Delays in screening programs and the reluctance of patients to seek medical attention because of the outbreak of SARS-CoV-2 could be associated with the risk of more advanced colorectal cancers at diagnosis. OBJECTIVE To evaluate whether the SARS-CoV-2 pandemic was associated with more advanced oncologic stage and change in clinical presentation for patients with colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS This retrospective, multicenter cohort study included all 17 938 adult patients who underwent surgery for colorectal cancer from March 1, 2020, to December 31, 2021 (pandemic period), and from January 1, 2018, to February 29, 2020 (prepandemic period), in 81 participating centers in Italy, including tertiary centers and community hospitals. Follow-up was 30 days from surgery. EXPOSURES Any type of surgical procedure for colorectal cancer, including explorative surgery, palliative procedures, and atypical or segmental resections. MAIN OUTCOMES AND MEASURES The primary outcome was advanced stage of colorectal cancer at diagnosis. Secondary outcomes were distant metastasis, T4 stage, aggressive biology (defined as cancer with at least 1 of the following characteristics: signet ring cells, mucinous tumor, budding, lymphovascular invasion, perineural invasion, and lymphangitis), stenotic lesion, emergency surgery, and palliative surgery. The independent association between the pandemic period and the outcomes was assessed using multivariate random-effects logistic regression, with hospital as the cluster variable. RESULTS A total of 17 938 patients (10 007 men [55.8%]; mean [SD] age, 70.6 [12.2] years) underwent surgery for colorectal cancer: 7796 (43.5%) during the pandemic period and 10 142 (56.5%) during the prepandemic period. Logistic regression indicated that the pandemic period was significantly associated with an increased rate of advanced-stage colorectal cancer (odds ratio [OR], 1.07; 95%CI, 1.01-1.13; P = .03), aggressive biology (OR, 1.32; 95%CI, 1.15-1.53; P < .001), and stenotic lesions (OR, 1.15; 95%CI, 1.01-1.31; P = .03). CONCLUSIONS AND RELEVANCE This cohort study suggests a significant association between the SARS-CoV-2 pandemic and the risk of a more advanced oncologic stage at diagnosis among patients undergoing surgery for colorectal cancer and might indicate a potential reduction of survival for these patients

The pharmacokinetics of recombinant FXIII (catridecacog) from the MENTORTM2 trial to a real-world study: a head-to-head comparison

FXIII deficiency is a very rare coagulation disorder that can affect equally males and females with an estimated incidence of 1 in 2 million persons worldwide. Due to this rarity, there are only few clinical and pharmacokinetic (PK) data deriving from the real-world

Pharmacokinetics and pharmacodynamics of continuous-infusion meropenem in pediatric hematopoietic stem cell transplant patients

This study explored the pharmacokinetics and the pharmacodynamics of continuous-infusion meropenem in a population of pediatric hematopoietic stem cell transplant (HSCT) patients who underwent therapeutic drug monitoring. The relationship between meropenem clearance (CLM) and estimated creatinine clearance (CLCR) was assessed by nonlinear regression. A Monte Carlo simulation was performed to investigate the predictive performance of five dosing regimens (15 to 90 mg/kg of body weight/day) for the empirical treatment of severe Gram-negative-related infections in relation to four different categories of renal function. The optimal target was defined as a probability of target attainment (PTA) of ≥90% at steady-state concentration-to-MIC ratios (C SS/MIC) of ≥1 and ≥4 for MICs of up to 8 mg/liter. A total of 21 patients with 44 meropenem C SS were included. A good relationship between CLM and estimated CLCR was observed (r (2) = 0.733). Simulations showed that at an MIC of 2 mg/liter, the administration of continuous-infusion meropenem at doses of 15, 30, 45, and 60 mg/kg/day may achieve a PTA of ≥90% at a C SS/MIC ratio of ≥4 in the CLCR categories of 40 to <80, 80 to <120, 120 to <200, and 200 to <300 ml/min/1.73 m(2), respectively. At an MIC of 8 mg/liter, doses of up to 90 mg/kg/day by continuous infusion may achieve optimal PTA only in the CLCR categories of 40 to <80 and 80 to <120 ml/min/1.73 m(2). Continuous-infusion meropenem at dosages up to 90 mg/kg/day might be effective for optimal treatment of severe Gram-negative-related infections in pediatric HSCT patients, even when caused by carbapenem-resistant pathogens with an MIC of up to 8 mg/liter

Population Pharmacokinetics and Dosing Considerations for the Use of Linezolid in Overweight and Obese Adult Patients

BACKGROUND: Linezolid is an anti-Gram-positive antimicrobial agent used at a fixed dose of 600 mg every 12 h. OBJECTIVES: The objective of this study was to assess the population pharmacokinetics and pharmacodynamics of linezolid in a retrospective cohort of overweight and obese hospitalized patients. PATIENTS AND METHODS: Population pharmacokinetic and Monte Carlo simulations were conducted to assess the probability of target attainment (PTA) of an area under the concentration-time curve from time zero to 24 h (AUC24)/minimum inhibitory concentration (MIC) ratio > 100, defined as the pharmacodynamic target of efficacy, with incremental candidate dosages. Maximum permissible doses were defined as those causing a 64 25% of probability of a linezolid trough of > 8.06 mg/L, associated with thrombocytopenia. The cumulative fraction of response was calculated for the permissible linezolid doses by testing the PTA against the MIC distributions of a large collection of Staphylococci and Enterococci. RESULTS: A total of 352 trough (minimum) and 293 peak (maximum) linezolid concentrations from 112 patients were included. The final mixed-saturative model accounted for 88% of drug concentrations variability over time, and estimated creatinine clearance [by means of the Chronic Kidney Diseases Epidemiology formula (CrCLCKD-EPI)] was the only covariate that improved the model fit. Dose reduction to 450 mg every 12 h may be optimal for patients with coagulase-negative staphylococcal infections and a CrCLCKD-EPI < 130 mL/min/1.73 m2. Dose escalation to 450 mg every 8 h may be optimal for patients with a CrCLCKD-EPI 65 60 mL/min/1.73 m2. Escalation to 600 mg every 8 h should not be recommended due to an unacceptable high risk of thrombocytopenia. Patients with CrCLCKD-EPI 65 130 mL/min/1.73 m2 and/or co-medication with P-glycoprotein modulators require therapeutic drug monitoring to optimize linezolid doses. CONCLUSIONS: Dosage adjustments of linezolid in this population should be based on CrCLCKD-EPI estimates, rather than on body size descriptors

Levofloxacin dosing regimen in severely morbidly obese patients (BMI 6540 kg/m2) should be guided by creatinine clearance estimates based on ideal body weight and optimized by therapeutic drug monitoring

BACKGROUND: Levofloxacin is a commonly prescribed antimicrobial where recommendations exist to reduce doses for renal impairment but not to increase doses for augmented renal function. Morbidly obese patients are increasing in prevalence, and represent a population that can have augmented renal function requiring higher-than-standard doses. OBJECTIVE: The current investigation was performed to characterize the pharmacokinetics (PK) and evaluate the influence of alternate body size descriptors and renal function as predictors of levofloxacin clearance (CL) and the area under the curve over 24 h (AUC24). METHODS: A database of patients undergoing levofloxacin therapeutic drug monitoring (TDM) were queried to identify patients 6518 years of age with a body mass index 6540 kg/m(2). A maximum a posteriori probability Bayesian approach using a two-compartment linear PK model was used to estimate individual PK parameters and AUC24. RESULTS: A total of 394 concentration-time data points (peaks and trough) from 68 patients between 98 and 250 kg were evaluated. The median (5th, 95th percentile) daily dose and AUC24 was 1,000 (250, 1,500) mg and 90.7 (44.4, 228) mg\ub7h/L, respectively. Levofloxacin CL was significantly (p 90 % probability of achieving an AUC24 of 50-150 mg\ub7h/L in morbidly obese patients. Subsequent application of TDM and integration with pathogen-specific information could then be applied to tailor the levofloxacin regimen. CONCLUSIONS: The proposed approach serves as a relevant alternative to the current fixed-dosing paradigm of levofloxacin in the morbidly obese

Dosing nomograms for attaining optimum concentrations of meropenem by continuous infusion in critically ill patients with severe gram-negative infections: A pharmacokinetics/pharmacodynamics-based approach

The worrisome increase in Gram-negative bacteria with borderline susceptibility to carbapenems and of carbapenemase-producing Enterobacteriaceae has significantly undermined their efficacy. Continuous infusion may be the best way to maximize the time-dependent activity of meropenem. The aim of this study was to create dosing nomograms in relation to different creatinine clearance (CL(Cr)) estimates for use in daily clinical practice to target the steady-state concentrations (C(ss)s) of meropenem during continuous infusion at 8 to 16 mg/liter (after the administration of an initial loading dose of 1 to 2 g over 30 min). The correlation between meropenem clearance (CL(m)) and CL(Cr) was retrospectively assessed in a cohort of critically ill patients (group 1, n = 67) to create a formula for dosage calculation to target C(ss). The performance of this formula was validated in a similar cohort (group 2, n = 56) by comparison of the observed and the predicted C(ss)s. A significant relationship between CL(m) and CL(Cr) was observed in group 1 (r = 0.72, P < 0.001). The application of the formula to meropenem dosing in group 2, infusion rate (g/24 h) = [0.078 × CL(Cr) (ml/min) + 2.85] × target C(ss) × (24/1,000), led to a significant correlation between the observed and the predicted C(ss)s (r = 0.92, P < 0.001). Dosing nomograms based on CL(Cr) were created to target the meropenem C(ss) at 8, 12, and 16 mg/liter in critically ill patients. These nomograms could be helpful in improving the treatment of severe Gram-negative infections with meropenem, especially in the presence of borderline susceptible pathogens or even of carbapenemase producers and/or of pathophysiological conditions which may enhance meropenem clearanc

Limited sampling strategies for determining the area under the plasma concentration\u2013time curve for isoniazid might be a valuable approach for optimizing treatment in adult patients with tuberculosis

This study aimed to develop clinically feasible models of limited sampling strategy (LSS) for estimation of the area under the concentration\u2013time curve (AUC24h) for isoniazid, that could be applied easily in daily clinical practice for dosage adjustment in adult patients with tuberculosis. Isoniazid plasma concentrations (n = 1665) from 185 adult tuberculous patients were used for the development and validation of LSS models to estimate AUC24h following administration of the standard 5 mg/kg dose of isoniazid. Population pharmacokinetic analysis for appropriate estimation of isoniazid pharmacokinetic parameters was performed in a modelling group (n = 100). The Bayesian estimates of AUC24h (AUCref) obtained for each individual were used as the dependent variable in the regression analysis for the development of various LSS models. The LSS models were validated in a separate cohort (n = 85). Several three and four time point LSS models were built and tested. Model H (AUC24h = 121.88 + 1.05 7 C1 + 0.78 7 C2 + 9.44 7 C5) and Model I (AUC24h= 120.65 + 1.00 7 C1 + 1.94 7 C2 + 15.45 7 C9) had the best performances [adj-R2 = 0.93, median prediction error (MPE) = 120.20, root median squared prediction error (RMSE) = 4.65 for Model H; adj-R2 = 0.96, MPE = 120.05 RMSE = 3.56 for Model I]. The very high R2 values ( 650.94) of these regression equations in the validation cohort confirmed their high reliability. These LSS models could be applied in the context of therapeutic drug monitoring programmes aiming to personalize isoniazid dosing regimens for adult patients with tuberculosis

Monitoring polypharmacy in healthcare systems through a multi-setting survey: Should we put more attention on long term care facilities?

Background. Polypharmacy is a main issue of patient safety in all healthcare settings (i.e. increase adverse drug reactions and incidence of drug-drug interactions, etc.). The main object of the study was to evaluate the prevalence of polypharmacy and the appropriateness of drugs prescriptions in the regional health system (RHS) of Friuli Venezia-Giulia Region, Italy. Design and methods. We carried out a point prevalence study in May 2014; 1582 patients 6565 years were included from: 14 acute hospitals, 46 Long Term Care Facilities (LTCFs) and 42 general practitioners\u2019 (GPs) clinics. Data analysis included the evaluation of potentially inappropriate prescriptions (PIPs) taking Beers criteria as a reference. Results. Patients in therapy with 10 drugs or more were 13.5%: 15.2% in hospitals, 9.7% in GPs\u2019 clinics and 15.6% in LTCFs. According to Beers criteria we identified 1152 PIPs that involved globally almost half of patients (46.0%): 41.9% in hospitals, 59.6% in LTCFs and 37.0% in GP\u2019s clinics. The 53.9% of patients received at least one mainly kidney excreted drug; for these patients the evaluation of serum creatinine was overall present in the 87.7% (747/852): 96.4% in hospital ones, 87.5% in GPs\u2019 clinics and 77.8% in LTCFs. LTCFs residents were significantly (P<0.05) more exposed to PIPs and less monitored for the renal function. Conclusions. A reliable estimation of the phenomenon in all the main healthcare settings is a necessary prerequisite to set tailored policies for facing polypharmacy within a RHS; the results showed the necessity to put a special attention on LTCFs

Linezolid underexposure in a patient co-treated with venlafaxine

none5sianoneCojutti P.; Crapis M.; Bassetti M.; Hope W.; Pea F.Cojutti P.; Crapis M.; Bassetti M.; Hope W.; Pea F