Pharmacotherapy最新文献

Background: Compared to soybean-oil and fish-oil formulations, the use of mixed-oil lipid injectable emulsion is associated with reduced catheter-related bloodstream infection rates in pediatric patients receiving parenteral nutrition. The objective of this study was to compare clinical outcomes of fungal catheter-related bloodstream infections in pediatric patients following receipt of parenteral nutrition with mixed-oil (SMOFlipid) lipid injectable emulsion or other formulations (soybean-oil [Intralipid] or fish-oil [Omegaven]).

Methods: A retrospective cohort study of pediatric patients with fungal catheter-related bloodstream infections following administration of parenteral nutrition and injectable lipid emulsion from five pediatric hospitals in the United States during a 5-year period was conducted. Differences in a composite outcome of 30-day mortality from first positive blood culture and/or infection persistence based on type of lipid injectable emulsion received prior to infection were assessed through generalized linear mixed models with binomial distribution.

Results: One-hundred twelve fungal catheter-related bloodstream infections were assessed from 104 patients who received mixed-oil lipid injectable emulsion (n = 43) or other formulations (n = 69) prior to infection. Thirty-nine infections met the composite outcome (32 with persistent infection, three with 30-day mortality, and four with both). On multivariable analysis, receipt of mixed-oil lipid injectable emulsion demonstrated a non-statistically significant increase in the composite outcome (odds ratio [OR] [95% confidence interval {CI}]: 1.80 [0.75-4.34]; p = 0.19). Factors independently associated with the composite outcome include receipt of systemic antifungal prophylaxis (OR [95% CI]: 5.72 [1.33-24.7]; p = 0.019) and delay in central venous catheter removal (OR [95% CI]: 1.09 [1.01-1.19]; p = 0.03). Notable factors not associated with the composite outcome included continued receipt of lipid injectable emulsion, empiric antifungal choice, time to antifungal administration, and gastrointestinal surgery within 90 days prior to infection.

Conclusion: Use of mixed-oil lipid injectable emulsion compared to other formulations (soybean-oil or fish-oil) demonstrated a non-statistically significant increase in 30-day mortality and/or infection persistence from fungal catheter-related bloodstream infections in pediatric patients receiving parenteral nutrition.

Background: Proton pump inhibitors (PPIs) have been commonly used for gastroesophageal reflux disease (GERD) and peptic ulcers (PU), which are even more prevalent in patients with chronic kidney disease (CKD). Although PPI-related adverse outcomes are well documented in the general population, evidence in patients with CKD remains limited. This study investigated the associations of PPI use and adverse outcomes in patients with CKD who had GERD or PU.

Methods: In this nationwide, retrospective cohort study, patients with CKD and also PU or GERD from 2006 to 2015 were enrolled and sorted into no-, short-term, and long-term PPI groups. Incidence and risks of outcome events between these three groups were analyzed with the Cochran-Armitage test and Cox proportional hazard analyses. Events-free probability was estimated with the Kaplan-Meier method during follow-up.

Results: In the study, 384,411 patients with CKD with PU or GERD were enrolled. The numbers of no-, short-term, and long-term PPI treatments were 147,976, 14,153, and 3459, respectively. Relative to the no-PPI group, the adjusted hazard ratios (aHRs) of admission for pneumonia and fracture, new diagnosis of type 2 diabetes mellitus (DM), and progression to end-stage kidney disease (ESKD) in the short-term (1.089, 1.083, 1.175, 1.22) and long-term PPI groups (1.882, 2.601, 1.951, 1.714) remained statistically significant, respectively, even after adjustment for significant baseline variables; the aHR of dialysis was significant only in the long-term PPI group. Kaplan-Meier analysis revealed significant outcome events in the long-term PPI group during follow-up.

Conclusion: PPI use is associated with an increased risk of pneumonia, fracture, incidence of type 2 DM, and progression to ESKD in patients with CKD, and the risk increases substantially with increased duration of PPI use.

Background: Clinically relevant drug-drug interactions (DDIs) are a common cause of adverse drug reactions (ADRs). Hepatic organic anion transporting polypeptides (OATPs) have recently been studied for their role in DDIs. The commonly prescribed antihypertensive angiotensin receptor blockers (ARBs) are known to be eliminated by hepatic OATPs. ARBs are commonly prescribed to patients with reduced kidney function, and kidney disease can result in profound changes to nonrenal drug elimination through reduced hepatic drug transport-mediated excretion. The antibiotic clarithromycin inhibits OATP activity whereas azithromycin does not, making them useful comparators to study DDIs with OATP substrate drugs.

Objective: To investigate whether co-prescription of ARBs and clarithromycin results in increased adverse events compared to azithromycin and whether kidney function modifies this risk.

Methods: We conducted a retrospective population-based cohort study in Ontario, Canada (2010-2021) using linked health care data for 106,322 older individuals (≥66 years) receiving an OATP substrate ARB (candesartan, olmesartan, telmisartan, valsartan) and newly co-prescribed clarithromycin (n = 32,693) or azithromycin (n = 73,629). Primary outcomes were hospital admissions or emergency department visits for hyperkalemia or acute kidney injury (AKI) within 14 days of antibiotic prescription. Adjusted risk ratios (aRR) were obtained using modified Poisson regression after controlling for eight potential confounders. Pre-specified effect measure modification analysis evaluated whether kidney function influenced these outcomes.

Results: Compared to those co-prescribed azithromycin, patients receiving clarithromycin had a significantly higher risk of hyperkalemia (aRR 2.05, 95% confidence interval (CI) 1.32-3.18) and AKI (aRR 1.75, 95% CI 1.41-2.17). The risk of hyperkalemia increased as kidney function declined (multiplicative interaction; p = 0.01).

Conclusions: This population-based retrospective cohort study provides evidence of OATP-mediated drug interactions between ARBs and clarithromycin that warrants further investigation to guide clinical practice, especially for patients with reduced kidney function.

Diphenhydramine overdose is a common toxicological emergency characterized by anticholinergic symptoms such as delirium, hallucinations, and cardiovascular instability. Physostigmine, a centrally acting acetylcholinesterase inhibitor, is the standard antidote but is currently unavailable within the United States due to supply limitations. We present the case of a 21-year-old female with confirmed diphenhydramine overdose (3600 mg) who demonstrated rapid clinical improvement after administration of a 9.5 mg/24-h rivastigmine transdermal patch. This case supports growing evidence suggesting that rivastigmine may serve as a safe and effective alternative when physostigmine is not accessible.

Background: Drug databases currently do not provide dosing guidance for sulbactam-durlobactam in continuous renal replacement therapy. Herein, we present the first in vivo pharmacokinetic (PK) evaluation of sulbactam-durlobactam during continuous venovenous hemofiltration (CVVH) in a patient with carbapenem-resistant Acinetobacter baumannii-calcoaceticus complex (CRAB) bacteremia and ventilator-associated bacterial pneumonia (VABP).

Methods: A 59-year-old critically ill patient (body mass index 60 kg/m²) required CVVH and developed CRAB bacteremia secondary to VABP. Sulbactam-durlobactam 2 g every 4 h infused over 3 h was initiated based on previous ex vivo data and the effluent rate of 6 L/h. The sulbactam-durlobactam minimum inhibitory concentration (MIC) was determined by reference broth microdilution, and whole genome sequencing (WGS) was performed. Steady-state pre-filter blood, post-filter blood, and effluent samples were collected on three different dosing intervals to characterize plasma exposure and estimate the sieving coefficient (SC).

Results: The sulbactam-durlobactam MIC was 4/4 mcg/mL (susceptible). WGS revealed penicillin-binding protein (PBP)-1b and PBP-3 mutations. The selected dose exceeded sulbactam and durlobactam PK/pharmacodynamic (PD) targets with 100% free time above MIC (fT > MIC) and the ratio of area under the unbound concentration-time curve to MIC (fAUC/MIC) = 139, respectively. The SC for sulbactam and durlobactam was 0.68 and 0.67, respectively, and protein binding was 54% and 51%, respectively. Sulbactam-durlobactam monotherapy resulted in initial microbiological clearance for CRAB bacteremia but recurred later in hospitalization 11 days after sulbactam-durlobactam treatment. The patient was ultimately transitioned to comfort care.

Conclusion: Sulbactam-durlobactam monotherapy dosed at 2 g every 4 h (3-h infusion) in CVVH achieved PD targets for this CRAB isolate with a MIC of 4/4 mcg/ml. Although sulbactam-durlobactam monotherapy resulted in initial microbiological clearance for the CRAB bacteremia, recurrence occurred, and the patient ultimately died.

Background: Oxaliplatin-induced peripheral neuropathy (OIPN) is a major clinical challenge because it leads to discontinuation of chemotherapy. Omeprazole, a proton pump inhibitor (PPI), has been shown to prevent OIPN in a rat model. Therefore, we aimed to test whether the concomitant use of a PPI reduces oxaliplatin discontinuation due to OIPN.

Methods: This retrospective study used data from 1015 patients who started treatment with oxaliplatin and evaluated two cohorts (PPI vs. non-PPI). The primary outcome measure was oxaliplatin discontinuation due to OIPN. A Kaplan-Meier curve was generated for cumulative doses and evaluated using the log-rank test and Cox proportional hazards analysis.

Results: The log-rank test showed that the number of patients who discontinued oxaliplatin due to OIPN was significantly lower in the PPI group (p = 0.0264). Cox proportional hazards analysis incorporated and analyzed factors previously reported as potentially affecting neuropathy (sex, age, use of PPIs, calcium channel antagonists, opioids and adjuvant analgesics, and the CAPOX [capecitabine + oxaliplatin] regimen). The analysis suggested that the concomitant use of PPIs was a factor in reducing oxaliplatin discontinuation (adjusted hazard ratio [HR] = 0.568, 95% confidence interval [CI], 0.344-0.937, p = 0.0269). Since there were significant differences in some patient demographics between the two groups, propensity score matching was performed to align the patient demographics and then reanalyzed. After propensity score matching, the same analysis as above showed that oxaliplatin discontinuation due to OIPN was significantly less common in the PPI group (p = 0.0081); cox proportional hazards analysis showed that PPI use was a factor that significantly reduced oxaliplatin discontinuation due to OIPN (adjusted HR = 0.478, 95% CI, 0.273-0.836, p = 0.0096).

Conclusions: These results suggest that concomitant PPI use may reduce oxaliplatin discontinuation due to OIPN in patients receiving oxaliplatin.

Background: Type 2 diabetes (T2D) is associated with an increased risk of nephrolithiasis. Emerging evidence suggests that sodium-glucose cotransporter 2 inhibitors (SGLT2i) may reduce this risk; however, data remain inconclusive.

Objective: To examine the risk of nephrolithiasis among users of SGLT2i compared to dipeptidyl peptidase-4 inhibitors (DPP4i) in a real-world population of older adults with T2D.

Methods: A retrospective cohort study was conducted using claims data from a sample of national Medicare beneficiaries. Individuals with T2D who initiated SGLT2i or DPP4i therapy between January 1, 2016, and December 31, 2018, were identified. The index date was defined as the date of the first prescription for either SGLT2i or DPP4i, with no prior use of either drug in the preceding year. Patients were followed from the index date until the earliest occurrence of a medical encounter with a primary diagnosis of nephrolithiasis, death, or December 31, 2018. Inverse probability of treatment weighting (IPTW) was used to balance baseline covariates, including sociodemographic characteristics, comorbidities, and comedication use. Cox proportional hazards regression models were applied to compare the risk of nephrolithiasis between SGLT2i and DPP4i users. Additional analyses were conducted within subgroups defined by sex, race, and baseline nephrolithiasis status.

Results: Of 116,506 included Medicare beneficiaries with T2D (mean age 72 ± 10 years, 53% women), 0.96% developed nephrolithiasis over a median follow-up of 360 days (interquartile range [IQR] 200-467 days). The incidence rate of nephrolithiasis was 9.89 (95% confidence interval [CI] 8.49-11.52) and 11.02 (95% CI 10.34-11.73) events per 1000 person-years in the SGLT2i and DPP4i groups, respectively. After applying IPTW, baseline characteristics were well balanced between the two groups. SGLT2i use was associated with a significantly lower risk of nephrolithiasis compared to DPP4i use (hazard ratio [HR], 0.81; 95% CI 0.66-0.99; p = 0.04). In subgroup analyses, SGLT2i use compared to DPP4i was associated with a significantly lower risk of nephrolithiasis among males (HR 0.75; 95% CI 0.58-0.98; p = 0.04), non-Hispanic Black (NHB) individuals (HR 0.22; 95% CI 0.07-0.64; p < 0.01), and those without baseline nephrolithiasis (HR 0.68; 95% CI 0.53-0.88; p < 0.01).

Conclusions: In older adults with T2D, SGLT2i use was associated with a lower risk of nephrolithiasis compared to DPP4i, particularly among men, NHB individuals, and those without baseline nephrolithiasis. Although causality cannot be established, these findings provide real-world evidence supporting a potential benefit of SGLT2is in reducing nephrolithiasis risk, offering valuable insights to guide the selection of glucose-lowering drugs in older adults with T2D.

Background: Model-informed precision dosing (MIPD) is a promising tool used to ensure therapeutic antimicrobial concentrations. Model selection and sampling strategy might lead to different pharmacokinetic (PK) parameter estimates. Herein, we assess the predictive performance for cefepime PK in two models implemented within the InsightRX software using differing sampling approaches.

Methods: Historic cefepime PK data and individual Bayesian estimates in predominantly critically ill patients, some of whom had extracorporeal support, served as the reference standard. Two population PK models (A; B) were evaluated using four sampling scenarios: (i) trough only, (ii) midpoint only, (iii) trough + midpoint, and (iv) peak + midpoint + trough. The median prediction error (MPE) and median absolute prediction error (MAPE) were calculated for clearance (CL) and volume of central compartment (V_c). Predicted categorical achievement of ≥70% time that the free drug concentration was greater than the minimum inhibitory concentration [fT>MIC_(8/16mg/L)] was compared.

Results: MAPE and MPE for CL and V_c resulted in variability that was dependent on model and sampling strategy. Both models' overall MPE and MAPE for CL were <±20 and <30% for all tested scenarios, respectively, with a low MPE of -2.4% to 4.4% on CL for sampling scenario 4. For V_c, MPE and MAPE were >±20 and >30% for the majority of test scenarios across both models, respectively. When excluding patients with extracorporeal support, MPE/MAPE for V_c decreased to 3.7-4.8/23.3%-34.5% and -7.9-2.5/25.2%-29.6% for model A and B, respectively. Using each model and sampling scheme, only four patients had discordant predicted achievement of ≥70% fT>MIC_(8/16mg/L).

Conclusions: These two population PK models and all sampling scenarios demonstrated acceptable prediction of cefepime PK parameters and pharmacodynamic exposures; therefore, they demonstrated suitability for utilizing MIPD for cefepime therapeutic drug monitoring.