Diagnostic Delay of Spinal Tuberculosis Causing Medullary Compression.

We present a case of a Philippine woman in her late twenties, diagnosed with spinal tuberculosis after surgical intervention due to medullary compression. The diagnosis was preceded by four months of unexplained back pain. Differential diagnoses included ulcer, liver-gallbladder disease, musculoskeletal causes, and cancer. This case highlights the importance of considering tuberculosis as a differential diagnosis in patients from high-endemic areas to avoid diagnostic delay and the risk of disease progression.

Strategies to Increase Cervical Cancer Screening With Mailed Human Papillomavirus Self-Sampling Kits: A Randomized Clinical Trial.

Importance: Optimal strategies for increasing cervical cancer screening may differ by patient screening history and health care setting. Mailing human papillomavirus (HPV) self-sampling kits to individuals who are overdue for screening increases adherence; however, offering self-sampling kits to screening-adherent individuals has not been evaluated in the US. Objective: To evaluate the effectiveness of direct-mail and opt-in approaches for offering HPV self-sampling kits to individuals by cervical cancer screening history (screening-adherent and currently due, overdue, or unknown). Design, Setting, and Participants: Randomized clinical trial conducted in Kaiser Permanente Washington, a US integrated health care delivery system. Individuals aged 30 to 64 years with female sex, a primary care clinician, and no hysterectomy were identified through electronic health records (EHRs) and enrolled between November 20, 2020, and January 28, 2022, with follow-up through July 29, 2022. Interventions: Individuals stratified as due (eg, at the time of randomization, these individuals have been previously screened and are due for their next screening in ≤3 months) were randomized to receive usual care (patient reminders and clinician EHR alerts [n = 3671]), education (usual care plus educational materials about screening [n = 3960]), direct mail (usual care plus educational materials and a mailed self-sampling kit [n = 1482]), or to opt in (usual care plus educational materials and the option to request a kit [n = 3956]). Individuals who were overdue for screening were randomized to receive usual care (n = 5488), education (n = 1408), or direct mail (n = 1415). Individuals with unknown history for screening were randomized to receive usual care (n = 2983), education (n = 3486), or to opt in (n = 3506). Main Outcomes and Measures: The primary outcome was screening completion within 6 months. Primary analyses compared direct-mail or opt-in participants with individuals randomized to the education group. Results: The intention-to-treat analyses included 31 355 randomized individuals (mean [SD] age, 45.9 [10.4] years). Among those who were due for screening, compared with receiving education alone (1885 [47.6%]), screening completion was 14.1% (95% CI, 11.2%-16.9%) higher in the direct-mail group (914 [61.7%]) and 3.5% (95% CI, 1.2%-5.7%) higher in the opt-in group (2020 [51.1%]). Among individuals who were overdue, screening completion was 16.9% (95% CI, 13.8%-20.0%) higher in the direct-mail group (505 [35.7%]) compared with education alone (264 [18.8%]). Among those with unknown history, screening was 2.2% (95% CI, 0.5%-3.9%) higher in the opt-in group (634 [18.1%]) compared with education alone (555 [15.9%]). Conclusions and Relevance: Within a US health care system, direct-mail self-sampling increased cervical cancer screening by more than 14% in individuals who were due or overdue for cervical cancer screening. The opt-in approach minimally increased screening. To increase screening adherence, systems implementing HPV self-sampling should prioritize direct-mail outreach for individuals who are due or overdue for screening. For individuals with unknown screening history, testing alternative outreach approaches and additional efforts to document screening history are warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT04679675.

The Association Between Cognitive Functions and Psychological Factors in Patients with Severe COPD.

Purpose: Patients with COPD experience anxiety, depression, and stress more frequently than in the age and gender-matched general population. This cross-sectional study aimed to examine the relationship between cognitive functions and the psychological factors of anxiety, depression and stress among patients with COPD. Patients and Methods: Between January 2021 and January 2023, patients with severe COPD were recruited, along with age-matched controls. Participants completed the Hospital Anxiety and Depression Scale (HADS) and the Perceived Stress Scale (PSS). The Montreal Cognitive Assessment (MoCA), a continuous reaction time test (CRT), and a driving simulator were used to assess cognitive impairment. Hierarchical multiple linear regression analyses were used to explain the variance of the correlations. Results: In total, 80 patients (mean age = 64yrs) and 22 controls (mean age = 61yrs) participated in the study. Patients reported significantly higher levels of psychological symptoms compared to the controls (p ≤ 0.001). We found no differences in anxiety (p = 0.31), depression (p = 0.66) and stress (p = 0.37) between patients with and without cognitive impairment. However, stress showed to be a significant predictor of decreased attention (higher stress score resulted in decreasing CRT-index, indication a reduced stability in reaction time) (p = 0.02). Psychological factors did not explain additional variance in cognitive functions beyond sociodemographic factors such as age and sex. Conclusion: Psychological symptom levels are higher in COPD than controls and perceived stress among patients with COPD appears to be associated with decreased attention. However, psychological factors in general did not appear to contribute to the variance in cognitive functions beyond sociodemographic, physical, and self-perceived symptoms.

Piperacillin Steady State Concentrations in Target Tissues Relevant for PJI Treatment-A Randomized Porcine Microdialysis Study Comparing Continuous Infusion with Intermittent Short-Term Infusion.

(1) Introduction: Piperacillin is a common antibiotic choice in the treatment of periprosthetic joint infections (PJI) caused by Pseudomonas aeruginosa. The aim of this study was to assess and compare the time with free piperacillin concentration above the minimum inhibitory concentration (fT > MIC) at steady state in target tissues relevant for PJI treatment following continuous and intermittent short-term infusion. (2) Methods: 16 pigs were randomized to receive either continuous or intermittent short-term infusion of piperacillin. Steady state piperacillin concentrations were assessed using microdialysis in tibial cortical bone, tibial cancellous bone, synovial fluid of the knee joint, and subcutaneous tissue. MIC-targets of 4, 8, 16, and 64 mg/L were applied. Plasma samples were obtained as reference. (3) Results: Continuous infusion resulted in longer fT > MIC for MIC targets of 4 mg/L and 8 mg/L compared to intermittent short-term infusion in all compartments with the exception of tibial cortical bone. For the MIC-target of 16 mg/L, continuous infusion resulted in a longer fT > MIC in all compartments except for the bone compartments. No differences between groups were seen when applying a MIC-target of 64 mg/L. (4) Conclusions: An aggressive dosing strategy may be necessary to obtain sufficient piperacillin concentrations in all bone compartments, particularly if more aggressive targets are applied. Based on the present study, continuous infusion should be considered in the treatment of PJI.

Steady-State Piperacillin Concentrations in the Proximity of an Orthopedic Implant: A Microdialysis Porcine Study.

Implant-associated osteomyelitis is one of the most feared complications following orthopedic surgery. Although the risk is low, sufficient antibiotic protection of the implant surface is important. The aim of this study was to assess steady-state piperacillin concentrations in the proximity of an orthopedic implant. Time above the minimal inhibitory concentration (fT>MIC) was evaluated for MIC of 8 (low target) and 16 µg/mL (high target). Six female pigs received an intravenous bolus infusion of 4 g/0.5 g piperacillin/tazobactam over 30 min every 6 h. Steady state was assumed achieved in the third dosing interval (12-18 h). Microdialysis catheters were placed in a cannulated screw in the proximal tibial cancellous bone, in cancellous bone next to the screw, and in cancellous bone on the contralateral tibia. Dialysates were collected from time 12 to 18 h and plasma samples were collected as reference. For the low piperacillin target (8 µg/mL), comparable mean fT>MIC across all the investigated compartments (mean range: 54-74%) was found. For the high target (16 µg/mL), fT>MIC was shorter inside the cannulated screw (mean: 16%) than in the cancellous bone next to the screw and plasma (mean range: 49-54%), and similar between the two cancellous bone compartments. To reach more aggressive piperacillin fT>MIC targets in relation to the implant, alternative dosing regimens such as continuous infusion may be considered.

Design of a pragmatic randomized controlled trial of home-based human papillomavirus (HPV) self-sampling for increasing cervical cancer screening uptake in a U.S. healthcare system: The STEP trial.

BACKGROUND: Mailing HPV self-sampling kits to overdue individuals increases cervical cancer screening adherence; offering self-sampling to previously adherent individuals has not been evaluated in the U.S. Given heterogeneity of the U.S. health system and population, data are needed to optimize how HPV self-sampling is offered to individuals who are overdue, due after successful past screening, or have an unknown screening history. METHODS: STEP is a pragmatic randomized controlled trial set within a U.S. integrated healthcare delivery system, designed to compare different outreach approaches for offering HPV self-sampling in populations defined by prior screening behavior (previously-adherent, overdue, or unknown screening history). Over 14 months, eligible individuals were identified through electronic medical record (EMR) data and randomized to Usual Care (UC), Education (UC + educational materials about cervical cancer screening), Direct-Mail (UC + Education + a mailed self-sampling kit) or Opt-In (UC + Education + option to request a kit), depending on screening history. The primary objective is to compare screening completion by outreach approach and screening history. Secondary objectives include evaluating incremental cost-effectiveness of outreach approaches, and identifying patient preference for, and satisfaction with, HPV self-screening, and barriers to abnormal results follow-up (measured through interviews and focus groups). CONCLUSIONS: The trial was designed to generate data that U.S. health systems can use to inform primary HPV screening implementation strategies that incorporate HPV self-sampling options to improve screening access, adherence, and patient satisfaction. The objective of this report is to describe the rationale and design of this pragmatic trial.

Intermittent Short-Term Infusion vs. Continuous Infusion of Piperacillin: Steady State Concentrations in Porcine Cervical Spine Tissue Evaluated by Microdialysis.

Background: Piperacillin is a central drug in the treatment of Pseudomonas aeruginosa spondylodiscitis. Intermittent short-term infusion (STI) remains standard treatment in most centres, although the application of continuous infusion (CI) has shown promising results in other clinical settings. We aimed to evaluate time above the minimal inhibitory concentration (fT > MIC) of the free fraction of piperacillin in steady state conditions in porcine cervical spine tissue following CI and STI using microdialysis with MIC targets of 4, 8, and 16 µg/mL. Methods: 16 female pigs were randomized to receive piperacillin/tazobactam as STI (4/0.5 g every 6 h) or CI (4/0.5 g as a bolus followed by 12/1.5 g) for 18 h. Microdialysis catheters were placed for sampling of piperacillin concentrations from the intervertebral disc, vertebral cancellous bone, paravertebral muscle, and adjacent subcutaneous tissue during the third dosing interval (12−18 h). Blood samples were collected as reference. Results: CI resulted in fT > MIC > 82% across all compartments and targets, except for intervertebral disc (37%) and vertebral cancellous bone (28%) at MIC = 16 µg/mL. In Group STI, >72% fT > MIC was reached for MIC = 4 µg/mL in all investigated compartments, while for MIC = 16 µg/mL only subcutaneous tissue exhibited fT > MIC > 50%. Conclusion: CI of piperacillin resulted in higher fT > MIC compared to STI infusion across the investigated tissues and targets. CI should therefore be considered in spondylodiscitis cases requiring piperacillin treatment.

Steady-state concentrations of flucloxacillin in porcine vertebral cancellous bone and intervertebral disc following oral and intravenous administration assessed by microdialysis.

AIMS: Flucloxacillin is a frequently used antibiotic in the treatment of spondylodiscitis. We assessed steady-state concentrations and time above minimal inhibitory concentration (fT > MIC) of flucloxacillin in the intervertebral disc, vertebral cancellous bone, subcutaneous tissue and plasma, after intravenous and oral administration. METHODS: Sixteen pigs were randomized into two groups; Group Peroral (Group PO) and Group Intravenous (Group IV) received 1 g flucloxacillin every 6 h for 24 h orally or intravenously. Microdialysis was used for sampling in the compartments of interest. A flucloxacillin target of 50% fT > MIC was applied for three MIC targets: 0.125, 0.5 and 2.0 µg/mL. RESULTS: Intravenous administration resulted in significantly longer fT > MIC for all targets. Target attainment was only reached for the low target of 0.125 µg/mL in Group IV in vertebral cancellous bone, subcutaneous tissue, and plasma (intervertebral disc 47%). In Group IV, mean fT > MIC values in the investigated compartments were in the range of 47-67% of the dosing interval for 0.125 µg/mL, 20-35% for 0.5 µg/mL, and 0-15% for 2.0 µg/mL. In Group PO, mean fT > MIC values for 0.125 µg/mL were in the range of 1-33%. No pigs reached a concentration of 0.5 µg/mL in any of the investigated compartments in Group PO. CONCLUSION: Administration of 1 g flucloxacillin every 6 h resulted in surprisingly low steady-state fT > MIC after intravenous and oral administration. However, intravenous administration resulted in significantly higher concentrations across compartments compared to oral administration. Sufficient target tissue concentrations for treatment of spondylodiscitis may require a dose increase or alternative dosing regimens.

Population Pharmacokinetics of Flucloxacillin In Bone and Soft Tissue- Standard Dosing is Not Sufficient to Achieve Therapeutic Concentrations.

PURPOSE: Flucloxacillin is a ß-lactam penicillin commonly used in the treatment of bone and soft tissue infections. In a recent porcine study, we found surprisingly low time for which the free concentration was maintained above the minimal inhibitory concentration (fT>MIC) in bone and soft tissue, following flucloxacillin oral (PO) and intravenous (IV) administration at 1g every 6h (q6h). In addition to plasma, sampling was obtained from subcutaneous tissue, knee joint, cancellous bone and cortical bone, using microdialysis. To identify flucloxacillin dosing regimens that result in theoretically therapeutic concentrations, we developed a population pharmacokinetic (PK) model for the porcine data, and combined it with a human flucloxacillin population PK model for simulations. METHODS: A four-compartment model was developed, and various dosing regimens and modes of administration were simulated. Predicted concentrations were compared to %fT>MIC (0.5 mg/L and 2 mg/L). RESULTS: Continuous infusion (CI) resulted in higher %fT>MIC compared to intermittent administration. For intermittent IV dosing (4, 8 and 12g/24h), fT>MIC (0.5 mg/L) was ≥70% in plasma, and ranged between 42-96% in the sampled tissue in a typical individual. By applying CI, 4g/day was sufficient to achieve ≥98% fT>MIC (0.5 mg/L) in all sampled tissues. For MIC 2 mg/L, ≥50% fT>MIC was only achieved in plasma at CI 8 and 12g/24h and IV 3g q6h. CONCLUSIONS: To reach efficacious flucloxacillin bone and tissue concentrations, dose increment or continuous infusion needs to be considered.

Flucloxacillin bone and soft tissue concentrations assessed by microdialysis in pigs after intravenous and oral administration.

AIMS: Flucloxacillin is commonly administered intravenously for perioperative antimicrobial prophylaxis, while oral administration is typical for prophylaxis following smaller traumatic wounds. We assessed the time, for which the free flucloxacillin concentration was maintained above the minimum inhibitory concentration (fT > MIC) for methicillin-susceptible Staphylococcus aureus in soft and bone tissue, after intravenous and oral administration, using microdialysis in a porcine model. METHODS: A total of 16 pigs were randomly allocated to either intravenous (Group IV) or oral (Group PO) flucloxacillin 1 g every six hours during a 24-hour period. Microdialysis was used for sampling in cancellous and cortical bone, subcutaneous tissue, and the knee joint. In addition, plasma was sampled. The flucloxacillin fT > MIC was evaluated using a low MIC target (0.5 µg/ml) and a high MIC target (2.0 µg/ml). RESULTS: Intravenous administration resulted in longer fT > MIC (0.5 µg/ml) compared to oral administration, except for cortical bone. In Group IV, all pigs reached a concentration of 0.5 µg/ml in all compartments. The mean fT > MIC (0.5 µg/ml) was 149 minutes (95% confidence interval (CI) 119 to 179; range 68 to 323) in subcutaneous tissue and 61 minutes (95% CI 29 to 94; range 0 to 121) to 106 minutes (95% CI 76 to 136; range 71 to 154) in bone tissue. In Group PO, 0/8 pigs reached a concentration of 0.5 µg/ml in all compartments. For the high MIC target (2.0 µg/ml), fT > MIC was close to zero minutes in both groups across compartments. CONCLUSION: Although intravenous administration of flucloxacillin 1 g provided higher fT > MIC for the low MIC target compared to oral administration, concentrations were surprisingly low, particularly for bone tissue. Achievement of sufficient bone and soft tissue flucloxacillin concentrations may require a dose increase or continuous administration. Cite this article: Bone Joint Res 2021;10(1):60-67.

Timing of Antimicrobial Prophylaxis and Tourniquet Inflation: A Randomized Controlled Microdialysis Study.

BACKGROUND: Tourniquets are widely used during extremity surgery. In order to prevent surgical site infection, correct timing of antimicrobial prophylaxis and tourniquet inflation is important. We aimed to evaluate the time for which the free drug concentration of cefuroxime is maintained above the minimum inhibitory concentration (t > MIC) in porcine subcutaneous adipose tissue and calcaneal cancellous bone during 3 clinically relevant tourniquet application scenarios. METHODS: Twenty-four female Danish Landrace pigs were included. Microdialysis catheters were placed bilaterally for sampling of cefuroxime concentrations in calcaneal cancellous bone and subcutaneous adipose tissue, and a tourniquet was applied to a randomly picked leg of each pig. Subsequently, the pigs were randomized into 3 groups to receive 1.5 g of cefuroxime by intravenous injection 15 minutes prior to tourniquet inflation (Group A), 45 minutes prior to tourniquet inflation (Group B), and at the time of tourniquet release (Group C). The tourniquet duration was 90 minutes in all groups. Dialysates and venous blood samples were collected for 8 hours after cefuroxime administration. Cefuroxime and various ischemic marker concentrations were quantified. RESULTS: Cefuroxime concentrations were maintained above the clinical breakpoint MIC for Staphylococcus aureus (4 µg/mL) in calcaneal cancellous bone and subcutaneous adipose tissue throughout the 90-minute tourniquet duration in Groups A and B. Cefuroxime administration at the time of tourniquet release (Group C) resulted in concentrations of >4 µg/mL for approximately of 3.5 hours in the tissues on the tourniquet side. Furthermore, tourniquet application induced ischemia (increased lactate:pyruvate ratio) and cell damage (increased glycerol) in subcutaneous adipose tissue and calcaneal cancellous bone. Tissue ischemia was sustained for 2.5 hours after tourniquet release in calcaneal cancellous bone. CONCLUSIONS: Administration of cefuroxime (1.5 g) in the 15 to 45-minute window prior to tourniquet inflation resulted in sufficient concentrations in calcaneal cancellous bone and subcutaneous adipose tissue throughout the 90-minute tourniquet application. Furthermore, tourniquet-induced tissue ischemia fully resolved 2.5 hours after tourniquet release. CLINICAL RELEVANCE: Cefuroxime administration 15 to 45 minutes prior to tourniquet inflation seems to be a safe window. If the goal is to maintain postoperative cefuroxime concentrations above relevant MIC values, our results suggest that a second dose of cefuroxime should be administered at the time of tourniquet release.

Salting Out-Assisted Liquid-Liquid Extraction for Liquid Chromatography-Tandem Mass Spectrometry Measurement of Tacrolimus, Sirolimus, Everolimus, and Cyclosporine a in Whole Blood.

BACKGROUND: Therapeutic drug monitoring of the immunosuppressants tacrolimus, sirolimus, everolimus, and cyclosporine A is effectively performed by analyzing whole-blood samples using liquid chromatography coupled with tandem mass spectrometry. Samples are usually prepared using simple protein precipitation (PPT) with methanol and zinc sulfate (ZnSO4). Significant sample dilution is necessary to obtain clean extracts but may increase the limit of quantification of the method. Salting out-assisted liquid-liquid extraction (SALLE) was explored as a novel sample preparation method for measuring these drugs in blood. METHOD: SALLE, which simply consists of LLE with a water-miscible solvent where phase separation is achieved by adding salt, was used to analyze treated blood samples. RESULTS: SALLE allowed direct injection of a 5-µL extract from the upper solvent phase into a reversed phase LC column, which would not be feasible using standard LLE. Compared with PPT, SALLE provided better extraction efficiencies and more ion enhancement, resulting in limit of quantification of 0.4, 1.4, 0.06, and 0.4 ng/mL for tacrolimus, sirolimus, everolimus, and cyclosporine A, respectively. Full-method validation was performed, including a comparison of results with those of another laboratory. A ≤10% bias was observed for tacrolimus and cyclosporine A, whereas further investigation of that for sirolimus (-12%) and everolimus (-18%) revealed that it was caused by the different calibrators used. CONCLUSIONS: This is the first report of the use of SALLE for the measurement of tacrolimus, sirolimus, everolimus, and cyclosporine A in whole blood. The advantages of SALLE over PPT and conventional LLE would make it an attractive sample preparation method for clinical laboratories.

Population Pharmacokinetics of Piperacillin following Continuous Infusion in Critically Ill Patients and Impact of Renal Function on Target Attainment.

Pharmacokinetic changes are often seen in patients with severe infections. Administration by continuous infusion has been suggested to optimize antibiotic exposure and pharmacokinetic/pharmacodynamic (PK/PD) target attainment for ß-lactams. In an observational study, unbound piperacillin concentrations (n = 196) were assessed in 78 critically ill patients following continuous infusion of piperacillin-tazobactam (ratio 8:1). The initial dose of 8, 12, or 16 g (piperacillin component) was determined by individual creatinine clearance (CRCL). Piperacillin concentrations were compared to the EUCAST clinical breakpoint MIC for Pseudomonas aeruginosa (16 mg/liter), and the following PK/PD targets were evaluated: 100% free time (fT) > 1× MIC and 100% fT > 4× MIC. A population pharmacokinetic model was developed using NONMEM 7.4.3 consisting of a one-compartment disposition model with linear elimination separated into nonrenal and renal (linearly increasing with patient CRCL) clearances. Target attainment was predicted and visualized for all individuals based on the utilized CRCL dosing algorithm. The target of 100% fT > 1× MIC was achieved for all patients based on the administered dose, but few patients achieved the target of 100% fT > 4× MIC. Probability of target attainment for a simulated cohort of patients showed that increasing the daily dose by 4-g increments (piperacillin component) did not result in substantially improved target attainment for the 100% fT > 4× MIC target. To conclude, in patients with high CRCL combined with high-MIC bacterial infections, even a continuous infusion (CI) regimen with a daily dose of 24 g may be insufficient to achieve therapeutic concentrations.

Pharmacokinetics of double-dose cefuroxime in porcine intervertebral disc and vertebral cancellous bone-a randomized microdialysis study.

BACKGROUND CONTEXT: Postoperative pyogenic spondylodiscitis is associated with prolonged antimicrobial therapy and high relapse rates. Cefuroxime is a time-dependent antimicrobial widely used for intravenous perioperative prophylaxis in spine surgery. A previous study has indicated that a single dose of cefuroxime (1.5 g) provides insufficient spine tissue concentrations for spine procedures lasting more than 2 to 3 hours. PURPOSE: To evaluate the time with concentrations above relevant minimal inhibitory concentrations (T>MIC) in plasma, subcutaneous adipose tissue, vertebral cancellous bone, and intervertebral disc after a twofold increase of the standard dosage of 1.5 g cefuroxime given as one double dose (1×3 g) or two single doses (2×1.5 g) with a four-hour interval. METHODS: Sixteen pigs were randomized into two groups: Group 1 received one double dose of cefuroxime (1×3 g) as an intravenous bolus and Group 2 received two single doses of cefuroxime (2×1.5 g) as an intravenous bolus with a four-hour interval. Cefuroxime measurements were obtained from plasma, subcutaneous adipose tissue, vertebral cancellous bone, and intervertebral disc for eight hours thereafter. Microdialysis was applied for sampling in solid tissues. The cefuroxime concentrations were determined using ultra-high performance liquid chromatography. This work was supported by grants from the Health Research Foundation of Central Denmark Region (Level E). The funding source did not play any role in the investigation. RESULTS: The time with concentrations above the Staphylococcus aureus clinical breakpoint minimal inhibitory concentration of 4 µg/mL was higher in all compartments for Group 2 compared to Group 1. The mean T>MIC (4 µg/mL) in all compartments ranged between 47% and 67% for Group 1 and 72% and 92% for Group 2. Furthermore, a delayed tissue penetration into all tissues for both groups was demonstrated. CONCLUSIONS: This study suggests that cefuroxime should be given at least 45 minutes prior to spine procedures and as two single doses at a maximum interval of four hours for extended spine procedures. Clinical studies verifying these results are warranted. CLINICAL SIGNIFICANCE: Administering cefuroxime as two single doses (2×1.5 g) with a four-hour interval compared to one double dose (1×3 g) resulted in higher T>MIC. Furthermore, we found delayed and incomplete cefuroxime tissue penetration.

Population pharmacokinetics of piperacillin in plasma and subcutaneous tissue in patients on continuous renal replacement therapy.

OBJECTIVES: Piperacillin is a ß-lactam antimicrobial frequently used in critically ill patients with acute kidney injury treated with continuous renal replacement therapy (CRRT). However, data regarding piperacillin tissue concentrations in this patient population are limited. A prospective observational study was conducted of free piperacillin concentrations during a single 8-h dosing interval in plasma (8 samples) and subcutaneous tissue (SCT) (13 samples), in 10 patients treated with CRRT following piperacillin 4 g given every 8 h as intermittent administration over 3 min. METHODS: A population pharmacokinetic model was developed using NONMEM 7.4.3, to simulate alternative administration modes and dosing regimens. SCT concentrations were obtained using microdialysis. Piperacillin concentrations were compared to the clinical breakpoint minimum inhibitory concentration (MIC) for Pseudomonas aeruginosa (16 mg/l), with evaluation of the following pharmacokinetic/pharmacodynamics targets: 50% fT > 1 × MIC, 100% fT > 1 × MIC, and 100% fT > 4 × MIC. RESULTS: SCT concentrations were generally lower than plasma concentrations. For the target of 50% free time (fT) > 1 × MIC and 100% fT > 1 × MIC, piperacillin 4 g every 8 h resulted in probability of target attainment (PTA) >90% in both plasma and SCT. PTA > 90% for the target of 100% fT > 4 × MIC was only achieved for continuous infusion. CONCLUSIONS: Piperacillin 4 g every 8 h is likely to provide sufficient exposure in both plasma and SCT to treat P.aeruginosa infections in critically ill patients on CRRT, given that targets of 50% fT > 1 × MIC or 100% fT > 1 × MIC are adequate. However, if a more aggressive target of 100% fT > 4 × MIC is adopted, continuous infusion is needed.

Simultaneous Retrodialysis by Drug for Cefuroxime Using Meropenem as an Internal Standard-A Microdialysis Validation Study.

Microdialysis is a valuable pharmacokinetic tool for obtaining samples of drug concentrations from tissues of interest. When an absolute tissue concentration is needed, a calibration of the microdialysis catheter is required. The use of an internal standard offers a number of advantages compared to standard calibration methods. However, meticulous validation both in vitro and in vivo is needed, as this method requires an internal standard with physiochemical similarities to the analyte of interest with no interference. A series of in vitro and in vivo setups were conducted to determine the relative recovery by gain and by loss for cefuroxime, with and without a constant meropenem concentration. The cefuroxime and meropenem concentrations were determined using ultra-HPLC. The main finding was that cefuroxime and meropenem relative recovery behaved similarly both in vitro and in vivo, signifying that meropenem is a representative internal standard for cefuroxime. Furthermore, cefuroxime relative recovery in vitro was not affected by either the cefuroxime concentration or the presence of meropenem, and the in vivo meropenem relative recovery was constant over 6 h.

Intubation rate, duration of noninvasive ventilation and mortality after noninvasive neurally adjusted ventilatory assist (NIV-NAVA).

BACKGROUND: Asynchrony is a common problem in patients treated with noninvasive ventilation (NIV). Neurally adjusted ventilatory assist (NAVA) has shown to improve patient-ventilator interaction. However, it is unknown whether NIV-NAVA improves outcomes compared to noninvasive pressure support (NIV-PS). METHODS: This observational cohort study included patients 18 years or older receiving noninvasive ventilation using an oro-nasal face mask for more than 2 hours in a Danish ICU. The study included a NIV-NAVA cohort (year 2013-2015) and two comparison cohorts: (a) a historical NIV-PS cohort (year 2011-2012) before the implementation of NIV-NAVA at the ICU in 2013, and (b) a concurrent NIV-PS cohort (year 2013-2015). Outcomes of NIV-NAVA (intubation rate, duration of NIV and 90-day mortality) were assessed and compared using multivariable linear and logistic regression adjusted for relevant confounders. RESULTS: The study included 427 patients (91 in the NIV-NAVA, 134 in the historic NIV-PS and 202 in the concurrent NIV-PS cohort). Patients treated with NIV-NAVA did not have improved outcome after adjustment for measured confounders. Actually, there were statistically imprecise higher odds for intubation in NIV-NAVA patients compared with both the historical [OR 1.48, CI (0.74-2.97)] and the concurrent NIV-PS cohort [OR 1.67, CI (0.87-3.19)]. NIV-NAVA might also have a longer length of NIV [63%, CI (19%-125%)] and [139%, CI (80%-213%)], and might have a higher 90-day mortality [OR 1.24, CI (0.69-2.25)] and [OR 1.39, CI (0.81-2.39)]. Residual confounding cannot be excluded. CONCLUSION: This present study found no improved clinical outcomes in patients treated with NIV-NAVA compared to NIV-PS.

Taking leave to bleed: Perceptions and attitudes toward menstrual leave policy.

Menstrual leave is offered in some countries and companies; however, there is a lack of research examining perceptions or effects of the policy. We examined the U.S. public's (N = 600) perceptions of a potential menstrual leave policy. Participants were asked open-ended questions about potential effects of menstrual leave in the U.S. Using thematic analysis, five themes emerged: (a) Supporting women and women in the workplace. (b) What do men get? (c) Concerns about the effects on the workplace. (d) Just deal with it [menstruation]. (e) This policy would make women look bad. These findings are important for policy makers to consider.

Practice-based evidence can help! Using the Group Questionnaire to enhance clinical practice.

Practice-based evidence (Burlingame & Beecher, 2008) is an approach to evidence-based practice that addresses treatment efficacy to remediate clinicians' inability to predict treatment response (Chapman et al., 2012; Hannan et al., 2005). The Group Questionnaire (GQ; Bormann, Burlingame, & Straub, 2011; Johnson, Burlingame, Olsen, Davies, & Gleave, 2005) is one practice-based evidence measure that supports clinical judgment to enhance psychotherapy outcomes by measuring 3 important group constructs: Positive Bond, Positive Work, and Negative Relationship. A clinical example of how one group leader used GQ data provided by group members regarding their weekly group experiences to support her interventions in a process-oriented therapy group for adults includes verbatim clinical exchanges among group members and the leader. The example also includes a GQ report with explanations of the group members' scores and numerical and graphical data. The authors detail how the leader used the data from the measure to promote curiosity about group cohesion and movement toward treatment goals, to reframe perceptions of group interaction, and to gauge outcomes of shared group experience. The group leader's examination of the GQ data outside the group allowed her to use this information for positive impact inside the group to guide interventions and explore content and process, warranting additional attention. The authors encourage curiosity about other interactions among other group members reflected in the GQ report and how this information could be used to positively impact the group in other ways. (PsycINFO Database Record

Population Pharmacokinetics of Piperacillin in Sepsis Patients: Should Alternative Dosing Strategies Be Considered?

Sufficient antibiotic dosing in septic patients is essential for reducing mortality. Piperacillin-tazobactam is often used for empirical treatment, but due to the pharmacokinetic (PK) variability seen in septic patients, optimal dosing may be a challenge. We determined the PK profile for piperacillin given at 4 g every 8 h in 22 septic patients admitted to a medical ward. Piperacillin concentrations were compared to the clinical breakpoint MIC for Pseudomonas aeruginosa (16 mg/liter), and the following PK/pharmacodynamic (PD) targets were evaluated: the percentage of the dosing interval that the free drug concentration is maintained above the MIC (fTMIC) of 50% and 100%. A two-compartment population PK model described the data well, with clearance being divided into renal and nonrenal components. The renal component was proportional to the estimated creatinine clearance (eCLCR) and constituted 74% of the total clearance in a typical individual (eCLCR, 83.9 ml/min). Patients with a high eCLCR (>130 ml/min) were at risk of subtherapeutic concentrations for the current regimen, with a 90% probability of target attainment being reached at MICs of 2.0 (50% fTMIC) and 0.125 mg/liter (100% fTMIC). Simulations of alternative dosing regimens and modes of administration showed that dose increment and prolonged infusion increased the chance of achieving predefined PK/PD targets. Alternative dosing strategies may therefore be needed to optimize piperacillin exposure in septic patients. (This study has been registered at ClinicalTrials.gov under identifier NCT02569086.).