Monte Carlo simulations of cefepime in children receiving continuous kidney replacement therapy support continuous infusions for target attainment.

BACKGROUND: Sepsis is a leading cause of acute kidney injury requiring continuous kidney replacement therapy (CKRT) and CKRT can alter drug pharmacokinetics (PK). Cefepime is used commonly in critically ill children and is cleared by CKRT, yet data regarding cefepime PK and pharmacodynamic (PD) target attainment in children receiving CKRT are scarce, so we performed Monte Carlo simulations (MCS) of cefepime dosing strategies in children receiving CKRT. METHODS: We developed a CKRT "module" in the precision dosing software Edsim++. The module was added into a pediatric cefepime PK model. 1000-fold MCS were performed using six dosing strategies in patients aged 2-25 years and ≥ 10 kg with differing residual kidney function (estimated glomerular filtration rate of 5 vs 30 mL/min/1.73 m2), CKRT prescriptions, (standard-dose total effluent flow of 2500 mL/h/1.73 m2 vs high-dose of 8000 mL/h/1.73 m2), and fluid accumulation (0-30%). Probability of target attainment (PTA) was defined by percentage of patients with free concentrations exceeding bacterial minimum inhibitory concentration (MIC) for 100% of the dosing interval (100% fT > 1xMIC) and 4xMIC using an MIC of 8 mg/L for Pseudomonas aeruginosa. RESULTS: Assuming standard-dose dialysis and minimal kidney function, > 90% PTA was achieved for 100% fT > 1x MIC with continuous infusions (CI) of 100-150 mg/kg/day (max 4/6 g) and 4-h infusions of 50 mg/kg (max 2 g), but > 90% PTA for 100% fT > 4x MIC was only achieved by 150 mg/kg CI. Decreased PTA was seen with less frequent dosing, shorter infusions, higher-dose CKRT, and higher residual kidney function. CONCLUSIONS: Our new CKRT-module was successfully added to an existing cefepime PK model for MCS in young patients on CKRT. When targeting 100% fT > 4xMIC or using higher-dose CKRT, CI would allow for higher PTA than intermittent dosing.

Cystatin C Outperforms Creatinine in Predicting Cefepime Clearance in Pediatric Stem Cell Transplant Recipients.

Pediatric hematopoietic stem cell transplant (HSCT) patients are at risk of developing both sepsis and altered kidney function. Cefepime is used for empiric coverage post-HSCT and requires dose adjustment based on kidney function. Since cefepime's antimicrobial efficacy is determined by the time free concentrations exceed bacterial minimum inhibitory concentration (MIC), it is important to assess kidney function accurately to ensure adequate concentrations. Serum creatinine (SCr) is routinely used to estimate glomerular filtration rate (eGFR) but varies with muscle mass, which can be significantly lower in HSCT patients, making SCr an inaccurate kidney function biomarker. Cystatin C (CysC) eGFR is independent of muscle mass, though steroid use increases CysC. Objectives of this study were to describe how eGFR impacts cefepime pharmacokinetic/pharmacodynamic (PK/PD) target attainment in pediatric HSCT patients, to investigate which method of estimating GFR (SCr, CysC, combined) best predicts cefepime clearance, and to explore additional predictors of cefepime clearance. Patients admitted to the pediatric HSCT unit who received ≥2 cefepime doses were prospectively enrolled. We measured total cefepime peak/trough concentrations between the second and fourth cefepime doses and measured SCr and CysC if not already obtained clinically within 24h of cefepime samples. eGFRs were calculated with Chronic Kidney Disease in Children U25 equations. Bayesian estimates of cefepime clearance were determined with a pediatric cefepime PK model and PK software MwPharm++. Simple linear regression was used to compare cefepime clearance normalized to body surface area (BSA) to BSA-normalized SCr-, CysC-, and SCr-/CysC-eGFRs, while multiple linear regression was used to account for additional predictors of cefepime clearance. For target attainment, we assessed the percentage of time free cefepime concentrations exceeded 1x MIC (%fT>1x MIC) and 4x MIC (%fT>4x MIC) using a susceptibility breakpoint of 8 mg/L for Pseudomonas aeruginosa. We enrolled 53 patients (ages 1 to 30 years, median 8.9 years). SCr- and CysC-eGFRs were lower in patients who attained 100% fT>1xMIC compared to those who did not attain this target: 115 versus 156 mL/min/1.73m2 (p = .01) for SCr-eGFR and 73.5 versus 107 mL/min/1.73m2 (p < .001) for CysC-eGFR. SCr-eGFR was weakly positively correlated with cefepime clearance (adjusted [a]r2= 0.14), while CysC-eGFR and SCr-/CysC-eGFR had stronger positive correlations (ar2 = 0.30 CysC, ar2 = 0.28 combo. There was a weak, significant linear association between increasing CysC-eGFR and decreased %fT>1xMIC (ar2 = 0.32) and %fT>4xMIC (ar2 = 0.14). No patients with a CysC-eGFR >120 mL/min/1.73 m2 achieved 100% fT>1xMIC or 50% fT>4x MIC. In multiple regression models, underlying diagnosis of hemoglobinopathy (in all models) and being pretransplant (in SCr and combined models) were associated with increased cefepime clearance, while concomitant use of calcineurin inhibitors was associated with decreased cefepime clearance in all models. Overall, the combo-eGFR model with timing pretransplant, hemoglobinopathy, and use of calcineurin inhibitors had the best performance (ar2 = 0.63). CysC-based eGFRs (CysC alone and combined) predicted cefepime clearance better than SCr-eGFR, even after considering steroid use. Increasing CysC eGFR correlated with decreased probability of PD target attainment, raising concerns for underdosing at high eGFRs. CysC should be included when estimating kidney function to provide adequate dosing of cefepime in pediatric HSCT patients.

Perceived Candidacy for Pre-exposure Prophylaxis (PrEP) Among Men Who Have Sex with Men in Paris, France.

Low perception of HIV risk is a challenge to PrEP implementation. We analyzed associations between perceptions of PrEP candidacy, behavioral indications for PrEP, and sexual behaviors. We recruited a sample of 580 MSM from a geosocial-networking smartphone application in Paris, France. A modified Poisson regression model was conducted to examine associations between perceived candidacy for PrEP and behavioral indications for PrEP, and relationships among engagement in group sex, transactional sex, HIV test history, and indications for PrEP. Adjusted risk ratios (aRR) and 95% confidence intervals (CIs) were calculated. For the outcome of perceived candidacy for PrEP, a multinomial logistic regression was performed, and adjusted relative risk ratios (aRRR) were calculated. Multivariate analyses were adjusted for socio-demographics. Respondents who considered themselves PrEP candidates were more likely to meet PrEP eligibility criteria compared to those who did not consider themselves candidates (aRR 1.65; 95% CI 1.34-2.03). Those who had engaged in group or transactional sex were more likely to have behavioral indications for PrEP (aRR 1.27; 95% CI 1.07-1.50, aRR 1.32; 95% CI 1.13-1.56, respectively), whereas HIV test history was not significantly associated with behavioral indications for PrEP. Respondents who had engaged in group sex or transactional sex were more likely to perceive themselves as candidates for PrEP (aRRR 2.24; 95% CI 1.21-4.16, aRRR 2.58; 95% CI 1.09-6.13, respectively), although those never tested for HIV were less likely to perceive themselves as candidates for PrEP (aRRR 0.18; 95% CI 0.03-0.91). The elucidation of candidacy perceptions and risk behaviors is key to furthering the effective implementation of PrEP engagement interventions.

Factors Predicting Parent Anxiety Around Infant and Toddler Postoperative and Pain.

BACKGROUND AND OBJECTIVES: Understanding of parent anxiety and its effect on infant postoperative pain is limited. We sought to identify psychological factors associated with preoperative anxiety for parents of infants and toddlers undergoing elective surgery and to determine whether parent anxiety is associated with child postoperative pain. METHODS: This was a prospective cohort study of consecutively eligible patients aged ≤18 months undergoing craniofacial surgery and their parents. Preoperative parent assessment included anxiety, coping, parent health locus of control, and self-efficacy. Postoperative inpatient child pain scores and medication use were collected. Analyses included hierarchical multivariable logistic and linear regression models. RESULTS: Parents (n = 71, 90% female) of young children (mean age 6.6 months) undergoing cleft lip or palate (n = 59) or cranial vault repair (n = 13) were enrolled. Maladaptive coping (odds ratio 1.3; 95% confidence interval, 1.1-1.6), low parent self-efficacy (odds ratio 2.4; 95% confidence interval, 1.3-4.5), and external locus of control (odds ratio 1.74; 95% confidence interval, 1.1-2.9) were independently associated with high parental anxiety. The adjusted odds of moderate/severe parent anxiety was 3.6 (95% confidence interval, 1.5-9.1) higher with each SD increase in maladaptive coping. High parental anxiety was correlated with significantly higher hospital mean child pain scores (1.87 points on 0-10 scale; 95% confidence interval, 0.42-3.70; P = .045). CONCLUSIONS: Coping and self-efficacy are modifiable factors that contribute to parent anxiety before and during hospitalization and may be targets for intervention. Infants and toddlers undergoing elective craniofacial surgery with highly anxious parents may be at greater risk for higher postoperative pain.

A Systematic Review of the Use of Telemedicine in Plastic and Reconstructive Surgery and Dermatology.

BACKGROUND: Telemedicine, the use of information technology and telecommunication to provide healthcare at a distance, is a burgeoning field with applications throughout medicine. Given the visual nature of plastic surgery and dermatology, telemedicine has a myriad of potential applications within the field. METHODS: A comprehensive literature review of articles published on telemedicine since January 2010 was performed. Articles were selected for their relevance to plastic and reconstructive surgery and dermatology, and then reviewed for their discussion of the applications, benefits, and limitations of telemedicine in practice. RESULTS: A total of 3119 articles were identified in the initial query. Twenty-three articles met the inclusion criteria in plastic surgery (7 wound management, 5 burn management, 5 trauma, 4 free flap care, 2 in cleft lip/palate repair). Twenty-three (100%) reported a benefit of telemedicine often related to improved postoperative monitoring, increased access to expertise in rural settings, and cost savings, either predicted or actualized. Eight (35%) reported limitations and barriers to the application of telemedicine, including overdiagnosis and dependence on functional telecommunication systems. Sixty-six articles focused on telemedicine in dermatology and also demonstrated significant promise. CONCLUSIONS: Telemedicine holds special promise in increasing the efficiency of postoperative care for microsurgical procedures, improving care coordination and management of burn wounds, facilitating interprofessional collaboration across time and space, eliminating a significant number of unnecessary referrals, and connecting patients located far from major medical centers with professional expertise without impinging on-and in some cases improving-the quality or accuracy of care provided. Teledermatology consultation was found to be safe and has a comparable or superior efficacy to the traditional in-patient consultation. The system was consistently rated as convenient and easy to use by patients, referring physicians, and consulting dermatologists. Teledermatology has also been used as an educational tool for patients. A significant number of studies detailed strategies to improve the current state of teledermatology, either by implementing new programs or improving technologies. Telemedicine use is widespread among plastic surgeons and is enabling the spread of expertise beyond major medical centers. Further research is needed to conclusively demonstrate benefit in routine clinical care.