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Supplemental Digital Content is available in the text., Background: Ceftobiprole, the active moiety of the prodrug ceftobiprole medocaril, is an advanced-generation, broad-spectrum, intravenous cephalosporin, which is currently approved for the treatment of adults with hospital-acquired or community-acquired pneumonia. Methods: Noncompartmental pharmacokinetics and safety were analyzed from 2 recently completed pediatric studies, a single-dose, phase 1 study in neonates and infants up to 3 months of age (7.5 mg/kg) and a phase 3 study in patients 3 months to 17 years of age with pneumonia (10–20 mg/kg with a maximum of 500 mg per dose every 8 hours for up to 14 days). Results: Total ceftobiprole plasma concentrations peaked at the end of infusion. Half life (median ranging from 1.9 to 2.9 hours) and overall exposure (median AUC ranging from 66.6 to 173 μg•h/mL) were similar to those in adults (mean ± SD, 3.3 ± 0.3 hours and 102 ± 11.9 μg•h/mL, respectively). Calculated free-ceftobiprole concentrations in the single-dose study remained above a minimum inhibitory concentration (MIC) of 4 mg/L (fT > MIC of 4 mg/L) for a mean of 5.29 hours after dosing. In the pneumonia study, mean fT > MIC of 4 mg/L was ≥5.28 hours in all dose groups. Ceftobiprole was well tolerated in both studies. Conclusions: Pharmacokinetic parameters of ceftobiprole characterized in the pediatric population were within the range of those observed in adults. In the pneumonia study, the lowest percentage of the dosing interval with fT > MIC of 4 mg/L was 50.8%, which suggests that pharmacokinetic-pharmacodynamic target attainment can be sufficient in pediatric patients. Ceftobiprole was well tolerated.

Purpose To investigate the rate of return to the operating room after vitrectomy surgery for vitreous opacities. Design Retrospective registry cohort. Participants Individuals receiving care in ophthalmology practices participating in the Intelligent Research in Sight (IRIS®) Registry. Methods Data from the IRIS Registry were analyzed for patients who underwent vitrectomy for vitreous opacities. Cases were identified by the combination of International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM), and International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM), codes (379.21, 379.22, 379.24, and 379.25), and a Current Procedural Terminology (CPT) code for vitrectomy surgery. Main Outcome Measures The number and percentage of eyes that underwent additional eye surgery within 1 year after vitrectomy for vitreous opacities were identified, as was the nature of the additional procedures per CPT code. Results Fifty thousand eight hundred thirty-six eyes that underwent vitrectomy surgery linked to one of the ICD-9-CM or ICD-10-CM codes for vitreous opacities were identified. In 17 615 eyes, the surgery was linked to the vitreous opacities code exclusively, and not to epiretinal membrane or macular hole codes. Of these, 2187 eyes (12.4%) returned to the operating room for cataract surgery, and 643 eyes (3.7%) returned to the operating room for a noncataract procedure. Four hundred fifty-seven eyes (2.6%) returned to the operating room for retinal detachment repair. Conclusions In the IRIS Registry, eyes undergoing vitrectomy for vitreous opacities returned to the operating room for an ophthalmic surgery other than cataract extraction 3.7% of the time, and retinal detachment repair was performed 2.6% of the time.

Background and Objectives Use of parenteral amikacin to treat refractory nontuberculous mycobacterial (NTM) lung disease is limited by systemic toxicity. A population pharmacokinetic model was developed using data pooled from two randomized trials to evaluate the pharmacokinetic properties of once-daily amikacin liposome inhalation suspension (ALIS) in patients with treatment-refractory NTM lung disease. Methods In phase 2 (TR02-112) and phase 3 (CONVERT) studies, patients with sputum cultures positive for Mycobacterium avium complex (both studies) or M. abscessus (TR02-112) despite ≥ 6 months of guideline-based therapy were treated with once-daily ALIS 590 mg. Results Fifty-three patients (28 Japanese; 25 White) were assessed. At baseline and ≈ 6 months after daily dosing, median maximum concentration (Cmax) was < 2 mg/L and median area under the concentration-time curve (AUC0–24) was

Cefazolin is an antibiotic frequently used for perioperative prophylaxis. Data from healthy adults and pediatric surgery patients were pooled to refine a previously developed population pharmacokinetic (PK) model and to determine the optimal body weight cutoff for selecting fixed doses of either 1 or 2 g cefazolin to produce exposures in pediatric surgery patients similar to a single 2‐g dose in adults. Regardless of dose used, cefazolin was well tolerated in pediatric patients. A total of 1102 plasma samples from 62 patients from 3 studies were available to assess the previous model. The pooled data set allowed for simplification of the model such that allometrically scaled clearance and volume parameters were found to provide a robust fit while removing unnecessary covariate relationships. Monte Carlo simulations using the final cefazolin population PK model suggested an optimal weight cutoff of 50 kg, in contrast to the previously suggested 60 kg for a single 2‐g dose. Patients at or above this 50‐kg cutoff would receive a 2‐g dose of cefazolin, and those below 50 kg but ≥25 kg would receive a 1‐g dose of cefazolin.

A luteoma is a benign ovarian mass that can have malignant characteristics on sonography. Pelvic sonography is used to help distinguish benign from malignant masses. The workup of adnexal masses during pregnancy may involve the use of both transabdominal and transvaginal sonography as well as Doppler imaging, magnetic resonance imaging, and serum tumor markers to identify the risk of malignancy. This study presents a case of a benign ovarian luteoma of pregnancy detected during sonography. The mass was removed during the first trimester due to malignant sonographic features. Counseling and treatment regarding ovarian masses should consist of a multidisciplinary team made up of physicians in maternal-fetal medicine, radiology, neonatology, and sonographers.

Ceftobiprole is an advanced-generation cephalosporin for intravenous administration with activity against Gram-positive and Gram-negative organisms. A population pharmacokinetic (PK) model characterizing the disposition of ceftobiprole in plasma using data from patients in three pediatric studies was developed. Model-based simulations were subsequently performed to assist in dose optimization for the treatment of pediatric patients with hospital-acquired or community-acquired pneumonia. The population PK data set comprised 518 ceftobiprole plasma concentrations from 107 patients from 0 (birth) to 17 years of age. Ceftobiprole PK was well described by a three-compartment model with linear elimination. Ceftobiprole clearance was modeled as a function of glomerular filtration rate; other PK parameters were scaled to body weight. The final population PK model provided a robust and reliable description of the PK of ceftobiprole in the pediatric study population. Model-based simulations using the final model suggested that a ceftobiprole dose of 15 mg/kg of body weight infused over 2 h and administered every 12 h in neonates and infants

Rezafungin is a novel antifungal agent of the echinocandin class with potent activity against species of Candida and Aspergillus, including subsets of resistant strains, and Pneumocystis jirovecii. The objective of this analysis was to develop a population pharmacokinetic (PK) model to characterize the disposition of rezafungin in plasma following intravenous (IV) administration in healthy volunteers and in patients with candidemia and/or invasive candidiasis. The population PK model was based on a previous model from phase 1 data; formal covariate analyses were conducted to identify any relationships between subject characteristics and rezafungin PK variability. A four-compartment model with linear elimination and zero-order drug input provided a robust fit to the pooled data. Several statistically significant relationships between subject descriptors (sex, infection status, serum albumin, and body surface area [BSA]) and rezafungin PK parameters were identified, but none were deemed clinically relevant. Previous dose justification analyses conducted using data from phase 1 subjects alone are expected to remain appropriate. The final model provided a precise and unbiased fit to the observed concentrations and can be used to reliably predict rezafungin PK in infected patients.

Meropenem-vaborbactam is a broad-spectrum carbapenem-beta-lactamase inhibitor combination approved in the USA and Europe to treat patients with complicated urinary tract infections and in Europe, other serious bacterial infections, including hospital- acquired and ventilator-associated pneumonia. Population pharmacokinetic (PK) models were developed to characterize the time-course of meropenem and vaborbactam using pooled data from two Phase 1 and two Phase 3 studies. Multi-compartment disposition model structures with linear elimination processes were fit to the data using NONMEM 7.2. Since both drugs are cleared primarily by the kidneys, estimated glomerular filtration rate (eGFR) was evaluated as part of the base structural models. For both agents, a two-compartment model with zero-order input and first-order elimination best described the pharmacokinetic PK data and a sigmoidal Hill-type equation best described the relationship between renal clearance and eGFR. For meropenem, the following significant covariate relationships were identified: clearance (CL) decreased with increasing age, CL was systematically different in subjects with end stage renal disease, and all PK parameters increased with increasing weight. For vaborbactam, the following significant covariate relationships were identified: CL increased with increasing height, volume of the central compartment (Vc) increased with increasing body surface area, and CL, Vc, and volume of the peripheral compartment were systematically different in Phase 1 non-infected subjects relative to Phase 3 infected patients, respectively. Visual predictive checks demonstrated minimal bias, supporting the robustness of the final models. These models were useful for generating individual PK exposures for pharmacokinetic-pharmacodynamic (PK-PD) analyses for efficacy and Monte Carlo simulations to evaluate PK-PD target attainment.

Purpose To assess the safety and efficacy of less dense panretinal photocoagulation after intravitreal bevacizumab in aggressive posterior retinopathy of prematurity infants. Methods Retrospective consecutive case series of premature infants diagnosed with aggressive posterior retinopathy of prematurity between August 2012 and November 2015 who received intravitreal bevacizumab with subsequent modified indirect diode laser panretinal photocoagulation for reactivation or incomplete vascularization. Main outcome measures included postprocedural reactivation, retinal detachments, or anterior segment ischemia. Results Sixty-one eyes of 31 premature infants were identified. The average gestational age was 24 ± 2.2 weeks (range 22-27), and the average birth weight was 661.5 ± 167.1 g (range 340.0-930.5 g). The average follow-up was 3.9 ± 1.3 years (range 1.3-5.4 years). At the last follow-up, no patient had experienced postlaser reactivation, retinal detachments, anterior segment ischemia, or other laser complications. Conclusion This study suggests that nonconfluent panretinal photocoagulation for aggressive posterior retinopathy of prematurity infants who have received intravitreal bevacizumab may be safe and effective. This study's strengths include a sizeable sample size, long-term follow-up of nearly 4 years, and consistency in treatment among patients by a single, experienced retinopathy of prematurity specialist.

Background Hydromethylthionine is a potent inhibitor of pathological aggregation of tau and TDP-43 proteins. Objective To compare hydromethylthionine treatment effects at two doses and to determine how drug exposure is related to treatment response in bvFTD. Methods We undertook a 52-week Phase III study in 220 bvFTD patients randomized to compare hydromethylthionine at 200 mg/day and 8 mg/day (intended as a control). The principal outcomes were change on the Addenbrookes Cognitive Examination - Revised (ACE-R), the Functional Activities Questionnaire (FAQ), and whole brain volume. Secondary outcomes included Modified Clinical Global Impression of Change (Modified-CGIC). A population pharmacokinetic exposure-response analysis was undertaken in 175 of the patients with available blood samples and outcome data using a discriminatory plasma assay for the parent drug. Results There were no significant differences between the two doses as randomized. There were steep concentration-response relationships for plasma levels in the range 0.3-0.6 ng/ml at the 8 mg/day dose on clinical and MRI outcomes. There were significant exposure-dependent differences at 8 mg/day for FAQ, Modified-CGIC, and whole brain atrophy comparing patients with plasma levels greater than 0.346 ng/ml with having minimal drug exposure. The exposure-response is biphasic with worse outcomes at the high concentrations produced by 200 mg/day. Conclusions Hydromethylthionine has a similar concentration-response profile for effects on clinical decline and brain atrophy at the 8 mg/day dose in bvFTD as recently reported in AD. Treatment responses in bvFTD are predicted to be maximal at doses in the range 20-60 mg/day. A confirmatory placebo-controlled trial is now planned.

Use of parenteral amikacin to treat refractory nontuberculous mycobacterial (NTM) lung disease is limited by systemic toxicity. A population pharmacokinetic model was developed using data pooled from two randomized trials to evaluate the pharmacokinetic properties of once-daily amikacin liposome inhalation suspension (ALIS) in patients with treatment-refractory NTM lung disease.In phase 2 (TR02-112) and phase 3 (CONVERT) studies, patients with sputum cultures positive for Mycobacterium avium complex (both studies) or M. abscessus (TR02-112) despite ≥ 6 months of guideline-based therapy were treated with once-daily ALIS 590 mg.Fifty-three patients (28 Japanese; 25 White) were assessed. At baseline and ≈ 6 months after daily dosing, median maximum concentration (CSystemic exposure to amikacin in serum and urine following once-daily ALIS administration in patients with treatment-refractory NTM lung disease was notably lower than that previously reported for parenteral amikacin.ClinicalTrials.gov NCT01315236 (registered March 15, 2011) and NCT02344004 (registered January 22, 2015).

Background Rezafungin is a novel echinocandin antifungal in development for treatment as well as prevention (prophylaxis) of invasive fungal infections. STRIVE (NCT02734862) is a global, randomized, double-blind, placebo-controlled, Phase 2 trial evaluating safety and efficacy of IV rezafungin once weekly (QWk) for treatment of candidemia and/or invasive candidiasis compared with standard-of-care (IV caspofungin once daily with optional oral stepdown). Here we report pharmacokinetic (PK) data from the completed STRIVE trial analyzed by patient demographics at baseline. Methods Rezafungin Day 8 trough (Cmin) concentrations from patients treated with rezafungin were summarized categorically by race (black or white), sex (male or female), and geographic region (North America [NA], or Europe [EU]), or plotted versus continuous variables of age, body weight, body mass index (BMI), and body surface area (BSA). As the first dose of rezafungin was 400 mg for all rezafungin-treated patients, data from both dose groups (Group 1: 400 mg QWk; Group 2: 400 mg in Week 1 followed by 200 mg QWk) were combined in this analysis. Results Rezafungin mean Cmin (SD) values were 1.8 (0.7) and 2.3 (1.2) in black and white patients, 1.9 (1.0) and 2.6 (1.2) in males and females, and 1.9 (0.6) and 2.4 (1.3) in patients from NA and EU. There were small differences in point estimates between the groups, but there was a great deal of overlap and the differences are not expected to be clinically meaningful (Figure). Similarly, no trends in Cmin values were observed across a range of ages (20-80 years), weights (~40-155 kg), BMI (~15-65 kg/m2), and BSA (~1.4-2.4 m2). Figure Conclusion No meaningful differences in rezafungin Cmin values were observed in patients grouped by sex, race, or geographic region, or across a wide range of patient factors, including age and body weight and size. These findings indicate that a single rezafungin dose regimen can be expected to provide consistent PK across diverse patient populations. Disclosures Shawn Flanagan, PhD, Cidara Therapeutics, Inc. (Employee, Shareholder) Christopher M. Rubino, PharMD, Institute for Clinical Pharmacodynamics, Inc. (Employee)Spero Therapeutics (Grant/Research Support) Taylor Sandison, MD, MPH, Cidara Therapeutics, Inc. (Employee, Shareholder)

Pharmacokinetics and antithrombotic effects of the Factor Xa inhibitor rivaroxaban were studied in subjects with mild renal insufficiency concurrently taking the P-glycoprotein and moderate CYP3A inhibitor verapamil, a drug commonly administered to patients with hypertension, ischemic heart disease, or atrial fibrillation. Age-matched controls with normal renal function were studied concurrently. Subjects' overall mean age was 59 years. Mean creatinine clearance values in the 2 groups were 105 and 71 mL/min. After single 20-mg oral doses, rivaroxaban area under the curve (AUC) was increased by a factor of 1.11 (ratio of geometric means [RGM]) in mild renal insufficiency compared to controls. Verapamil coadministration independently increased AUC to the same extent in both the mild renal insufficiency and control groups (RGM, 1.39 and 1.43). Concurrent mild renal insufficiency and verapamil produced additive inhibition compared to controls without verapamil (RGM, 1.58). Prothrombin time (PT) prolongation and Factor Xa inhibition tracked plasma rivaroxaban, and were enhanced by verapamil. Concentration-response relationships for PT (linear) and Factor Xa inhibition (hyperbolic) were unaffected by renal function or verapamil. The absolute and relative increases in rivaroxaban AUC caused by verapamil in mild renal insufficiency subjects are potentially associated with an increased bleeding risk. Modification of recommended dosage may be required in this combination of circumstances to reduce risk to patients.

Choroidal melanoma is the most common primary intraocular malignancy, yet metastatic disease remains the most common malignancy of the eye. Differentiating these entities is essential as treatment, systemic associations, and prognosis vary dramatically between the two. Established diagnostic criteria are accurate for the diagnosis of uveal melanoma. Yet, metastatic disease may be misdiagnosed as a uveal melanoma in rare cases. We report a case of metastatic clear-cell renal cell carcinoma masquerading as uveal melanoma. A 73-year-old Caucasian man with a history of renal cell carcinoma presented with a 15 × 12 × 7 mm homogenous, pigmented, and acoustically hollow mass without hemorrhage or exudation. The patient was initially treated with plaque radiotherapy with good tumor regression. However, the patient developed pain and vision loss due to total exudative retinal detachment. Subsequent enucleation allowed histopathologic confirmation of clear-cell renal cell carcinoma. Nine years following enucleation, the patient remains in complete remission without evidence of other systemic metastases. Renal cell carcinoma should be considered when evaluating patients with probable uveal melanoma. Delayed-onset ocular metastasis from renal cell carcinoma exhibits an atypical clinical course with the possibility of durable remission following enucleation.

We describe a technique for treating Eaton stage IV osteoarthritis of the first ray, which is a development of our previously published technique for treating trapeziometacarpal arthritis. This simple technique is based on a limited resection arthroplasty of the first trapeziometacarpal and the scaphotrapezial joints, with the aim of inducing the formation of a narrow pseudoarthrosis at both sites. A total of 26 consecutive patients were treated for Eaton stage IV arthritis at a mean follow-up of 4.7 years (range 3.2–6.6). There were statistically significant improvements in all clinical parameters: mean appositional and oppositional pinch strength, mean DASH score (65 points pre-operatively to 8.7 points at final follow-up), and in mean visual analogue scale score (8.6 to 0.2 points). Although a larger cohort and a longer follow-up will be necessary to evaluate this new technique fully, these results encourage us to believe that the limited excision arthroplasty of the trapeziometacarpal and scaphotrapezial joints is a viable alternative to the existing surgical treatments for stage IV thumb arthritis.Level of evidence: 4

The original version of this article contained incorrect Supplementary Files. The correct Supplementary Files are published with this erratum.

Background Omadacycline is a novel aminomethylcycline with activity against Gram-positive and -negative organisms, including tetracycline-resistant pathogens. Omadacycline was recently approved in the United States for treatment of adult patients with community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections. Analyses were undertaken to determine whether PORT risk class and CURB-65 score influence the pharmacokinetics of omadacycline in patients with CABP. Methods Omadacycline pharmacokinetic data were available from omadacycline-treated patients with CABP enrolled in the Phase 3 OPTIC Study. Patients received omadacycline 100 mg IV q12h on Day 1 followed by 100 mg IV q24h. After Day 3, patients could be switched to 300 mg PO q24h if predefined clinical stability criteria were met. Four pharmacokinetic samples per patient were collected between Days 2 and 5. These data were previously utilized in the development of a population pharmacokinetic model describing the disposition of omadacycline [Microbe 2018; Abstr SAT-628]. Individual post-hoc parameter estimates for patients enrolled in the OPTIC study were utilized to compute Day 1 total-drug plasma area under the concentration-time curve (AUC) values following administration of omadacycline 100 mg IV q12h. Differences among these AUC values by PORT risk class and CURB-65 score were assessed using a one-way ANOVA. Results A total of 187 pharmacokinetic samples were available from 50 patients. Among the patients classified as PORT risk class II, III, and IV (n = 12, 28, and 10, respectively), mean Day 1 omadacycline AUC values were 10.2, 11.0, and 12.0 mg L/h, respectively. Among patients with CURB-65 scores of 0, 1, and 2 (n = 23, 23, and 4, respectively), mean Day 1 omadacycline AUC values were 10.6, 11.6, and 9.7 mg L/h, respectively. The differences in mean AUC values were not statistically significant among patients by PORT risk class (P = 0.248) and CURB-65 score groups (P = 0.745). Moreover, variability was similar across these groups as displayed in Figure 1. Conclusion Omadacycline exposures were similar across PORT risk class and CURB-65 score groups; thus, omadacycline dose adjustments based on these classifications are likely not warranted. Disclosures All authors: No reported disclosures.

Background Rezafungin (RZF) is a novel echinocandin in development for prevention of invasive fungal infections caused by Candida, Aspergillus, and Pneumocystis spp. in patients at high risk of infection. RZF has demonstrated in vivo prophylaxis efficacy and low risk of drug-drug interactions. Furthermore, the stability and PK profile of RZF allow for once-weekly dosing. RZF is also in development for treatment of candidemia and invasive candidiasis using a dosing regimen of RZF 400 mg followed by 200 mg once-weekly, which achieved >90% target attainment against Candida. While lower doses might be useful to prevent Candida and Pneumocystis, invasive aspergillosis is a different challenge. We evaluated RZF dosing for prophylaxis against Aspergillus fumigatus in bone marrow transplant (BMT) patients using PK/PD simulations of the treatment dosing regimen. Methods A previous population PK model was refined using data from Phase 1 and Phase 2 trials of IV RZF (NONMEM Vers 7.2). Stepwise forward selection (α = 0.01) and backward elimination (α = 0.001) were used to assess for relationships between interindividual PK variability and covariates, such as age, sex, BSA), albumin, liver and renal function markers, and infection status. The final model was validated by comparing model-based predictions to observed data. The model and demographic data from BMT recipients at Stanford Medical Center (Table 1) were used for Monte Carlo simulation (n=2,000) of expected RZF concentration-time profiles in BMT patients receiving IV RZF 400 mg on Week 1 followed by 200 mg weekly x 11. Free-drug concentration-time profiles were evaluated (97.4% human protein-binding) relative to the A. fumigatus minimal effective concentration required to inhibit 100% of isolates tested (MEC100; JMI 2014-2017 SENTRY international surveillance data). Results The population PK model was a linear, 4-compartment model with zero order IV input. Albumin was a statistically significant predictor of interindividual variability. Non-significant relationships were found with sex, BSA, presence of cirrhosis, and infection status. The model provided precise, unbiased fits to the observed data (r2=0.993 observed vs individual-predicted). RZF plasma free-drug concentrations at weeks 1, 2, and 12 were above the A. fumigatus MEC100 (0.03 mg/L) for the entire dosing interval in 98.4%, 93.3%, and 91.9% of simulated patients, respectively, and in ≥99.9% for all 12 weeks based on the MEC90 (0.015 mg/L). Conclusions These data modeled from BMT patients support the RZF dosing regimen of 400 mg IV followed by 200 mg once-weekly for prophylaxis against A. fumigatus. Current antifungal prophylaxis may be limited by toxicity, DDIs, or patient factors such as mucositis. The PK of RZF and its spectrum, safety, tolerability, and lack of DDIs may address challenges in IFI prophylaxis for BMT and other immunocompromised patients.

Despite over 40 years of worldwide usage, relatively few data have been published on the pharmacokinetics of cefazolin in pediatric surgical patients. The primary objectives of this study were to examine the pharmacokinetics and safety of cefazolin in children 10 to 12 years of age (inclusive) receiving 1 or 2 g of cefazolin, based on body weight. This multiple-center, open-label study enrolled pediatric patients electively scheduled for surgical procedures who required cefazolin as part of their routine clinical management. Patients weighing ≥25 to

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.

Vaborbactam is a member of a new class of β-lactamase inhibitors with inhibitory activity against serine carbapenemases (e.g., Klebsiella pneumoniae carbapenemase) that has been developed in combination with meropenem. The pharmacokinetics of the combination was evaluated in 41 subjects with chronic renal impairment in a phase 1, open-label, single-dose study. Subjects were assigned to one of five groups based on renal function: normal (creatinine clearance of ≥90 ml/min), mild (estimated glomerular filtration rate [eGFR] of 60 to 89 ml/min/1.73 m 2 ), moderate (eGFR of 30 to P < 0.001) and vaborbactam (mean of 5.11-fold increase, P = 0.0235) relative to drug administration off dialysis, consistent with dose recovery rates of 38.3% and 52.9% for meropenem and vaborbactam, respectively, in dialysate. Plasma clearance of meropenem and vaborbactam is reduced with renal impairment, requiring dose adjustment. Hemodialysis removes both drugs. (This study has been registered at ClinicalTrials.gov under identifier NCT02020434.)

To provide support for in vitro susceptibility test interpretive criteria decisions for ceftaroline against Staphylococcus aureus and Streptococcus pneumoniae , as well as dose adjustment recommendations for renal impairment, pharmacokinetic-pharmacodynamic (PK-PD) target attainment was evaluated for simulated patients administered intravenous (i.v.) ceftaroline fosamil at 600 mg twice daily (q12h) and simulated patients with renal impairment administered various dosing regimens. Using a previously developed population PK model, Monte Carlo simulation was used to generate ceftaroline plasma concentration profiles for simulated patients with normal renal function or mild, moderate, or severe renal impairment. Using these profiles, the percentage of time during the dosing interval that free-drug concentrations remained above the MIC ( f % T >MIC) for ceftaroline at steady state was calculated. Percentages of simulated patients achieving f % T >MIC targets for S. aureus and S. pneumoniae based on murine infection models were calculated by MIC. At MICs of 2 mg/liter for S. aureus and 1 mg/liter for S. pneumoniae , the percentages of simulated patients with normal renal function and mild renal impairment following administration of ceftaroline fosamil at 600 mg q12h, moderate renal impairment following administration of ceftaroline fosamil at 400 mg q12h, and severe renal impairment following administration of ceftaroline fosamil at 300 mg q12h achieving f % T >MIC targets (≥26 for S. aureus and ≥44 for S. pneumoniae ) exceeded 90%. The results of these analyses, which suggested that in vitro susceptibility test interpretive criteria defining susceptible could be as high as MICs of ≤2 and ≤1 mg/liter for ceftaroline against S. aureus and S. pneumoniae , respectively, provide support for current FDA and CLSI criteria, which define susceptible as MICs of 1 and 0.5 mg/liter, respectively. Recommendations for dose adjustments for patients with renal impairment were also supported by the results of these analyses.

Objectives/Hypothesis To evaluate vocal outcomes in 10 patients 1 year after autologous transplantation of temporalis fascia into Reinke's space (ATFV) for vocal fold scar and sulcus vocalis. Study Design Retrospective, clinical case series. Methods Subjective and objective evaluation was performed 12 months after surgery using laryngovideostroboscopy (LVS) in all patients, the Voice Handicap Index-10 (VHI-10) in seven patients, GRBAS (grade, roughness, breathiness, asthenia, strain) scale in nine patients, and noise-to-harmonics ratio (NHR), phonatory range (PR) and maximum phonation time (MPT) in six patients. Results LVS improved in all but one patient. A significant decrease was noted in the GRBAS subscales grade, roughness, asthenia, and strain (P

Combined posterior and supraglottic stenosis (CS) often presents as debilitating dysphonia or dyspnea, secondary to blunt trauma or traumatic intubation. However, CS has proven to be a late complication of chemoradiation therapy. Traditional treatment of combined posterior and supraglottic stenosis (CS) secondary to chemoradiation has been frequently complicated by poor tissue healing. This case study illustrates a novel endoscopic surgical technique employing a large laterally-based flap as a posterior glottic keel by rotating it anteroinferiorly and suturing it in place. As a result of the procedure, the bilateral vocal folds, which were midline and immobile preoperatively, regained normal motion. The supraglottic airway was also restored. Successful endoscopic treatment of CS with bilateral vocal fold immobility is possible using a large laterally-based flap, even in the face of tissue changes secondary to chemoradiation.

Purpose: To describe an unusual case of Bartonella henselae neuroretinitis complicated by macular hole (MH) development. Observations: A full-thickness macular hole developed in a 12-year-old boy in association with serology-confirmed Bartonella henselae neuroretinitis. Following a period of observation, the MH closed without intervention. Conclusion and importance: MH may occur as a complication of neuroretinitis secondary to Cat-Scratch Disease. Keywords: Retina, Macular hole, Neuroretinitis

The objective of this study is to investigate bone metabolism, density, and quality in patients with diabetes type 2 using DEXA and spinal deformity index (SDI), a surrogate index of bone quality. Fifty-six patients with type 2 diabetes were studied; exclusion criteria were diseases and medications that affect bone and mineral metabolism. Mean age was 65 ± 7 years. Mean diabetes duration was 10 ± 7 years and mean HbA1C was 6.6 ± 0.5 %. BMI was 30 ± 4. Fifty-six sex, age, and BMI matched served as controls. All subjects underwent a clinical and biochemical examination. Spinal and femoral neck BMD were measured by DEXA, and a spine radiography was performed to assess vertebral fractures and to calculate SDI. Mean serum 25-OH vitamin D levels were 19.6 ± 3.7 ng/ml in patients and 30 ± 14 ng/ml in controls (p < 0.01). PTH serum levels were 47.9 ± 40 pg/ml in patients versus 37 ± 5.3 pg/ml in controls (p < 0.01). At lumbar spine there was a significant difference between patients and controls only for T-score (p =

Antimicrobial stewardship programs face many challenges, one of which is a lack of guidance regarding antimicrobial dose, interval, and duration. There is no tool that considers patient demographic, pathogen susceptibility, and pharmacokinetic-pharmacodynamic (PK-PD) targets for efficacy in order to evaluate appropriate antimicrobial dosing regimens. The PK-PD Compass, an educational mobile application, was developed to address this unmet need. The application consists of a Monte Carlo simulation algorithm which integrates pharmacokinetic (PK) and PK-PD data, patient-specific characteristics, and pathogen susceptibility data. Through the integration of these data, the application allows practitioners to assess the percent probability of PK-PD target attainment for 35 intravenous antimicrobial agents across 29 infection categories. Population PK models for each drug were identified, evaluated, and refined as needed. Susceptibility breakpoints were based upon FDA and CLSI criteria. By incorporating these data into one interface, clinicians can select the infection, pathogen, and antimicrobial agents of interest and obtain the percent probability of PK-PD target attainment for each regimen based upon patient-specific characteristics. The antimicrobial dosing regimens provided include those recommended by standard guidelines and reference texts. However, unlike these references, potential choices are prioritized based on percent probabilities of PK-PD target attainment. Such data will educate clinicians on selecting optimized antibiotic regimens through the lens of PK-PD.

Effective treatment of obesity could reduce the burden of diseases primarily driven by excess body weight (e.g., Type 2 diabetes). At present, effective nonsurgical weight management tools are scarce. This paper reviews the investigational combination of phentermine, a weight-loss drug available for over half a century, and topiramate, an antiepileptic drug with known weight-loss effects, as a proposed anti-obesity intervention. The combination therapy achieves weight loss of a magnitude that meets the expectations of the US FDA along with improvement of some obesity-related risks. The safety profile is consistent with known adverse effects of individual constituents; cognitive and psychiatric adverse events were dose dependent. Other safety concerns include a small increase in heart rate and potential teratogenicity associated with topiramate.

Pharmacokinetic and clinical data from tigecycline-treated patients with hospital-acquired pneumonia (HAP) who were enrolled in a phase 3 clinical trial were integrated in order to evaluate pharmacokinetic-pharmacodynamic (PK-PD) relationships for efficacy. Univariable and multivariable analyses were conducted to identify factors associated with clinical and microbiological responses, based on data from 61 evaluable HAP patients who received tigecycline intravenously as a 100-mg loading dose followed by 50 mg every 12 h for a minimum of 7 days and for whom there were adequate clinical, pharmacokinetic, and response data. The final multivariable logistic regression model for clinical response contained albumin and the ratio of the free-drug area under the concentration-time curve from 0 to 24 h ( f AUC 0–24 ) to the MIC ( f AUC 0–24 :MIC ratio). The odds of clinical success were 13.0 times higher for every 1-g/dl increase in albumin ( P < 0.001) and 8.42 times higher for patients with f AUC 0–24 :MIC ratios of ≥0.9 compared to patients with f AUC 0–24 :MIC ratios of P = 0.008). Average model-estimated probabilities of clinical success for the albumin/ f AUC 0–24 :MIC ratio combinations of P < 0.001) and 8.59 times higher for patients without VAP compared to those with VAP ( P = 0.003). Among the remaining variables evaluated, the MIC had the greatest statistical significance, an observation which was not surprising given the differences in MIC distributions between VAP and non-VAP patients (MIC 50 and MIC 90 values of 0.5 and 0.25 mg/liter versus 16 and 1 mg/liter for VAP versus non-VAP patients, respectively; P = 0.006). These findings demonstrated the impact of pharmacological and patient-specific factors on the clinical and microbiological responses.

Exposure-response analyses for efficacy and safety were performed for tigecycline-treated patients suffering from community-acquired pneumonia. Data were collected from two randomized, controlled clinical trials in which patients were administered a 100-mg loading dose followed by 50 mg of tigecycline every 12 h. A categorical endpoint, success or failure, 7 to 23 days after the end of therapy (test of cure) and a continuous endpoint, time to fever resolution, were evaluated for exposure-response analyses for efficacy. Nausea/vomiting, diarrhea, headache, and changes in blood urea nitrogen concentration (BUN) and total bilirubin were evaluated for exposure-response analyses for safety. For efficacy, ratios of the free-drug area under the concentration-time curve at 24 h to the MIC of the pathogen ( f AUC 0-24 :MIC) of ≥12.8 were associated with a faster time to fever resolution; patients with lower drug exposures had a slower time to fever resolution ( P = 0.05). For safety, a multivariable logistic regression model demonstrated that a tigecycline AUC above a threshold of 6.87 mg · hr/liter ( P = 0.004) and female sex were predictive of the occurrence of nausea and/or vomiting ( P = 0.004). Although statistically significant, the linear relationship between tigecycline exposure and maximum change from baseline in total bilirubin is unlikely to be clinically significant.

The choice of an antimicrobial agent must balance optimization of efficacy endpoints with the minimization of safety events. The risk versus benefit of daptomycin for patients with Staphylococcus aureus bacteremia with or without infective endocarditis receiving daptomycin at 6, 8, and 10 mg/kg of body weight/day was assessed. The relationships between the area under the concentration-time curve over 24 h (AUC)/MIC ratio and both clinical response and time to decreased susceptibility were evaluated using data from patients with such infections who received daptomycin at 6 mg/kg/day. Using these relationships, plus the previously identified relationship between the minimum concentration and an elevation in the creatine phosphokinase (CPK) concentration (CPK elevation) (S. M. Bhavnani, C. M. Rubino, P. G. Ambrose, and G. L. Drusano, Clin Infect Dis 50:1568–1574, 2010) and Monte Carlo simulation, the probability of each outcome by MIC for daptomycin at 6, 8, and 10 mg/kg/day was calculated. The function for exposure-response relationships for clinical response ( P = 0.06) and time to decreased susceptibility ( P = 0.01) resembled U and inverted U shapes, respectively. Multivariable analyses demonstrated AUC/MIC ratio, creatinine clearance, albumin concentration, and disease category to be predictors of clinical response. The results of simulations failed to demonstrate large improvements in the probabilities of clinical success among cohorts of simulated patients defined by the above-described predictive factors or the probability of decreased susceptibility at 30 days when the daptomycin dose was increased from 6 to 10 mg/kg/day. The probability of CPK elevation increased from 0.073 to 0.156 over this dose range. These data can be used to inform risk-versus-benefit decisions for daptomycin dose selection in patients with S. aureus bacteremia with or without infective endocarditis. The risk of CPK elevation, which is reversible, should be weighed in the context of the mortality and severe morbidity associated with these types of serious staphylococcal infections.

Background The importance of delivering appropriate therapy to patients at the onset of treatment is well established. However, this goal is easier said than done given the complexity and uniqueness of each patient case. Nonetheless, treatment decisions driven by pharmacokinetic-pharmacodynamic (PK-PD) can account for patient variability and assist in selecting patient-specific therapies. Using data obtained from electronic decision support software (EDSS), we evaluated the relationship between the probability of PK-PD target attainment (PTA) and patient outcomes. Methods Data obtained over a 20-month period from an EDSS were evaluated and included: (1) patient demographics; (2) infection type; (3) pathogen; (4) clinician-selected antimicrobials; (4) pathogen susceptibility; (5) clinician-provided early and late outcomes. Data calculated by the EDSS included the PTA for all evaluated antimicrobial regimens. Using logistic regression, relationships between the probability of PTA and clinical improvement and clinical success at 48 hours and Days 7–10, respectively, were assessed. Results Data for 121 patient cases with various infection types were available. The most common pathogens reported were MRSA (14.9%) and K. pneumoniae (14.9%). Overall, 76.3% of patients demonstrated clinical improvement at 48 hours while 70.3% of patients demonstrated clinical success at Days 7–10. Based on the relationship between the probability of PTA and clinical improvement at 48 hours (Figure 1), for every 10% increase in PTA, patients were 1.74 times more likely to demonstrate clinical improvement (OR [95% CI] 1.74 [1.28–2.37], P Conclusion Statistically significant positive relationships between PTA and clinical outcomes at 48 hours and Days 7–10 were identified. These data demonstrate the value of PK-PD in dosing regimen selection and provide a path toward delivering appropriate initial therapy to optimize patient outcomes. Disclosures S. M. Bhavnani, ICPD Technologies: Shareholder, stock options; C. M. Rubino, ICPD Technologies: Shareholder, stock options; P. G. Ambrose, ICPD Technologies: Shareholder, stock options

Background: Rezafungin is a novel antifungal of the echinocandin class being developed as a single agent for prevention of invasive fungal infections (IFIs) caused by Candida, Aspergillus, and Pneumocystis spp. in patients at high risk of infection. Rezafungin exhibits an exceptionally long half-life (~133 h) which enables the administration of once-weekly dosing regimens. Treatment efficacy in a mouse Pneumocystis model is achieved at a human equivalent dose of 90% target attainment for treatment of Candida [AAC. 2018. 62:e02614-17]. Although lower doses of rezafungin might be useful for prevention of Pneumocystis and Candida infections, prevention of invasive aspergillosis in immunosuppressed populations is often considered more challenging. Pharmacokinetic-pharmacodynamic simulations were performed, at the dosing regimen for treatment of Candida, to evaluate the appropriateness of rezafungin for prophylaxis against A. fumigatus among bone marrow transplant (BMT) patients. Methods: A previously developed rezafungin population pharmacokinetic (PK) model [AAC. 2018. 62:e02603-17] was refined in NONMEM Version 7.2 using intravenous (IV) data from additional Phase 1 and Phase 2 studies. The ability of covariates such as body size, age, sex, albumin, markers of liver and renal function, and infection status to explain a portion of the interindividual variability on select PK parameters was explored using stepwise forward selection (α = 0.01) and backward elimination (α = 0.001). The final model was validated by comparing model-based predictions to observed data. Baseline demographic data were available from 100 patients who underwent a BMT at Stanford Medical Center. Using this dataset and the developed population PK model, a Monte Carlo simulation (n=2,000) was conducted to simulate expected rezafungin concentration-time profiles in BMT patients following administration of rezafungin 400 mg IV on Week 1 then 200 mg IV weekly x11. Using a human protein-binding value of 97.4%, free-drug concentration-time profiles were evaluated relative to the maximum observed A. fumigatus minimal effective concentration to inhibit 100% of isolates tested (MEC100) from surveillance data collected in 2016 [ASM Microbe 2018. Abstr Friday-485]. Results: The final population PK model was a linear, 4-compartment model with zero order IV input. Albumin was an important predictor of the interindividual variability in rezafungin PK, as significant relationships were found between serum albumin concentration and clearance and volume of peripheral compartment 1. Additional relationships were found between PK parameters and sex, body surface area, presence of cirrhosis, and infection status. The model provided precise and unbiased fits to the observed data (r2=0.993 observed vs individual-predicted concentrations). The demographic dataset utilized for the simulations contained 100 BMT patients, of which 39 were female. Median (range) baseline body surface area and albumin were 1.84 m2 (1.27 - 2.61) and 3.35 g/dL (1.8 - 4.43), respectively. None of the patients had a baseline infection nor did any of the patients have cirrhosis. Following administration of rezafungin 400 mg IV on Week 1 then 200 mg IV weekly x11, free-drug plasma concentration-time profiles for Weeks 1, 2, and 12 relative to the A. fumigatus MEC100 (0.03 mg/L) are displayed in Figure 1. On Weeks 1, 2, and 12, 98.4%, 93.3%, and 91.9% of simulated patients, respectively, had rezafungin free-drug concentrations above the MEC100 value for the entire dosing interval (one week). This result was ≥99.9% for all 12 weeks when based on the MEC90 (0.015 mg/L). Conclusions: These data provide support for a once-weekly rezafungin dosing regimen for prevention of A. fumigatus infections among BMT patients. The effectiveness of current antifungal prophylactic regimens is frequently limited by safety, tolerability, drug interactions, adherence, pill burden and patient factors such as mucositis or background chemotherapeutic regimens. In addition to the excellent safety, tolerability, and lack of drug interactions exhibited by echinocandin agents, the favorable PK profile of rezafungin presents the opportunity to mitigate the typical challenges faced when administering IFI prophylaxis in BMT and other immunocompromised patients. Disclosures Lakota: Cidara Therapeutics: Research Funding. Flanagan:Cidara Therapeutics: Employment, Equity Ownership. Sandison:Cidara Therapeutics: Employment, Equity Ownership. Brown:Cidara Therapeutics: Consultancy. Rubino:Cidara Therapeutics: Research Funding.

Background. The objective of this analysis was to evaluate the relationship between daptomycin exposure and the probability of an elevation in the creatine phosphokinase (CPK) level (hereafter, “CPK elevation”) in patients with Staphylococcus aureus bacteremia with or without infective endocarditis. Methods. Phase 3 data for patients with S. aureus bacteremia, with or without infective endocarditis, who received intravenous daptomycin (6 mg/kg daily) and in whom pharmacokinetic data were collected were evaluated. On the basis of univariate logistic regression, the relationship between Bayesian post hoc exposure estimates and the probability of a CPK elevation was evaluated. Time to CPK elevation was examined with Kaplan-Meier analysis and Cox proportional hazards regression. Results. Significant relationships between the minimum concentration of drug (Cmin) and area under the plasma concentration time curve and probability of CPK elevation were observed in 108 evaluable patients. Of the 108 patients evaluated, 6 (5.56%) demonstrated a defined CPK elevation, regardless of treatment relationship. Cmin (breakpoint of 24.3 mg/L) was most significantly associated with CPK elevation (P p .002). The probabilities of a CPK elevation with a Cmin 24.3 mg/L and !24.3 mg/L were 0.5 and 0.029, respectively. Increases in Cmin, evaluated as a continuous variable, were also significantly associated with CPK elevation (P p .01). Stratified Kaplan-Meier analysis and Cox proportional hazards regression demonstrated Cmin to be a significant predictor of time to a CPK elevation (P .003). The probability of a CPK elevation was 0 and 0.01 after 7 days of treatment in patients with a Cmin 24.3 mg/L or !24.3 mg/L, respectively. After 14 days, the probabilities were 0.5 and 0.025, respectively. Conclusions. This analysis demonstrated that a daptomycin Cmin 24.3 mg/L was associated with an increased probability of a CPK elevation. Clinical trials registration. Clinical trials.gov NCT00093067.

Patients with intra-abdominal infections differ with regard to the type of infection and the severity of illness. However, the impact of these factors, together with differences in drug exposure, on clinical response is not well understood. Using phase 2 and 3 data for patients with complicated intra-abdominal infections, the relative importance of tigecycline exposure, host factors, and disease factors, alone or in combination, for the probability of clinical response was examined. Patients with complicated intra-abdominal infections who received tigecycline intravenously as a 100-mg loading dose followed by 50 mg every 12 h for 5 to 14 days and who had adequate clinical, pharmacokinetic, and response data were evaluated. Multivariable logistic regression was used to identify factors associated with clinical response. A final multivariable logistic regression model demonstrated six factors based on 123 patients to be predictive of clinical success: a weight of P = 0.026), the absence of Pseudomonas aeruginosa in baseline cultures ( P = 0.021), an APACHE II score of P = 0.029), non-Hispanic race ( P = 0.005), complicated appendicitis or cholecystitis ( P = 0.004), and a ratio of the area under the concentration-time curve (AUC) to the MIC (AUC/MIC ratio) of ≥3.1 ( P = 0.003). The average model-predicted probability of clinical success when one unfavorable factor was present was 0.940. This probability was lower (0.855) when the AUC/MIC ratio was

Oritavancin is a lipoglycopeptide antibiotic with activity against Gram-positive bacteria. Here we describe oritavancin population pharmacokinetics and the impact of patient-specific covariates on drug exposure variability. Concentration-time data were analyzed from two phase 3 clinical trials, SOLO I and SOLO II, in which oritavancin was administered as a single 1,200-mg dose to patients with acute bacterial skin and skin structure infections. A total of 1,337 drug concentrations from 297 patients (90% of whom had 4 or 5 pharmacokinetic samples) were available for analysis. A previously derived population model based on data from 12 phase 1, 2, and 3 oritavancin studies was applied to the SOLO data set. Alterations to the structural model were made, as necessary, based on model fit. Analyses utilized Monte Carlo parametric expectation maximization (S-ADAPT 1.5.6). The previous population pharmacokinetic model fit the data well ( r 2 = 0.972), and population pharmacokinetic parameters were estimated with acceptable precision and lack of bias. Covariate evaluations revealed statistically significant relationships between central compartment volume and age and between clearance and height; however, these relationships did not indicate a clinically relevant impact on oritavancin exposure over the range of age and height observed in the SOLO studies. The mean (coefficient of variation [CV]) area under the plasma concentration-time curve from time zero to 72 h (AUC 0–72 ) and maximum plasma concentration ( C max ) were 1,530 (36.9%) μg · h/ml and 138 (23%) μg/ml, respectively. The mean (CV) half-life at alpha phase ( t 1/2α ), t 1/2β , and t 1/2γ were 2.29 (49.8%), 13.4 (10.5%), and 245 (14.9%) hours, respectively. These analyses are the first to describe oritavancin pharmacokinetics following a single 1,200-mg dose. Covariate analyses suggested that no dose adjustments are required for renal impairment (creatinine clearance, >29 ml/min), mild or moderate hepatic impairment, age, weight, gender, or diabetes status.

Stephen J Farr,1 Cynthia Y Robinson,1 Christopher M Rubino2,3 1Zogenix, Inc., Emeryville, CA, 2Institute for Clinical Pharmacodynamics, Latham, NY, 3School of Pharmacy and Pharmaceutical Sciences, The State University of New York, University at Buffalo, Buffalo, NY, USA Background: The purpose of this study was to evaluate the pharmacokinetics, bioavailability, and safety of oral extended-release hydrocodone (HC-ER) when administered with food or alcohol. Methods: Two single-center, open-label, randomized, crossover studies were conducted in healthy volunteers. In a two-period food-interaction study, 12 subjects received HC-ER 20 mg after an overnight fast and a high-fat meal. In a three-period alcohol-interaction study, 30 naltrexone-blocked subjects received HC-ER 50 mg with a 0%, 20%, or 40% alcohol/orange juice solution after an overnight fast. Pharmacokinetic parameters were derived from plasma concentrations of hydrocodone and its metabolites. Results: Exposure to hydrocodone after HC-ER 20 mg was similar in the fed and fasted states, as assessed by area under the plasma concentration versus time curve from time of dosing to time of last detectable concentration (AUC0–t; 316.14 versus 311.94 ng · h/mL); relative bioavailability (Frel) was 101.74%. Differences (fed versus fasted) in hydrocodone mean maximum plasma concentration (Cmax; 28.86 versus 22.74 ng/mL) and median time to Cmax (tmax; 6 versus 8 hours) were not clinically significant. Administration of 20% alcohol with HC-ER 50 mg did not increase systemic exposure relative to 0% alcohol (AUC0–t 878 versus 832 ng · h/mL; Frel 105%) or result in clinically meaningful changes in Cmax (51.8 versus 46.3 ng/mL) or tmax (5.44 versus 6.16 hours). Administration with 40% alcohol increased AUC0–t (1,008 ng · h/mL versus 832 ng · h/mL; Frel 120%) and Cmax (109 versus 46.3 ng/mL), and shortened tmax (2.43 versus 6.16 hours). Adverse events occurred in 10.0%, 24.1%, and 66.7% of subjects after 0%, 20%, and 40% alcohol, respectively. Conclusion: HC-ER can be administered without regard to meals. While there was no evidence of "dose-dumping" (an unintended, rapid release in a short time period of all or most of the hydrocodone from HC-ER), even with 40% alcohol, as with all opioids, alcohol should not be ingested while using HC-ER. Keywords: opioid, food interaction, alcohol interaction, bioavailability, norhydrocodone, hydromorphone

Neck flexion may play a role in the pathogenesis of Hirayama disease. Upper limb somatosensory evoked potentials were recorded in five patients with Hirayama disease, six patients with ALS, and 14 healthy subjects. Neck flexion caused a significant amplitude decrease of the N13 cervical response only in patients with Hirayama disease. Direct cord compression or microvascular changes can in theory account for this position-related dysfunction.

Background VL-2397 is a novel antifungal agent in clinical development for treatment of invasive aspergillosis (IA). The analysis objectives were to: 1) develop a population PK model using data from a Phase 1 trial in healthy adult volunteers, 2) define the PK-PD driver of efficacy in a mouse model of IA, and 3) conduct PK-PD target attainment analyses to aid in Phase 2 dose selection for patients with IA. Methods Data from two studies were used: a dose fractionation study in a mouse model of IA and a Phase 1 study in healthy adult volunteers receiving single- and multiple-ascending doses of intravenous (IV) VL-2397 ranging from 3 mg to 1200 mg daily. Mouse lung fungal burden (LFB) measured on Day 4 after infection with Aspergillus fumigatus FP1305 (MIC of 1 µg/mL) was used to assess the predictive value of three measures of VL-2397 exposure: total-drug AUC0-24:MIC (tAUC0-24:MIC), total-drug Cmax:MIC, and total-drug %T>MIC; total drug was used because serum protein binding is similar in mice and humans. A population PK model for VL-2397 in humans was developed in NONMEM v7.1.2 and formed the basis of Monte Carlo simulations. The model was also fit to mouse PK data to estimate the VL-2397 exposure in mice. Results VL-2397 concentration-time data in humans revealed nonlinear PK behavior consistent with highly-bound compounds. A robust fit to the data was obtained using a two-compartment model with linear elimination and concentration-dependent binding in both central and peripheral compartments. The results of the dose fractionation study suggested that tAUC0-24:MIC was the most predictive (r2 = 0.713) driver of efficacy, with a value of 21.8 on Day 1 associated with a 2-log reduction in LFB on Day 4. Comparisons of the simulated VL-2397 tAUC0-24:MIC on Day 1 in humans receiving daily dosing regimens of 300 mg, 600 mg, and 900 mg of VL-2397 to the 2-log target (figure) suggested that a dose of 600 mg Q24 would provide robust (99.9%) PK-PD target attainment up to an A. fumigatus MIC of 2 µg/mL. Conclusion The PK-PD driver of efficacy for VL-2397 was tAUC0-24:MIC and a value of 21.8 was associated with a 2-log reduction in LFB in a mouse model of IA. PK-PD target attainment assessments indicate that a VL-2397 dose of 600 mg IV Q24 will provide adequate target attainment up to an MIC of 2 µg/mL. Disclosures C. M. Rubino, Vical Incorporated: Consultant, Consulting fee; L. R. Smith, Vical Incorporated: Employee, Salary and Stock Options; M. P. Mammen, Vical Incorporated: Employee, Salary and Stock Options; A. M. Hopkins, Vical Incorporated: Employee, Salary and Stock Options; E. A. Lakota, Vical Incorporated: Consultant, Consulting fee; S. M. Sullivan, Vical Incorporated: Employee, Salary and Stock Options

Background While many have advocated for the use of EDSS to enhance patient care, EDSS that incorporates PK-PD, the science behind antimicrobial stewardship, has thus far been an unattainable goal. Herein, we describe the use of such a technology and clinicians’ therapy decisions when treating patients with pneumonia. Methods Data for patients with pneumonia entered into EDSS over a 20-month period that were evaluated included: 1) patient demographics, creatinine clearance, and pneumonia severity score; 2) pneumonia type; 3) pathogen; 4) clinician-selected antimicrobials; 5) EDSS-presented regimens; and 6) clinician-reported outcomes. Clinicians were provided probabilities of attaining PK-PD targets associated with efficacy for both clinician-selected and EDSS-presented regimens. A regimen with a probability of PK-PD target attainment ≥90% was considered PK-PD optimized. Results Data for 126 cases were available. The median (min, max) age and creatinine clearance were 56.5 (18, >90) years and 72.5 (2.5, 193.3) mL/minute/1.73 m2, respectively. Pneumonia types included community-acquired (39%), healthcare-associated (30%), ventilator-associated (18%), and hospital-acquired (13%). CURB-65 pneumonia scoring was used in 66% of cases with a median (min, max) score of 3 (0, 5). The most common pathogens were P. Aeruginosa (32%), MRSA (15%), and S. pneumoniae (14%). Multi-drug-resistant pathogens comprised 15% of all pathogens. PK-PD optimized regimens were selected in only 65% of cases despite such a regimen being presented in 91% of cases. For those cases in which outcome data were available (n = 36), 81% of patients were considered improved at 48 hours while only 64% were deemed clinically improved or a success at the final outcome assessment on Days 7–10. Among those cases for whom PK-PD optimized and non-optimized regimens were selected (64 and 36%, respectively), 78 and 62% of patients had successful clinical outcomes on Days 7–10, respectively. Conclusion Given that patients with pneumonia represent a vulnerable population and that options for therapy can be limited, selection of optimal early therapy is crucial. PK-PD integrated EDSS presents clinicians the opportunity to optimize therapy and improve outcomes for patients with pneumonia. Disclosures S. M. Bhavnani, ICPD Technologies: Shareholder, stock options. C. M. Rubino, ICPD Technologies: Shareholder, stock options. P. G. Ambrose, ICPD Technologies: Shareholder, stock options.