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This phase I study evaluated the safety of the optimal ceftazidime-avibactam (CZA) with aztreonam (ATM) regimens identified in hollow fiber infection models of MBL-producing Enterobacterales. Eligible healthy subjects aged 18 to 45 years were assigned to one of six cohorts: 2.5 g CZA over 2 h every 8 h (approved dose), CZA continuous infusion (CI) (7.5 g daily), 2 g ATM over 2 h every 6 h, ATM CI (8 g daily), CZA (approved dose) with 1.5 g ATM over 2 h every 6 h, and CZA (approved dose) with 2 g ATM over 2 h every 6 h. Study drug(s) were administered for 7 days. The most frequently observed adverse events (AEs) were hepatic aminotransferase (ALT/AST) elevations (n = 19 subjects). Seventeen of the 19 subjects with ALT/AST elevations received ATM alone or CZA-ATM. The incidence of ALT/AST elevations was comparable between the ATM-alone and CZA-ATM cohorts. Two subjects in the ATM CI cohort experienced severe ALT/AST elevation AEs. All subjects with ALT/AST elevations were asymptomatic with no other findings suggestive of liver injury. Most other AEs were of mild to moderate severity and were similar across cohorts, except for prolonged prothrombin time (more frequent in CZA-ATM cohorts). These results suggest that CZA-ATM administered as 2-h intermittent infusions is safe and that some caution should be exercised with the use of ATM CI at an ATM dose of 8 g daily. If CZA-ATM is prescribed, clinicians are advised to monitor liver function, hematologic, and coagulation parameters. Future controlled studies are required to better define the safety and efficacy of the CZA-ATM regimens evaluated in this phase I study.

Background The combination of CZA-ATM is frequently used to treat patients with metallo-β-lactamase (MBL)-producing Enterobacterales (EB) infections, but its safety has not been established in controlled trials. This phase 1 study evaluated the safety of the optimal CZA-ATM regimens identified in the hollow fiber infection model of MBL-producing EB (PMID: 32464664). Methods The phase I, open-label, single center study enrolled healthy adults aged 18-45 years (NCT03978091). Subjects were sequentially assigned to 1 of 6 Cohorts and administered investigational product(s) (IP) for 7 days (Table 1). Study safety was monitored by assessments of adverse events (AEs), vital signs, and clinical laboratory safety tests. Results Of 48 subjects enrolled, 50% were female and 60% were Black. The mean (SD) age was 33.5 (6.2) years and mean (SD) weight was 75.7 (12.1) kg. The number of subjects who had ≥ 1 AE and experienced ≥ 1 IP related AE was 46 (96%) and 41 (85%), respectively. Frequency of IP related AEs by MedDRA system organ class, severity, and Cohort are shown in Figure 1. The occurrence of IP related investigation AEs were more frequent in the combination vs single IP Cohorts (Table 2). The most common IP related investigation AEs were ALT/AST elevations (35%) with 94% occurring in subjects who received ATM alone or in combination. The incidence of ALT/AST elevation AEs in the combination Cohorts were comparable to the ATM alone Cohorts. In the ATM single IP Cohorts, 3 subjects experienced severe ALT/AST elevation AEs, which halted the study. All subjects who experienced ALT/AST elevations were asymptomatic, had no other clinical findings suggestive of liver injury, and all resolved without intervention. Most other IP related AEs were of mild severity and similar across Cohorts except prolonged prothrombin time (PT) AEs, which was more frequent in combination Cohorts. Conclusion Clinicians should only consider using CZA-ATM when the benefits outweigh the risks. If CZA-ATM is prescribed, clinicians are advised to monitor for hepatic injury. Close monitoring of coagulation parameters may also be prudent with CZA-ATM. Future comparator-controlled randomized clinical trials are required to better define the safety and efficacy of the CZA-ATM regimens. Disclosures Thomas Lodise, Jr., Pharm.D., PhD, BioFire Diagnostics: Grant/Research Support|cidara: Advisor/Consultant|cidara: Honoraria|Entasis: Grant/Research Support|Merck: Advisor/Consultant|Merck: Grant/Research Support|Paratek: Advisor/Consultant|Shionogi: Advisor/Consultant|Spero: Advisor/Consultant|Venatrox: Advisor/Consultant J Nicholas O'Donnell, Pharm.D., Merck & Co, Inc: Grant/Research Support|Paratek Pharmaceuticals: Grant/Research Support Stephen Balevic, MD, Purdue Pharma: Grant/Research Support|UCB: Advisor/Consultant Jeffrey Guptill, MD, argenx: Stocks/Bonds Vance G. Fowler, Jr, MD, MHS, Affinergy: Grant/Research Support|Affinergy: Honoraria|Affinium: Honoraria|Amphliphi Biosciences: Honoraria|ArcBio: Stocks/Bonds|Basilea: Grant/Research Support|Basilea: Honoraria|Bayer: Honoraria|C3J: Honoraria|Cerexa/Forest/Actavis/Allergan: Grant/Research Support|Contrafect: Grant/Research Support|Contrafect: Honoraria|Cubist/Merck: Grant/Research Support|Debiopharm: Grant/Research Support|Deep Blue: Grant/Research Support|Destiny: Honoraria|Genentech: Grant/Research Support|Genentech: Honoraria|Integrated Biotherapeutics: Honoraria|Janssen: Grant/Research Support|Janssen: Honoraria|Karius: Grant/Research Support|Medicines Co.: Honoraria|MedImmune: Grant/Research Support|MedImmune: Honoraria|NIH: Grant/Research Support|Novartis: Grant/Research Support|Novartis: Honoraria|Pfizer: Grant/Research Support|Regeneron: Grant/Research Support|Regeneron: Honoraria|Sepsis diagnostics: Sepsis diagnostics patent pending|UpToDate: Royalties|Valanbio: Stocks/Bonds henry chambers, MD, Merck: DSMB member|Merck: Stocks/Bonds|Moderna: Stocks/Bonds.

Background Scant PK data are available with CZA-ATM in combination. Occurrence of ALT/AST elevations are common with ATM, and it is unknown if it is exacerbated by use of CZA-ATM. This analysis of COMBINE sought to describe the popPK of CZA-ATM and to assess the association between ATM exposures and ALT/AST elevations. Methods COMBINE was a Phase I study of 48 healthy subjects aged 18-45 years (NCT03978091). Subjects were enrolled into 1 of 6 Cohorts (Table 1). Drug(s) were administered for 7 D and intensive plasma and urine PK sampling was performed. PopPK models were developed for ceftazidime (CAZ), avibactam (AVI), and ATM. Empirical Bayesian estimates from the ATM PopPK model were used to simulate ATM day 1 (D1) exposures. Associations between D1 ATM exposures and highest observed ALT/AST were assessed with curvilinear regression (CR) and generalized linear models (GLM). Results Of enrolled 48 subjects, 35% had ALT/AST elevations; 94% occurred in ATM/CZA-ATM Cohorts. Two severe study product related ALT/AST AEs were observed with in the continuous infusion (CI) ATM Cohort. All subjects with ALT/ATS elevations were asymptomatic with no other signs of liver injury. In the ATM PopPK model, CZA-ATM administration reduced ATM non-renal clearance (CLNR) by 1 L/hr (16% of total CL) (Table 2). Administration of CAZ-ATM had a negligible effect on total CAZ CL in the CAZ PopPK model and CZA-ATM was not a covariate in final AVI PopPK model. In the CR, no ATM exposure-ALT/AST associations were identified in overall analyses. Associations (R2=0.18-0.22, p< 0.05) between D1 AUC and ALT/AST were observed in CR analyses restricted to the intermittent infusion (II) ATM Cohorts (Figure 1). In GLM, D1 AUC was significantly associated with ALT/AST in the ATM II Cohort analyses. Administration of CZA-ATM was not associated with ALT/AST in the GLM analyses. Figure 1 Conclusion Administration of CZA-ATM was found to reduce ATM CL, resulting in higher daily ATM AUCs, but did not exacerbate AST/ALT elevations relative to ATM alone. The observed association between ATM AUC and ALT/AST elevations in subjects who received II ATM suggest the risks vs benefits of using II of ATM 8 g/daily vs 6 g/daily with CZA should be considered. Use of CI ATM should be used with caution given the 2 severe ALT/ASTs in the CI ATM Cohort. Disclosures Thomas Lodise, Jr., Pharm.D., PhD, BioFire Diagnostics: Grant/Research Support|cidara: Advisor/Consultant|cidara: Honoraria|Entasis: Grant/Research Support|Merck: Advisor/Consultant|Merck: Grant/Research Support|Paratek: Advisor/Consultant|Shionogi: Advisor/Consultant|Spero: Advisor/Consultant|Venatrox: Advisor/Consultant J Nicholas O'Donnell, Pharm.D., Merck & Co, Inc: Grant/Research Support|Paratek Pharmaceuticals: Grant/Research Support Stephen Balevic, MD, Purdue Pharma: Grant/Research Support|UCB: Advisor/Consultant Jeffrey Guptill, MD, argenx: Stocks/Bonds Vance G. Fowler, Jr, MD, MHS, Affinergy: Grant/Research Support|Affinergy: Honoraria|Affinium: Honoraria|Amphliphi Biosciences: Honoraria|ArcBio: Stocks/Bonds|Basilea: Grant/Research Support|Basilea: Honoraria|Bayer: Honoraria|C3J: Honoraria|Cerexa/Forest/Actavis/Allergan: Grant/Research Support|Contrafect: Grant/Research Support|Contrafect: Honoraria|Cubist/Merck: Grant/Research Support|Debiopharm: Grant/Research Support|Deep Blue: Grant/Research Support|Destiny: Honoraria|Genentech: Grant/Research Support|Genentech: Honoraria|Integrated Biotherapeutics: Honoraria|Janssen: Grant/Research Support|Janssen: Honoraria|Karius: Grant/Research Support|Medicines Co.: Honoraria|MedImmune: Grant/Research Support|MedImmune: Honoraria|NIH: Grant/Research Support|Novartis: Grant/Research Support|Novartis: Honoraria|Pfizer: Grant/Research Support|Regeneron: Grant/Research Support|Regeneron: Honoraria|Sepsis diagnostics: Sepsis diagnostics patent pending|UpToDate: Royalties|Valanbio: Stocks/Bonds henry chambers, MD, Merck: DSMB member|Merck: Stocks/Bonds|Moderna: Stocks/Bonds.

This review critically appraises the published microbiologic and clinical data on the treatment of patients with carbapenem-resistant Acinetobacter baumannii infections. Despite being recognized as an urgent threat pathogen by the CDC and WHO, optimal treatment of patients with serious CRAB infections remains ill-defined. Few commercially available agents exhibit reliable in vitro activity against CRAB. Historically, polymyxins have been the most active agents in vitro, though interpretations of susceptibility data are difficult given issues surrounding MIC testing methodologies and lack of correlation between MICs and clinical outcomes. Most available preclinical and clinical data involve use of polymyxins, tetracyclines, and sulbactam, alone and in combination. As the number of viable treatment options is limited, combination therapy with a polymyxin is often used for patients with CRAB infections, despite the significant risk of nephrotoxicity. However, no treatment regimen has been found to reduce mortality, which exceeds 40% across most studies, or substantially improve clinical response. While some newer agents, such as eravacycline and cefiderocol, have demonstrated in vitro activity, clinical efficacy has not been fully established. New agents with clinically relevant activity against CRAB isolates and favorable toxicity profiles are sorely needed.

Imipenem (IMI)/cilastatin/relebactam (REL) (I/R) is a novel β-lactam/β-lactamase inhibitor combination with expanded microbiologic activity against carbapenem-resistant non-Morganellaceae Enterobacterales (CR-NME) and difficult-to-treat (DTR) Pseudomonas aeruginosa. Relebactam, a bicyclic diazabicyclooctane, has no direct antimicrobial activity but provides reliable inhibition of many Ambler class A and class C enzymes. It is currently approved for the treatment of adult patients with hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP) and those with complicated urinary tract infections (cUTIs) and complicated intra-abdominal infections (cIAIs) when limited or no alternative treatments are available. Given the number of recently approved β-lactams with expanded activity against highly resistant Gram-negative pathogens, this review summarizes the published literature on I/R, with a focus on its similar and distinguishing characteristics relative to those of other recently approved agents. Overall, available data support its use for the treatment of patients with HABP/VABP, cUTI, and cIAI due to CR-NME and DTR P. aeruginosa. Data indicate that I/R retains some activity against CR-NME and DTR P. aeruginosa isolates that are resistant to the newer β-lactams and vice versa, suggesting that susceptibility testing be performed for all the newer agents to determine optimal treatment options for patients with CR-NME and DTR P. aeruginosa infections. Further comparative PK/PD and clinical studies are warranted to determine the optimal role of I/R, alone and in combination, for the treatment of patients with highly resistant Gram-negative infections. Until further data are available, I/R is a potential treatment for patients with CR-NME and DTR P. aeruginosa infections when the benefits outweigh the risks.

BackgroundVancomycin is a first line antibiotic for many common infectious diseases and is the most commonly prescribed antibiotic in the United States hospital setting. Vancomycin is also well known to cause kidney injury; two recent prospective studies have identified that increasing vancomycin area under the concentration curve predicts vancomycin induced kidney injury (VIKI). However, outside of clinical trials, it is unclear if pre-clinical data can quantitatively describe VIKI in patients.MethodsData were simultaneously analyzed from a pre-clinical rat model and two prospective clinical studies. Logged vancomycin area under the concentration curve (AUC) data for rats (n=48) and patients from PROVIDE (n=263) and CAMERA2 (n=291) were included. VIKI was defined as urinary KIM-1 concentrations ≥9.42 ng/mL in the rat and according to KDIGO stage 1 kidney injury for all human patients. Multiple generalized linear models were explored, and the order of magnitude was calculated between the probability of acute kidney injury (AKI) from the average obtained in the clinical studies (i.e. CAMERA2 and PROVIDE) and the rat for 0.1 increments in Log10AUC bounded common concentrations obtained in the therapeutic range (i.e. ~200 −800 mg*24h/L).ResultsA logit link model best fit the data. When calculating the multiplicative factors between the studies therapeutic range AUCs, the rat was an average 2.7 to 4.2 times more sensitive to AKI between AUCs of 199.5 (i.e. log 10 AUC=2.3) and 794.3 mg*h/L (i.e. log 10 AUC=2.9), respectively.ConclusionsA pre-clinical rat model was quantitatively linked to toxicity data from two large human studies. The rat is an attractive pre-clinical model to explore exposure toxicity relationships with vancomycin. External validation is required.

The Accelerate Pheno and BacT/Alert Virtuo systems may improve bacteremia management. Here, we evaluated the impact of both devices on outcomes in patients with sepsis and concurrent Gram-negative bacteremia. This quasiexperimental study included a retrospective preimplementation and a prospective postimplementation group. Patients ≥18 years old with Gram-negative bacteremia were included. Patients with neutropenia, pregnant patients, those who were transferred from an outside hospital with active bloodstream infections, and those with polymicrobial bacteremia were excluded. Blood culture incubation in the BacT/Alert 3D device and microdilution antimicrobial susceptibility testing from culture plate growth were used prior to implementation of the BacT/Alert Virtuo and Accelerate Pheno systems. Matrix-assisted laser desorption ionization–time of flight (MALDI-TOF) identification directly from blood culture was used pre- and postimplementation. Time to Gram stain results, identification, susceptibility reporting, initiation of narrow-spectrum Gram-negative therapy at 72 h, 30-day inpatient mortality, sepsis resolution, and length of hospital stay were evaluated. A total of 116 patients were included (63 preimplementation, 53 postimplementation). Median times to Gram stain and susceptibility results were significantly shorter postimplementation (P

Antimicrobial stewardship intervention (ASI) appears to be necessary to realize the full benefits of rapid diagnostic technologies in clinical practice. This study aimed to compare clinical outcomes between early ASI paired with matrix-associated laser desorption ionization-time of flight mass spectrometry (MALDI-TOF) compared with MALDI-TOF with standard of care (SOC) reporting in patients with positive blood cultures.Adult patients with positive blood cultures and organism speciation via MALDI-TOF admitted between February 2015 and September 2015 were randomized to ASI or SOC in a 1:1 fashion. Patients admitted for at least 48 h following positive culture were included in analyses. ASI was defined as a clinical assessment by a stewardship team member with non-binding treatment recommendations offered to the primary team. The primary outcome was time to definitive therapy. Secondary outcomes included post-culture length of stay (LOS), time to first change in antibiotics, and in-hospital mortality.In total, 149 patients were included in the analyses (76 in the ASI group and 73 in the SOC group). ASI and SOC arms did not differ according to age, sex, comorbidities or severity of illness. Gram-positive organisms were common in both SOC and ASI arms (74.0 vs. 61.8%, P=0.11). Time to definitive therapy was reduced, on average, by 30.3 h in the ASI group (71.6 vs. 41.3 h, P=0.01). Hospital LOS following the first positive blood culture was significantly shorter in the ASI group (8.7 vs. 11.2 days, P=0.049).ASI combined with MALDI-TOF reduced the time to definitive therapy and time to first change in antibiotics, and was associated with a shorter post-culture LOS.

Background Carbapenems have shown efficacy in treating nosocomial pneumonias in clinical trials despite a reported low lung penetration compared with other β-lactams. Preserving the clinical activity of carbapenems through stewardship efforts is essential. The aim of this review was to identify any differences in outcomes potentially as a function of decreased penetration. Methods PubMed and the Cochrane Library were systematically searched for clinical trials comparing carbapenems with other anti-pseudomonal β-lactams for treatment of nosocomial pneumonia through to end December 2016. Trials reporting clinical and microbiological outcomes associated with treatment were included. Pediatric studies and those with uneven comparators (e.g., carbapenem vs. combination Gram-negative therapy) were excluded. Fixed effects models were used to evaluate the impact of treatment on the odds of clinical failure, death, or microbiological failure. Results 252 unique articles were identified; five met inclusion criteria and comprised 640 patients in the carbapenem group and 634 patients in the β-lactam group. No differences in clinical failure (odds ratio [OR] 1.08, 95% confidence interval [CI] [0.81-1.44], I2=16%) or mortality (OR 0.75, CI 0.57-1.11, I2=0%) were noted between groups. Patients infected with P. aeruginosa and treated with imipenem were more likely to experience clinical failure (OR 4.21, CI 1.51-11.12, I2=44%) and to develop resistance to the study carbapenem (OR 2.86, CI 1.08-6.44, I2= 13%) than those treated with alternative β-lactams. Conclusions No differences in clinical outcomes were observed between carbapenems and non-carbapenem β-lactams in nosocomial pneumonias. Those infected with P. aeruginosa fared worse and were more likely to have resistance develop if they were treated with imipenem. Additional studies are warranted.

Vancomycin induces exposure-related acute kidney injury. However, the pharmacokinetic-toxicodynamic (PK-TD) relationship remains unclear. Sprague-Dawley rats received intravenous (i.v.) vancomycin doses of 300 mg/kg/day and 400 mg/kg/day, divided into once-, twice-, three-times-, or four-times-daily doses (i.e., QD, BID, TID, or QID) over 24 h. Up to 8 samples plus a terminal sample were drawn during the 24-h dosing period. Twenty-four-hour urine was collected and assayed for kidney injury molecule-1 (KIM-1). Vancomycin was quantified via liquid chromatography-tandem mass spectrometry (LC-MS/MS). Following terminal sampling, nephrectomy and histopathologic analyses were conducted. PK analyses were conducted using Pmetrics. PK exposures (i.e., area under the concentration-time curve from 0 to 24 h [AUC0-24] and maximum concentration from 0 to 24 h [Cmax0-24]) were calculated for each rat, and PK-TD relationships were discerned. A total of 53-rats generated PK-TD data. A 2-compartment model fit the data well (Bayesian observed versus predicted concentrations; R2 = 0.96). KIM-1 values were greater in QD and BID groups (P for QD versus TID

Vancomycin induces exposure-related acute kidney injury. However, the pharmacokinetic-toxicodynamic (PK-TD) relationship remains unclear. Sprague-Dawley rats received intravenous (i.v.) vancomycin doses of 300 mg/kg/day and 400 mg/kg/day, divided into once-, twice-, three-times-, or four-times-daily doses (i.e., QD, BID, TID, or QID) over 24 h. Up to 8 samples plus a terminal sample were drawn during the 24-h dosing period. Twenty-four-hour urine was collected and assayed for kidney injury molecule-1 (KIM-1). Vancomycin was quantified via liquid chromatography-tandem mass spectrometry (LC-MS/MS). Following terminal sampling, nephrectomy and histopathologic analyses were conducted. PK analyses were conducted using Pmetrics. PK exposures (i.e., area under the concentration-time curve from 0 to 24 h [AUC(0–24)] and maximum concentration from 0 to 24 h [C(max0–24)]) were calculated for each rat, and PK-TD relationships were discerned. A total of 53-rats generated PK-TD data. A 2-compartment model fit the data well (Bayesian observed versus predicted concentrations; R(2) = 0.96). KIM-1 values were greater in QD and BID groups (P for QD versus TID

BackgroundVancomycin induces exposure-related acute kidney injury. However, the pharmacokinetic-toxicodynamic (PK-TD) relationship remains unclear.MethodsSprague-Dawley rats received IV vancomycin doses of 300mg/kg/day and 400mg/kg/day, divided once, twice, thrice or 4xdaily (i.e., QD, BID, TID or QID) over 24-hours. Up to 8-samples were drawn during the 24-hour dosing period. Twenty-four-hour urine was collected and assayed for kidney injury molecule-1 (KIM-1). Vancomycin was quantified via LC-MS/MS. Following terminal sampling, nephrectomy and histopathologic analyses were conducted. PK analyses were conducted using Pmetrics. PK exposures (i.e. AUC0-24h, CMAX0-24h,) were calculated for each rat, and PK-TD relationships were discerned.ResultsA total of 53-rats generated PK-TD data. A 2-compartment model fit the data well (Bayesian observed vs. predicted concentrations, R2=0.96). KIM-1 values were greater in QD and BID groups (P-values: QD vs TID:0–24h and AUC0-24h (R2□=□ 0.7 and 0.68). Corrected Akaike’s information criterion showed CMAX0-24h as most predictive PK-TD driver for vancomycin-induced kidney injury (VIKI) (−5.28 versus −1.95).ConclusionsWhile PK-TD indices are often inter-correlated, maximal concentrations and fewer doses (for the same total daily amount) resulted in increased VIKI in our rat model.

Clostridioides difficile infection (CDI) is a significant cause of morbidity and mortality. Oral vancomycin is a cornerstone of CDI treatment, but dosing strategies in clinical practice may differ from guideline recommendations. This study aimed to determine differences in outcomes between patients treated with standard (125 mg QID) and high-dose (≥250 mg QID) oral vancomycin. This dual-centre study evaluated adult patients admitted between January 2013 and July 2017. Patients were included in the study if they had a positive C. difficile toxin PCR, symptomatic infection and received ≥48 h of oral vancomycin. Disease severity was characterised using a variety of classifiers, including guideline definitions. The primary outcome was 90-day CDI recurrence; secondary outcomes included clinical failure, in-hospital mortality and 90-day re-admission. Inverse probability of treatment weighting (IPTW) was conducted to balance differences between groups. A total of 535 patients were included; 261 received standard and 274 received high-dose vancomycin. Baseline demographics were similar between groups, except that patients receiving high-dose vancomycin were more likely to have more severe disease and to be admitted to the ICU. Few patients had fulminant disease (14.4%). No significant differences in recurrence (OR, 1.52, 95% CI 0.82-2.84), clinical failure (OR, 0.64, 95% CI 0.328-1.26), mortality (OR, 1.44, 95% CI 0.78-2.66) or re-admission (OR, 1.03, 95% CI 0.70-1.51) were identified between patients receiving standard and high-dose vancomycin in the IPTW analyses. No differences in recurrence, mortality or re-admission were identified between standard and high-dose vancomycin for the treatment of CDI not requiring surgery.

Background The purpose of this single-center, ecologic study is to characterize the relationship between facility-wide (FacWide) antibiotic consumption and incident health care facility-onset Clostridium difficile infection (HO-CDI). Methods FacWide antibiotic consumption and incident HO-CDI were tallied on a monthly basis and standardized, from January 2013 through April 2015. Spearman rank-order correlation coefficients were calculated using matched-months analysis and a 1-month delay. Regression analyses were performed, with P Results FacWide analysis identified a matched-months correlation between ceftriaxone and HO-CDI (ρ = 0.44, P = .018). A unit of stem cell transplant recipients did not have significant correlation between carbapenems and HO-CDI in matched months (ρ = 0.37, P = .098), but a significant correlation was observed when a 1-month lag was applied (ρ = 0.54, P = .014). Discussion Three statistically significant lag associations were observed between FacWide/unit-level antibiotic consumption and HO-CDI, and 1 statistically significant nonlagged association was observed FacWide. Antibiotic consumption may convey extended ward-level risk for incident CDI. Conclusions Consumption of antibiotic agents may have immediate and prolonged influence on incident CDI. Additional studies are needed to investigate the immediate and delayed associations between antibiotic consumption and C difficile colonization, infection, and transmission at the hospital level.

Background Although the exposure-dependent efficacy thresholds of vancomycin have been probed, less is known about acute kidney injury (AKI) thresholds for this drug. Sensitive urinary biomarkers, such as kidney injury molecule 1 (KIM-1), have shown high sensitivity and specificity for vancomycin-associated AKI. The aims of the study were to determine if there were dose–response curves with urinary KIM-1, and to evaluate the impact of therapy duration and sex on observed relationships. Methods A systematic review was conducted via PubMed/MEDLINE. Data were compiled from preclinical studies that reported individual subject data for urinary KIM-1 concentrations, vancomycin dose (mg/kg), duration of treatment, and sex. Sigmoidal Hill-type models were fit to the individual dose-response data. Results A total of 15 studies were identified, 6 of which reported vancomycin dose and KIM-1 data. Of these, three included individual animal-level data suitable for analysis. For all pooled rats, increasing total daily vancomycin doses displayed a dose-response curve with urinary KIM-1 concentrations (50% maximal toxic response=130.4 mg/kg/day). Dose-response curves were shifted left for females vs. males (P = 0.05) and for long (i.e. ≥7 days) vs. short (i.e. Conclusions The collective findings demonstrate a clear dose–response relationship between vancomycin dose and AKI. As these analyses focused exclusively on dose-response relationships, additional preclinical data are needed to more clearly define vancomycin exposures that predict the onset of AKI.

Vancomycin has been associated with acute kidney injury (AKI). However, the pharmacokinetic/toxicodynamic relationship for AKI is not well defined. Allometrically scaled vancomycin exposures were used to assess the relationship between vancomycin exposure and AKI. Male Sprague-Dawley rats received clinical-grade vancomycin in normal saline (NS) as intraperitoneal (i.p.) injections for 24- to 72-h durations with doses ranging 0 to 200 mg/kg of body weight divided once or twice daily. Urine was collected over the protocol's final 24 h. Renal histopathology was qualitatively scored. Urinary biomarkers (e.g., cystatin C, clusterin, kidney injury molecule 1 [KIM-1], osteopontin, lipocalin 2/neutrophil gelatinase-associated lipocalin 2) were assayed using a Luminex xMAP system. Plasma vancomycin concentrations were assayed by high-performance liquid chromatography with UV detection. A three-compartment vancomycin pharmacokinetic model was fit to the data with the Pmetrics package for R. The exposure-response in the first 24 h was evaluated using Spearman's nonparametric correlation coefficient ( r s ) values for the area under the concentration-time curve during the first 24 h (AUC 0–24 ), the maximum concentration in plasma during the first 24 h (C max 0–24 ), and the lowest (minimum) concentration in plasma after the dose closest to 24 h (C min 0–24 ). A total of 52 rats received vancomycin ( n = 42) or NS ( n = 10). The strongest exposure-response correlations were observed between AUC 0–24 and C max 0–24 and urinary AKI biomarkers. Exposure-response correlations ( r s values) for AUC 0–24 , C max 0–24 , and C min 0–24 were 0.37, 0.39, and 0.22, respectively, for clusterin; 0.42, 0.45, and 0.26, respectively, for KIM-1; and 0.52, 0.55, and 0.42, respectively, for osteopontin. However, no differences in histopathological scores were observed. Optimal sampling times after administration of the i.p. dose were 0.25, 0.75, 2.75, and 8 h for the once-daily dosing schemes and 0.25, 1.25, 14.5, and 17.25 h for the twice-daily dosing schemes. Our observations suggest that AUC 0–24 or C max 0–24 correlates with increases in urinary AKI biomarkers.

In 2010, the Clinical and Laboratory Standards Institute (CLSI) lowered carbapenem breakpoints to reduce the proportion of ‘susceptible’ organisms that produced carbapenemases. Few studies have evaluated the effect of this change on clinical outcomes. This systematic review aimed to evaluate the effect of carbapenem MICs on 30-day mortality from pooled patient-level data from studies of patients treated with carbapenems across a range of meropenem MICs. PubMed was searched to March 2019 with the terms ‘carbapenem’, ‘meropenem’, ‘imipenem’, ‘doripenem’, ‘ertapenem’, ‘susceptibility’ and ‘outcomes’. Studies were included in the analysis if patients had Enterobacteriaceae bacteraemia treated with a carbapenem for ≥48 h and mortality was reported. Studies were excluded if all isolates were either susceptible or resistant to meropenem based on CLSI 2010 breakpoints or if only carbapenemase-producing isolates were included. Authors were contacted for patient-level data. The primary outcome was 30-day mortality, with planned subset analyses of patients treated with meropenem, receiving active combination therapy, treated in the ICU or infected with Klebsiella pneumoniae. Of 157 articles identified, 4 met the inclusion criteria (115 eligible patients). The odds of mortality increased with each increasing meropenem MIC dilution (OR = 1.51, 95% CI 1.06–2.15) as a continuous variable. A similar increase in odds was observed in patients treated with meropenem, treated in the ICU, infected with K. pneumoniae or receiving no other active antimicrobials. Increasing meropenem MICs in Enterobacteriaceae were associated with increased mortality; however, more work is needed to define optimal clinical decision rules for infections within the susceptible range.

Urinary biomarkers are superior to serum creatinine for defining onset and extent of kidney injury. This study classifies the temporal predictive ability of biomarkers for vancomycin-induced kidney injury (VIKI) as defined by histopathologic damage. Male Sprague-Dawley rats (n = 125) were randomized to receive 150 to 400 mg/kg of body weight/day vancomycin via once or twice daily intraperitoneal injection over 1, 3, or 6 days. Urine was collected once during the 24 h prior to euthanasia or twice for rats treated for 6 days. Receiver operating characteristic (ROC) curves were employed to assess the urinary biomarker performances of kidney injury molecule 1 (KIM-1), clusterin, osteopontin (OPN), cystatin C, and neutrophil gelatinase-associated lipocalin (NGAL) to predict histopathologically defined VIKI (using a national standard pathological assessment scheme from hematoxylin and eosin stained kidneys). Urinary KIM-1, clusterin, and OPN outperformed cystatin C and NGAL with regard to sensitivity and specificity. For the earliest injury, urinary KIM-1 (area under the receiver operating characteristic curve [AUC], 0.662; P < 0.001) and clusterin (AUC, 0.706; P < 0.001) were the most sensitive for predicting even low-level histopathologic damage at 24 h compared to NGAL. KIM-1 and clusterin are the earliest and most sensitive predictors of VIKI. As injury progresses, KIM-1, clusterin, and OPN best define the extent of damage.

In this paper, I introduce Plan Your Brisbane, a web-based, mobile-responsive game produced by Brisbane City Council. The game was developed as a platform for civic engagement with Brisbane residents to seek feedback and build consensus around a charter of principles to help guide future city planning decisions and the need to accommodate an estimated additional 386,000 residents by 2041. Plan Your Brisbane was available online between 18 February and 16 April 2018 and attracted 100,869 players. The game was particularly successful in engaging residents in the usually difficult to reach 18--24 and 25--34 age demographics. Plan Your Brisbane contributes to the game design community by demonstrating that games can facilitate civic engagement across all age demographics, even on complex issues such as city planning. This paper introduces the design process and design rationales of the game and shares some of the results.

Objectives To identify the pharmacokinetic (PK) and toxicodynamic (TD) relationship for vancomycin-induced kidney injury. Methods Male Sprague–Dawley rats received intravenous (iv) vancomycin. Doses ranging from 150 mg/kg/day to 400 mg/kg/day were administered as a single or twice-daily injection over 24 h (total protocol duration). Controls received iv saline. Plasma was sampled with up to eight samples in 24 h per rat. Twenty-four hour urine was collected and assayed for kidney injury molecule 1 (KIM-1), osteopontin and clusterin. Vancomycin in plasma was quantified via LC-MS/MS. PK analyses were conducted using Pmetrics for R. PK exposures during the first 24 h (i.e. AUC0–24h, Cmax 0–24h and Cmin 0–24h) were calculated. PK/TD relationships were assessed with Spearman’s rank coefficient (rs) and the best-fit mathematical model. Results PK/TD data were generated from 45 vancomycin-treated and 5 control rats. A two-compartment model fit the data well (Bayesian: observed versus predicted R2 = 0.97). Exposure–response relationships were found between AUC0–24h versus KIM-1 and osteopontin (R2 = 0.61 and 0.66) and Cmax 0–24h versus KIM-1 and osteopontin (R2 = 0.50 and 0.56) using a four-parameter Hill fit. Conversely, Cmin 0–24h was less predictive of KIM-1 and osteopontin (R2 = 0.46 and 0.53). A vancomycin AUC0–24h of 482.2 corresponded to a 90% of maximal rise in KIM-1. Conclusions Vancomycin-induced kidney injury as defined by urinary biomarkers is driven by vancomycin AUC or Cmax rather than Cmin. Further, an identified PK/TD target AUC0–24h of 482.2 mg·h/L may have direct relevance to human outcomes.

tudy Objective To evaluate the steady-state pharmacokinetic parameters of standard cefepime dosing regimens in a hematologic malignancy and hematopoietic cell transplant patient population with febrile neutropenia. Design Open-label, single-center, prospective pharmacokinetic study. Setting National Cancer Institute–designated cancer center. Patients Nine adults with hematologic malignancies or hematopoietic cell transplants who had febrile neutropenia and were admitted to a hematology-oncology service between January and July 2014. Intervention Patients received empirical cefepime 2 g every 8 hours, administered as a 30-minute intravenous infusion, for febrile neutropenia. Measurements and Main Results Steady-state cefepime serum concentrations were measured after at least 2 days of continuous therapy. Venous blood samples were intensively sampled between 0 and 8 hours after the start of the 30-minute infusion at steady state. Seven of the nine patients had a hematologic malignancy diagnosis of acute leukemia, lymphoma, or myeloma, and two patients had a germ cell tumor diagnosis. Noncompartmental analysis revealed mean ± SD parameters as follows at steady state: area under the plasma concentration–time curve from 0–8 hours 222.9 ± 72.9 mg hour/L, maximum concentration 120.9 ± 21.8 mg/L, clearance 9.7 ± 3.7 L/hour, apparent volume of distribution 19.2 ± 4.65 L, and elimination half-life 1.4 ± 0.3 hours. A one-compartment pharmacokinetic model identified a mean ± SD volume of distribution of 20.9 ± 1.3 L and an elimination rate constant of 0.39 ± 0.03 hour−1. The mean estimated percentage of time that drug concentration remains above the pathogen minimum inhibitory concentration (fT>MIC) in serum was 55%, 77%, and 99% at MICs of 16, 8, and 4 mg/L, respectively. Conclusion Patients with hematologic malignancies or hematopoietic cell transplants who had febrile neutropenia demonstrated homogeneous calculated cefepime volumes and clearances. The population parameters presented in this study may aid in the calculation of patient-specific fT>MIC for similar patients.

Objectives Centhaquin citrate is a novel agent that is being developed for use in the resuscitation of patients with haemorrhagic shock. While pharmacokinetics have been described in small animal models, the pharmacokinetic parameters of centhaquin citrate in large mammals have yet to be described. Methods Four healthy Beagle dogs (two males and two females) were given an intravenous bolus of 1.0 mg/kg centhaquin citrate. Plasma concentrations were measured at baseline and at ten time points within 24 h after administration. Multiple compartmental models were built and compared. The nonparametric adaptive grid function within the Pmetrics package for R was used for parameter estimation. Predicted concentrations were calculated using population mean and individual Bayesian posterior parameters. Key Findings Centhaquin citrate pharmacokinetic parameters were best described using a two-compartment model. Median (IQR) values for Ke, Vc, Vp, Kcp and Kpc were 4.9 (4.4–5.2) h−1, 328.4 (304.0–331.9) l, 1000.6 (912.3–1042.4) l, 10.6 (10.3–11.1) h−1 and 3.2 (2.9–3.7) h−1, respectively. Conclusions Pharmacokinetic parameters of centhaquin citrate in a large mammal have been described. A large volume of distribution and rapid elimination were observed, consistent with previous work in rats.

Purpose The objective of this communication was to determine the intravenous compatibility of ceftazidime/avibactam and aztreonam using simulated and actual Y-site administration. Methods Ceftazidime–avibactam was reconstituted and diluted to concentrations of 8, 25, and 50 mg/mL in 0.9% sodium chloride. Aztreonam was reconstituted and diluted to concentrations of 10 and 20 mg/mL. Each combination of concentrations was tested for compatibility using visual, Tyndall beam, microscopy, turbidity, and pH assessments. Microscopy results were compared to those from sodium chloride 0.9% in water, pH was compared to that at time 0, and turbidity of combinations was compared to that of individual agents. Actual Y-site mixing was conducted over 2-h infusions with samples collected at 0, 1, and 2 h. Test results were evaluated at 0, 1, 2, 4, 8, and 12 h after mixing. All experiments were completed in triplicate. Findings Across simulated and actual Y-site experiments, no evidence of incompatibility between combinations of ceftazidime–avibactam + aztreonam was observed. Visual and microscopic tests revealed no particulate matter, color changes, or turbidity. Tyndall beam tests were negative with all combinations. No evidence of incompatibility was observed in turbidity testing. The pH values were consistent across each of the 6 combinations, from immediately after mixing until 12 h after mixing. When the addition of agents was reversed in simulated Y-site experiments, no differences in compatibility were observed. No differences in compatibility between actual and simulated Y-site administration were observed, and there was minimal variability across all replicate experiments. Implications Ceftazidime–avibactam, at concentrations of 8, 25, and 50 mg/mL, appeared compatible with aztreonam at concentrations of 10 and 20 mg/mL.

The efficacy of cefazolin with high-inoculum methicillin-susceptible Staphylococcus aureus (MSSA) infections remains in question due to therapeutic failure inferred as being due to an inoculum effect (InE). This study investigated the local prevalence of a cefazolin InE (CInE) and its association with staphylococcal blaZ gene types among MSSA isolates in the Chicago area. Four medical centers in Chicago, IL, contributed MSSA isolates. Cefazolin MICs (C-MIC) were determined at 24 h by the broth microdilution method using a standard inoculum (SI; 5 × 105 CFU/ml) and a high inoculum (HI; 5 × 107 CFU/ml). The CInE was defined as (i) a ≥4-fold increase in C-MIC between SI and HI and/or (ii) a pronounced CInE, i.e., a nonsusceptible C-MIC of ≥16 μg/ml at HI. PCR was used to amplify the blaZ gene, followed by agarose gel electrophoresis and sequencing to determine the gene type. Approximately 269 MSSA isolates were included. All but one isolate were susceptible to cefazolin at SI, and 97% remained susceptible at HI. A total of 196 isolates (73%) were blaZ positive, with the blaZ types led by gene type C (40%). CInE was seen in 45 blaZ-positive isolates (23%), with 44 (22%) presenting a ≥4-fold increase in C-MIC (SI to HI) and 5 (3%) a pronounced CInE. Four of the five met both definitions of CInE, two of which expressed the type A gene. The prevalence of a pronounced CInE associated with the type A blaZ gene from MSSA isolates in Chicago is low. Our predilection for cefazolin use, even early in the management of hospitalized MSSA infections, is tenable.

Background Combination therapy is often employed in the treatment of PSA infections. Agents commonly used in combination with β-lactams include aminoglycosides, polymyxins, and fluoroquinolones but are limited by resistance and toxicity concerns. The use of dual β-lactam therapy is an emerging area of interest for the treatment of patients with resistant Gram-negative pathogens. This study evaluated synergy between β-lactam agents and aztreonam (ATM) against PSA isolates with varying degrees of susceptibility. Methods 4 PSA clinical isolates were collected from Albany Medical Center; 1 ATCC isolate was used (Table 1). Synergy with cefepime (FEP), meropenem (MER), and ceftazidime (CAZ), each in combination with ATM, was assessed using fractional inhibitory concentration index determined by checkerboard method. Synergistic combinations were tested in 24-hour time-kill, utilizing minimum and steady-state physiological concentrations (Cmin and Css). Tested bacteria were grown to late log phase, diluted to 1 × 106 cfu/mL and incubated at 37°C for 24 hours. Samples were drawn at 0, 2, 4, 6 and 24 hours. Synergy in time-kill was defined as ≥ 2 log10 cfu/mL kill greater than the most active individual agent at 24 hours. Results In checkerboard studies, combinations with ATM resulted in 80% synergy with FEP and 60% synergy with MER or CAZ combinations. ATM/MER and ATM/CAZ time-kill experiments resulted in indifference for most organisms and concentrations tested. For both single and combination regimens, initial killing was observed but varying degrees of regrowth occurred by 24 hours. The only strain with no regrowth at 24 hours was AMC-PSA2 (bactericidal activity and no regrowth at 24 hours observed for MER Cmin MER Css, and MER+ATM Css). Against AMC-PSA2, CAZ+ATM at Cmin was synergistic with limited regrowth observed. Conclusion Against PSA, tested β-lactam combinations with ATM resulted in lack of synergy in time-kill experiments, despite checkerboard results. Due to the extent of regrowth observed with nearly all single agent and combination regimens, testing of alternative combinations, including those that evade common resistance mechanisms such as efflux pumps or β-lactamases, and studies of dynamic concentrations are warranted. Disclosures All authors: No reported disclosures.

PURPOSE OF REVIEW: Hospital-acquired and ventilator-associated pneumonia (VAP) are frequent causes of infection among critically ill patients. VAP is the most common hospital-acquired bacterial infection among mechanically ventilated patients. Unfortunately, many of the nosocomial Gram-negative bacteria that cause VAP are increasingly difficult to treat. Additionally, the evolution and dissemination of multi- and pan-drug resistant strains leave clinicians with few treatment options. VAP patients represent a dynamic population at risk for antibiotic failure and under-dosing due to altered antibiotic pharmacokinetic parameters. Since few antibiotic agents have been approved within the last 15 years, and no new agents specifically targeting VAP have been approved to date, it is anticipated that this problem will worsen. Given the public health crisis posed by resistant Gram-negative bacteria, it is essential to establish a firm understanding of the current epidemiology of VAP, the changing trends in Gram-negative resistance in VAP, and the current issues in drug development for Gram-negative bacteria that cause VAP. RECENT FINDINGS: Rapid identification technologies and phenotypic methods, new therapeutic strategies, and novel treatment paradigms have evolved in an attempt to improve treatment outcomes for VAP; however, clinical data supporting alternative treatment strategies and adjunctive therapies remain sparse. Importantly, new classes of antimicrobials, novel virulence factor inhibitors, and beta-lactam/beta-lactamase inhibitor combinations are currently in development. Conscientious stewardship of new and emerging therapeutic agents will be needed to ensure they remain effective well into the future.

Background Bacteraemias caused by MSSA are associated with significant morbidity and mortality. Controversy exists over the optimal treatment of severe infections caused by MSSA. This systematic review and meta-analysis aims to identify whether differences in clinical outcomes exist between cefazolin and antistaphylococcal penicillins (ASPs). Methods PubMed, Cochrane Library and Embase were systematically searched for publications reporting clinical outcomes of cefazolin and ASPs for adult patients with MSSA bacteraemias throughout November 2017. Comparative studies reporting 90 day mortality associated with each treatment were included. Random effects models were used to evaluate the impact of directed treatment agent on the odds of 30 and 90 day mortality, clinical failure, discontinuation due to adverse effects and infection recurrence. Results Five hundred and ninety-nine articles were evaluated for inclusion, of which seven met all inclusion criteria. Across all studies, 1589 patients received cefazolin and 2802 received an ASP. All-cause 90 day mortality was lower in patients who received cefazolin (OR 0.63, 95% CI 0.41-0.99; I2 = 58%). Odds of discontinuation due to adverse events was significantly lower in patients receiving cefazolin (OR 0.25, 95% CI 0.11-0.56; I2 = 13%). No differences in clinical failure were observed (OR 0.85, 95% CI 0.41-1.76; I2 = 74%). Conclusions This meta-analysis identified a significant decrease in mortality associated with cefazolin therapy for MSSA bacteraemia compared with ASPs, though no differences in clinical failure were observed. Additionally, cefazolin appeared to be better tolerated. These results should be interpreted with caution given the uncontrolled and retrospective nature of the included studies.

Piperacillin-tazobactam is a commonly used antibiotic in critically ill patients; however, controversy exists as to whether mortality in serious infections can be decreased through administration by prolonged infusion compared with intermittent infusion. The purpose of this systematic review and meta-analysis was to describe the impact of prolonged infusion piperacillin-tazobactam schemes on clinical endpoints in severely ill patients.We conducted a systematic literature review and meta-analysis searching MEDLINE, Cumulative Index to Nursing and Allied Health Literature, and the Cochrane Library from inception to April 1, 2017, for studies.Mortality rates were compared between severely ill patients receiving piperacillin-tazobactam via prolonged infusion or intermittent infusion. Included studies must have reported severity of illness scores, which were transformed into average study-level mortality probabilities.Two investigators independently screened titles, abstracts, and full texts of studies meeting inclusion criteria for this systematic review and meta-analysis. Variables included author name, publication year, study design, demographics, total daily dose(s), average estimated creatinine clearance, type of prolonged infusion, prevalence of combination therapy, severity of illness scores, infectious sources, all-cause mortality, clinical cure, microbiological cure, and hospital and ICU length of stay. The review identified 18 studies including 3,401 patients who received piperacillin-tazobactam, 56.7% via prolonged infusion. Across all studies, the majority of patients had an identified primary infectious source. Receipt of prolonged infusion was associated with a 1.46-fold lower odds of mortality (95% CI, 1.20-1.77) in the pooled analysis. Patients receiving prolonged infusion had a 1.77-fold higher odds of clinical cure (95% CI, 1.24-2.54) and a 1.22-fold higher odds of microbiological cure (95% CI, 0.84-1.77). Subanalyses were conducted according to high (≥ 20%) and low (20%) average study-level mortality probabilities. In studies reporting higher mortality probabilities, effect sizes were variable but similar to the pooled results.Receipt of prolonged infusion of piperacillin-tazobactam was associated with reduced mortality and improved clinical cure rates across diverse cohorts of severely ill patients.

Vancomycin has been associated with acute kidney injury in preclinical and clinical settings; however, the precise exposure profiles associated with vancomycin-induced acute kidney injury have not been defined. We sought to determine pharmacokinetic/pharmacodynamics indices associated with the development of acute kidney injury using sensitive urinary biomarkers. Male Sprague-Dawley rats received clinical-grade vancomycin or normal saline as an intraperitoneal injection. Total daily doses between 0 and 400 mg/kg of body weight were administered as a single dose or 2 divided doses over a 24-h period. At least five rats were utilized for each dosing protocol. A maximum of 8 plasma samples per rat were obtained, and urine was collected over the 24-h period. Kidney injury molecule-1 (KIM-1), clusterin, osteopontin, cystatin C, and neutrophil gelatinase-associated lipocalin levels were determined using Milliplex multianalyte profiling rat kidney panels. Vancomycin plasma concentrations were determined via a validated high-performance liquid chromatography methodology. Pharmacokinetic analyses were conducted using the Pmetrics package for R. Bayesian maximal a posteriori concentrations were generated and utilized to calculate the 24-h area under the concentration-time curve (AUC), the maximum concentration ( C max ), and the minimum concentration. Spearman's rank correlation coefficient ( r s ) was used to assess the correlations between exposure parameters, biomarkers, and histopathological damage. Forty-seven rats contributed pharmacokinetic and toxicodynamic data. KIM-1 was the only urinary biomarker that correlated with both composite histopathological damage ( r s = 0.348, P = 0.017) and proximal tubule damage ( r s = 0.342, P = 0.019). The vancomycin AUC and C max were most predictive of increases in KIM-1 levels ( r s = 0.438 and P = 0.002 for AUC and r s = 0.451 and P = 0.002 for C max ). Novel urinary biomarkers demonstrate that kidney injury can occur within 24 h of vancomycin exposure as a function of either AUC or C max .

Gamification has been repeatedly framed as an emerging multidisciplinary research field. However, it is unclear how multidisciplinary the field actually is. To answer this question, this paper presents initial results of a broader scoping review of gamification research published between 2010 and 2016. Close to 2,000 peer-reviewed English-language journal and conference papers were identified across 11 databases and categorized by discipline. Results indicate an explosive growth of literature peaking in 2015. Early on, Information and Computing Science dominated the field, to be overtaken by the sum of other disciplines in 2013, education, economics and tourism in specific. This indicates that gamification was initially a field within computer science and HCI and has only recently become truly multi-disciplinary.

While we know that gamification works in some contexts to increase motivation, engagement and enjoyment [14] we don't know if it works in the context of online forms acting as an interface for government digital transactions. In particular, we don't know which form elements lend themselves to gamification; and we don't know how gamification might change the objective measures associated with these kinds of transactions, including: improved user experiences, increases in the uptake of online self-service channels and digital transactions, increases in successfully submitted digital transactions, and decreases in abandoned digital transactions. My research will present recommendations for future use in the design, development, implementation and evaluation of gamified government digital transactions.

Vancomycin has been associated with acute kidney injury (AKI). However, the pharmacokinetic/toxicodynamic relationship for AKI is not well defined. Allometrically scaled vancomycin exposures were used to assess the relationship between vancomycin exposure and AKI. Male Sprague-Dawley rats received clinical-grade vancomycin in normal saline (NS) as intraperitoneal (i.p.) injections for 24- to 72-h durations with doses ranging 0 to 200 mg/kg of body weight divided once or twice daily. Urine was collected over the protocol's final 24 h. Renal histopathology was qualitatively scored. Urinary biomarkers (e.g., cystatin C, clusterin, kidney injury molecule 1 [KIM-1], osteopontin, lipocalin 2/neutrophil gelatinase-associated lipocalin 2) were assayed using a Luminex xMAP system. Plasma vancomycin concentrations were assayed by high-performance liquid chromatography with UV detection. A three-compartment vancomycin pharmacokinetic model was fit to the data with the Pmetrics package for R. The exposure-response in the first 24 h was evaluated using Spearman's nonparametric correlation coefficient (rs) values for the area under the concentration-time curve during the first 24 h (AUC0-24), the maximum concentration in plasma during the first 24 h (Cmax0-24 ), and the lowest (minimum) concentration in plasma after the dose closest to 24 h (Cmin0-24 ). A total of 52 rats received vancomycin (n = 42) or NS (n = 10). The strongest exposure-response correlations were observed between AUC0-24 and Cmax0-24 and urinary AKI biomarkers. Exposure-response correlations (rs values) for AUC0-24, Cmax0-24 , and Cmin0-24 were 0.37, 0.39, and 0.22, respectively, for clusterin; 0.42, 0.45, and 0.26, respectively, for KIM-1; and 0.52, 0.55, and 0.42, respectively, for osteopontin. However, no differences in histopathological scores were observed. Optimal sampling times after administration of the i.p. dose were 0.25, 0.75, 2.75, and 8 h for the once-daily dosing schemes and 0.25, 1.25, 14.5, and 17.25 h for the twice-daily dosing schemes. Our observations suggest that AUC0-24 or Cmax0-24 correlates with increases in urinary AKI biomarkers.

Vancomycin is one of the most commonly utilized antibiotics in US hospitals. It remains the drug of choice for the treatment of methicillin-resistant Staphylococcus aureus infections in serious infections. For many of these deep-seated infections, guidelines recommend achieving troughs of 15–20 mg/L for treatment efficacy. At our institution we observed a number of cases of presumed vancomycin-induced acute tubular necrosis clinically diagnosed by the nephrology service. We report eight cases of presumed vancomycin-induced acute tubular necrosis, three of which required hemodialysis before resolution of nephrotoxicity. Only three of the eight patients received nephrotoxins prior to development of nephrotoxicity. All eight patients ultimately recovered renal function following discontinuation.

Alterations in cefepime pharmacokinetic (PK) exposure and decreased bacterial susceptibility increase the risk of treatment failure. The impact of susceptible-dose-dependent (SDD) minimum inhibitory concentrations (MICs), i.e. 4-8 µg/mL, on target attainment rates for cefepime in febrile neutropenia (FN) is unclear. We sought to identify optimal cefepime regimens against SDD cefepime MICs in FN using a modelling and simulation approach. Creatinine clearance (CLCr) and body surface area (BSA) covariate-adjusted models of clearance were evaluated. Monte Carlo simulations representing 10 000 patients were completed to assess various dosing strategies (i.e. 3-8 g/day infused over 0.5-24 h, replaced every 6-24 h) and predict probabilities of target attainment (PTAs) for unbound cefepime. Nine patients received cefepime 2 g every 8 h (q8h) (0.5-h infusion). A two-compartment PK model with BSA- and CLCr-adjusted clearance was fit to the data. Mean population values for total clearance (6.3 ± 1.1 L/h), intercompartmental clearance (6.9 ± 2.8 L/h), and central (14.8 ± 3.8 L) and peripheral (10.9 ± 4.6 L) distribution volumes were all estimated with

Background Novel antibiotics will not be available to combat the threat of MBLs until 2021. One strategy to overcome MBLs is to combine CAZ-AVI + ATM. ATM is not hydrolysed by MBLs and AVI offers protection for ATM and CAZ vs. ESBLs and AmpCs. The combination also offers a theoretical advantage to inactivating multiple PBPs by using dual β-lactam therapy. Our objective was to define optimal dosing profiles for clinical use of ATM to add to CAZ-AVI in the hollow fiber infection model (HFIM). Methods E. coli ARLG-1013 (blaNDM-1, blaCTX-M, blaCMY, blaTEM) and K. pneumoniae ARLG-1002 (blaNDM-1, blaCTXM-15, blaDHA, blaSHV, blaTEM) were studied at a 7.5 log10 CFU/mL in the HFIM. Human dosing regimens of CAZ-AVI 2 g/0.5 g q8h (2 hours infusion) and ATM 2 g q8h (2 hours infusion) were simulated in alone and in combination. Continuous infusion (CI) regimens of CAZ-AVI 6 g/1.5 g per day CI + ATM 6 g/day CI and q8h regimens were given simultaneously and sequentially (ATM given 2 hours after CAZ-AVI). Resistant subpopulations were profiled on single (ATM), double (CAZ/AVI) and triple (ATM/CAZ/AVI) drug plates containing 2/2/4, 8/8/4, or 32/32/4 mg/L over 7 days. Results Against E. coli ARLG-1013, ATM alone mirrored growth control (+3.14 at 168 hours) (All units Log10 CFU/mL change vs. baseline). CAZ-AVI alone showed some intrinsic activity (+1.19 at 168 hours). CAZ-AVI 2g/0.5g q8h (2 hours infusion) + ATM 2g q8h (2 hours infusion) given sequentially resulted regrowth and stasis (+0.34 at 168 hours) vs. the simultaneous combination resulted initial bactericidal activity (-3.53 killing within 28 hours) which regrew at (−0.90 at 168 hours). All CI regimens were effective. CAZ-AVI 6g/1.5g per day CI + ATM 6 g/day CI resulted in dramatic killing (up to -5.78 killing within 50 hours) which was sustained (up to -3.90 killing at 168 hours). Comparing the infusion time of CAZ/AVI + ATM on bacterial killing: CI + CI > 2 hours + 2 hours > 30 minutes + 30 minutes. CI + CI resulted in complete suppression of resistance over 7 days. Against K. pneumoniae ARLG-1002, CAZ/AVI (CI) + ATM (CI) resulted in early synergy (>5.0 log killing within 24 hours) and suppression of resistance for more than 168 hours. Conclusion The combination of CAZ-AVI + ATM was highly synergistic and suppressed resistance against MBL Enterobacteriaceae in HFIM. ATM efficacy in combination was driven by %T > MIC. A Phase I study will assess safety to provide patients a critically important solution against “untreatable” Gram negatives. Disclosures T. P. Lodise, paratek: Consultant and Scientific Advisor, Consulting fee. B. T. Tsuji, Nabriva: Consultant, Consulting fee. Achaogen: Grant Investigator, Educational grant. ARLG, DCRI: Grant Investigator, Grant recipient. NIH/NIAID: Grant Investigator, Grant recipient.

Background Clostridium difficile infection (CDI) is a significant cause of morbidity and mortality. IDSA guidelines recommend oral vancomycin (VAN) for the treatment of CDI, although doses used in practice vary substantially. The purpose of this study was to determine differences in outcomes between patients treated with high dose (HD; ≥250 mg four times daily [QID]) vs. standard dose (SD; 125 mg QID) VAN for CDI. Methods This multicenter study evaluated patients at two hospitals in Albany, NY diagnosed with CDI and treated with oral VAN between January 2013 and August 2017. Hospitalized patients were included if: age ≥18 years, positive C. difficile toxin polymerase chain reaction (PCR), symptomatic infection (e.g., new onset or increased frequency of loose stools), and received ≥48 hours of VAN QID. Patients were excluded if: received ≥48 hours of metronidazole prior to VAN initiation, VAN per rectum, required surgical intervention ≤48 hours from PCR, had a history of fecal microbiota transplant, received ≥1 dose of fidaxomicin or tigecycline prior to or within 48 hours from PCR, or died ≤48 hours from PCR. The primary outcome was 90-day CDI recurrence; secondary outcomes included 30-day all-cause mortality and 90-day readmission. Variables with a P-value Results Four hundred fifty-eight patients were included (site 1: 270; site 2: 188). Two hundred twenty-four patients received SD VAN (48.9%); 234 received HD VAN [250 mg QID: 199 (43.5%); 500 mg QID: 35 (7.6%)]. Baseline demographics were similar between groups. Patients treated with HD were more likely to present with colitis (19.2 vs. 29.5%, P = 0.01) and have higher infection severity based on IDSA (P < 0.01), Zar (P < 0.01), and American College of Gastroenterology (P < 0.02) criteria. Modified APACHE II scores were similar between SD and HD groups (median: 12.2 vs. 12.9, P = 0.17). MV analysis identified no difference in 90-day recurrence with HD (OR 1.65, P = 0.13) after controlling for solid tumor cancers, immunosuppression, and IDSA severity. Similarly, no significant differences between SD and HD were observed for 30-day mortality and 90-day readmission. Conclusion No differences in recurrence, mortality, or readmission were identified between SD and HD oral VAN for the treatment of CDI, though HD VAN patients primarily received 250 mg QID. Disclosures All authors: No reported disclosures.

Carbapenems are primary agents used to treat a variety of Gram-negative multi-drug resistant infections. In parallel with increasing use, increasing resistance to carbapenem agents has manifested as increased minimum inhibitory concentrations (MICs). To attempt to improve clinical outcomes with carbapenems, the Clinical Laboratory Standards Institute and the Food Drug Administration decreased susceptibility breakpoints. The European equivalent expert committee, the European Committee on Antimicrobial Susceptibility Testing, also utilizes lower MIC susceptibility breakpoints. This review focuses on the rationale for recent breakpoint changes and the associated clinical outcomes for patients treated with carbapenems for infections with varying MICs proximal to the breakpoint. Supporting pharmacokinetics and pharmacodynamics that underpin the breakpoints are also reviewed.

Purpose The compatibility of vancomycin and piperacillin–tazobactam in concentrations typically used in extended-infusion dosing schemes was evaluated. Methods Piperacillin–tazobactam was reconstituted and diluted to concentrations of 33.75, 45, 50, 60, 67.5, 80, and 90 mg/mL. Vancomycin was diluted to concentrations of 4–8, 10, and 12 mg/mL. The resultant admixtures were visually observed after preparation against black and white backgrounds each hour between hours 1 through 4 and after 24 hours. Frozen products of each medication and brand-name Zosyn powder for reconstitution also were studied. Each combination of products and concentrations was tested for precipitation using simulated Y-site administration. Absorbance and microscopic analyses were performed to discern less perceptible incompatibilities in combinations that did not result in visual precipitation. Changes in absorbance were evaluated using two-way repeated-measures analysis of variance with post hoc Bonferroni corrections. Results No tested concentrations of piperacillin–tazobactam showed precipitations with vancomycin up to concentrations of 7 mg/mL. Piperacillin–tazobactam 80–90 mg/mL formed reversible precipitation with vancomycin 8 mg/mL. All tested concentrations of piperacillin–tazobactam formed a reversible precipitate with vancomycin 10 mg/mL. Irreversible precipitation was noted with all combinations of piperacillin–tazobactam and vancomycin 12 mg/mL. No significant changes in absorbance analyses were identified for all tested piperacillin–tazobactam concentrations and vancomycin 4–10 mg/mL compared with 0.9% sodium chloride injection ( p > 0.05). Similar results were observed using frozen preparations and brand-name Zosyn. Conclusion Visual, microscopic, and absorbance analyses showed no evidence of incompatibility when piperacillin–tazobactam 33.75–90 mg/mL was combined with vancomycin ≤7 mg/mL. Reversible and irreversible precipitates formed when piperacillin–tazobactam was combined with vancomycin ≥8 mg/mL.

Increasingly, infectious disease studies employ tree-based approaches, e.g., classification and regression tree modeling, to identify clinical thresholds. We present tree-based-model-derived thresholds along with their measures of uncertainty. We explored individual and pooled clinical cohorts of bacteremic patients to identify modified acute physiology and chronic health evaluation (II) (m-APACHE-II) score mortality thresholds using a tree-based approach. Predictive performance measures for each candidate threshold were calculated. Candidate thresholds were examined according to binary logistic regression probabilities of the primary outcome, correct classification predictive matrices, and receiver operating characteristic curves. Three individual cohorts comprising a total of 235 patients were studied. Within the pooled cohort, the mean (± standard deviation) m-APACHE-II score was 13.6 ± 5.3, with an in-hospital mortality of 16.6%. The probability of death was greater at higher m-APACHE II scores in only one of three cohorts (odds ratio for cohort 1 [OR 1 ] = 1.15, 95% confidence interval [CI] = 0.99 to 1.34; OR 2 = 1.04, 95% CI = 0.94 to 1.16; OR 3 = 1.18, 95% CI = 1.02 to 1.38) and was greater at higher scores within the pooled cohort (OR 4 = 1.11, 95% CI = 1.04 to 1.19). In contrast, tree-based models overcame power constraints and identified m-APACHE-II thresholds for mortality in two of three cohorts ( P = 0.02, 0.1, and 0.008) and the pooled cohort ( P = 0.001). Predictive performance at each threshold was highly variable among cohorts. The selection of any one predictive threshold value resulted in fixed sensitivity and specificity. Tree-based models increased power and identified threshold values from continuous predictor variables; however, sample size and data distributions influenced the identified thresholds. The provision of predictive matrices or graphical displays of predicted probabilities within infectious disease studies can improve the interpretation of tree-based model-derived thresholds.