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Cefepime is a broad-spectrum fourth-generation cephalosporin with activity against Gram-positive and Gram-negative pathogens. It is generally administered as an infusion over 30-60 min or as a prolonged infusion with infusion times from 3 h to continuous administration. Cefepime is widely distributed in biological fluids and tissues with an average volume of distribution of ~ 0.2 L/kg in healthy adults with normal renal function. Protein binding is relatively low (20%), and elimination is mainly renal. About 85% of the dose is excreted unchanged in the urine, with an elimination half-life of 2-2.3 h. The pharmacokinetics of cefepime is altered under certain pathophysiological conditions, resulting in high inter-individual variability in cefepime volume of distribution and clearance, which poses challenges for population dosing approaches. Consequently, therapeutic drug monitoring of cefepime may be beneficial in certain patients including those who are critically ill, have life-threatening infections, or are infected with more resistant pathogens. Cefepime is generally safe and efficacious, with a goal exposure target of 70% time of the free drug concentration over the minimum inhibitory concentration for clinical efficacy. In recent years, reports of neurotoxicity have increased, specifically in patients with impaired renal function. This review summarizes the pharmacokinetics, pharmacodynamics, and toxicodynamics of cefepime contemporarily in the setting of increasing cefepime exposures. We explore the potential benefits of extended or continuous infusions and therapeutic drug monitoring in special populations.

Enteropathy is prevalent in tuberculosis-endemic areas, and it has been shown to impair intestinal absorptive function; therefore, enteropathogen burden might negatively affect antimycobacterial pharmacokinetics, particularly among malnourished children. We sought to quantify enteropathogen burden among children initiating tuberculosis treatment in rural Tanzania and determine the effect of enteropathogen burden on serum antimycobacterial pharmacokinetics.We performed a prospective cohort study at one site in rural Tanzania as an exploratory substudy of a large multicountry cohort study. We included children younger than 15 years of age with confirmed or probable tuberculosis undergoing treatment with first-line tuberculosis therapy; children were excluded from the study if they were unable to undergo sample collection. Participants were consecutively recruited from the inpatient paediatric wards or the outpatient tuberculosis clinic at Haydom Lutheran Hospital, Tanzania. The main outcome was to quantify symptomatic enteropathogen burden and the effect on serum antimycobacterial pharmacokinetics. We quantified enteropathogen burden (defined as the sum of distinct enteropathogens detected in stool) using a multipathogen PCR capable of simultaneous detection of 37 bacterial, viral, and parasitic species or species groups from stool collected within 72 h of treatment initiation. Comprehensive clinical assessment, including presence of gastrointestinal symptoms, was performed at baseline, and serum was collected approximately 2 weeks after treatment initiation at steady state and throughout the dosing interval with concentrations of isoniazid, rifampicin, pyrazinamide, and ethambutol measured by liquid chromatography with a tandem mass spectrometry assay to quantify peak (C58 children were assessed for eligibilty and enrolled between June 25, 2016, and Feb 6, 2018; 44 had complete stool testing and serum pharmacokinetic data, and they were included in the analyses. 20 (45%) were female, and 24 (55%) were male. 37 (84%) had moderate or severe malnutrition. A mean of 2·1 (SD 1·3) enteropathogens were detected per participant. Target peak concentrations of rifampicin were reached in eight (18%) of 44 participants, isoniazid in 24 (54%) of 44 participants, pyrazinamide in 28 (74%) of 38 participants, and ethambutol in six (15%) of 39 participants. Compared with controlled comparisons, each summative additional bacterial enteropathogen detected was associated with a 40% lower rifampicin CTanzanian children undergoing tuberculosis treatment rarely attained pharmacokinetic targets; enteropathogen carriage was common and enteropathogen burden was associated with significant reductions in the concentrations of some antimycobacterial drugs. Further research should explore mechanistic relationships of individual pathogens and antimycobacterial pharmacokinetics in larger cohorts, or determine if screening for and treating enteropathogens at tuberculosis treatment initiation improves pharmacokinetic target attainment.National Institute of Allergy and Infectious Diseases, National Institutes of Health.For the Swahili translation of the abstract see Supplementary Materials section.

Although linezolid is effective for multidrug-resistant TB (MDR-TB) tuberculosis treatment, it is associated with cytopenias after 4 weeks of administration. Data on toxicities with long-term use of linezolid and drug pharmacodynamics in MDR-TB treatment are limited, and concerns about toxicity present barriers to wider implementation. This was a secondary analysis of a prospective cohort study of patients treated for MDR-TB in the country of Georgia from 2015 to 2017. Intensive blood sampling 4 to 6 weeks after treatment initiation with linezolid 600 mg daily was performed for pharmacokinetic (PK) analysis, including linezolid trough concentration (C(min)) and area under the curve from 0 to 24 hours (AUC(0–24)). Linezolid exposure was defined using literature-reported thresholds. Cytopenias were defined using an NIH adverse event (AE) scale. Logistic regression was used to evaluate the relationship between linezolid exposure and cytopenias. Among 76 patients receiving linezolid in their baseline treatment regimen and who had PK data available, cytopenia AEs occurred in 30 (39.5%) for an incidence rate of 46 per 100 person-years. The median duration of linezolid therapy was 526 days. No patients required dose reduction or interruption due to cytopenias. Median linezolid C(min) was 0.235 mg/L (interquartile range [IQR], 0.069 to 0.529), and median AUC(0–24) was 89.6 mg·h/L (IQR, 69.2 to 116.2). Cytopenias were associated with linezolid PK parameters (C(min) > 2 mg/L and AUC(0–24) > 160 mg·h/L). Cytopenias occurred frequently with long-term use of linezolid 600 mg/day and were associated with PK parameters but did not result in the need for treatment interruption in the management of a cohort of patients with MDR-TB.

Background Beta-lactam therapeutic drug monitoring (BL TDM; drug level testing) can facilitate improved outcomes in critically ill patients. Yet less than 20% of hospitals have implemented BL TDM. The purpose of this study was to characterize provider perceptions and key considerations for successful implementation of BL TDM. Methods This was a sequential mixed methods study from 2020 to 2021 of stakeholders at three academic medical centers with varying degrees of BL TDM implementation - Mayo Clinic (BL TDM not implemented), University of Florida Health Shands (partially implemented), and Royal Brisbane and Women’s Hospital (fully implemented). Stakeholders completed a survey to characterize their knowledge, perceptions, and experience with BL TDM. A diverse group of 30 respondents were then purposively sampled for semi-structured interviews. Results from the two strands were integrated, themes were identified, and findings were situated within implementation science frameworks. Results Among the 138 survey respondents (22% response rate), the majority were physicians (38%) and pharmacists (33%). 71% practiced in critical care and 21% in infectious diseases. The majority of respondents felt BL TDM was relevant to their practice and improved medication effectiveness and safety (Figure 1). Two implementation themes were identified: individual internalization and organizational features. Individuals needed to internalize, make sense of, and agree to BL TDM implementation which was positively influenced by repeated exposure to evidence and expertise. The process of internalization seemed more complex with BL TDM than with other antibiotics (i.e., vancomycin). Organizational considerations relevant to BL TDM implementation included adequate physical and informational infrastructure, access to trained personnel, supportive governance/leadership, and robust process and workflow development. Conclusion We found broad enthusiasm about the relevance and potential benefits of BL TDM among stakeholders. Prior literature suggested the primary barrier to implementation was assay availability, but we identified many more individual and organizational attributes which impacted the scale and spread of BL TDM. Disclosures Sara Ausman, PharmD, Gilead: Honoraria Christina G. Rivera, PharmD, Gilead: Grant/Research Support|Gilead: Honoraria|Insmed: Honoraria Jason Roberts, BPharm(Hons), PhD, FSHP, FISAC, British Society of Chemotherapy: Grant/Research Support|Cipla: Honoraria|Gilead: Advisor/Consultant|MSD: Advisor/Consultant|MSD: Honoraria|Pfizer: Board Member|Pfizer: Honoraria|Qpex: Grant/Research Support|Sandoz: Board Member|Summit: Advisor/Consultant|Wolters Kluwer: Advisor/Consultant Marc H. Scheetz, PharmD, MSc, Abbvie: Advisor/Consultant|Allecra: Grant/Research Support|Merck: Advisor/Consultant|Nevakar: Advisor/Consultant|Nevakar: Grant/Research Support|Premier Healthcare Solutions: Honoraria|Spero: Advisor/Consultant|SuperTrans Medical: Advisor/Consultant|SuperTrans Medical: Grant/Research Support|Takeda: Advisor/Consultant|Third Pole Therapeutics: Advisor/Consultant.

Background Tuberculosis (TB) is the leading cause of death in human immunodeficiency virus (HIV) infected people worldwide. Patients with HIV who have latent TB are 20-30 times more likely to develop active TB. Integrated antiretroviral therapy (ART) early in the treatment for tuberculosis is recommended due to improved morbidity and mortality, however, there can be serious drug interactions. Rifamycins are potent inducers of the CYP3A4 isoform, which can cause sub-therapeutic concentrations of anti-retroviral drugs, among these, rifabutin (RBN) is a less potent inducer of CYP3A4. Pharmacokinetic (PK) studies done on healthy adults showed that rifampin decreased dolutegravir (DTG) concentrations by more than 50 % whereas RBN decreased it by 30%. RBN has been preferred given that its favorable pharmacokinetic and toxicity profile. Currently there are no studies examining the use of RBN and DTG in co-infected persons. This is a case series of 4 co-infected patients receiving both agents who underwent PK analysis. Methods Retrospective analysis of patients in the respiratory care unit (RCU) at Jackson Memorial Hospital in Miami. We included adult patients, admitted to the RCU, with a concomitant diagnosis of HIV and active TB disease who received DTG and RBN, and for which DTG and RBN plasma concentrations were measured for therapeutic drug monitoring (TDM). A non-compartmental analysis was performed and the area under the concentration-time curve (AUC) was calculated for DTG and RBN. Results We report 4 patients (Figure 1) that met criteria and underwent PK analysis. All patients with TB who were treated with RBN had low concentrations of DTG, requiring higher doses of DTG (Table 1 & 2). After adjustments based on PK analysis, there was evidence of a favorable response to treatment in 2 patients, with a less than robust in the 2 others. Adequate suppression of viral load could not be determined for 3 of the patients because of the short observation time. Figure 1:Timelines of patients describing admission and HIV and tuberculosis treatment providedDTG, dolutegravir. RFB, rifabutin. VL, viral load. AFB, Acid fast bacilli. LAD, lymphadenopathy. TAF, Tenofovir alafenamide. FTC, Emtricitabine. TDF, Tenofovir Disoproxil Fumarate. INH, Isoniazid. PYZ, Pyrazinamide. BID, twice a day. QD, daily. IRIS, Immune reconstitution inflammatory syndrome. GU, genitourinary. TB, tuberculosis.Table 1:Patients’ pharmacokinetics of DTGAUCX-Y, area under the concentration-time curve from time X to Y hours; AUC0-tau, area under the concentration-time curve from time zero to the end of the dosing interval; DTG, dolutegravir; TDM, therapeutic drug monitoring. a) AUC0-6 was calculated.Table 2:Patients’ pharmacokinetics of RBNAUCX-Y, area under the concentration-time curve from time X to Y hours; AUC0-tau, area under the concentration-time curve from time zero to the end of the dosing interval; RBN, Rifabutin; TDM, therapeutic drug monitoring. a) All RBN doses given every 24 hours, b) RBN value was trace and AUC was not calculated. Conclusion All patients with HIV and TB who were treated with RBN had low concentrations of DTG. This case series demonstrates that for optimal concomitant use of rifabutin and dolutegravir it is highly recommended to use TDM. Prospective clinical studies are needed to further determine the PK interactions between RBN and DTG and virologic response to treatment. Disclosures All Authors: No reported disclosures.

Data evaluating cefepime thresholds associated with neurotoxicity remain limited. The objectives of this study were to evaluate the incidence of cefepime-related neurotoxicity (CRN) in patients with plasma cefepime concentrations, assess the relationship between cefepime exposure and CRN, investigate clinical factors associated with CRN, and describe electroencephalogram (EEG) abnormalities in CRN.This was a retrospective study of adult inpatients admitted between 2016 and 2018 who received cefepime therapeutic drug monitoring (TDM). Potential CRN cases were identified utilizing a standard definition. The primary outcomes of the study were to determine the incidence of CRN and evaluate the relationship between cefepime trough concentrations, the average daily AUC, and neurotoxicity. Bayesian posteriors were generated for each patient using a cefepime pharmacokinetic (PK) model, and the mean daily area under the concentration-time curve (AUC) was calculated. Multiple regression was performed to assess the association between CRN, cefepime PK, and clinical predictors of neurotoxicity.Four hundred eighty-one patients with 503 hospital encounters received cefepime TDM and were included in the analysis. The incidence of CRN was 4.4% (22/503). Patients with CRN had a higher incidence of renal dysfunction, hypertension, and diabetes mellitus compared to patients without CRN (non-NT). The mean cefepime trough concentration was significantly greater in the CRN patients than in the non-NT group (61.8 ± 33.7 vs. 30 ± 27.7 mg/L, respectively, p = 0.0002). Cefepime trough concentration and renal dysfunction were independently associated with increased risk of CRN in the adjusted multiple regression model. Moderate generalized slowing of the background rhythm was the most common EEG pattern associated with CRN. Delaying cefepime TDM greater than 72 h after the initiation of cefepime was associated with a 3-fold increased risk of CRN.Cefepime should be used cautiously in hospitalized patients with renal dysfunction due to the risk of neurotoxicity. Dose optimization utilizing TDM early in cefepime treatment may minimize adverse effects and improve patient safety.

Hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) are the most common intensive care unit (ICU) infections. We aimed to evaluate the association of early and cumulative beta-lactam pharmacokinetic/pharmacodynamic (PK/PD) parameters with therapy outcomes in pneumonia. Adult ICU patients who received cefepime, meropenem, or piperacillin-tazobactam for HAP or VAP and had its concentration measured were included. Beta-lactam exposure was generated for every patient for the entire duration of therapy, and the time free concentration remained above the MIC (fT(>MIC)) and the time free concentration remained above four multiples of the MIC (fT(>4×MIC)) were calculated for time frames of 0 to 24 h, 0 to 10 days, and day 0 to end of therapy. Regression analyses and machine learning were performed to evaluate the impact of PK/PD on therapy outcomes. A total of 735 patients and 840 HAP/VAP episodes (47% HAP) were included. The mean age was 56 years, and the mean weight was 80 kg. Sequential organ failure assessment (SOFA), hemodialysis, age, and weight were significantly associated with the clinical outcomes and kept in the final model. In the full cohort including all pneumonia episodes, PK/PD parameters at different time windows were associated with a favorable composite outcome, clinical cure, and mechanical ventilation (MV)-free days. In patients who had positive cultures and reported MICs, almost all PK/PD parameters were significant predictors of therapy outcomes. In the machine learning analysis, PK/PD parameters ranked high and were the primary overall predictors of clinical cure. Early target attainment and cumulative target attainment have a great impact on pneumonia outcomes. Beta-lactam exposure should be optimized early and maintained through therapy duration.

Purpose To describe the implementation and operationalization of a β-lactam (BL) therapeutic drug monitoring (TDM) program at a large academic center. Summary BLs are the most used class of antibiotics. Suboptimal antibiotic exposure is a significant concern in hospitalized patients, particularly in those with altered pharmacokinetics. BL-TDM provides clinicians the opportunity to optimize drug concentrations to ensure maximal therapeutic efficacy while minimizing toxicity. However, BL-TDM has not been widely adopted due to the lack of access to assays. The University of Florida Shands Hospital developed a BL-TDM program in 2015. This is a consultative service primarily run by pharmacists and is conducted in all patient care areas. An analysis was performed on the first BL-TDM encounter for 1,438 patients. BL-TDM was most frequently performed for cefepime (61%, n = 882), piperacillin (15%, n = 218), and meropenem (11%, n = 151). BL-TDM was performed a median of 3 days (interquartile range, 1-5 days) from BL initiation. Among patients with available minimum inhibitory concentration (MIC) values and trough concentrations, the pharmacokinetic/pharmacodynamic (PK/PD) target of 100% fT>MIC was attained in 308 patients (88%). BL-TDM resulted in a dosage adjustment in 25% (n = 361) of patients. Conclusion Implementation of a BL-TDM program requires the concerted efforts of physicians, pharmacists, nursing staff, phlebotomists, and personnel in the analytical laboratory. Standard antibiotic dosing failed to achieve optimal PK/PD targets in all patients; utilizing BL-TDM, dose adjustments were made in 1 of every 4 patients.

Background Rifampin-resistant and/or multidrug-resistant tuberculosis (RR/MDR-TB) treatment requires multiple drugs, and outcomes remain suboptimal. Some drugs are associated with improved outcome. It is unknown whether particular pharmacokinetic-pharmacodynamic relationships predict outcome. Methods Adults with pulmonary RR/MDR-TB in Tanzania, Bangladesh, and the Russian Federation receiving local regimens were enrolled from June 2016 to July 2018. Serum was collected after 2, 4, and 8 weeks for each drug’s area under the concentration-time curve over 24 hours (AUC0–24). Quantitative susceptibility of the M. tuberculosis isolate was measured by minimum inhibitory concentrations (MICs). Individual drug AUC0–24/MIC targets were assessed by adjusted odds ratios (ORs) for favorable treatment outcome, and hazard ratios (HRs) for time to sputum culture conversion. K-means clustering algorithm separated the cohort of the most common multidrug regimen into 4 clusters by AUC0–24/MIC exposures. Results Among 290 patients, 62 (21%) experienced treatment failure, including 30 deaths. Moxifloxacin AUC0–24/MIC target of 58 was associated with favorable treatment outcome (OR, 3.75; 95% confidence interval, 1.21–11.56; P = .022); levofloxacin AUC0–24/MIC of 118.3, clofazimine AUC0–24/MIC of 50.5, and pyrazinamide AUC0–24 of 379 mg × h/L were associated with faster culture conversion (HR >1.0, P < .05). Other individual drug exposures were not predictive. Clustering by AUC0–24/MIC revealed that those with the lowest multidrug exposures had the slowest culture conversion. Conclusions Amidst multidrug regimens for RR/MDR-TB, serum pharmacokinetics and M. tuberculosis MICs were variable, yet defined parameters to certain drugs—fluoroquinolones, pyrazinamide, clofazimine—were predictive and should be optimized to improve clinical outcome. Clinical Trials Registration NCT03559582.

Cefepime is the second most common cephalosporin used in U.S. hospitals. We aim to develop and validate a cefepime population pharmacokinetic (PK) model and integrate it into a precision dosing tool for implementation. Two data sets (680 patients) were used to build the cefepime PK model in Pmetrics, and three data sets (34 patients) were used for the validation. A separate application data set (115 patients) was used for the implementation and validation of a precision dosing tool. The model support points and covariates were used to generate the optimal initial dose (OID). Cefepime PK was described by a two-compartment model including weight and creatinine clearance (CrCl) as covariates. The median rate of elimination was 0.30 h(−1) (adults) and 0.96 h(−1) (children), the central volume of distribution was 13.85 L, and the rate of transfer from the central to the peripheral compartments was 1.22 h(−1) and from the peripheral to the central compartments was 1.38 h(−1). After integration in BestDose, the observed versus predicted cefepime concentration fit using the application data set was excellent (R(2) > 0.98), and the median difference between what was observed and what BestDose predicted on a second occasion was 4%. For the OID, cefepime at a 0.5- to 1-g 4-h infusion every 8 to 24 h (q8 to 24 h) with a CrCl of

This study presents the compression response of additively manufactured novel soft porous structures with architected microstructure. Six porous additively manufactured architected periodic structures with two‐fold and four‐fold symmetry were considered. The effect of pore shape and fold symmetry of microstructure on the non‐linear response of a square array of architected pores in a soft polymeric matrix is experimentally investigated. The digital image correlation (DIC) is used for investigating the evolution of strains and deformation during uniaxial tensile tests and compression tests of porous structures. Compression induced instability lead to negative Poisson's ratio, and compaction of porous structures, which is found to depend not only on the shape of the architecture but also the fold symmetry exists in the microstructure's unit cell. Unique architectures with multiple buckling modes and shape transformation are also observed. Two‐fold symmetry structures are found to buckle at lower strains compared to the four‐fold symmetric structure at the same porosity level and produced high compaction and negative Poisson's ratio. The results showed that in addition to pore shape, the fold symmetry could be used effectively to design a new class of soft, active, and reconfigurable devices over a wide range of length scales with desired characteristics.