Association of Skin Microbiome Dynamics With Radiodermatitis in Patients With Breast Cancer.

Importance: The interindividual differences in severity of acute radiation dermatitis are not well understood. To date, the pathomechanism and interplay of microbiome and radiodermatitis before and during treatment remain largely unknown. Objective: To assess the association of skin microbiome baseline composition and dynamics with severity of radiodermatitis in patients undergoing adjuvant radiotherapy for breast cancer. Design, Setting, and Participants: A longitudinal prospective pilot observational study was conducted between January 2017 and January 2019. Sequencing results were received in March 2021, and the data were analyzed from August 2021 to March 2023. This study was performed at an urban academic university cancer center. A total of 21 female patients with breast cancer after surgery were consecutively approached, of which 1 patient withdrew consent before the study started. Exposure: Adjuvant radiotherapy for breast cancer for 7 weeks. Main Outcomes and Measures: The main outcome was the association of baseline skin microbiome composition and its dynamics with the severity of radiodermatitis. A total of 360 skin microbiome samples from patients were analyzed, taken before, during, and after radiotherapy, from both the treated and contralateral healthy sides. The skin microbiome samples were analyzed using 16S (V1-V3) amplicon sequencing and quantitative polymerase chain reaction bacterial enumeration. Results: Twenty female patients with breast cancer after surgery who underwent radiotherapy enrolled in the study had a median (range) age of 61 (37-81) years. The median (range) body mass index of the patients was 24.2 (17.6-38.4). The 16S sequencing revealed that low (<5%) relative abundance of commensal skin bacteria (Staphylococcus epidermidis, Staphylococcus hominis, Cutibacterium acnes) at baseline composition was associated with the development of severe radiodermatitis with an accuracy of 100% (sensitivity and specificity of 100%, P < .001). Furthermore, in patients with severe radiodermatitis, quantitative polymerase chain reaction bacterial enumeration revealed a general non-species-specific overgrowth of skin bacterial load before the onset of severe symptoms. Subsequently, the abundance of commensal bacteria increased in severe radiodermatitis, coinciding with a decline in total bacterial load. Conclusions and Relevance: The findings of this observational study indicated a potential mechanism associated with the skin microbiome for the pathogenesis of severe radiodermatitis, which may be a useful biomarker for personalized prevention of radiodermatitis in patients undergoing adjuvant radiotherapy for breast cancer.

Predicting quantity of cannabis smoked in daily life: An exploratory study using machine learning.

BACKGROUND: Cannabis use is prevalent in the United States and is associated with a host of negative consequences. Importantly, a robust indicator of negative consequences is the amount of cannabis consumed. METHODS: Data were obtained from fifty-two adult, regular cannabis flower users (3+ times per week) recruited from the community; participants completed multiple ecological momentary assessment (EMA) surveys each day for 14 days. In this exploratory study, we used various machine learning algorithms to build models to predict the amount of cannabis smoked since participants' last report including forty-three EMA measures of mood, impulsivity, pain, alcohol use, cigarette use, craving, cannabis potency, cannabis use motivation, subjective effects of cannabis, social context, and location in daily life. RESULTS: Our best-fitting model (Gradient Boosted Trees; 71.15% accuracy, 72.46% precision) found that affects, subjective effects of cannabis, and cannabis use motives were among the best predictors of cannabis use amount in daily life. The social context of being with others, and particularly with a partner or friend, was moderately weighted in the final prediction model, but contextual items reflecting location were not strongly weighted in the final prediction model, the one exception being not at work. CONCLUSIONS: Machine learning approaches can help identify additional environmental and psychological phenomena that may be clinically-relevant to cannabis use.

Enhancement of Hydrate Stability through Substitutional Defects.

Cytosine monohydrate (CM) and anhydrate crystal forms reversibly interconvert under high temperatures or high humidity conditions. Here, we demonstrate through defect engineering the ability to expand the thermal stability range of CM through the targeted creation of quantifiable defects in low-level concentrations. Twelve different molecular dyes with a variety of core structures and charges were screened as potential dopants in CM. CM-dye phases prepared with Congo red (CR), Evans blue (EB), and Azocarmine G (AG) exhibited the highest inclusion levels (up to 1.1 wt %). In these doped isomorphous materials, each dye is presumed to substitute for 4-7 cytosine molecules within the low-rugosity (102) planes of the CM matrixes, thereby creating a quantifiable substitutional defect and an impediment to the cooperative molecular motions which enable the transformation to the anhydrate. Dehydration of materials with these engineered defects requires significantly higher temperatures and proceeds with slower kinetics compared to pure CM. The CM-dye phases also exhibit a reduction in the thermal expansion along key crystallographic axes and yield dehydration products with altered particle morphologies.

Effect of Concurrent Proton Pump Inhibitors With Palbociclib Tablets for Metastatic Breast Cancer.

BACKGROUND: Palbociclib is indicated for the treatment of hormone receptor positive (HR+) human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer (MBC) in combination with an aromatase inhibitor or fulvestrant. Two retrospective studies found that concurrent proton pump inhibitor (PPI) use with palbociclib capsules significantly reduced progression free survival (PFS) versus patients without a PPI. Palbociclib tablets were released in 2020 without restriction on PPI use. No study to date has evaluated the combination of palbociclib tablets with concurrent PPI use. METHODS: Patients were retrospectively evaluated after they received palbociclib tablets for the treatment of HR+ HER2- MBC in the first line setting with or without a PPI. Patients were assigned to the no PPI use arm if they never used a PPI and the PPI use arm if they used a PPI for >50% of the duration of palbocicib therapy. The primary endpoint was PFS. The secondary endpoints included overall survival (OS) and adverse events. RESULTS: Eighty-two patients were identified; 50 in the no PPI use group and 32 in the PPI use group. The median PFS was 20.6 months (95% confidence interval [CI], 16.07 to not estimable) in the no PPI use arm versus 21.0 months (95% CI, 15.15 to not estimable) in the PPI use arm (P = 0.95). Median OS was not reached in either arm. Adverse effects did not differ between arms. CONCLUSION: Use of a concurrent PPI with palbociclib tablets does not significantly reduce PFS in patients treated for HR+ HER2- MBC.

Measuring affect in daily life: A multilevel psychometric evaluation of the PANAS-X across four ecological momentary assessment samples.

While there is strong evidence for the psychometric reliability of the Positive and Negative Affect Schedule-Expanded Form (PANAS-X) in cross-sectional studies, the between- and within-person psychometric performance of the PANAS-X in an intensive longitudinal framework is less understood. As affect is thought to be dynamic and responsive to context, this study investigated the multilevel reliability of PANAS-X Positive Affect, Negative Affect, Fear, Sadness, and Hostility scales. Generalizability theory and structural equation modeling techniques (coefficient ω) were employed in four ecological momentary assessment samples (N = 309; 41,261 reports). Results demonstrate that the PANAS-X scales, including short versions of the Positive and Negative Affect scales, can reliably detect between-person differences. PANAS-X scales also were able to reliably measure within-person change, though these estimates may be impacted by scale content and study design. These results support the use of the PANAS-X in daily life research to intensively measure affect in the natural environment. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Agreement between momentary and retrospective reports of cannabis use and alcohol use: Comparison of ecological momentary assessment and timeline followback indices.

OBJECTIVE: This study compares three methods of cannabis and of alcohol use assessment in a sample of regular cannabis users: (a) ecological momentary assessment (EMA) repeated momentary surveys aggregated to the daily level, (b) EMA morning reports (MR) where participants reported on their total use from the previous day, and (c) retrospective timeline followback (TLFB) interviews covering the same period of time as the EMA portion of the study. We assessed the overall correspondence between these methods in terms of cannabis and alcohol use occasions and also investigated predictors of agreement between methods. METHOD: Forty-nine individuals aged 18-50 (Mage = 24.49, 49% female, 84% White) who reported regular cannabis use completed a 14-day EMA study. At the end of the EMA period, participants returned to the laboratory to complete a TLFB (administered via computer) corresponding to the same dates of the EMA period. RESULTS: Daily aggregated EMA and TLFB reports showed a low to modest agreement for both alcohol and cannabis use. Overall, agreement between EMA and MR was better than agreement between EMA and TLFB, likely because less retrospection is required when only reporting on behavior from the previous day. Quantity and frequency of use differentially predicted agreement across reporting methods when assessing alcohol compared to cannabis. When reporting cannabis use, but not alcohol use, individuals who used more demonstrated higher agreement between EMA and TLFB. CONCLUSIONS: Results suggest that retrospective reporting methods assessing alcohol and cannabis should not be considered a direct "substitute" for momentary or daily assessments. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Outcomes of patients with diffuse large B-cell and high-grade B-cell lymphomas with synchronous CNS and systemic involvement at diagnosis treated with high-dose methotrexate and R-CHOP: a single-center retrospective study.

Background: The optimal treatment of patients with systemic diffuse large B-cell (DLBCL) or high-grade B-cell (HGBL) lymphomas with synchronous central nervous system (CNS) involvement at diagnosis is not well defined. High-dose methotrexate administered concurrently with R-CHOP (RM-CHOP) is a commonly used regimen, but data on outcomes achieved with this regimen are limited. Objective: To report our experience with RM-CHOP in patients with systemic DLBCL or HGBL with synchronous CNS involvement at diagnosis. Design: A single-center retrospective analysis. Methods: We identified consecutive patients with systemic DLBCL or HGBL with synchronous CNS involvement at diagnosis who were treated with RM-CHOP from January 2012 to January 2021. Results: Fifty patients were included with a median age of 62 years; 82% had DLBCL (n = 41) and 18% had HGBL (n = 9). Treatment with RM-CHOP was followed by consolidative autologous hematopoietic cell transplantation in 14 patients (28%). The complete response (CR) rate following RM-CHOP was 62%. With a median follow-up of 40 months, the median progression-free (PFS) and overall (OS) survivals were 16 and 58 months, and the 2-year PFS and OS were 41% and 57%, respectively. The 2-year cumulative incidence of CNS progression/relapse was 29%. Outcomes were particularly poor in HGBL, with median PFS and OS of 6 and 7 months, compared with median PFS and OS of 22 months and not reached in DLBCL, respectively. The outcomes of patients with relapsed/progressive disease were poor, with only 63% of patients receiving subsequent treatments and only 21% achieving CR to next subsequent treatment. Most patients (58%) with disease relapse/progression had CNS involvement which was associated with very poor outcomes (median OS of 2 months). Conclusion: CNS involvement in aggressive B-cell non-Hodgkin lymphoma at diagnosis dictates clinical outcomes and requires more effective treatment options.

Using ecological momentary assessment and a portable device to quantify standard tetrahydrocannabinol units for cannabis flower smoking.

AIMS: To evaluate the feasibility and validity of a new method of quantifying cannabis flower use, integrating the amount of cannabis flower smoked, and the potency of the cannabis flower. DESIGN: Ecological momentary assessment (EMA) for 14 days. SETTING: Participants' daily lives in Columbia, Missouri, USA. PARTICIPANTS: A total of 50 community participants, who were regular cannabis flower smokers (48% female). MEASUREMENTS: Momentary subjective intoxication ratings following cannabis flower smoking; momentary quantity of cannabis flower smoked; potency of cannabis flower smoked in terms of percentage of tetrahydrocannabinol (THC) concentration assessed with a portable device, the Purpl Pro; and time since finished smoking. FINDINGS: Participants completed our field testing of their cannabis flower (96.2%) and were compliant with our 2-week EMA protocol (73% for random prompts and 91% for morning reports). Momentary subjective intoxication ratings trended down as a function of time since smoking (r = -0.10, P = 0.004, 95% CI, [-0.17, -0.03]). Multi-level model (MLM) results indicated the momentary standard THC units (mg THC) were positively associated with momentary subjective intoxication ratings (b = 0.01, P = 0.03, 95% CI, [0.01, 0.012]). CONCLUSIONS: There is evidence to support the feasibility and initial validity of a new method of quantifying cannabis flower use into standard tetrahydrocannabinol units. Researchers investigating the effects of cannabis flower use on a range of outcomes (e.g. neurobehavioral effects, emotional sequelae, and driving impairment) as well as in clinical treatment trials might adopt this method to provide estimates of cannabis flower use.

Co-use of medication and alcohol: The influence on subjective effects of intoxication and affect.

Co-use of alcohol and medication can have serious negative health effects (e.g., overdose risk, liver damage). Research has primarily focused on older adults or the pharmacokinetics of specific medication-alcohol combinations. Little work has focused on the subjective experience of persons who take alcohol-interactive (AI) medications and also drink alcohol, particularly in psychiatric samples at high risk for problematic alcohol use and high rates of prescription medication use, such as individuals with borderline personality disorder (BPD). Data from a larger ecological momentary assessment study of alcohol use in 52 persons diagnosed with BPD (83% women; Mage = 26 years) were used to examine the influence of alcohol intoxication (i.e., estimated blood alcohol concentration [eBAC]) and medication co-use on momentary subjective experience while drinking. Participants reported AI medication use at baseline and completed multiple ecological momentary assessment reports per day over 21 days, which included reports of alcohol use, subjective effects of alcohol (e.g., pleasure, feeling worse), and negative and positive affect. AI medications significantly moderated the association between eBAC and pleasurable effects of alcohol, such that at higher levels of eBAC, those taking AI medications experienced blunted subjective pleasure compared with those not taking AI medications. AI medications did not moderate the associations between eBAC and subjective relief, feeling worse, positive affect, or negative affect. Attenuated pleasure during drinking could lead to increased drinking in an attempt to achieve a desirable state among individuals who co-use psychiatric medications and alcohol, and therefore may represent a useful target for prevention and intervention. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Relations between lab indices of emotion dysregulation and negative affect reactivity in daily life in two independent studies.

BACKGROUND: We investigated the extent to which physiological/biological measures of emotion dysregulation collected in the lab, resting respiratory sinus arrhythmia (RSA) in Study 1 and amygdala activation in response to negative stimuli in Study 2, combined with daily measures of interpersonal stressors predicted negative emotional states in outpatients better than the stressors alone. METHODS: Participants were adult outpatients with emotional distress disorders (N=30 individuals in Study 1, and N=26 women in Study 2). After completing a laboratory session that collected physiological/biological measures of emotion dysregulation, participants then completed 1-3 weeks of ambulatory assessment during which they reported on interpersonal stressors and negative affective states several times per day. RESULTS: Laboratory measures of emotion dysregulation were largely unrelated to either momentary or mean levels of daily-life hostility, sadness, and fear in both studies. However, resting RSA significantly moderated the association between day-level interpersonal stressors and momentary fear such that low resting RSA strengthened this association. Similarly, amygdala activation tended to moderate this relationship in the predicted direction. LIMITATIONS: Both samples were relatively small and focused on only a limited set of diagnoses associated with emotion dysregulation. Only two possible physiological/biological markers of emotion dysregulation were examined. CONCLUSIONS: The current studies support the collection of physiological/biological data on emotion dysregulation when indexing daily-life emotion dysregulation as the degree of emotional reactivity to stressors in daily life among outpatients with emotional distress disorders.

Feasibility of high-dose methotrexate administered on day 1 of (R)CHOP in aggressive non-Hodgkin lymphomas.

The optimal timing for administering high-dose methotrexate (HDMTX) when combined with (R)CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone, with/without rituximab) is unclear. Recent data showed that the administration of prophylactic HDMTX before day 10 of R- CHOP may lead to fewer treatment delays. Herein, we report our experience with HDMTX administered on day 1 of (R)CHOP in patients with aggressive non-Hodgkin lymphoma (NHL). We identified 140 patients treated with ≥1 cycle of HDMTX combined with (R)CHOP for prophylaxis against (n = 84) or treatment of (n = 56) central nervous system (CNS) involvement. Overall, (R)CHOP treatment delays ≥7 days (4% of cycles, 13% of patients), doxorubicin, and/or cyclophosphamide dose reductions (1% of cycles, 6% of patients) or (R)CHOP discontinuations due to toxicity (4% of patients) were uncommon. Neutropenic fever (NF) occurred in 7% of cycles and 24% of patients and was more common during HDMTX-containing cycles. Acute kidney injury (AKI) occurred in 19% of cycles but was mostly grade ≤2. Grade ≥3 hepatotoxicity and mucositis were uncommon (each 2% of cycles). In the prophylaxis cohort, the rates of NF and grade ≥2 AKI were lower in patients who initiated HDMTX with cycle 2 or later (11% vs 30%, P = .03 and 16% vs 39%, P = .03, respectively). Our data show that HDMTX administration on day 1 of (R)CHOP may improve the deliverability of (R)CHOP and the overall safety of the regimen compared with historical data of HDMTX administration on day 10 or later of R-CHOP. Delaying prophylactic HDMTX beyond cycle 1 of (R)CHOP may reduce the risk of NF and AKI.

A daily-life study of interpersonal stressors and alcohol use in individuals with borderline personality disorder and community controls.

BACKGROUND: Interpersonal stressors (ISs) are major factors in relapse in alcohol use disorder (AUD) and are theorized to play a role in drinking behaviors. Past work has examined this association using ecological momentary assessment (EMA), but the unique effects of rejections and disagreements on alcohol use are unknown. Research suggests the two ISs functionally differ and may display distinct associations with drinking. Further, these associations may differ in people with borderline personality disorder (BPD), a population reporting frequent IS and co-occurring AUD. METHODS: 113 drinkers (community: n = 59; BPD: n = 54) reported alcohol use and ISs using EMA for 21 days. Using generalized estimating equations, we expected that rejection and disagreement would predict increased likelihood of drinking each day. We examined both cumulative (throughout each day) and immediate momentary effects of ISs predicting subsequent drinking on that same day. Further, we predicted that these associations would be stronger in individuals with BPD. RESULTS: Greater rejections throughout the day were associated with a reduced likelihood of drinking that day (OR = 0.56, 95 % CI:[0.32, 0.97], p < .040). In contrast, disagreements immediately prior to drinking were associated with an increased likelihood of drinking that day (OR = 0.60, 95 % CI:[1.02, 2.50], p = .039). However, the effect of disagreement on drinking was moderated by BPD diagnosis (OR = 2.56, 95 % CI:[1.13, 5.80], p = .025), such that the effect was only present for individuals with BPD. CONCLUSIONS: Assessing ISs as an aggregate predictor may mask potentially opposite effects on alcohol use. Additionally, disagreements may be a risk factor for subsequent alcohol use in BPD.

Mother Nature's Fury: Antagonist Metaphors for Natural Disasters Increase Forecasts of Their Severity and Encourage Evacuation.

Natural disasters are often described as having antagonistic qualities (e.g., wildfires ravage). The information deficit model presumes that when people assess the risk of weather hazards, they ignore irrelevant metaphoric descriptors. However, metaphoric frames affect reasoning. The current research assessed whether antagonist metaphors for natural disasters affect perceptions of the risk they pose. Three studies (N = 1,936) demonstrated that participants forecasted an antagonist-framed natural hazard as being more severe, and intended to evacuate more often, than a literal-framed natural hazard. Thus, the metaphorical language used to discuss natural disasters deserves consideration in the development of effective risk communication.

Considerations for the Ethical Implementation of Psychological Assessment Through Social Media via Machine Learning.

The ubiquity of social media usage has led to exciting new technologies such as machine learning. Machine learning is poised to change many fields of health, including psychology. The wealth of information provided by each social media user in combination with machine learning technologies may pave the way for automated psychological assessment and diagnosis. Assessment of individuals' social media profiles using machine learning technologies for diagnosis and screening confers many benefits (i.e., time and cost efficiency, reduced recall bias, information about an individual's emotions and functioning spanning months or years, etc.); however the implementation of these technologies will pose unique challenges to the professional ethics of psychology. Namely, psychologists must understand the impact of these assessment technologies on privacy and confidentiality, informed consent, recordkeeping, bases for assessments, and diversity and justice. This paper offers a brief review of the current applications of machine learning technologies in psychology and public health, provides an overview of potential implementations in clinical settings, and introduces ethical considerations for professional psychologists. This paper presents considerations which may aid in the extension of the current Ethical Principles of Psychologists and Code of Conduct to address these important technological advancements in the field of clinical psychology.

Antiemetic medication efficacy during EPOCH and R-EPOCH treatment.

INTRODUCTION: This study aims to determine the adequacy of current institutional standard practice for CINV prophylaxis for EPOCH and R-EPOCH at The Ohio State University James Cancer Hospital. METHODS: Single-center, retrospective analysis was performed including all patients receiving EPOCH or R-EPOCH chemotherapy for Non-Hodgkin's lymphomas from 1/1/2012 to 6/30/2017. The primary endpoint was rate of CINV events, which included usage of more than 50 percent of available doses of breakthrough antiemetics while inpatient, hospitalization due to CINV or related complications, or adjustments made to the CINV prophylactic or breakthrough regimen during current or subsequent cycles. Secondary endpoints included determining prescriber adherence to institutional standard CINV prophylaxis, characterization of adjustments to the antiemetic regimen following the incidence of CINV, and identification of high-risk patients that may benefit from additional CINV prophylaxis. RESULTS: Of 111 patients, 54 (48.6%) experienced CINV events with any cycle of EPOCH or R-EPOCH chemotherapy. Of those patients, 17 (31.5%) received institutional standard CINV prophylaxis at baseline, 8 (14.8%) received additional scheduled antiemetics, and 26 (48.1%) were prescribed additional breakthrough antiemetics with their first cycle of EPOCH or R-EPOCH. Younger age, diagnosis of anxiety, and previous susceptibility to nausea were significantly associated with CINV events. CONCLUSION: This study illustrates the inadequacy of current institutional standard for CINV prophylaxis for patients receiving EPOCH and R-EPOCH, highly emetogenic chemotherapy regimens. With nearly half of included patients experiencing CINV events, and most initially receiving more than our standard prophylaxis, changes to our standard antiemetics used with this chemotherapy regimen are needed.

Multiple chemical sensitivity (MCS) - a guide for dermatologists on how to manage affected individuals.

Multiple chemical sensitivity (MCS) is a condition characterized by a subjectively perceived increase in sensitivity to environmental chemicals. Individuals affected report a wide variety of nonspecific complaints, and frequently attribute cutaneous and mucosal symptoms to chemical exposures. Dermatologists should therefore be familiar with this condition. MCS is a diagnosis of exclusion. Other causes for the patients' symptoms should be ruled out by routine laboratory tests, allergy tests and, if indicated, monitoring for toxic (environmental) substances. The primary job of dermatologists is to rule out skin diseases or hypersensitivities as possible causes of the complaints. Interdisciplinary patient management is essential, especially in severe cases in which those affected have problems coping with everyday life. Relevant specialties in this context include environmental medicine, psychosomatic medicine as well as occupational and social medicine. Cutaneous symptoms are usually addressed with symptomatic treatment using basic skin care products. There are currently no evidence-based treatment recommendations for MCS. It is crucial that MCS patients be protected from unnecessary treatments and thus from mental, social and financial strain. In addition to medical skills, managing MCS patients requires communicative and psychosocial competence in particular. Physicians involved in the treatment will benefit from training in psychotherapy. Irrespective of the mechanisms that lead to MCS, diagnosis and treatment of this condition require an actively supportive attitude towards these patients, a good doctor-patient relationship and interdisciplinary cooperation.

Detection of intramyocardially injected DiR-labeled mesenchymal stem cells by optical and optoacoustic tomography.

The distribution of intramyocardially injected rabbit MSCs, labeled with the near-infrared dye 1,1'-dioctadecyl-3,3,3',3'-tetramethylindotricarbo-cyanine-iodide (DiR) using hybrid Fluorescence Molecular Tomography-X-ray Computed Tomography (FMT-XCT) and Multispectral Optoacoustic Tomography (MSOT) imaging technologies, was investigated. Viability and induction of apoptosis of DiR labeled MSCs were assessed by XTT- and Caspase-3/-7-testing in vitro. 2 × 106, 2 × 105 and 2 × 104 MSCs labeled with 5 and 10 µg DiR/ml were injected into fresh frozen rabbit hearts. FMT-XCT, MSOT and fluorescence cryosection imaging were performed. Concentrations up to 10 µg DiR/ml did not cause apoptosis in vitro (p > 0.05). FMT and MSOT imaging of labeled MSCs led to a strong signal. The imaging modalities highlighted a difference in cell distribution and concentration correlated to the number of injected cells. Ex-vivo cryosectioning confirmed the molecular fluorescence signal. FMT and MSOT are sensitive imaging techniques offering high-anatomic resolution in terms of detection and distribution of intramyocardially injected stem cells in a rabbit model.

Population Pharmacokinetics and Pharmacodynamics of Doripenem in Obese, Hospitalized Patients.

BACKGROUND: Doripenem population pharmacokinetics and dosing recommendations are limited in obesity. OBJECTIVE: To evaluate the population pharmacokinetics and pharmacodynamics of doripenem in obese patients. METHODS: Hospitalized adults with a body mass index (BMI) ≥ 40 kg/m2 or total body weight (TBW) ≥45.5 kg over their ideal body weight received doripenem 500 mg every 8 hours, infused over 1 hour. Population pharmacokinetic analyses were performed using NONMEM, and Monte Carlo simulations were performed for 5 intermittent and prolonged infusion dosing regimens to calculate probability of target attainment (PTA) at 40% and 100% fT>MIC (free drug concentrations above the minimum inhibitory concentration). RESULTS: A total of 20 patients were studied: 10 in an intensive care unit (ICU) and 10 in a non-ICU. A 2-compartment model with first-order elimination best described the serum concentration-time data. Doripenem clearance (CL) was significantly associated with creatinine CL (CRCL), volume of the central compartment with TBW and ICU residence, and volume of the peripheral compartment with TBW ( P < 0.05). Using 40% fT>MIC, PTA was >90% for all simulated dosing regimens at MICs ≤2 mg/L. Using 100% fT>MIC, prolonged infusions of 1 g every 6 hours and 2 g every 8 hours achieved >90% PTA at MICs ≤2 mg/L. CONCLUSIONS: CRCL, ICU residence, and TBW are significantly associated with doripenem pharmacokinetics. Currently approved dosing regimens provide adequate pharmacodynamic exposures at 40% fT>MIC for susceptible bacteria in obese patients. However, prolonged infusions of larger doses are needed if a higher pharmacodynamic target is desired.