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Objective: Large inter-individual variability in the pharmacokinetics of rilpivirine and cabotegravir has been reported in the first weeks after starting long-acting injectable (LAI) therapy. Here, we assessed the distribution of rilpivirine and cabotegravir trough concentrations in people with HIV (PWH) on long-term LAI treatment., Methods: Adult PWH treated with LAI for at least 32 weeks with an assessment of drug plasma trough concentrations were considered. The proportion of rilpivirine and cabotegravir plasma trough concentrations below four-times the protein-adjusted concentrations required for 90% inhibition of viral replication (4×PA-IC90) was estimated., Results: Sixty-seven PWH were identified. LAI treatment duration was 216 ± 80 weeks (range 32-320 weeks). Cabotegravir concentrations were associated with lower inter-individual variability compared with rilpivirine (45% versus 84%; P < 0.05). No differences were found in rilpivirine (160 ± 118 versus 189 ± 81 ng/mL; P = 0.430) and cabotegravir (1758 ± 807 versus 1969 ± 802 ng/mL; P = 0.416) trough concentrations in males (n = 55) versus females (n = 12). A non-significant trend for lower cabotegravir concentrations was found in PWH with a body mass index >30 kg/m2 (n = 9) versus non-obese participants (1916 ± 905 versus 1606 ± 576 ng/mL; P = 0.131). Three out of the 67 PWH had at least one drug concentration <4×PA-IC90: 100% of PWH had undetectable HIV viral load., Conclusions: At steady state, optimal systemic exposure of cabotegravir and rilpivirine was found in most PWH; cabotegravir trough concentrations were associated with lower inter-individual variability compared with rilpivirine. The study was not powered to assess the contribution of sex and/or body weight on LAI exposure due to the small number of females and obese PWH included., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Avibactam is a β-lactamase inhibitor that is combined with aztreonam against Enterobacterales co-expressing serine- and metallo-β-lactamases (MBL). Optimal dosing of aztreonam with avibactam is not well-defined in critically ill patients and contingent on ceftazidime/avibactam product labelling., Objectives: To identify a pragmatic dosing strategy for aztreonam with avibactam to maximize the probability of target attainment (PTA)., Methods: We conducted a prospective observational pharmacokinetic study. Five blood samples were collected around the fourth dose of aztreonam or ceftazidime/avibactam and assayed for all three drugs. Population pharmacokinetic (PK) analysis coupled with Monte Carlo simulations were used to create a dosing nomogram for aztreonam and ceftazidime/avibactam based on drug-specific pharmacodynamic (PD) targets., Results: A total of 41 participants (59% male) median age of 75 years (IQR 63-79 years) were enrolled. They were critically ill (46%) with multiple comorbidities and complications including burns (20%). Population PK analysis identified higher volume of distribution and lower clearance (CL) compared with typical value expectations for aztreonam and ceftazidime/avibactam. Estimated glomerular filtration (eGFR) rate using the CKD-EPI equation predicted CL for all three drugs. The need for high doses of aztreonam and ceftazidime/avibactam above those in the existing product labels are not predicted by this analysis with the exception of ceftazidime/avibactam for patients with eGFR of 6-15 mL/min, in whom suboptimal PTA of ≤71% is predicted., Conclusions: Pragmatic and lower daily-dose options are predicted for aztreonam and ceftazidime/avibactam when the eGFR is <90 mL/min. These options should be tested prospectively., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Little is known about the clinical outcomes of patients with human immunodeficiency virus infected with SARS-CoV-2. We describe 47 patients referred to our hospital between 21 February and 16 April 2020 with proven/probable COVID-19, 45 (96%) of whom fully recovered and 2 who died., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Objectives: Liver transplantation (LTx) is considered a safe procedure in selected HIV-infected patients. In this clinical setting raltegravir is the antiretroviral of choice due to its optimal tolerability and its negligible interactions with immunosuppressive drugs. We aimed at providing data on the pharmacokinetics of raltegravir in LTx recipients, on which the available information is inconclusive., Methods: In this retrospective multicentre study we characterized the pharmacokinetics of raltegravir in a consecutive series of HIV-infected LTx recipients referred to our laboratory for therapeutic drug monitoring (TDM) and compared the obtained profiles with those collected from a control group of HIV-infected patients., Results: Seventeen HIV-infected LTx patients were considered. LTx recipients had significantly higher raltegravir AUC0-12 compared with the control group of HIV-infected patients [14 314 (11 627-19 998) versus 8795 (5218-12 954) ng·h/mL; P < 0.01]. Two LTx patients experienced moderate increments in serum transaminases, nausea and vomiting that improved after raltegravir dose reduction., Conclusions: High raltegravir exposure and acceptable safety profile were observed in HIV-infected LTx recipients. Our results highlight that some patients may obtain an advantage from TDM-guided raltegravir dose adjustments with potential benefits in terms of drug tolerability., (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: It is unknown how impairments caused by multiple sclerosis (MS) affect upper limb capacity, performance, and community integration., Objective: The aim of this study was to investigate the extent to which impairments explained the variance in activity level and participation level measures of the International Classification of Functioning, Disability and Health (ICF) and the extent to which upper limb capacity measures explained perceived performance on the activity level in people with MS and different dexterity levels., Design: This was a cross-sectional study., Methods: A total of 105 people with MS (median Expanded Disability Status Scale=6.5) were assessed with measures on the ICF body functions and structures level (strength, active range of motion of the wrist, tactile sensitivity, tremor, spasticity, and pain), activity level (Nine-Hole Peg Test [NHPT], Action Research Arm Test, and Manual Ability Measure-36 [MAM-36]), and participation level (Community Integration Questionnaire). The sample was divided into low- and high-dexterity subgroups on the basis of the median score on the NHPT., Results: In the total group, muscle strength, tactile sensitivity of the thumb, and intention tremor explained 53% to 64% of the variance in activity level measures. In the low-dexterity subgroup, muscle strength and active range of motion explained 43% to 71% of the variance in activity level measures. In the high-dexterity subgroup, only 35% of the variance in the MAM-36 was explained by muscle strength. Capacity measures (NHPT and Action Research Arm Test) were moderately to highly associated with perceived performance (MAM-36) in the low-dexterity subgroup., Limitations: Some outcome measures showed ceiling effects in people with MS and a high dexterity level., Conclusions: Upper limb muscle strength is the most important impairment affecting capacity and perceived performance in daily life. Associations among outcome measures differ in people with MS and different dexterity levels., (© 2015 American Physical Therapy Association.)

A 34-week infant born from a mother with a history of drug abuse developed neonatal abstinence syndrome (NAS) in the first hours of life. Urine drug screening was positive for cocaine and heroin. The infant developed acute kidney injury and bilateral hydronephrosis while receiving oral morphine for control of NAS. Cessation of morphine therapy and urinary catheterization resulted in a rapid and complete resolution of the symptoms. Our patient was homozygous for the C3435T polymorphism in the ABCB1 gene, a polymorphism previously associated with impaired P-glycoprotein activity. We hypothesize that acute renal toxicity was related to accumulation of morphine within urothelial cells due to genetically determined impaired P-glycoprotein activity.

Objectives: Limited studies in healthy volunteers and in HIV-1-infected patients have shown that raltegravir pharmacokinetics are characterized by high inter-patient variability. Only scanty data are, however, available on intra-patient raltegravir variability. The present study was designed to evaluate in parallel the inter- and intra-patient variability of raltegravir pharmacokinetics in HIV-1-infected patients during routine therapeutic drug monitoring (TDM)., Methods: Fifteen HIV-infected patients treated with highly active antiretroviral therapy containing 400 mg of raltegravir twice daily were included in the study. Pharmacokinetic evaluations were performed during two consecutive visits. Only patients given raltegravir for at least 1 month and with no changes in antiretroviral and concomitant therapy between the two pharmacokinetic evaluations were considered. Raltegravir plasma concentrations were determined by a validated HPLC method. Blood samples were collected at 0, 1, 2, 3 and 4 h after the morning drug dose. Raltegravir AUC(0-12) was estimated using a recently developed algorithm., Results: The pharmacokinetic evaluation was repeated after an average of 52 ± 68 days. Raltegravir AUC(0-12) values ranged from 1495 to 49 051 ng · h/mL. The main finding was that intra-patient variability was a large component of the overall variability in raltegravir pharmacokinetics. In some instances the difference between raltegravir AUC(0-4) and AUC(0-12) measured in the same patient during two consecutive evaluations exceeded 110% and 75%, respectively., Conclusions: The pharmacokinetics of raltegravir in HIV-1-infected subjects are characterized not only by inter-patient variability but also by high intra-patient variability. This condition limits the application of TDM for raltegravir, and might potentially affect patient outcome.

The nonconventional yeast Zygosaccharomyces bailii has been proposed as a new host for biotechnological processes due to convenient properties such as its resistance to high sugar concentrations, relatively high temperatures and especially to acidic environments. We describe a series of new expression vectors specific for Z. bailii and the resulting improvements in production levels. By exploiting the sequences of the endogenous plasmid pSB2, 2microm-like multicopy vectors were obtained, giving a fivefold increase in production. A specific integrative vector was developed which led to 100% stability in the absence of selective pressure; a multiple-integration vector was constructed, based on an rRNA gene unit portion cloned and sequenced for this purpose, driving the insertion of up to 80 copies of the foreign construct. Moreover, we show the construction of the first stable auxotrophic mutant of Z. bailii, obtained by targeted gene deletion applied to ZbLEU2. The development of molecular tools for the Z. bailii manipulation has now reached a level that may be compatible with its industrial exploitation; the production of organic acids is a prominent field of application.

A high-performance liquid chromatographic method for the determination of atazanavir (ATV) in human plasma is developed and validated. The method involves a rapid and simple solid-phase extraction (SPE) of ATV using Bond-elut C18 3 mL cartridge. The separation of ATV from internal standard and endogenous components is achieved using an isocratic elution on an octyl column and an UV detector set at 260 nm. The method is linear from 20 to 10,000 ng/mL (mean r2 = 0.9991, n = 10). The observed intra- and inter-day assay precision ranged from 2.2% to 14.7%[at the lower limit of quantitation (LOQ)], whereas accuracy varies between 1.0% and 14% (at LOQ). Mean drug recovery is 80.5% for ATV and 78.4% for IS. The method is found to be precise and accurate, practical enough for therapeutic drug monitoring in routine clinical practice and is applied for the assessment of 24-h ATV plasma concentration-time profiles in HIV-infected pregnant women.

Background: In transplant patients, current cyclosporine (CsA) dose monitoring with classic pharmacokinetics has demonstrated limitations. Evaluation of the activity of calcineurin (CN), the serine-threonine phosphatase enzyme target of CsA, has been proposed as a reliable way to optimize CsA dosing., Methods: CN activity was measured in whole blood in an attempt to overcome the high variability of results obtained previously with peripheral blood mononuclear cells (PBMCs). We also explored, in vitro, a possible relationship between the CsA concentration and CN inhibition in whole blood. Finally, we assessed whether the CsA blood trough concentration correlates with whole-blood CN activity in kidney transplant recipients (n = 15) on maintenance immunosuppression with CsA., Results: In 14 healthy individuals, less scattered CN activity values were documented in whole blood than in the PBMC fraction. Whole-blood CN activity was higher than the sum of the enzyme activity in each cell blood fraction. After ex vivo incubation of whole blood from healthy subjects (n = 5) with increasing concentrations of CsA (50-1000 microg/L for 1 h), a concentration-dependent inhibition of CN activity was found comparable to that in the PBMC fraction. Moreover, in 15 kidney transplant recipients, no relationship was found between CsA pharmacokinetic parameters and CN activity at time 0. However, a highly significant correlation was found between CN area under the CN activity-time curve, which represents the extent of the CN daily inhibition, and CN activity at time 0 (r = 0.79; P <0.01) and at 12 h postdosing (r = 0.96; P <0.01)., Conclusions: Measuring CN activity in whole-blood samples is a reproducible method. In kidney transplant recipients, CsA trough concentrations do not predict baseline CN activity. Moreover, a single CN activity monitoring at baseline or at time 12 h post-CsA dosing may be a useful surrogate for the inhibition of this enzyme by CsA during 12 h.