Population pharmacokinetics and target attainment analysis of vancomycin after intermittent dosing in adults with cystic fibrosis.

Vancomycin is the first-line agent to treat pulmonary infections caused by methicillin-resistant Staphylococcus aureus (MRSA) in people with cystic fibrosis (PwCF). However, there is no consensus on vancomycin initial dosing in this population among health institutions, and there is a large variability in initial dosing across the United States. In this study, we characterized the pharmacokinetics (PK) of vancomycin in PwCF using a population PK approach. The clinical PK data to develop the population PK model were obtained from vancomycin therapeutic monitoring data from PwCF undergoing treatment for infections due to MRSA. The population PK model was then used to perform comprehensive Monte Carlo simulations to evaluate the probability of target attainment (PTA) of 12 different initial dosing scenarios. The area under the curve to minimum inhibitory concentration (MIC) ratio ≥400 mg*h/L and <650 mg*h/L were used as efficacy and toxicity targets for PTA analysis. A total of 181 vancomycin plasma concentrations were included in the analysis. A one-compartment model with first-order elimination best described the data. Weight significantly influenced the vancomycin PK (P < 0.05). In the final model, clearance was estimated as 5.52 L/h/70 kg, and the volume of distribution was 31.5 L/70 kg. The PTA analysis showed that at MIC = 1 µg/mL, doses 1,500 q8h and 2,000 q12h showed the highest %PTA in achieving both efficacy and toxicity targets. The PTA results from this study may potentially inform the initial dosing regimens of vancomycin to treat pulmonary infections due to MRSA in PwCF.

Vaginal misoprostol versus vaginal dinoprostone for cervical ripening and induction of labour: An individual participant data meta-analysis of randomised controlled trials.

BACKGROUND: Induction of labour (IOL) is common practice and different methods carry different effectiveness and safety profiles. OBJECTIVES: To compare the effectiveness, and maternal and perinatal safety outcomes of IOL with vaginal misoprostol versus vaginal dinoprostone using individual participant data from randomised clinical trials. SEARCH STRATEGY: The following databases were searched from inception to March 2023: CINAHL Plus, ClinicalTrials.gov, Cochrane Pregnancy and Childbirth Group Trial Register, Ovid Embase, Ovid Emcare, Ovid MEDLINE, Scopus and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). SELECTION CRITERIA: Randomised controlled trials (RCTs), with viable singleton gestation, no language restrictions, and all published and unpublished data. DATA COLLECTION AND ANALYSIS: An individual participant data meta-analysis was carried out. MAIN RESULTS: Ten of 52 eligible trials provided individual participant data, of which two were excluded after checking data integrity. The remaining eight trials compared low-dose vaginal misoprostol versus dinoprostone, including 4180 women undergoing IOL, which represents 32.8% of all participants in the published RCTs. Of these, 2077 were assigned to low-dose vaginal misoprostol and 2103 were assigned to vaginal dinoprostone. Compared with vaginal dinoprostone, low-dose vaginal misoprostol had a comparable rate of vaginal birth. Composite adverse perinatal outcomes did not differ between the groups. Compared with vaginal dinoprostone, composite adverse maternal outcomes were significantly lower with low-dose vaginal misoprostol (aOR 0.80, 95% CI 0.65-0.98, P = 0.03, I2 = 0%). CONCLUSIONS: Low-dose vaginal misoprostol and vaginal dinoprostone for IOL are comparable in terms of effectiveness and perinatal safety. However, low-dose vaginal misoprostol is likely to lead to a lower rate of composite adverse maternal outcomes than vaginal dinoprostone.

Incremental net monetary benefit of biologic therapies in moderate to severe asthma: a systematic review and meta-analysis of economic evaluation studies.

OBJECTIVES: This meta-analysis was conducted to quantitatively pool the incremental net benefit (INB) of using biologic therapies as an add-on treatment to standard therapy in patients with moderate to severe asthma. METHODS: We performed a comprehensive search in several databases published until April 2022. Studies were included if they were cost-effectiveness analyses reporting cost per quality-adjusted life-year or life-year on any biologic therapies as an add-on treatment for moderate to severe asthma in patients of all ages. Various monetary units were converted to purchasing power parity, adjusted to 2021 US dollars. The INBs were pooled across studies using a random-effects model, stratified by country income level (high-income countries (HICs) and low- and middle-income countries (LMICs)) and perspectives (health care or payer perspective (HCPP) and societal perspective (SP)) and age group (>12 years and 6-11 years). Heterogeneity was assessed using the I2 statistic. RESULTS: A total of 32 comparisons from 25 studies were included. Pooled INB indicated that the use of omalizumab as an add-on treatment to standard therapy in those aged >12 years was not cost-effective in HICs from the HCPP (n = 8, INB, -6,341 (95% CI, -$25,000 to $12,210), I2=86.18%) and SP (n = 5, -$14,000 (-$170,000 to $140,000), I2=75.64%). A similar finding was observed in those aged 6-11 years from the HCPP in LMICs (n = 2, -$45,000 (-$73,000 to $17,000), I2=00.00%). Subgroup analyses provided no explanations of the potential sources of heterogeneity. CONCLUSION: The use of biologic therapies in moderate to severe asthma is not cost-effective compared to standard treatment alone.

Self-Assembly Synthesis of a [2]Catenane CoII Single-Molecule Magnet.

We describe herein the self-assembly synthesis of an octanuclear CoII [2]catenane {[Co4 (H2 L)6 ]2 16+ } formed by the mechanical interlocking of two {[Co4 (H2 L)6 ]8+ } rectangles of unprecedented topology. Subtle manipulation of the synthetic conditions allows the isolation of a mixed-valence [Co2 III /Co2 II ]10+ non-catenated rectangle. The CoII centers in the [2]catenane exhibit slow relaxation of their magnetic moment, i. e. single-molecule magnet properties, dominated by quantum tunneling and Raman relaxation processes. This work shows that metallo-supramolecular chemistry can precisely control the organization of single-molecule magnets in topologically complex arrangements.

On-off-on Control of Molecular Inversion Symmetry via Multi-stage Protonation: Elucidating Vibronic Laporte Rule.

The Laporte rule dictates that one- and two-photon absorption spectra of inversion-symmetric molecules should display alternatively forbidden electronic transitions; however, for organic fluorophores, drawing clear distinction between the symmetric- and non-inversion symmetric two-photon spectra is often obscured due to prevalent vibronic interactions. We take advantage of consecutive single- and double-protonation to break and then reconstitute inversion symmetry in a nominally symmetric diketopyrrolopyrrole, causing large changes in two-photon absorption. By performing detailed one- and two-photon titration experiments, with supporting quantum-chemical model calculations, we explain how certain low-frequency vibrational modes may lead to apparent deviations from the strict Laporte rule. As a result, the system may be indeed considered as an on-off-on inversion symmetry switch, opening new avenues for two-photon sensing applications.

Mycobacterium tuberculosis releases an antacid that remodels phagosomes.

Mycobacterium tuberculosis (Mtb) is the world's most deadly pathogen. Unlike less virulent mycobacteria, Mtb produces 1-tuberculosinyladenosine (1-TbAd), an unusual terpene nucleoside of unknown function. In the present study 1-TbAd has been shown to be a naturally evolved phagolysosome disruptor. 1-TbAd is highly prevalent among patient-derived Mtb strains, where it is among the most abundant lipids produced. Synthesis of TbAd analogs and their testing in cells demonstrate that their biological action is dependent on lipid linkage to the 1-position of adenosine, which creates a strong conjugate base. Furthermore, C20 lipid moieties confer passage through membranes. 1-TbAd selectively accumulates in acidic compartments, where it neutralizes the pH and swells lysosomes, obliterating their multilamellar structure. During macrophage infection, a 1-TbAd biosynthesis gene (Rv3378c) confers marked phagosomal swelling and intraphagosomal inclusions, demonstrating an essential role in regulating the Mtb cellular microenvironment. Although macrophages kill intracellular bacteria through phagosome acidification, Mtb coats itself abundantly with antacid.

Structural determination of lipid antigens captured at the CD1d-T-cell receptor interface.

Glycolipid antigens recognized by αß T-cell receptors (TCRs) drive the activation of invariant natural killer T (iNKT) cells, a specialized subset of innate T lymphocytes. Glycolipids with α-linked anomeric carbohydrates have been identified as potent microbial lipid antigens for iNKT cells, and their unusual α-anomeric linkage has been thought to define a "foreign" lipid antigen motif. However, mammals use endogenous lipids to select iNKT cells, and there is compelling evidence for iNKT cell responses in various types of sterile inflammation. The nature of endogenous or environmental lipid antigens encountered by iNKT cells is not well defined. Here, we sought to identify lipid antigens in cow's milk, a prominent part of the human diet. We developed a method to directly capture lipid antigens within CD1d-lipid-TCR complexes, while excluding CD1d bound to nonantigenic lipids, followed by direct biochemical analysis of the lipid antigens trapped at the TCR-CD1d interface. The specific antigens captured by this "TCR trap" method were identified as α-linked monohexosylceramides by mass spectrometry fragmentation patterns that distinguished α- from ß-anomeric monohexosylceramides. These data provide direct biochemical evidence for α-linked lipid antigens from a common dietary source.

Population Pharmacokinetics of Amikacin in Adult Patients with Cystic Fibrosis.

Practitioners commonly use amikacin in patients with cystic fibrosis. Establishment of the pharmacokinetics of amikacin in adults with cystic fibrosis may increase the efficacy and safety of therapy. This study was aimed to establish the population pharmacokinetics of amikacin in adults with cystic fibrosis. We used serum concentration data obtained during routine therapeutic drug monitoring and explored the influence of patient covariates on drug disposition. We performed a retrospective chart review to collect the amikacin dosing regimens, serum amikacin concentrations, blood sampling times, and patient characteristics for adults with cystic fibrosis admitted for treatment of acute pulmonary exacerbations. Amikacin concentrations were retrospectively collected for 49 adults with cystic fibrosis, and 192 serum concentrations were available for analysis. A population pharmacokinetic model was developed using nonlinear mixed-effects modeling with the first-order conditional estimation method. A two-compartment model with first-order elimination best described amikacin pharmacokinetics. Creatinine clearance and weight were identified as significant covariates for clearance and the volume of distribution, respectively, in the final model. Residual variability was modeled using a proportional error model. Typical estimates for clearance, central and peripheral volumes of distribution, and intercompartmental clearance were 3.06 liters/h, 14.4 liters, 17.1 liters, and 0.925 liters/h, respectively. The pharmacokinetics of amikacin in individuals with cystic fibrosis seems to differ from those in individuals without cystic fibrosis. However, further investigations are needed to confirm these results and, thus, the need for variations in amikacin dosing. Future pharmacodynamic studies will potentially establish the optimal amikacin dosing regimens for the treatment of acute pulmonary exacerbations in adult patients with CF.

Lipidomic analysis links mycobactin synthase K to iron uptake and virulence in M. tuberculosis.

The prolonged survival of Mycobacterium tuberculosis (M. tb) in the host fundamentally depends on scavenging essential nutrients from host sources. M. tb scavenges non-heme iron using mycobactin and carboxymycobactin siderophores, synthesized by mycobactin synthases (Mbt). Although a general mechanism for mycobactin biosynthesis has been proposed, the biological functions of individual mbt genes remain largely untested. Through targeted gene deletion and global lipidomic profiling of intact bacteria, we identify the essential biochemical functions of two mycobactin synthases, MbtK and MbtN, in siderophore biosynthesis and their effects on bacterial growth in vitro and in vivo. The deletion mutant, ΔmbtN, produces only saturated mycobactin and carboxymycobactin, demonstrating an essential function of MbtN as the mycobactin dehydrogenase, which affects antigenicity but not iron uptake or M. tb growth. In contrast, deletion of mbtK ablated all known forms of mycobactin and its deoxy precursors, defining MbtK as the essential acyl transferase. The mbtK mutant showed markedly reduced iron scavenging and growth in vitro. Further, ΔmbtK was attenuated for growth in mice, demonstrating a non-redundant role of hydroxamate siderophores in virulence, even when other M. tb iron scavenging mechanisms are operative. The unbiased lipidomic approach also revealed unexpected consequences of perturbing mycobactin biosynthesis, including extreme depletion of mycobacterial phospholipids. Thus, lipidomic profiling highlights connections among iron acquisition, phospholipid homeostasis, and virulence, and identifies MbtK as a lynchpin at the crossroads of these phenotypes.

Total Synthesis of Mycobacterium tuberculosis Dideoxymycobactin-838 and Stereoisomers: Diverse CD1a-Restricted T Cells Display a Common Hierarchy of Lipopeptide Recognition.

Mycobacterium tuberculosis produces dideoxymycobactin-838 (DDM-838), a lipopeptide that potently activates T cells upon binding to the MHC-like antigen-presenting molecule CD1a. M. tuberculosis produces DDM-838 in only trace amounts and a previous solid-phase synthesis provided sub-milligram quantities. We describe a high-yielding solution-phase synthesis of DDM-838 that features a Mitsunobu substitution that avoids yield-limiting epimerization at lysine during esterification, and amidation conditions that prevent double-bond isomerization of the Z-C20:1 acyl chain, and provides material with equivalent antigenicity to natural DDM-838. Isomers of DDM-838 that varied in stereochemistry at the central lysine and the C20:1 acyl chain were compared for their ability to be recognised by CD1a-restricted T cell receptors (TCRs). These TCRs, derived from unrelated human donors, exhibited a similar spectrum of reactivity towards the panel of DDM-838 isomers, highlighting the exquisite sensitivity of lipopeptide-reactive T cells for the natural DDM stereochemistry.

An Isoreticular Series of Zinc(II) Metal-Organic Frameworks Derived from Terpyridylcarboxylate Ligands.

An isoreticular family of seven microporous metal-organic frameworks of the general form [ZnL] have been synthesized, where L is a 4'-substituted 2,2':6',2″-terpyridine-4,4″-dicarboxylate ligand. Each framework adopts an interpenetrated zeolitic gismondine (gis-c) topology and possesses one-dimensional square channels with ca. 9.0 Šapertures running down the crystallographic c axis. Gas adsorption measurements with N2, H2, CH4, and CO2 confirm their permanent porosity. The ligand functional groups, which include phenyl, 2-tolyl, 4-chlorophenyl, 4-nitrophenyl, 2-thienyl, 3-thienyl, and 4-pyridyl, line the channel walls and tune the gas adsorption properties of these materials.

Molecular profiling of Mycobacterium tuberculosis identifies tuberculosinyl nucleoside products of the virulence-associated enzyme Rv3378c.

To identify lipids with roles in tuberculosis disease, we systematically compared the lipid content of virulent Mycobacterium tuberculosis with the attenuated vaccine strain Mycobacterium bovis bacillus Calmette-Guérin. Comparative lipidomics analysis identified more than 1,000 molecular differences, including a previously unknown, Mycobacterium tuberculosis-specific lipid that is composed of a diterpene unit linked to adenosine. We established the complete structure of the natural product as 1-tuberculosinyladenosine (1-TbAd) using mass spectrometry and NMR spectroscopy. A screen for 1-TbAd mutants, complementation studies, and gene transfer identified Rv3378c as necessary for 1-TbAd biosynthesis. Whereas Rv3378c was previously thought to function as a phosphatase, these studies establish its role as a tuberculosinyl transferase and suggest a revised biosynthetic pathway for the sequential action of Rv3377c-Rv3378c. In agreement with this model, recombinant Rv3378c protein produced 1-TbAd, and its crystal structure revealed a cis-prenyl transferase fold with hydrophobic residues for isoprenoid binding and a second binding pocket suitable for the nucleoside substrate. The dual-substrate pocket distinguishes Rv3378c from classical cis-prenyl transferases, providing a unique model for the prenylation of diverse metabolites. Terpene nucleosides are rare in nature, and 1-TbAd is known only in Mycobacterium tuberculosis. Thus, this intersection of nucleoside and terpene pathways likely arose late in the evolution of the Mycobacterium tuberculosis complex; 1-TbAd serves as an abundant chemical marker of Mycobacterium tuberculosis, and the extracellular export of this amphipathic molecule likely accounts for the known virulence-promoting effects of the Rv3378c enzyme.

Stereoselective Synthesis of 1-Tuberculosinyl Adenosine; a Virulence Factor of Mycobacterium tuberculosis.

Despite its status as one of the world's most prevalent and deadly bacterial pathogens, Mycobacterium tuberculosis (Mtb) infection is not routinely diagnosed by rapid and highly reliable tests. A program to discover Mtb-specific biomarkers recently identified two natural compounds, 1-tuberculosinyl adenosine (1-TbAd) and N(6)-tuberculosinyl adenosine (N(6)-TbAd). Based on their association with virulence, the lack of similar compounds in nature, the presence of multiple stereocenters, and the need for abundant products to develop diagnostic tests, synthesis of these compounds was considered to be of high value but challenging. Here, a multigram-scale stereoselective synthesis of 1-TbAd and N(6)-TbAd is described. As a key-step, a chiral auxiliary-mediated Diels-Alder cycloaddition was developed, introducing the three stereocenters with a high exo endo ratio (10:1) and excellent enantioselectivity (>98% ee). This constitutes the first entry into the stereoselective synthesis of diterpenes with the halimane skeleton. Computational studies explain the observed stereochemical outcome.

Biomarkers for Tuberculosis Based on Secreted, Species-Specific, Bacterial Small Molecules.

Improved biomarkers are needed for tuberculosis. To develop tests based on products secreted by tubercle bacilli that are strictly associated with viability, we evaluated 3 bacterial-derived, species-specific, small molecules as biomarkers: 2 mycobactin siderophores and tuberculosinyladenosine. Using liquid chromatography-tandem mass spectrometry, we demonstrated the presence of 1 or both mycobactins and/or tuberculosinyladenosine in serum and whole lung tissues from infected mice and sputum, cerebrospinal fluid (CSF), or lymph nodes from infected patients but not uninfected controls. Detection of the target molecules distinguished host infection status in 100% of mice with both serum and lung as the target sample. In human subjects, we evaluated detection of the bacterial small molecules (BSMs) in multiple body compartments in 3 patient cohorts corresponding to different forms of tuberculosis. We detected at least 1 of the 3 molecules in 90%, 71%, and 40% of tuberculosis patients' sputum, CSF, and lymph node samples, respectively. In paucibacillary forms of human tuberculosis, which are difficult to diagnose even with culture, detection of 1 or more BSM was rapid and compared favorably to polymerase chain reaction-based detection. Secreted BSMs, detectable in serum, warrant further investigation as a means for diagnosis and therapeutic monitoring in patients with tuberculosis.

Cutting Edge: CD1a tetramers and dextramers identify human lipopeptide-specific T cells ex vivo.

Human CD1a mediates foreign Ag recognition by a T cell clone, but the nature of possible TCR interactions with CD1a/lipid are unknown. After incubating CD1a with a mycobacterial lipopeptide Ag, dideoxymycobactin (DDM), we identified and measured binding to a recombinant TCR (TRAV3/ TRBV3-1, KD of ≈100 µM). Detection of ternary CD1a/lipid/TCR interactions enabled development of CD1a tetramers and CD1a multimers with carbohydrate backbones (dextramers), which specifically stained T cells using a mechanism that was dependent on the precise stereochemistry of the peptide backbone and was blocked with a soluble TCR. Furthermore, sorting of human T cells from unrelated tuberculosis patients for bright DDM-dextramer staining allowed recovery of T cells that were activated by CD1a and DDM. These studies demonstrate that the mechanism of T cell activation by lipopeptides occurs via ternary interactions of CD1a/Ag/TCR. Furthermore, these studies demonstrate the existence of lipopeptide-specific T cells in humans ex vivo.

Lipidomic discovery of deoxysiderophores reveals a revised mycobactin biosynthesis pathway in Mycobacterium tuberculosis.

To measure molecular changes underlying pathogen adaptation, we generated a searchable dataset of more than 12,000 mass spectrometry events, corresponding to lipids and small molecules that constitute a lipidome for Mycobacterium tuberculosis. Iron is essential for M. tuberculosis survival, and the organism imports this metal using mycobactin and carboxymycobactin siderophores. Detection of an unexpected siderophore variant and deletions of genes for iron scavenging has led to a revised mycobactin biosynthesis model. An organism-wide search of the M. tuberculosis database for hypothetical compounds predicted by this model led to the discovery of two families of previously unknown lipids, designated monodeoxymycobactins and monodeoxycarboxymycobactins. These molecules suggest a revised biosynthetic model that alters the substrates and order of action of enzymes through the mycobactin biosynthetic pathway. We tested this model genetically by solving M. tuberculosis lipidomes after deletion of the iron-dependent regulator (ideR), mycobactin synthase B (mbtB), or mycobactin synthase G (mbtG). These studies show that deoxymycobactins are actively regulated during iron starvation, and also define essential roles of MbtG in converting deoxymycobactins to mycobactin and in promoting M. tuberculosis growth. Thus, lipidomics is an efficient discovery tool that informs genetic relationships, leading to a revised general model for the biosynthesis of these virulence-conferring siderophores.

Quality of prenatal care questionnaire: instrument development and testing.

BACKGROUND: Utilization indices exist to measure quantity of prenatal care, but currently there is no published instrument to assess quality of prenatal care. The purpose of this study was to develop and test a new instrument, the Quality of Prenatal Care Questionnaire (QPCQ). METHODS: Data for this instrument development study were collected in five Canadian cities. Items for the QPCQ were generated through interviews with 40 pregnant women and 40 health care providers and a review of prenatal care guidelines, followed by assessment of content validity and rating of importance of items. The preliminary 100-item QPCQ was administered to 422 postpartum women to conduct item reduction using exploratory factor analysis. The final 46-item version of the QPCQ was then administered to another 422 postpartum women to establish its construct validity, and internal consistency and test-retest reliability. RESULTS: Exploratory factor analysis reduced the QPCQ to 46 items, factored into 6 subscales, which subsequently were validated by confirmatory factor analysis. Construct validity was also demonstrated using a hypothesis testing approach; there was a significant positive association between women's ratings of the quality of prenatal care and their satisfaction with care (r = 0.81). Convergent validity was demonstrated by a significant positive correlation (r = 0.63) between the "Support and Respect" subscale of the QPCQ and the "Respectfulness/Emotional Support" subscale of the Prenatal Interpersonal Processes of Care instrument. The overall QPCQ had acceptable internal consistency reliability (Cronbach's alpha = 0.96), as did each of the subscales. The test-retest reliability result (Intra-class correlation coefficient = 0.88) indicated stability of the instrument on repeat administration approximately one week later. Temporal stability testing confirmed that women's ratings of their quality of prenatal care did not change as a result of giving birth or between the early postpartum period and 4 to 6 weeks postpartum. CONCLUSION: The QPCQ is a valid and reliable instrument that will be useful in future research as an outcome measure to compare quality of care across geographic regions, populations, and service delivery models, and to assess the relationship between quality of care and maternal and infant health outcomes.

Discovery of deoxyceramides and diacylglycerols as CD1b scaffold lipids among diverse groove-blocking lipids of the human CD1 system.

Unlike the dominant role of one class II invariant chain peptide (CLIP) in blocking MHC class II, comparative lipidomics analysis shows that human cluster of differentiation (CD) proteins CD1a, CD1b, CD1c, and CD1d bind lipids corresponding to hundreds of diverse accurate mass retention time values. Although most ions were observed in association with several CD1 proteins, ligands binding selectively to one CD1 isoform allowed the study of how differing antigen-binding grooves influence lipid capture. Although the CD1b groove is distinguished by its unusually large volume (2,200 Å(3)) and the T' tunnel, the average mass of compounds eluted from CD1b was similar to that of lipids from CD1 proteins with smaller grooves. Elution of small ligands from the large CD1b groove might be explained if two small lipids bind simultaneously in the groove. Crystal structures indicate that all CD1 proteins can capture one antigen with its hydrophilic head group exposed for T-cell recognition, but CD1b structures show scaffold lipids seated below the antigen. We found that ligands selectively associated with CD1b lacked the hydrophilic head group that is generally needed for antigen recognition but interferes with scaffold function. Furthermore, we identified the scaffolds as deoxyceramides and diacylglycerols and directly demonstrate a function in augmenting presentation of a small glycolipid antigen to T cells. Thus, unlike MHC class II, CD1 proteins capture highly diverse ligands in the secretory pathway. CD1b has a mechanism for presenting either two small or one large lipid, allowing presentation of antigens with an unusually broad range of chain lengths.

Pharmacokinetic and pharmacodynamic optimisation of intravenous tobramycin dosing among children with cystic fibrosis.

This study aimed to characterize the pharmacokinetics of tobramycin administered one, two, or three times daily and to develop an optimal dosing scheme for children with cystic fibrosis. Therapeutic drug monitoring data were obtained from children hospitalized at three academic medical centres from 2006 to 2012. Population pharmacokinetic models were constructed using NONMEM 7.2. Model-based simulations were performed in Matlab R2012b to identify optimal dosing regimens using pharmacodynamic targets. The pharmacokinetic analysis involved 257 patients with a median age of 8.1 years (range 0.1-18.8). Clearance was estimated as 5.59 L/h and the volume of distribution was 18.90 L. Mean (±SD) maximum serum concentrations were highest among patients dosed once per day (24.1 ± 8.9 µg/mL) and were lower among patients dosed two and three times per day (11.2 ± 1.4 and 8.1 ± 2.4 µg/mL, respectively). Simulations revealed that once daily dosing was the only effective regimen for a Pseudomonas aeruginosa MIC of 1.5 µg/mL and none of the tested regimens reliably achieved the pharmacodynamic target for MICs ≥2 µg/mL. Once daily dosing resulted in higher maximum serum concentrations when compared to multiple-daily dosing. In simulations, once daily dosing was the only regimen to achieve the pharmacodynamic target for all subjects with MICs <2 µg/mL.

The pharmacokinetics and pharmacodynamics of continuous infusion vancomycin in adult people with cystic fibrosis.

BACKGROUND: The American Thoracic Society Guidelines recommend vancomycin as first line option for treatment of methicillin-resistant Staphylococcus aureus. Two studies have described the pharmacokinetics (PK) of intermittent intravenous (IV) vancomycin in adult people with cystic fibrosis (PwCF). Currently, there have not been any studies describing the PK of continuous infusion vancomycin in PwCF. Our study aimed to describe the PK of continuous infusion vancomycin in adult PwCF. METHODS: Included patients were adult PwCF, who were admitted to University of Utah Hospital between May 11, 2014 and August 31, 2020, and received continuous infusion vancomycin for the treatment of an pulmonary exacerbations. The primary outcome was to describe vancomycin clearance rate (CLvanco ) and total daily dose (TDD). Secondary outcomes included rates of acute kidney injury (AKI), liver injury, and infusion-related reactions. RESULTS: Twenty patients were included in this study. The mean CLvanco was 5.08 L/h on Day 3 and 4.58 L/h on Day 7 (p = .04), and the TDD increased from 2444 mg on Day 3 to 2556 on Day 7, although not statistically significant (p = 0.26). Zero patients experienced an AKI, two patients experienced liver injury, and no patients experienced infusion-related reactions. CONCLUSIONS: This study demonstrates that continuous infusion vancomycin PK, namely CLvanco , is similar to previously reported CLvanco for intermittent dosed IV vancomycin in adult PwCF. This study suggests that continuous infusion vancomycin is likely safe to use in adult PwCF.