Caspofungin has a liver-dependent metabolism. Reduction of the dose is recommended based on Child-Pugh (C-P) score. In critically ill patients, drug pharmacokinetics (PK) may be altered. The aim of ...this study was to investigate the prevalence of abnormal liver function tests, increased C-P scores, their effects on caspofungin PK, and whether pharmacokinetic-pharmacodynamic (PK/PD) targets were attained in patients with suspected candidiasis. Intensive care unit patients receiving caspofungin were prospectively included. PK parameters were determined on days 2, 5, and 10, and their correlations to the individual liver function tests and the C-P score were analyzed. Forty-six patients were included with C-P class A (
= 5), B (
= 40), and C (
= 1). On day 5 (steady state), the median and interquartile range for area under the curve from 0 to 24 h (AUC
), clearance (CL), and central volume of distribution (
) were 57.8 (51.6 to 69.8) mg·h/liter, 0.88 (0.78 to 1.04) liters/h, and 11.9 (9.6 to 13.1) liters, respectively. The C-P score did not correlate with AUC
(
= 0.03;
= 0.84), CL (
= -0.07;
= 0.68), or
(
= 0.19;
= 0.26), but there was a bilirubin-driven negative correlation with the elimination rate constant (
= -0.46;
= 0.004). Hypoalbuminemia correlated with low AUC
(
= 0.45;
= 0.005) and was associated with higher clearance (
= -0.31;
= 0.062) and somewhat higher
(
= -0.15;
= 0.37), resulting in a negative correlation with the elimination rate constant (
= -0.34;
= 0.042). For
strains with minimal inhibitory concentrations of ≥0.064 μg/ml, PK/PD targets were not attained in all patients. The caspofungin dose should not be reduced in critically ill patients in the absence of cirrhosis, and we advise against the use of the C-P score in patients with trauma- or sepsis-induced liver injury.
Critically ill patients with severe infections are at high risk of suboptimal antimicrobial dosing. The pharmacokinetics (PK) and pharmacodynamics (PD) of antimicrobials in these patients differ ...significantly from the patient groups from whose data the conventional dosing regimens were developed. Use of such regimens often results in inadequate antimicrobial concentrations at the site of infection and is associated with poor patient outcomes. In this article, we describe the potential of in vitro and in vivo infection models, clinical pharmacokinetic data and pharmacokinetic/pharmacodynamic models to guide the design of more effective antimicrobial dosing regimens. Individualised dosing, based on population PK models and patient factors (e.g. renal function and weight) known to influence antimicrobial PK, increases the probability of achieving therapeutic drug exposures while at the same time avoiding toxic concentrations. When therapeutic drug monitoring (TDM) is applied, early dose adaptation to the needs of the individual patient is possible. TDM is likely to be of particular importance for infected critically ill patients, where profound PK changes are present and prompt appropriate antibiotic therapy is crucial. In the light of the continued high mortality rates in critically ill patients with severe infections, a paradigm shift to refined dosing strategies for antimicrobials is warranted to enhance the probability of achieving drug concentrations that increase the likelihood of clinical success.
Levodopa-entacapone-carbidopa intestinal gel (LECIG) provides continuous drug delivery through intrajejunal infusion. The aim of this study was to characterize the population pharmacokinetics of ...levodopa following LECIG and levodopa-carbidopa intestinal gel (LCIG) infusion to investigate suitable translation of dose from LCIG to LECIG treatment, and the impact of common variations in the dopa-decarboxylase (DDC) and catechol-O-methyltransferase (COMT) genes on levodopa pharmacokinetics. A non-linear mixed-effects model of levodopa pharmacokinetics was developed using plasma concentration data from a double-blind, cross-over study of LCIG compared with LECIG in patients with advanced Parkinson's disease (n = 11). All patients were genotyped for rs4680 (polymorphism of the COMT gene), rs921451 and rs3837091 (polymorphisms of the DDC gene). The final model was a one compartment model with a high fixed absorption rate constant, and a first order elimination, with estimated apparent clearances (CL/F), of 27.9 L/h/70 kg for LCIG versus 17.5 L/h/70 kg for LECIG, and apparent volume of distribution of 74.4 L/70 kg. Our results thus suggest that the continuous maintenance dose of LECIG, on a population level, should be decreased by approximately 35%, to achieve similar drug exposure as with LCIG. An effect from entacapone was identified on all individuals, regardless of COMT rs4680 genotype. The individuals with higher DDC and COMT enzyme activity showed tendencies towards higher levodopa CL/F. The simultaneous administration of entacapone to LCIG administration results in a 36.5% lower apparent levodopa clearance, and there is a need for lower continuous maintenance doses, regardless of patients' COMT genotype.
Uncontrolled proliferation is a hallmark of cancer. In breast cancer, immunohistochemical assessment of the proportion of cells staining for the nuclear antigen Ki67 has become the most widely used ...method for comparing proliferation between tumor samples. Potential uses include prognosis, prediction of relative responsiveness or resistance to chemotherapy or endocrine therapy, estimation of residual risk in patients on standard therapy and as a dynamic biomarker of treatment efficacy in samples taken before, during, and after neoadjuvant therapy, particularly neoadjuvant endocrine therapy. Increasingly, Ki67 is measured in these scenarios for clinical research, including as a primary efficacy endpoint for clinical trials, and sometimes for clinical management. At present, the enormous variation in analytical practice markedly limits the value of Ki67 in each of these contexts. On March 12, 2010, an international panel of investigators with substantial expertise in the assessment of Ki67 and in the development of biomarker guidelines was convened in London by the cochairs of the Breast International Group and North American Breast Cancer Group Biomarker Working Party to consider evidence for potential applications. Comprehensive recommendations on preanalytical and analytical assessment, and interpretation and scoring of Ki67 were formulated based on current evidence. These recommendations are geared toward achieving a harmonized methodology, create greater between-laboratory and between-study comparability, and allow earlier valid applications of this marker in clinical practice.
Deriving suitable dosing regimens for antibiotic combination therapy poses several challenges as the drug interaction can be highly complex, the traditional pharmacokinetic–pharmacodynamic (PKPD) ...index methodology cannot be applied straightforwardly, and exploring all possible dose combinations is unfeasible. Therefore, semi-mechanistic PKPD models developed based on in vitro single and combination experiments can be valuable to suggest suitable combination dosing regimens.
To outline how the interaction between two antibiotics has been characterized in semi-mechanistic PKPD models. We also explain how such models can be applied to support dosing regimens and design future studies.
PubMed search for published semi-mechanistic PKPD models of antibiotic drug combinations.
Thirteen publications were identified where ten had applied subpopulation synergy to characterize the combined effect, i.e. independent killing rates for each drug and bacterial subpopulation. We report the various types of interaction functions that have been used to describe the combined drug effects and that characterized potential deviations from additivity under the PKPD model. Simulations from the models had commonly been performed to compare single versus combined dosing regimens and/or to propose improved dosing regimens.
Semi-mechanistic PKPD models allow for integration of knowledge on the interaction between antibiotics for various PK and PD profiles, and can account for associated variability within the population as well as parameter uncertainty. Decisions on suitable combination regimens can thereby be facilitated. We find the application of semi-mechanistic PKPD models to be essential for efficient development of antibiotic combination regimens that optimize bacterial killing and/or suppress resistance development.
This study aimed to explore the interactions of polymyxin B in combination with 13 other antibiotics against carbapenemase-producing Klebsiella pneumoniae.
Five clinical isolates of ...multidrug-resistant K. pneumoniae producing KPC-2, KPC-3, NDM-1, OXA-48 and VIM-1 carbapenemases were used. Polymyxin B was tested alone and in combination with amikacin, aztreonam, cefepime, chloramphenicol, ciprofloxacin, fosfomycin, linezolid, meropenem, minocycline, rifampicin, temocillin, thiamphenicol and trimethoprim. Inhibition of growth during antibiotic exposure was evaluated in 24-hr automated time-lapse microscopy experiments. Combinations that showed positive interactions were subsequently evaluated in static time-kill experiments.
All strains carried multiple (≥9) resistance genes as determined by whole-genome sequencing. In the initial screening the combination of polymyxin B and minocycline was most active with enhanced activity compared with the single antibiotics detected against all strains. Positive interactions were also observed with polymyxin B in combination with rifampicin and fosfomycin against four of five strains and less frequently with other antibiotics. Time-kill experiments demonstrated an additive or synergistic activity (1–2 log10 or ≥2 log10 CFU/mL reduction, respectively, compared with the most potent single antibiotic) with 21 of 23 tested combinations. However, because of regrowth, only 13 combinations were synergistic at 24 hr. Combinations with minocycline or rifampicin were most active, each showing synergy and bacteriostatic or bactericidal effects resulting in 1.93–3.97 and 2.55–5.91 log10 CFU/mL reductions, respectively, after 24 hr against four strains.
Polymyxin B in combination with minocycline, rifampicin or fosfomycin could be of potential clinical interest. Time-lapse microscopy showed some discrepancy in results compared with the time-kill data but was useful for screening purposes.
Essentials
A population pharmacokinetic model and sparse factor IX (FIX) levels may be used in dose individualization.
FIX sampling schedules for dose individualization were explored and compared ...with fixed doses.
Individual FIX doses were acceptably predicted with only two samples drawn post dose (days 2 and 3).
Pharmacokinetic dose individualization resulted in better target attainment than a fixed‐dose regimen.
Summary
Background
Population pharmacokinetic (POPPK) models describing factor IX (FIX) activity levels in plasma, in combination with individual FIX measurements, may be used to individualize dosing in the treatment of hemophilia B.
Objectives
The aim was to reevaluate a previously developed POPPK model for FIX activity and to explore the number and timing of FIX samples required in pharmacokinetic (PK) dose individualization.
Methods
The POPPK model was reevaluated using an extended data set. Several sampling schedules, varying with respect to the timing and number of samples, were evaluated in a simulation study with relative dose errors compared between schedules. The performance of individually calculated doses was compared with commonly prescribed FIX doses with respect to the number of patients with a trough FIX activity > 0.01 U mL−1.
Results and conclusions
A three‐compartment PK model best described the FIX activity levels. The number and timing of samples greatly influenced imprecision in dose prediction. Schedules with single samples taken on both day 2 and day 3 were identified as being convenient schedules with an acceptable performance level. Individually calculated doses performed better with respect to patient target attainment than a fixed 40 U kg−1 dose regardless of how many samples were available to calculate individual doses. The results of this study suggest that PK dose tailoring with limited sampling may be applicable for plasma‐derived FIX products.
This study investigated the disposition of coagulation factor VIII activity in 754 patients with moderate to severe hemophilia A following the administration of moroctocog alfa, a B‐domain deleted ...recombinant factor VIII. Data analyzed included patients aged 1 day to 73 years enrolled in 13 studies conducted over a period of 20 years in 25 countries. A two‐compartment population pharmacokinetic model with a baseline model described the pooled data well. Body size, age, inhibitors, race, and analytical assay were identified as significant predictors of factor VIII disposition. In addition, simulations of prophylactic dosing schedules in several pediatric cohorts showed large variability and suggest that younger patients would require higher weight‐adjusted doses than adolescents to achieve target factor VIII trough activity when receiving every other day or twice weekly dosing.
Objective To determine the association between self reported job insecurity and incident coronary heart disease. Design A meta-analysis combining individual level data from a collaborative consortium ...and published studies identified by a systematic review. Data sources We obtained individual level data from 13 cohort studies participating in the Individual-Participant-Data Meta-analysis in Working Populations Consortium. Four published prospective cohort studies were identified by searches of Medline (to August 2012) and Embase databases (to October 2012), supplemented by manual searches. Review methods Prospective cohort studies that reported risk estimates for clinically verified incident coronary heart disease by the level of self reported job insecurity. Two independent reviewers extracted published data. Summary estimates of association were obtained using random effects models. Results The literature search yielded four cohort studies. Together with 13 cohort studies with individual participant data, the meta-analysis comprised up to 174 438 participants with a mean follow-up of 9.7 years and 1892 incident cases of coronary heart disease. Age adjusted relative risk of high versus low job insecurity was 1.32 (95% confidence interval 1.09 to 1.59). The relative risk of job insecurity adjusted for sociodemographic and risk factors was 1.19 (1.00 to 1.42). There was no evidence of significant differences in this association by sex, age (<50 v ≥50 years), national unemployment rate, welfare regime, or job insecurity measure. Conclusions The modest association between perceived job insecurity and incident coronary heart disease is partly attributable to poorer socioeconomic circumstances and less favourable risk factor profiles among people with job insecurity.
Abstract
We make use of JWST medium-band and broadband NIRCam imaging, along with ultradeep MIRI 5.6
μ
m imaging, in the Hubble eXtreme Deep Field to identify prominent line emitters at
z
≃ 7–8. Out ...of a total of 58 galaxies at
z
≃ 7–8, we find 18 robust candidates (≃31%) for (H
β
+ O
iii
) emitters, based on their enhanced fluxes in the F430M and F444W filters, with EW
0
(H
β
+O
iii
) ≃87–2100 Å. Among these emitters, 16 lie in the MIRI coverage area and 12 exhibit a clear flux excess at 5.6
μ
m, indicating the simultaneous presence of a prominent H
α
emission line with EW
0
(H
α
) ≃200–3000 Å. This is the first time that H
α
emission can be detected in individual galaxies at
z
> 7. The H
α
line, when present, allows us to separate the contributions of H
β
and O
iii
to the (H
β
+O
iii
) complex and derive H
α
-based star formation rates (SFRs). We find that in most cases O
iii
/H
β
> 1. Instead, two galaxies have O
iii
/H
β
< 1, indicating that the NIRCam flux excess is mainly driven by H
β
. Most prominent line emitters are very young starbursts or galaxies on their way to/from the starburst cloud. They make for a cosmic SFR density
log
10
(
ρ
SFR
H
α
/
(
M
⊙
yr
−
1
Mpc
−
3
)
)
≃
−
2.35
, which is about a quarter of the total value (
log
10
(
ρ
SFR
tot
/
(
M
⊙
yr
−
1
Mpc
−
3
)
)
≃
−
1.76
) at
z
≃ 7–8. Therefore, the strong H
α
emitters likely had a significant role in reionization.
PDF
![MIDIS: Strong (Hβ+[O iii]) ...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/0004-637X/small "MIDIS: Strong (Hβ+[O iii]) and Hα Emitters at Redshift z ≃ 7–8 Unveiled with JWST NIRCam and MIRI Imaging in the Hubble eXtreme Deep Field")