Population pharmacokinetics/pharmacodynamics of minocycline plus rifampicin in patients with complicated skin and skin structure infections caused by MRSA.

BACKGROUND: The population pharmacokinetics/pharmacodynamics (PK/PD) of minocycline, rifampicin and linezolid in patients with complicated skin and soft tissue infections (cSSTIs) caused by MRSA are described. METHODS: Samples were collected in a Phase 4 study of oral minocycline plus rifampicin versus linezolid showing minocycline plus rifampicin to be non-inferior to linezolid. Antibiotics were assayed by HPLC or LC-MS, and a population PK model was developed using Pmetrics. The association between PK/PD indices and patient outcomes was explored. RESULTS: A three-compartment model (with an absorption compartment) with first-order input and elimination best described the data for the three drugs. No covariates were included in the final model. The population median values (95% credibility limits) of the clearance and volume of distribution were 7.412 L/h (5.121-8.361) and 14.155 L (6.799-33.901) for minocycline, 5.683 L/h (3.703-7.726) and 7.736 L (6.031-8.948) for rifampicin, and 1.970 L/h (1.326-2.499) and 20.169 L (12.857-32.629) for linezolid, respectively. Maximum a posteriori probability-Bayesian estimation plots of observed versus predicted had a slope of 0.999 r20.967 for minocycline, slope 0.998 r20.769 for rifampicin and slope 0.998 r20.895 for linezolid. PK/PD indices were not related to clinical outcome. Taking a translational minocycline fAUC24h/MIC target of >0.5 for minocycline in the presence of rifampicin, 96% (49/51) of patients reached the target. CONCLUSIONS: Population PK models of minocycline, rifampicin and linezolid were developed in patients with MRSA cSSTI and almost all patients reached the predefined PD index targets. As a result, neither AUC, MIC nor the AUC/MIC ratio could be related to clinical outcome.

The effect of duration of therapy for treatment of Staphylococcus aureus blood stream infection: an application of cloning to deal with immortal-time bias in an analysis of data from a cohort study (BSI-FOO).

OBJECTIVE: To estimate the effect of treatment duration on in-hospital mortality in patients with Staphylococcus aureus blood stream infection and demonstrate the biases that can arise when immortal-time bias is ignored. EXPOSURE: We compared three treatment strategies: short therapy (<10 days), intermediate (10-18 days) and long (>18 days). MAIN OUTCOME MEASURES: Twenty-eight-day all-cause in-hospital mortality. METHODS: Using data from the BSI-FOO study, we implemented an approach proposed by Hernán to overcome confounding and immortal-time biases. The first stage is to clone all participants, so that each participant is assigned to each treatment strategy. Second, observations are censored when their data becomes inconsistent with their assigned strategy. Finally, inverse-probability weights are applied to adjust for potential selection. We compared our results to a naïve approach where immortal-time bias is ignored. RESULTS: Of the 1903 participants in BSI-FOO, 587 were eligible and included in the analysis. After cloning, the weighted estimates of hazard ratio of mortality for short versus long therapy was 1.74 (95% CI 1.36, 2.24) and for intermediate versus long therapy was 1.09 (0.98, 1.22). In the naïve approach, the hazard ratios with reference to the long therapy group are 37.4 (95% CI 18.9 to 74.4) in the short therapy group and 4.1 (95% CI 1.9 to 8.9) in the intermediate therapy group. CONCLUSIONS: Our findings suggest that duration of therapy >18 days is beneficial with respect to 28-day in-hospital mortality, however, there remains uncertainty around the efficacy of reducing duration of treatment to 10-18 days.

Long-term Visual Outcomes after Release from Protocol in Patients who Participated in the Inhibition of VEGF in Age-related Choroidal Neovascularisation (IVAN) Trial.

PURPOSE: To describe visual outcomes, frequency of treatment and monitoring visits, and anti-vascular endothelial growth factor drugs used in usual care in participants who exited a trial in which treatment for neovascular age-related macular degeneration (nAMD) was initiated with bevacizumab or ranibizumab. DESIGN: Multicenter cohort study up to 7 years after trial exit. PARTICIPANTS: Patients enrolled in the Inhibition of VEGF in Age-related choroidal Neovascularisation (IVAN) trial; after excluding participants from 2 sites and who died or withdrew during the trial, 537 were included in this follow-up cohort. METHODS: Data were collected between May 26, 2016, and August 24, 2017. Distance visual acuity (DVA) (letters read) in both eyes and treatments for nAMD administered to either eye at all usual care visits were extracted from medical records of all participants until the point of data collection (duration of study eye monitoring). MAIN OUTCOME MEASURES: Rate of change of DVA during active surveillance of the study eye (study eye monitoring), estimated using a multivariable linear random effects model. Other outcome measures were visit and treatment frequency and switches in anti-vascular endothelial growth factor (VEGF) drug. RESULTS: Data were obtained for 99% (532/537) of eligible participants. The median duration of study eye monitoring after IVAN exit was 3.3 years (interquartile range [IQR], 1.3-4.7), and median DVA was 58.0 letters (IQR, 34.0-73.0). Study eye DVA deteriorated by 4.3 (95% confidence interval [CI], 3.7-4.9) letters per year. Injection rate did not influence the rate of change in DVA after adjusting for key covariates. After IVAN exit, 174 participants (32%) received no treatment; 332 of 358 (93%) were treated first with ranibizumab, 78 (23%) of whom switched to aflibercept. The DVA was similar among participants who switched or did not switch at the end of study monitoring. CONCLUSIONS: Approximately 5 years after the IVAN study finished, with unprecedented completeness of follow-up for such a trial, the trajectory of functional decline in the study eye was shown to be greater than that previously reported for incomplete trial cohorts. Anti-VEGF injection rates and treatment switches were not important factors in determining visual acuity outcomes.

Modifiable healthcare factors affecting 28-day survival in bloodstream infection: a prospective cohort study.

BACKGROUND: Bloodstream infection is common in the UK and has significant mortality depending on the pathogen involved, site of infection and other patient factors. Healthcare staffing and ward activity may also impact on outcomes in a range of conditions, however there is little specific National Health Service (NHS) data on the impact for patients with bloodstream infection. Bloodstream Infections - Focus on Outcomes is a multicentre cohort study with the primary aim of identifying modifiable risk factors for 28-day mortality in patients with bloodstream infection due to one of six key pathogens. METHODS: Adults under the care of five NHS Trusts in England and Wales between November 2010 and May 2012 were included. Multivariable Cox regression was used to quantify the association between modifiable risk factors, including staffing levels and timing of appropriate therapy, and 28-day mortality, after adjusting for non-modifiable risk factors such as patient demographics and long-term comorbidities. RESULTS: A total of 1676 patients were included in the analysis population. Overall, 348/1676 (20.8%) died within 28 days. Modifiable factors associated with 28-day mortality were ward speciality, ward activity (admissions and discharges), movement within ward speciality, movement from critical care, and time to receipt of appropriate antimicrobial therapy in the first 7 days. For each additional admission or discharge per 10 beds, the hazard increased by 4% (95% CI 1 to 6%) in medical wards and 11% (95% CI 4 to 19%) in critical care. Patients who had moved wards within speciality or who had moved out of a critical care ward had a reduction in hazard of mortality. In the first 7 days, hazard of death increased with increasing time to receipt of appropriate antimicrobial therapy. CONCLUSION: This study underlines the importance of appropriate antimicrobials within the first 7 days, and the potential for ward activity and ward movements to impact on survival in bloodstream infection.

Long versus short course anti-microbial therapy of uncomplicated Staphylococcus aureus bacteraemia: a systematic review.

BACKGROUND: Current guidelines recommend at least 2 weeks duration of antibiotic therapy (DOT) for patients with uncomplicated Staphylococcus aureus bacteraemia (SAB) but the evidence for this recommendation is unclear. OBJECTIVES: To perform a systematic literature review assessing current evidence for recommended DOT for patients with SAB. METHODS: The following are the methods used for this study. DATA SOURCES: We searched MEDLINE, ISI Web of Science, the Cochrane Database and clinicaltrials.gov from inception to March 30, 2024. References of eligible studies were screened and experts in the field contacted for additional articles. STUDY ELIGIBILITY CRITERIA: All clinical studies, regardless of design, publication status and language. PARTICIPANTS: Adult patients with uncomplicated SAB. INTERVENTIONS: Long (>14 days; >18 days; 11-16 days) vs. short (≤14 days; 10-18 days; 6-10 days, respectively) DOT with the DOT being defined as the first until the last day of antibiotic therapy. ASSESSMENT OF RISK OF BIAS: Risk of bias was assessed using the ROBINS-I-tool. METHODS OF DATA SYNTHESIS: The primary outcome was 90-day all-cause mortality. Only studies presenting results of adjusted analyses for mortality were included. Data synthesis could not be performed. RESULTS: Eleven nonrandomized studies were identified that fulfilled the pre-defined inclusion criteria, of which three studies reported adjusted effect ratios. Only these were included in the final analysis. We did not find any RCT. Two studies with 1230 patients reported the primary endpoint 90-day all-cause mortality. Neither found a statistically significant superiority for longer (>14 days; 11-16 days) or shorter DOT (≤14 days; 6-10 days, respectively) for patients with uncomplicated SAB. Two studies investigated the secondary endpoint 30-day all-cause mortality (>18 days; 11-16 days vs. 10-18 days; 6-10 days, respectively) and did not find a statistically significant difference. All included studies had a moderate risk of bias. CONCLUSIONS: Sound evidence that supports any duration of antibiotic treatment for patients with uncomplicated SAB is lacking.

The relationship between minimum inhibitory concentration and 28†day mortality in patients with a Gram-negative bloodstream infection: an analysis of data from a cohort study (BSI-FOO).

Objectives: To explore the association between MIC/EUCAST breakpoint ratio and 28 day mortality in patients with a Gram-negative bloodstream infection (BSI). Methods: Using data from the Bloodstream Infection-Focus on Outcomes (BSI-FOO) observational study, we defined an average MIC/EUCAST breakpoint ratio that was updated daily to reflect changes in treatment in the first 7 days after blood culture. Cox regression analysis was performed to estimate the association between MIC/EUCAST breakpoint ratio and mortality, adjusting for organism and a risk score calculated using potential confounding variables. The primary outcome was 28 day all-cause mortality from the date of blood culture. Results: Of the 1903 study participants, 514 met the eligibility criteria and were included in the analysis (n = 357 Escherichia coli, n = 6 Klebsiella and n = 151 Pseudomonas aeruginosa). The average age was 74.0 years (IQR 60.0-82.0). The mortality rate varied from 11.1% (in patients treated with an average MIC/EUCAST breakpoint ratio of 1) to 27.6% (in patients treated with antibiotics with an average MIC/EUCAST breakpoint ratio >1). After adjusting for risk score and organism, MIC/EUCAST breakpoint ratio was not associated with 28 day mortality (P = 0.148). Conclusions: In an adjusted model controlling for potential confounding variables, there was no evidence to suggest a relationship between MIC/EUCAST breakpoint ratio and 28 day mortality in patients with a Gram-negative BSI.

Emulating the MERINO randomised control trial using data from an observational cohort and trial of rapid diagnostic (BSI-FOO).

OBJECTIVE: The aim of this study was to emulate the MERINO trial of piperacillin-tazobactam vs meropenem for the definitive treatment of bloodstream infection (BSI) caused by ceftriaxone-nonsusceptible E coli or Klebsiella spp. METHODS: Data from an observational study of BSI and a randomised controlled trial of a rapid diagnostic in BSI were used to emulate the MERINO trial. The primary outcome of the emulated trial was 28-day mortality after blood culture. Outcomes were compared using logistic regression adjusted for propensity score for emulated intervention. RESULTS: Of the 6,371 observational study and RCT participants, 1,968 had a bloodstream infection with E. coli or Klebsiella spp. of which 121 met the eligibility criteria. In the emulated trial, a total of 14/82 patients (17.1%) allocated to piperacillin-tazobactam met the primary outcome compared with 6/39 (15.4%) in the meropenem group (unadjusted odds ratio 1.13 (95% CI 0.40 to 3.21)). After adjustment for propensity score, the odds ratio increased to 1.31 (95% CI 0.40 to 4.26). This difference is in the same direction but of a smaller magnitudethan observed in the MERINO trial, where 30-day mortality was met by 23/187 patients (12.3%) in the piperacillin-tazobactam and 7/191 (3.7%) in the meropenem group (unadjusted odds ratio of 3.69 (95% CI 1.48 to 10.41)). CONCLUSIONS: The mortality rate in an emulated trial population was more than double the mortality rate in the MERINO trial. The methodology used attempts to address the concern that previous results could be explained by biases such as selection bias and uncontrolled confounding and provides information on how a trial such as the MERINO trial may have performed in the NHS.

A cohort study of circulating progenitor cells after ST-segment elevation and non-ST segment elevation myocardial infarction in non-diabetic and diabetic patients.

Background: Myocardial infarction induces elevation of progenitor cells in the circulation, a reparative response inhibited by type-2 diabetes. Objectives: Determine if myocardial infarct severity and diabetes interactively influence the migratory activity of CD34+/CXCR4+ progenitor cells and if the migratory test predicts cardiac outcomes. Materials and methods: A longitudinal study was conducted on patients with or without diabetes with a STEMI or NSTEMI. CD34+/CXCR4+ cells were measured in the peripheral blood using flow cytometry, and migratory activity was tested in vitro on cells isolated from samples collected on days 0 and 4 post-infarct. Cardiac function was assessed at three months using cardiac MRI. Results: Of 1,149 patients screened, 71 (6.3%) were eligible and consented. Fifty had STEMI (16 with diabetes) and 21 NSTEMI (8 with diabetes). The proportion of CD34+/CXCR4+ cells within blood mononuclear cells was 1.96 times higher after STEMI compared with NSTEMI (GMR = 1.96, 95% CI 0.87, 4.37) and 1.55 times higher in patients with diabetes compared to patients without diabetes (GMR = 1.55, 95% CI 0.77, 3.13). In the latter, STEMI was associated with a 2.42-times higher proportion of migrated CD34 + /CXCR4 + cells compared with NSTEMI (GMR = 2.42, 95% CI 0.66, 8.81). In patients with diabetes, the association was the opposite, with a 55% reduction in the proportion of migrated CD34+/CXCR4+ cells. No statistically significant associations were observed between the frequency in peripheral blood or in vitro migration capacity of CD34+/CXCR4+ cells and MRI outcomes. Conclusion: We document the interaction between infarct and diabetes on the migratory activity of CD34+/CXCR4+ cells. The test did not predict functional outcomes in the studied cohort.

Long-term Retinal Morphology and Functional Associations in Treated Neovascular Age-Related Macular Degeneration: Findings from the Inhibition of VEGF in Age-Related Choroidal Neovascularisation Trial.

PURPOSE: To describe the frequency of long-term morphologic features and their relationships with visual function in participants who exited the Inhibition of VEGF in Age-Related Choroidal Neovascularisation (IVAN; ISRCTN92166560) trial. DESIGN: Multicenter cohort study up to 7 years after enrollment. PARTICIPANTS: Patients enrolled in the IVAN trial, excluding participants who died or withdrew during the trial. METHODS: Multimodal fundus images, best-corrected visual acuity (BCVA), and low-luminance visual acuity (LLVA) were obtained for a subset of 199 participants who attended a research visit. Clinical sites (n = 20) also provided all visual acuity and clinical information from usual care records for 532 participants and submitted the most recent color, OCT, and other fundus images for 468 participants to a reading center. MAIN OUTCOME MEASURES: Assessed the following from the most recent images: intralesional macular atrophy (ILMA) within the footprint of the neovascular lesion; hyperreflective material (HRM); intraretinal fluid (IRF); subretinal fluid (SRF); pigment epithelial detachment (PED); and disorganized retinal outer layers (DROLs). Cross-sectional relationships between morphologic features and BCVA/LLVA were estimated. RESULTS: Intralesional macular atrophy was present in 31.8% of the study eyes at IVAN exit (mean follow-up, 1.96 years) and 89.5% at the most recent imaging visit (mean follow-up, 6.18 years). Hyperreflective material, IRF, SRF, PED, and DROLs were present in 78.8%, 47.7%, 7.6%, 94.5%, and 55% of the study eyes, respectively. In the subset with complete imaging data, in eyes without DROL, the BCVA was worst in the thinnest outer fovea tertile (thinnest minus middle and thickest tertiles, -19.7 and -19.5 letters, respectively), whereas in eyes with DROL, the BCVA was worst in the thickest (thinnest and middle tertiles minus thickest, 12.5 and 12.2, respectively). Regression models showed that the presence of ILMA and HRM was independently associated with BCVA (22 letters worse [95% confidence interval {CI}, -11.2 to -32.8; P < 0.001] and 9.8 letters worse [95% CI, -0.1 to -19.4; P = 0.047], respectively). Subretinal fluid and foveal PED were associated with better BCVA (5.9 letters [95% CI, -7.9 to 19.7; P = 0.399] and 6.4 letters [95% CI, -1.1 to 14.0; P = 0.094], respectively). The model with LLVA was similar. A sensitivity analysis involving the entire eligible cohort yielded similar estimates. CONCLUSIONS: Macular atrophy and HRM were common after 7 years of follow-up and strongly associated with visual outcomes.

Associations of Variation in Retinal Thickness With Visual Acuity and Anatomic Outcomes in Eyes With Neovascular Age-Related Macular Degeneration Lesions Treated With Anti-Vascular Endothelial Growth Factor Agents.

Importance: When initiating anti-vascular endothelial growth factor (VEGF) treatment for patients with neovascular age-related macular degeneration (nAMD), knowledge of prognostic factors is important for advising patients and guiding treatment. We hypothesized that eyes with greater fluctuation in retinal thickness over time have worse outcomes than eyes with less variation. Objective: To investigate whether visual and anatomic outcomes in eyes with nAMD initiating anti-VEGF treatment are associated with fluctuations in retinal thickness. Design, Setting, and Participants: In this study using data from the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) and the Inhibition of VEGF in Age-Related Choroidal Neovascularization (IVAN) randomized clinical trial, people with previously untreated nAMD were included. Data were collected from February 2008 to November 2012, and data were analyzed from April 2017 to April 2020. Main Outcomes and Measures: Foveal center point thicknesses (FCPTs) were extracted from 1165 study eyes from CATT and 566 study eyes from the IVAN trial, excluding those with 3 measurements or less. For each eye, the SD of FCPT was calculated. Eyes were grouped by FCPT SD quartile. Associations of FCPT SD quartile with outcomes were quantified at month 24 or the last available visit by linear or logistic regression, adjusting for baseline best-corrected visual acuity (BCVA) and randomized allocations to drug and treatment regimen, for BCVA, development of fibrosis, and development of macular atrophy. Results: Of the 1731 included patients, 1058 (61.1%) were female, and the mean (SD) age was 78.6 (7.4) years. The median (interquartile range) FCPT SD was 40.2 (27.1-61.2) in the IVAN cohort and 59.0 (38.3-89.4) in the CATT cohort. After adjustment for baseline BCVA and trial allocations, BCVA worsened significantly across the quartiles of FCPT SD; the difference between the first and fourth quartiles was -6.27 Early Treatment Diabetic Retinopathy Study letters (95% CI, -8.45 to -4.09). The risk of developing fibrosis and macular atrophy also increased across FCPT SD quartiles. Odds ratios ranged from 1.40 (95% CI, 1.03 to 1.91) for quartile 2 to 1.95 (95% CI, 1.42 to 2.68) for quartile 4 for fibrosis and from 1.32 (95% CI, 0.90 to 1.92) for quartile 2 to 2.10 (95% CI, 1.45 to 3.05) for quartile 4 for macular atrophy. Conclusions and Relevance: Greater variation in retinal thickness in eyes with nAMD during treatment with anti-VEGF was associated with worse BCVA and development of fibrosis and macular atrophy in these post hoc analyses, despite protocol-directed treatment frequency. Practitioners may want to consider variation in retinal thickness when advising patients about their prognosis.