Development and validation of a dosing nomogram for continuous infusion cloxacillin in infective endocarditis.

BACKGROUND: Cloxacillin is the first-line treatment for methicillin-susceptible staphylococcal infective endocarditis (IE). The recommended dose is 12 g per day regardless of the patient characteristics, despite the importance of renal function on its pharmacokinetics. OBJECTIVES: We sought to build a population pharmacokinetics model of continuous infusion cloxacillin in IE patients to evaluate the influence of multiple covariates and then develop a nomogram based on significant covariates for individual adaptation. PATIENTS AND METHODS: We included patients of a local IE cohort who were treated with cloxacillin administered by continuous infusion, excluding those who received intermittent or continuous dialysis, extracorporeal membrane oxygenation or extracorporeal circulation. The population pharmacokinetic analysis was performed using Pmetrics. The influence of weight, ideal weight, height, body mass index, body surface area, glomerular filtration rate (GFR) calculated with the Chronic Kidney Disease Epidemiology Collaboration formula (both expressed in mL/min/1.73 m² and in mL/min) and serum protein level on cloxacillin pharmacokinetics was assessed. Accounting for relevant covariates, a dosing nomogram was developed to determine the optimal daily dose required to achieve a steady-state plasma concentration range of 20-50 mg/L with a probability ≥0.9. RESULTS: A total of 114 patients (331 plasma concentrations) were included. A one-compartment model including GFR expressed in mL/min as a covariate was chosen. Using the nomogram, achieving the cloxacillin concentration target requires a daily dose ranging from 3.5 to 13.1 g for a GFR ranging from 20 to 125 mL/min. CONCLUSIONS: This work provided a practical tool for cloxacillin dose adjustment in IE according to renal function.

Dalbavancin plasma concentrations in 133 patients: a PK/PD observational study.

OBJECTIVES: Limited pharmacokinetics data support dalbavancin long-term use in off-label indications and the optimal dosing regimen is debated. We aimed to describe dalbavancin concentrations in an observational retrospective multicentre study. METHODS: Patients from 13 French hospitals, treated with 1500 mg doses of dalbavancin and for whom therapeutic drug monitoring was performed from June 2018 to March 2021 were included. Dalbavancin plasma concentrations were described at peak and 1, 2, 3, 4, 6 and 8 weeks after the last 1500 mg dose. Concentrations in patients weighing more or less than 75 kg and with a GFR greater or less than 60 mL/min were compared. Microbiological data were collected and dalbavancin MIC was measured when possible. RESULTS: One hundred and thirty-three patients were included (69% treated for bone and joint infections, 16% for endocarditis). Thirty-five patients received a single dose of dalbavancin and 98 received several administrations. Two, 3 and 4 weeks after the last dose, median plasma concentrations were respectively 25.00, 14.80 and 9.24 mg/L for the first doses and 34.55, 22.60 and 19.20 mg/L for the second or subsequent doses. Weight and renal function had an impact on pharmacokinetics. Infection was documented in 105 patients (Staphylococcus spp. in 68% of cases). Staphylococcus aureus was isolated in 32.5% of cases (median MIC: 0.047 mg/L) and Staphylococcus epidermidis in 27% of cases (median MIC of 0.047 mg/L). CONCLUSIONS: Plasma concentrations of dalbavancin were consistent with those described in clinical trials and those sought during the industrial development of the molecule.

CSF concentration of cefotaxime in adult patients with pneumococcal meningitis: a multicentre retrospective study.

BACKGROUND AND OBJECTIVES: Pneumococcal meningitis is a devastating disease that requires adequate meningeal antibiotic penetration to limit the mortality. Despite a large usage in this indication, data about CSF concentration of cefotaxime during pneumococcal meningitis in adults are scarce. Therefore, we aimed to describe the CSF concentration obtained after high-dose cefotaxime administration in adult patients treated for Streptococcus pneumoniae meningitis. PATIENTS AND METHODS: In this multicentre, observational, retrospective study, cases of adult patients with S. pneumoniae meningitis hospitalized between January 2013 and October 2019 for whom cefotaxime concentration was measured in CSF were reviewed. RESULTS: Cefotaxime concentration was analysed in 44 CSF samples collected among 31 patients. Median (IQR) age was 61 years (52-69). Dexamethasone was administered in 27 subjects. Median (IQR) cefotaxime daily dosage was 15 g (12-19), corresponding to 200 mg/kg (150-280). CSF samples were collected approximately 5 days after cefotaxime initiation. Median (IQR, range) cefotaxime CSF concentration was 10.3 mg/L (4.8-19.3, 1.2-43.4). Median (range) MIC for Streptococcus pneumoniae was 0.25 mg/L (0.008-1) (n = 22). The median (IQR, range) CSF/MIC ratio was 38 (12-146, 4-1844). Twenty-five CSF concentrations (81%) were above 10 times the MIC. Cefotaxime was discontinued in two patients for toxicity. In-hospital mortality rate was 29%. CONCLUSIONS: Adult patients with pneumococcal meningitis treated with a high dose of cefotaxime (200 mg/kg/day) had elevated CSF concentrations with satisfying pharmacokinetics/pharmacodynamics parameters and tolerability profile. This study brings reassuring pharmacological data regarding the use of high-dose cefotaxime monotherapy for treating pneumococcal meningitis with susceptible strains to cefotaxime.

Development and validation of a dosing nomogram for amoxicillin in infective endocarditis.

BACKGROUND: Amoxicillin is the first-line treatment for streptococcal or enterococcal infective endocarditis (IE) with a dose regimen adapted to weight. OBJECTIVES: Covariates influencing pharmacokinetics (PK) of amoxicillin were identified in order to develop a dosing nomogram based on identified covariates for individual adaptation. PATIENTS AND METHODS: Patients treated with amoxicillin administered by continuous infusion for IE were included retrospectively. The population PK analysis was performed using the Pmetrics package for R (NPAG algorithm). Influence of weight, ideal weight, height, BMI, body surface area, glomerular filtration rate adapted to the body surface area and calculated by the CKD-EPI method (mL/min), additional ceftriaxone treatment and serum protein level on amoxicillin PK was tested. A nomogram was then developed to determine the daily dose needed to achieve a steady-state free plasma concentration above 4× MIC, 100% of the time, without exceeding a total plasma concentration of 80 mg/L. RESULTS: A total of 160 patients were included. Population PK analysis was performed on 540 amoxicillin plasma concentrations. A two-compartment model best described amoxicillin PK and the glomerular filtration rate covariate significantly improved the model when included in the calculation of the elimination constant Ke. CONCLUSIONS: This work allowed the development of a dosing nomogram that can help to increase achievement of the PK/pharmacodynamic targets in IE treated with amoxicillin.

Adaptive resistance to cefiderocol in carbapenem-resistant Acinetobacter baumannii (CRAB): Microbiological and clinical issues.

Objectives: Determining the best available therapy for carbapenem-resistant Acinetobacter baumannii (CRAB) infections is a challenge. Cefiderocol is an attractive alternative drug effective against many resistance mechanisms in Gram-negative bacteria. However, its place in the treatment of Acinetobacter baumannii infections remains unclear and much debated, with contradictory results. Methods: We describe here the case of a 37-year-old man with ventilator-associated bacteraemic CRAB pneumonia in an intensive care unit. He was initially treated with a combination of colistin and tigecycline, and was then switched onto colistin and cefiderocol. We then used a new accessible protocol to test 30 CRAB isolates (OXA-23/OXA-24/OXA-58/NDM-1) for adaptive resistance to cefiderocol (ARC) after exposure to this drug. Results: After clinical failure with the initial combination, we noted a significant clinical improvement in the patient on the second combination, leading to clinical cure. No ARC was detected in the two OXA-23 case-CRAB isolates. All NDM-1 CRAB isolates were resistant to cefiderocol in standard tests; the OXA-23, OXA-24 and OXA-58 CRAB isolates presented 84.2 %, 50 % and 0 % ARC, respectively. Conclusions: ARC is not routinely assessed for CRAB isolates despite frequently being reported in susceptible isolates (69.2 %). Subpopulations displaying ARC may account for treatment failure, but this hypothesis should be treated with caution in the absence of robust clinical data. The two main findings of this work are that (i) cefiderocol monotherapy should probably not be recommended for OXA-23/24 CRAB infections and (ii) the characterisation of carbapenemases in CRAB strains may be informative for clinical decision-making.

Qualitative assessment of the national initiative to implement antimicrobial stewardship centres in French administrative regions.

BACKGROUND: In May 2020, the French Ministry of Health funded the creation of regional antimicrobial stewardship (AMS) coordination centres (CRAtb) in preparation for the new national framework for the prevention of antimicrobial resistance. This study aimed to assess through qualitative methods the implementation process, the activities carried out, and the interactions with other regional stakeholders of the newly created CRAtb. METHODS: We conducted a mixed-method study based on a cross-sectional survey and semi-structured interviews by French regions among implemented CRAtb. Of the eight eligible French regions with an existing CRAtb, seven participated to the online survey. Regional partners involved in AMS from the eight regions were interviewed between September 2021 and April 2022. The survey questionnaire addressed, through closed questions, the organization of the CRAtb, articulation with other regional actors involved in AMS and infection prevention and control (IPC), and AMS activities. The semi-structured interviews approached the implementation and the role of CRAtb, and the collaboration of other AMS and IPC stakeholders. Interview transcripts were analysed using thematic content analysis methodology. RESULTS: AMS activities carried out by CRAtb were mainly focusing on hospitals (n = 3), primary care (n = 2) and nursing homes (n = 1). Education mostly relied on training days and AMS help lines, communication on websites and newsletters. CRAtb members reported still being more engaged in providing advice to professionals for individual antibiotic treatments rather than collective-level AMS activities. Interactions were frequent between CRAtb, IPC regional centres and health authorities, but rarely involved other stakeholders. Interviews were performed with 28 professionals involved in AMS from eight regions. Pre-existing networks and working relationships in AMS and more broadly facilitated the implementation of CRAtb. Streamlining and decompartmentalizing IPC and AMS regional activities were considered a way to optimise the prevention of antimicrobial resistance across sectors. The engagement with liberal health professionals was identified as a significant obstacle for CRAtb. CONCLUSIONS: Two years after the launch of a new national framework, the implementation of CRAtb appeared complex in most regions. An integrative model joining IPC and AMS efforts, relying on existing networks, with engagement from liberal health profession organisations may be the next pivotal step.

Assessment of a fully automated RPR assay (Mediace RPR) for serological diagnosis and follow-up of syphilis: a retrospective study.

OBJECTIVES: This study assessed the Mediace RPR assay, an automated RPR (aRPR), for syphilis diagnosis and serological follow-up. METHODS: Serums from patients positively screened for syphilis between January 2017 and December 2019 were retrospectively selected. A focus was performed on patients with a serological follow-up after treatment and/or a reinfection. Serums were tested by both manual (mRPR) and aRPR tests. Categorical and Quantitative Agreements (CA and QA), and serological follow-up conclusions were analyzed. RESULTS: 236 serums from 85 patients (99% of male, 66% of HIV-infected) were included. The overall QA was 54.2%. CA was low (79.7%) especially for samples with low RPR titers. No prozone effect was observed. Serological follow-up after treatment led to similar conclusions, although aRPR titers often decreased faster. Over 26 episodes of reinfection, 4 (15.4%) were misdiagnosed with the aRPR. CONCLUSIONS: While the Mediace aRPR presents the advantages of an automated test, its poor sensitivity in low titers may limit its use.

Could Azithromycin Be Part of Pseudomonas aeruginosa Acute Pneumonia Treatment?

Azithromycin (AZM) is a 15-membered-ring macrolide that presents a broad-spectrum antimicrobial activity against Gram-positive bacteria and atypical microorganisms but suffers from a poor diffusion across the outer-membrane of Gram-negative bacilli, including Pseudomonas aeruginosa (PA). However, AZM has demonstrated clinical benefits in patients suffering from chronic PA respiratory infections, especially cystic fibrosis patients. Since the rise of multidrug-resistant PA has led to a growing need for new therapeutic options, this macrolide has been proposed as an adjunctive therapy. Clinical trials assessing AZM in PA acute pneumonia are scarce. However, a careful examination of the available literature provides good rationales for its use in that context. In fact, 14- and 15-membered-ring macrolides have demonstrated immunomodulatory and immunosuppressive effects that could be of major interest in the management of acute illness. Furthermore, growing evidence supports a downregulation of PA virulence dependent on direct interaction with the ribosomes, and based on the modulation of several key regulators from the Quorum Sensing network. First highlighted in vitro, these interesting properties of AZM have subsequently been confirmed in the animal models. In this review, we systematically analyzed the literature regarding AZM immunomodulatory and anti-PA effects. In vitro and in vivo studies, as well as clinical trials were reviewed, looking for rationales for AZM use in PA acute pneumonia.

Antibiotic resistance heterogeneity and LasR diversity within Pseudomonas aeruginosa populations from pneumonia in intensive care unit patients.

This study investigated within-host heterogeneity of 66 Pseudomonas aeruginosa populations from pneumonia in 51 critically ill ventilated patients by examining 30 colonies per bronchoalveolar lavage (BAL). Differences in antibiotic susceptibility and quorum-sensing (QS) phenotypes were observed between the members of 14 (21.2%) and 10 (15.2%) populations, respectively. A significant association was found between QS deficiency and ceftazidime resistance. QS deficiency was associated with various lasR modifications, and was observed in 25 of 51 (49.0%) patients, including seven patients who received ≤48 h of ventilation. This study confirms the need to examine diverse colonies when analysing BAL cultures, particularly in ß-lactam-exposed patients, to avoid missing ceftazidime- or imipenem-resistant isolates.