Doravirine Exposure Decreased by Dialysis in a HIV Patient: A Grand Round

International audienceBackground: The authors report the case of a 66-year-old male patient who was hemodialyzed 3 times per week for chronic renal failure and treated with 100 mg of doravirine once daily in combination with dolutegravir for HIV-1. No dose adjustment is required for doravirine in cases of severe renal injury, but the effect of dialysis on its exposure is poorly understood.Methods & Results: Two series of 2 samples were drawn before and after 4-hour hemodialysis and showed an average doravirine concentration decrease of 48.1 ± 6.7%. The effects of hemodialysis were important, contrary to what was expected and has been previously reported. In addition, intraindividual variability was low. Nevertheless, because the concentrations reported were largely above the inhibitory concentration 50 (IC50), no dose adjustment was required.Conclusions: The decrease in doravirine concentration due to hemodialysis observed in this case report was quite significant. Therefore, therapeutic drug monitoring might be recommended in certain patients undergoing doravirine treatment also on hemodialysis

Local and Global Protein Interactions Contribute to Residue Entrenchment in Beta-Lactamase TEM-1

Due to their rapid evolution and their impact on healthcare, beta-lactamases, protein degrading beta-lactam antibiotics, are used as generic models of protein evolution. Therefore, we investigated the mutation effects in two distant beta-lactamases, TEM-1 and CTX-M-15. Interestingly, we found a site with a complex pattern of genetic interactions. Mutation G251W in TEM-1 inactivates the protein’s function, just as the reciprocal mutation, W251G, does in CTX-M-15. The phylogenetic analysis revealed that mutation G has been entrenched in TEM-1’s background: while rarely observed throughout the phylogeny, it is essential in TEM-1. Using a rescue experiment, in the TEM-1 G251W mutant, we identified sites that alleviate the deviation from G to W. While few of these mutations could potentially involve local interactions, most of them were found on distant residues in the 3D structure. Many well-known mutations that have an impact on protein stability, such as M182T, were recovered. Our results therefore suggest that entrenchment of an amino acid may rely on diffuse interactions among multiple sites, with a major impact on protein stability

A Machine Learning Algorithm to Predict the Starting Dose of Daptomycin

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A machine learning approach to predict daptomycin exposure from two concentrations based on Monte Carlo simulations

International audienceABSTRACT Daptomycin is a concentration-dependent lipopeptide antibiotic for which exposure/effect relationships have been shown. Machine learning (ML) algorithms, developed to predict the individual exposure to drugs, have shown very good performances in comparison to maximum a posteriori Bayesian estimation (MAP-BE). The aim of this work was to predict the area under the blood concentration curve (AUC) of daptomycin from two samples and a few covariates using XGBoost ML algorithm trained on Monte Carlo simulations. Five thousand one hundred fifty patients were simulated from two literature population pharmacokinetics models. Data from the first model were split into a training set (75%) and a testing set (25%). Four ML algorithms were built to learn AUC based on daptomycin blood concentration samples at pre-dose and 1 h post-dose. The XGBoost model (best ML algorithm) with the lowest root mean square error (RMSE) in a 10-fold cross-validation experiment was evaluated in both the test set and the simulations from the second population pharmacokinetic model (validation). The ML model based on the two concentrations, the differences between these concentrations, and five other covariates (sex, weight, daptomycin dose, creatinine clearance, and body temperature) yielded very good AUC estimation in the test (relative bias/RMSE = 0.43/7.69%) and validation sets (relative bias/RMSE = 4.61/6.63%). The XGBoost ML model developed allowed accurate estimation of daptomycin AUC using C0, C1h, and a few covariates and could be used for exposure estimation and dose adjustment. This ML approach can facilitate the conduct of future therapeutic drug monitoring (TDM) studies

Impact of Enterococcus faecalis endocarditis treatment on risk of relapse

International audienceAbstract Background Enterococcus faecalis infective endocarditis (EFIE) are characterized by a higher frequency of relapses than other infective endocarditis. The role of the treatment on their occurrence remains poorly understood. The aim of this study was to investigate whether the antibiotic regimen could impact the risk of relapse in EFIE. Materials This was a multicenter retrospective study of patients diagnosed with definite EFIE between 2015 and 2019 in 14 French hospitals. The primary endpoint was the occurrence of relapses within the year following endocarditis diagnosis. As death was a competing risk for relapse, Fine & Gray models were used for studying risk factors and impact of treatment. Results Of the 279 patients included, 83 (29.7%) received the amoxicillin-gentamicin (A-G) combination, 114 (40.9%) amoxicillin-ceftriaxone (A-C), 63 (22.6%) A-G and A-C (A-G/A-C) sequentially, 9 (3.2%) amoxicillin (A), and 10 received other treatments. One-year-relapse rate was 9.3% (26 patients). Relapse occurred after a median delay of 107 days from EFIE diagnosis; 6 occurred after 6 months, and 6 were diagnosed by blood cultures in asymptomatic patients. In multivariate analysis, surgery during treatment was a protective factor against one-year relapse and death. The cumulative incidence of relapse one year after endocarditis was 46.2% for patients treated with amoxicillin, 13.4% with A-G, 14.7% with A-C, and 4.3% with A-G/A-C (P≥.05 in multivariate analysis). Conclusion Relapses after treatment of EFIE are frequent, frequently asymptomatic, and may occur more than 6 months after the initial episode

Retrospective multicentric study on Campylobacter spp. bacteremia in France: the Campylobacteremia study

International audienceAbstract Background Campylobacter spp. bacteremia is a severe infection. A nationwide 5-year retrospective study was conducted to characterize its clinical features and prognostic factors. Methods Patients diagnosed with Campylobacter spp. bacteremia in 37 French hospitals participating in the surveillance network of the National Reference Center for Campylobacter and Helicobacter were included from January 1, 2015, to December 31, 2019. The goal was to analyze the effects of a delay of appropriate antibiotic therapy and other risk factors on 30-day mortality, antibiotic resistance, patient characteristics and prognosis according to the Campylobacter species. Findings Among the 592 patients, Campylobacter jejuni and Campylobacter fetus were the most commonly identified species (42.9 and 42.6%, respectively). The patients were elderly (median age 68 years), and most had underlying conditions, mainly immunodepression (43.4%), hematologic malignancies (25.9%), solid neoplasms (23%) and diabetes (22.3%). C. jejuni and Campylobacter coli were associated with gastrointestinal signs, and C. fetus was associated with secondary localizations. Among the 80 patients (13.5%) with secondary localizations, 12 had endocarditis, 38 vascular, 24 osteo-articular and 9 ascitic fluid infections. The thirty-day mortality rate was 11.7%, and an appropriate antibiotic treatment was independently associated with 30-day survival (odds ratio [OR]=0.47, 95% CI [0.24–0.93], p=0.03). The median efficient therapy initiation delay was quite short (2 days, IQR [0–4]) but it had no significant impact on 30-day mortality (p=0.78). Interpretation Campylobacter spp. bacteremia mainly occurred in elderly immunocompromised individuals with variable clinical presentations according to the species involved. Appropriate antimicrobial therapy was associated with improved 30-day survival

Multicenter Retrospective Study of Vascular Infections and Endocarditis Caused by Campylobacter spp., France

The incidence of campylobacteriosis has substantially increased over the past decade, notably in France. Secondary localizations complicating invasive infections are poorly described. We aimed to describe vascular infection or endocarditis caused by Campylobacter spp. We included 57 patients from a nationwide 5-year retrospective study on Campylobacter spp. bacteremia conducted in France; 44 patients had vascular infections, 12 had endocarditis, and 1 had both conditions. Campylobacter fetus was the most frequently involved species (83%). Antibiotic treatment involved a β-lactam monotherapy (54%) or was combined with a fluoroquinolone or an aminoglycoside (44%). The mortality rate was 25%. Relapse occurred in 8% of cases and was associated with delayed initiation of an efficient antimicrobial therapy after the first symptoms, diabetes, and coexistence of an osteoarticular location. Cardiovascular Campylobacter spp. infections are associated with a high mortality rate. Systematically searching for those localizations in cases of C. fetus bacteremia may be warranted