HIV Productively Infects Highly Differentiated and Exhausted CD4+ T Cells During AIDS

Background: Throughout HIV infection, productively infected cells generate billions of viral particles and are thus responsible for body-wide HIV dissemination, but their phenotype during AIDS is unknown. As AIDS is associated with immunological changes, analyzing the phenotype of productively infected cells can help understand HIV production during this terminal stage. Methods: Blood samples from 15 untreated viremic participants (recent infection, n=5; long-term infection, n=5; active opportunistic AIDS-defining disease, n=5) and 5 participants virologically controlled on antiretroviral therapy (ART) enrolled in the Analysis of the Persistence, Reservoir and HIV Latency (APRIL) study (NCT05752318) were analyzed. Cells expressing the capsid protein p24 (p24+ cells) after 18 hours of resting or 24 hours of stimulation (HIV-Flow) revealed productively infected cells from viremic participants or translation-competent reservoir cells from treated participants, respectively. Results: The frequency of productively infected cells tended to be higher during AIDS in comparison with recent and long-term infections (median, 340, 72, and 32/million CD4+ T cells, respectively) and correlated with the plasma viral load at all stages of infection. Altogether, these cells were more frequently CD4low, HLA-ABClow, CD45RA-, Ki67+, PD-1+, with a non-negligible contribution from pTfh (CXCR5+PD-1+) cells, and were not significantly enriched in HIV coreceptors CCR5 nor CXCR4 expression. The comparison markers expression between stages showed that productively infected cells during AIDS were enriched in memory and exhausted cells. In contrast, the frequencies of infected pTfh were lower during AIDS compared to non-AIDS stages. A UMAP analysis revealed that total CD4+ T cells were grouped in 7 clusters and that productive p24+ cells were skewed to given clusters throughout the course of infection. Overall, the preferential targets of HIV during the latest stages seemed to be more frequently highly differentiated (memory, TTD-like) and exhausted cells and less frequently pTfh-like cells. In contrast, translation-competent reservoir cells were less frequent (5/million CD4+ T cells) and expressed more frequently HLA-ABC and less frequently PD-1. Conclusions: In long-term infection and AIDS, productively infected cells were differentiated and exhausted. This could indicate that cells with these given features are responsible for HIV production and dissemination in an immune dysfunction environment occurring during the last stages of infection

Infections à entérobactéries productrices de carbapénémases aux Hôpitaux universitaires de Strasbourg : épidémiologie descriptive et facteurs de risque d'infection en cas de colonisation/thèse présentée pour le diplôme d'État de docteur en médecine, diplô

Médecine (maladies infectieuses et tropicales)Les infections à entérobactéries productrices de carbapénémases (EPC) sont des infections émergentes en France et peuvent représenter un défi thérapeutique. La colonisation rectale à EPC est associée aux voyages et hospitalisations en zone de circulation endémique ou épidémique de ces souches, à l’utilisation non raisonnée des antibiotiques et à une insuffisance de respect des mesures d’hygiène standard en hospitalisation. Contrairement aux infections à entérobactéries productrices de bêta-lactamase à spectre étendu (BLSE), il n’existe pas de recommandation sur la prise en charge des infections chez les patients colonisés à EPC. Une étude rétrospective monocentrique cas-témoin sur la période de janvier 2011 à décembre 2020 a été menée aux Hôpitaux Universitaires de Strasbourg pour caractériser l’épidémiologie des infections à EPC et identifier des facteurs de risques d’infections à EPC en cas de colonisation à EPC. 67 patients ont développé au moins une infection à EPC sur la période de recueil. 90,9% des patients avaient été hospitalisés dans les 6 derniers mois et 78,5% exposés aux antibiotiques dans les 6 derniers mois, parmi lesquels 19,5 % aux carbapénémèmes. 40,3% des patients présentaient au moins 4 comorbidités. Seuls 22,1% des patients avaient séjourné à l’étranger dans l’année. La mortalité toute cause à 1 mois était de 25,4%. La mortalité toute cause en cas d’infection à EPC en réanimation était de 34,5%. 274 colonisations à EPC ont été recueillies et 67 patients (24,5%) ont développé une infection à EPC. 54,2% des épisodes infectieux dans les 6 mois du diagnostic de colonisation à EPC étaient documentés à EPC. Ces épisodes infectieux surviennent avec une médiane de 15,0 jours après le diagnostic de colonisation contre 51,0 jours pour les épisodes infectieux non documentés à EPC (p-0,01). En analyse multivariée, la survenue d’une infection en réanimation (OR 5,54 [1,37-26,40]) et la survenue d’une bactériémie dans les 30 jours précédant le diagnostic d’une colonisation (OR 5,45 [1,76-18,50]) étaient associées à la survenue d’une infection à EPC chez les patients colonisés à EPC. Cette étude souligne la prévalence élevée et la mortalité élevée des épisodes infectieux à EPC chez les patients colonisés. En cas d’infection, l’instauration d’une antibiothérapie probabiliste couvrant l’EPC pourrait se justifier chez les patients colonisés, notamment en cas de prise en charge en réanimation. Des études prospectives sur de plus grandes cohortes pourrait permettre de mieux caractériser la prise en charge des infections chez les patients colonisés à EPCCarbapenemase-producing Enterobacteriaceae (CPE) infections are emerging infections in France and may represent a therapeutic challenge. Rectal colonization with EPC is associated with travel and hospitalization in an area of endemic or epidemic circulation of these strains, the reckless use of antibiotics and insufficient compliance with standard hygiene precautions during hospitalization. Unlike extended spectrum beta-lactamase-producing Enterobacteriaceae (ESBL) infections, there are no guidelines for the management of infections in patients colonized with CPE. We conducted a retrospective single-center case-control study over the period of January 2011 to December 2020 at the University Hospitals of Strasbourg to characterize the epidemiology of CPE infections and identify risk factors for CPE infections in case of CPE colonization. 67 patients developed at least one EPC infection during the study period. 90.9% of patients had been hospitalized in the last 6 months and 78.5% exposed to antibiotics in the last 6 months, including 19.5% to carbapenemems. 40.3% of patients presented at least 4 comorbidities. Only 22.1% of the patients had travelled abroad the previous year. All-cause mortality at 1 month was 25.4%. The mortality from CPE infection in intensive care was 34.5%. During the study period, there were 274 patients with CPE colonization and 67 of them (24.5%) developed a CPE infection. CPE infection represented 54.2% of the infectious episodes within 6 months of the diagnosis of CPE colonization. These infectious episodes occur with a median of 15.0 days after the diagnosis of colonization compared to 51.0 days for the non-CPE infectious episodes (p -0.01). In multivariate analysis, the occurrence of an infection in an intensive care unit (OR 5.54 [1.37-26.40]) and the occurrence of bacteremia in the 30 days preceding the diagnosis of colonization (OR 5.45 [1.76-18.50]) were associated with a CPE infection in patients colonized with CPE. This study highlights the high prevalence and high mortality of CPE infections in colonized patients. In case of infection, the initiation of a probabilistic antibiotic therapy covering the CPE may be justified in colonized patients, especially in an intensive care unit. Prospective studies on larger cohorts could better characterize the management of infections in patients colonized with CP

High Incidence of Acute Kidney Injury in Patients Treated with High-Dose Amoxicillin and Cloxacillin Combination Therapy

High-dose amoxicillin and cloxacillin combination therapy is recommended for the empiric treatment of selected patients with infective endocarditis despite a low level of evidence. The main objective of this study was to evaluate the renal tolerance of high-dose intravenous amoxicillin and cloxacillin combination. We studied 27 patients treated with amoxicillin and cloxacillin (≥100 mg/kg daily) for at least 48 h. The primary endpoint was the occurrence of acute kidney injury (AKI). The median patient age was 68 ± 8 years, and 16 (59%) were male. The indication for this combination therapy was suspected or confirmed endocarditis with no bacterial identification in 22 (81%) patients. The primary endpoint occurred in 16 (59%) patients after initiating this combination therapy within an average of 4.4 ± 3.6 days. Among them, seven (26%) patients developed severe AKI, including four (15%) patients who required hemodialysis. Other risk factors for AKI were identified in all patients, including injection of iodinated contrast media in 21 (78%), acute heart failure in 18 (67%), cardiac surgery in 11 (41%), and aminoglycoside use in 9 (33%) patients. This study reports an incidence of 59% of AKI after initiating amoxicillin and cloxacillin combination therapy in a population at high renal risk

Two Cases of Viral Re-suppression After M184V+R263K Selection on Dolutegravir/Lamivudine Without Treatment Modification

Dolutegravir/lamivudine (DTG/3TC) has a high genetic barrier against the development of human immunodeficiency virus drug resistance. We report 2 cases of R263K + M184V mutations during DTG/3TC failure followed by viral suppression after adherence intervention without treatment change that we attribute to residual drug activity, reduced viral fitness, and robust immune competence

Two Cases of Viral Re-suppression After M184V+R263K Selection on Dolutegravir/Lamivudine Without Treatment Modification

Dolutegravir/lamivudine (DTG/3TC) has a high genetic barrier against the development of human immunodeficiency virus drug resistance. We report 2 cases of R263K + M184V mutations during DTG/3TC failure followed by viral suppression after adherence intervention without treatment change that we attribute to residual drug activity, reduced viral fitness, and robust immune competence

Cefepime vs carbapenems for treating third-generation cephalosporin-resistant AmpC β-lactamase-hyperproducing Enterobacterales bloodstream infections: a multicenter retrospective study

Objectives: AmpC β-lactamase-hyperproducing Enterobacterales (ABLHE) bloodstream infections (BSI) are emerging and leading to therapeutic challenges worldwide. Prescriptions of carbapenems may lead to the emergence of resistance. This study aimed to compare cefepime with carbapenems for the treatment of third-generation cephalosporin-resistant ABLHE BSI. Methods: This retrospective multicenter study included patients with ABLHE BSI from two tertiary hospitals in France, between July 2017 and July 2022. Non-AmpC-producing Enterobacterales, extended-spectrum β-lactamase, and carbapenemase-producing Enterobacterales were excluded. Cefepime was prescribed only in case of minimal inhibitory concentration ≤1 mg/l. The primary outcome was 30-day in-hospital mortality from the date of index blood culture. Secondary outcomes were infection recurrence and treatment toxicity. An inverse probability of treatment weighting approach was used to balance the baseline characteristics between the two groups. Results: We analyzed 164 BSI, which included 77 in the cefepime group and 87 in the carbapenem group. In the weighted cohort, the 30-day mortality rates were similar between the cefepime group (23.3%) and the carbapenem group (19.6%) with a relative risk of 1.19 (95% confidence interval, 0.61-2.33 P = 0.614). No significant difference in recurrence or toxicity was found between the two groups. Conclusion: This study adds evidence in favor of the use of cefepime for treating third-generation cephalosporin-resistant ABLHE BSI in case of minimal inhibitory concentration ≤ 1 mg/l, which could spare carbapenems

Staphylococcus epidermidis bloodstream infections are a cause of septic shock in intensive care unit patients

Objectives: Staphylococcus epidermidis (SE) is a supposedly low-virulence agent, which may cause proven bloodstream infections (BSIs), with little-known consequences on intensive care unit (ICU) patients. We aimed at studying ICU patients diagnosed with BSIs caused by SE (SE-BSIs). Methods: We constituted a retrospective cohort in two medical ICUs. SE-BSIs were defined by two or more independent SE-positive blood cultures of the same strain, within 48 hours, without concurrent infection. Results: We included 59 patients; 58% were men (n = 34), with median age of 67 (interquartile range 60-74) years and a simplified acute physiology score II of 59 (36-74) points, and 56% were immunocompromised (n = 33). Among the 37 (63%) patients requiring norepinephrine initiation or increase at the onset of SE-BSI versus patients not requiring vasopressors (37%; n = 22), concomitant arterial lactate levels reached 2.8 (1.9-5.8) versus 1.5 (1.3-2.2) mmol/l (P <0.01), whereas the mean blood pressure was 49 (42-54) versus 61 (56-65) mm Hg (P = 0.01) and the mortality was 46% (n = 17) vs 14% (n = 3) at day 28 (P = 0.01), respectively. Regarding antibiotics, the susceptibility rates toward linezolid and vancomycin were 71% (n = 41/58) and 100% (n = 54/54), respectively. At the time of SE-BSI, all but one patient had a central venous access device. Conclusion: This work highlights SE-BSIs as a cause of septic shock, mostly in immunocompromised ICU patients, with increasing concerns about resistance to antibiotics and central line management

Distribution of Achromobacter species in 12 French cystic fibrosis centers in 2020 by a retrospective MALDI-TOF MS spectrum analysis

International audienceAchromobacter spp. are nonfermenting Gram-negative bacilli mainly studied among cystic fibrosis (CF) patients. The identification of the 19 species within the genus is time-consuming (nrdA-sequencing), thus data concerning the distribution of the species are limited to specific studies. Recently, we built a database using MALDI-TOF mass spectrometry (MS) (Bruker) that allows rapid and accurate species identification and detection of the multiresistant epidemic clones: A xylosoxidans ST137 spreading among CF patients in various French and Belgium centers, and A. ruhlandii DES in Denmark. Here, we first assessed whether species identification could be achieved with our database solely by analysis of MS spectra without availability of isolates. Then, we conducted a multicentric study describing the distribution of Achromobacter species and of the clone ST137 among French CF centers. We collected and analyzed with our local database the spectra of Achromobacter isolates from 193 patients (528 samples) from 12 centers during 2020. In total, our approach enabled to conclude for 502/528 samples (95.1%), corresponding to 181 patients. Eleven species were detected, only five being involved in chronic colonization, A. xylosoxidans (86.4%), A. insuavis (9.1%), A. mucicolens (2.3%), A. marplatensis (1.1%) and A. genogroup 3 (1.1%). This study confirmed the high prevalence of A. xylosoxidans in chronic colonizations and the circulation of the clone A. xylosoxidans ST137 in France: four patients in two centers. The present study is the first to report the distribution of Achromobacter species from CF patients samples using retrospective MALDI-TOF/MS data. This easy approach could enable future large-scale epidemiological studies