OVERESTIMATION OF THORACIC GAS VOLUME DURING THE AIRWAY RESISTANCE MANEUVER A POTENTIAL ERROR IN THE DIAGNOSIS OF AIR TRAPPING

Abstract There are no data published about the agreement between the measurement of thoracic gas volume (TGV) during the airway resistance (TGV-Raw) and the conventional technique described by Dubois. The aim of this study was to establish the agreement between both methods to measure TGV. We studied eighty consecutive subjects. Only sixty-six performed acceptable plethysmography maneuvers. The patients were measured with a constant volume plethysmograph (Medical Graphics 1085 DL). TGV was performed in the same patient with two techniques: 1) during the airway resistance (Raw) measurement (TGV-Raw) and 2) during quiet breathing at the end of expiration (TGV). The panting frequency was 1 to 2 Hz with both maneuvers. The differences between both techniques were expressed in percentage (∆TGV %) and absolute values (∆TGV). The TGV-Raw of the whole group was higher than TGV (3.69 ± 1.08l vs 3.28 ± 1.05l, p < 0.001). Similarly, the subgroups of patients had a greater TGV-Raw than TGV (Normal: 3.44 ± 0.77l vs 2.98 ± 0.72l, p < 0.001; Obstructive: 4.08 ± 1.19l vs 3.71 ± 1.15l, p < 0.001; Restrictive: 2.62 ± 0.49l vs 2.25 ± 0.51l, p < 0.01). There was a considerable lack of agreement between the TGV-Raw and TGV, with discrepancies of up to +0.95l or +34%. The ∆TGV % was similar between the patients' subgroups and between the subjects with different degree of airflow obstruction (Normal: 16.5 ± 10%, Obstructive: 10.8 ± 9.4%, Restrictive: 18 ± 14.3%, p NS; mild obstruction: 10.7 ± 11%, moderate obstruction: 12.3 ± 5.7, severe obstruction: 10.1± 6.6, p NS). In conclusion, TGV-Raw was larger than TGV. This was because the patients generally panted at a volume above FRC when performing the TGV-Raw maneuver. TGV-Raw should not be used to estimate FRC because FRC would be overestimated and the diagnosis of air trapping may be erroneous. Key words: static lung volume, thoracic gas volume, body plethysmography Resumen Sobreestimación del volumen de gas torácico durante la maniobra de resistencia de la vía aérea. Un error potencial en el diagnóstico de atrapamiento aéreo. No hay datos publicados sobre el acuerdo entre la medición del volumen de gas torácico (VGT) durante la maniobra de resistencia de la vía aérea (Raw) y la técnica de medición convencional del VGT descripta por Dubois. El objetivo del estudio fue establecer el grado de acuerdo entre ambos métodos para medir VGT. Se estudiaron 80 sujetos consecutivos que concurrieron al laboratorio pulmonar para hacerse un examen funcional respiratorio. Solo 66 individuos realizaron maniobras pletismográficas adecuadas. Los pacientes fueron medidos con un pletismógrafo de volumen constante (MG 1085 DL). El VGT fue realizado en el mismo paciente con dos técnicas: 1) Durante la maniobra de la Raw (VGT-Raw); 2) Durante la respiración tranquila al final de la espiración (VGT). Las diferencias entre ambas técnicas se expresaron en porcentaje (∆TGV %) y en valores absolutos (∆TGV). El VGT-Raw del grupo total fue mayor que el VGT (3.69 ± 1.08l vs 3.28 ± 1.05l, p < 0.001). Del mismo modo el VGT-Raw de los diferentes subgrupos fue mayor que el VGT (Normal: 3.44 ± 0.77l vs 2.98 ± 0.72l, p < 0.001; Obstructivo: 4.08 ± 1.19l vs 3.71 ± 1.15l, p < 0.001; Restrictivo: 2.62 ± 0.49L vs 2.25 ± 0.51l, p < 0.01). Se observó falta de acuerdo entre el VGT-Raw y el VGT con diferencias de hasta +0.95L o +34% entre ambos métodos. El ∆TGV % fue similar entre los subgrupos y con los diferentes grados de obstrucción al flujo aéreo (Normal: 16.5 ± 10%, Obstructivo: 10.8 ± 9.4%, Restrictivo: 18 ± 14.3%, p NS; obstrucción leve: 10.7 ± 11%, obstrucción moderada: 12.3 ± 5.7, obstrucción grave: 10.1± 6.6, p NS). El VGT-Raw fue sistemáticamente mayor que el VGT. Esto se debió a que los pacientes generalmente jadearon a un volumen pulmonar por arriba de FRC cuando realizaron la maniobra de Raw. No debería usarse el VGT-Raw para estimar FRC ya que la misma puede sobreestimarse y el diagnóstico de atrapamiento aéreo puede ser erróneo. Palabras clave: volúmenes pulmonares estáticos, volumen de gas torácico, pletismografía corpora

Australian Group on Antimicrobial Resistance (AGAR) Australian Gram-negative Sepsis Outcome Programme (GNSOP) Annual Report 2017

The Australian Group on Antimicrobial Resistance (AGAR) performs regular period-prevalence studies to monitor changes in antimicrobial resistance in selected enteric Gram-negative pathogens. The 2017 survey was the fifth year to focus on blood stream infections, and included Enterobacterales, Pseudomonas aeruginosa and Acinetobacter species. Seven thousand nine hundred and ten isolates, comprising Enterobacterales (7,100, 89.8%), P. aer-uginosa (697, 8.8%) and Acinetobacter species (113, 1.4%), were tested using commercial automated methods. The results were analysed using Clinical and Laboratory Standards Institute (CLSI) and European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints (January 2018). Of the key resistances, non-susceptibility to the third-generation cephalosporin, ceftriaxone, was found in 11.3%/11.3% of Escherichia coli (CLSI/EUCAST criteria), 8.8%/8.8% of Klebsiella pneu¬moniae, and 5.7%/5.7% of K. oxytoca. Non-susceptibility rates to ciprofloxacin were 12.1%/18.0% for E. coli, 4.4%/11.2% for K. pneumoniae, 1.3%/3.5% for K. oxytoca, 3.0%/8.5% for Enterobacter cloacae complex, and 5.1%/9.8% for P. aeruginosa. Resistance rates to piperacillin-tazobactam were 2.8%/5.9%, 3.7%/7.3%, 9.6%/11.0%, 22.5%/27.6%, and 6.4%/13.2% for the same five species respectively. Twenty-seven isolates from 25 patients were shown to harbour a carbapenemase gene: 12 bla IMP (11 patients), five bla OXA-181 (four patients), three bla OXA-23, two bla NDM, two bla KPC, two bla VIM, and one bla GES

HIV-1 drug resistance mutations emerging on darunavir therapy in PI-naive and -experienced patients in the UK

BACKGROUND: Darunavir is considered to have a high genetic barrier to resistance. Most darunavir-associated drug resistance mutations (DRMs) have been identified through correlation of baseline genotype with virological response in clinical trials. However, there is little information on DRMs that are directly selected by darunavir in clinical settings. OBJECTIVES: We examined darunavir DRMs emerging in clinical practice in the UK. PATIENTS AND METHODS: Baseline and post-exposure protease genotypes were compared for individuals in the UK Collaborative HIV Cohort Study who had received darunavir; analyses were stratified for PI history. A selection analysis was used to compare the evolution of subtype B proteases in darunavir recipients and matched PI-naive controls. RESULTS: Of 6918 people who had received darunavir, 386 had resistance tests pre- and post-exposure. Overall, 2.8% (11/386) of these participants developed emergent darunavir DRMs. The prevalence of baseline DRMs was 1.0% (2/198) among PI-naive participants and 13.8% (26/188) among PI-experienced participants. Emergent DRMs developed in 2.0% of the PI-naive group (4 mutations) and 3.7% of the PI-experienced group (12 mutations). Codon 77 was positively selected in the PI-naive darunavir cases, but not in the control group. CONCLUSIONS: Our findings suggest that although emergent darunavir resistance is rare, it may be more common among PI-experienced patients than those who are PI-naive. Further investigation is required to explore whether codon 77 is a novel site involved in darunavir susceptibility

Factors associated with HIV-1 resistance to integrase strand transfer inhibitors in Spain: Implications for dolutegravir-containing regimens

Integrase strand transfer inhibitor (INSTI)-containing regimens in HIV-1-infected patients have experienced a global increase. Recently, WHO has emphasized the need to fast-track the transition to dolutegravir (DTG)-based antiretroviral (ARV) treatments. However, continued surveillance of INSTI resistance is recommended. In this study, clinical, epidemiological, and virological features associated with INSTI resistance diagnosed in Spain were analyzed. Samples collected between 2008 and 2021 from HIV-1-infected patients were analyzed in integrase, protease, and reverse transcriptase using Sanger population sequencing. ARV drug resistance was evaluated with the Stanford University HIVdb program. Among 2,696 patients, 174 (6.5%) had INSTI resistance, all of them to first-generation INSTIs, and 71 (2.6%) had also resistance to second-generation INSTIs. Of these, only 5 individuals were exposed to DTG as the only INSTI, in whom resistance development was associated with poor treatment adherence and/or resistance to other ARV classes. Of newly HIV-1-diagnosed individuals, 0.92% harbored INSTI-resistant viruses, with low prevalences maintained along time, and only one had low-level resistance to DTG. Persons who inject drugs, age over 39 years, resistance to other ARV classes, and longer time from diagnosis were associated with INSTI resistance (p < 0.001). Non-subtype B INSTI-resistant viruses lacked the Q148H + G140S resistance pathway and showed lower INSTI resistance levels than subtype B viruses. In conclusion, INSTI resistance is uncommon and associated with long-term infections, older age and additional resistance to other ARV drug classes, and is rare in newly diagnosed HIV-1 infections. Our results also support the preferential use of DTG-containing regimens in first-line treatments, although surveillance of INSTI resistance is encouraged.This work was funded through Acción Estratégica en Salud Intramural (AESI), Instituto de Salud Carlos III, projects “Estudios sobre vigilancia epidemiológica molecular del VIH-1 en España,” PI16CIII/00033 and “Epidemiología molecular del VIH-1 en España y su utilidad para investigaciones biológicas y en vacunas”, PI19CIII/0042; and scientific agreements with Consellería de Sanidade, Government of Galicia (MVI 1004/16) and Osakidetza-Servicio Vasco de Salud, Government of Basque Country (MVI 1001/16).S

Predicted residual activity of rilpivirine in HIV-1 infected patients failing therapy including NNRTIs efavirenz or nevirapine

This is an open access article under the CC BY-NC-ND license - http://creativecommons.org/licenses/by-nc-nd/4.0/"Rilpivirine is a second-generation nonnucleoside reverse-transcriptase inhibitor (NNRTI) currently indicated for first-line therapy, but its clinical benefit for HIV-1 infected patients failing first-generation NNRTIs is largely undefined. This study quantified the extent of genotypic rilpivirine resistance in viral isolates from 1212 patients upon failure of efavirenz- or nevirapine-containing antiretroviral treatment, of whom more than respectively 80% and 90% showed high-level genotypic resistance to the failing NNRTI. Of all study patients, 47% showed a rilpivirine resistance-associated mutation (RPV-RAM), whereas preserved residual rilpivirine activity was predicted in half of the patients by three genotypic drug resistance interpretation algorithms. An NNRTI-dependent impact on rilpivirine resistance was detected. Compared with the use of nevirapine, the use of efavirenz was associated with a 32% lower risk of having a RPV-RAM and a 50% lower risk of predicted reduced rilpivirine susceptibility. Most prevalent RPV-RAMs after nevirapine experience were Y181C and H221Y, whereas L100I+K103N, Y188L and K101E occurred most in efavirenz-experienced patients. Predicted rilpivirine activity was not affected by HIV-1 subtype, although frequency of individual mutations differed across subtypes. In conclusion, this genotypic resistance analysis strongly suggests that the latest NNRTI, rilpivirine, may retain activity in a large proportion of HIV-1 patients in whom resistance failed while they were on an efavirenz- or nevirapine-containing regimen, and may present an attractive option for second-line treatment given its good safety profile and dosing convenience. However, prospective clinical studies assessing the effectiveness of rilpivirine for NNRTI-experienced patients are warranted to validate knowledge derived from genotypic and phenotypic drug resistance studies.

Epidemiology of carbapenem-resistant and carbapenemase-producing Enterobacterales in the Netherlands 2017–2019

Background: The Netherlands is currently considered a low endemic country for carbapenem-resistant Enterobacterales (CRE) and carbapenemase-producing Enterobacterales (CPE), experiencing only sporadic hospital outbreaks. This study aims to describe susceptibility to carbapenems and the epidemiology of carbapenemase production in Enterobacterales in the Netherlands in 2017–2019. Methods: Three complementary nationwide surveillance systems are in place to monitor carbapenem susceptibility in the Netherlands. Routine antimicrobial susceptibility test results from medical microbiology laboratories were used to study phenotypic susceptibility of Escherichia coli and Klebsiella pneumoniae. Pathogen surveillance (of all Enterobacterales species) and mandatory notifications were used to describe the characteristics of CPE positive isolates and affected persons. Results: The prevalence of isolates with gradient strip test-confirmed elevated meropenem (> 0.25 mg/L) or imipenem (> 1 mg/L) minimum inhibitory concentration (MIC) in the Netherlands was very low in 2017–2019, with percentages of 0.06% in E. coli and 0.49% in K. pneumoniae, and carbapenem resistances of 0.02% and 0.18%, respectively. A total of 895 unique species/carbapenemase-encoding allele combinations of CPE from 764 persons were submitted between 2017 and 2019, with the annual number of submissions increasing slightly each year. Epidemiological data was available for 660 persons. Screening because of presumed colonisation risk was the reason for sampling in 70.0% (462/660) of persons. Hospitalization abroad was the most common risk factor, being identified in 45.9% of persons. Conclusions: Carbapenem resistance of E. coli and K. pneumoniae remains low in the Netherlands. The annual number of CPE isolates slightly increased during the period 2017–2019. Recent hospitalization abroad is the main risk factor for acquisition of CPE

Associations between baseline characteristics, CD4 cell count response and virological failure on first-line efavirenz + tenofovir + emtricitabine for HIV

Objectives: The aim of this study was to investigate associations between baseline characteristics and CD4 cell count response on first-line antiretroviral therapy and risk of virological failure (VF) with or without drug resistance. Methods: We conducted an analysis of UK Collaborative HIV Cohort data linked to the UK HIV Drug Resistance Database. Inclusion criteria were viral sequence showing no resistance prior to initiation of first-line efavirenz + tenofovir disoproxil fumarate + emtricitabine and virological suppression within 6 months. Outcomes of VF (≥200 copies/mL) with or without drug resistance were assessed using a competing risks approach fitted jointly with a model for CD4 cell count recovery. Hazard ratios for each VF outcome were estimated for baseline CD4 cell count and viral load and characteristics of CD4 cell count response using latent variables on a standard normal scale. Results: A total of 3640 people were included with 338 VF events; corresponding viral sequences were available in 134 with ≥1 resistance mutation in 36. VF with resistance was associated with lower baseline CD4 (0.30, 0.09-0.62), lower CD4 recovery (0.04, 0.00-0.17) and higher CD4 variability (4.40, 1.22-12.68). A different pattern of associations was observed for VF without resistance, but the strength of these results was less consistent across sensitivity analyses. Cumulative incidence of VF with resistance was estimated to be <2% at 3 years for baseline CD4 ≥350 cells/μL. Conclusion: Lower baseline CD4 cell count and suboptimal CD4 recovery are associated with VF with drug resistance. People with low CD4 cell count before ART or with suboptimal CD4 recovery on treatment should be a priority for regimens with high genetic barrier to resistance

Glycopeptide resistance in Enterococcus spp. and coagulase-negative staphylococci from hospitalised patients in Germany: occurrence, characteristics and dalbavancin susceptibility

Objectives: The aim of this study was to evaluate the occurrence of glycopeptide resistance in enterococci and coagulase-negative staphylococci (CoNS) and to determine the susceptibilities of the identified glycopeptide-resistant isolates to dalbavancin. Methods: Twenty-two medical laboratories participated in the study conducted in 2016/17 by the Paul-Ehrlich-Society for Chemotherapy. Each laboratory was asked to collect 30 Enterococcus spp. (limited to Enterococcus faecalis and Enterococcus faecium) and 30 CoNS isolates consecutively from hospitalised patients with a proven or suspected infection. Results: A total of 1285 isolates were collected, comprising 364 E. faecalis, 291 E. faecium and 630 CoNS. No E. faecalis isolates (0%) but 76 E. faecium isolates (26.1%) were vancomycin-resistant, of which 21 showed the VanA type and 55 the VanB type. The proportion of vancomycin-resistant strains among E. faecium isolates from patients in intensive care units (21.6%) was significantly lower than that from patients on regular wards (30.5%). Among the CoNS, 67 isolates (10.6%) were teicoplanin-resistant but none were vancomycin-resistant, with resistance only detected in Staphylococcus epidermidis (12.2%), Staphylococcus haemolyticus (17.9%) and Staphylococcus hominis (13.2%). Dalbavancin at ≤0.25 mg/L inhibited all VanB-type enterococci and 95.5% of teicoplanin-resistant CoNS. Conclusion: The level of glycopeptide resistance in E. faecalis remains very low in Germany but achieved 26% in E. faecium and was >10% in CoNS. Dalbavancin appears to be a feasible option for treating infections caused by VanB-type vancomycin-resistant E. faecium and teicoplanin-resistant CoNS.Peer Reviewe