Clinical evaluation of guidelines and therapeutic approaches in multi drug-resistant urinary tract infections

Antibiotic resistance represents a real health emergency worldwide, mostly due to the lack of new antibiotics active against multidrug-resistant Enterobacteriaceae. Considering the global epidemiological situation in several infections, including urinary tract infections (UTIs), some antibiotics, such as fluoroquinolones and trimethoprim/sulphamethoxazole, can no longer be used for empiric treatment due to high resistance rates. However, some old antibiotics maintain high microbiological activity against UTI pathogens: according to many recent guidelines, fosfomycin trometamol, nitrofurantoin and pivmecillinam are recommended for the first-line treatment of uncomplicated UTIs. This article provides an overview of the therapeutic management of UTIs, especially uncomplicated and recurrent cystitis, as well as complicated UTIs such as catheter-related UTIs, and UTIs in males, post-menopausal women and diabetic patients, based on the main international guidelines

New antibiotic development: barriers and opportunities

Antibiotic resistance represents a serious threat to public health worldwide, leading to increased healthcare costs, prolonged hospital stays, treatment failures and deaths. To address the emergency of multidrug-resistance, the major international societies of infectious diseases and public health have developed strategies and guidelines to reduce unnecessary antimicrobial use as well as to incite the development of new antibiotics targeting multidrug-resistant pathogens. Even though pharmaceutical companies have been developing new antibiotics since 2010, the global situation is still worrisome. Indeed, the currently available data regarding new antibiotics are limited to microbiological activity and pharmacokinetic profile and their use for the treatment of life-threatening infections (i.e., sepsis) is often off-label. The aim of this article is to present the antibiotic molecules recently commercialized and with which clinicians will deal quite often in next years. We describe ceftolozane/tazobactam, ceftazidime/avibactam, eravacycline, plazomicin, dalbavancin, oritavancin and tedizolid in terms of mechanism of action, antimicrobial spectrum, trials behind the approval and possible indications for the future. In last few years, the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) approved many new antibiotic molecules but, unfortunately, they lack in biological innovation and in wide clinical indications. These agents show appealing properties for off-label use, as we propose in the article, but caution is still needed considering that high-quality clinical data are limited

Efficacy and safety of baricitinib in hospitalized adults with severe or critical COVID‑19 (Bari‑SolidAct): a randomised, double‑blind, placebo‑controlled phase 3 trial

Background Baricitinib has shown efcacy in hospitalized patients with COVID-19, but no placebo-controlled trials have focused specifcally on severe/critical COVID, including vaccinated participants. Methods Bari-SolidAct is a phase-3, multicentre, randomised, double-blind, placebo-controlled trial, enrolling participants from June 3, 2021 to March 7, 2022, stopped prematurely for external evidence. Patients with severe/ critical COVID-19 were randomised to Baricitinib 4 mg once daily or placebo, added to standard of care. The primary endpoint was all-cause mortality within 60 days. Participants were remotely followed to day 90 for safety and patient related outcome measures. Results Two hundred ninety-nine patients were screened, 284 randomised, and 275 received study drug or placebo and were included in the modifed intent-to-treat analyses (139 receiving baricitinib and 136 placebo). Median age was 60 (IQR 49–69) years, 77% were male and 35% had received at least one dose of SARS-CoV2 vaccine. There were 21 deaths at day 60 in each group, 15.1% in the baricitinib group and 15.4% in the placebo group (adjusted absolute diference and 95% CI −0.1% [−8·3 to 8·0]). In sensitivity analysis censoring observations after drug discontinuation or rescue therapy (tocilizumab/increased steroid dose), proportions of death were 5.8% versus 8.8% (−3.2% [−9.0 to 2.7]), respectively. There were 148 serious adverse events in 46 participants (33.1%) receiving baricitinib and 155 in 51 participants (37.5%) receiving placebo. In subgroup analyses, there was a potential interaction between vaccination status and treatment allocation on 60-day mortality. In a subsequent post hoc analysis there was a signifcant interac‑ tion between vaccination status and treatment allocation on the occurrence of serious adverse events, with more respiratory complications and severe infections in vaccinated participants treated with baricitinib. Vaccinated partici‑ pants were on average 11 years older, with more comorbidities. Conclusion This clinical trial was prematurely stopped for external evidence and therefore underpowered to con‑ clude on a potential survival beneft of baricitinib in severe/critical COVID-19. We observed a possible safety signal in vaccinated participants, who were older with more comorbidities. Although based on a post-hoc analysis, these fnd‑ ings warrant further investigation in other trials and real-world studies

Efficacy and safety of baricitinib in hospitalized adults with severe or critical COVID-19 (Bari-SolidAct): a randomised, double-blind, placebo-controlled phase 3 trial

© The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.[Background] Baricitinib has shown efficacy in hospitalized patients with COVID-19, but no placebo-controlled trials have focused specifically on severe/critical COVID, including vaccinated participants.[Methods] Bari-SolidAct is a phase-3, multicentre, randomised, double-blind, placebo-controlled trial, enrolling participants from June 3, 2021 to March 7, 2022, stopped prematurely for external evidence. Patients with severe/critical COVID-19 were randomised to Baricitinib 4 mg once daily or placebo, added to standard of care. The primary endpoint was all-cause mortality within 60 days. Participants were remotely followed to day 90 for safety and patient related outcome measures.[Results] Two hundred ninety-nine patients were screened, 284 randomised, and 275 received study drug or placebo and were included in the modified intent-to-treat analyses (139 receiving baricitinib and 136 placebo). Median age was 60 (IQR 49–69) years, 77% were male and 35% had received at least one dose of SARS-CoV2 vaccine. There were 21 deaths at day 60 in each group, 15.1% in the baricitinib group and 15.4% in the placebo group (adjusted absolute difference and 95% CI − 0.1% [− 8·3 to 8·0]). In sensitivity analysis censoring observations after drug discontinuation or rescue therapy (tocilizumab/increased steroid dose), proportions of death were 5.8% versus 8.8% (− 3.2% [− 9.0 to 2.7]), respectively. There were 148 serious adverse events in 46 participants (33.1%) receiving baricitinib and 155 in 51 participants (37.5%) receiving placebo. In subgroup analyses, there was a potential interaction between vaccination status and treatment allocation on 60-day mortality. In a subsequent post hoc analysis there was a significant interaction between vaccination status and treatment allocation on the occurrence of serious adverse events, with more respiratory complications and severe infections in vaccinated participants treated with baricitinib. Vaccinated participants were on average 11 years older, with more comorbidities.[Conclusion] This clinical trial was prematurely stopped for external evidence and therefore underpowered to conclude on a potential survival benefit of baricitinib in severe/critical COVID-19. We observed a possible safety signal in vaccinated participants, who were older with more comorbidities. Although based on a post-hoc analysis, these findings warrant further investigation in other trials and real-world studies. Trial registration Bari-SolidAct is registered at NCT04891133 (registered May 18, 2021) and EUClinicalTrials.eu (2022-500385-99-00).EU-SolidAct is part of the European pandemic preparedness network EU RESPONSE, funded by the EU Horizon 2020 Research and Innovation programme, under grant number 101015736. EU-SolidAct has also received funding from CAPNET (France) and Klinbeforsk (Norway).Peer reviewe

A point prevalence survey of healthcare-associated infections, antimicrobial use and rectal colonisation with extended-spectrum beta-lactamase and carbapenemase-producing Gram-negative bacteria in seven long-term care facilities

Introduzione Nonostante le strutture di lungodegenza siano gravate da un elevato rischio di colonizzazione/infezione da batteri multi-resistenti (MDR) agli antibiotici, i dati relativi alla prevalenza di colonizzazione da batteri Gram-negativi MDR sono esegui in questo specifico contesto, dove, peraltro, le misure di controllo e prevenzione delle infezioni atte a ridurre la diffusione di tali patogeni non sono ben definite. Lo studio si propone di valutare la prevalenza e le caratteristiche epidemiologiche della colonizzazione rettale da batteri Gram-negativi (GNB) produttori di beta-lattamasi a spettro-esteso (ESBL) e di carbapenemasi tra i degenti in sette lungodegenze della Provincia di Verona. Metodi Uno studio pilota, multicentrico, di prevalenza puntuale (PPS) \ue8 stato condotto in sette lungodegenze della Provincia di Verona. Un tampone rettale \ue8 stato raccolto per identificare isolati produttori di ESBL e carbapenemasi, utilizzando test rapidi fenotipici e, successivamente, genotipici (PCR). Nel giorno prescelto per l\u2019esecuzione della PPS, sono state valutate variabili cliniche ed epidemiologiche, tra cui durata della degenza in LTCF, eventuale ospedalizzazione nei tre mesi precedenti, eventuale intervento chirurgico nel mese precedente, somministrazione di antibiotico-terapia nel mese precedente, grado di autonomia funzionale e capacit\ue0 cognitive, presenza di dispositivi medici e lesioni cutanee croniche. Proporzioni ed intervalli di confidenza sono stati stimati considerando l\u2019effetto cluster determinato dalla struttura gerarchica del campione (in base alla struttura in cui sono stati raccolti i dati). Le associazioni tra colonizzazione e fattori di rischio sono state stimate mediante un modello di regressione logistica multivariata multilivello, considerando la singola struttura come componente random. Sono state prese in considerazione le variabili caratterizzate da p < 0.05 nell\u2019analisi bivariata. Le associazioni sono state valutate calcolando Odds Ratios (ORs) e CI95. p < 0.05 sono stati considerati significativi. Risultati Nello studio sono stati arruolati complessivamente 453 residenti nelle lungodegenze (74.6% di sesso femminile; et\ue0 media, 83.7 anni [SD 10.4 anni]). La maggior parte dei soggetti reclutati era residente da pi\uf9 di un anno in LTCF (78.4%) ed era caratterizzato da incontinenza urinaria e/o fecale (81%) nonch\ue9 da un considerevole deterioramento delle capacit\ue0 cognitive (70.2%) e del grado di autonomia funzionale (65.8%). Complessivamente, era stato somministrato un antibiotico nel mese precedente al 27.1% dei residenti, in particolare nel 9.3% dei soggetti erano state somministrate penicilline associate ad inibitori delle f-lattamasi, nel 4.2% cefalosporine di terza generazione, nell\u20198.6% fluorochinoloni e nel 9.7% cotrimossazolo. Il 16.6% dei soggetti reclutati aveva un catetere urinario, il 14.6% ulcere da decubito, il 15.7% lesioni cutanee; il 9.5% era stato ospedalizzato nei tre mesi precedenti, il 3.8% disponeva di un catetere vascolare e l\u20191.1% era stato sottoposto ad intervento chirurgico nel mese precedente. Durante il giorno della rilevazione, il 7.7% (n = 35) era affetto da infezione ed il 4.6% (n = 21) stava assumendo terapia antibiotica. I degenti colonizzati con ceppi produttori di ESBL (88.8% Enterobacteriaceae e 11.2% GNB non-fermentanti) e GNB produttori di carbapenemasi (77.8% Enterobacteriaceae e 22.2% GNB non-fermentanti) erano 39.5% (CI95, 32.5%-47%) e 4% (CI95, 2.8%-5.6%), rispettivamente. La prevalenza di colonizzazione a livello di singola struttura variava dal 14.3% al 57.1% per i ceppi produttori di ESBL e da 0 a 9.5% per i GNB produttori di carbapenemasi. I fattori di rischio significativamente associati alla colonizzazione da MDR-GNB differivano tra i residenti colonizzati con GNB produttori di ESBL e quelli colonizzati con ceppi produttori di carbapenemasi. L\u2019appartenenza al genere maschile (OR, 2.2; CI95, 1.4-3.7; p = 0.002), una pregressa esposizione alle cefalosporine di terza generazione (OR, 3.9; CI95, 1.3-12; p = 0.016) e l\u2019allettamento (OR, 1.7; CI95, 1-2.9; p = 0.04) erano indipendentemente associati con la colonizzazione da GNB produttori di ESBL, mentre la pregressa ospedalizzazione (OR, 4.1; CI95, 1.3- 13.1; p = 0.02) rappresentava l\u2019unico fattore di rischio indipendentemente associato con la colonizzazione da ceppi produttori di carbapenemasi. Conclusioni Lo studio conferma un\u2019elevata prevalenza di colonizzazione da GNB produttori di ESBL tra i residenti nelle LTCFs ed evidenzia un allarmante tasso di colonizzazione da GNB produttori di carbapenemasi. Da questi dati emerge la necessit\ue0 urgente di promuovere e coordinare a livello nazionale un sistema di sorveglianza attiva di MDR-GNB in LTCF, che guidi le attivit\ue0 di prevenzione e controllo delle infezioni. Le differenze rilevate nell\u2019associazione di specifici fattori di rischio suggeriscono che la diffusione di GNB produttori di ESBL e carbapenemasi segua percorsi differenti. Le misure di controllo e prevenzione delle infezioni dovrebbero, pertanto, essere mirate in funzione del tipo di GNB antibiotico-resistente.Background Although long-term care facility (LTCF) residents are at increased risk for colonisation/infection with multidrug-resistant (MDR) organisms, few data are available on the prevalence of colonisation due to MDR-gram negative bacteria (GNB) in this setting, where infection control and preventive measures to reduce the spread of MDR bacteria are not well defined. The study investigated the prevalence and differences in the epidemiology of rectal colonisation with extended-spectrum beta-lactamase (ESBL) and carbapenemase-producing GNB among residents in LTCFs. Methods A multicenter point prevalence survey (PPS) was conducted in seven LTCFs in Italy. A rectal swab was collected to identify ESBL and carbapenemase-producing isolates, using rapid phenotypic methods and, subsequently, multiplex and single PCR. Clinical and epidemiological variables were assessed on the day of the PPS, including LTCF length of stay, hospitalization within three months and surgery and antimicrobial therapy within one month, functional and mental status, presence of medical devices and chronic skin lesions. Proportions and 95% confidence interval (CI95) were estimated accounting for cluster effect of the sample hierarchical structure (data collection site). The associations between colonisation and risk factors were estimated with a multilevel multivariate logistic regression model, with the data collection site as random component, assessing variables with p < 0.05 from bivariate analysis. Odds ratios (ORs) and CI95 were calculated to evaluate the associations. A p value < 0.05 was considered significant. Results A total of 453 residents were enrolled (74.6% females; mean age 83.7 years, SD 10.4 years). The majority of residents had urinary and/or faecal incontinence (81%), had spent more than one year in LTCF (78.4%), and had a low mental (70.2%) and functional (65.8%) status. 9.3% residents were administered penicillins/ f-lactamase inhibitors within the previous month, 4.2% were administered third-generation cephalosporins, 8.6% fluoroquinolones, and 9.7% cotrimoxazole (27.1% had received an antibiotic within the previous month). 16.6% had a urinary catheter, 15.7% had skin lesions, 14.6% had pressure sores, 9.5% had been hospitalised within 3 months, 3.8% had a vascular catheter, and 1.1% underwent surgery within the previous month. 7.7% (n = 35) was the prevalence of active infections on the PPS day. 21 residents (4.6%) received at least one antibiotic on the PPS day. Residents colonised with ESBL (88.8% Enterobacteriaceae and 11.2% non-fermenting GNB) and carbapenemase-producing GNB (77.8% Enterobacteriaceae and 22.2% non-fermenting GNB) were 39.5% (CI95, 32.5%-47%) and 4% (CI95, 2.8%-5.6%), respectively. Prevalence of colonisation at site level ranged from 14.3% to 57.1% for ESBL and from no detected cases to 9.5% for carbapenemase-producing GNB. Risk factors differed between residents colonised with ESBL and those with carbapenemase-producing strains. Male gender (OR, 2.2; CI95, 1.4-3.7; p = 0.002), previous exposure to third-generation cephalosporins (OR, 3.9; CI95, 1.3-12; p = 0.016) and bedridden status (OR, 1.7; CI95, 1-2.9; p = 0.04) were independently associated with ESBL colonisation, while previous hospitalization (OR, 4.1; CI95, 1.3-13.1; p = 0.02) was the only risk factor independently associated with carbapenemase-producing GNB colonisation. Conclusions The study confirms a high colonisation prevalence with ESBL-producing GNB among LTCFs residents and shows an alarming rate of residents colonised with carbapenemase-producing GNB. A national comprehensive effort is needed to promote and coordinate active surveillance of MDR-GNB in LTCFs to inform infection control teams. Differences in risk factors suggest that the spreading of ESBL and carbapenemase-producing GNB follows different routes. Infection control and preventive measures should be tailored on the type of antimicrobial-resistant GNB

Rapid accurate point-of-care tests combining diagnostics and antimicrobial resistance prediction for Neisseria gonorrhoeae and Mycoplasma genitalium

In addition to inadequate access to early diagnosis and treatment with antimicrobial agents for patients and sexual contacts, management and control of STIs is significantly challenged by emergence and spread of antimicrobial resistance (AMR), particularly for STIs such as Neisseria gonorrhoeae and Mycoplasma genitalium. This is further compounded by use of nucleic acid amplification techniques for diagnosis, resulting in reduced phenotypic AMR testing for N. gonorrhoeae and absence or suboptimal AMR surveillance for guiding treatment of both STIs in many settings. Rapid accurate point-of-care (POC) tests for diagnosis of all STIs would be valuable but to significantly impact treatment precision and management of N. gonorrhoeae and M. genitalium infections, combinations of rapid POC diagnostic and AMR testing (POC-AMR) will likely be required. This strategy would combat STI burden and AMR emergence and spread by enabling diagnosis and individualised treatment at the first healthcare visit, potentially reducing selection pressure on recommended antimicrobials, reducing transmission of resistant strains and providing means for AMR surveillance. Microfluidic and nanotechnology platforms under development for rapid detection of STIs provide a basis to also develop molecular rapid POC-AMR prediction. A number of prototypic devices are in the pipeline but none as yet approved for routine use. However, particularly for N. gonorrhoeae, more knowledge is required to assess which antimicrobials lend themselves to a genotypic POC-AMR approach, in relation to genotypic-phenotypic associations and potential impact clinically and epidemiologically. Key for successful deployment will include also understanding cost-effectiveness, cost-consequences and acceptability for key stakeholders

Terapia empirica delle infezioni batteriche profilassi antibiotica in medicina e chirurgia

La terapia antibiotica, sia essa empirica o mirata, deve essere basata su dati microbiologici, farmacologici e clinici. Le recenti conoscenze di farmacocinetica e farmacodinamica hanno consentito di ottimizzare la posologia e il ritmo di somministrazione degli antibiotici. Non si devono dimenticare, nel contesto dei criteri di scelta, le conoscenze di farmaco economia, nonch\ue8 l'impatto degli antibiotici sulla ecologia dell'ospedale. Questo nuovo testo rappresenta una revisione della terapia empirica e della profilassi antibiotica ed \ue8 rivolto sia ai medici che operano sul territorio che a quelli che lavorano in ospedale

Monoclonal gammopathy in HIV-Infected patients on stable antiretroviral therapy: disappearance or deep reduction?

Comment on Monoclonal Gammopathy in HIV-1-Infected Patients: Factors Associated With Disappearance Under Long-Term Antiretroviral Therapy. [J Acquir Immune Defic Syndr. 2015

Excessive vitamin B12 and poor outcome in COVID-19 pneumonia

No abstract available; Lette

Modelling and Simulation of the Effect of Targeted Decolonisation on Incidence of Extended-Spectrum Beta-Lactamase-Producing Enterobacterales Bloodstream Infections in Haematological Patients

Haematological patients are at higher risk of bloodstream infections (BSI) after chemotherapy. The aim of this study was to develop a simulation model assessing the impact of selective digestive decontamination (SDD) of haematological patients colonised with extended-spectrum beta-lactamase-producing Enterobacterales (ESBL-E) on the incidence of ESBL-E BSI after chemotherapy