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PURPOSE OF REVIEW: To discuss novel antibiotics under clinical development, focusing on agents showing in-vitro activity against metallo-ß-lactamases (MBL)-producing carbapenem-resistant Gram-negative bacteria (CR-GNB). RECENT FINDINGS: Currently, only a few approved agents show activity, alone or in synergistic combinations, against MBL-producing CR-GNB. If approved by regulatory agencies in case of favorable results from ongoing (and, for some agents, already completed) phase-3 studies, some novel ß-lactam/ß-lactamase inhibitor (BL/BLI) combinations could become available in the next few years as additional important options for treating MBL-producing CR-GNB infections. Additional interesting agents that belong both to BL/BLI combinations and to antibiotic classes other than BL and BL/BLI combinations have also shown activity against MBL-producing CR-GNB, with most of them being in early phases of clinical development. SUMMARY: Improving the use of these novel agents through virtuous antimicrobial stewardship frameworks able to guarantee both the efficacious treatment of infections requiring their use and the avoidance of their use whenever not necessary remains a challenge of utmost importance that should not be overlooked.
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PURPOSE OF REVIEW: To provide a brief overview of drugs in Phase II and III of development for the treatment of acute bacterial skin and skin structure infections (ABSSSI), offering insights into potential customized treatment options. RECENT FINDINGS: Several drugs are currently in advanced stages of evaluation for the treatment of ABSSSI, and numerous molecules are entering in the early development phases. Notably, many of these drugs exhibit unique mechanisms of action and interesting antimicrobial spectrum. SUMMARY: Tailoring antibiotic therapy based on patient characteristics, likely pathogens, type, site and severity of ABSSSI is crucial. Given the inherent limitations of available treatments, the development of novel agents is a pivotal avenue. Such advancements hold promise for enhancing treatment efficacy and simplifying drug selection for ABSSSI in everyday clinical practice.
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Dermatopatias Bacterianas , Infecções dos Tecidos Moles , Humanos , Infecções dos Tecidos Moles/tratamento farmacológico , Dermatopatias Bacterianas/tratamento farmacológico , Dermatopatias Bacterianas/microbiologia , Antibacterianos , Resultado do TratamentoRESUMO
BACKGROUND: Isavuconazole is first-line treatment of invasive aspergillosis. Therapeutic drug monitoring (TDM) is deemed not necessary, since most patients reached therapeutic levels (>1â mg/L) in large studies. Low levels were reported in some critically ill patients admitted to the ICU. The aim was to compare isavuconazole levels between critically ill and non-critically ill patients. MATERIALS AND METHODS: Retrospective analysis of data from all patients treated with standard-dose isavuconazole between 1 January 2019 and 26 October 2022 was performed. The following data were collected: TDM results from the first 30â days of therapy; ward of admission; demographic and clinical characteristics; continuous renal replacement therapy; extracorporeal membrane oxygenation; and co-administered drugs. RESULTS: Seventy-two patients (median age 65â years) and 188 TDM measurements (mean number of samples per patient 2.6â±â1.7) were included; 33 (45.8%) were ICU patients (3 also had haematological disorders); 39 (54.2%) were non-ICU patients, of whom 31 had haematological disorders. In all patients, the mean isavuconazole blood level was 3.33â±â2.26â mg/L. Significantly lower levels were observed in the ICU versus the non-ICU population: mean 2.02â±â1.22 versus 4.15â±â2.31â mg/L (Pâ<â0.001). Significantly higher rates of subtherapeutic levels were observed in ICU patients compared with the non-ICU population: all determinations <2â mg/L in 33.3% versus 7.7%, and all determinations <1â mg/L in 12.1% versus 0%, respectively. Predictors of lower isavuconazole levels were admission to the ICU, BMIâ>â25â kg/m2, bilirubinâ>â1.2â mg/dL and the absence of haematological disorder. CONCLUSIONS: ICU patients had significantly lower isavuconazole blood levels compared to non-ICU population. The TDM of isavuconazole for efficacy should be performed in ICU.
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Estado Terminal , Monitoramento de Medicamentos , Nitrilas , Piridinas , Humanos , Idoso , Monitoramento de Medicamentos/métodos , Estudos Retrospectivos , TriazóisRESUMO
BACKGROUND: We assessed the laboratory diagnosis and treatment of invasive fungal disease (IFD) in Italy to detect limitations and potential for improvement. METHODS: The survey was available online at www.clinicalsurveys.net/uc/IFI management capacity/, and collected variables such as (a) institution profile, (b) perceptions of IFD in the respective institution, (c) microscopy, (d) culture and fungal identification, (e) serology, (f) antigen detection, (g) molecular tests, (h) susceptibility testing and (i) therapeutic drug monitoring (TDM). RESULTS: The laboratory capacity study received responses from 49 Italian centres, with an equitable geographical distribution of locations. The majority of respondents (n = 36, 73%) assessed the occurrence of IFD as moderate-high, with Aspergillus spp. being the pathogen of highest concern, followed by Candida spp. and Mucorales. Although 46 (94%) of the institutions had access to microscopy, less than half of them performed direct microscopy on clinical specimens always when IFD was suspected. Cultures were available in all assessed laboratories, while molecular testing and serology were available in 41 (83%), each. Antigen detection tests and antifungal drugs were also generally accessible (> 90%) among the participating institutions. Nevertheless, access to TDM was limited (n = 31, 63%), with a significant association established between therapeutic drug monitoring availability and higher gross domestic product per capita. CONCLUSIONS: Apart from TDM, Italy is adequately prepared for the diagnosis and treatment of IFD, with no significant disparities depending on gross domestic product. Future efforts may need to focus on enhancing the availability and application of direct microscopic methods, as well as TDM, to promote optimal treatment and better patient outcomes.
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Infecções Fúngicas Invasivas , Laboratórios , Humanos , Infecções Fúngicas Invasivas/diagnóstico , Infecções Fúngicas Invasivas/tratamento farmacológico , Infecções Fúngicas Invasivas/microbiologia , Antifúngicos/uso terapêutico , Candida , AspergillusRESUMO
OBJECTIVES: Candidemia is the most frequent invasive fungal disease and the fourth most frequent bloodstream infection in hospitalized patients. Its optimal management is crucial for improving patients' survival. The quality of candidemia management can be assessed with the EQUAL Candida Score. The objective of this work is to support its automatic calculation by extracting central venous catheter-related information from Italian text in clinical notes of electronic medical records. MATERIALS AND METHODS: The sample includes 4,787 clinical notes of 108 patients hospitalized between January 2018 to December 2020 in the Intensive Care Units of the IRCCS San Martino Polyclinic Hospital in Genoa (Italy). The devised pipeline exploits natural language processing (NLP) to produce numerical representations of clinical notes used as input of machine learning (ML) algorithms to identify CVC presence and removal. It compares the performances of (i) rule-based method, (ii) count-based method together with a ML algorithm, and (iii) a transformers-based model. RESULTS: Results, obtained with three different approaches, were evaluated in terms of weighted F1 Score. The random forest classifier showed the higher performance in both tasks reaching 82.35%. CONCLUSION: The present work constitutes a first step towards the automatic calculation of the EQUAL Candida Score from unstructured daily collected data by combining ML and NLP methods. The automatic calculation of the EQUAL Candida Score could provide crucial real-time feedback on the quality of candidemia management, aimed at further improving patients' health.
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Algoritmos , Candidemia , Estado Terminal , Registros Eletrônicos de Saúde , Unidades de Terapia Intensiva , Processamento de Linguagem Natural , Humanos , Aprendizado de Máquina , Itália , Cateteres Venosos Centrais/microbiologia , Candida/isolamento & purificação , Feminino , Masculino , Idoso , Pessoa de Meia-IdadeRESUMO
Despite advancements in health systems and intensive care unit (ICU) care, along with the introduction of novel antibiotics and microbiologic techniques, mortality rates in severe community-acquired pneumonia (sCAP) patients have not shown significant improvement. Delayed admission to the ICU is a major risk factor for higher mortality. Apart from choosing the appropriate site of care, prompt and appropriate antibiotic therapy significantly affects the prognosis of sCAP. Treatment regimens involving ceftaroline or ceftobiprole are currently considered the best options for managing patients with sCAP. Additionally, several other molecules, such as delafloxacin, lefamulin, and omadacycline, hold promise as therapeutic strategies for sCAP. This review aims to provide a comprehensive summary of the key challenges in managing adults with severe CAP, focusing on essential aspects related to antibiotic treatment and investigating potential strategies to enhance clinical outcomes in sCAP patients.
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Infecções Comunitárias Adquiridas , Pneumonia , Adulto , Humanos , Antibacterianos/uso terapêutico , Pneumonia/tratamento farmacológico , Infecções Comunitárias Adquiridas/microbiologia , Prognóstico , Hospitalização , Unidades de Terapia IntensivaRESUMO
BACKGROUND: The natural history of candidemia in kidney transplant recipients (KTR) remains poorly understood. This study aimed to evaluate mortality, prognostic factors and overall graft loss after candidemia in KTRs. METHODS: This is a retrospective multicentre study enrolling all KTRs ≥15 years old with candidemia diagnosed at hospitals in Brazil, Spain and Italy from 2010 to 2020. Primary endpoints were mortality rates at 14 and 30 days. Secondary endpoints were prognostic factors of 14-day mortality and overall graft loss. RESULTS: We enrolled 93 KTRs of which 75 were from Brazil. The mean time interval from transplantation to the onset of candidemia was 45.2 ± 61.5 months. 42% of all patients were on haemodialysis, 31.3% had an episode of sepsis and 39% underwent surgery within 30 days before fungemia. European patients were more likely to receive echinocandin (32 vs. 72%, p < .001). 22.7% of Brazilian patients did not receive any antifungal before death. All-cause mortality at 14 days was higher in Brazil (41.3 vs. 11.1%, p = .016). Candida colonisation (OR 6.91 [95% CI: 1.08-44.3], p = .042) and hypotension (OR 4.87 [95% CI: 1.62-14.66], p = .005) were associated with 14-day mortality. Echinocandin treatment had a protective effect (OR 0.19 [95% CI: 0.05-0.73], p = .015). Graft loss at 90 days occurred in 48% of patients (70.7 in Brazil vs. 22.2% in Europe, p < .01). CONCLUSIONS: Candidemia in KTR is usually documented late after engraftment in patients requiring HD, surgical procedures and dysbiosis secondary to antibiotic use. Mortality was higher in Brazil. Echinocandin therapy was associated with improved survival.
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Candidemia , Transplante de Rim , Adolescente , Humanos , Antifúngicos/uso terapêutico , Candidemia/tratamento farmacológico , Candidemia/epidemiologia , Candidemia/microbiologia , Equinocandinas/uso terapêutico , Transplante de Rim/efeitos adversos , Prognóstico , Estudos Retrospectivos , Fatores de Risco , AdultoRESUMO
Lamivudine (3TC)/dolutegravir (DTG) single tablet regimen (STR) has shown long-term efficacy and tolerability in people living with HIV (PLWH). Dolutegravir has been approved for use in children, while data on the efficacy of 3TC plus DTG in maintaining virological suppression in this population are still under evaluation. In this case series, we describe three children with perinatally acquired HIV who maintained virological suppression after switching antiretroviral therapy to DTG/3TC. We present three case reports of three children enrolled in the Italian Register for HIV Infection in Children: a 9-year-old boy, a 10-year-old girl, and a 2-year-old girl with perinatally acquired HIV who immediately started antiretroviral therapy with a three-drug regimen upon diagnosis, which occurred at delivery, after 6 months of life, and after 2 years of life, respectively. They achieved and maintain virological suppression after 1, 6, and 7 months of therapy, respectively; then a switch strategy was performed with a two-drug regimen with DTG/3TC STR at the age of 7 years for the first child and at the age of 9 years for the second, while the third was switched to a DTG plus 3TC not STR, owing to weight requirements, at the age of 2 years and 10 months. All children maintained virological suppression at last follow-up visit (January 2024), showing an excellent growth curve and maintaining good adherence and tolerability to DTG plus 3TC. A two-drug regimen with DTG/3TC demonstrated efficacy in maintaining virological suppression in a switch strategy in these children, with important advantages such as better tolerability and comfort of taking a single tablet once daily.
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Fármacos Anti-HIV , Infecções por HIV , Compostos Heterocíclicos com 3 Anéis , Lamivudina , Oxazinas , Piperazinas , Piridonas , Humanos , Lamivudina/uso terapêutico , Lamivudina/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Masculino , Criança , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Pré-Escolar , Fármacos Anti-HIV/uso terapêutico , Fármacos Anti-HIV/administração & dosagem , HIV-1/efeitos dos fármacosRESUMO
The clinical spectrum of invasive pulmonary aspergillosis (IPA) has expanded in recent decades. A large group of patients admitted to intensive care units (ICU) is indeed susceptible to the development of IPA. Although timely diagnosis and antifungal therapy of IPA in this expanding population is crucial to prevent IPA-related deaths, the magnitude of the favorable prognostic impact of antifungal therapy is difficult to measure precisely. In our opinion, the development of standardized research definitions could have favorable implications for further improving our ability both to measure the favorable effect of antifungal treatment and to prevent IPA-related death in ICU patients.
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Antifúngicos , Unidades de Terapia Intensiva , Aspergilose Pulmonar Invasiva , Aspergilose Pulmonar Invasiva/tratamento farmacológico , Aspergilose Pulmonar Invasiva/mortalidade , Aspergilose Pulmonar Invasiva/diagnóstico , Aspergilose Pulmonar Invasiva/prevenção & controle , Humanos , Antifúngicos/uso terapêutico , Antifúngicos/administração & dosagemRESUMO
BACKGROUND: Severely immunocompromised patients are at risk for prolonged or relapsed Coronavirus Disease 2019 (COVID-19), leading to increased morbidity and mortality. We aimed to evaluate efficacy and safety of combination treatment in immunocompromised COVID-19 patients. METHODS: We included all immunocompromised patients with prolonged/relapsed COVID-19 treated with combination therapy with 2 antivirals (remdesivir plus nirmatrelvir/ritonavir, or molnupiravir in case of renal failure) plus, if available, anti-spike monoclonal antibodies (mAbs), between February and October 2022. The main outcomes were virological response at day 14 (negative Severe Acute Respiratory Syndrome Coronavirus 2 [SARS-CoV-2] swab) and virological and clinical response (alive, asymptomatic, with negative SARS-CoV-2 swab) at day 30 and the last follow-up. RESULTS: Overall, 22 patients (Omicron variant in 17/18) were included: 18 received full combination of 2 antivirals and mAbs and 4 received 2 antivirals only; in 20 of 22 (91%) patients, 2 antivirals were nirmatrelvir/ritonavir plus remdesivir. Nineteen (86%) patients had hematological malignancy, and 15 (68%) had received anti-CD20 therapy. All were symptomatic; 8 (36%) required oxygen. Four patients received a second course of combination treatment. The response rate at day 14, day 30, and last follow-up was 75% (15/20 evaluable), 73% (16/22), and 82% (18/22), respectively. Day 14 and 30 response rates were significantly higher when combination therapy included mAbs. Higher number of vaccine doses was associated with better final outcome. Two patients (9%) developed severe side effects (bradycardia leading to remdesivir discontinuation and myocardial infarction). CONCLUSIONS: Combination therapy including 2 antivirals (mainly remdesivir and nirmatrelvir/ritonavir) and mAbs was associated with high rate of virological and clinical response in immunocompromised patients with prolonged/relapsed COVID-19.
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Anticorpos Monoclonais , Anticorpos Neutralizantes , Antivirais , Tratamento Farmacológico da COVID-19 , COVID-19 , Hospedeiro Imunocomprometido , Quimioterapia Combinada , Antivirais/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Tratamento Farmacológico da COVID-19/efeitos adversos , Tratamento Farmacológico da COVID-19/métodos , Recidiva , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Combinação de Medicamentos , Anticorpos Neutralizantes/uso terapêutico , Resultado do TratamentoRESUMO
Outcome of early treatment of COVID-19 with antivirals or anti-spike monoclonal antibodies (MABs) in patients with haematological malignancies (HM) is unknown. A retrospective study of HM patients treated for mild/moderate COVID-19 between March 2021 and July 2022 was performed. The main composite end-point was treatment failure (severe COVID-19 or COVID-19-related death). We included 328 consecutive patients who received MABs (n = 120, 37%; sotrovimab, n = 73) or antivirals (n = 208, 63%; nirmatrelvir/ritonavir, n = 116) over a median of two days after symptoms started; 111 (33.8%) had non-Hodgkin lymphoma (NHL); 89 (27%) were transplant/CAR-T (chimaeric antigen receptor T-cell therapy) recipients. Most infections (n = 309, 94%) occurred during the Omicron period. Failure developed in 31 patients (9.5%). Its independent predictors were older age, fewer vaccine doses, and treatment with MABs. Rate of failure was lower in the Omicron versus the pre-Omicron period (7.8% versus 36.8%, p < 0.001). During the Omicron period, predictors of failure were age, fewer vaccine doses and diagnosis of acute myeloid leukaemia/myelodysplastic syndrome (AML/MDS). Independent predictors of longer viral shedding were age, comorbidities, hospital admission at diagnosis, NHL/CLL, treatment with MABs. COVID-19-associated mortality was 3.4% (n = 11). The mortality in those who developed severe COVID-19 after early treatment was 26% in the Omicron period. Patients with HM had a significant risk of failure of early treatment, even during the Omicron period, with high mortality rate.
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COVID-19 , Doenças Hematológicas , Neoplasias Hematológicas , Humanos , Estudos Retrospectivos , SARS-CoV-2 , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/terapia , Anticorpos Monoclonais , Antivirais/uso terapêuticoRESUMO
PURPOSE OF REVIEW: The aim of this article is to review skin and soft tissue infections due to rapidly growing mycobacteria (RGM), with a particular focus on recently published literature (2021-2022). RECENT FINDINGS: RGM are increasingly reported as a cause of skin and soft tissue infections, both in the community setting and as a cause of nosocomial outbreaks. Recent advances in molecular methods have expanded the number of species of RGM and resulted in increased diagnosis. New treatment options are under evaluation particularly for Mycobacterium abscessus , the most difficult-to-treat among RGM. SUMMARY: RGM are an uncommon cause of skin and soft tissue infections and a high clinical suspicion together with advanced laboratory facilities are required for diagnosis. Species identification and antimicrobial susceptibility testing are essential to drive appropriate treatment, which combines surgical debridement with prolonged antimycobacterial combination therapy.
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Infecções por Mycobacterium não Tuberculosas , Mycobacterium , Infecções dos Tecidos Moles , Humanos , Infecções dos Tecidos Moles/diagnóstico , Infecções dos Tecidos Moles/tratamento farmacológico , Infecções por Mycobacterium não Tuberculosas/diagnóstico , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Antibacterianos/uso terapêutico , Pele/microbiologia , Testes de Sensibilidade MicrobianaRESUMO
PURPOSE OF REVIEW: In the present narrative review, we discuss the characteristics and differences between the Infectious Diseases Society of America (IDSA) and European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guidelines in terms on their recommendations/suggestions for the treatment of Pseudomonas aeruginosa and Acinetobacter baumannii infections. RECENT FINDINGS: Treatment of severe infections caused by nonfermenting gram-negative bacteria (NF-GNB) is posing both novel hopes and novel challenges to physicians worldwide, and both the IDSA and the ESCMID have recently updated/released their guidelines or guidance documents, based on different philosophies and providing recommendations for the treatment of NF-GNB infections. In order to correctly exploit recent advances in the treatment of such infections, IDSA and ESCMID approaches should be viewed as complementary and evolving, and should not preclude further revision based on accumulating evidence on the use of novel ß-lactams and ß-lactam/ß-lactamase inhibitor combinations. SUMMARY: A joint consideration of both philosophies should leave the door opened for the wise use of novel agents, ultimately building precious experience on their use that could favorably influence future guidelines revisions.
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Infecções por Acinetobacter , Doenças Transmissíveis , Humanos , Antibacterianos/uso terapêutico , Antibacterianos/farmacologia , Bactérias Gram-Negativas , Inibidores de beta-Lactamases/uso terapêutico , beta-Lactamas/uso terapêutico , Infecções por Acinetobacter/tratamento farmacológico , Monobactamas/uso terapêuticoRESUMO
PURPOSE OF REVIEW: Serious infections caused by nonfermenting Gram-negative bacteria (NF-GNB) pose a significant challenge for clinicians due to the limited treatment options available, which are frequently associated with issues of toxicity and unfavourable pharmacokinetic profiles. The aim of this review is to provide a brief overview of the existing data concerning the ongoing development of antiinfective agents targeting NF-GNB. RECENT FINDINGS: Several agents exhibiting efficacy against NF-GNB are under clinical investigation. Durlobactam-sulbactam and cefepime-taniborbactam emerge as promising therapeutic avenues against carbapenem-resistant Acinetobacter baumanii . Cefepime-zidebactam may serve as a suitable treatment option for urinary tract infections caused by a wide range of NF-GNB. Cefepime-enmetazobactam demonstrates potent in vitro activity against various NF-GNB strains; however, its role as an anti- Pseudomonal agent is inadequately substantiated by available data. Xeruborbactam is a wide ß-lactamase inhibitor that can be associated with a range of agents, enhancing in-vitro activity of these against many NF-GNB, including those resistant to newer, broader spectrum options. Lastly, murepavadin appears to be a potential pathogen-specific solution for severe Pseudomonas infections; however, additional investigation is necessary to establish the safety profile of this compound. SUMMARY: Each of the novel molecules reviewed possesses an interesting range of in-vitro activity against NF-GNB. In addition, some of them have already been proved effective in vivo, underscoring their potential as future treatment options.
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Infecções por Bactérias Gram-Negativas , Humanos , Cefepima/farmacologia , Cefepima/uso terapêutico , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Infecções por Bactérias Gram-Negativas/microbiologia , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Bactérias Gram-Negativas , Cefalosporinas/uso terapêutico , Testes de Sensibilidade MicrobianaRESUMO
OBJECTIVES: To assess the impact of carbapenem resistance on mortality in Klebsiella pneumoniae bloodstream infection (BSI) in the era of novel ß-lactam/ß-lactamase inhibitor combinations. MATERIAL AND METHODS: Retrospective study of patients with K. pneumoniae BSI between January and August 2020 in 16 centres (CARBANEW study within the MULTI-SITA project). RESULTS: Overall, 426 patients were included: 107/426 (25%) had carbapenem-resistant K. pneumoniae (CR-Kp) BSI and 319/426 (75%) had carbapenem-susceptible K. pneumoniae (CS-Kp) BSI. Crude cumulative 30 day mortality was 33.8% and 20.7% in patients with, respectively, CR-Kp BSI and CS-Kp BSI (Pâ=â0.027). Carbapenemase production or carbapenemase-encoding genes were detected in 84/98 tested CR-Kp isolates (85.7%), mainly KPC (78/84; 92.9%). Ceftazidime/avibactam was the most frequently used appropriate therapy for CR-Kp BSI (80/107; 74.7%). In multivariable analyses, variables showing an unfavourable association with mortality after correction for multiple testing were age-adjusted Charlson comorbidity index (HR 1.20; 95% CI 1.10-1.31, Pâ<â0.001) and Pitt score (HR 1.33; 95% CI 1.15-1.55, Pâ<â0.001), but not carbapenem resistance (HR 1.28, 95% CI 0.74-2.22, Pâ=â0.410). In a propensity score-matched analysis, there was no difference in mortality between patients appropriately treated with ceftazidime/avibactam for CR-Kp BSI and patients appropriately treated with other agents (mainly meropenem monotherapy or piperacillin/tazobactam monotherapy) for CS-Kp BSI (HR 1.07; 95% CI 0.50-2.29, Pâ=â0.866). CONCLUSIONS: Our results suggest that the increased mortality in CR-Kp BSI compared with CS-Kp BSI is not (or no longer) dependent on the type of therapy in areas where ceftazidime/avibactam-susceptible KPC-producing isolates are the most prevalent type of CR-Kp.
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Bacteriemia , Infecções por Klebsiella , Sepse , Humanos , Ceftazidima/farmacologia , Klebsiella pneumoniae , Infecções por Klebsiella/tratamento farmacológico , Infecções por Klebsiella/epidemiologia , Estudos Retrospectivos , Bacteriemia/tratamento farmacológico , Compostos Azabicíclicos/uso terapêutico , Compostos Azabicíclicos/farmacologia , beta-Lactamases/genética , Proteínas de Bactérias/genética , Sepse/tratamento farmacológico , Carbapenêmicos/farmacologia , Carbapenêmicos/uso terapêutico , Inibidores de beta-Lactamases/uso terapêutico , Combinação de Medicamentos , Suscetibilidade a Doenças , Antibacterianos/farmacologia , Antibacterianos/uso terapêuticoRESUMO
The SARS-CoV-2 infection causes severe respiratory involvement (COVID-19) in 5-20% of patients through initial immune derangement, followed by intense cytokine production and vascular leakage. Evidence of immune involvement point to the participation of T, B, and NK cells in the lack of control of virus replication leading to COVID-19. NK cells contribute to early phases of virus control and to the regulation of adaptive responses. The precise mechanism of NK cell dysregulation is poorly understood, with little information on tissue margination or turnover. We investigated these aspects by multiparameter flow cytometry in a cohort of 28 patients hospitalized with early COVID-19. Relevant decreases in CD56brightCD16+/- NK subsets were detected, with a shift of circulating NK cells toward more mature CD56dimCD16+KIR+NKG2A+ and "memory" KIR+CD57+CD85j+ cells with increased inhibitory NKG2A and KIR molecules. Impaired cytotoxicity and IFN-γ production were associated with conserved expression of natural cytotoxicity receptors and perforin. Moreover, intense NK cell activation with increased HLA-DR and CD69 expression was associated with the circulation of CD69+CD103+ CXCR6+ tissue-resident NK cells and of CD34+DNAM-1brightCXCR4+ inflammatory precursors to mature functional NK cells. Severe disease trajectories were directly associated with the proportion of CD34+DNAM-1brightCXCR4+ precursors and inversely associated with the proportion of NKG2D+ and of CD103+ NK cells. Intense NK cell activation and trafficking to and from tissues occurs early in COVID-19, and is associated with subsequent disease progression, providing an insight into the mechanism of clinical deterioration. Strategies to positively manipulate tissue-resident NK cell responses may provide advantages to future therapeutic and vaccine approaches.
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COVID-19/imunologia , Células Matadoras Naturais/imunologia , Idoso , Idoso de 80 Anos ou mais , COVID-19/mortalidade , Estudos de Coortes , Feminino , Citometria de Fluxo/métodos , Humanos , Interferon gama/metabolismo , Itália/epidemiologia , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de DoençaRESUMO
PURPOSE OF REVIEW: Antimicrobial resistance (AMR) in Gram-negative bacteria (GNB) poses a significant global health concern, contributing to increased infections, mortality rates, and healthcare costs. This review discusses the main clinical manifestations, therapeutic options, and recent findings in managing antibiotic-resistant GNB, with a focus on difficult-to-treat infections. RECENT FINDINGS: Difficult-to-treat resistance (DTR) is a novel classification that identifies GNB exhibiting intermediate or resistant phenotypes to first-line agents in the carbapenem, beta-lactam, and fluoroquinolone categories. The main pathogens implicated in severe infections include DTR Enterobacterales, DTR Pseudomonas aeruginosa , and DTR Acinetobacter baumannii. Although the clinical implications of DTR strains are still under investigation, certain studies have linked them to prolonged hospital stays and poor patient outcomes. SUMMARY: Severe infections caused by DTR-GNB pose a formidable challenge for healthcare providers and represent a growing global health issue. The proper administration and optimization of novel antibiotics at our disposal are of paramount importance for combating bacterial resistance and improving patient prognosis.
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Acinetobacter baumannii , Humanos , Antibacterianos/uso terapêutico , Carbapenêmicos/farmacologia , Carbapenêmicos/uso terapêutico , Bactérias Gram-Negativas , Tempo de InternaçãoRESUMO
BACKGROUND: Pneumocystis jirovecii pneumonia (PJP) is an opportunistic, life-threatening disease commonly affecting immunocompromised patients. The distribution of predisposing diseases or conditions in critically ill patients admitted to intensive care unit (ICU) and subjected to diagnostic work-up for PJP has seldom been explored. MATERIALS AND METHODS: The primary objective of the study was to describe the characteristics of ICU patients subjected to diagnostic workup for PJP. The secondary objectives were: (i) to assess demographic and clinical variables associated with PJP; (ii) to assess the performance of Pneumocystis PCR on respiratory specimens and serum BDG for the diagnosis of PJP; (iii) to describe 30-day and 90-day mortality in the study population. RESULTS: Overall, 600 patients were included in the study, of whom 115 had presumptive/proven PJP (19.2%). Only 8.8% of ICU patients subjected to diagnostic workup for PJP had HIV infection, whereas hematological malignancy, solid tumor, inflammatory diseases, and solid organ transplants were present in 23.2%, 16.2%, 15.5%, and 10.0% of tested patients, respectively. In multivariable analysis, AIDS (odds ratio [OR] 3.31; 95% confidence interval [CI] 1.13-9.64, p = 0.029), non-Hodgkin lymphoma (OR 3.71; 95% CI 1.23-11.18, p = 0.020), vasculitis (OR 5.95; 95% CI 1.07-33.22, p = 0.042), metastatic solid tumor (OR 4.31; 95% CI 1.76-10.53, p = 0.001), and bilateral ground glass on CT scan (OR 2.19; 95% CI 1.01-4.78, p = 0.048) were associated with PJP, whereas an inverse association was observed for increasing lymphocyte cell count (OR 0.64; 95% CI 0.42-1.00, p = 0.049). For the diagnosis of PJP, higher positive predictive value (PPV) was observed when both respiratory Pneumocystis PCR and serum BDG were positive compared to individual assay positivity (72% for the combination vs. 63% for PCR and 39% for BDG). Cumulative 30-day mortality and 90-day mortality in patients with presumptive/proven PJP were 52% and 67%, respectively. CONCLUSION: PJP in critically ill patients admitted to ICU is nowadays most encountered in non-HIV patients. Serum BDG when used in combination with respiratory Pneumocystis PCR could help improve the certainty of PJP diagnosis.
Assuntos
Infecções por HIV , Pneumonia por Pneumocystis , Humanos , Pneumonia por Pneumocystis/complicações , Pneumonia por Pneumocystis/diagnóstico , Estado Terminal , Unidades de Terapia Intensiva , Cuidados CríticosRESUMO
To achieve the World Health Organization goal of hepatitis C virus (HCV) eradication, barriers to treatment should be investigated and overcome. The aim of this study was to identify those barriers and describe the strategies adopted to achieve HCV micro-elimination in a cohort of coinfected people living with HIV (PLWH-HCV). Adult PLWH-HCV followed at our hospital with detectable serum HCV-RNA in 2018 were enrolled. After a three-year follow-up, barriers to HCV treatment were investigated and strategies to overcome them were described. Of 492 PLWH-HCV seen in 2018, 29 (5.9%) had detectable serum HCV-RNA. Eight out of 29 (27.6%) were excluded because they were already under treatment, while 2 others were excluded because they moved to other outpatient clinics. Among the remaining 19 study participants, the most common barriers to treatment were poor adherence to therapies and follow-up visits (n=9, 47%), recent HCV diagnosis awaiting proper staging (n=3, 16%) and treatment hesitancy (n=2, 10%). During the following three years, direct-acting antivirals (DAAs) treatment was completed in 11/19 (58%) cases, with achievement of sustained virological response in 100% of cases. For the remaining cases, 2/19 (10.5%) were lost to follow-up, 2/19 (10.5%) died before treatment initiation and 4/19 (21.0%) are still awaiting treatment. Despite 3 years of effort, HCV micro-elimination has not been achieved at our center. We observed that poor adherence and treatment hesitancy were the main barriers to treatment. Strategies addressing these issues need to be implemented.
Assuntos
Hepatite C Crônica , Hepatite C , Adulto , Humanos , Hepacivirus , Antivirais/uso terapêutico , Hepatite C/tratamento farmacológico , RNARESUMO
PURPOSE OF REVIEW: Acute bacterial skin and skin structure infections (ABSSSI) are a leading cause of morbidity, with a considerable variety of clinical presentation and a wide range of etiological pathogens. Of importance, the spread of multidrug-resistant (MDR) strains (i.e. methicillin-resistant Staphylococcus aureus or Gram-negative bacteria) is increasingly reported in some regions. in this review, we summarize the current clinical approach to patients with ABSSSI. RECENT FINDINGS: Accurate diagnosis and identification of risk factors for MDR pathogens are key determinants for administering appropriate therapy in patients with ABSSSI. In daily clinical practice, this can be critical as there are many features defining the 'high risk patient' including both disease and host-associated risk factors. SUMMARY: Antibiotic therapy should be based according to the different clinical spectrum of disease belonging to the ABSSSI, on the pathogens most likely to be involved and local resistance. Careful evaluation of antibiotic therapy after 48-72âh of initial therapy could help clinicians to early identify patients with treatment failure and to consider an alternative approach. Close monitoring of patients with multiple comorbidities, drug-drug interaction or adverse host factors are also necessary.