Rezafungin versus caspofungin for treatment of candidaemia and invasive candidiasis (ReSTORE): a multicentre, double-blind, double-dummy, randomised phase 3 trial.

BACKGROUND: Rezafungin is a next-generation, once-a-week echinocandin in development for the treatment of candidaemia and invasive candidiasis and for the prevention of invasive fungal disease caused by Candida, Aspergillus, and Pneumocystis spp after blood and marrow transplantation. We aimed to compare the efficacy and safety of intravenous rezafungin versus intravenous caspofungin in patients with candidaemia and invasive candidiasis. METHODS: ReSTORE was a multicentre, double-blind, double-dummy, randomised phase 3 trial done at 66 tertiary care centres in 15 countries. Adults (≥18 years) with systemic signs and mycological confirmation of candidaemia or invasive candidiasis were eligible for inclusion and randomly assigned (1:1) to receive intravenous rezafungin once a week (400 mg in week 1, followed by 200 mg weekly, for a total of two to four doses) or intravenous caspofungin (70 mg loading dose on day 1, followed by 50 mg daily) for no more than 4 weeks. The primary endpoints were global cure (consisting of clinical cure, radiological cure, and mycological eradication) at day 14 for the European Medical Agency (EMA) and 30-day all-cause mortality for the US Food and Drug Administration (FDA), both with a target non-inferiority margin of 20%, assessed in the modified intention-to-treat population (all patients who received one or more doses of study drug and had documented Candida infection based on a culture from blood or another normally sterile site obtained within 96 h before randomisation). Safety was evaluated by the incidence and type of adverse events and deaths in the safety population, defined as all patients who received any amount of study drug. The trial is registered with ClinicalTrials.gov, NCT03667690, and is complete. FINDINGS: Between Oct 12, 2018, and Aug 29, 2021, 222 patients were screened for inclusion, and 199 patients (118 [59%] men; 81 [41%] women; mean age 61 years [SD 15·2]) were randomly assigned (100 [50%] patients to the rezafungin group and 99 [50%] patients to the caspofungin group). 55 (59%) of 93 patients in the rezafungin group and 57 (61%) of 94 patients in the caspofungin group had a global cure at day 14 (weighted treatment difference -1·1% [95% CI -14·9 to 12·7]; EMA primary endpoint). 22 (24%) of 93 patients in the rezafungin group and 20 (21%) of 94 patients in the caspofungin group died or had an unknown survival status at day 30 (treatment difference 2·4% [95% CI -9·7 to 14·4]; FDA primary endpoint). In the safety analysis, 89 (91%) of 98 patients in the rezafungin group and 83 (85%) of 98 patients in the caspofungin group had at least one treatment-emergent adverse event. The most common treatment-emergent adverse events that occurred in at least 5% of patients in either group were pyrexia, hypokalaemia, pneumonia, septic shock, and anaemia. 55 (56%) patients in the rezafungin group and 52 (53%) patients in the caspofungin group had serious adverse events. INTERPRETATION: Our data show that rezafungin was non-inferior to caspofungin for the primary endpoints of day-14 global cure (EMA) and 30-day all-cause mortality (FDA). Efficacy in the initial days of treatment warrants evaluation. There were no concerning trends in treatment-emergent or serious adverse events. These phase 3 results show the efficacy and safety of rezafungin and support its ongoing development. FUNDING: Cidara Therapeutics and Mundipharma.

Infection epidemiology in relation to different therapy phases in patients with haematological malignancies receiving CAR T-cell therapy.

BACKGROUND: We described the real-life epidemiology and causes of infections on the different therapy phases in patients undergoing chimeric antigen receptor (CAR) T-cells directed towards CD19+ or BCMA+ cells. METHODS: All consecutive patients receiving CAR T-cell therapy at our institution were prospectively followed-up. We performed various comparative analyses of all patients and subgroups with and without infections. RESULTS: Ninety-one adults mainly received CAR T-cell therapy for acute leukaemia (53%) and lymphoma (33%). We documented a total of 77 infections in 47 (52%) patients, 37 (48%) during the initial neutropenic phase and 40 (52%) during the non-neutropenic phase. Infections during the neutropenic phase were mainly due to bacterial (29, 78%): catheter infections (11 [38%] cases), endogenous source (5 [17%]), and Clostridioides difficile (5 [17%]). Patients receiving corticosteroids after CAR T-cell therapy had a higher risk of endogenous infection (100% vs. 16%; p = .006). During the non-neutropenic phase, bacterial infections remained very frequent (24, 60%), mainly with catheter source (8, 33%). Respiratory tract infections were common (17, 43%). CONCLUSIONS: Infections after CAR T-cell therapy were frequent. During the neutropenic phase, it is essential to prevent nosocomial infections and balance the use of antibiotics to lower endogenous bacteraemia and Clostridial infection rates.

Report of three azole-resistant Aspergillus fumigatus cases with TR34/L98H mutation in hematological patients in Barcelona, Spain.

OBJECTIVES: We aimed to report the emergence of azole-resistant invasive aspergillosis in hematologic patients admitted to a tertiary hospital in Spain during the last 4 months. METHODS: Prospective, descriptive study was performed to describe and follow all consecutive proven and probable invasive aspergillosis resistant to azoles from hematological cohort during the last 4 months. All patients had fungal cultures and antifungal susceptibility or real-time PCR detection for Aspergillus species and real-time PCR detection for azole-resistant mutation. RESULTS: Four cases of invasive aspergillosis were diagnosed in 4 months. Three of them had azole-resistant aspergillosis. Microbiological diagnosis was achieved in three cases by means of fungal culture isolation and subsequent antifungal susceptibility whereas one case was diagnosed by PCR-based aspergillus and azole resistance detection. All the azole-resistant aspergillosis presented TR34/L98H mutation. Patients with azole-resistant aspergillosis had different hematologic diseases: multiple myeloma, lymphoblastic acute leukemia, and angioimmunoblastic T lymphoma. Regarding risk factors, one had prolonged neutropenia, two had corticosteroids, and two had viral co-infection. Two of the patients developed aspergillosis under treatment with azoles. CONCLUSION: We have observed a heightened risk of azole-resistant aspergillosis caused by A. fumigatus harboring the TR34/L98H mutation in patients with hematologic malignancies. The emergence of azole-resistant aspergillosis raises concerns for the community, highlighting the urgent need for increased surveillance and the importance of susceptibility testing and new drugs development.

Multiplex real-time PCR FilmArray performance in the diagnosis of meningoencephalitis: lights and shadows.

PURPOSE: We aimed to evaluate the performance of the FilmArray (FA) meningitis/encephalitis (ME) panel. Secondarily, we analyzed the false positive (FP) and false negative (FN) results, as well as the predictive values of the technique, regarding the cerebrospinal fluid (CSF) characteristics. METHODS: FA is a multiplex real-time PCR detecting 14 of the most common ME pathogens in CSF. All FA performed at our hospital (2018-2022) were retrospectively reviewed. FA was compared to conventional techniques and its performance was assessed based on the final diagnosis of the episode. RESULTS: FA was performed in 313 patients with suspicion of ME. Most patients had altered mental status (65.2%) and fever (61%). Regarding CSF characteristics, 49.8% and 53.7% presented high CSF proteins and pleocytosis, respectively. There were 84 (26.8%) positive FA results, mainly for HSV-1 (10.9%), VZV (5.1%), Enterovirus (2.6%), and S. pneumoniae (1.9%). In the 136 cases where both FA and routine methods were performed, there was a 25.7% lack of agreement. We identified 6.6% FN results, but 28.6% FP, mainly due to HSV-1. This resulted in a high negative predictive value (NPV) of 93.4%, but a positive predictive value (PPV) of 73%. Remarkably, PPV as low as 36.9%, and 70.2%, were found in cases without pleocytosis, or lack of high CSF protein levels, respectively. CONCLUSION: FA was associated with high NPV, but frequent FP results and low PPV, particularly for HSV-1, and especially in patients without high CSF protein levels or pleocytosis.

Impact of Positive Cultures During the Second Stage of a Two-Stage Exchange: Systematic Review and Meta-Analysis.

BACKGROUND: Two-stage exchange is a frequently performed procedure in patients who have a periprosthetic joint infection. Positive cultures when performing the second stage are perceived as a risk factor for reinfection. This study aimed to determine the impact of positive cultures during the second stage on the outcome of patients undergoing a 2-stage septic exchange and the impact of stopping the antibiotic treatment before reimplantation. METHODS: We systematically searched four databases. We performed a meta-analysis on the risk of complications after positive cultures during second stage and a subgroup analysis by antibiotic holiday period. We included 24 studies. RESULTS: Failure in the positive group was 37.0% and in the negative group was 13.7% with an odds ratio (OR) of 4.05. In the subgroup analysis by antibiotic holidays, failure rate without holidays was 15% and with holidays was 17.3% (P = .21). Failure in each group was higher when cultures were positive (without holidays, 25 versus 12.2%, P = .0003, and with holidays 41.1 versus 12.7%, P < .0001), but the risk of failure when cultures were positive was higher in the holiday group (OR 4.798) than in the nonholiday group (OR 2.225) in comparison to those patients who were culture negative at the second stage. CONCLUSIONS: Microbiological eradication at second stage was not obtained in 18% of cases and it was associated with a higher failure rate. In patients with positive cultures, withholding antibiotic treatment was associated with lower failure rate. Further studies to define the antibiotic strategy in 2-stage exchange procedure are necessary.

Information Delay of Significant Bloodstream Isolates and Patient Mortality: A Retrospective Analysis of 6225 Adult Patients With Bloodstream Infections.

BACKGROUND: Our aim in this study was to evaluate the clinical and prognostic impact of communicating microbiological information in real time for adult patients with bloodstream infections (BSIs). METHODS: We retrospectively reviewed 6225 clinical episodes of bacteremia in a teaching hospital from January 2013 to December 2019. Bacteremia-associated mortality was compared when blood culture results were relayed to the infectious diseases specialist (IDS) in real time and periods when results were relayed the following morning. The impact of information availability using mortality at 30 days was used as the main outcome of the study. RESULTS: The initial analysis (all microorganisms included) did not show an association of mortality and information delay to the IDS (odds ratio [OR], 1.18; 95% confidence interval [CI], .99-1.42). However, information delay of BSIs caused by fast-growing microorganisms such as Enterobacterales was associated with a significant increase in the odds of death at 30 days both in the univariate (OR, 1.76; 95% CI, 1.30-2.38) and multivariate analysis (OR, 2.22; 95% CI, 1.50-3.30). Similar results were found with mortality at 14 days and 7 days in the univariate (OR, 1.54; 95% CI, 1.08-2.20 and OR, 1.56; 95% CI, 1.03-2.37, respectively) and the multivariate analysis (OR, 2.05; 95% CI, 1.27-3.32 and OR, 1.92; 95% CI, 1.09-3.40, respectively). CONCLUSIONS: Information delivered in real time has prognostic relevance and is likely to improve survival of patients with documented BSIs. Future studies should address the prognostic impact of adequate resource allocation (microbiologist/IDS with 24/7 coverage) in BSIs.

Qualitative Subgenomic RNA to Monitor the Response to Remdesivir in Hospitalized Patients With Coronavirus Disease 2019: Impact on the Length of Hospital Stay and Mortality.

BACKGROUND: There is no reliable microbiological marker to guide the indication and the response to antiviral treatment in patients with coronavirus disease 2019 (COVID-19). We aimed to evaluate the dynamics of subgenomic RNA (sgRNA) in patients with COVID-19 before and after receiving treatment with remdesivir. METHODS: We included consecutive patients admitted for COVID-19 who received remdesivir according to our institutional protocol and accepted to participate in the study. A nasopharyngeal swab for quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) was collected at baseline and after 3 and 5 days of treatment with remdesivir. Genomic and sgRNA were analyzed in those samples and main comorbidities and evolution were collected for the analyses. The main outcomes were early discharge (≤10 days) and 30-day mortality. RESULTS: A total of 117 patients were included in the study, of whom 24 had a negative sgRNA at baseline, with 62.5% (15/24) receiving early discharge (≤10 days) and no deaths in this group. From the 93 remaining patients, 62 had a negative sgRNA at day 5 with 37/62 (59.6%) with early discharge and a mortality rate of 4.8% (3/62). In the subgroup of 31 patients with positive sgRNA after 5 days of remdesivir, the early discharge rate was 29% (9/31) and the mortality rate was 16.1% (5/31). In multivariable analyses, the variables associated with early discharge were negative sgRNA at day 3 and not needing treatment with corticosteroids or intensive care unit admission. CONCLUSIONS: Qualitative sgRNA could help in monitoring the virological response in patients who receive remdesivir. Further studies are needed to confirm these findings.

Prevention and treatment of C. difficile in cancer patients.

PURPOSE OF REVIEW: We provide an update on the recent literature on Clostridioides difficile infection (CDI) in cancer patients. RECENT FINDINGS: Distinguishing between colonization and infection remains challenging in cancer patients. Many patients with negative toxin analysis are still treated for CDI, and some meet criteria for severe cases. The incidence of CDI is high in cancer patients, especially those with haematological malignancies. Disruption of the gut microbiome due to antibiotic consumption, chemotherapy and radiotherapy is the primary factor contributing to CDI development. The severity of CDI in cancer patients is often unclear due to the absence of well-defined severity criteria. Certain microbiome species predominance and specific ribotypes have been associated with worse outcomes. Whole genome sequencing could be helpful for differentiating recurrence from reinfection and exploring potential nosocomial transmission. While certain new drugs such as fidaxomicin or bezlotoxumab show promise, the optimal treatment and prevention strategies for CDI in cancer patients remain uncertain. Faecal microbiota transplantation (FMT) holds potential for reducing CDI recurrence rates. SUMMARY: Further studies are needed to provide robust recommendations for diagnosis, grading severity, and therapeutic management of CDI in cancer patients. Recurrences are particularly concerning due to subsequent exposition to CDI risk factors.

Invasive candidiasis: current clinical challenges and unmet needs in adult populations.

Invasive candidiasis (IC) is a serious infection caused by several Candida species, and the most common fungal disease in hospitals in high-income countries. Despite overall improvements in health systems and ICU care in the last few decades, as well as the development of different antifungals and microbiological techniques, mortality rates in IC have not substantially improved. The aim of this review is to summarize the main issues underlying the management of adults affected by IC, focusing on specific forms of the infection: IC developed by ICU patients, IC observed in haematological patients, breakthrough candidaemia, sanctuary site candidiasis, intra-abdominal infections and other challenging infections. Several key challenges need to be tackled to improve the clinical management and outcomes of IC patients. These include the lack of global epidemiological data for IC, the limitations of the diagnostic tests and risk scoring tools currently available, the absence of standardized effectiveness outcomes and long-term data for IC, the timing for the initiation of antifungal therapy and the limited recommendations on the optimal step-down therapy from echinocandins to azoles or the total duration of therapy. The availability of new compounds may overcome some of the challenges identified and increase the existing options for management of chronic Candida infections and ambulant patient treatments. However, early identification of patients that require antifungal therapy and treatment of sanctuary site infections remain a challenge and will require further innovations.

Current outcomes of SARS-CoV-2 Omicron variant infection in high-risk haematological patients treated early with antivirals.

OBJECTIVES: We aimed to describe the clinical outcomes and duration of viral shedding in high-risk patients with haematological malignancies hospitalized with COVID-19 during Omicron variant predominance who received early treatment with antivirals. METHODS: We conducted a prospective observational study on high-risk haematological patients admitted in our hospital between December 2021 and March 2022. We performed detection techniques on viral subgenomic mRNAs until negative results were obtained to document active, prolonged viral replication. RESULTS: This analysis included 60 consecutive adults with high-risk haematological malignancies and COVID-19. All of these patients underwent early treatment with remdesivir. Thirty-two (53%) patients received combined antiviral strategies, with sotrovimab or hyperimmune plasma being added to remdesivir. The median length of viral replication-as measured by real-time RT-PCR and/or subgenomic RNA detection-was 20 (IQR 14-28) days. Prolonged viral replication (6 weeks after diagnosis) was documented in six (10%) patients. Only two patients had prolonged infection for more than 2 months. Overall mortality was 5%, whereas COVID-19-related mortality was 0%. CONCLUSIONS: Current outcomes of high-risk patients with haematological malignancies hospitalized with COVID-19 during Omicron variant predminance are good with the use of early antiviral strategies. Persistent viral shedding is uncommon.

Real-life epidemiology and current outcomes of hospitalized adults with invasive fungal infections.

We aimed to describe the current epidemiology of both hosts with invasive fungal infections (IFIs) and causative fungi. And, detail outcomes of these infections at 12 weeks in a real-life cohort of hospitalized patients. The study was retrospective and observational to describe IFI diagnosed in a tertiary hospital (February 2017-December 2021). We included all consecutive patients meeting criteria for proven or probable IFI according to EORTC-MSG and other criteria. A total of 367 IFIs were diagnosed. 11.7% were breakthrough infections, and 56.4% were diagnosed in the intensive care unit. Corticosteroid use (41.4%) and prior viral infection (31.3%) were the most common risk factors for IFI. Lymphoma and pneumocystis pneumonia were the most common baseline and fungal diseases. Only 12% of IFI occurred in patients with neutropenia. Fungal cultures were the most important diagnostic tests (85.8%). The most frequent IFIs were candidemia (42.2%) and invasive aspergillosis (26.7%). Azole-resistant Candida strains and non-fumigatus Aspergillus infections represented 36.1% and 44.5% of the cases, respectively. Pneumocystosis (16.9%), cryptococcosis (4.6%), and mucormycosis (2.7%) were also frequent, as well as mixed infections (3.4%). Rare fungi accounted for 9.5% of infections. Overall, IFI mortality at 12 weeks was 32.2%; higher rates were observed for Mucorales (55.6%), Fusarium (50%), and mixed infections (60%). We documented emerging changes in both hosts and real-life IFI epidemiology. Physicians should be aware of these changes to suspect infections and be aggressive in diagnoses and treatments. Currently, outcomes for such clinical scenarios remain extremely poor.

Current epidemiology of the host and fungi and IFI treatments are changing. Real-life data on this subject are scarce. We present our most recent evidence to highlight the importance of the ongoing challenges that require further investigation and clinical adjustments.

Remdesivir-related cost-effectiveness and cost and resource use evidence in COVID-19: a systematic review.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has been a global health emergency since December 2019, leading to millions of deaths worldwide and placing significant pressures, including economic burden, on individual patients and healthcare systems. As of February 2022, remdesivir is the only US Food and Drug Administration (FDA)-approved treatment for severe COVID-19. This systematic literature review (SLR) aimed to summarise economic evaluations, and cost and resource use (CRU) evidence related to remdesivir during the COVID-19 pandemic. METHODS: Searches of MEDLINE, Embase the International Health Technology Assessment (HTA) database, reference lists, congresses and grey literature were performed in May 2021. Articles were reviewed for relevance against pre-specified criteria by two independent reviewers and study quality was assessed using published checklists. RESULTS: Eight studies reported resource use and five reported costs related to remdesivir. Over time, the prescription rate of remdesivir increased and time from disease onset to remdesivir initiation decreased. Remdesivir was associated with a 6% to 21.3% decrease in bed occupancy. Cost estimates for remdesivir ranged widely, from $10 to $780 for a 10-day course. In three out of four included economic evaluations, remdesivir treatment scenarios were cost-effective, ranging from ~ 8 to ~ 23% of the willingness-to-pay threshold for the respective country. CONCLUSIONS: Economic evidence relating to remdesivir should be interpreted with consideration of the broader clinical context, including patients' characteristics and the timing of its administration. Nonetheless, remdesivir remains an important option for physicians in aiming to provide optimal care and relieve pressure on healthcare systems through shifting phases of the pandemic.

Time from symptoms onset to remdesivir is associated with the risk of ICU admission: a multicentric analyses.

BACKGROUND: Shorter duration of symptoms before remdesivir has been associated with better outcomes. Our goal was to evaluate variables associated with the need of ICU admission in a cohort of hospitalized patients for COVID-19 under remdesivir including the period from symptoms onset to remdesivir. METHODS: We conducted a retrospective multicentric study analysing all patients admitted with COVID-19 in 9 Spanish hospitals who received treatment with remdesivir in October 2020. The main outcome was the need of ICU admission after 24 h of the first dose of remdesivir. RESULTS: In our cohort of 497 patients, the median of days from symptom onset to remdesivir was 5 days, and 70 of them (14.1%) were later admitted into ICU. The clinical outcomes associated with ICU admission were days from symptoms onset (5 vs. 6; p = 0.023), clinical signs of severe disease (respiratory rate, neutrophil count, ferritin levels and very-high mortality rate in SEIMC-Score) and the use of corticosteroids and anti-inflammatory drugs before ICU. The only variable significatively associated with risk reduction in the Cox-regression analyses was ≤ 5 days from symptoms onset to RDV (HR: 0.54, CI95%: 0.31-0.92; p = 0.024). CONCLUSION: For patients admitted to the hospital with COVID-19, the prescription of remdesivir within 5 days from symptoms onset diminishes the need of ICU admission.

Do Cultures Obtained During Primary THA Predict the Likelihood of Revision?

BACKGROUND: There can be unexpectedly positive culture results during elective hip arthroplasty, but the degree to which these are associated with an increased risk of subsequent premature revision is not known. QUESTION/PURPOSE: Are unexpectedly positive culture results obtained during elective THA associated with an increased likelihood of revision within 5 years of the procedure? METHODS: Between March 2007 and March 2011, the hip unit at our institution performed elective primary THA in 829 patients. We systematically collected three samples in 52% (428 of 829) of the interventions. Of those, 26 patients were excluded because of sampling errors; 94% (402 of 428) had samples that were collected systematically and were eligible for the study. We only considered one hip randomly in bilateral procedures (4% [15 of 428]); patients presenting with acute (< 3 months) periprosthetic joint infection undergoing open debridement (4% [16 of 402]) and patients who died before 5 years of follow-up (2% [seven of 402]) were excluded from the study, leaving 91% (364 of 402) eligible for analysis in this retrospective study of a previous prospective trial. No patient included in the final analysis was lost to follow-up within 5 years from the index surgery. The patient group consisted of 52% (188 of 364) women, with a mean ± SD age of 64.8 ± 13.9 years. RESULTS: Positives culture results were associated with a higher risk of revision within 5 years of the index surgery. The proportion of revision surgery was higher in the group with positive culture results than in those with negative results (10% [eight of 77] versus 2% [seven of 290]; p = 0.01). The difference was mainly attributable to a higher proportion of aseptic loosening in those with positive culture results than in those with negative results (8% [six of 74] versus 1% [four of 290]; p = 0.01). After a multivariable analysis, the only independent variable associated with 5-year revision surgery was the presence of positive results during THA (odds ratio 4.9 [95% confidence interval 1.72 to 13.99]). CONCLUSION: Our findings suggest that bacterial contamination during THA is associated with an increased likelihood of early revision. This higher risk of revision is mainly because of presumed aseptic loosening; thus, efforts should focus on the need to rule out infection. These results not only open new questions that should be answered in new prospective and well-designed studies, but also may help to better select patients to obtain a more favorable outcome after THA. LEVEL OF EVIDENCE: Level III, therapeutic study.

The European Bone and Joint Infection Society definition of periprosthetic joint infection is meaningful in clinical practice: a multicentric validation study with comparison with previous definitions.

BACKGROUND AND PURPOSE: A new periprosthetic joint infection (PJI) definition has recently been proposed by the European Bone and Joint Infection Society (EBJIS). The goals of this paper are to evaluate its diagnostic accuracy and compare it with previous definitions and to assess its accuracy in preoperative diagnosis. PATIENTS AND METHODS: We retrospectively evaluated a multicenter cohort of consecutive revision total hip and knee arthroplasties. Cases with minimum required diagnostic workup were classified according to EBJIS, 2018 International Consensus Meeting (ICM 2018), Infectious Diseases Society of America (IDSA), and modified 2013 Musculoskeletal Infection Society (MSIS) definitions. 2 years' minimum follow-up was required to assess clinical outcome. RESULTS: Of the 472 cases included, PJI was diagnosed in 195 (41%) cases using EBJIS; 188 (40%) cases using IDSA; 172 (36%) using ICM 2018; and 145 (31%) cases using MSIS. EBJIS defined fewer cases as intermediate (5% vs. 9%; p = 0.01) compared with ICM 2018. Specificity was determined by comparing risk of subsequent PJI after revision surgery. Infected cases were associated with higher risk of subsequent PJI in every definition. Cases classified as likely/confirmed infections using EBJIS among those classified as not infected in other definitions showed a significantly higher risk of subsequent PJI compared with concordant non-infected cases using MSIS (RR = 3, 95% CI 1-6), but not using ICM 2018 (RR = 2, CI 1-6) or IDSA (RR = 2, CI 1-5). EBJIS showed the highest agreement between pre-operative and definitive classification (k = 0.9, CI 0.8-0.9) and was better at ruling out PJI with an infection unlikely result (sensitivity 89% [84-93], negative predictive value 90% [85-93]). CONCLUSION: The newly proposed EBJIS definition emerged as the most sensitive of all major definitions. Cases classified as PJI according to the EBJIS criteria and not by other definitions seem to have increased risk of subsequent PJI compared with concordant non-infected cases. EBJIS classification is accurate in ruling out infection preoperatively.

Personalized Therapy Approach for Hospitalized Patients with Coronavirus Disease 2019.

Hospitalized patients with coronavirus disease 2019 (COVID-19) experiencing respiratory symptoms have different complications (inflammatory, co-infection, and thrombotic) that are identifiable by analytics patterns. Personalized treatment decisions decreased early mortality (odds ratio [OR] .144; 95% confidence interval [CI] .03-.686; P = .015). Increasing age (OR 1.06; P = .038) and therapeutic effort limitation (OR 9.684; P < .001) were associated with higher mortality.

New Perspectives on Antimicrobial Agents: Long-Acting Lipoglycopeptides.

The long-acting lipoglycopeptides (LGPs) dalbavancin and oritavancin are semisynthetic antimicrobials with broad and potent activity against Gram-positive bacterial pathogens. While they are approved by the Food and Drug Administration for acute bacterial skin and soft tissue infections, their pharmacological properties suggest a potential role of these agents for the treatment of deep-seated and severe infections, such as bloodstream and bone and joint infections. The use of these antimicrobials is particularly appealing when prolonged therapy, early discharge, and avoidance of long-term intravascular catheter access are desirable or when multidrug-resistant bacteria are suspected. This review describes the current evidence for the use of oritavancin and dalbavancin in the treatment of invasive infections, as well as the hurdles that are preventing their optimal use. Moreover, this review discusses the current knowledge gaps that need to be filled to understand the potential role of LGPs in highly needed clinical scenarios and the ongoing clinical studies that aim to address these voids in the upcoming years.

Impact of Empirical Antibiotic Regimens on Mortality in Neutropenic Patients with Bloodstream Infection Presenting with Septic Shock.

We analyzed risk factors for mortality in febrile neutropenic patients with bloodstream infections (BSI) presenting with septic shock and assessed the impact of empirical antibiotic regimens. A multicenter retrospective study (2010 to 2019) of two prospective cohorts compared BSI episodes in patients with or without septic shock. Multivariate analysis was performed to identify independent risk factors for mortality in episodes with septic shock. Of 1,563 patients with BSI, 257 (16%) presented with septic shock. Those patients with septic shock had higher mortality than those without septic shock (55% versus 15%, P < 0.001). Gram-negative bacilli caused 81% of episodes with septic shock, Gram-positive cocci caused 22%, and Candida species caused 5%. Inappropriate empirical antibiotic treatment (IEAT) was administered in 17.5% of septic shock episodes. Empirical ß-lactam combined with other active antibiotics was associated with the lowest mortality observed. When amikacin was the only active antibiotic, mortality was 90%. Addition of empirical specific Gram-positive coverage had no impact on mortality. Mortality was higher when IEAT was administered (76% versus 51%, P = 0.002). Age of >70 years (odds ratio [OR], 2.3; 95% confidence interval [CI], 1.2 to 4.7), IEAT for Candida spp. or Gram-negative bacilli (OR, 3.8; 95% CI, 1.3 to 11.1), acute kidney injury (OR, 2.6; 95% CI, 1.4 to 4.9), and amikacin as the only active antibiotic (OR, 15.2; 95% CI, 1.7 to 134.5) were independent risk factors for mortality, while the combination of ß-lactam and amikacin was protective (OR, 0.32; 95% CI, 0.18 to 0.57). Septic shock in febrile neutropenic patients with BSI is associated with extremely high mortality, especially when IEAT is administered. Combination therapy including an active ß-lactam and amikacin results in the best outcomes.

Impact of ceftazidime/avibactam versus best available therapy on mortality from infections caused by carbapenemase-producing Enterobacterales (CAVICOR study).

BACKGROUND: Infections caused by carbapenemase-producing Enterobacterales (CPE) are not well represented in pivotal trials with ceftazidime/avibactam. The best strategy for the treatment of these infections is unknown. METHODS: We conducted a multicentre retrospective observational study of patients who received ≥48 h of ceftazidime/avibactam or best available therapy (BAT) for documented CPE infections. The primary outcome was 30 day crude mortality. Secondary outcomes were 21 day clinical response and microbiological response. A multivariate logistic regression model was used to identify factors predictive of 30 day crude mortality. A propensity score to receive treatment with ceftazidime/avibactam was used as a covariate in the analysis. RESULTS: The cohort included 339 patients with CPE infections. Ceftazidime/avibactam treatment was used in 189 (55.8%) patients and 150 (44.2%) received BAT at a median of 2 days after diagnosis of infection. In multivariate analysis, ceftazidime/avibactam treatment was associated with survival (OR 0.41, 95% CI 0.20-0.80; P = 0.01), whereas INCREMENT-CPE scores of >7 points (OR 2.57, 95% CI 1.18-1.5.58; P = 0.01) and SOFA score (OR 1.20, 95% CI 1.08-1.34; P = 0.001) were associated with higher mortality. In patients with INCREMENT-CPE scores of >7 points, ceftazidime/avibactam treatment was associated with lower mortality compared with BAT (16/73, 21.9% versus 23/49, 46.9%; P = 0.004). Ceftazidime/avibactam was also an independent factor of 21 day clinical response (OR 2.43, 95% CI 1.16-5.12; P = 0.02) and microbiological eradication (OR 0.40, 95% CI 0.18-0.85; P = 0.02). CONCLUSIONS: Ceftazidime/avibactam is an effective alternative for the treatment of CPE infections, especially in patients with INCREMENT-CPE scores of >7 points. A randomized controlled trial should confirm these findings.

Efficacy of early transfusion of convalescent plasma with high-titer SARS-CoV-2 neutralizing antibodies in hospitalized patients with COVID-19.

BACKGROUND: Despite most controlled trials have shown no measurable benefit of COVID-19 convalescent plasma (CCP) in patients with COVID-19, some studies suggest that early administration of CCP with high-titer anti-SARS-CoV-2 can be beneficial in selected patients. We investigated the efficacy of early administration of high-titer CCP to patients with COVID-19 who required hospitalization, STUDY DESIGN AND METHODS: Observational, propensity score (PS) matched case-control study of COVID-19 patients treated with CCP within 72 h of hospital admission and untreated controls from August 2020 to February 2021. All CCP donations had a Euroimmun anti-SARS-CoV-2 sample-to-cutoff ratio ≥3. PS matching was based on prognostic factors and presented features with high-standardized differences between the treated and control groups. The primary endpoint was mortality within 30 days of diagnosis. RESULTS: A total of 1604 patients were analyzed, 261 of whom received CCP, most (82%) within 24 h after admission. Median age was 67 years (interquartile range: 56-79), and 953 (60%) were men. Presenting factors independently associated with higher 30-day mortality were increased age, cardiac disease, hypoxemic respiratory failure, renal failure, and plasma d-dimer >700 ng/ml. After PS matching, transfusion of CCP was associated with a significant reduction in the 30-day mortality rate (odds ratio [OR]; 0.94, 95% confidence interval [CI]: 0.91-0.98; p = .001) that extended to the 60th day after COVID-19 diagnosis (OR: 0.95; 95% CI: 0.92-0.99; p = .01). CONCLUSION: Our results suggest that CCP can still be helpful in selected patients with COVID-19 and call for further studies before withdrawing CCP from the COVID-19 therapeutic armamentarium.