Emergence of carbapenem-resistant Pseudomonas aeruginosa ST179 producing both IMP-16 and KPC-2: a case study of introduction from Peru to Spain.

We describe four cases of a novel carbapenem-resistant Pseudomonas aeruginosa ST179 clone carrying the blaKPC-2 or blaKPC-35 gene together with blaIMP-16, imported from Peru to Spain and isolated from leukemia patients. All isolates were multidrug-resistant but remained susceptible to fosfomycin, cefiderocol, and colistin. Whole-genome sequencing revealed that blaKPC-2 and blaKPC-35 were located in an IncP6 plasmid, whereas blaIMP-16 was in a chromosomal type 1 integron. This study highlights the global threat of multidrug-resistant P. aeruginosa clones and underscores the importance of monitoring and early detection of emerging resistance mechanisms to guide appropriate treatment strategies. The importation and spread of such clones emphasize the urgent need to implement strict infection control measures to prevent the dissemination of carbapenem-resistant bacteria. IMPORTANCE: This is the first documented case of a Pseudomonas aeruginosa ST179 strain carrying the blaKPC-35 gene, and it represents the first report of a P. aeruginosa co-harboring blaIMP-16 and either blaKPC-2 or blaKPC-35, which wre imported from Peru to Spain, highlighting a threat due to the capacity of spreading carbapenem-resistance via plasmid conjugation.

Real-Life Comparison of Antivirals for SARS-CoV-2 Omicron Infection in Patients With Hematologic Malignancies.

BACKGROUND: We aimed to describe a cohort of hematologic patients with COVID-19 treated with antivirals early. METHODS: Non-interventional chart review study. Comparison of baseline characteristics and outcomes in high-risk hematologic patients treated with remdesivir between December 2021 and April 2022 versus those treated with nirmatrelvir/ritonavir between May and August 2022. RESULTS: Eighty-three patients were analyzed. Forty-two received remdesivir, and 41 nirmatrelvir/ritonavir. Patients with remdesivir were younger, vaccinated with lower number of doses, and received prior corticosteroids less frequently and sotrovimab, hyperimmune plasma and corticosteroids more often. Viral shedding median (IQR) duration was 18 (13-23) and 11 (8-21) days in the remdesivir and nirmatrelvir/ritonavir groups, respectively (p = 0.004). Median (IQR) Ct values before treatment were similar in both groups. Within 5 days of treatment, median (IQR) Ct values were 26 (23-29) and 33 (30-37) in the remdesivir and nirmatrelvir/ritonavir groups, respectively (p < 0.0001). All patients were hospitalized for remdesivir administration and only four (9.8%) in the nirmatrelvir/ritonavir group. The overall outcomes in this cohort of COVID-19 patients with Omicron variant was good, as no patient needed oxygen or ICU admission. One patient in remdesivir group died from septic shock. No severe adverse event was recorded in both treatment groups. CONCLUSIONS: Patients with hematologic malignancies and non-severe COVID-19 who received nirmatrelvir/ritonavir experienced faster decrease in viral load and shorter viral shedding. Furthermore, besides the advantage of oral administration, nirmatrelvir/ritonavir administration reduced the need of hospital admission.

Improving management of febrile neutropenia in oncology patients: the role of artificial intelligence and machine learning.

INTRODUCTION: Artificial intelligence (AI) and machine learning (ML) have the potential to revolutionize the management of febrile neutropenia (FN) and drive progress toward personalized medicine. AREAS COVERED: In this review, we detail how the collection of a large number of high-quality data can be used to conduct precise mathematical studies with ML and AI. We explain the foundations of these techniques, covering the fundamentals of supervised and unsupervised learning, as well as the most important challenges, e.g. data quality, 'black box' model interpretation and overfitting. To conclude, we provide detailed examples of how AI and ML have been used to enhance predictions of chemotherapy-induced FN, detection of bloodstream infections (BSIs) and multidrug-resistant (MDR) bacteria, and anticipation of severe complications and mortality. EXPERT OPINION: There is promising potential of implementing accurate AI and ML models whilst managing FN. However, their integration as viable clinical tools poses challenges, including technical and implementation barriers. Improving global accessibility, fostering interdisciplinary collaboration, and addressing ethical and security considerations are essential. By overcoming these challenges, we could transform personalized care for patients with FN.

Surgical Treatment of Persistent Pseudomonas aeruginosa Bacteraemia After n-Butyl-2-cyanoacrylate for Gastric Bleeding Varices.

n-Butyl-2-cyanoacrylate (NCBA) is an effective therapeutic option for bleeding gastric varices but can sometimes be associated with adverse effects. Persistent bacteraemia is an unusual complication with a high mortality rate. We report the case of a 34-year-old man with history of cirrhosis due to Wilson's disease and severe portal hypertension who was hospitalized as a result of upper gastrointestinal bleeding secondary to fundic varices that were treated with NCBA. Eight weeks after the bleeding episode he was readmitted with a 14-day history of fever and chills. Pseudomonas aeruginosa was isolated from blood cultures. He presented with persistent P. aeruginosa bacteraemia despite correct antibiotic treatment. A PET-CT scan was performed to rule out infection source, and inflammatory changes at the NCBA site plug were found. A presumptive diagnosis of NCBA plug infection was considered. The case was evaluated by multidisciplinary board and indicated liver transplantation as treatment. However, the patient's bacteraemia persisted and therefore a vertical gastrectomy to remove the NCBA plug was performed. P. aeruginosa was also isolated from the plug. The patient was discharged with ceftazidime plus ciprofloxacin to complete 6 weeks after surgery and he remained asymptomatic. Any foreign material such as NCBA is susceptible to being infected and should be considered in patients with persistent breakthrough bloodstream infections. The individualized treatment is recommended in this complex scenario.

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.

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.

Should We Use Rifampicin in Periprosthetic Joint Infections Caused by Staphylococci When the Implant Has Been Exchanged? A Multicenter Observational Cohort Study.

Background: Previous studies demonstrated the efficacy of a rifampicin-based regimen in the treatment of acute staphylococcal periprosthetic joint infections (PJIs) treated with surgical debridement. However, evidence is lacking to support the use of rifampicin in cases where the implant is exchanged during revision. Methods: We included all consecutive cases of staphylococcal PJIs treated from January 2013 to December 2018 with revision surgery in this international, retrospective, multicenter observational cohort study. PJI was defined according to the European Bone and Joint Infection Society diagnostic criteria. A relapse or reinfection during follow-up, the need for antibiotic suppressive therapy, the need for implant removal, and PJI-related death were defined as clinical failure. Cases without reimplantation or with follow-up <12 months were excluded. Results: A total of 375 cases were included in the final analysis, including 124 1-stage exchanges (33.1%) and 251 2-stage exchanges (66.9%). Of those, 101 cases failed (26.9%). There was no statistically significant difference in failure of patients receiving rifampicin (22.5%, 42/187) and those not receiving rifampicin (31.4%, 59/188; P = .051). A subanalysis of chronic PJIs treated by 2-stage exchange arthroplasty demonstrated a lower failure rate in cases treated with rifampicin (15%) compared with the no-rifampicin group (35.5%; P = .005). In this subgroup, the use of rifampicin and an antibiotic holiday of >2 weeks were independent predictors of clinical success (odds ratio [OR], 0.36; 95% CI, 0.15-0.88; and OR, 0.19; 95% CI, 0.04-0.90; respectively). Conclusions: Combination treatment with rifampicin increases treatment success in patients with chronic staphylococcal PJI treated with 2-stage exchange arthroplasty.

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.

Epidemiology and risk factors for recurrence in biliary source bloodstream infection episodes in oncological patients.

We aimed to describe the characteristics and outcomes of biliary source bloodstream infections (BSIs) in oncological patients. Secondarily, we analyzed risk factors for recurrent BSI episodes. All episodes of biliary source BSIs in oncological patients were prospectively collected (2008-2019) and retrospectively analyzed. Logistic regression analyses were performed. A rule to stratify patients into risk groups for recurrent biliary source BSI was conducted. Four hundred biliary source BSIs were documented in 291 oncological patients. The most frequent causative agents were Escherichia coli (42%) and Klebsiella spp. (27%), and 86 (21.5%) episodes were caused by multidrug-resistant Gram-negative bacilli (MDR-GNB). The rates of MDR-GNB increased over time. Overall, 73 patients developed 118 recurrent BSI episodes. Independent risk factors for recurrent BSI episodes were prior antibiotic therapy (OR 3.781, 95% CI 1.906-7.503), biliary prosthesis (OR 2.232, 95% CI 1.157-4.305), prior admission due to suspected biliary source infection (OR 4.409, 95% CI 2.338-8.311), and BSI episode caused by an MDR-GNB (OR 2.857, 95% CI 1.389-5.874). With these variables, a score was generated that predicted recurrent biliary source BSI with an area under the receiver operating characteristic (ROC) curve of 0.819. Inappropriate empirical antibiotic treatment (IEAT) was administered in 23.8% of patients, and 30-d mortality was 19.5%. As a conclusion, biliary source BSI in oncological patients is mainly caused by GNB, with high and increasing MDR rates, frequent IEAT, and high mortality. Recurrent BSI episodes are frequent. A simple score to identify recurrent episodes was developed to potentially establish prophylactic strategies. IMPORTANCE This study shows that biliary source bloodstream infections (BSIs) in oncological patients are mainly caused by Gram-negative bacilli (GNB), with high and increasing rates of multidrug resistance. Importantly, recurrent biliary source BSI episodes were very frequent and associated with delays in chemotherapy, high rates of inappropriate empirical antibiotic therapy, and high 30-d mortality (19.5%). Using the variable independently associated with recurrent BSI episodes, a score was generated that predicted recurrent biliary source BSI with high accuracy. This score could be used to establish prophylactic strategies and lower the risk of relapsing episodes and the associated morbidity and mortality.

Description of reinfection of joint prosthesis after 2-stage replacement (infection of the 2nd stage prosthesis): A multicenter study.

INTRODUCTION: Two-stage exchange is the gold standard in the surgical management of prosthetic joint infection (PJI). However, perioperative reinfections (RePJI) can occur to newly inserted prosthesis, which highlights the importance of an adequate antibiotic prophylaxis, although there is scarce evidence in this field. Our objective was to evaluate the characteristics of RePJI, its prognosis and the antibiotic prophylaxis that is commonly used in second-stage surgery. METHODS: Multicentric retrospective observational study in Spanish hospitals including patients with RePJI between 2009 and 2018. RESULTS: We included 92 patients with RePJI from 12 hospitals. The most frequent isolated microorganism was Staphylococcus epidermidis in 35 cases (38.5%); 61.1% of staphylococci were methiciliin-resistant. In 12 cases (13%), the same microoganism causing the primary PJI was isolated in RePJI. When comparing with the microbiology of primary PJI, there were more cases caused by Gram-negative bacteria (the most frequent was Pseudomonas spp.) and less by Gram-positive bacteria. Failure occured in 69 cases (75%). There were 43 different courses of antibiotic prophylaxis after the second-stage surgery; the most frequent was a unique preoperative cefazolin dose, but most patients received prophylaxis before and after the second-stage surgery (61 cases). CONCLUSIONS: The most frequent microorganisms in RePJI are coagulase-negative staphylococci, although Gram-negative bacteria, especially Pseudomonas spp. are also common. There is a significant heterogeneity in antibiotic prophylaxis for a second-stage surgery. ReIPJI treatment has a high failure rate.

Is an isolated positive sonication fluid culture in revision arthroplasties clinically relevant?

OBJECTIVES: The aim of this study was to investigate the clinical relevance of an isolated positive sonication fluid culture (SFC) in patients who underwent revision surgery of a prosthetic joint. We hypothesized that cases with a positive SFC have a higher rate of infection during follow-up compared with controls with a negative SFC. METHODS: This retrospective multicentre observational study was performed within the European Study Group of Implant-Associated Infections. All patients who underwent revision surgery of a prosthetic joint between 2013 and 2019 and had a minimum follow-up of 1 year were included. Patients with positive tissue cultures or synovial fluid cultures were excluded from the study. RESULTS: A total of 95 cases (positive SFC) and 201 controls (negative SFC) were included. Infection during follow-up occurred in 12 of 95 cases (12.6%) versus 14 of 201 controls (7.0%) (p = 0.125). In all, 79.8% of cases were with treated with antibiotics (76/95). Of the non-treated cases, 89% (17/19) had a positive SFC with a low virulent microorganism. When solely analysing patients who were not treated with antibiotics, 16% of the cases (3/19) had an infection during follow-up versus 5% of the controls (9/173) (p = 0.08). DISCUSSION: Although not statistically significant, infections were almost twice as frequent in patients with an isolated positive SFC. These findings require further exploration in larger trials and to conclude about the potential benefit of antibiotic treatment in these cases.

High Rate of Inappropriate Antibiotics in Patients with Hematologic Malignancies and Pseudomonas aeruginosa Bacteremia following International Guideline Recommendations.

Optimal coverage of Pseudomonas aeruginosa is challenging in febrile neutropenic patients due to a progressive increase in antibiotic resistance worldwide. We aimed to detail current rates of resistance to antibiotics recommended by international guidelines for P. aeruginosa isolated from bloodstream infections (BSI) in patients with hematologic malignancies. Secondarily, we aimed to describe how many patients received inappropriate empirical antibiotic treatment (IEAT) and its impact on mortality. We conducted a retrospective, multicenter cohort study of the last 20 BSI episodes caused by P. aeruginosa in patients with hematologic malignancies from across 14 university hospitals in Spain. Of the 280 patients with hematologic malignancies and BSI caused by P. aeruginosa, 101 (36%) had strains resistant to at least one of the ß-lactam antibiotics recommended in international guidelines, namely, cefepime, piperacillin-tazobactam, and meropenem. Additionally, 21.1% and 11.4% of the strains met criteria for MDR and XDR P. aeruginosa, respectively. Even if international guidelines were followed in most cases, 47 (16.8%) patients received IEAT and 66 (23.6%) received inappropriate ß-lactam empirical antibiotic treatment. Thirty-day mortality was 27.1%. In the multivariate analysis, pulmonary source (OR 2.22, 95% CI 1.14 to 4.34) and IEAT (OR 2.67, 95% CI 1.37 to 5.23) were factors independently associated with increased mortality. We concluded that P. aeruginosa-causing BSI in patients with hematologic malignancies is commonly resistant to antibiotics recommended in international guidelines, which is associated with frequent IEAT and higher mortality. New therapeutic strategies are needed. IMPORTANCE Bloodstream infection (BSI) caused by P. aeruginosa is related with an elevated morbidity and mortality in neutropenic patients. For this reason, optimal antipseudomonal coverage has been the basis of all historical recommendations in the empirical treatment of febrile neutropenia. However, in recent years the emergence of multiple types of antibiotic resistances has posed a challenge in treating infections caused by this microorganism. In our study we postulated that P. aeruginosa-causing BSI in patients with hematologic malignancies is commonly resistant to antibiotics recommended in international guidelines. This observation is associated with frequent IEAT and increased mortality. Consequently, there is a need for a new therapeutic strategy.

Breakthrough invasive fungal infection among patients with haematologic malignancies: A national, prospective, and multicentre study.

OBJECTIVES: We describe the current epidemiology, causes, and outcomes of breakthrough invasive fungal infections (BtIFI) in patients with haematologic malignancies. METHODS: BtIFI in patients with ≥ 7 days of prior antifungals were prospectively diagnosed (36 months across 13 Spanish hospitals) according to revised EORTC/MSG definitions. RESULTS: 121 episodes of BtIFI were documented, of which 41 (33.9%) were proven; 53 (43.8%), probable; and 27 (22.3%), possible. The most frequent prior antifungals included posaconazole (32.2%), echinocandins (28.9%) and fluconazole (24.8%)-mainly for primary prophylaxis (81%). The most common haematologic malignancy was acute leukaemia (64.5%), and 59 (48.8%) patients had undergone a hematopoietic stem-cell transplantation. Invasive aspergillosis, principally caused by non-fumigatus Aspergillus, was the most frequent BtIFI with 55 (45.5%) episodes recorded, followed by candidemia (23, 19%), mucormycosis (7, 5.8%), other moulds (6, 5%) and other yeasts (5, 4.1%). Azole resistance/non-susceptibility was commonly found. Prior antifungal therapy widely determined BtIFI epidemiology. The most common cause of BtIFI in proven and probable cases was the lack of activity of the prior antifungal (63, 67.0%). At diagnosis, antifungal therapy was mostly changed (90.9%), mainly to liposomal amphotericin-B (48.8%). Overall, 100-day mortality was 47.1%; BtIFI was either the cause or an essential contributing factor to death in 61.4% of cases. CONCLUSIONS: BtIFI are mainly caused by non-fumigatus Aspergillus, non-albicans Candida, Mucorales and other rare species of mould and yeast. Prior antifungals determine the epidemiology of BtIFI. The exceedingly high mortality due to BtIFI warrants an aggressive diagnostic approach and early initiation of broad-spectrum antifungals different than those previously used.

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.

Pseudomonas aeruginosa Bloodstream Infection, Resistance, and Mortality: Do Solid Organ Transplant Recipients Do Better or Worse?

BACKGROUND: The prevalence of antimicrobial resistance of Pseudomonas aeruginosa (P. aeruginosa) in solid organ transplant (SOT) recipients is higher than that of the general population. However, the literature supporting this statement is scarce. Identifying patients at risk of carbapenem resistance (CR) is of great importance, as CR strains more often receive inappropriate empiric antibiotic therapy, which is independently associated with mortality in bloodstream infections (BSIs). METHODS: We prospectively recorded data from all consecutive BSIs from January 1991 to July 2019 using a routine purpose-designed surveillance database. The following variables were included: age, sex, type of transplant, use of vascular and urinary catheters, presence of neutropenia, period of diagnosis, treatment with steroids, origin of BSI, source of bacteremia, septic shock, ICU admission, mechanical ventilation, previous antibiotic treatment, treatment of bacteremia, and 30-day all-cause mortality. RESULTS: We identified 2057 episodes of P. aeruginosa BSI. Of these, 265 (13%) episodes corresponded to SOT recipients (130 kidney transplants, 105 liver, 9 hearts, and 21 kidney-pancreas). Hematologic malignancy [OR 2.71 (95% CI 1.33-5.51), p = 0.006] and prior carbapenem therapy [OR 2.37 (95% CI 1.46-3.86), p < 0.001] were associated with a higher risk of having a CR P. aeruginosa BSI. Age [OR 1.03 (95% CI 1.02-1.04) p < 0.001], urinary catheter [OR 2.05 (95% CI 0.37-3.06), p < 0.001], shock at onset [OR 6.57 (95% CI 4.54-9.51) p < 0.001], high-risk source [OR 4.96 (95% CI 3.32-7.43) p < 0.001], and bacteremia caused by CR strains [OR 1.53 (95% CI 1.01-2.29) p = 0.036] were associated with increased mortality. Correct empirical therapy was protective [OR 0.52 (95% CI 0.35-0.75) p = 0.001]. Mortality at 30 days was higher in non-SOT patients (21% vs. 13%, p = 0.002). SOT was not associated with a higher risk of having a CR P. aeruginosa BSI or higher mortality. CONCLUSIONS: In our cohort of 2057 patients with P. aeruginosa BSIs, hematologic malignancies and previous carbapenem therapy were independently associated with a risk of presenting CR P. aeruginosa BSI. Age, urinary catheter, high-risk source, bacteremia caused by carbapenem-resistant strains, and severity of the infection were independently associated with mortality, whereas correct empirical therapy was a protective factor. An increasing trend in the resistance of P. aeruginosa was found, with >30% of the isolates being resistant to carbapenems in the last period. SOT was not associated with a higher risk of carbapenem-resistant BSIs or higher mortality.

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.

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.

Genetic Study of SARS-CoV-2 Non Structural Protein 12 in COVID-19 Patients Non Responders to Remdesivir.

Remdesivir (RDV) was the first antiviral drug approved by the FDA to treat severe coronavirus disease-2019 (COVID-19) patients. RDV inhibits SARS-CoV-2 replication by stalling the non structural protein 12 (nsp12) subunit of the RNA-dependent RNA polymerase (RdRp). No evidence of global widespread RDV-resistance mutations has been reported, however, defining genetic pathways to RDV resistance and determining emergent mutations prior and subsequent antiviral therapy in clinical settings is necessary. This study identified 57/149 (38.3%) patients who did not respond to one course (5-days) (n = 36/111, 32.4%) or prolonged (5 to 20 days) (n = 21/38, 55.3%) RDV therapy by subgenomic RNA detection. Genetic variants in the nsp12 gene were detected in 29/49 (59.2%) non responder patients by Illumina sequencing, including the de novo E83D mutation that emerged in an immunosuppressed patient after receiving 10 + 8 days of RDV, and the L838I detected at baseline and/or after prolonged RDV treatment in 9/49 (18.4%) non responder subjects. Although 3D protein modeling predicted no interference with RDV, the amino acid substitutions detected in the nsp12 involved changes on the electrostatic outer surface and in secondary structures that may alter antiviral response. It is important for health surveillance to study potential mutations associated with drug resistance as well as the benefit of RDV retreatment, especially in immunosuppressed patients and in those with persistent replication. IMPORTANCE This study provides clinical and microbiologic data of an extended population of hospitalized patients for COVID-19 pneumonia who experienced treatment failure, detected by the presence of subgenomic RNA (sgRNA). The genetic variants found in the nsp12 pharmacological target of RDV bring into focus the importance of monitoring emergent mutations, one of the objectives of the World Health Organization (WHO) for health surveillance. These mutations become even more crucial as RDV keeps being prescribed and new molecules are being repurposed for the treatment of COVID-19. The present article offers new perspectives for the clinical management of non responder patients treated and retreated with RDV and emphasizes the need of further research of the benefit of combinatorial therapies and RDV retreatment, especially in immunosuppressed patients with persistent replication after therapy.

Role of joint aspiration before re-implantation in patients with a cement spacer in place.

BACKGROUND: The usefulness of a mandatory joint aspiration before re-implantation in patients with a cement spacer already in place is unclear. AIM: To evaluate the role of culturing synovial fluid obtained by joint aspiration before re-implantation in patients who underwent a two-stage septic revision. METHODS: A retrospective observational study was conducted, including patients that underwent a two-stage septic revision (hip or knee) from 2010 to 2017. After the first stage revision and according to intraoperative culture results, all patients were treated with an antibiotic protocol for 6-8 wk. Following 2 wk without antibiotics, a culture of synovial fluid was obtained. The results of these cultures were recorded and compared with cultures obtained during re-implantation surgery. RESULTS: Forty-one patients (20 hip and 21 knee spacers) were included in the final analysis. In 39 cases, the culture of synovial fluid was negative, while in the remaining 2 cases (knee spacers) no analysis was possible due to dry tap. In 5 of the patients, two or more intraoperative cultures taken during the re-implantation surgery were positive. CONCLUSION: We found no evidence to support mandatory joint aspiration before re-implantation in patients with a cement spacer in place.