Serious Infections In Patients Research Articles

The saga of PI3K inhibitors in haematological malignancies: survival is the ultimate safety endpoint.

The saga of PI3K inhibitors in haematological malignancies: survival is the ultimate safety endpoint.

Pseudomonas aeruginosa Pneumonia: Evolution of Antimicrobial Resistance and Implications for Therapy.

Pseudomonas aeruginosa (PA), a non-lactose-fermenting gram-negative bacillus, is a common cause of nosocomial infections in critically ill or debilitated patients, particularly ventilator-associated pneumonia (VAP), and infections of urinary tract, intra-abdominal, wounds, skin/soft tissue, and bloodstream. PA rarely affects healthy individuals, but may cause serious infections in patients with chronic structural lung disease, comorbidities, advanced age, impaired immune defenses, or with medical devices (e.g., urinary or intravascular catheters, foreign bodies). Treatment of pseudomonal infections is difficult, as PA is intrinsically resistant to multiple antimicrobials, and may acquire new resistance determinants even while on antimicrobial therapy. Mortality associated with pseudomonal VAP or bacteremias is high (> 35%) and optimal therapy is controversial. Over the past three decades, antimicrobial resistance (AMR) among PA has escalated globally, via dissemination of several international multidrug resistant "epidemic" clones. We discuss the importance of PA as a cause of pneumonia including health care-associated pneumonia, hospital-acquired pneumonia, VAP, the emergence of AMR to this pathogen, and approaches to therapy (both empirical and definitive).

Chronic Indolent Community-acquired Pneumonia due to Pseudomonas Infection in an Immunocompetent Patient- A Case Report

Pseudomonas is an uncommon cause of community-acquired pneumonia in immunocompetent patients. It is an opportunistic pathogen resulting in serious infection in patients who are hospitalised, mechanically ventilated, or immunocompromised. A 47-year-old male, forest worker without any co-morbidities presented with a history of chronic cough, fever, and shortness of breath complicated with pseudohemoptysis for 45 days. This patient was admitted and treated as a lower respiratory tract infection. Work-up for tuberculosis, invasive fungal balls, was negative but sputum culture revealed Pseudomonas aeruginosa growth. This case report demonstrates a rare Pseudomonas infection which can also cause chronic indolent respiratory illness in immunocompetent.

Infectious complications of immune checkpoint inhibitors in solid organ malignancies.

BackgroundImmune checkpoint inhibitors (ICIs) are targeted cancer therapies regarded to have less toxicity than chemotherapy. Immune‐related adverse events (irAEs) of ICIs are well described in the literature but limited data exist on their infectious complications. The objective is to describe the spectrum and risk factors for developing serious infections in patients receiving ICIs.MethodsRetrospective review of patients with melanoma, renal cell carcinoma, or nonsmall‐cell lung cancer on nivolumab, pembrolizumab, and/or ipilimumab from January 1, 2017 to November 30, 2017. Exclusion: receipt of less than two ICI doses or history of other malignancy. Characteristics: age, sex, prior chemotherapy, steroid use, and temozolomide or infliximab use. Data identified from microbiology, radiography, serology, or physician note documentation. Serious infection is defined as infections requiring hospitalization and/or IV antibiotics from initiation of ICI until the end of the study period.ResultsOne hundred and eleven pts received ICIs. Suspected or confirmed bacterial infections occurred in 24% (27/111) with 8% (9/111) confirmed bacterial cultures. The overall serious infection rate was 14% (16/111) with 25% (4/16) confirmed bacterial cultures. Suspected or confirmed infection sites: genitourinary 20% (22/111), pneumonia 5% (7/111), skin/soft tissue 7% (8/111). Noninfectious pneumonitis (NIP) occurred in 5% (5/111). No association regarding the risk of infection between the type of malignancy and ICI used. Steroid use was the only risk factor significantly associated with serious infection: 12/16 (75%) on steroids versus 27/95 (28.4%) without steroid use (p = 0.0003).ConclusionThe rate of serious infection with ICI was higher in our study compared with previous reports of pts treated with melanoma. Infectious complications are encountered with ICIs and correlate with steroid use.

Serious infections in patients with rheumatoid arthritis and psoriatic arthritis treated with tumour necrosis factor inhibitors: data from register linkage of the NOR-DMARD study

ObjectivesTo estimate the incidence of serious infections (SIs) in patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA) treated with tumour necrosis factor inhibitor (TNFi), and compare risk of SIs...

Epidemiology, Time Trends, and Outcomes of Serious Infections in Patients With Vasculitis: A Nineteen-Year National Study.

To examine the epidemiology, time trends, and outcomes and types of serious infections in people with vasculitis in the US. We identified people with vasculitis who were hospitalized with a primary diagnosis of pneumonia, sepsis/bacteremia, urinary tract infection (UTI), skin and soft tissue infections, or opportunistic infections in the 1998-2016 US National Inpatient Sample. We used adjusted logistic regression to examine the predictors of a hospital stay >3 days, total hospital charges greater than the median, discharge to a non-home setting, and in-hospital mortality. We noted 111,345 serious infections in patients with vasculitis (14% of all vasculitis hospitalizations). Among the patients, the mean age was 67.3 years, the Deyo-Charlson comorbidity index score was ≥2 in 54%, 37% were male, and 67% were White. The serious infection hospitalization rate per 100,000 US National Inpatient Sample claims in 1998-2000 versus 2015-2016 (and rates of increase) in patients with vasculitis was as follows: overall, 12.14 versus 25.15 (2.1-fold); opportunistic infections, 0.78 versus 0.83 (1.1-fold); skin and soft tissue infections, 1.38 versus 2.52 (1.8-fold); UTI, 0.35 versus 1.48 (4.2-fold); pneumonia, 7.10 versus 6.23 (0.9-fold); and sepsis, 2.53 versus 14.10 (5.6-fold). Pneumonia was the most common serious infection in 1998-2000 (58%) versus sepsis in 2015-2016 (56%). Sepsis, older age, Deyo-Charlson comorbidity index score of ≥2, urban hospital, or medium/large hospital (by number of beds) were associated with higher health care utilization and in-hospital mortality rates; Northeast region and Medicare and Medicaid payer type were associated with higher rates of health care utilization. Serious infection hospitalization rates are increasing in patients with vasculitis except among those with pneumonia. Sepsis was the most common serious infection in 2015-2016. Several patient and hospital factors are associated with health care utilization and mortality in serious infection hospitalization in vasculitis.

Incidence and associated risk factors for invasive fungal infections and other serious infections in patients on ibrutinib

BackgroundIbrutinib is a small molecule tyrosine kinase inhibitor that blocks the activity of B cells and other immune effectors and is used in a variety of hematologic malignancies. There have been numerous reports of increased frequency of serious infections including invasive fungal infections (IFI) in patients on ibrutinib. MethodsDemographic and clinical features of all patients receiving ibrutinib at a single tertiary care center were collected from electronic medical records. Univariate and multivariate statistical analyses were performed to find out the factors associated with infection. ResultsA total of 244 patients received ibrutinib for hematologic malignancies, of which 44 (18.0%) experienced ≥ 1 serious infection including 5 (2.0%) with IFI (1 pulmonary cryptococcosis, 4 pulmonary aspergillosis), 39 (16.0%) with bacterial infections and 8 (3.3%) with viral infections. Ten patients (4.1%) experienced multiple infections or co-infections while on ibrutinib and 10 (4.1%) expired or were transferred to hospice as a result of infection. In multivariate analysis risk factors that were less common in uninfected versus infected patients included advanced age (73 years vs. 77 years), Eastern Cooperative Oncologic Grade (ECOG) performance score ≥ 2 (6.5% vs. 31.8%) and concurrent use of steroids (4.5% vs. 20.5%) or other cytotoxic agents (0% vs. 4.6%). ConclusionsThere was a high rate of serious infection but relatively few IFI in patients receiving ibrutinib. Most patients who developed serious infections while on ibrutinib had additional predisposing risk factors including concurrent use of steroids or other cytotoxic agents, advanced age and frailty.

Association Between Biologics Use and Risk of Serious Infection in Patients With Psoriasis

Biologics and targeted therapies, such as apremilast, are efficient treatments to manage moderate to severe psoriasis. More information about the risk of serious infection is needed for the newest treatment options in a real-world setting. To assess the risk of serious infection among biologics and apremilast used to treat psoriasis, with etanercept as the comparator. This nationwide cohort study from France involved data from the National Health Data System covering approximately 99% of the French population. All adults with psoriasis, defined as receiving at least 2 prescriptions of a topical vitamin D derivative within a 2-year period, registered in the database between January 1, 2008, and May 31, 2019, were eligible. The study population included those who were new users of biologic agents or apremilast (ie, without any prescriptions of a biologic or apremilast during the previous year). Patients with HIV infection or a history of cancer, transplant, or serious infection were excluded. End of follow-up was January 31, 2020. The primary end point was a serious infection in a time-to-event analysis using propensity score-weighted Cox proportional hazards regression models, estimating weighted hazard ratios (wHRs) and 95% CIs. A total of 44 239 new users of biologic treatment were identified (mean [SD] age, 48.4 [13.8] years; 22 866 [51.7%] men; median follow-up, 12 months [interquartile range, 7-24 months]). A total of 29 618 (66.9%) were prescribed a tumor necrosis factor inhibitor first, 6658 (15.0%) an interleukin (IL) 12/23 inhibitor, 4093 (9.3%) an IL-17 inhibitor, 526 (1.2%) an IL-23 inhibitor, and 3344 (7.6%) apremilast. The total number of serious infections was 1656, and the overall crude incidence rate was 25.0 (95% CI, 23.8-26.2) per 1000 person-years. The most frequent serious infections were gastrointestinal infections (645 patients [38.9%]). After adjusting for time-dependent covariables, risk of serious infections was higher for new users of adalimumab (wHR, 1.22; 95% CI, 1.07-1.38) or infliximab (wHR, 1.79; 95% CI 1.49-2.16) vs etanercept, whereas ustekinumab was associated with a lower risk of having a serious infection (wHR, 0.79; 95% CI, 0.67-0.94). Risk of serious infections was not increased for new users of IL-17 and the IL-23 inhibitor guselkumab or apremilast vs etanercept. Risk of serious infections was increased with concomitant nonsteroidal anti-inflammatory drugs or systemic corticosteroids. In this cohort study of individuals with moderate to severe psoriasis, risk of serious infections was increased in new users of infliximab and adalimumab vs etanercept, whereas ustekinumab users had lower risk of having a serious infection but not new users of IL-17 and IL-23 inhibitors or apremilast. Other observational studies are needed to confirm results for the most recent drugs.

High-dose corticosteroid use and risk of hospitalization for infection in patients treated with immune checkpoint inhibitors--A nationwide register-based cohort study.

High‐dose corticosteroids have been associated with increased risk of serious infection in patients with metastatic melanoma treated with immune checkpoint inhibitors targeting cytotoxic T‐lymphocyte antigen 4. This potential association needs to be examined further among patients with other cancer types and for other immune checkpoint inhibitors. We examined whether receipt of high‐dose corticosteroids was associated with increased rates of hospitalization for infection among 981 Danish renal, urothelial, and lung cancer patients followed from first administration of programmed death receptor 1 (PD‐1)/programmed death ligand 1 (PD‐L1) immune checkpoint inhibitors. Our cohort analysis was based on the information from national medical registries. During follow‐up, 522 patients (53.2%) initiated treatment with high‐dose corticosteroids and 317 patients (32.3%) experienced at least one hospitalization for infection. In analyses adjusted for age, sex, and previous use of chemotherapy/targeted therapy, initiation of high‐dose systemic corticosteroids was associated with increased rate of hospitalization for infections (hazard ratio (HR) = 2.96, 95% confidence interval (CI) = 2.41–3.65) even in patients not receiving any chemotherapy/targeted therapy (HR = 3.66, 95% CI = 2.25–5.96). Our findings showed that high‐dose corticosteroid initiation is associated with hospitalization for infection in patients treated with PD‐1/PD‐L1 immune checkpoint inhibitors. Clinicians and patients should be aware of this risk of infection when initiating treatment with high‐dose corticosteroids.

Serious Infections in Patients With Gout in the US: ANational Study of Incidence, Time Trends, and Outcomes.

To study the epidemiology of serious infections in patients hospitalized with gout. We identified patients with gout hospitalized with a primary diagnosis of pneumonia, sepsis/bacteremia, urinary tract infection (UTI), skin and soft tissue infections (SSTIs), or opportunistic infections (OIs) in a US National Inpatient Sample from 1998 to 2016 and examined factors associated with utilization and mortality. We noted 1,140,085 hospitalizations of patients with serious infections and gout (11% of all hospitalizations of patients with gout; 1998-2000 [8.9%], 2015-2016 [14.5%]). Compared to patients without gout, patients with gout hospitalized with serious infections were older (median age 65 versus 74 years), more of them had a Charlson-Deyo comorbidity index score ≥2 (42% versus 65%), and fewer were female (53% versus 35%) or non-White (40% versus 35%), respectively. The most common infection was pneumonia (52%) in 1998-2000 and sepsis (52%) in 2015-2016. Median hospital charges and hospital stays were higher for patients with sepsis and OIs in 2015-2016 ($41,000-$42,000; 5.1-5.5 days) versus those with UTI, pneumonia, or SSTIs ($15,000-$17,000; 3.0-3.9 days). Compared to patients with sepsis, the multivariable-adjusted odds of health care utilization and in-hospital mortality were significantly lower for patients with UTI, SSTIs, and pneumonia, and non-home discharge or in-hospital mortality were lower in patients with OIs. Among patients hospitalized with infections, older age, Medicaid coverage, a higher Charlson-Deyo comorbidity index score, Black race, and Northeast and nonrural hospital location were associated with significantly higher health care utilization and mortality, while female sex, Medicare insurance, and lower income were associated with higher utilization. Given an increasing rate of serious infections, especially sepsis and pneumonia, in individuals with gout, development of effective interventions targeting factors associated with health care utilization and mortality will improve outcomes and reduce burden.

Evaluation of Bundled Interventions for Patients With Opioid Use Disorder Experiencing Homelessness Receiving Extended Antibiotics for Severe Infection.

Hospitalizations for serious infections in patients with opioid use disorder (OUD) experiencing homelessness are common. Patients receiving 4 interventions (infectious disease consultation, addiction consultation, case management, and medications for OUD [MOUD]) had higher odds of clinical cure (unadjusted odds ratio [OR], 3.15; P = .03; adjusted OR, 3.03; P = .049) and successful retention in addiction care at 30 days (unadjusted OR, 5.46; P = .01; adjusted OR, 6.36; P = .003).

AB0153 REAL LIFE SEVERE INFECTIONS IN PATIENTS WITH RHEUMATOID ARTHRITIS ON TREATMENT WITH BIOLOGICAL THERAPY AND JAKI

Background:Infections are one of the main complications among patients with rheumatoid arthritis (RA) with immunosuppressive treatment. The differences between treatments and the influence of other factors is unclear.Objectives:To evaluate the frequency and factors associated with serious infections in patients with RA treated with biological therapy (BT) and JAKi and the differences between treatments.Methods:Descriptive and retrospective study (January 2015-December 2020) of patients with RA treated with BT (TNFi, non-TNFi) and JAKi (tofacitinib, bariticinib, upadacitinib) in a single center. Severe infection was considered a life-threatening infection or one that required hospitalization and intravenous treatment. Epidemiological variables, clinical characteristics, Charlson comorbidity index, type of BT or JAKi and concomitant treatment were collected.For the analysis frequencies and percentages are used in qualitative variables and mean ± SD in the quantitative ones. Statistical analysis was performed with IBM SPSS v 23.Results:We registered 257 patients (84.4% women) mean aged 56.1±13.4 years. RF was positive in 86.8%, anti-CCP in 75.9% and 16.5 % presented extra-articular manifestations (nodulosis 9.7%, intersticial lung disease 4.3%, other 1.5%). At the start of the study, 157 (61.1%) patients were with TNFi, 80 (31.1%) with non-TNFi and 20 (7.8%) with JAKi. Conventional synthetic DMARDs (csDMARDs) were used in 86% of cases (methotrexate 71.1%, leflunomide 21.2%, other 7.7%).During the study, 162 (63%) patients continued with the same treatment and in 95 (37%) it was changed at least once. 3 patients discontinued the treatment. At the end of the study, 126 (49%) patients were with TNFi, 81 (31.5%) with non-TNFi and 47 (18.3%) with JAKi.Severe infection was developed in 28 (10.9%) patients (13 respiratory, 5 urinary, 5 cellulitis, 4 sepsis, 1 osteomyelitis) among them 2 patients had severe infection and herpes zoster at the same time and 3 developed a second infection. 14 (50%) patients were with TNFi, 8 (28.6%) with non-TNFi and 6 (21.4%) with JAKi. Table 1The inflammatory activity of RA was mild at the time of infection (DAS28: 2.6±1.1). The median time until infection was: TNFi 45.25 [4.9-202.3] months, non- TNFi 19.14 [4.9-72.5] months and JAKi 17.63 [1.1-29.2] months.The Charlson index, concomitant use of glucocorticoids (GCC) at lower doses than 10mg/d, chronic obstructive pulmonary disease (COPD), diabetes (DM), moderate-severe renal insufficiency, congestive heart failure (CHF) and peripheral vascular disease were statistically significantly associated with infection. Table 1.TABLE 1.CHARACTERISTICS OF PATIENTS WITH INFECTION VS. WITHOUT INFECTIONINFECTIONYES n:28NO n:229pFEMALE, n (%)22 (78.6)195 (85.2)0.406AGE years, (mean±SD)57.7 ± 13.955.9 ± 13.40.507AGE ≥ 65 n (%)10 (35.7)68 (29.7)0.513RF +, n (%)25 (89.3)198 (86.5)0.677ANTI-CCP +, n (%)21 (75)174 (75.1)1.00ILD, n (%)1 (3.5)10 (4.3)0.809ALCOHOL, n (%)3 (10.7)17 (7.4)0.465SMOKER, n (%)10 (35.7)60 (26.2)0.244COPD, n (%)7 (25)24 (10.5)0.026*DM, n (%)7 (25)19 (8.3)0.013*CHF, n (%)4 (14.3)1 (0.4)0.001*RENAL INSUFFICIENCY, n (%)3 (10.7)2 (0.9)0.010*PERIPHERAL VASCULAR DISEASE, n (%)9 (32.1)22 (9.6)0.002*CHARLSON INDEX (mean±SD)1.64 ± 2.10.63 ± 1.20.001*TNFi, n (%) NON-TNFi n (%) JAKi, n (%)14 (50)112 (48.9)8 (28.6)73 (31.9)6 (21.4)41 (17.9)csDMARDs, n (%)22 (78.6)159 (69.4)0.317GCC dose <10mg/d, n (%)17 (60.8)111 (48.5)0.007*Conclusion:In our study, 10.9% of patients with RA treated with BT or JAKi developed severe infection during 5 years of follow-up. Concomitant GCC therapy and comorbidity increased the risk of presenting this complication.Disclosure of Interests:None declared

The Risk of Infections Associated With JAK Inhibitors in Rheumatoid Arthritis: A Systematic Review and Network Meta-analysis.

The Janus kinases (JAKs) are cytoplasmic tyrosine kinases associated with membrane cytokine receptors that mediate signaling of multiple cytokines and growth factors, contributing to the pathogenesis of multiple autoimmune disorders. The JAK inhibitors are a new class of targeted therapies with proven efficacy in treating rheumatoid arthritis but are associated with an increased risk of infections. This study is aimed at comparing the relative safety of the different JAK inhibitors with regard to the risk of serious infections in patients with rheumatoid arthritis. PubMed, EMBASE, Cochrane Library, and clinicaltrials.gov were searched to identify randomized controlled trials evaluating the efficacy and safety of JAK inhibitors in patients with rheumatoid arthritis. The outcomes assessed were the risk of total and serious infections, tuberculosis, and herpes zoster. Sensitivity analysis disaggregated the results according to background therapy and licensed doses of JAK inhibitors. Thirty-seven randomized controlled trials that were included met the inclusion criteria. Compared with filgotinib, adalimumab (4.81; 95% confidence interval [CI], 1.39-16.66), etanercept (6.04; 95% CI, 1.79-20.37), peficitinib (7.56; 95% CI, 1.63-35.12), tofacitinib (4.29; 95% CI, 1.43-12.88), and upadacitinib (4.35; 95% CI, 1.46-13.00) have an increased risk of herpes zoster infection. Risk differences between the drugs became statistically nonsignificant when the sensitivity analysis was conducted. The risk of infections seems to be similar among the currently approved JAK inhibitor drugs. Although the initial results suggested that filgotinib could have a reduced risk of herpes zoster, the sensitivity analyses did not support those findings.

Comparative Risk of Serious Infections With Tumor Necrosis Factor α Antagonists vs Vedolizumab in Patients With Inflammatory Bowel Diseases

We conducted a retrospective cohort study comparing the risk of serious infections between patients treated with tumor necrosis factor-a (TNFa) antagonists vs. vedolizumab in patients with inflammatory bowel diseases (IBD). Using an administrative claims database, we identified patients with IBD who were new-users of either TNFa antagonists or vedolizumab between 2014-2018 and had insurance coverage for at least 1y before and after treatment initiation. We compared the risk of serious infections (infections requiring hospitalization) between patients treated with vedolizumab or TNFa antagonists using marginal structural Cox proportional hazard models adjusted for baseline disease characteristics, healthcare utilization, comorbidities, and time-varying use of corticosteroids, immunomodulators and opiates. We included 4881 patients treated with TNFa antagonists (age, 41 ± 15y, 60% with Crohn's disease [CD]) of whom 434 developed serious infections over 5786 person-year [PY] follow-up, and 1106 patients treated with vedolizumab (age, 44 ± 16y, 39% with CD) of whom 86 developed serious infections over 1040-PY follow-up. Vedolizumab was associated with 46% lower risk of serious infections as compared with TNFa antagonists in patients with ulcerative colitis (HR,0.54 [95% CI,0.35-0.83), but no significant differences were observed in patients with CD (HR,1.30 [0.80-2.11]). Vedolizumab was associated with lower risk of extra-intestinal serious infections in patients with UC, but higher risk of gastrointestinal serious infections in patients with CD. In an observational study of patients with IBD, vedolizumab was associated with lower risk of serious infections as compared with TNFa antagonists, in patients with UC, but not in patients with CD.

Detection of ERG11 Overexpression in Candida albicans isolates from environmental sources and clinical isolates treated with inhibitory and subinhibitory concentrations of fluconazole.

Candida species can cause serious infection in patients with changes in defence mechanisms and/or when anatomical barriers are compromised. Mutations and overexpression in the ERG11 gene are described as molecular mechanisms of azole resistance. Information is limited on these mechanisms in the presence of subinhibitory concentrations of fluconazole. This study aimed to evaluate the expression of ERG11 gene from Candida albicans isolates, from clinical and hospital environments, in the absence and presence of inhibitory and subinhibitory concentrations of fluconazole. The American Type Culture Collection 10231 strain, five clinical isolates and three isolates from hospital environment colonisation were exposed to inhibitory and subinhibitory concentrations of fluconazole. Susceptibility tests were performed according to EUCAST 7.1 guidelines, and the relative expression analysis of ERG11 was performed by qPCR. Differences in response to fluconazole concentrations were observed, with the exception only one clinical isolate when treated with 1/4 of the FLU-minimum inhibitory concentration (MIC). All the other isolates, regardless of the isolation source, had an increase in expression. The overexpression occurred in a very broad range, from 1.086 to 126.105 times. In general, treatment with the highest dose of fluconazole (MIC) was the one that most influenced the ERG11 expression, followed by treatments with 1/2 and 1/4 MIC. The increased expression of ERG11 by Calbicans in the presence of different concentrations of fluconazole is relevant, raising concerns in the care and cleaning of the hospital environment and the prophylactic use of fluconazole that could lead to the selection of potential azole-resistant isolates.

Dupilumab and the risk of conjunctivitis and serious infection in patients with atopic dermatitis: A propensity score–matched cohort study

Dupilumab is an effective treatment for moderate to severe atopic dermatitis (AD) with limited safety data in clinical practice. To assess the 6-month risk of conjunctivitis and serious infections in patients with AD who initiated dupilumab. In a cohort study using US claims data, we compared the risk of conjunctivitis and serious infections in patients with AD who initiated either dupilumab, methotrexate (MTX), cyclosporine, or mycophenolate. Relative risks (RRs) were computed after 1:1 propensity score matching. We identified 1775 dupilumab, 1034 MTX, 186 cyclosporine, and 257 mycophenolate users. The 6-month risk for any conjunctivitis was 6.5% for dupilumab, 3.3% for MTX, 4.8% for cyclosporine, and 1.2% for mycophenolate initiators. After PS matching, the RR of any conjunctivitis was increased in dupilumab users versus MTX (RR, 2.45; 95% confidence interval [CI], 1.47-4.08), versus cyclosporine (RR, 1.56; 95% CI, 0.69-3.50), and versus mycophenolate (RR, 7.00; 95% CI, 2.12-23.2). The risk of serious infection was 0.6% in dupilumab and 1.0% in MTX initiators (RR, 0.90; 95% CI, 0.37-2.20). Analyses were based on few events, and differential surveillance is a concern. Although dupilumab shows a low risk of serious infections, it is associated with a clinically meaningful increase in conjunctivitis that needs to be managed in practice.

Identification and validation of a novel anti-virulent that binds to pyoverdine and inhibits its function

ABSTRACT Pseudomonas aeruginosa: causes serious infections in patients with compromised immune systems and exhibits resistance to multiple antibiotics. The rising threat of antimicrobial resistance means that new methods are necessary for treating microbial infections. We conducted a high-throughput screen for compounds that can quench the innate fluorescence of the chromophore region of the P. aeruginosa siderophore pyoverdine, a key virulence factor. Several hits were identified that effectively quench pyoverdine fluorescence, and two compounds considerably improved the survival of Caenorhabditis elegans when worms were challenged with P. aeruginosa. Commercially available analogs of the best hit, PQ3, were tested for their ability to rescue C. elegans from P. aeruginosa and to interact with pyoverdine via fluorescence and solution NMR spectroscopy. 1H-15N and 1H-13C HSQC NMR were used to identify the binding site of PQ3c. The structure model of pyoverdine in complex with PQ3c was obtained using molecular docking and molecular dynamics simulations. PQ3c occupied a shallow groove on pyoverdine formed by the chromophore and N-terminal residues of the peptide chain. Electrostatic interactions and π-orbital stacking drove stabilization of this binding. PQ3c may serve as a scaffold for the development of pyoverdine inhibitors with higher potency and specificity. The discovery of a small-molecule binding site on apo-pyoverdine with functional significance provides a new direction in the search of therapeutically effective reagent to treat P. aeruginosa infections. Abbreviations: NMR: nuclear magnetic resonance; SAR: structure–activity relationship; MD: molecular dynamics; RMSF: root-mean-square fluctuation; HSQC: heteronuclear single quantum correlation; DMSO: dimethyl sulfoxide; Δδavg: average amide chemical shift change; DSS: 2,2-dimethyl-2-silapentane-5-sulfonate; RMSD: root-mean-square deviation; LJ-SR: Lennard–Jones short-range; Coul-SR: Coulombic short-range; FRET: fluorescence resonance energy transfer

Multicentre retrospective cohort study assessing the incidence of serious infections in patients with lupus nephritis, compared with non-renal systemic lupus erythematosus.

ObjectivesThe incidence of serious infections is poorly defined in patients with lupus nephritis (LN). It is also unclear if LN influences risk of serious infections in a longitudinal analysis. The aim of this study was to determine the incidence of serious infections in patients with SLE and LN, compared with patients with SLE without LN.MethodsA multicentre retrospective cohort study was conducted. Patients with LN identified at two tertiary centres were matched where possible with age and gender-matched patients with SLE without LN.Any infection requiring inpatient admission, occurring in the 6 months following index clinical visit, was considered serious. Cox regression was employed to investigate the association between risk of serious infection and LN status, and other relevant covariates.ResultsA total of 173 patients were included within the analysis (n=87 LN, n=86 SLE only). A total of 9.2% (n=8) of patients with LN experienced at least one serious infection within the study period, compared with 5.8% (n=5) of patients without LN, equivalent to 19.5 and 12.0 infections per 100 patient-years with and without LN, respectively. Univariable and multivariable analyses found no significant increased risk of serious infection in patients with LN versus controls (HR 1.61; 95% CI 0.53 to 4.92 and adjusted HR (aHR) 0.91; 95% CI 0.27 to 3.06, respectively). Increased prednisone dose and modified SLE comorbidity index were strongly associated with serious infection (aHR (per 5 mg) 1.21; 95% CI 1.07 to 1.37; p=0.003 and aHR 1.13; 95% CI 1.02 to 1.25; p=0.018, respectively).ConclusionsIn this cohort, adjusting for cofactors, the presence of LN alone does not appear to increase the risk of serious infections compared with patients with SLE without LN. However, increased prednisone dose at baseline visit and increasing comorbidity were independently associated with the incidence of serious infection.

In silico integrative analysis predicts relevant properties of exotoxin-derived peptides for the design of vaccines against Pseudomonas aeruginosa

Pseudomonas aeruginosa (PA) is an opportunistic human pathogen responsible for causing serious infections in patients with cystic fibrosis. Infections caused by PA are difficult to treat and eradicate due to intrinsic and added resistance to antibiotic therapy. Therefore, it is necessary to establish effective prevention strategies against this infectious agent. In this study, a combination of immunoinformatic tools was applied to predict immunogenic and immunodominant regions in the structure of exotoxins commonly secreted as virulence factors in PA infection (ExoA, ExoS, ExoT, ExoU and ExoY). The peptides derived from exotoxins were evaluated for the potential affinity for human leukocyte antigen (HLA) I and HLA-II molecules, antigenicity score and toxicity profile. From an initial screening of 941 peptides, 13 (1.38%) were successful in all analyzes. The peptides with relevant immunogenic properties were mainly those derived from Exo A (10 / 76.9%). All peptides selected in the last analysis present a high population coverage rate based on the interaction of HLA alleles (95.36 ± 7.83%). Therefore, the peptides characterized in this study are recommended for in vitro and in vivo studies and can provide the basis for the rational design of a vaccine against PA.

Malignancy and infection risk during adalimumab therapy in hidradenitis suppurativa.

The association of adalimumab therapy with malignancy and infection is established in other inflammatory diseases; however, rates of hidradenitis suppurativa (HS) are based on case reports or retrospective healthcare data and the effect of adalimumab therapy on these rates is unknown. Previously reported rates in the PIONEER OLE Phase 3 study reported on rates only in a subpopulation of 88 participants rather than the entire cohort. To quantify rates of malignancy and serious infection in all patients with HS treated with adalimumab 40mg weekly. Reanalysis was undertaken of individual patient data from the PIONEER 1, PIONEER 2 and PIONEER open-label extension Phase 3 trial data encompassing 591 unique patients with HS administered adalimumab 40mg weekly without concurrent antibiotic exposure. Incidence rates of serious infection and malignancy were calculated. Incidence rates of serious infection and malignancy were 2.14 and 0.46 per 100 patient-years, respectively. Rates of infection and malignancy were comparable to those in other inflammatory conditions examined. Incidence of serious infection in patients with HS on adalimumab is comparable to those with psoriasis and inflammatory arthropathies, but the incidence of malignancy is increased. This may reflect disease-specific malignancy risk rather than an effect of adalimumab.