Ciprofloxacin in combination with bacteriophage cocktails against multi-drug resistant Pseudomonas aeruginosa in ex vivo simulated endocardial vegetation models.

Pseudomonas aeruginosa-associated infective endocarditis represents difficult-to-treat, deep-seated infections. Phage-antibiotic combinations have shown to eradicate multi-drug resistant (MDR) P. aeruginosa, limit the development of phage resistance, and restore antibiotic sensitivity. The objective of this study was to evaluate the activity of phage-ciprofloxacin (CIP) combinations in 4-day ex vivo simulated endocardial vegetation (SEV) models against drug-resistant P. aeruginosa isolates. Two P. aeruginosa isolates, extensively drug-resistant AR351 and MDR I0003-1, were selected for their drug resistance and sensitivity to phage. Three phages [LL-5504721-AH (LL), E2005-C (EC), and 109] and CIP were evaluated alone and in combination for their activity and influence on drug and phage resistance using 24-h time-kill analysis. The three-phage cocktail (q24h) in combination with CIP (400 mg q12h) was then tested in dynamic 4-day ex vivo SEV models, with reduction of log10 CFU/mL compared using ANOVA with Bonferroni analysis. Compared to other combinations, CIP-LL-EC-109 demonstrated synergistic and bactericidal activity from starting CFU/g against AR351 and I0003-1 (-Δ5.65 and 6.60 log10 CFU/g, respectively; P < 0.001). Additionally, CIP-LL-EC-109 mitigated phage resistance, while all other therapies had a high degree of resistance to >1 phages, and all phage-containing regimens prevented CIP mean inhibitory concentration increases compared to CIP alone for both AR351 and I0003-1 at 96 h.

Phage-antibiotic combinations against multidrug-resistant Pseudomonas aeruginosa in in vitro static and dynamic biofilm models.

Biofilm-producing Pseudomonas aeruginosa infections pose a severe threat to public health and are responsible for high morbidity and mortality. Phage-antibiotic combinations (PACs) are a promising strategy for combatting multidrug-resistant (MDR), extensively drug-resistant (XDR), and difficult-to-treat P. aeruginosa infections. Ten MDR/XDR P. aeruginosa strains and five P. aeruginosa-specific phages were genetically characterized and evaluated based upon their antibiotic susceptibilities and phage sensitivities. Two selected strains, AR351 (XDR) and I0003-1 (MDR), were treated singly and in combination with either a broad-spectrum or narrow-spectrum phage, phage EM-T3762627-2_AH (EM), or 14207, respectively, and bactericidal antibiotics of five classes in biofilm time-kill analyses. Synergy and/or bactericidal activity was demonstrated with all PACs against one or both drug-resistant P. aeruginosa strains (average reduction: -Δ3.32 log10 CFU/cm2). Slightly improved ciprofloxacin susceptibility was observed in both strains after exposure to phages (EM and 14207) in combination with ciprofloxacin and colistin. Based on phage cocktail optimization with four phages (EM, 14207, E20050-C (EC), and 109), we identified several effective phage-antibiotic cocktails for further analysis in a 4-day pharmacokinetic/pharmacodynamic in vitro biofilm model. Three-phage cocktail, EM + EC + 109, in combination with ciprofloxacin demonstrated the greatest biofilm reduction against AR351 (-Δ4.70 log10 CFU/cm2 from baseline). Of remarkable interest, the addition of phage 109 prevented phage resistance development to EM and EC in the biofilm model. PACs can demonstrate synergy and offer enhanced eradication of biofilm against drug-resistant P. aeruginosa while preventing the emergence of resistance.

Considerations for the Use of Phage Therapy in Clinical Practice.

Increasing antimicrobial resistance and medical device-related infections have led to a renewed interest in phage therapy as an alternative or adjunct to conventional antimicrobials. Expanded access and compassionate use cases have risen exponentially but have varied widely in approach, methodology, and clinical situations in which phage therapy might be considered. Large gaps in knowledge contribute to heterogeneity in approach and lack of consensus in many important clinical areas. The Antibacterial Resistance Leadership Group (ARLG) has convened a panel of experts in phage therapy, clinical microbiology, infectious diseases, and pharmacology, who worked with regulatory experts and a funding agency to identify questions based on a clinical framework and divided them into three themes: potential clinical situations in which phage therapy might be considered, laboratory testing, and pharmacokinetic considerations. Suggestions are provided as answers to a series of questions intended to inform clinicians considering experimental phage therapy for patients in their clinical practices.

Bacteriophage-antibiotic combination therapy for multidrug-resistant Pseudomonas aeruginosa: In vitro synergy testing.

AIMS: Here, we investigate the impact of phage-antibiotic combinations (PAC) on bacterial killing, resistance development and outer membrane vesicle (OMV) production in multidrug-resistant (MDR) P. aeruginosa. METHODS AND RESULTS: After screening 10 well-characterized MDR P. aeruginosa strains against three P. aeruginosa phages, representative strains, R10266 and R9316, were selected for synergy testing based on high phage sensitivity and substantial antibiotic resistance patterns, while phage EM was chosen based on host range. To understand the impact of phage-antibiotic combinations (PAC) against MDR P. aeruginosa, time-kill analyses, OMV quantification and phage/antibiotic resistance testing were performed. Phage and meropenem demonstrated synergistic activity against both MDR strains. Triple combination regimens, phage-meropenem-colistin and phage-ciprofloxacin-colistin, resulted in the greatest CFU reduction for strains R9316 (3.50 log10 CFU ml-1 ) and R10266 (4.50 log10 CFU ml-1 ) respectively. PAC resulted in regained and improved antibiotic susceptibility to ciprofloxacin (MIC 2 to 0.0625) and meropenem (MIC 32 to 16), respectively, in R9316. Phage resistance was prevented or reduced in the presence of several classes of antibiotics and OMV production was reduced in the presence of phage for both strains, which was associated with significantly improved bacterial eradication. CONCLUSIONS: These findings support the potential of phage-antibiotic synergy (PAS) to augment killing of MDR P. aeruginosa. Systematic in vitro and in vivo studies are needed to better understand phage interactions with antipseudomonal antibiotics, to define the role of OMV production in P. aeruginosa PAC therapy and to outline pharmacokinetic and pharmacodynamic parameters conducive to PAS. SIGNIFICANCE AND IMPACT OF STUDY: This study identifies novel bactericidal phage-antibiotic combinations capable of thwarting resistance development in MDR and XDR P. aeruginosa strains. Furthermore, phage-mediated OMV reduction is identified as a potential mechanism through which PAC potentiates bacterial killing.

Cefiderocol for the Treatment of Adult and Pediatric Patients With Cystic Fibrosis and Achromobacter xylosoxidans Infections.

Treatment options for Achromobacter xylosoxidans are limited. Eight cystic fibrosis patients with A. xylosoxidans were treated with 12 cefiderocol courses. Pretreatment in vitro resistance was seen in 3 of 8 cases. Clinical response occurred after 11 of 12 treatment courses. However, microbiologic relapse was observed after 11 of 12 treatment courses, notably without emergence of resistance.

Drug survival of anti-tumour necrosis factor α therapy in spondyloarthropathies: results from the Spanish emAR II Study.

OBJECTIVE: To assess drug survival and the reasons for switching anti-TNF-α therapy in SpA patients in a Spanish nationwide study. METHODS: A cross-sectional study was performed. Sample size was calculated to represent all regions and hospitals throughout the country. Demographic data, patient characteristics and disease activity parameters were obtained. Drug survival and reasons for switching anti-TNF therapy were also recorded. RESULTS: A total of 467 SpA patients receiving at least one anti-TNF agent were identified. Among patients who received a first, second and third anti-TNF course, 39.4%, 37.4% and 23.1% discontinued treatment, respectively. The main reasons for switching anti-TNF agents in the first course were lack or loss of efficacy (LOE) and adverse events (AEs) in 40% and 30% of switchers, respectively. Similarly, reasons for switching during the second anti-TNF course were LOE in 48% and AEs in 28% of switchers. Of the 467 SpA patients starting anti-TNF therapy, 28% switched to a second and 8% switched to a third therapy. Mean drug survival for the first, second and third anti-TNF courses were 84.4 (95% CI 78.4, 90.5), 70.2 (95% CI 61.6, 78.9) and 64.8 (95% CI 51.1, 78.5) months, respectively (P = 0.315). CONCLUSION: Twenty-eight per cent of SpA patients starting anti-TNF therapy switched to a second anti-TNF agent. Drug survival did not differ among anti-TNF courses. The main reason for switching anti-TNF therapy was LOE. Switchers were more frequently women and had higher disease activity parameters at the time of the study than non-switchers.

Life-threatening vasculo-Behçet following discontinuation of infliximab after three years of complete remission.

Behçet's disease (BD) is a chronic, complex multisystem vasculitis of unknown cause characterised for its ability to involve blood vessels of all sizes on both the arterial and venous sides of the circulation. It has been suggested that TNF-alpha plays a main role in the pathogenesis of BD. This hypothesis is supported by the efficacy of TNF-blocking antibodies in these patients, which have been shown to be very powerful in the induction of remission and as maintenance treatment on different BD manifestations, including severe vascular involvement. However, little is known about when and how to stop IFX after long-standing complete remission of these patients to avoid relapses. We describe a case of BD without previous vascular involvement that developed myocardial infarction and severe venous thromboses only four months after discontinuation of infliximab (IFX) after more than three years of complete remission. The patient did not respond to corticosteroids and intravenous cyclophosphamide and only recovered completely after reintroducing IFX.

Association of 25-hydroxyvitamin D serum levels and metabolic parameters in psoriatic patients with and without arthritis.

BACKGROUND: Psoriasis has been related to a higher prevalence of cardiovascular risk factors. Vitamin-D deficiency has been associated with metabolic syndrome, cardiovascular disease, and psoriasis. However, there has been no comparative study on the effects of vitamin-D status between patients with and without psoriatic arthritis. OBJECTIVE: The objective was to assess the relationship of 25-hydroxyvitamin D [25-(OH)D] levels with lipid and glucose metabolism parameters in psoriatic patients with and without arthritis. METHODS: We studied 122 patients with psoriasis (61 without arthritis and 61 with arthritis) from the psoriasis unit (dermatology department) and rheumatology department of our hospital, analyzing lipid and glucose metabolism variables and serum 25-(OH)D concentrations. Measurements were conducted within a 2-month period to minimize seasonal bias in 25-(OH)D levels. RESULTS: In the psoriatic patients without arthritis, serum 25-(OH)D levels were inversely correlated with fasting glucose (r = -0.285; P = .026), total cholesterol (r = -0.440; P = .000), low-density lipoprotein (r = -0.415; P = .001), total cholesterol/high-density lipoprotein (r = -0.303; P = .01), and triglyceride (r = -0.280; P = .029) values. This association remained statistically significant for glucose, total cholesterol, and low-density lipoprotein after controlling for confounding factors in multivariate analysis. No association was found between serum 25-(OH)D levels and any metabolic parameter in the patients with psoriatic arthritis. LIMITATIONS: This is a cross-sectional study that supports the hypothesis of an association between vitamin D and metabolic parameters but does not establish a causal relationship. CONCLUSIONS: Serum 25-(OH)D was inversely related to lipid and glucose metabolism parameters in psoriatic patients without arthritis, whereas no such association was observed in psoriatic patients with arthritis. Interventional studies are warranted to assess the effects of vitamin-D supplements on the metabolic profile of psoriatic patients without arthritis.

Inguinal syndrome secondary to Prevotella bivia after accidental bite in orogenital sex.

The authors report a case of an inguinal bubo in a young man caused by an anaerobe, Prevotella bivia, which was acquired during oral sexual intercourse. As far as the authors know, this is the first reported case of a sexually transmitted infection by Prevotella. Prevotella spp. inhabit the oral cavity and are highly prevalent in bacterial vaginosis, a polymicrobial syndrome resulting from replacement of the normal vaginal Lactobacillus spp. flora by high concentrations of anaerobic microorganisms such as Prevotella spp., Mobiluncus spp., Gardnerella vaginalis and other uncultivated anaerobes.

Overcoming Stenotrophomonas maltophilia Resistance for a More Rational Therapeutic Approach.

Stenotrophomonas maltophilia is an underappreciated source of morbidity and mortality among gram-negative pathogens. Effective treatment options with acceptable toxicity profiles are limited. Phenotypic susceptibility testing via commercial automated test systems is problematic and no Food and Drug Administration breakpoints are approved for any of the first-line treatment options for S maltophilia. The lack of modern pharmacokinetic/pharmacodynamic data for many agents impedes dose optimization, and the lack of robust efficacy and safety data limits their clinical utility. Levofloxacin has demonstrated similar efficacy to trimethoprim-sulfamethoxazole, although rapid development of resistance is a concern. Minocycline demonstrates the highest rate of in vitro susceptibility, however, evidence to support its clinical use are scant. Novel agents such as cefiderocol have exhibited promising activity in preclinical investigations, though additional outcomes data are needed to determine its place in therapy for S maltophilia. Combination therapy is often employed despite the dearth of adequate supporting data.

Primary Sjögren's syndrome as independent risk factor for subclinical atherosclerosis.

OBJECTIVE: To assess the prevalence of subclinical atherosclerosis in patients with primary Sjögren's syndrome (pSS) and its possible association with clinical and analytical parameters of the disease. METHODS: In this cross-sectional study, 38 consecutive patients with pSS were compared with 38 age and sex healthy controls. Demographic variables and classic cardiovascular risk factors (CVRFs): Hypertension, dyslipidemia, diabetes mellitus, obesity, and smoking habit were assessed in both groups, and also disease-related features were collected in pSS group. The presence of subclinical atherosclerosis was assessed by carotid ultrasound, with carotid intima-media thickness (CIMT) measurement and determination of the presence of atheromatous plaques. RESULTS: Subclinical atherosclerosis presence was remarkably greater in patients with pSS than in healthy controls (OR = 4.17, 95%CI [1.27-16.54]), as well as CIMT values (0.79 ± 0.43mm vs. 0.66 ± 0.27mm; P = .02). No differences for classic CVRFs were found between both groups. An association of subclinical atherosclerosis with erythrocyte sedimentation rate (ESR) and rheumatoid factor (RF) was observed in patients with pSS. CONCLUSION: This cohort showed a greater prevalence of subclinical atherosclerosis in patients with pSS, indicating this disease as an independent risk factor for presence of early vascular damage.

Septic arthritis due to Cellulosimicrobium cellulans.

Cellulosimicrobium cellulans has been reported as a rare cause of human pathogenesis. Infections mainly occur in immunocompromised patients and very often are associated with a foreign body. We report the first case of septic arthritis caused by C. cellulans in an immunocompetent patient. Our patient suffered a penetrating palm tree thorn injury to his left knee 8 weeks before admission. Although no foreign objects were found, they were suspected because previous reports suggest a frequent association with this microorganism, and open debridament was performed. Removal of foreign bodies related to this organism must be considered a high-priority treatment in these patients to achieve a complete recovery.

Clinical Pharmacology of Bacteriophage Therapy: A Focus on Multidrug-Resistant Pseudomonas aeruginosa Infections.

Pseudomonas aeruginosa is one of the most common causes of healthcare-associated diseases and is among the top three priority pathogens listed by the World Health Organization (WHO). This Gram-negative pathogen is especially difficult to eradicate because it displays high intrinsic and acquired resistance to many antibiotics. In addition, growing concerns regarding the scarcity of antibiotics against multidrug-resistant (MDR) and extensively drug-resistant (XDR) P. aeruginosa infections necessitate alternative therapies. Bacteriophages, or phages, are viruses that target and infect bacterial cells, and they represent a promising candidate for combatting MDR infections. The aim of this review was to highlight the clinical pharmacology considerations of phage therapy, such as pharmacokinetics, formulation, and dosing, while addressing several challenges associated with phage therapeutics for MDR P. aeruginosa infections. Further studies assessing phage pharmacokinetics and pharmacodynamics will help to guide interested clinicians and phage researchers towards greater success with phage therapy for MDR P. aeruginosa infections.

Doble colédoco, variante anatómica infrecuente de la vía biliar. Presentación de caso / Double common bile duct, a rare anatomical variant of the bile tract. Case report

Introducción: la presencia de un conducto colédoco doble es una variante anatómica infrecuente con menos de 200 casos publicados en la literatura hasta la fecha, siendo fundamental los estudios preoperatorios que se le deben realizar a los pacientes, a fin de tener la sospecha o el diagnóstico confirmado, no sólo de la variante anatómica, sino de la patología asociada, siendo estas la coledocolitiasis y las patologías malignas del árbol biliar las más frecuentes, aunque gran parte de los casos son hallazgos incidentales e intraoperatorios.Caso clínico : se presenta el caso de masculino de 81 años de edad, con antecedente de colecistectomía 20 años previos, con diagnóstico de síndrome ictérico obstructivo, y estudios de colangiorresonancia y CPRE que reportan coledocolitiasis. Se decide llevar a acto quirúrgico y se diagnóstica la presencia de conducto colédoco doble como hallazgo. Se realiza derivación biliodigestiva de tipo hepaticoyeyunoanastomosis más ligadura de conducto colédoco accesorio con evolución satisfactoria, con alta médica a los 5 días posteriores, y resultado de biopsia negativo para malignidad.Conclusión : el doble colédoco debe ser adecuadamente diagnosticado y estudiado, así no se confirme el diagnóstico preoperatorio los pacientes deben acudir con estos estudios realizados al acto quirúrgico, ya que, dicho tratamiento dependerá fundamentalmente de la patología asociada(AU)

Introduction: the presence of a double common bile duct is an infrequent anatomical variant with less than 200 cases published in the literature to the date, and preoperative studies that must be performed on patients are essential in order to have the suspicion or diagnosis confirmed, not only of the anatomical variant, but also of the associated pathology, these being choledocholithiasis and malignant pathologies of the biliary tract the most frequent, although most of the cases are incidental and intraoperative findings.Clinical case : the case of an 81-year-old male is presented, with a history of cholecystectomy 20 years prior, with a diagnosis of obstructive icteric syndrome, and magnetic resonance cholangiography and ERCP studies that reported choledocholithiasis. It was decided to carry out surgery and the presence of double common bile duct was diagnosed as a finding. Biliodigestive derivation hepaticojejunoanastomosis type and accessory common bile duct ligation was performed with satisfactory evolution, with medical discharge 5 days later, and biopsy result negative for malignancy.Conclusion : the double common bile duct should be properly diagnosed and studied, even if the preoperative diagnosis is not confirmed, patients should attend the surgical procedure with these studies, since said treatment will depend fundamentally on the associated pathology(AU)

Recommendations by the Spanish Society of Rheumatology on the Use of Biological Therapies in Axial Spondyloarthritis. / Recomendaciones de la Sociedad Española de Reumatología sobre el uso de terapias biológicas en espondiloartritis axial.

OBJECTIVE: Recent data published on biological therapy in axial spondyloarthritis (axSpA) since the last publication of the recommendations of the Spanish Society of Rheumatology (SER) has led to the generation of a review of these recommendations based on the best possible evidence. These recommendations should be a reference for rheumatologists and those involved in the treatment of patients with axSpA. METHODS: Recommendations were drawn up following a nominal group methodology and based on systematic reviews. The level of evidence and grade of recommendation were classified according to the model proposed by the Centre for Evidence Based Medicine at Oxford. The level of agreement was established through the Delphi technique. RESULTS: In this review, we did an update of the evaluation of disease activity and treatment objectives. We included the new drugs with approved therapeutic indication for axSpA. We reviewed both the predictive factors of the therapeutic response and progression of radiographic damage. Finally, we drafted some recommendations for the treatment of patients refractory to anti-tumor necrosis factor, as well as for the possible optimization of biological therapy. The document also includes a table of recommendations and a treatment algorithm. CONCLUSIONS: We present an update of the SER recommendations for the use of biological therapy in patients with axSpA.

Journal Impact Factor Shapes Scientists' Reward Signal in the Prospect of Publication.

The incentive structure of a scientist's life is increasingly mimicking economic principles. While intensely criticized, the journal impact factor (JIF) has taken a role as the new currency for scientists. Successful goal-directed behavior in academia thus requires knowledge about the JIF. Using functional neuroimaging we examined how the JIF, as a powerful incentive in academia, has shaped the behavior of scientists and the reward signal in the striatum. We demonstrate that the reward signal in the nucleus accumbens increases with higher JIF during the anticipation of a publication and found a positive correlation with the personal publication record (pJIF) supporting the notion that scientists have incorporated the predominant reward principle of the scientific community in their reward system. The implications of this behavioral adaptation within the ecological niche of the scientist's habitat remain unknown, but may also have effects which were not intended by the community.

Calcium pyrophosphate crystal deposition disease: diagnosis and treatment.

Calcium pyrophosphate dihydrate crystal deposition disease (CPPD) is an inflammatory arthritis produced by the deposition of calcium pyrophosphate (CPP) crystals in the synovium and periarticular soft tissues. It is the third most common inflammatory arthritis. Diagnosis is suspected on the basis of the clinical picture and radiographic/laboratory findings. The reference standard for the diagnosis of CPPD is based on the identification of CPP crystals in synovial fluid by light microscopy, compensated polarized light microscopy, or phase contrast microscopy. Most treatment approaches for CPPD are based upon clinical experience and not upon controlled trials. They range - depending on the subtype and the characteristics of symptoms - from no treatment to interleukin-1 blockade antibodies or specific therapy for an underlying disease. This review summarizes all we know so far about the diagnosis and management of CPPD.

Cardiovascular risk assessment according to a national calibrated score risk index in psoriatic arthritis patients without clinically evident cardiovascular disease or classic atherosclerosis risk factors.

OBJECTIVE: To assess cardiovascular (CV) risk in psoriatic arthritis (PsA) patients without clinically evident CV disease or classic atherosclerosis risk factors according to the SCORE chart following the EULAR recommendations. METHODS: Eighty PsA patients without previous CV events or atherosclerosis risk factors and eighty matched controls were included. Information on demographic, anthropometric and clinical-serological data of disease was assessed. The national calibrated Systematic Coronary Risk Evaluation (SCORE) index was calculated and the association between this SCORE and clinical-serological data of these patients was analyzed. RESULTS: PsA patients had higher acute phase reactants as well as higher SCORE mean values than healthy controls (1.99±3.52 vs. 1.0±1.74; P=0.028). According to SCORE definitions, 71 (89%) patients had low-intermediate CV risk and 9 (11%) were above the threshold of high risk. In the control group, 76 (95%) had low-intermediate risk and four (5%) had high CV risk. However, there were no differences in CV risk stratification between both groups (P=0.148). PsA patients with high-very high CV risk had longer disease duration (P=0.001) and higher levels of triglycerides (P=0.009). PsA patients showed a significant correlation between SCORE values and disease duration (ß=0.185; P=0.0001) and the average annual levels of C reactive protein (CRPa), ß=2.38; P=0.014. CONCLUSION: CV risk assessment in PsA patients without clinically evident CV disease or classic atherosclerosis risk factors may be underestimated by using only the SCORE chart. In these patients, disease duration and the CRPa may help to establish a better stratification of the actual CV risk.