Search

The surgical repair of a ruptured tendon faces two major problems: specifically increased fibrous adhesion to the surrounding tissue and inferior mechanical properties of the scar tissue compared to the native tissue. Bacterial attachment to implant materials is an additional problem as it might lead to severe infections and impaired recovery. To counteract adhesion formation, two novel implant materials were fabricated by electrospinning, namely, a random fiber mesh containing hyaluronic acid (HA) and poly(ethylene oxide) (PEO) in a ratio of 1:1 (HA/PEO 1:1) and 1:4 (HA/PEO 1:4), respectively. Electrospun DegraPol (DP) treated with silver nanoparticles (DP-Ag) was developed to counteract the bacterial attachment. The three novel materials were compared to the previously described DP and DP with incorporated insulin-like growth factor-1 (DP-IGF-1), two implant materials that were also designed to improve tendon repair. To test whether the materials are prone to bacterial adhesion and biofilm formation, we assessed 10 strains of Staphylococcus aureus, Staphylococcus epidermidis, Pseudomonas aeruginosa,and Enterococcus faecalis, known for causing nosocomial infections. Fiber diameter, pore size, and water contact angle, reflecting different degrees of hydrophobicity, were used to characterize all materials. Generally, we observed higher biofilm formation on the more hydrophobic DP as compared to the more hydrophilic DP-IGF-1 and a trend toward reduced biofilm formation for DP treated with silver nanoparticles. For the two HA/PEO implants, a similar biofilm formation was observed. All tested materials were highly prone to bacterial adherence and biofilm formation, pointing toward the need of further material development, including the optimized incorporation of antibacterial agents such as silver nanoparticles or antibiotics.

Viruses have been present during all evolutionary steps on earth and have had a major effect on human history. Viral infections are still among the leading causes of death. Another public health concern is the increase of non-communicable metabolic diseases in the last four decades. In this Review, we revisit the scientific evidence supporting the presence of a strong bidirectional feedback loop between several viral infections and metabolic diseases. We discuss how viruses might lead to the development or progression of metabolic diseases and conversely, how metabolic diseases might increase the severity of a viral infection. Furthermore, we discuss the clinical relevance of the current evidence on the relationship between viral infections and metabolic disease and the present and future challenges that should be addressed by the scientific community and health authorities.

•Allogeneic hematopoietic cell transplantation (allo-HCT) recipients display impaired immune response to SARS-CoV-2 vaccination.•Vaccination resulted in only weak immunity in patients at <12 months post allo-HCT.•Patients age >65 years and/or with immunosuppression had the lowest responses to vaccination.•Antibody levels waned over time in allo-HCT recipients and healthy controls.

Timely recognition and elimination of invasive group A Streptococcus (GAS) by innate immunity is crucial to control infection. The intracellular pattern recognition receptor Toll-like receptor 9 (TLR9) promotes macrophage hypoxia-inducible factor-1α levels, oxidative burst and nitric oxide production in response to GAS. TLR9 contributes to GAS clearance in vivo in both localized cutaneous and systemic infection models.

Streptococcal necrotizing fasciitis (NF) causes high morbidity and mortality despite state-of-the-art therapy. Low incidence and rapid disease progression, necessitating immediate initiation of therapy, have proven challenging aspects for setting up prospective randomized trials. This has resulted in little therapeutic progress over the past decade. The validation of reliable murine NF models to study both pathogenesis and optimized therapeutic regimens of streptococcal NF are thus essential. In this study, we characterized a murine NF model and compared the pathology with an in-depth tissue analysis of streptococcal NF in patients. We found that the streptococcal murine NF model closely reflected all histologic characteristics encountered in human streptococcal NF. This murine NF model helps understanding of human NF pathology better in a time-dependent manner and will allow studying novel therapeutic options in the future.

Zusammenfassung.Wir präsentieren den Fall eines 49-jährigen Patienten mit linksseitiger Carotidynie. Als Ursache fand sich eine Lymphknotentuberkulose. Unter tuberkulostatischer Therapie zeigte sich eine rasche Besserung der Symptome.

Staphylococcus aureuscan cause infections that are often chronic and difficult to treat, even when the bacteria are not antibiotic resistant because most antibiotics act only on metabolically active cells. Subpopulations of persister cells are metabolically quiescent, a state associated with delayed growth, reduced protein synthesis, and increased tolerance to antibiotics. Serine-threonine kinases and phosphatases similar to those found in eukaryotes can fine-tune essential bacterial cellular processes, such as metabolism and stress signaling. We found that acid stress–mimicking conditions that S. aureusexperiences in host tissues delayed growth, globally altered the serine and threonine phosphoproteome, and increased threonine phosphorylation of the activation loop of the serine-threonine protein kinase B (PknB). The deletion of stp, which encodes the only annotated functional serine-threonine phosphatase in S. aureus, increased the growth delay and phenotypic heterogeneity under different stress challenges, including growth in acidic conditions, the intracellular milieu of human cells, and abscesses in mice. This growth delay was associated with reduced protein translation and intracellular ATP concentrations and increased antibiotic tolerance. Using phosphopeptide enrichment and mass spectrometry–based proteomics, we identified targets of serine-threonine phosphorylation that may regulate bacterial growth and metabolism. Together, our findings highlight the importance of phosphoregulation in mediating bacterial quiescence and antibiotic tolerance and suggest that targeting PknB or Stp might offer a future therapeutic strategy to prevent persister formation during S. aureusinfections.

ABSTRACTDiagnosis of Propionibacterium acnesbone and joint infection is challenging due to the long cultivation time of up to 14 days. We retrospectively studied whether reducing the cultivation time to 7 days allows accurate diagnosis without losing sensitivity. We identified patients with at least one positive P. acnessample between 2005 and 2015 and grouped them into “infection” and “no infection.” An infection was defined when at least two samples from the same case were positive. Clinical and microbiological data, including time to positivity for different cultivation methods, were recorded. We found 70 cases of proven P. acnesinfection with a significant faster median time to positivity of 6 days (range, 2 to 11 days) compared to 9 days in 47 cases with P. acnesidentified as a contamination (P< 0.0001). In 15 of 70 (21.4%) patients with an infection, tissue samples were positive after day 7 and in 6 patients (8.6%) after day 10 when a blind subculture of the thioglycolate broth was performed. The highest sensitivity was detected for thioglycolate broth (66.3%) and the best positive predictive values for anaerobic agar plates (96.5%). A prolonged transportation time from the operating theater to the microbiological laboratory did not influence time to positivity of P. acnesgrowth. By reducing the cultivation time to 7 days, false-negative diagnoses would increase by 21.4%; thus, we recommend that biopsy specimens from bone and joint infections be cultivated to detect P. acnesfor 10 days with a blind subculture at the end.

ABSTRACTStaphylococcus aureusbiofilms are extremely difficult to treat. They provide a protected niche for the bacteria, rendering them highly recalcitrant toward host defenses as well as antibiotic treatment. Bacteria within a biofilm are shielded from the immune system by the formation of an extracellular polymeric matrix, composed of polysaccharides, extracellular DNA (eDNA), and proteins. Many antibiotics do not readily penetrate biofilms, resulting in the presence of subinhibitory concentrations of antibiotics. Here, we show that subinhibitory concentrations of clindamycin triggered a transcriptional stress response in S. aureusvia the alternative sigma factor B (σB) and upregulated the expression of the major biofilm-associated genes atlA, lrgA, agrA, the psmgenes, fnbA, and fnbB. Our data suggest that subinhibitory concentrations of clindamycin alter the ability of S. aureusto form biofilms and shift the composition of the biofilm matrix toward higher eDNA content. An understanding of the molecular mechanisms underlying biofilm assembly and dispersal in response to subinhibitory concentrations of clinically relevant antibiotics such as clindamycin is critical to further optimize antibiotic treatment strategies of biofilm-associated S. aureusinfections.

ABSTRACTWe analyzed the diagnostic value of microorganisms cultured from negative-pressure-wound-therapy (NPWT) foam samples compared to that of microorganisms cultured from deep tissue samples from patients with vascular graft infections. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 58%, 86%, 81%, and 66%, respectively. The diagnostic value of microbiological cultures from NPWT foams was poor.

OBJECTIVEIn-hospital transmission of methicillin-susceptible Staphylococcus aureus(MSSA) among neonates remains enigmatic. We describe the epidemiology of MSSA colonization and infection in a 30-bed neonatal ward.DESIGNMultimodal outbreak investigationSETTINGA public 800-bed tertiary care university hospital in SwitzerlandMETHODSInvestigations in 2012–2013, triggered by a MSSA infection cluster, included prospective MSSA infection surveillance, microbiologic screening of neonates and environment, onsite observations, and a prospective cohort study. MSSA isolates were characterized by pulsed-field gel electrophoresis (PFGE) and selected isolates were examined for multilocus sequence type (MLST) and virulence factors.RESULTSAmong 726 in 2012, 30 (4.1%) patients suffered from MSSA infections including 8 (1.1%) with bacteremia. Among 655 admissions in 2013, 13 (2.0%) suffered from MSSA infections including 2 (0.3%) with bacteremia. Among 177 neonates screened for S. aureuscarriage, overall 77 (44%) tested positive. A predominant PFGE-1-ST30 strain was identified in 6 of 30 infected neonates (20%) and 30 of 77 colonized neonates (39%). This persistent clone was pvl-negative, tst-positive and belonged to agrgroup III. We found no environmental point source. MSSA carriage was associated with central vascular catheter use but not with a particular midwife, nurse, physician, or isolette. Observed healthcare worker behavior may have propagated transmission via hands and fomites. Despite multimodal interventions, clonal transmission and colonization continued and another clone, PFGE-6-ST5, became predominant.CONCLUSIONSHospital-acquired MSSA clones represent a high proportion of MSSA colonization but not MSSA infections in neonate inpatients. In contrast to persisting MSSA, transmission infection rates decreased concurrently with interventions. It remains to be established whether eradication of hospital-acquired MSSA strains would reduce infection rates further.Infect. Control Hosp. Epidemiol.2015;36(11):1305–1312

AbstractM1 protein contributes to Group A Streptococcus(GAS) systemic virulence by interfering with phagocytosis and through proinflammatory activities when released from the cell surface. Here we identify a novel role of M1 protein in the stimulation of neutrophil and mast cell extracellular trap formation, yet also subsequent survival of the pathogen within these DNA-based innate defense structures. Targeted mutagenesis and heterologous expression studies demonstrate M1 protein promotes resistance to the human cathelicidin antimicrobial peptide LL-37, an important effector of bacterial killing within such phagocyte extracellular traps. Studies with purified recombinant protein fragments mapped the inhibition of cathelicidin killing to the M1 hypervariable N-terminal domain. A survey of GAS clinical isolates found that strains from patients with necrotizing fasciitis or toxic shock syndrome were significantly more likely to be resistant to cathelicidin than GAS M types not associated with invasive disease; M1 isolates were uniformly resistant. We conclude increased resistance to host cathelicidin and killing within phagocyte extracellular traps contribute to the propensity of M1 GAS strains to produce invasive infections.Copyright © 2009 S. Karger AG, Basel

ABSTRACTVoriconazole (VRC) is an antifungal drug that effectively treats keratitis caused by yeasts and molds when administered orally. We retrospectively evaluated clinical outcomes and plasma and aqueous humor drug concentrations in five patients with fungal keratitis and one patient with posttraumatic endophthalmitis who were treated with VRC. VRC was administered either topically (1% eye drops every hour) or orally (400 mg twice a day). Plasma and aqueous humor samples from affected eyes were taken 12 h after oral administration or 1 h after eye drop application. The drug concentration was measured by liquid chromatography with UV or mass spectrometric detection. All six patients responded well to VRC treatment. The VRC concentration ranged from 2.93 to 3.40 mg/liter in the aqueous humor and from 3.20 to 4.20 mg/liter in the plasma after combined oral and topical treatment. Topical administration alone resulted in highly variable trough VRC concentrations of 0.61 to 3.30 mg/liter in the aqueous humor. VRC concentrations were above the MIC for Candida albicans Aspergillus fumigatusand clinical improvement was seen in all four patients with C. albicansand A. fumigatuskeratitis. Combined orally and topically administered VRC resulted in aqueous humor drug concentrations of ≥2.93 mg/liter, which is above the VRC MIC for most fungi. Topical VRC treatment resulted in an aqueous humor drug concentration >0.61 mg/liter, which is above the MIC for most Candidaspecies. The results from this small series of patients suggest that both topical and combined systemic and topical VRC therapy can be effective in treating fungal keratitis. Furthermore, the data provide preliminary support for initiation of VRC treatment with a combined topical and systemic administration until the causative fungus and its MIC are identified.

Hepcidin is an antimicrobial peptide secreted by the liver during inflammation that plays a central role in mammalian iron homeostasis. Here we demonstrate the endogenous expression of hepcidin by macrophages and neutrophils in vitro and in vivo. These myeloid cell types produced hepcidin in response to bacterial pathogens in a toll-like receptor 4 (TLR4)-dependent fashion. Conversely, bacterial stimulation of macrophages triggered a TLR4-dependent reduction in the iron exporter ferroportin. In vivo, intraperitoneal challenge with Pseudomonas aeruginosa induced TLR4-dependent hepcidin expression and iron deposition in splenic macrophages, findings mirrored in subcutaneous infection with group A Streptococcus where hepcidin induction was further observed in neutrophils migrating to the tissue site of infection. Hepcidin expression in cultured hepatocytes or in the livers of mice infected with bacteria was independent of TLR4, suggesting the TLR4-hepcidin pathway is restricted to myeloid cell types. Our findings identify endogenous myeloid cell hepcidin production as a previously unrecognized component of the host response to bacterial pathogens.

Hepcidin is an antimicrobial peptide secreted by the liver during inflammation that plays a central role in mammalian iron homeostasis. Here we demonstrate the endogenous expression of hepcidin by macrophages and neutrophils in vitro and in vivo. These myeloid cell types produced hepcidin in response to bacterial pathogens in a toll-like receptor 4 (TLR4)-dependent fashion. Conversely, bacterial stimulation of macrophages triggered a TLR4-dependent reduction in the iron exporter ferroportin. In vivo, intraperitoneal challenge with Pseudomonas aeruginosainduced TLR4-dependent hepcidin expression and iron deposition in splenic macrophages, findings mirrored in subcutaneous infection with group A Streptococcuswhere hepcidin induction was further observed in neutrophils migrating to the tissue site of infection. Hepcidin expression in cultured hepatocytes or in the livers of mice infected with bacteria was independent of TLR4, suggesting the TLR4-hepcidin pathway is restricted to myeloid cell types. Our findings identify endogenous myeloid cell hepcidin production as a previously unrecognized component of the host response to bacterial pathogens.

Background Morbidity and mortality of individuals co-infected with HIV and hepatitis C virus (HCV) is often determined by the course of their HCV infection. Only a selected proportion of those in need of HCV treatment are studied in randomized controlled trials (RCTs). We analysed the prevalence of HCV infection in a large cohort, the number of individuals requiring treatment, the eligibility for HCV treatment, and the outcome of the combination therapy with pegylated interferon-a and ribavirin in routine practice.Methods We analysed prescription patterns of HCV treatment and treatment outcomes among participants from the Swiss HIV Cohort Study with detectable hepatitis C viraemia (between January 2001 and October 2004). Efficacy was measured by the number of patients with undetectable HCV RNA at the end of therapy (EOTR) and at 6 months after treatment termination (SVR). Intention-to-continue-treatment principles were used.Results A total of 2,150 of 7,048 (30.5%) participants were coinfected with HCV; HCV RNA was detected in 60%, and not assessed in 26% of HCV-antibody-positive individuals. One hundred and sixty (12.5%) of HCV-RNA-positive patients started treatment. In patients infected with HCV genotypes 1/4 or 2/3, EOTR was achieved in 43.3% and 81.2% of patients, respectively, and SVR rates were 28.4% and 51.8%, respectively. More than 50% of the HCV-treated patients would have been excluded from two large published RCTs due to demographic, clinical and laboratory criteria.Conclusions Despite clinical and psychosocial obstacles encountered in clinical practice, HCV treatment in HIV-coinfected individuals is feasible with results similar to those obtained in RCTs.

The impact of secondary bacterial infections (superinfections) in coronavirus disease 2019 (COVID-19) is not well understood. In this prospective, monocentric cohort study, we aim to investigate the impact of superinfections in COVID-19 patients with acute respiratory distress syndrome. Patients are assessed for concomitant microbial infections by longitudinal analysis of tracheobronchial secretions, bronchoalveolar lavages, and blood cultures. In 45 critically ill patients, we identify 19 patients with superinfections (42.2%). Superinfections are detected on day 10 after intensive care admission. The proportion of participants alive and off invasive mechanical ventilation at study day 28 (ventilator-free days [VFDs] at 28 days) is substantially lower in patients with superinfection (subhazard ratio 0.37; 95% confidence interval [CI] 0.15–0.90; p = 0.028). Patients with pulmonary superinfections have a higher incidence of bacteremia, virus reactivations, yeast colonization, and required intensive care treatment for a longer time. Superinfections are frequent and associated with reduced VFDs at 28 days despite a high rate of empirical antibiotic therapy.

Life-threatening infections with Staphylococcus aureusare often difficult to treat due to the increasing prevalence of antibiotic-resistant bacteria and their ability to persist in protected niches in the body. Bacteriolytic enzymes are promising new antimicrobials because they rapidly kill bacteria, including drug-resistant and persisting cells, by destroying their cell wall. However, when injected into the bloodstream, these enzymes are not retained long enough to clear an infection. Here, we describe a modification to increase blood circulation time of the enzymes and enhance treatment efficacy against S. aureus-induced bloodstream infections. This was achieved by preselecting enzyme candidates for high activity in human blood and coupling them to serum albumin, thereby preventing their elimination by kidney filtration and blood vessel cells.

The increasing prevalence of antibiotic-resistant bacteria is one of the most urgent problems of our time. Staphylococcus aureusis an important human pathogen that has acquired several mechanisms to evade antibiotic treatment. In addition, S. aureusis able to invade and persist within human cells, hiding from the immune response and antibiotic therapies. For these reasons, novel antibacterial strategies against these pathogens are needed. Here, we developed lytic enzymes which are able to effectively target drug-resistant and intracellular S. aureus. Fusion of these so-called enzybiotics to cell-penetrating peptides enhanced their uptake and intracellular bactericidal activity in cell culture and in an abscess mouse model. Our results suggest that cell-penetrating enzybiotics are a promising new class of therapeutics against staphylococcal infections.

Bacterial membrane vesicle research has so far focused mainly on Gram-negative bacteria. Only recently have Gram-positive bacteria been demonstrated to produce and release extracellular membrane vesicles (MVs) that contribute to bacterial virulence.

Corynebacteriumspp. are rarely considered pathogens, but data on Corynebacteriumspp.

ABSTRACTIf a bone or joint infection is suspected, perioperative antibiotic prophylaxis is frequently withheld until intraoperative microbiological sampling has been performed. This practice builds upon the hypothesis that perioperative antibiotics could render culture results negative and thus impede tailored antibiotic treatment of infections. We aimed to assess the influence of antibiotic prophylaxis within 30 to 60 min before surgery on time to positivity of microbiological samples and on proportion of positive samples in Cutibacterium acnesbone and joint infections. Patients with at least one sample positive for C. acnesbetween January 2005 and December 2015 were included and classified as having an “infection” if at least 2 samples were positive; otherwise they were considered to have a sample “contamination.” Kaplan-Meier curves were used to illustrate time to culture positivity. We found 64 cases with a C. acnesinfection and 46 classified as having a C. acnescontamination. Application of perioperative prophylaxis significantly differed between the infection and contamination groups (72.8% versus 55.8%; P< 0.001). Within the infection group, we found no difference in time to positivity between those who had or had not received a perioperative prophylaxis (7.07 days; 95% confidence interval [CI], 6.4 to 7.7, versus 7.11 days; 95% CI, 6.8 to 7.5; P= 0.3). Also, there was no association between the proportion of sample positivity and the application of perioperative prophylaxis (71.6% versus 65.9%; P= 0.39). Since perioperative prophylaxis did not negatively influence the microbiological yield in C. acnesinfections, antibiotic prophylaxis can be routinely given to avoid surgical site infections.

Hematopoietic cell transplant (HCT) recipients are at increased risk for infections. Staphylococcus aureus(SA) colonizes 20-50% of healthy individuals and is a risk factor for subsequent invasive SA infections. Colonization rates in patients undergoing allogeneic HCT and clinical relevance for the time of aplasia and severely reduced immune function following HCT are not known. Only some retrospective data on methicillin-resistant SA infection rates are available. In this study, we prospectively assessed the prevalence of SA colonization in 110 consecutive patients before and during allo-HCT in a single-center observational study from June 2013 to January 2016.

No relevant conflicts of interest to declare.