- [Show abstract] [Hide abstract] ABSTRACT: Objectives: Inhibitors of uridine diphosphate-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC, which catalyses the first, irreversible step in lipid A biosynthesis) are a promising new class of antibiotics against Gram-negative bacteria. The objectives of the present study were to: (i) compare the antibiotic activities of three LpxC inhibitors (LPC-058, LPC-011 and LPC-087) and the reference inhibitor CHIR-090 against Gram-negative bacilli (including MDR and XDR isolates); and (ii) investigate the effect of combining these inhibitors with conventional antibiotics. Methods: MICs were determined for 369 clinical isolates (234 Enterobacteriaceae and 135 non-fermentative Gram-negative bacilli). Time-kill assays with LPC-058 were performed on four MDR/XDR strains, including Escherichia coli producing CTX-M-15 ESBL and Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii producing KPC-2, VIM-1 and OXA-23 carbapenemases, respectively. Results: LPC-058 was the most potent antibiotic and displayed the broadest spectrum of antimicrobial activity, with MIC90 values for Enterobacteriaceae, P. aeruginosa, Burkholderia cepacia and A. baumannii of 0.12, 0.5, 1 and 1 mg/L, respectively. LPC-058 was bactericidal at 1× or 2× MIC against CTX-M-15, KPC-2 and VIM-1 carbapenemase-producing strains and bacteriostatic at ≤4× MIC against OXA-23 carbapenemase-producing A. baumannii. Combinations of LPC-058 with β-lactams, amikacin and ciprofloxacin were synergistic against these strains, albeit in a species-dependent manner. LPC-058's high efficacy was attributed to the presence of the difluoromethyl-allo-threonyl head group and a linear biphenyl-diacetylene tail group. Conclusions: These in vitro data highlight the therapeutic potential of the new LpxC inhibitor LPC-058 against MDR/XDR strains and set the stage for subsequent in vivo studies.
- [Show abstract] [Hide abstract] ABSTRACT: Tularaemia is an emerging anthropozoonosis transmitted by contact with infected animals and through arthropod bites, inhalation, or ingestion. We describe a pulmonary nodule suggesting cancer in a 70-year-old man. Histological analysis excluded neoplasia, and bacteriological culture excluded tuberculosis. Serological testing and PCR Francisella were positive for this hunter patient, then treated by ciprofloxacin with a favourable outcome.
Dataset: Supplementary Information[Show abstract] [Hide abstract] ABSTRACT: Supplementary Figures 1-5, Supplementary Tables 1-6, Supplementary Methods and Supplementary References
- [Show abstract] [Hide abstract] ABSTRACT: Data on the tolerance and effectiveness of rifampicin-levofloxacin combination therapy (RLCT) in patients treated for prosthetic joint infections (PJIs) according to daily dosage are lacking. A review of the clinical data from patients treated with RLCT for PJIs in a French referent center for PJIs was conducted. A total of 154 patients (75 F/79 M), with a median age of 64.1 years and median body weight of 83.1 kg, were included. The median daily dosages of rifampicin and levofloxacin were, respectively, 1,200 mg (range 300-2,100) and 750 mg (range 500-1,500), corresponding to a mean daily dose per kg of, respectively, 16.2 ± 4.3 mg/kg and 10.1 ± 3.0 mg/kg. After a mean follow-up period of 55.6 ± 27.1 months (range 24-236), 127 patients (82.5 %) were in remission. Adverse events attributable to rifampicin and levofloxacin were reported in 48 (31.2 %) and 13 (8.4 %) patients (p < 0.001), respectively. Patients who experienced rifampicin-related adverse events had been given higher rifampicin daily doses than the other patients (p = 0.04). The rifampicin daily dosage did not influence patient outcome and nor did the levofloxacin daily dosage on both tolerance and patient outcome. Our results suggest that adjusting rifampicin daily doses to the patient total body weight when combined with levofloxacin for the treatment of PJIs is associated with a poor tolerance. High daily doses of rifampicin (>600 mg) and levofloxacin (750 mg) do not improve patient outcome when compared to lower daily doses in this setting.
- [Show abstract] [Hide abstract] ABSTRACT: Background: Staphylococci, especially coagulase-negative staphylococci (CoNS) represent the most frequent micro-organism associated with osteoarticular infections (OAIs), especially those involving orthopedic devices. The antibiotic susceptibility profile of the bacteria mostly responsible for OAIs is therefore crucial information for choosing the appropriate antibiotic regimen administered during the removal procedure until the first results of the conventional culture. Methods: The antibiotic susceptibility profile of staphylococci isolated from OAIs in a referent center for osteoarticular infection was studied over a 10-y period to adapt antibiotic protocols to the ecology. Results: From 2002 to 2011, the resistance of Staphylococcus aureus to methicillin and rifampicin decreased (27.9% versus 20.6% and 13% versus 1%, respectively); the resistance to fluoroquinolones (FQ) was stable (24% on average), and all the isolates were susceptible to glycopeptides. For CoNS, the resistance to methicillin, rifampicin, and FQ increased (30.4% versus 43.9%, 13% versus 18.5%, and 20.3% versus 34.1%, respectively) over the same period. Resistance of the CoNS to vancomycin was observed in 2011 for the first time (2.3%), and 3.8% were resistant to teicoplanin in 2002 compared with 22% in 2011, with 3.5% resistant to linezolid in 2011. Conclusion: The sensibility of bacteria over 10 y remained stable, except for CoNS. The increase of the resistances for CoNS led us to exclude teicoplanin from the first-line empiric antibiotic treatment, to avoid linezolid, and to prefer vancomycin or daptomycin.
- [Show abstract] [Hide abstract] ABSTRACT: Ruminococcus gnavus is an anaerobic Gram positive coccus that can be found in the gastrointestinal tract of animals and humans. We report a case of septic arthritis caused by R. gnavus that was identified by mass spectrometry and confirmed by 16S rRNA sequencing.
- [Show abstract] [Hide abstract] ABSTRACT: Plague is transmitted by fleas or contaminated aerosols. To successfully produce disease, the causal agent (Yersinia pestis) must rapidly sense and respond to rapid variations in its environment. Here, we investigated the role of 2-component regulatory systems (2CSs) in plague because the latter are known to be key players in bacterial adaptation to environmental change. Along with the previously studied PhoP-PhoQ system, OmpR-EnvZ was the only one of Y. pestis’ 23 other 2CSs required for production of bubonic, septicemic, and pneumonic plague. In vitro, OmpR-EnvZ was needed to counter serum complement and leukocytes but was not required for the secretion of antiphagocyte exotoxins. In vivo, Y. pestis lacking OmpR-EnvZ did not induce an early immune response in the skin and was fully virulent in neutropenic mice. We conclude that, throughout the course of Y. pestis infection, OmpR-EnvZ is required to counter toxic effectors secreted by polymorphonuclear leukocytes in the tissues.
- [Show abstract] [Hide abstract] ABSTRACT: One year after the occurrence of the first case of infection by the Middle East Respiratory Syndrome coronavirus (MERS-CoV) there is no clear consensus on the best treatment to propose. The World Health Organization, as well as several other national agencies, are still working on different clinical approaches to implement the most relevant treatment in MERS-CoV infection. We compared innate and adaptive immune responses of two patients infected with MERS-CoV to understand the underlying mechanisms involved in the response and propose potential therapeutic approaches. Broncho-alveolar lavage (BAL) of the first week and sera of the first month from the two patients were used in this study. Quantitative polymerase chain reaction (qRTPCR) was performed after extraction of RNA from BAL cells of MERS-CoV infected patients and control patients. BAL supernatants and sera were used to assess cytokines and chemokines secretion by enzyme-linked immunosorbent assay. The first patient died rapidly after 3 weeks in the intensive care unit, the second patient still recovers from infection. The patient with a poor outcome (patient 1), compared to patient 2, did not promote type-1 Interferon (IFN), and particularly IFNα, in response to double stranded RNA (dsRNA) from MERS-CoV. The absence of IFNα, known to promote antigen presentation in response to viruses, impairs the development of a robust antiviral adaptive Th-1 immune response. This response is mediated by IL-12 and IFNγ that decreases viral clearance; levels of both of these mediators were decreased in patient 1. Finally, we confirm previous in vitro findings that MERS-CoV can drive IL-17 production in humans. Host recognition of viral dsRNA determines outcome in the early stage of MERS-CoV infection. We highlight the critical role of IFNα in this initial stage to orchestrate a robust immune response and bring substantial arguments for the indication of early IFNα treatment during MERS-CoV infection.
- [Show abstract] [Hide abstract] ABSTRACT: La prise en charge des infections ostéo-articulaires (IOA) associe au traitement chirurgical une antibiothérapie qui pour certaines équipes en période postopératoire immédiate est du moins en partie probabiliste à large spectre dans l’attente des résultats microbiologiques. Cette attitude expose le patient à la sélection de bactéries résistantes et le service hospitalier à une modification de son écologie bactérienne. L’objectif de ce travail était d’évaluer rétrospectivement l’évolution de l’épidémiologie microbienne des services de traumatologie et orthopédie du CHU de Lille sur dix ans (2002–2011).
- [Show abstract] [Hide abstract] ABSTRACT: Management of osteoarticular infections combines surgical treatment with antibiotic therapy. For some teams the immediate postoperative regimen requires at least partly wide-spectrum probabilistic treatment while waiting for the microbiological results. This protocol exposes the patient to the selection of resistant bacteria and the hospital unit to a modification of its bacterial ecology. The objective of this study was to retrospectively describe the microbial epidemiology of the Traumatology and Orthopaedics Department of the Lille University Hospital over 10 years (2002–2011).
- [Show abstract] [Hide abstract] ABSTRACT: Real-time polymerase chain reaction (PCR) methods are able to rapidly detect a wide panel of microorganisms. These methods are of interest in critically ill patients to determine the presence of bacteria in blood samples, especially in patients with prior antimicrobial treatment. In the intensive care unit (ICU), the most frequently used kit is the LightCycler® SeptiFast (LC-SF) Test providing 1.5- to 2-fold higher positivity rate compared with conventional blood cultures. Although identification of the bacterium by LC-SF is rapid and sensitive, susceptibility test can not be performed using this technique, except for methicillin-resistance of Staphylococci. Thus conventional cultures remain necessary for blood samples due to the high incidence of multidrugresistant bacteria in the CIU and the need of antimicrobial susceptibility in order to initiate appropriate antimicrobial treatments. A negative result for a Gram positive or negative bacterium could allow deescalating the initial antimicrobial treatment, decreasing the pressure of selection. Moreover, it is necessary to the clinicians to understand and interpret a deoxyribonucleic acid (DNA) signal knowing that a dead bacterial material may be detected in a patient without any infection. What is the clinical relevance of bacterial DNA present in the blood? Does the DNAemia reflect a true infection? Does a positive DNA signal without positive blood cultures correspond to an unfavorable outcome? Cost-effectiveness of the real-time PCR should be investigated. Meanwhile, this test should be restricted to severe clinical situations, especially to ICU patients with severe sepsis. In the future, real-time PCR tests should include more pathogens and antimicrobial resistance targets.
- [Show abstract] [Hide abstract] ABSTRACT: In case of periprosthetic joint infections, the antibiotic treatment administered intraoperatively entails consequences on bacterial ecology with potential secondary effects. This study evaluates the rapid detection of methicillin-resistant staphylococci (MRS) by Xpert® technology directly on intraoperative samples. Xpert® technology was compared to conventional culture for 104 clinical specimens performed on 30 patients. The performance of the test expressed in terms of sensitivity, specificity, positive predictive value, and negative predictive value was, respectively, 87.1%, 100%, 100%, and 94.5% for the 104 specimens, and 92.3%, 100%, 100%, and 94.4% for the 30 patients. With the rapid detection of MRS, the use of vancomycin was limited for 17 of these 30 patients. In conclusion, this technique would allow the implementation of first-line antibiotic treatment adapted to the presence of MRS or not within approximately 1 h and would strongly reduce the use of broad-spectrum antibiotics.