Oral tetracyclines for bone and joint infections: what do we know?

Background and aim: Complex bone and joint infections (BJIs), including prosthetic joint infections (PJIs) and infections associated with osteosynthetic materials, present significant treatment challenges that often require surgical intervention and prolonged antibiotic therapy. In France, the incidence of PJIs in knee and hip arthroplasties ranges from 0.79 % to 2.4 %, with staphylococci being the primary pathogens involved. Recent studies have suggested that oral antibiotic therapy may be as effective as intravenous therapy and that 12 weeks of antibiotic treatment are needed. Tetracyclines, particularly doxycycline and minocycline, are of interest because of their broad-spectrum activities, good oral bioavailability, and potential efficacy in treating BJIs. We aimed to provide a literature review on the role of oral tetracyclines in the management of BJIs. Method: We performed a systematic review of the literature identified via an electronic search of PubMed and ScienceDirect. Results: A total of 648 articles were screened, and 31 studies were included. Pharmacological studies demonstrated that the bone to blood penetration ratio ranged from 0.06 to 0.75. Less than 20 % of strains implicated in BJIs exhibited resistance to oral tetracyclines. Four studies demonstrated potential inhibition of strain growth. Eight studies that included 62 patients reported curative treatment, with a success rate ranging from 82 % to 100 % for PJIs regardless of the surgical management. For suppressive therapy, 10 studies that included 201 patients reported success rates ranging from 57 % to 100 %. The rate of adverse effects ranged from 0 % to 14 % for curative treatment and from 0 % to 57 % for suppressive treatment, leading to treatment discontinuation in less than 20 % of cases. Conclusion: This review highlights that the number of studies supporting the use of oral tetracyclines for the treatment of BJIs is limited. More robust pharmacological and clinical studies are needed to confirm the safety and efficacy profiles of oral tetracyclines for the treatment of BJIs.</p

Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

Background: We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15–20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in ~ 80% of cases. Methods: We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded. Results: No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5–528.7, P = 1.1 × 10−4) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR = 3.70[95%CI 1.3–8.2], P = 2.1 × 10−4). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR = 19.65[95%CI 2.1–2635.4], P = 3.4 × 10−3), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR = 4.40[9%CI 2.3–8.4], P = 7.7 × 10−8). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD] = 43.3 [20.3] years) than the other patients (56.0 [17.3] years; P = 1.68 × 10−5). Conclusions: Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60&nbsp;years old

Autoantibodies against type I IFNs in patients with life-threatening COVID-19

Interindividual clinical variability in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is vast. We report that at least 101 of 987 patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia had neutralizing immunoglobulin G (IgG) autoantibodies (auto-Abs) against interferon-w (IFN-w) (13 patients), against the 13 types of IFN-a (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 of the 101 were men. A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men