ABSTRACT
Like the sword of Damocles, the threat of a post-antibiotic era is hanging over humanity's head. The scientific and medical community is thus reconsidering bacteriophage therapy (BT) as a ...partial but realistic solution for treatment of difficult-to-eradicate bacterial infections. Here, we summarize the latest developments in clinical BT applications, with a focus on developments in the following areas: (i) pharmacology of bacteriophages of major clinical importance and their synergy with antibiotics; (ii) production of therapeutic phages; and (iii) clinical trials, case studies and case reports in the field. We address regulatory concerns, which are of paramount importance insofar as they dictate the conduct of clinical trials, which are needed for broader BT application. The increasing amount of new available data confirms the particularities of BT as being innovative and highly personalized. The current circumstances suggest that the immediate future of BT may be advanced within the framework of national BT centers in collaboration with competent authorities, which are urged to adopt incisive initiatives originally launched by some national regulatory authorities.
The increasing amount of available data confirms the peculiarities of phage therapy as an innovative and highly personalized therapy and its immediate future likely in the frame of national phage therapy reference centers.
Bone and joint infections (BJI) are severe infections that require a tailored and protracted antibiotic treatment. Yet, the diagnostic based on culturing samples lacks sensitivity, especially for ...hardly culturable bacteria. Metagenomic sequencing could potentially address those limitations. Here, we assessed the performances of metagenomic sequencing on 24 BJI samples for the identification of pathogens and the prediction of their antibiotic susceptibility. For monomicrobial samples in culture (n = 8), the presence of the pathogen was confirmed by metagenomics in all cases. For polymicrobial samples (n = 16), 32/55 bacteria (58.2%) were found at the species level (and 41/55 74.5% at the genus level). Conversely, 273 bacteria not found in culture were identified, 182 being possible pathogens and 91 contaminants. A correct antibiotic susceptibility could be inferred in 94.1% and 76.5% cases for monomicrobial and polymicrobial samples, respectively. Altogether, we found that clinical metagenomics applied to BJI samples is a potential tool to support conventional culture.
With the aging of population, the number of indications for total joint replacement is continuously increasing. However, prosthesis loosening can happen and is related to two major mechanisms: (1) ...aseptic loosening due to prosthesis micromotion and/or corrosion and release of wear particles from the different components of the implanted material and (2) septic loosening due to chronic prosthetic joint infection (PJI). The "aseptic" character of prosthesis loosening has been challenged over the years, especially considering that bacteria can persist in biofilms and be overlooked during diagnosis. Histological studies on periprosthetic tissue samples reported that macrophages are the principle cells associated with aseptic loosening due to wear debris. They produce cytokines and favor an inflammatory environment that induces formation and activation of osteoclasts, leading to bone resorption and periprosthetic osteolysis. In PJIs, the presence of infiltrates of polymorphonuclear neutrophils is a major criterion for histological diagnosis. Neutrophils are colocalized with osteoclasts and zones of osteolysis. A similar inflammatory environment also develops, leading to bone resorption through osteoclasts.
,
, and
are the main staphylococci observed in PJIs. They share the common feature to form biofilm. For
and
, the interaction between biofilm and immunes cells (macrophages and polymorphonuclear neutrophils) differs regarding the species. Indeed, the composition of extracellular matrix of biofilm seems to impact the interaction with immune cells. Recent papers also reported the major role of myeloid-derived suppressor cells in biofilm-associated PJIs with
. These cells prevent lymphocyte infiltration and facilitate biofilm persistence. Moreover, the role of T lymphocytes is still unclear and potentially underestimates. In this review, after introducing the cellular mechanism of aseptic and septic loosening, we will focus on the interrelationships between staphylococcal biofilm, immune cells, and bone cells.
There is a strong rationale for using phages in patients with bone and joint infections (BJIs). Indeed, specific phages can infect and replicate in bacterial pathogens and have also demonstrated ...their activity in vitro against biofilm produced by different bacteria. However, there is a high variability of the different clinical forms of BJI, and their management is complex and frequently includes surgery followed by the administration of antibiotics. Regardless of the availability of active phages, optimal ways of phage administration in patients with BJIs are unknown. Otherwise, all BJIs are not relevant for phage therapy. Except for diabetic foot infection, a BJI with bone exposure is potentially not a relevant indication for phage therapy. On the counterpart, prosthetic joint infections in patients for whom a multidisciplinary expert team judges a conservative approach as the best option to keep the patient's function seem to be a relevant indication with the hypothesis that phage therapy could increase the rate of infection control. The ESCMID Study Group for Non-traditional Antibacterial Therapy (ESGNTA) was created in 2022. One century after the first use of phages as a therapy, the phage therapy 2.0 era, with the possibility to evaluate personalized phage therapy in modern medicine and orthopedic surgery, is just open.
Actinomycosis is a rare chronic disease caused by Actinomyces spp., anaerobic Gram-positive bacteria that normally colonize the human mouth and digestive and genital tracts. Physicians must be aware ...of typical clinical presentations (such as cervicofacial actinomycosis following dental focus of infection, pelvic actinomycosis in women with an intrauterine device, and pulmonary actinomycosis in smokers with poor dental hygiene), but also that actinomycosis may mimic the malignancy process in various anatomical sites. Bacterial cultures and pathology are the cornerstone of diagnosis, but particular conditions are required in order to get the correct diagnosis. Prolonged bacterial cultures in anaerobic conditions are necessary to identify the bacterium and typical microscopic findings include necrosis with yellowish sulfur granules and filamentous Gram-positive fungal-like pathogens. Patients with actinomycosis require prolonged (6- to 12-month) high doses (to facilitate the drug penetration in abscess and in infected tissues) of penicillin G or amoxicillin, but the duration of antimicrobial therapy could probably be shortened to 3 months in patients in whom optimal surgical resection of infected tissues has been performed. Preventive measures, such as reduction of alcohol abuse and improvement of dental hygiene, may limit occurrence of pulmonary, cervicofacial, and central nervous system actinomycosis. In women, intrauterine devices must be changed every 5 years in order to limit the occurrence of pelvic actinomycosis.
New approaches to define factors underlying the immunopathogenesis of pulmonary diseases including sarcoidosis and tuberculosis are needed to develop new treatments and biomarkers. Comparing the ...blood transcriptional response of tuberculosis to other similar pulmonary diseases will advance knowledge of disease pathways and help distinguish diseases with similar clinical presentations.
To determine the factors underlying the immunopathogenesis of the granulomatous diseases, sarcoidosis and tuberculosis, by comparing the blood transcriptional responses in these and other pulmonary diseases.
We compared whole blood genome-wide transcriptional profiles in pulmonary sarcoidosis, pulmonary tuberculosis, to community acquired pneumonia and primary lung cancer and healthy controls, before and after treatment, and in purified leucocyte populations.
An Interferon-inducible neutrophil-driven blood transcriptional signature was present in both sarcoidosis and tuberculosis, with a higher abundance and expression in tuberculosis. Heterogeneity of the sarcoidosis signature correlated significantly with disease activity. Transcriptional profiles in pneumonia and lung cancer revealed an over-abundance of inflammatory transcripts. After successful treatment the transcriptional activity in tuberculosis and pneumonia patients was significantly reduced. However the glucocorticoid-responsive sarcoidosis patients showed a significant increase in transcriptional activity. 144-blood transcripts were able to distinguish tuberculosis from other lung diseases and controls.
Tuberculosis and sarcoidosis revealed similar blood transcriptional profiles, dominated by interferon-inducible transcripts, while pneumonia and lung cancer showed distinct signatures, dominated by inflammatory genes. There were also significant differences between tuberculosis and sarcoidosis in the degree of their transcriptional activity, the heterogeneity of their profiles and their transcriptional response to treatment.
Daptomycin has been recommended in the treatment of bone and joint infection. Previous work showed that the approved dosage of daptomycin may be insufficient to achieve optimal exposure in patients ...with bone and joint infection. However, those studies assumed that bone exposure was similar to steady-state daptomycin-free plasma concentrations. We sought to establish a physiologically based pharmacokinetic (PBPK) model of daptomycin to describe the dynamics of daptomycin disposition in bone and skin tissue.
A PBPK model of daptomycin was built using PK-Sim
. Daptomycin concentrations in plasma and bone were obtained from three previously published studies. Physicochemical drug characteristics, mass balance, anthropometrics, and experimental data were used to build and refine the PBPK model. Internal validation of the PBPK model was performed using the usual diagnostic plots. The final PBPK model was then used to run simulations with doses of 6, 8, 10, and 12 mg/kg/24 h. Pharmacokinetic profiles were simulated in 1000 subjects and the probabilities of target attainment for the area under the concentration-time curve over the bacterial minimum inhibitory concentration were computed in blood, skin, and bone compartments.
The final model showed a good fit of all datasets with an absolute average fold error between 0.5 and 2 for all pharmacokinetic quantities in blood, skin and bone tissues. Results of dosing simulations showed that doses ≥10 mg/kg should be used in the case of bacteremia caused by Staphylococcus aureus with a minimum inhibitory concentration >0.5 mg/L or Enterococcus faecalis with a minimum inhibitory concentration >1 mg/L, while doses ≥12 mg/kg should be used in the case of bone and joint infection or complicated skin infection. When considering a lower minimum inhibitory concentration, doses of 6-8 mg/kg would likely achieve a sufficient success rate. However, in the case of infections caused by E. faecalis with a minimum inhibitory concentration >2 mg/L, a higher dosage and combination therapy would be necessary to maximize efficacy.
We developed the first daptomycin PBPK/pharmacodynamic model for bone and joint infection, which confirmed that a higher daptomycin dosage is needed to optimize exposure in bone tissue. However, such higher dosages raise safety concerns. In this setting, therapeutic drug monitoring and model-informed precision dosing appear necessary to ensure the right exposure on an individual basis.
To study the association between CD4/CD8 ratio and morbidity in HIV-infected patients on antiretroviral therapy (ART).
The APROCO/COPILOTE cohort enrolled patients initiating a protease ...inhibitor-containing ART in 1997-1999. The association between occurrence of first non AIDS-defining severe events (NADE) and time-dependent measures of immune restoration was assessed by 4 Cox models with different definitions of restoration, CD4+ cell counts (CD4), CD4/CD8 ratio, both CD4 and CD4/CD8 ratio, or a composite variable (CD4< 500/mm3, CD4 > 500/mm3 and CD4/CD8 ratio < 1, CD4 > 500/mm3 and CD4/CD8 ratio > 1). Models adjusted on baseline characteristics and time-dependent viral load were compared using Akaike Information Criterion.
We included 1227 patients. Median duration of follow-up was 9.2 years (IQR: 4.2-11.4). Median CD4 was 530/mm3 at 9 years. Median CD4/CD8 ratio was 0.3 (IQR: 0.2-0.5) at baseline and 0.6 (IQR: 0.4-0.9) after 9 years. Incidence of first NADE was 7.4/100 person-years, the most common being bacterial infections (21%), cardiovascular events (14%) and cancers (10%). For both bacterial infections and cardiovascular events, the CD4/CD8 ratio did not add predictive information to the CD4 cell count. However, low CD4/CD8 ratio was the best predictor of non-AIDS cancers (adjusted HR = 2.13 for CD4/CD8 < 0.5; 95% CI = 1.32-3.44).
CD4/CD8 ratio remains < 1 in most HIV-infected patients despite long-term CD4+ cell counts restoration on ART. A CD4/CD8 ratio < 0.5 could identify patients who require a more intensive strategy of cancer prevention or screening.
Tularemia is a zoonotic infection caused by Francisella tularensis. Its most typical manifestations in humans are ulceroglandular and glandular; infections in prosthetic joints are rare. We report 3 ...cases of F. tularensis subspecies holarctica-related prosthetic joint infection that occurred in France during 2016-2019. We also reviewed relevant literature and found only 5 other cases of Francisella-related prosthetic joint infections worldwide, which we summarized. Among those 8 patients, clinical symptoms appeared 7 days to 19 years after the joint placement and were nonspecific to tularemia. Although positive cultures are typically obtained in only 10% of tularemia cases, strains grew in all 8 of the patients. F. tularensis was initially identified in 2 patients by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry; molecular methods were used for 6 patients. Surgical treatment in conjunction with long-term antimicrobial treatment resulted in favorable outcomes; no relapses were seen after 6 months of follow-up.
Syphilis is an important public health problem and an increasing incidence has been noted in recent years. Characterization of strain diversity through molecular data plays a critical role in the ...epidemiological understanding of this re-emergence. We here propose a new high-resolution multilocus sequence typing (MLST) scheme for Treponema pallidum subsp. pallidum (TPA). We analyzed 30 complete and draft TPA genomes obtained directly from clinical samples or from rabbit propagated strains to identify suitable typing loci and tested the new scheme on 120 clinical samples collected in Switzerland and France. Our analyses yielded three loci with high discriminatory power: TP0136, TP0548, and TP0705. Together with analysis of the 23S rRNA gene mutations for macrolide resistance, we propose these loci as MLST for TPA. Among clinical samples, 23 allelic profiles as well as a high percentage (80% samples) of macrolide resistance were revealed. The new MLST has higher discriminatory power compared to previous typing schemes, enabling distinction of TPA from other treponemal bacteria, distinction between the two main TPA clades (Nichols and SS14), and differentiation of strains within these clades.
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