RESUMEN
BACKGROUND: The indications of daptomycin have been extended to off-label indications including prosthesis-related infection, and bone and joint infection (BJI). However, efficacy and safety have not been thoroughly demonstrated compared with the standard of care. This systematic review and meta-analysis aimed to compare the treatment effect of daptomycin and glycopeptides for complicated infections. MATERIALS AND METHODS: MEDLINE, Embase and Web of Science were searched for randomized controlled trials (RCTs) comparing daptomycin and standard of care for Gram-positive infections, published until 30 June 2021. The primary outcome was defined as all-cause mortality. Secondary outcomes were clinical and microbiological success. The main safety outcome was any severe adverse event (SAE) (grade â≥3). RESULTS: Overall, eight RCTs were included in the meta-analysis, totalling 1095 patients. Six (75%) were in complicated skin and soft-structure infections, one (12.5%) in bacteraemia and one (12.5%) in a BJI setting. Six RCTs used vancomycin as a comparator and two used either vancomycin or teicoplanin. All-cause mortality and clinical cure were not different between groups. The microbiological cure rate was superior in patients who received daptomycin [risk ratio (RR)â=â1.17 (95% CI: 1.01-1.35)]. The risk of SAEs [RRâ=â0.57 (95% CI: 0.36-0.90)] was lower in the daptomycin arm. CONCLUSIONS: While daptomycin is associated with a significantly lower risk of SAEs and a better microbiological eradication, substantial uncertainty remains about the best treatment strategy in the absence of good-quality evidence, especially in bacteraemia and endocarditis where further RCTs should be conducted.
Asunto(s)
Antibacterianos , Daptomicina , Glicopéptidos , Infecciones por Bacterias Grampositivas , Daptomicina/uso terapéutico , Daptomicina/efectos adversos , Humanos , Antibacterianos/uso terapéutico , Antibacterianos/efectos adversos , Infecciones por Bacterias Grampositivas/tratamiento farmacológico , Infecciones por Bacterias Grampositivas/mortalidad , Glicopéptidos/uso terapéutico , Glicopéptidos/efectos adversos , Resultado del Tratamiento , Ensayos Clínicos Controlados Aleatorios como Asunto , Vancomicina/uso terapéutico , Vancomicina/efectos adversosRESUMEN
Solutions for bone and joint infection (BJI) are needed where conventional treatments are inadequate. Bacteriophages (phages) are naturally occurring viruses that infect bacteria and have been harnessed for refractory bone and joint infections (BJI) in many case reports. Here we examine the safety and efficacy of English-language published cases of BJI since 2010 with phage therapy. From 33 reported cases of BJI treated with phage therapy, 29 (87%) achieved microbiological or clinical success, 2 (5.9%) relapsed with the same organisms, and 2 (5.9%) with a different organism. Of these 4 relapses, all but 1 had eventual clinical resolution with additional surgery or phage treatments. Eight out of 33 cases (24%) reported mild, transient adverse events with no serious events reported. Further work is needed to understand the true efficacy of phages and the role of phages in BJI. Opportunities lay ahead for thoughtfully designed clinical trials adapted to individualized therapies.
Asunto(s)
Artritis Infecciosa , Bacteriófagos , Terapia de Fagos , Humanos , Artritis Infecciosa/tratamiento farmacológico , Bacterias , Antibacterianos/uso terapéuticoRESUMEN
BACKGROUND: High-dose daptomycin is increasingly used in patients with bone and joint infection (BJI). This raises concerns about a higher risk of adverse events (AEs), including daptomycin-induced eosinophilic pneumonia (DIEP) and myotoxicity. We aimed to examine pharmacokinetic and other potential determinants of DIEP and myotoxicity in patients with BJI receiving daptomycin. METHODS: All patients receiving daptomycin for BJI were identified in a prospective cohort study. Cases were matched at a 1:3 ratio, with controls randomly selected from the same cohort. Bayesian estimation of the daptomycin daily area under the concentration-time curve over 24 hours (AUC24h) was performed with the Monolix software based on therapeutic drug monitoring (TDM) data. Demographic and biological data were also collected. Risk factors of AEs were analyzed using Cox proportional hazards model. RESULTS: From 1130 patients followed over 7 years, 9 with DIEP, 26 with myotoxicity, and 106 controls were included in the final analysis. Daptomycin AUC24h, C-reactive protein, and serum protein levels were associated with the risk of AEs. The adjusted hazard ratio of DIEP or myotoxicity was 3.1 (95% confidence interval [CI], 1.48-6.5; P < .001) for daptomycin AUC24h > 939 mg/h/L, 9.8 (95% CI, 3.94-24.5; P < .001) for C-reactive protein > 21.6 mg/L, and 2.4 (95% CI, 1.02-5.65; P = .04) for serum protein <72 g/L. CONCLUSIONS: We identified common determinants of DIEP and myotoxicity in patients with BJI. Because the risk of AEs was associated with daptomycin exposure, daptomycin TDM and model-informed precision dosing may help optimize the efficacy and safety of daptomycin treatment in this setting. A target AUC24h range of 666 to 939 mg/h/L is suggested.
Asunto(s)
Daptomicina , Eosinofilia Pulmonar , Humanos , Daptomicina/uso terapéutico , Antibacterianos/uso terapéutico , Eosinofilia Pulmonar/inducido químicamente , Eosinofilia Pulmonar/tratamiento farmacológico , Miotoxicidad/tratamiento farmacológico , Estudios Prospectivos , Teorema de Bayes , Proteína C-Reactiva , Factores de RiesgoRESUMEN
BACKGROUND: Determining the etiology of aortitis is often challenging, in particular to distinguish infectious aortitis (IA) and noninfectious aortitis (NIA). This study aims to describe and compare the clinical, biological, and radiological characteristics of IA and NIA and their outcomes. METHODS: A multicenter retrospective study was performed in 10 French centers, including patients with aortitis between 1 January 2014 and 31 December 2019. RESULTS: One hundred eighty-three patients were included. Of these, 66 had IA (36.1%); the causative organism was Enterobacterales and streptococci in 18.2% each, Staphylococcus aureus in 13.6%, and Coxiella burnetii in 10.6%. NIA was diagnosed in 117 patients (63.9%), mainly due to vasculitides (49.6%), followed by idiopathic aortitis (39.3%). IA was more frequently associated with aortic aneurysms compared with NIA (78.8% vs 17.6%, P < .001), especially located in the abdominal aorta (69.7% vs 23.1%, P < .001). Crude and adjusted survival were significantly lower in IA compared to NIA (P < .001 and P = .006, respectively). In the IA cohort, high American Society of Anesthesiologists score (hazard ratio [HR], 2.47 [95% confidence interval {CI}, 1.08-5.66]; P = .033) and free aneurysm rupture (HR, 9.54 [95% CI, 1.04-87.11]; P = .046) were significantly associated with mortality after adjusting for age, sex, and Charlson comorbidity score. Effective empiric antimicrobial therapy, initiated before any microbial documentation, was associated with a decreased mortality (HR, 0.23, 95% CI, .08-.71]; P = .01). CONCLUSIONS: IA was complicated by significantly higher mortality rates compared with NIA. An appropriate initial antibiotic therapy appeared as a protective factor in IA.
Asunto(s)
Aneurisma de la Aorta , Aortitis , Enfermedades Transmisibles , Humanos , Aortitis/epidemiología , Aortitis/complicaciones , Aortitis/diagnóstico , Estudios Retrospectivos , Aneurisma de la Aorta/complicaciones , Aneurisma de la Aorta/diagnóstico , Enfermedades Transmisibles/complicacionesRESUMEN
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.
Asunto(s)
Francisella tularensis , Tularemia , Animales , Humanos , Francisella tularensis/genética , Tularemia/diagnóstico , Tularemia/tratamiento farmacológico , Zoonosis , Francia/epidemiologíaRESUMEN
Histopathology is the gold standard for fungal infection (FI) diagnosis, but it does not provide a genus and/or species identification. The objective of the present study was to develop targeted next-generation sequencing (NGS) on formalin-fixed tissue samples (FTs) to achieve a fungal integrated histomolecular diagnosis. Nucleic acid extraction was optimized on a first group of 30 FTs with Aspergillus fumigatus or Mucorales infection by macrodissecting the microscopically identified fungal-rich area and comparing Qiagen and Promega extraction methods through DNA amplification by A. fumigatus and Mucorales primers. Targeted NGS was developed on a second group of 74 FTs using three primer pairs (ITS-3/ITS-4, MITS-2A/MITS-2B, and 28S-12-F/28S-13-R) and two databases (UNITE and RefSeq). A prior fungal identification of this group was established on fresh tissues. Targeted NGS and Sanger sequencing results on FTs were compared. To be valid, the molecular identifications had to be compatible with the histopathological analysis. In the first group, the Qiagen method yielded a better extraction efficiency than the Promega method (100% and 86.7% of positive PCRs, respectively). In the second group, targeted NGS allowed fungal identification in 82.4% (61/74) of FTs using all primer pairs, in 73% (54/74) using ITS-3/ITS-4, in 68.9% (51/74) using MITS-2A/MITS-2B, and in 23% (17/74) using 28S-12-F/28S-13-R. The sensitivity varied according to the database used (81% [60/74] using UNITE compared to 50% [37/74] using RefSeq [P = 0.000002]). The sensitivity of targeted NGS (82.4%) was higher than that of Sanger sequencing (45.9%; P < 0.00001). To conclude, fungal integrated histomolecular diagnosis using targeted NGS is suitable on FTs and improves fungal detection and identification.
Asunto(s)
Micosis , Humanos , Adhesión en Parafina , Micosis/diagnóstico , Formaldehído , Reacción en Cadena de la Polimerasa , Fijación del Tejido , Secuenciación de Nucleótidos de Alto RendimientoRESUMEN
PURPOSE: Increasing evidence supports daptomycin therapeutic drug monitoring. The author's reference center used to perform therapeutic drug monitoring in patients who receive high-dose daptomycin for bone and joint infections, with a three-sample strategy to estimate the daptomycin daily area under the concentration-time curve (AUC). The objective of this study was to evaluate simpler strategies based on only 2 or 1 sample(s). METHODS: The authors used the BestDose software to estimate the daptomycin AUC after Bayesian posterior estimation of individual pharmacokinetic (PK) parameters at steady state. The reference AUC (AUC full ) was based on 3 samples obtained predose (T0) and approximately 1 hour (T1) and 6 hours (T6) after the start of a 30-minute infusion of IV daptomycin. It was compared with the AUC based on all possible 2-sample and 1-sample strategies. Bias, imprecision, regression, and Bland-Altman plots were used to assess the performance of the alternative strategies. RESULTS: Data from 77 patients were analyzed. The mean AUC full value was 936 ± 373 mg·h/L. The best 2-sample strategy was T0 + T6, with a mean prediction bias of 0.13 mg·h/L and absolute imprecision of 3%. The T0 + T1 strategy also performed well with a mean bias of -10 mg·h/L and imprecision of 3%. The best 1-sample strategy was the T6 sample only with a bias of 2.19 mg·h/L and imprecision of 6%. CONCLUSIONS: Bayesian estimation of daptomycin AUC based on a two-sample strategy was associated with negligible bias and imprecision compared with the author's usual three-sample strategy. The trough and peak strategy may shorten and simplify patient visits and reduce assay labor and costs.
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Daptomicina , Humanos , Teorema de Bayes , Área Bajo la Curva , Programas Informáticos , Manejo de EspecímenesRESUMEN
The pharmacokinetics of ceftolozane-tazobactam (TOL-TAZ) and ceftazidime-avibactam (CEF-AVI) is influenced by renal function. Application of recommended dosages in patients with renal impairment requires the use of fractions of the full dose, as only one dosage is available for both antibiotics. The objective of this study was to evaluate the adequacy of alternative dosage regimens based on the full dose. We performed pharmacokinetic/pharmacodynamic (PK/PD) simulations of recommended and alternative dosage regimens in patients with various degrees of renal impairment by using the Pmetrics program. Alternative regimens included longer dosage interval and prolonged infusions of the full dose for both drugs. Probabilities of target attainment (PTA) were assessed considering PK/PD targets defined for cephalosporins and beta-lactamase inhibitors as well as MIC breakpoints. The risk of overexposure was also assessed. Results showed that alternative dosage regimens based on a full dose of TOL-TAZ and CEF-AVI administered every 12 or 24 h were associated with PTA similar to that of recommended dosages, especially when administered as prolonged infusion. The alternative dosage regimens were not associated with overexposure in most cases. In addition, those regimens could reduce dosing errors, drug cost, and nurse labor. Clinical investigation ovf those alternative dosage regimens would be required before implementation.
Asunto(s)
Ceftazidima , Cefalosporinas , Antibacterianos/farmacología , Compuestos de Azabiciclo/farmacocinética , Compuestos de Azabiciclo/uso terapéutico , Ceftazidima/farmacocinética , Ceftazidima/uso terapéutico , Cefalosporinas/farmacocinética , Análisis Costo-Beneficio , Combinación de Medicamentos , Humanos , Pruebas de Sensibilidad Microbiana , Tazobactam/farmacocinética , Tazobactam/uso terapéuticoRESUMEN
Staphylococcus epidermidis is one of the main pathogens responsible for bone and joint infections, especially those involving prosthetic materials, due to its ability to form biofilms. In these cases, biofilm formation, combined with increased antimicrobial resistance, often results in therapeutic failures. In this context, the development of innovative therapies active against S. epidermidis is a priority. The aim of this study was to evaluate the in vitro activity of the lysin exebacase (CF-301) against biofilms formed by 19 S. epidermidis clinical strains isolated from prosthetic joint infections (PJI). We determined the biomass and the remaining viable bacteria inside biofilms after 24 h of exposure to exebacase. Exebacase activity was compared to that of rifampicin, vancomycin, and daptomycin. The use of exebacase in addition to antibiotics was also assessed. Exebacase displayed (i) a significant anti-biomass activity on S. epidermidis biofilms at concentrations ≥5 mg/L (mean decrease up to 66% at 150 mg/L), (ii) significant bactericidal activity on biofilms at concentrations ≥50 mg/L (mean decrease up to 1.7 log CFU at 150 mg/L), (iii) synergistic effects when used in addition to rifampicin, vancomycin, or daptomycin. The extent of these activities varied by isolate. Exebacase can be considered a promising therapy in addition to rifampicin, vancomycin, or daptomycin in the context of PJI. Further in vitro studies are needed to understand its mechanism of action on S. epidermidis biofilms and in vivo investigations are required to confirm these data.
Asunto(s)
Daptomicina , Infecciones Estafilocócicas , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Biopelículas , Daptomicina/farmacología , Daptomicina/uso terapéutico , Endopeptidasas , Humanos , Pruebas de Sensibilidad Microbiana , Rifampin/farmacología , Rifampin/uso terapéutico , Infecciones Estafilocócicas/tratamiento farmacológico , Infecciones Estafilocócicas/microbiología , Staphylococcus epidermidis , Vancomicina/farmacología , Vancomicina/uso terapéuticoRESUMEN
BACKGROUND: Necrotizing external otitis (NEO) is a severe infection of the skull base that occurs generally in the elderly and/or in diabetic recipients. There are few data in the literature about the therapeutic management of this complex bone infection. OBJECTIVES: To analyse relapses after NEO treatment completion, and to describe the clinical features of NEO. METHODS: We performed a retrospective cohort study in the Lyon regional reference centre for the management of complex bone and joint infections. Consecutive cases of NEO from 1 January 2006 to 31 December 2018 were included. The primary outcome was the relapse of NEO. Variables were analysed using Cox regression survival analysis with adjusted hazard ratio (aHR) and Kaplan-Meier curve. RESULTS: Sixty-six patients were included. Median age was 75 (IQR 69-81) years and 46 (70%) patients were diabetic. Eleven patients (17%) had temporomandibular arthritis, 10 (15%) cranial nerve paralysis, 2 (3%) cerebral thrombophlebitis, and 2 (3%) contiguous abscess. Microbiological documentation was obtained in 56 patients and revealed Pseudomonas aeruginosa in 44/56 patients (79%). Nine (14%) cases had no microbiological documentation. Antibiotic therapy was dual for 63 (95%) patients. During a median follow-up of 27 (IQR 12-40) months, 16 out of 63 (25%) patients experienced a relapse. Fungal infection was significantly associated with relapse [aHR 4.1 (95% CI 1.1-15); Pâ=â0.03]. CONCLUSIONS: NEO is a severe bone infection, mainly (but not exclusively) caused by P. aeruginosa, which occurs in elderly and diabetic recipients. Fungal infections at baseline significantly impact the outcome.
Asunto(s)
Diabetes Mellitus , Osteomielitis , Otitis Externa , Infecciones por Pseudomonas , Anciano , Humanos , Osteomielitis/tratamiento farmacológico , Osteomielitis/microbiología , Otitis Externa/tratamiento farmacológico , Otitis Externa/microbiología , Infecciones por Pseudomonas/tratamiento farmacológico , Pseudomonas aeruginosa , Recurrencia , Estudios Retrospectivos , Factores de RiesgoRESUMEN
OBJECTIVES: Long-acting lipoglycopeptides are promising therapeutic options in Staphylococcus aureus bone and joint infections (BJIs). This study evaluated the ability of dalbavancin to eradicate the intraosteoblastic reservoir of S. aureus, associated with BJI chronicity. METHODS: Osteoblastic cells were infected with a standardized inoculum of the S. aureus reference strain HG001 and incubated for 24 h with dalbavancin, vancomycin or rifampicin using the MIC, 10×MIC, 100×MIC and/or the intraosseous concentrations reached using standard therapeutic doses (i.e. vancomycin, 10 mg/L; rifampicin, 2 mg/L; and dalbavancin, 6 mg/L). The remaining intracellular bacteria were quantified by plating cell lysates. RESULTS: MICs of dalbavancin, vancomycin and rifampicin were 0.125, 1 and 0.004 mg/L, respectively. Dalbavancin significantly reduced the intracellular inoculum of S. aureus starting at a concentration equal to the MIC, with a significant dose effect, ranging from a reduction of 31.4% (95% CI = 17.6%-45.2%) at MIC to 51.6% (95% CI = 39.8%-63.4%) at 100×MIC compared with untreated cells. Of note, dalbavancin was the only molecule to significantly reduce the intraosteoblastic inoculum at low concentration (MIC). At intraosseous concentrations, dalbavancin reduced the intracellular inoculum by 49.6% (95% CI = 45.1%-54.1%) compared with untreated cells (P < 0.001), with no significant difference compared with vancomycin (38.1%; 95% CI = 19.2%-57.0%; P = 0.646), and was less efficient than rifampicin (69.0%; 95% CI = 63.2-74.8; P < 0.001). CONCLUSIONS: Dalbavancin was able to decrease the intraosteoblastic S. aureus inoculum by 50% at intraosseous concentrations reached during standard human therapeutic dosing, with no difference compared with vancomycin, and remained less efficient than rifampicin. However, it was the only molecule significantly active at low concentration.
Asunto(s)
Infecciones Estafilocócicas , Staphylococcus aureus , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Humanos , Pruebas de Sensibilidad Microbiana , Infecciones Estafilocócicas/tratamiento farmacológico , Teicoplanina/análogos & derivados , Teicoplanina/farmacologíaRESUMEN
BACKGROUND: Daptomycin is increasingly used in the treatment of bone and joint infection (BJI), but its pharmacokinetics (PK) and dosage requirements have not been thoroughly investigated in this indication. Daptomycin may be co-administered with rifampicin, which raises questions about a potential drug interaction. OBJECTIVES: To investigate the population PK and dosage requirements of daptomycin in patients with BJI, and examine the influence of rifampicin co-administration. METHODS: A population approach was used to analyse PK data from patients who received daptomycin in our regional reference for BJI. We examined the influence of available covariates, including rifampicin co-administration on daptomycin PK. Simulations performed with the final model investigated the influence of dosages and covariates on PTA for both efficacy and safety. RESULTS: A total of 1303 daptomycin concentrations from 183 patients were analysed. A two-compartment model best described the data. Significant intra-individual variability was observed. Daptomycin clearance was influenced by renal function and sex, with females having a 26% lower typical clearance than males. Central volume of distribution (V1) was influenced by body weight, age, sex and rifampicin co-administration. Typical V1 was 11% lower in patients who were co-administered rifampicin. In PK/PD simulations, sex influenced the probability of AUC24/MIC target attainment, while rifampicin had a marginal effect. CONCLUSIONS: A daptomycin dosage of 8 mg/kg/24 h in women and 10 mg/kg/24 h in men should optimize efficacy but may lead to excessive trough concentrations in many patients, especially in women. Therapeutic drug monitoring appears necessary for precision dosing of daptomycin.
Asunto(s)
Daptomicina , Antibacterianos , Monitoreo de Drogas , Femenino , Humanos , Masculino , Rifampin , Caracteres SexualesRESUMEN
BACKGROUND: Prosthetic joint infections (PJI) are one of the most serious complication of arthroplasty. The management of PJI needs a multidisciplinary collaboration between orthopaedic surgeon, infectious disease specialist and microbiologist. In France, the management of PJI is organized around reference centres (CRIOACs). Our main objective was to perform an audit through a questionnaire survey based on clinical cases, to evaluate how French physicians manage PJI. Eligible participants were all physicians involved in care of patients presenting a PJI. Physicians could answer individually, or collectively during a multidisciplinary team meeting dedicated to PJI. The survey consisted as three questionnaires organized in a total of six clinical cases. RESULTS: Answers from the CRIOACs to the three questionnaires were 92, 77, and 53%. Between 32 and 39% of respondents did not administer antibiotic prophylaxis despite positive S. aureus pre-operative documentation. One-stage exchange strategy was widely preferred in all clinical cases, with no difference between CRIOACs and other centres. Rifampicin was prescribed for S. aureus PJI, in a situation with (90-92%) or without any prosthesis (70%). There was no consensus for the total antibiotic regimen duration, with prescriptions from six to 12 weeks for a majority of respondents. CONCLUSIONS: Surgical strategy for the management of PJI was homogenous with a preference for a one-stage exchange strategy. Medical management was more heterogenous, which reflects the heterogeneity of those infections and difficulties to perform studies with strong conclusions.
Asunto(s)
Antibacterianos/uso terapéutico , Infecciones Relacionadas con Prótesis/tratamiento farmacológico , Infecciones Relacionadas con Prótesis/prevención & control , Infecciones Relacionadas con Prótesis/cirugía , Antibacterianos/administración & dosificación , Profilaxis Antibiótica , Artritis Infecciosa/tratamiento farmacológico , Artritis Infecciosa/prevención & control , Francia , Hospitales , Humanos , Médicos , Rifampin/uso terapéutico , Infecciones Estafilocócicas/tratamiento farmacológico , Staphylococcus aureus/patogenicidad , Encuestas y CuestionariosRESUMEN
Individuals with pre-existing chronic systemic low-grade inflammation are prone to develop severe COVID-19 and stronger anti-SARS-CoV-2 antibody responses. Whether this phenomenon reflects a differential expansion of antiviral B cells or a failure to regulate antibody synthesis remains unknown. Here, we compared the antiviral B cell repertoire of convalescent healthcare personnel to that of hospitalized patients with pre-existing comorbidities. Out of 277,500 immortalized B cell clones, antiviral B cell frequencies were determined by indirect immunofluorescence screening on SARS-CoV-2 infected cells. Surprisingly, frequencies of SARS-CoV-2 specific clones from the two groups were not statistically different, despite higher antibody levels in hospitalized patients. Moreover, functional analyses revealed that several B cell clones from healthcare personnel with low antibody levels had neutralizing properties. This study reveals for the first time a key qualitative defect of antibody synthesis in severe patients and calls for caution regarding estimated protective immunity based only on circulating antiviral antibodies.
Asunto(s)
Anticuerpos Antivirales/sangre , Linfocitos B/inmunología , COVID-19/patología , SARS-CoV-2/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Neutralizantes/sangre , Anticuerpos Antivirales/inmunología , Formación de Anticuerpos , Linfocitos B/citología , Linfocitos B/metabolismo , COVID-19/inmunología , COVID-19/virología , Comorbilidad , Femenino , Personal de Salud , Humanos , Masculino , Persona de Mediana Edad , SARS-CoV-2/aislamiento & purificación , SARS-CoV-2/metabolismo , Índice de Severidad de la Enfermedad , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/inmunologíaRESUMEN
BACKGROUND: Prospective data on the natural history of anal human papillomavirus (HPV) infection are scarce in human immunodeficiency virus (HIV)-infected men who have sex with men (MSM). METHODS: We analyzed incidence and clearance of HPV-16 and HPV-18 in a French cohort of HIV-infected MSM, aged ≥35 years, followed-up annually (n = 438, 2014-2018). RESULTS: Human papillomavirus-16 and HPV-18 incidence were similar (~10% incident infections at 24 months). Human papillomavirus-16 incidence was higher among high-grade versus no lesion at baseline (adjusted incidence rate ratio = 3.0; 95% confidence interval, 1.07-8.18). Human papillomavirus-16 cleared significantly slower than HPV-18 (32% versus 54% by 24 months). CONCLUSIONS: In conclusion, anal HPV-16 is more persistent than HPV-18, and its incidence correlates with a prior detection of high-grade lesions.
Asunto(s)
Enfermedades del Ano/epidemiología , Infecciones por VIH/epidemiología , Infecciones por Papillomavirus/epidemiología , Minorías Sexuales y de Género , Enfermedades del Ano/virología , Francia/epidemiología , Infecciones por VIH/complicaciones , Infecciones por VIH/virología , Homosexualidad Masculina , Papillomavirus Humano 16 , Papillomavirus Humano 18 , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/virología , Estudios Prospectivos , Factores de Riesgo , Conducta SexualRESUMEN
BACKGROUND: We assessed prevalence of multimorbidity (MM) according to year of human immunodeficiency virus (HIV) diagnosis in elderly people living with HIV (PLWH). METHODS: This was a cross-sectional study of MM in PLWH aged ≥70 years from the Dat'AIDS French multicenter cohort. MM was defined as at least 3 coexistent morbidities of high blood pressure, diabetes mellitus, osteoporosis, non-AIDS cancer, chronic renal failure, cardiovascular and cerebrovascular disease, obesity, undernutrition, or hypercholesterolemia. Logistic regression models evaluated the association between MM and calendar periods of HIV diagnosis (1983-1996, 1997-2006, and 2007-2018). The secondary analysis evaluated MM as a continuous outcome, and a sensitivity analysis excluded PLWH with nadir CD4 count <200 cells/µL. RESULTS: Between January 2017 and September 2018, 2476 PLWH were included. Median age was 73 years, 75% were men, median CD4 count was 578 cells/µL, and 94% had controlled viremia. MM prevalence was 71%. HBP and hypercholesterolemia were the most prevalent comorbidities. After adjustment for age, gender, smoking status, hepatitis C and hepatitis B virus coinfection, group of exposure, nadir CD4 count, CD4:CD8 ratio, and last CD4 level, calendar period of diagnosis was not associated with MM (Pâ =â .169). MM was associated with older age, CD4/CD8 ratio <0.8, and nadir CD4 count <200 cells/µL. Similar results were found with secondary and sensitivity analyses. CONCLUSIONS: MM prevalence was high and increased with age, low CD4/CD8 ratio, and nadir CD4 count <200 cells/µL but was not associated with calendar periods of HIV diagnosis. Known duration of HIV diagnosis does not seem to be a criterion for selecting elderly PLWH at risk of MM.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida , Infecciones por VIH , Anciano , Recuento de Linfocito CD4 , Estudios de Cohortes , Estudios Transversales , Femenino , Infecciones por VIH/complicaciones , Infecciones por VIH/diagnóstico , Infecciones por VIH/epidemiología , Humanos , Masculino , MultimorbilidadRESUMEN
Data on immunogenicity and safety of the recommended revaccination schedule against diphtheria, tetanus, poliomyelitis, pertussis, Haemophilus influenzae type b (Hib), and hepatitis B in adult allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients are limited. This prospective single-center cohort study (April 2014 to March 2018) included adult allo-HSCT recipients referred to a dedicated vaccinology consultation and vaccinated with the pediatric combined diphtheria, tetanus, acellular pertussis, hepatitis B virus, inactivated poliovirus, and Haemophilus influenzae type b (DTaP(±HB)-IPV-Hib) vaccine (3 doses 1 month apart, booster dose 1 year later). The proportion of responders to tetanus, diphtheria, Hib, and hepatitis B vaccine and geometric mean concentrations (GMCs) of antibodies were assessed before and up to 24 months after vaccination. A total of 106 patients were vaccinated at a median (interquartile range) time of 12.4 (10 to 18.4) months post-transplant. At 5.3 (4.8 to 6.6) and 23.1 (21.1 to 25.1) months after vaccine initiation, high and sustained rates of protective antibody titers were achieved for tetanus (97.8% [95% confidence interval (95% CI), 92.4% to 99.7%], n = 91/93 and 100% [95% CI, 92% to 100%], n = 44/44), diphtheria (94.6% [95% CI, 87.9% to 98.2%], n = 88/93 and 90.9% [95% CI, 78.3% to 97.5%], n = 40/44), Hib (96.6% [95% CI, 90.4% to 99.3%], n = 85/88 and 93% [95% CI, 80.9% to 98.5%], n = 40/43), and hepatitis B (83.5% [95% CI, 73.5% to 90.9%], n = 66/79 and 81.1% [95% CI, 64.8% to 92%], n = 30/37). Underlying disease, stem cell source, chronic graft-versus-host-disease, and extracorporeal photopheresis differentially influenced GMCs of tetanus, diphtheria, and hepatitis B antibodies after 3 doses but not in the long term (24 months). Six (5.7%) patients experienced mild side effects. The pediatric DTaP(±HB)-IPV-Hib vaccine was safe and effective in eliciting a sustained protective humoral response in adult allo-HSCT recipients. Hepatitis B revaccination might be optimized by using higher antigen doses.
Asunto(s)
Difteria , Vacunas contra Haemophilus , Haemophilus influenzae tipo b , Trasplante de Células Madre Hematopoyéticas , Tétanos , Adulto , Anticuerpos Antibacterianos , Niño , Estudios de Cohortes , Difteria/prevención & control , Vacuna contra Difteria, Tétanos y Tos Ferina , Virus de la Hepatitis B , Humanos , Esquemas de Inmunización , Inmunización Secundaria , Lactante , Vacuna Antipolio de Virus Inactivados , Estudios Prospectivos , Tétanos/prevención & control , Vacunas CombinadasRESUMEN
Staphylococcus aureus is responsible for difficult-to-treat bone and joint infections (BJIs). This is related to its ability to form biofilm and to be internalized and persist inside osteoblasts. Recently, bacteriophage therapy has emerged as a promising option to improve treatment of such infections, but data on its activity against the specific bacterial lifestyles presented above remain scarce. We evaluated the activity of a combination of three bacteriophages, recently used for compassionate treatment in France, against S. aureus HG001 in a model of staphylococcal biofilm and a model of osteoblasts infection, alone or in association with vancomycin or rifampin. The activity of bacteriophages against biofilm-embedded S. aureus was dose dependent. In addition, synergistic effects were observed when bacteriophages were combined with antibiotics used at the lowest concentrations. Phage penetration into osteoblasts was observed only when the cells were infected, suggesting a S. aureus-dependent Trojan horse mechanism for internalization. The intracellular bacterial count of bacteria in infected osteoblasts treated with bacteriophages as well as with vancomycin was significantly higher than in cells treated with lysostaphin, used as a control condition, owing to the absence of intracellular activity and the rapid killing of bacteria released after the death of infected cells. These results suggest that bacteriophages are both inactive in the intracellular compartment after being internalized in infected osteoblasts and present a delayed killing effect on bacteria released after cell lysis into the extracellular compartment, which avoids preventing them from infecting other osteoblasts. The combination of bacteriophages tested was highly active against S. aureus embedded in biofilm but showed no activity against intracellular bacteria in the cell model used.
Asunto(s)
Antibacterianos/farmacología , Bacteriófagos/patogenicidad , Biopelículas/efectos de los fármacos , Osteoblastos/microbiología , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/virología , Pruebas de Sensibilidad Microbiana , Vancomicina/farmacologíaRESUMEN
BACKGROUND: Targeting biofilm-embedded and intraosteoblastic Staphylococcus aureus, rifampicin gained a pivotal role in bone and joint infection (BJI) treatment. Two other rifamycins, rifabutin and rifapentine, may represent better-tolerated alternatives, but their activity against bacterial reservoirs associated with BJI chronicity has never been evaluated. OBJECTIVES: To evaluate the activities of rifampicin, rifabutin and rifapentine in osteoblast infection models. METHODS: Using three S. aureus isolates, rifamycins were compared regarding: (i) their intracellular activity in 'acute' (24 h) and 'chronic' (7 days) osteoblast infection models at 0.1× MIC, 1× MIC, 10× MIC and 100× MIC, while impacting infection-induced cytotoxicity (MTT assay), intracellular phenol-soluble modulin (PSM) secretion (RT-PCR), resistance selection and small colony variant (SCV) emergence; and (ii) their minimal biofilm eradication concentration (MBEC) and their MIC to prevent biofilm formation (bMIC). RESULTS: At 0.1× MIC, only rifabutin significantly reduced intracellular inoculum and PSM secretion. All rifamycins allowed a 50% reduction of intraosteoblastic inoculum at higher concentrations, with no difference between acute and chronic infection models, while reducing infection-induced cytotoxicity and PSM secretion. Dose-dependent emergence of intracellular SCVs was observed for all molecules. No intracellular emergence of resistance was detected. bMICs were equivalent for all molecules, but MBEC90s of rifapentine and rifabutin were 10- to 100-fold lower than those of rifampicin, respectively. CONCLUSIONS: All rifamycins are efficient in reducing the S. aureus intraosteoblastic reservoir while limiting infection-induced cytotoxicity, with a higher activity of rifabutin at low concentrations. All molecules prevent biofilm formation, but only rifapentine and rifabutin consistently reduce formed biofilm-embedded bacteria for all isolates. The activity of rifabutin at lower doses highlights its therapeutic potential.