Risk Factors of Daptomycin-Induced Eosinophilic Pneumonia in a Population with Osteoarticular Infection

Background: Daptomycin-induced eosinophilic pneumonia (DEP) is a rare but severe adverse effect and the risk factors are unknown. The aim of this study was to determine risk factors for DEP. Methods: A retrospective cohort study was performed at the Bone and Joint Infection Unit of the Hospital Universitari Bellvitge (January 2014-December 2018). To identify risk factors for DEP, cases were divided into two groups: those who developed DEP and those without DEP. Results: Among the whole cohort (n = 229) we identified 11 DEP cases (4.8%) and this percentage almost doubled in the subgroup of patients ≥70 years (8.1%). The risk factors for DEP were age ≥70 years (HR 10.19, 95%CI 1.28-80.93), therapy >14 days (7.71, 1.98-30.09) and total cumulative dose of daptomycin ≥10 g (5.30, 1.14-24.66). Conclusions: Clinicians should monitor cumulative daptomycin dosage to minimize DEP risk, and be cautious particularly in older patients when the total dose of daptomycin exceeds 10 g

The Different Microbial Etiology of Prosthetic Joint Infections According to Route of Acquisition and Time After Prosthesis Implantation, Including the Role of Multidrug-Resistant Organisms

The aim of our study was to characterize the etiology of prosthetic joint infections (PJIs)-including multidrug-resistant organisms (MDRO)-by category of infection. A multicenter study of 2544 patients with PJIs was performed. We analyzed the causative microorganisms according to the Tsukayama's scheme (early postoperative, late chronic, and acute hematogenous infections (EPI, LCI, AHI) and "positive intraoperative cultures" (PIC)). Non-hematogenous PJIs were also evaluated according to time since surgery: 12 months. AHIs were mostly caused by Staphylococcus aureus (39.2%) and streptococci (30.2%). EPIs were characterized by a preponderance of virulent microorganisms (S. aureus, Gram-negative bacilli (GNB), enterococci), MDROs (24%) and polymicrobial infections (27.4%). Conversely, coagulase-negative staphylococci (CoNS) and Cutibacterium species were predominant in LCIs (54.5% and 6.1%, respectively) and PICs (57.1% and 15.1%). The percentage of MDROs isolated in EPIs was more than three times the percentage isolated in LCIs (7.8%) and more than twice the proportion found in AHI (10.9%). There was a significant decreasing linear trend over the four time intervals post-surgery for virulent microorganisms, MDROs, and polymicrobial infections, and a rising trend for CoNS, streptococci and Cutibacterium spp. The observed differences have important implications for the empirical antimicrobial treatment of PJIs.Acknowledgments: This work was supported by the Instituto de Salud Carlos III, Spanish Ministry of Economy and Competitiveness (grant number PI15/1026) (Co-funded by European Regional Development Fund/European Social Fund "Investing in your future"). REIPI (Spanish Network for Research in Infectious Disease) is supported by the Instituto de Salud Carlos III, Spanish Ministry of Economy and Competitiveness, and by the European Development Regional Fund “A way to achieve Europe”

Orthopaedic device-related infections: some thoughts on management and antimicrobial efficacy from a clinical and experimental perspective

[eng] Orthopaedic device-related infections represent a health care problem of first magnitude due to the increasing incidence, complexity of management, and elevated cost. These device related infections have etio-pathogenic features that involve the participation of bacteria in the stationary growth phase as well as mature biofilms, which makes their diagnosis and treatment more challenging. Several studies have been performed to ameliorate the present guidelines. Nevertheless, there are still many points of uncertainty and many relevant clinical questions remain unanswered. This thesis explores some of these unanswered questions in the field of orthopaedic device related infections from the perspective of an infectious diseases specialist. A. On the management of orthopaedic device-related infections A.1. Diagnostic aspects of PJI • Aim 1: to analyse the microbiological and clinical findings in patients with suspected prosthetic joint aseptic loosening, and to compare them to patients with chronic PJI Conclusions: 1.1 Several patients with suspected prosthetic aseptic loosening have misdiagnosed PJI or some microorganisms in their samples. 1.2 Sonication samples provide additional microbiological information that should help clinicians with the diagnosis of delayed low-grade infections that mimic natural aseptic failure. 1.3 Clinical parameters that determine the final prosthesis removal are correlated with the number of positive peri-prosthetic samples. A.2. Surgical management of PJI • Aim 2: to evaluate the risk of re-infection following one-stage and to-stage surgical revision with hip PJI Conclusions: 2.1 The one-stage revision strategy may be as effective as the two-stage revision strategy. B. On the assessment of antimicrobial efficacy for the treatment of orthopaedic devicerelated infections B.1. Infections by Streptococcus spp • Aim 3: to assess the efficacy of adding rifampicin to β-lactams for the treatment of streptococcal PJI managed with implant retention, and its impact on the prognosis Conclusions: 3.1 For the largest case series of stretopcoccal PJI managed with DAIR, this pathology showed a not-so-good prognosis as expected. 3.2 The treatment with β-lactams seems ideal for fighting the planktonic component of streptococcal PJI; the addition of rifampin some days or weeks after debridement could have a role in the antibiofilm profile to improve the current modest outcomes. 3.3 A concomitant and optimal surgical procedure is advised, following IDSA criteria and ensuring the exchange of removal components during the debridement. Similar prognosis results were observed when the IDSA criteria for DAIR were cutoff at the third month of revision. B.2. Infections by MDR Gram-negative bacilli B.2.1 The use of β-lactams in continuous infusion • Aim 4: to standardize a measurement procedure based on UHPLC-MS/MS for the simultaneous determination of multiple β-lactam concentrations in human plasma Conclusions: 4.1 The development of a single UHPLC-MS/MS method for the simultaneous measurement of multiple β-lactam concentrations in human plasma enable the applicability of this method to routine clinical practice and the validation of an easy-to use equation for clinical use. • Aim 5: to evaluate the efficacy and safety of β-lactams in continuous infusion for difficult-to-treat osteoarticular infections caused by Gram-negative bacilli, and to validate an easy method for clinical use Conclusions: 5.1 The use of β-lactams in continuous infusion is safe and effective, and may recover previously resistant strains that became susceptible in terms of their pharmacodynamic parameters. Lower doses could be used by BL-CI for susceptible strains. 5.2 A simple equation could help clinicians to estimate the β-lactams continuous infusion dosage and its plasma levels in the early hours of treatment. B.2.2 The use of antibiotic combinations with colistin • Aim 6: to evaluate the benefits of the combination of colistin and β-lactams when treating patients with MDR Pseudomonas aeruginosa infections Conclusions: 6.1 Current recommendations should consider the combination of low-dose colistin with β-lactams as an optimized treatment for osteoarticular infections caused by MDR P.aeruginosa. 6.2 This antibiotic combination is essential for achieving positive outcomes for these difficult-to-treat infections. • Aim 7: to study the effect of adding colistin to β-lactams against ESBL-producing klebsiella pneumoniae biofilm in an in vitro experimental model Conclusions 7.1 As expected, colistin in monotherapy was ineffective against biofilm-embedded bacteria and resulted in the emergence of colistin resistant strains. 7.2 Meropenem in monotherapy and its combination with colistin achieved rapid killing rates that were maintained until the end of treatment. However, only the combination showed bactericidal activity in one of the tested strains of ESBL-producing Klebsiella pneumoniae and its effect was more pronounced under conditions that produced a greater biofilm. The combined therapy avoided the emergence of colistin-resistant strains. 7.3 Our preliminary results may indicate a slight overall superiority in vitro of adding colistin to β-lactams against carbapenem-susceptible ESBL-producing K. pneumoniae.[cat] Les infeccions osteoarticulars relacionades amb implants ortopèdics són un problema de salut de primera magnitud: per la seva incidència creixent, la seva complexitat i l’alt cost sanitari. Suposen un gran repte per l’especialista en malalties infeccioses, principalment per les seves particularitats etio-patogènicas amb participació de bacteris en fase estacionària de creixement i la formació de biofilm. Els objectius d’aquesta tesi pretenen explorar alguns aspectes no resolts sobre el maneig i la eficàcia antimicrobiana en el marc de la infecció osteoarticular relacionada amb l’implant. Al través de 7 treballs s’han desenvolupat els següents punts: • Estudi de les característiques clíniques i microbiològiques dels casos d’afluixament asèptic protèsic sotmesos a revisió, amb l’objectiu d’entendre millor aquesta entitat (interpretació dels cultius positius aïllats). • Estudi comparatiu del maneig quirúrgic de la infecció protèsica crònica: recanvi en un o dos temps. • Estudi de la infecció protèsica estreptocòccica manejada amb desbridament, antibiòtics i retenció de l’implant (DAIR); amb l’objectiu d’avaluar el pronòstic d’aquesta entitat i els factors que poden millorar la seva taxa de curació. • Estudi sobre l’ús de betalactàmics en infusió continua en les infeccions osteoarticulars relacionades amb implants causades per BGN, amb els objectius: 1) estandarditzar un procediment basat en UHPLC-MS/MS para la determinació dels nivells plasmàtics de betalactàmics, 2) validar una equació senzilla per estimar la dosis de betalactàmics òptima en perfusió continua i els nivells plasmàtics. 3) avaluar la seguretat i eficàcia antimicrobiana de l’ús de betalactàmics en infusió continua. • Estudis sobre l’eficàcia d’afegir colistina al tractament amb betalactàmics en el maneig d’infeccions gram-negatives multiresistents: 1) estudi clínic , 2) model in vitro per la formació de biofilm. Les principals troballes: • Alguns casos amb sospita d’afluixament protèsic asèptic són realment infeccions o presenten microorganismes aïllats sobre la superfície de l’implant. • L`estratègia de revisió protèsica pel tractament de les infeccions de pròtesis articulars en un temps pot ser (en general) tan efectiva com la revisió en dos temps. • La infecció protèsica estreptocòccica manejada amb DAIR va mostrar un pitjor pronòstic del descrit prèviament a la literatura. Un bon maneig de les guies IDSA, el recanvi dels components mòbils i la potencial eficàcia del tractament combinat amb rifampicina podrien millorar aquest modest pronòstic. • L’estandardització d’un mètode UHLPC-MS/MS per la determinació de betalactàmics permet la monitorització de nivells en pacients tractats amb perfusió contínua. • Mitjançant la comparació amb els resultats UHLPC-MS/MS s’ha pogut validar una equació simple per una estimació individualitzada de la dosi òptima de betalactàmics en perfusió continua i de nivells en plasma . • L’ús clínic de betalactàmics en perfusió continua és segur y eficaç. • Afegir colistina als betalactàmics en el tractament de les infeccions osteoarticulars produïdes per BGN multiresistents mostra millors resultats que el tractament en monoteràpia amb betalactàmic. • En el model in vitro per la formació de biofilm, també hem objectivat el benefici de la teràpia combinada amb colistina