Efficacy of β-lactam/β-lactamase inhibitors to treat extended-spectrum beta-lactamase-producing Enterobacterales bacteremia secondary to urinary tract infection in kidney transplant recipients (INCREMENT-SOT Project)

REIPI/INCREMENT-SOT Group.[Background] Whether active therapy with β-lactam/β-lactamase inhibitors (BLBLI) is as affective as carbapenems for extended-spectrum β-lactamase-producing Enterobacterales (ESBL-E) bloodstream infection (BSI) secondary to urinary tract infection (UTI) in kidney transplant recipients (KTRs) remains unclear.[Methods] We retrospectively evaluated 306 KTR admitted to 30 centers from January 2014 to October 2016. Therapeutic failure (lack of cure or clinical improvement and/or death from any cause) at days 7 and 30 from ESBL-E BSI onset was the primary and secondary study outcomes, respectively.[Results] Therapeutic failure at days 7 and 30 occurred in 8.2% (25/306) and 13.4% (41/306) of patients. Hospital-acquired BSI (adjusted OR [aOR]: 4.10; 95% confidence interval [CI]: 1.50-11.20) and Pitt score (aOR: 1.47; 95% CI: 1.21-1.77) were independently associated with therapeutic failure at day 7. Age-adjusted Charlson Index (aOR: 1.25; 95% CI: 1.05-1.48), Pitt score (aOR: 1.72; 95% CI: 1.35-2.17), and lymphocyte count ≤500 cells/μL at presentation (aOR: 3.16; 95% CI: 1.42-7.06) predicted therapeutic failure at day 30. Carbapenem monotherapy (68.6%, primarily meropenem) was the most frequent active therapy, followed by BLBLI monotherapy (10.8%, mostly piperacillin-tazobactam). Propensity score (PS)-adjusted models revealed no significant impact of the choice of active therapy (carbapenem-containing vs any other regimen, BLBLI- vs carbapenem-based monotherapy) within the first 72 hours on any of the study outcomes.[Conclusions] Our data suggest that active therapy based on BLBLI may be as effective as carbapenem-containing regimens for ESBL-E BSI secondary to UTI in the specific population of KTR. Potential residual confounding and unpowered sample size cannot be excluded (ClinicalTrials.gov identifier: NCT02852902).This work was supported by: (1) Plan Nacional de I+D+i 2013-2016 and Instituto de Salud Carlos III (ISCIII), Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Ciencia, Innovación y Universidades, Spanish Network for Research in Infectious Diseases [RD16/0016/0001, RD16/0016/0002, REIPI RD16/0016/0008; RD16/0016/00010], co-financed by European Development Regional Fund “A way to achieve Europe”, Operative Program Intelligent Growth 2014-2020; (2) European Society of Clinical Microbiology and Infectious diseases Study Group for Infections in Compromised Hosts (ESGICH, grant to J.M.A.); (3) Sociedad Andaluza de Trasplante de Órgano Sólido (SATOT, grant to L.M.M.); (4) Research project PI16/01631 integrated into the Plan Estatal de I+D+I 2013-2016 and co-financed by the ISCIII-Subdirección General de Evaluación y Fomento de la Investigación and the Fondo Europeo de Desarrollo Regional (FEDER); (5) M.F.R. holds a research contract “Miguel Servet” (CP 18/00073) from ISCIII, Ministerio de Ciencia, Innovación y Universidades. The work was also supported by the following European Society of Clinical Microbiology and Infectious diseases (ESCMID) study groups: Infections in Compromised Hosts (ESGICH), Bloodstream Infections and Sepsis (ESGBIS) and Antimicrobial Resistance Surveillance (ESGARS).Peer reviewe

Integrating clinical and molecular epidemiology to determine the effectiveness of a screen-and-treat strategy for asymptomatic bacteriuria after kidney transplantation

Dans le domaine des maladies infectieuses, l’épidémiologie clinique utilise les principes de l’épidémiologie pour répondre à des questions cliniques relatives aux infections survenant chez nos patients, constituant ainsi le socle de l’« evidence-based medicine ». L’épidémiologie moléculaire consiste quant à elle à étudier une infection en fonction des caractéristiques moléculaires du pathogène et/ou de l’hôte. Mes collègues et moi- même avons combiné épidémiologies clinique et moléculaire afin de clarifier la pertinence de notre pratique historique de dépistage et traitement de la bactériurie asymptomatique chez les patients transplantés de rein.Plusieurs travaux d’épidémiologie clinique ont été conduits. Dans une enquête de pratique européenne, nous avons constaté que la bactériurie asymptomatique était fréquemment dépistée et traitée par antibiotiques chez les transplantés de rein. Dans une revue systématique et méta-analyse Cochrane, nous n’avons cependant pas identifié de preuves en faveur du traitement antibiotique de la bactériurie asymptomatique chez ces patients. Les preuves disponibles étant peu nombreuses et de faible qualité, nous avons réalisé un essai clinique randomisé multicentrique comparant antibiotiques et abstention thérapeutique chez les transplantés de rein ayant un épisode de bactériurie asymptomatique après les deux premiers mois post-greffe. Dans cet essai, l’antibiothérapie n’a pas réduit significativement l’incidence des infections urinaires symptomatiques. Enfin, dans une étude transversale multicentrique, nous avons observé que la prévalence de la bactériurie asymptomatique était basse chez les transplantés de rein après les deux premiers mois post-greffe (environ 3%). L’ensemble de nos travaux plaide contre une politique systématique de dépistage et traitement de la bactériurie asymptomatique chez les patients transplantés de rein, après les deux premiers mois post-greffe.L’épidémiologie moléculaire a été utilisée afin d’identifier les caractéristiques du pathogène et/ou de l’hôte associés à la pyélonéphrite à Escherichia coli, en comparaison à la bactériurie asymptomatique à E. coli, chez les transplantés de rein. Les épisodes de pyélonéphrite différaient significativement de ceux de bactériurie asymptomatique quant à la prévalence de l’opéron pap, un groupe de gênes permettant la production du P- fimbriae, un des facteurs de virulence d’E. coli les plus étudiés. Notre travail suggère que l’adhésion bactérienne joue un rôle important dans la pathogenèse de la pyélonéphrite de greffe rénale, malgré la présence d’une immunodépression et d’anomalies anatomiques de l’arbre urinaire. Le bénéfice potentiel des thérapies ciblées –vaccination, inhibiteurs de l’adhésion, – reste à déterminer chez les transplantés de rein.Les résultats de nos recherches ont des implications directes pour la pratique clinique. Tout d’abord, nous devons concevoir et mettre en place des interventions limitant l’usage d’antibiotiques chez les transplantés de rein ayant un épisode de bactériurie asymptomatique après les deux premiers mois post-greffe. Ces prescriptions d’antibiotiques survenant typiquement en réponse à un résultat positif de culture d’urine demandée systématiquement dans le cadre de la surveillance post-greffe routinière, il semble prioritaire de lutter contre la prescription systématique des cultures d’urines dans le suivi de ces patients. Par ailleurs, il est urgent d’identifier des stratégies innovantes permettant de prévenir les infections urinaires symptomatiques, qui restent un problème fréquent et important chez les transplantés de rein, sans recourir aux antibiotiques.In the field of infectious diseases, clinical epidemiology can be defined as the application of principles of epidemiology to conduct studies that answer clinical questions related to infections; it serves as the basic science of evidence-based medicine. Molecular epidemiology can be defined as the study of an infection in relation to the molecular characteristics of the causative microorganism and/or the host. My colleagues and I combined clinical and molecular epidemiology studies to determine the usefulness of a screen-and-treat strategy for asymptomatic bacteriuria among kidney transplant recipients.Clinical epidemiology was used to directly evaluate the practice of screening for and treating asymptomatic bacteriuria among kidney transplant recipients. In a survey of practice across Europe, we found that asymptomatic bacteriuria was frequently screened for and treated by kidney transplant physicians. However, a Cochrane systematic review and meta-analysis found no evidence to support the routine treatment of asymptomatic bacteriuria in kidney transplant recipients. Because data were scarce and of low-quality, we performed a pragmatic, multicenter randomized trial to compare antibiotic versus no antibiotic therapy in kidney transplant recipients who have asymptomatic bacteriuria beyond the second month post-transplant. In this trial, antibiotics did not significantly reduce the incidence of symptomatic urinary tract infection. Moreover, in a multicenter, cross-sectional study, the prevalence of asymptomatic bacteriuria was lower than expected in kidney transplant recipients. Specifically, only around 3% of screened kidney transplant recipients had asymptomatic bacteriuria beyond two months post-transplant. Taken together, our clinical epidemiology studies do not support the effectiveness of a screen-and-treat strategy for asymptomatic bacteriuria in kidney transplant recipients who are beyond two months post-transplant.Molecular epidemiology was used to identify pathogen and/or host factor(s) associated with the risk of Escherichia coli pyelonephritis, as compared with asymptomatic E. coli bacteriuria, after kidney transplantation. E. coli pyelonephritis episodes differed significantly from asymptomatic E. coli bacteriuria episodes in the prevalence of the pap operon, a gene cluster that encodes the proteins required for production of P fimbriae, one of the best-studied E. coli virulence factors. These findings suggest that bacterial adherence plays a role in the pathogenesis of pyelonephritis in kidney transplant recipients despite significantly altered host urinary tract anatomy and weakened immunity. Whether kidney transplant recipients might benefit from targeted therapies (e.g. vaccination or inhibitors of fimbrial adhesion) has yet to be studied.Our findings have direct implications. It is now time to design and implement antimicrobial stewardship interventions to limit unwarranted antimicrobial use in kidney transplant recipients who have asymptomatic bacteriuria beyond two months post-transplant. Because antibiotic prescribing for asymptomatic bacteriuria typically occurs in response to the positive result from a urine culture requested during routine screening for bacteriuria in post-transplant follow-up, a priority should be to reduce systematic urine culture in these patients. It is also important that innovative non-antibiotic-based approaches should be developed to prevent symptomatic urinary tract infections, which remain prevalent and detrimental after kidney transplantation.Doctorat en Sciences médicales (Médecine)info:eu-repo/semantics/nonPublishe

Should we treat asymptomatic bacteriuria after renal transplantation?

SCOPUS: re.jSCOPUS: re.jinfo:eu-repo/semantics/publishe

Antibiotic treatment duration for bacteraemic pneumonia

SCOPUS: le.jinfo:eu-repo/semantics/publishe

Risk Factors Associated With Early Invasive Pulmonary Aspergillosis in Kidney Transplant Recipients: Results From a Multinational Matched Case–Control Study

Risk factors for invasive pulmonary aspergillosis (IPA) after kidney transplantation have been poorly explored. We performed a multinational case–control study that included 51 kidney transplant (KT) recipients diagnosed with early (first 180 posttransplant days) IPA at 19 institutions between 2000 and 2013. Control recipients were matched (1:1 ratio) by center and date of transplantation. Overall mortality among cases was 60.8%, and 25.0% of living recipients experienced graft loss. Pretransplant diagnosis of chronic pulmonary obstructive disease (COPD; odds ratio [OR]: 9.96; 95% confidence interval [CI]: 1.09–90.58; p = 0.041) and delayed graft function (OR: 3.40; 95% CI: 1.08–10.73; p = 0.037) were identified as independent risk factors for IPA among those variables already available in the immediate peritransplant period. The development of bloodstream infection (OR: 18.76; 95% CI: 1.04–339.37; p = 0.047) and acute graft rejection (OR: 40.73, 95% CI: 3.63–456.98; p = 0.003) within the 3 mo prior to the diagnosis of IPA acted as risk factors during the subsequent period. In conclusion, pretransplant COPD, impaired graft function and the occurrence of serious posttransplant infections may be useful to identify KT recipients at the highest risk of early IPA. Future studies should explore the potential benefit of antimold prophylaxis in this group.0SCOPUS: ar.jFLWINSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Clinical Presentation and Determinants of Mortality of Invasive Pulmonary Aspergillosis in Kidney Transplant Recipients: A Multinational Cohort Study

The prognostic factors and optimal therapy for invasive pulmonary aspergillosis (IPA) after kidney transplantation (KT) remain poorly studied. We included in this multinational retrospective study 112 recipients diagnosed with probable (75.0% of cases) or proven (25.0%) IPA between 2000 and 2013. The median interval from transplantation to diagnosis was 230 days. Cough, fever, and expectoration were the most common symptoms at presentation. Bilateral pulmonary involvement was observed in 63.6% of cases. Positivity rates for the galactomannan assay in serum and bronchoalveolar lavage samples were 61.3% and 57.1%, respectively. Aspergillus fumigatus was the most commonly identified species. Six- and 12-week survival rates were 68.8% and 60.7%, respectively, and 22.1% of survivors experienced graft loss. Occurrence of IPA within the first 6 months (hazard ratio [HR]: 2.29; p-value = 0.027) and bilateral involvement at diagnosis (HR: 3.00; p-value = 0.017) were independent predictors for 6-week all-cause mortality, whereas the initial use of a voriconazole-based regimen showed a protective effect (HR: 0.34; p-value = 0.007). The administration of antifungal combination therapy had no apparent impact on outcome. In conclusion, IPA entails a dismal prognosis among KT recipients. Maintaining a low clinical suspicion threshold is key to achieve a prompt diagnosis and to initiate voriconazole therapy.0SCOPUS: ar.jFLWINinfo:eu-repo/semantics/publishe

Multinational case-control study of risk factors for the development of late invasive pulmonary aspergillosis following kidney transplantation

Objectives: To assess the risk factors for development of late-onset invasive pulmonary aspergillosis (IPA) after kidney transplantation (KT). Methods: We performed a multinational case-control study that retrospectively recruited 112 KT recipients diagnosed with IPA between 2000 and 2013. Controls were matched (1:1 ratio) by centre and date of transplantation. Immunosuppression-related events (IREs) included the occurrence of non-ventilator-associated pneumonia, tuberculosis, cytomegalovirus disease, and/or de novo malignancy. Results: We identified 61 cases of late (>180 days after transplantation) IPA from 24 participating centres (accounting for 54.5% (61/112) of all cases included in the overall study). Most diagnoses (54.1% (33/61)) were established within the first 36 post-transplant months, although five cases occurred more than 10 years after transplantation. Overall mortality among cases was 47.5% (29/61). Compared with controls, cases were significantly older (p 0.010) and more likely to have pre-transplant chronic obstructive pulmonary disease (p 0.001) and a diagnosis of bloodstream infection (p 0.016) and IRE (p <0.001) within the 6 months prior to the onset of late IPA. After multivariate adjustment, previous occurrence of IRE (OR 19.26; 95% CI 2.07–179.46; p 0.009) was identified as an independent risk factor for late IPA. Conclusion: More than half of IPA cases after KT occur beyond the sixth month, with some of them presenting very late. Late IPA entails a poor prognosis. We identified some risk factors that could help the clinician to delimit the subgroup of KT recipients at the highest risk for late IPA.0SCOPUS: ar.jinfo:eu-repo/semantics/publishe