Epidemiología y optimización del manejo clínico de la candidemia: Resultados de un estudio poblacional en España

La candidemia es una de las manifestaciones clínicas más frecuentes de la infección fúngica invasora, con una incidencia globalmente superior a la aspergilosis y una elevada morbi-mortalidad asociada. El colectivo de pacientes susceptibles para desarrollar esta infección es amplio y heterogéneo, siendo especialmente vulnerables los pacientes afectos de una enfermedad neoplásica, aquellos ingresados en las Unidades de Cuidados Intensivos (UCIs) y la población neonatal. Sin embargo, la candidemia es una infección en constante evolución, cuyos cambios epidemiológicos se relacionan estrechamente con las prácticas sanitarias. Por ello, conocer su epidemiología, la distribución de especies de Candida y el patrón de resistencia a los diferentes antifúngicos en cada zona geográfica es fundamental para guiar la selección de un tratamiento empírico adecuado y mejorar así el pronóstico de los pacientes. En este contexto clínico, a principios de la década del año 2010, aún existían en España lagunas de conocimiento a nivel epidemiológico, microbiológico y clínico-terapéutico sobre el manejo de la candidemia. Por este motivo, entre mayo del año 2010 y abril del 2011 se realizó el primer estudio poblacional nacional (estudio CANDIPOP) que pretendía resolver estas cuestiones a partir de la información obtenida en cinco grandes áreas metropolitanas: Barcelona, Bilbao, Madrid, Sevilla y Valencia. La presente tesis doctoral "Epidemiología y optimización del manejo clínico de la candidemia: Resultados de un estudio poblacional en España", escrita como un compendio de 4 publicaciones muestra los principales resultados del estudio CANDIPOP. El primer artículo, "Epidemiology and predictive factors for early and late mortality in Candida bloodstream infections: a population-based surveillance in Spain" proporciona una perspectiva global del problema y una estimación de la incidencia de la candidemia en nuestro entorno geográfico. En resumen, la incidencia poblacional de candidemia fue de 8,1 casos/100.000 habitantes/año y las especies predominantes fueron Candida albicans (45,4%), C. parapsilosis (24,9%) y C. glabrata (13,4%). La sensibilidad global a fluconazol fue del 79%. La mortalidad acumulada a los 7 y 30 días fue del 12,8% y del 30,6%, respectivamente. En el análisis multivariado se observó que el inicio de un tratamiento antifúngico adecuado en las primeras 48 horas (OR 0,51, IC95% 0,27-0,95) y la retirada precoz del catéter venoso central (OR 0,43, IC95% 0,21-0,87) estaban asociados con una menor mortalidad a los 7 días. En contraposición, la mortalidad tardía (8-30 días) estaba asociada principalmente con las comorbilidades propias del paciente y con una presentación clínica grave de la infección. Los artículos segundo y tercero, "Impact of therapeutic strategies on the prognosis of candidemia in the intensive care unit " y "Epidemiology and outcome of candidaemia in patients with oncological and haematological malignancies: results from a population-based surveillance in Spain" se centran en dos subpoblaciones de alto riesgo para desarrollar un episodio de candidemia, como son los enfermos adultos ingresados en las UCIs y los pacientes con una neoplasia oncohematológica de base. El objetivo de ambos trabajos es proporcionar nuevos conocimientos que permitan optimizar las estrategias terapéuticas en grupos poblacionales con características propias diferenciales. Finalmente, el cuarto artículo, "Propensity score analysis of the role of initial antifungal therapy in the outcome of Candida glabrata bloodstream infections", evalúa la eficacia de fluconazol en comparación con las equinocandinas y/o anfotericina B liposomal como tratamiento inicial de la candidemia por C. glabrata. Los resultados de este análisis muestran que el tratamiento inicial con fluconazol no se asocia con un peor pronóstico de los pacientes (OR para mortalidad a los 14 días: 1,16, IC95% 0,22-6,17 y OR para fracaso terapéutico: 0,83, IC95% 0,27-2,61). Estos datos sugieren que en contextos epidemiológicos con una baja tasa de resistencias a fluconazol, este antifúngico aún podría ser una opción razonable como tratamiento empírico de la candidemia, antes de tener la identificación de especie y descartar la posibilidad de una infección por C. glabrata.Candidaemia is one of the most common manifestations of invasive fungal infection, with an incidence higher than aspergillosis and significant morbidity and mortality. A large and heterogeneous group of patients is susceptible to develop this infection, being especially vulnerable those with neoplastic diseases, those admitted to intensive care units (ICUs), and the neonatal population. However, candidaemia is an evolving disease, whose epidemiological changes are closely related to healthcare practices. Therefore, a basic knowledge of its epidemiology, the distribution of Candida species and the antifungal susceptibility pattern of each geographical region is essential to guide the selection of adequate empirical treatment and, ultimately, to improve the patients' prognosis. In this clinical scenario, in early 2010, updated information regarding the epidemiology of candidaemia, the microbiological features of the isolated species, and basic clinical and therapeutic information about the management of this condition was still lacking in Spain. Hence, between May 2010 and April 2011 the first national population-based study (CANDIPOP) was conducted in 5 of the largest metropolitan areas of Spain (Barcelona, Bilbao, Madrid, Seville, and Valencia), with the aim of filling these local gaps of uncertainty. This thesis, "Epidemiology and optimization of the clinical management of candidaemia: Results of a population-based study in Spain", written as a compendium of 4 publications, attempts to show the main results of the CANDIPOP study. The first article, "Epidemiology and predictive factors for early and late mortality in Candida bloodstream infections: a population-based surveillance in Spain" offers an updated, general overview of this infection and estimates the incidence of candidaemia in Spain. Briefly, the annual incidence of candidaemia was 8.1 cases/100 000 inhabitants and the predominant Candida species were Candida albicans (45.4%), C. parapsilosis (24.9%), and C. glabrata (13.4%). Overall, 79% of Candida isolates were susceptible to fluconazole. Cumulative mortality at 7 and 30 days after the first episode of candidaemia was 12.8% and 30.6%, respectively. Multivariate analysis showed that therapeutic measures within the first 48 hours might improve 7-day mortality: antifungal treatment (OR 0.51, 95%CI 0.27-0.95) and central venous catheter removal (OR 0.43, 95%CI 0.21-0.87). Conversely, predictors of late death (8-30 days) were mainly related to the patients' comorbid status and infection severity at onset. The second and third articles, "Impact of therapeutic strategies on the prognosis of candidemia in the intensive care unit" and "Epidemiology and outcome of candidaemia in patients with oncological and haematological malignancies: results from a population-based surveillance in Spain" focus on two populations at high risk for developing an episode of candidaemia: adult patients admitted to ICUs and patients with oncological and haematological malignancies. The main objective of these publications was to provide further information that would allow physicians to optimise therapeutic strategies in patients who have some differential characteristics. Finally, the fourth article, "Propensity score analysis of the role of initial antifungal therapy in the outcome of Candida glabrata bloodstream infections", aimed to evaluate whether the choice of initial antifungal treatment (fluconazole vs. echinocandins or liposomal amphotericin B-based regimens) has an impact on the outcome of candidaemia caused by C. glabrata. Our results show that initial use of fluconazole is not associated with an unfavourable evolution (adjusted OR for 14-day mortality: 1.16, 95%CI 0.22-6.17; adjusted OR for treatment failure: 0.83, 95%CI 0.27-2.61). These data suggest that in settings with low rates of fluconazole-resistant strains, this agent may be still a reasonable option for treating stable patients with candidaemia before the Candida species is identified

Comparative effectiveness of daptomycin versus vancomycin among patients with methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections: A systematic literature review and meta-analysis

Background In the treatment of methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections (BSIs), vancomycin stands as the prevalent therapeutic agent. Daptomycin remains an alternative antibiotic to treat MRSA BSIs in cases where vancomycin proves ineffective. However, studies have conflicted on whether daptomycin is more effective than vancomycin among patients with MRSA BSI. Objective To compare the effectiveness of daptomycin and vancomycin for the prevention of mortality among adult patients with MRSA BSI. Methods Systematic searches of databases were performed, including Embase, PubMed, Web of Science, and Cochrane Library. The Newcastle Ottawa Scale (NOS) and Revised Cochrane risk-of-bias tool for randomized trials (RoB 2) were used to assess the quality of individual observational and randomized control studies, respectively. Pooled odd ratios were calculated using random effects models. Results Twenty studies were included based on a priori set inclusion and exclusion criteria. Daptomycin treatment was associated with non-significant lower mortality odds, compared to vancomycin treatment (OR = 0.81; 95% CI, 0.62, 1.06). Sub-analyses based on the time patients were switched from another anti-MRSA treatment to daptomycin demonstrated that switching to daptomycin within 3 or 5 days was significantly associated with 55% and 45% decreased odds of all-cause mortality, respectively. However, switching to daptomycin any time after five days of treatment was not significantly associated with lower odds of mortality. Stratified analysis based on vancomycin minimum inhibitory concentration (MIC) revealed that daptomycin treatment among patients infected with MRSA strains with MIC >= 1 mg/L was significantly associated with 40% lower odds of mortality compared to vancomycin treatment. Conclusion Compared with vancomycin, an early switch from vancomycin to daptomycin was significantly associated with lower odds of mortality. In contrast, switching to daptomycin at any time only showed a trend towards reduced mortality, with a non-significant association. Therefore, the efficacy of early daptomycin use over vancomycin against mortality among MRSA BSIs patients may add evidence to the existing literature in support of switching to daptomycin early over remaining on vancomycin. More randomized and prospective studies are needed to assess this association

Viremia por citomegalovirus y relación con en el pronóstico de los enfermos VIH con de 50 linfocitos

La introducció del tractament antirretroviral d'alta eficàcia ha contribuït a reduir dràsticament la incidència global de la malaltia per CMV en pacients VIH. A l'era actual, els coneixements sobre el significat clínic de la virèmia per CMV són escassos. L'objectiu del present estudi restrospectiu és estudiar la prevalença de la replicació per CMV en pacients amb la infecció per VIH i de 50 limfòcits CD4, i avaluar l'impacte que té la replicació de CMV (mitjançant la tècnica quantitativa de PCR) en el pronòstic d'aquests malalts.La introducción del tratamiento antiretroviral de alta eficacia contribuyó a reducir drásticamente la incidencia global de enfermedad por CMV en pacientes VIH. En la etapa actual, el conocimiento sobre el significado clínico de la viremia por CMV es escaso. El objetivo del presente estudio restrospectivo es estudiar la prevalencia de replicación por CMV en pacientes con infección por VIH y de 50 linfocitos CD4 y evaluar el impacto que tiene la replicación de CMV (mediante la técnica cuantitativa de PCR) en el pronóstico de estos enfermos

Prolonged vs short-term infusion of β-lactam antibiotics for the treatment of febrile neutropenia: A systematic review and meta-analysis

Background: The optimisation of the use of beta-lactam antibiotics (BLA) via prolonged infusions in life-threatening complications such as febrile neutropenia (FN) is still controversial. This systematic review and meta-analysis aim to evaluate the efficacy of this strategy in onco-haematological patients with FN. Methods: A systematic search was performed of PubMed, Web of Science, Cochrane, EMBASE, World Health Organization, and ClinicalTrials.gov, from database inception until December 2022. The search included randomised controlled trials (RCTs) and observational studies that compared prolonged vs short-term infusions of the same BLA. The primary outcome was all-cause mortality. Secondary outcomes were defervescence, requirement of vasoactive drugs, length of hospital stay and adverse events. Pooled risk ratios were calculated using random effects models. Results: Five studies were included, comprising 691 episodes of FN, mainly in haematological patients. Prolonged infusion was not associated with a reduction in all-cause mortality (pRR 0.83; 95% confidence interval 0.47-1.48). Nor differences were found in secondary outcomes. Conclusions: The limited data available did not show significant differences in terms of all-cause mortality or significant secondary outcomes in patients with FN receiving BLA in prolonged vs. short-term infusion. High-quality RCTs are needed to determine whether there are subgroups of FN patients who would benefit from prolonged BLA infusion. (c) 2023 The Author(s). Published by Elsevier Ltd on behalf of The British Infection Association. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Daptomycin Plus Fosfomycin Versus Daptomycin Alone for Methicillin-resistant Staphylococcus aureus Bacteremia and Endocarditis: A Randomized Clinical Trial

Bacteremia; Daptomycin; FosfomycinBacterièmia; Daptomicina; FosfomicinaBacteriemia; Daptomicina; FosfomicinaBackground We aimed to determine whether daptomycin plus fosfomycin provides higher treatment success than daptomycin alone for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia and endocarditis. Methods A randomized (1:1) phase 3 superiority, open-label, and parallel group clinical trial of adult inpatients with MRSA bacteremia was conducted at 18 Spanish hospitals. Patients were randomly assigned to receive either 10 mg/kg of daptomycin intravenously daily plus 2 g of fosfomycin intravenously every 6 hours, or 10 mg/kg of daptomycin intravenously daily. Primary endpoint was treatment success 6 weeks after the end of therapy. Results Of 167 patients randomized, 155 completed the trial and were assessed for the primary endpoint. Treatment success at 6 weeks after the end of therapy was achieved in 40 of 74 patients who received daptomycin plus fosfomycin and in 34 of 81 patients who were given daptomycin alone (54.1% vs 42.0%; relative risk, 1.29 [95% confidence interval, .93–1.8]; P = .135). At 6 weeks, daptomycin plus fosfomycin was associated with lower microbiologic failure (0 vs 9 patients; P = .003) and lower complicated bacteremia (16.2% vs 32.1%; P = .022). Adverse events leading to treatment discontinuation occurred in 13 of 74 patients (17.6%) receiving daptomycin plus fosfomycin, and in 4 of 81 patients (4.9%) receiving daptomycin alone (P = .018). Conclusions Daptomycin plus fosfomycin provided 12% higher rate of treatment success than daptomycin alone, but this difference did not reach statistical significance. This antibiotic combination prevented microbiological failure and complicated bacteremia, but it was more often associated with adverse events.This work was supported by the Spanish Ministry of Science, Innovation and Universities (PI12/01907); Spanish Network for Research in Infectious Diseases (RD16/0016/0005); Instituto de Salud Carlos III (ISCIII); and Spanish Ministry of Economy, Industry and Competitiveness. This work was also supported by the European Development Regional Fund “A way to achieve Europe,” Operational Programme Intelligent Growth 2014–2020; Spanish Clinical Research Network (SCReN), co-financed by the Plan Nacional de I+D and ISCIII, Subdirección General de Evaluación y Fomento de la Investigación (PT13/0002/0007); and the Grupo de Estudio de la Infección Relacionada con la Asistencia Sanitaria. J. M.-M. received a personal 80:20 research grant from the Institut d’Investigacions Biomèdiques Agust Pi i Sunyer, Barcelona, Spain, during 2017–2021

Global Emergence of Resistance to Fluconazole and Voriconazole in Candida parapsilosis in Tertiary Hospitals in Spain During the COVID-19 Pandemic

Candida parapsilosis; Antifungal resistance; OutbreaksCandida parapsilosis; Resistencia antifúngica; BrotesCandida parapsilosis; Resistència antifúngica; BrotsBackground Candida parapsilosis is a frequent cause of candidemia worldwide. Its incidence is associated with the use of medical implants, such as central venous catheters or parenteral nutrition. This species has reduced susceptibility to echinocandins, and it is susceptible to polyenes and azoles. Multiple outbreaks caused by fluconazole-nonsusceptible strains have been reported recently. A similar trend has been observed among the C. parapsilosis isolates received in the last 2 years at the Spanish Mycology Reference Laboratory. Methods Yeast were identified by molecular biology, and antifungal susceptibility testing was performed using the European Committee on Antimicrobial Susceptibility Testing protocol. The ERG11 gene was sequenced to identify resistance mechanisms, and strain typing was carried out by microsatellite analysis. Results We examined the susceptibility profile of 1315 C. parapsilosis isolates available at our reference laboratory between 2000 and 2021, noticing an increase in the number of isolates with acquired resistance to fluconazole, and voriconazole has increased in at least 8 different Spanish hospitals in 2020–2021. From 121 recorded clones, 3 were identified as the most prevalent in Spain (clone 10 in Catalonia and clone 96 in Castilla-Leon and Madrid, whereas clone 67 was found in 2 geographically unrelated regions, Cantabria and the Balearic Islands). Conclusions Our data suggest that concurrently with the coronavirus disease 2019 pandemic, a selection of fluconazole-resistant C. parapsilosis isolates has occurred in Spain, and the expansion of specific clones has been noted across centers. Further research is needed to determine the factors that underlie the successful expansion of these clones and their potential genetic relatedness.O.Z. was funded by grants SAF2017–86912-R and PID2020–114546RB-I00 from the Spanish Ministry for Science and Innovation. This work was also funded by the National Centre for Microbiology (Instituto de Salud Carlos III) through the Surveillance Program of Antifungal Resistance and the Center for Biomedical Research in Network of Infectious Diseases CIBERINFECTCB21/13/00105 (O.Z. and L.A.F.), CIBERINFEC-CB21/13/00009 (M.P.-A.), CIBERES-CB06/06/0037 (C.A.-T.), and CIBERES-CB06/06/0058 (J.G). L.A.-F. was supported by Fondo de Investigación Sanitaria (MPY 117/18 and MPY 305/20). We thank Dr. David Campany Herrero (Vall d’Hebron Hospital), Noelia Garrido Peño (Móstoles Hospital), David Gómez Gómez y Aitziber Illaro Uranga (Marqués de Valdecilla Hospital), María Ángeles Machín Morón (Burgos Hospital), Jose Manuel Caro Teller (Doce de Octubre Hospital), Marina Calvo (Puerta de Hierro Hospital), and Ariadna Padulles (Bellvitge Hospital) for providing the data on antifungal consumption from their hospitals. We also thank Ángel Zaballos and Pilar Jiménez from the Genomics Core Facility from Instituto de Salud Carlos III for their technical help with the microsatellite analysis technique

Oral antibiotic prophylaxis lowers surgical site infection in elective colorectal surgery: results of a pragmatic cohort study in Catalonia

Background: The role of oral antibiotic prophylaxis (OAP) and mechanical bowel preparation (MBP) in the prevention of surgical site infection (SSI) after colorectal surgery is still controversial. The aim of this study was to analyze the effect of a bundle including both measures in a National Infection Surveillance Network in Catalonia. Methods: Pragmatic cohort study to assess the effect of OAP and MBP in reducing SSI rate in 65 hospitals, comparing baseline phase (BP: 2007-2015) with implementation phase (IP: 2016-2019). To compare the results, a logistic regression model was established. Results: Out of 34,421 colorectal operations, 5180 had SSIs (15.05%). Overall SSI rate decreased from 18.81% to 11.10% in BP and IP, respectively (OR 0.539, CI95 0.507-0.573, p < 0.0001). Information about bundle implementation was complete in 61.7% of cases. In a univariate analysis, OAP and MBP were independent factors in decreasing overall SSI, with OR 0.555, CI95 0.483-0.638, and OR 0.686, CI95 0.589-0.798, respectively; and similarly, organ/space SSI (O/S-SSI) (OR 0.592, CI95 0.494-0.710, and OR 0.771, CI95 0.630-0.944, respectively). However, only OAP retained its protective effect at both levels at multivariate analyses. Conclusions: oral antibiotic prophylaxis decreased the rates of SSI and O/S-SSI in a large series of elective colorectal surger

Voriconazole Pharmacokinetics in Critically Ill Patients and Extracorporeal Membrane Oxygenation Support: A Retrospective Comparative Case-Control Study

Voriconazole, an antifungal agent, displays high intra- and inter-individual variability. The predictive pharmacokinetic (PK) index requires a minimum plasma concentration (C-min) in patient serum of between 1-5.5 mg/L. It is common to encounter fungal infections in patients undergoing extracorporeal membrane oxygenation (ECMO) support, and data regarding voriconazole PK changes during ECMO are scarce. Our study compared voriconazole PKs in patients with and without ECMO support in a retrospective cohort of critically-ill patients. Fifteen patients with 26 voriconazole C-min determinations in the non-ECMO group and nine patients with 27 voriconazole C-min determinations in the ECMO group were recruited. The ECMO group had lower C-min (0.38 & PLUSMN; 2.98 vs. 3.62 & PLUSMN; 3.88, p < 0.001) and higher infratherapeutic C-min values (16 vs. 1, p < 0.001) than the non-ECMO group. Multivariate analysis identified ECMO support (-0.668, CI95 -0.978--0.358) and plasma albumin levels (-0.023, CI95 -0.046--0.001) as risk factors for low C-min values. When comparing pre- and post-therapeutic drug optimisation samples from the ECMO group, the dose required to achieve therapeutic C-min was 6.44 mg/kg twice a day. Therapeutic drug optimisation is essential to improve target attainment

Long-Term Effects of a Stepwise, Multimodal, Non-Restrictive Antimicrobial Stewardship Programme for Reducing Broad-Spectrum Antibiotic Use in the ICU

Information on the long-term effects of non-restrictive antimicrobial stewardship (AMS) strategies is scarce. We assessed the effect of a stepwise, multimodal, non-restrictive AMS programme on broad-spectrum antibiotic use in the intensive care unit (ICU) over an 8-year period. Components of the AMS were progressively implemented. Appropriateness of antibiotic prescribing was also assessed by monthly point-prevalence surveys from 2013 onwards. A Poisson regression model was fitted to evaluate trends in the reduction of antibiotic use and in the appropriateness of their prescription. From 2011 to 2019, a total of 12,466 patients were admitted to the ICU. Antibiotic use fell from 185.4 to 141.9 DDD per 100 PD [absolute difference, -43.5 (23%), 95% CI -100.73 to 13.73; p = 0.13] and broad-spectrum antibiotic fell from 41.2 to 36.5 [absolute difference, -4.7 (11%), 95% CI -19.58 to 10.18; p = 0.5]. Appropriateness of antibiotic prescribing rose by 11% per year [IRR: 0.89, 95% CI 0.80 to 1.00; p = 0.048], while broad-spectrum antibiotic use showed a dual trend, rising by 22% until 2015 and then falling by 10% per year since 2016 [IRR: 0.90, 95% CI 0.81 to 0.99; p = 0.03]. This stepwise, multimodal, non-restrictive AMS achieved a sustained reduction in broad-spectrum antibiotic use in the ICU and significantly improved appropriateness of antibiotic prescribing

Antimicrobial use and aetiology of bloodstream infections in critically ill patients during early stages of SARS-CoV-2 pandemic

Background: During early stages of COVID-19 pandemic, antimicrobials were commonly prescribed.Aim: To describe clinical, microbiological and antimicrobial use changes in bloodstream infections (BSI) of ICU patients during the first wave of COVID-19 pandemic compared to pre-COVID-19 era. Methods: Observational cohort study of patients admitted to ICU of Bellvitge University Hospital was conducted during the COVID-19 pandemic (March-June 2020) and before COVID-19 pandemic (March-June 2019). Differences in clinical characteristics, anti-microbial consumption and incidence and aetiology of BSI were measured.Findings: COVID-19 patients had significantly less comorbidities with obesity the only risk factor that increased in frequency. COVID-19 patients more frequently required invasive supportive care measures, had longer median ICU stay and higher mortality rates. The incidence of BSIs was higher in COVID-19 period (RR 3.2 [95%CI 2.2-4.7]), occurred in patients who showed prolonged median ICU stay (21days) and was associated with high mortality rate (47%). The highest increases in the aetiological agents were observed for AmpC-producing bacteria (RR 11.1 [95%CI 2.6-47.9]) and non-fermenting rods (RR 7.0 [95% CI 1.5-31.4]). The emergence of bacteraemia caused by Gram-negative rods resistant to amoxicillin-clavulanate, which was used as empirical therapy during early stages of the pandemic, led to an escalation towards broader-spectrum antimicrobials such as mer-openem and colistin which was also associated with the emergence of resistant isolates.Conclusions: The epidemiological shift towards resistant phenotypes in critically ill COVID-19 patients was associated with the selective use of antimicrobials. Our study provides evidence of the impact of empirical therapy on the selection of bacteria and their consequences on BSI over the subsequent months.& COPY; 2022 The Authors. Published by Elsevier Ltd on behalf of The Healthcare Infection Society.This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)