Efficacy and safety of a structured de-escalation from antipseudomonal ß-lactams in bloodstream infections due to Enterobacterales (SIMPLIFY): an open-label, multicentre, randomised trial.

BACKGROUND: De-escalation from broad-spectrum to narrow-spectrum antibiotics is considered an important measure to reduce the selective pressure of antibiotics, but a scarcity of adequate evidence is a barrier to its implementation. We aimed to determine whether de-escalation from an antipseudomonal ß-lactam to a narrower-spectrum drug was non-inferior to continuing the antipseudomonal drug in patients with Enterobacterales bacteraemia. METHODS: An open-label, pragmatic, randomised trial was performed in 21 Spanish hospitals. Patients with bacteraemia caused by Enterobacterales susceptible to one of the de-escalation options and treated empirically with an antipseudomonal ß-lactam were eligible. Patients were randomly assigned (1:1; stratified by urinary source) to de-escalate to ampicillin, trimethoprim-sulfamethoxazole (urinary tract infections only), cefuroxime, cefotaxime or ceftriaxone, amoxicillin-clavulanic acid, ciprofloxacin, or ertapenem in that order according to susceptibility (de-escalation group), or to continue with the empiric antipseudomonal ß-lactam (control group). Oral switching was allowed in both groups. The primary outcome was clinical cure 3-5 days after end of treatment in the modified intention-to-treat (mITT) population, formed of patients who received at least one dose of study drug. Safety was assessed in all participants. Non-inferiority was declared when the lower bound of the 95% CI of the absolute difference in cure rate was above the -10% non-inferiority margin. This trial is registered with EudraCT (2015-004219-19) and ClinicalTrials.gov (NCT02795949) and is complete. FINDINGS: 2030 patients were screened between Oct 5, 2016, and Jan 23, 2020, of whom 171 were randomly assigned to the de-escalation group and 173 to the control group. 164 (50%) patients in the de-escalation group and 167 (50%) in the control group were included in the mITT population. 148 (90%) patients in the de-escalation group and 148 (89%) in the control group had clinical cure (risk difference 1·6 percentage points, 95% CI -5·0 to 8·2). The number of adverse events reported was 219 in the de-escalation group and 175 in the control group, of these, 53 (24%) in the de-escalation group and 56 (32%) in the control group were considered severe. Seven (5%) of 164 patients in the de-escalation group and nine (6%) of 167 patients in the control group died during the 60-day follow-up. There were no treatment-related deaths. INTERPRETATION: De-escalation from an antipseudomonal ß-lactam in Enterobacterales bacteraemia following a predefined rule was non-inferior to continuing the empiric antipseudomonal drug. These results support de-escalation in this setting. FUNDING: Plan Nacional de I+D+i 2013-2016 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Ciencia, Innovación y Universidades, Spanish Network for Research in Infectious Diseases; Spanish Clinical Research and Clinical Trials Platform, co-financed by the EU; European Development Regional Fund "A way to achieve Europe", Operative Program Intelligence Growth 2014-2020.

Invasive aspergillosis in solid organ transplantation: Diagnostic challenges and differences in outcome in a Spanish national cohort (Diaspersot study).

BACKGROUND: The diagnosis of invasive aspergillosis (IA) can be problematic in solid organ transplantation (SOT). The prognosis greatly varies according to the type of transplant, and the impact of prophylaxis is not well defined. PATIENTS AND METHODS: The Diaspersot cohort analyses the impact of IA in SOT in Spain during the last 10 years. Proven and probable/putative IA was included. RESULTS: We analysed 126 cases of IA. The incidences of IA were as follows: 6.5%, 2.9%, 1.8% and 0.6% for lung, heart, liver and kidney transplantation, respectively. EORTC/MSG criteria confirmed only 49.7% of episodes. Tree-in-bud sign or ground-glass infiltrates were present in 56.3% of patients, while serum galactomannan (optical density index >0.5) was positive in 50.6%. A total of 41.3% received combined antifungal therapy. Overall mortality at 3 months was significantly lower (p < 0.001) in lung transplant recipients (14.8%) than in all other transplants [globally: 48.6%; kidney 52.0%, liver 58.3%, heart 31.2%, and combined 42.9%]. Fifty-four percent of episodes occurred despite the receipt of antifungal prophylaxis, and in 10%, IA occurred during prophylaxis (breakthrough infection), with both nebulised amphotericin (in lung transplant recipients) and candins (in the rest). CONCLUSIONS: Invasive aspergillosis diagnostic criteria, applied to SOT patients, may differ from those established for haematological patients. IA in lung transplants has a higher incidence, but is associated with a better prognosis than other transplants. Combination therapy is frequently used for IA in SOT. Prophylactic measures require optimisation of its use within this population.

Endophthalmitis caused by Fusarium: An emerging problem in patients with corneal trauma. A case series / Endoftalmitis por Fusarium: un problema emergente en pacientes con traumatismo corneal. Serie de casos

Background: Although fortunately very rare in countries with a temperate climate, certain factors, such as clinical or pharmacological immunosuppression, may cause Fusarium-related fungal infections to become an emerging problem. Moreover, Fusarium is one of the most important etiological agents in exogenous endophthalmitis, which is often favored by the disruption of the epithelial barriers. Aims: The aim of this series of clinical cases is to identify characteristic clinical findings that may allow an early diagnosis and more efficient management of this ophthalmologic emergency. Methods: Three cases of endophthalmitis due to Fusarium solani and Fusarium oxysporum, diagnosed in 2009, 2010, and 2014 in patients from two different health regions belonging to the same health system and separated by around 43 miles, are presented. The Fusarium isolates were initially identified microscopically and the species subsequently confirmed by sequencing the elongation factor alpha (EFalfa) and internal transcribed spacers (ITS). Susceptibility to antifungal agents was determined using the EUCAST broth dilution method. Results: Evolution was poor as two of the three patients progressed to phthisis bulbi despite surgical measures and broad-spectrum antifungal antibiotic therapy. Conclusions: It is essential to rapidly instigate multidisciplinary measures to combat suspected endophthalmitis due to Fusarium given the poor prognosis of this type of infection

Antecedentes: Afortunadamente, las infecciones por Fusarium son poco frecuentes en países de clima templado; sin embargo, determinados factores como la inmunodepresión clínica o farmacológica, pueden convertirlas en un problema emergente. Fusarium es uno de los microrganismos etiológicos más importantes de la endoftalmitis exógena, favorecida habitualmente por una rotura de las barreras epiteliales. Objetivos: En esta serie de casos clínicos queremos identificar hallazgos clínicos característicos que puedan establecer un diagnóstico temprano y un tratamiento más eficiente de esta urgencia oftalmológica. Métodos: Se presentan tres casos de endoftalmitis por Fusarium solani y Fusarium oxysporum que se produjeron en los años 2009, 2010 y 2014, en pacientes de dos áreas de salud diferentes, pero pertenecientes al mismo sistema sanitario, las cuales distan 43 millas una de la otra. Las cepas aisladas de Fusarium se identificaron inicialmente por microscopia y su identidad se confirmó posteriormente mediante secuenciación del factor de elongación alfa (EFalfa) y de la región codificadora espaciadora interna (ITS). La sensibilidad a los antifúngicos se llevó a cabo por el método de dilución en caldo del EUCAST. Resultados: Se produjo una mala evolución, ya que dos de los tres pacientes evolucionaron haca la atrofia ocular a pesar de las medidas quirúrgicas y el tratamiento antibiótico y antifúngico de amplio espectro. Conclusiones: Es importante actuar rápidamente con medidas multidisciplinarias ante la sospecha de una endoftalmitis por Fusarium por el mal pronóstico de este tipo de infecciones

Endophthalmitis caused by Fusarium: An emerging problem in patients with corneal trauma. A case series.

BACKGROUND: Although fortunately very rare in countries with a temperate climate, certain factors, such as clinical or pharmacological immunosuppression, may cause Fusarium-related fungal infections to become an emerging problem. Moreover, Fusarium is one of the most important etiological agents in exogenous endophthalmitis, which is often favored by the disruption of the epithelial barriers. AIMS: The aim of this series of clinical cases is to identify characteristic clinical findings that may allow an early diagnosis and more efficient management of this ophthalmologic emergency. METHODS: Three cases of endophthalmitis due to Fusarium solani and Fusarium oxysporum, diagnosed in 2009, 2010, and 2014 in patients from two different health regions belonging to the same health system and separated by around 43 miles, are presented. The Fusarium isolates were initially identified microscopically and the species subsequently confirmed by sequencing the elongation factor alpha (EFα) and internal transcribed spacers (ITS). Susceptibility to antifungal agents was determined using the EUCAST broth dilution method. RESULTS: Evolution was poor as two of the three patients progressed to phthisis bulbi despite surgical measures and broad-spectrum antifungal antibiotic therapy. CONCLUSIONS: It is essential to rapidly instigate multidisciplinary measures to combat suspected endophthalmitis due to Fusarium given the poor prognosis of this type of infection.

Prevalence and antifungal susceptibility patterns of new cryptic species inside the species complexes Candida parapsilosis and Candida glabrata among blood isolates from a Spanish tertiary hospital.

OBJECTIVES: There is scarce information on the clinical relevance and antifungal susceptibility of Candida bracarensis, Candida nivariensis, Candida orthopsilosis and Candida metapsilosis. The objective of this study was to assess the prevalence and in vitro antifungal susceptibility of these cryptic species among 173 blood isolates previously identified as Candida glabrata or Candida parapsilosis at the Hospital of Cruces (Barakaldo, Spain). The survey was extended to 518 clinical isolates from the culture collection of the Universidad del País Vasco-Euskal Herriko Unibertsitatea (UPV-EHU; Bilbao, Spain). METHODS: In vitro susceptibilities to 5-fluorocytosine, amphotericin B, anidulafungin, caspofungin, fluconazole, itraconazole, micafungin, posaconazole and voriconazole were tested. RESULTS: All isolates of C. glabrata were identified as C. glabrata sensu stricto. Inside the C. parapsilosis complex, 2.4% of isolates from the Hospital of Cruces and 5.8% from the UPV-EHU were C. metapsilosis or C. orthopsilosis. Of 457 isolates, 435 (95.19%) were C. parapsilosis sensu stricto, 11 (2.41%) C. metapsilosis and 11 (2.41%) C. orthopsilosis. Only seven blood isolates were C. metapsilosis (0.44%) or C. orthopsilosis (1.09%). These cryptic species were also isolated from other relevant clinical specimens. Four C. parapsilosis sensu stricto (5.6%) were susceptible dose-dependent, and one was resistant to both fluconazole and voriconazole (1.4%). Moreover, 19 isolates of C. parapsilosis sensu stricto (26.4%) were intermediately susceptible to itraconazole and higher concentrations of echinocandins were needed to inhibit this species. Most C. orthopsilosis and C. metapsilosis were susceptible to all antifungal agents tested, but one otic isolate of C. metapsilosis was resistant to fluconazole and 5-fluorocytosine. CONCLUSIONS: C. metapsilosis and C. orthopsilosis are associated with human disease and show a different antifungal susceptibility profile compared with C. parapsilosis sensu stricto.

HIV-1 transmission cluster with T215D revertant mutation among newly diagnosed patients from the Basque Country, Spain.

OBJECTIVE: To determine the introduction of HIV-1 genetic forms and to examine transmission clusters and resistance to antiretroviral inhibitors among newly diagnosed patients from the Basque Country, Spain, during 2004-2007. METHODS: A total of 261 samples, corresponding to 47.5% heterosexuals, 37.9% men who have sex with men (MSM), and 11.1% intravenous drug users were analyzed in protease and reverse transcriptase to examine phylogenetic relationships and drug resistance-associated mutations. RESULTS: Subtype B was detected in 220 (84.3%) samples and non-B subtype variants in 41 (15.7%) samples. Nearly half (47%) of the sequences grouped in transmission clusters. One of these comprised 14 individuals, 12 of them MSM, with the T215D revertan mutation. In largest transmission clusters, the percentage of MSM was higher than heterosexuals (P < 0.001). Resistance mutations were detected in 29 (11.1%) patients: 20 (7.6%) of them to nucleoside reverse transcriptase inhibitor; 6 (2.3%) to nonnucleoside reverse transcriptase inhibitor (NNRTI); and 1 each to protease inhibitors, protease inhibitor plus NNRTI, and nucleoside reverse transcriptase inhibitor plus NNRTI, respectively. CONCLUSIONS: Our findings underscore recommendations for HIV-1 genotyping in newly diagnosed patients not only to provide information on transmitted drug resistance as an issue in public health and as a guide to future therapy but also to document transmission clusters and to increase the necessary preventive measures.