SARS-CoV-2 infection in solid organ transplant recipients: Experience with molnupiravir

SARS-CoV-2 infection; Transplant recipients; Solid organInfecció per SARS-CoV-2; Receptors de trasplantament; Òrgans sòlidsInfección por SARS-CoV-2; Receptores de trasplantes; Órganos sólidosSolid organ transplant recipients (SOTR) constitute one of the groups at highest risk for the development of severe COVID-19. However, evidence on the effectiveness of treatments for SARS-CoV-2 infection in this group of patients is scarce. Molnupiravir is an orally administered antiviral drug that has demonstrated effectiveness in reducing the risk of progression to severe COVID-19 in high-risk outpatients, mainly in the unvaccinated population. Although its effectiveness is lower than that of other antivirals, on many occasions it is the only therapeutic option in transplant recipients given the absence of pharmacological interactions with immunosuppressive treatment, the oral route of administration and the good safety profile

Invasive mould infections in solid organ transplant patients: modifiers and indicators of disease and treatment response

Invasive mould infections, in particular invasive aspergillosis (IA), are comparatively frequent complications of immunosuppression in patients undergoing solid organ transplantation (SOT). Guidelines provide recommendations as to the procedures to be carried out to diagnose and treat IA, but only limited advice for SOT recipients. Literature review and expert consensus summarising the existing evidence related to prophylaxis, diagnosis, treatment and assessment of response to IA and infections by Mucorales in SOT patients Response to therapy should be assessed early and at regular intervals. No indications of improvement should lead to a prompt change of the antifungal treatment, to account for possible infections by Mucorales or other moulds such as Scedosporium. Imaging techniques, especially CT scan and possibly angiography carried out at regular intervals during early and long-term follow-up and coupled with a careful clinical diagnostic workout, should be evaluated as diagnostic tools and outcome predictors, and standardised to improve therapy monitoring. The role of biomarkers such as the galactomannan test and PCR, as well as selected inflammation parameters, has not yet been definitively assessed in the SOT population and needs to be studied further. The therapeutic workup should consider a reduction of immunosuppressive therapy. The role of immunosuppression and immune tolerance mechanisms in the response to invasive fungal infection treatment is an important factor in the SOT population and should not be underestimated. The choice of the antifungal should consider not only their toxicity but also their effects on the immune system, two features that are intertwined

Estudio caso-control de las cefalosporinas como tratamiento empírico de la peritonitis bacteriana espontánea en los receptores de trasplante hepático ortotópico. Epidemiología e impacto en la mortalidad

La peritonitis bacteriana espontánea consiste en la infección del líquido ascítico en ausencia de un foco evidente intraabdominal. Los microorganismos causales más frecuentes son bacilos Gram negativos y cocos Gram positivos. Son escasos los datos en los pacientes trasplantados hepáticos que evolucionan a cirrosis. Se diseñó un estudio caso-control con el objetivo de determinar la idoneidad del tratamiento empírico con ceftriaxona en dicha población. No se observaron diferencias etiológicas entre ambos grupos y la sensibilidad a cefalosporinas de tercera generación fue similar. Los trasplantados presentaron mayor incidencia de insuficiencia renal, y mayor mortalidad durante el episodio y a 6 meses.La peritonitis bacteriana espontània consisteix en la infecció del líquid ascític en absència d'un focus evident intraabdominal. Els microorganismes causals més freqüents son bacils Gram negatius i cocos Gram positius. Són escasses les dades en pacients trasplantats hepàtics que evolucionen a cirrosi. Es va dissenyar un estudi cas-control amb l'objectiu de determinar la idoneïtat del tractament empíric amb ceftriaxona en aquesta població. No es van observar diferències etiològiques entre ambdós grups i la sensibilitat a cefalosporines de tercera generació va ser similar. Els trasplantats van presentar major incidència d'insuficiència renal, i major mortalitat durant l'episodi i a 6 mesos

Improvement in detecting cytomegalovirus drug resistance mutations in solid organ transplant recipients with suspected resistance using next generation sequencing

Antiviral resistance; Solid organ transplant; Next-generation sequencingResistencia a los antivirales; Trasplante de órganos sólidos; Secuenciación de próxima generaciónResistència als antivirals; Trasplantament d'òrgans sòlids; Seqüenciació de pròxima generacióOBJETIVES: The aim of this study was to identify CMV drug resistance mutations (DRM) in solid organ transplant (SOT) recipients with suspected resistance comparing next-generation sequencing (NGS) with Sanger sequencing and assessing risk factors and the clinical impact of resistance. METHODS: Using Sanger sequencing as the reference method, we prospectively assessed the ability of NGS to detect CMV DRM in the UL97 and UL54 genes in a nationwide observational study from September 2013 to August 2016. RESULTS: Among 44 patients recruited, 14 DRM were detected by Sanger in 12 patients (27%) and 20 DRM were detected by NGS, in 16 (36%). NGS confirmed all the DRM detected by Sanger. The additional six mutations detected by NGS were present in <20% of the sequenced population, being located in the UL97 gene and conferring high-level resistance to ganciclovir. The presence of DRM by NGS was associated with lung transplantation (p = 0.050), the administration of prophylaxis (p = 0.039), a higher mean time between transplantation and suspicion of resistance (p = 0.038) and longer antiviral treatment duration before suspicion (p = 0.024). However, the latter was the only factor independently associated with the presence of DRM by NGS in the multivariate analysis (OR 2.24, 95% CI 1.03 to 4.87). CONCLUSIONS: NGS showed a higher yield than Sanger sequencing for detecting CMV resistance mutations in SOT recipients. The presence of DRM detected by NGS was independently associated with longer antiviral treatment.The present study was funded by Agency for Health Technology Assessment and Research and Ministerio de Economia y Competitividad, Instituto de Salud Carlos III (PS12/02131 and PI17/02150) and by the Agència de Gestió d'Ajuts Universitaris i de Recerca (AGAUR, FI-DGR 2017, Grant No. 00794), which is supported by the Secretaria d'Universitats i Recerca (Economy and Knowledge Department, Generalitat de Catalunya), and co-funded by the European Social Fund and by Fundacio Marato TV3 project (201824). The study sponsor had no role in the collection, analysis, or interpretation of the data

Hyperthermia Prevents In Vitro and In Vivo Biofilm Formation on Endotracheal Tubes

Animal model; Biofilm; HyperthermiaModel animal; Biofilm; HipertèrmiaModelo animal; Biofilm; HipertermiaThere is currently an urgent need to find new strategies to tackle antimicrobial resistance and biofilm-related infections. This study has two aims. First, we evaluated the in vitro efficacy of hyperthermia in preventing biofilm formation on the surfaces of polyvinyl chloride discs. Second, we assessed the in vivo efficacy of hyperthermia in preventing biofilm formation in endotracheal tubes (ETTs) of a rabbit model. For the in vitro studies, nine clinical extensively drug-resistant/multidrug-resistant Gram-negative isolates of Acinetobacter baumannii, Klebsiella pneumoniae, and Pseudomonas aeruginosa and three clinical methicillin-resistant Staphylococcus aureus strains were studied. For biofilm formation, an adhesion step of 30 or 90 min followed by a growth step of 24 h were performed with application of one, two, and three pulses at 42°C for 15 min each pulse after the adhesion step. For the in vivo studies, New Zealand rabbits were intubated with ETTs previously colonized with K. pneumoniae or P. aeruginosa strains, and three pulses at 42°C for 15 min were applied after the adhesion step. The application of three pulses at 42°C for 15 min each pulse was needed to achieve the prevention of the in vitro biofilm formation of 100% of the tested strains. The application of heat pulses in a rabbit intubation model led to biofilm prevention of 85% against two K. pneumoniae strains and 80% against two P. aeruginosa strains compared to the control group. Hyperthermia application through pulses at 42°C could be a new nonantibiotic strategy to prevent biofilm formation in ETTs. IMPORTANCE Biofilm-producing microorganisms are considered medically crucial since they cause 80% of the infections that occur in the human body. Medical devices such as endotracheal tubes (ETTs) can act as a reservoir for pathogens providing the surface to which microorganisms can adhere and cause biofilm-associated infections in critically ill patients. This biofilm has been related with the development of ventilator-associated pneumonia (VAP), with an incidence of 8 to 28%, a mortality rate up to 17% and its associated high extra costs. Although some VAP-preventive measures have been reported, they have not demonstrated a significant reduction of VAP incidence. Therefore, we present a new nonantibiotic strategy based on hyperthermia application to prevent biofilm formation inside ETTs. This technology could reduce VAP incidence, intubation duration, hospital and intensive care unit (ICU) length stays, and mortality rates. Consequently, this could decrease the antibiotics administered and influence the impact of antibiotic resistance in the ICU.This study was supported by research grants from the Ministerio de Sanidad y Consumo, Instituto de Salud Carlos III (FIS 01162), la Marató TV3 (472/U/2018), the CaixaImpulse Program (Fundació “LaCaixa”), the Fundación para la Innovación y la Prospectiva en Salud en España (FIPSE 3932-21), and the Spanish Network for the Research in Infectious Diseases (REIPI RD19/0016)

Antifungal prophylaxis with nebulized amphotericin-B in solid-organ transplant recipients with severe COVID-19: a retrospective observational study

Aspergillosis; COVID-19; ProphylaxisAspergilosis; COVID-19; ProfilaxisAspergilosi; COVID 19; ProfilaxiCOVID-19-associated pulmonary aspergillosis (CAPA) has emerged as a frequent complication in the intensive care unit (ICU). However, little is known about this life-threatening fungal superinfection in solid organ transplant recipients (SOTRs), including whether targeted anti-mold prophylaxis might be justified in this immunosuppressed population. We performed a multicentric observational retrospective study of all consecutive ICU-admitted COVID-19 SOTRs between August 1, 2020 and December 31, 2021. SOTRs receiving antifungal prophylaxis with nebulized amphotericin-B were compared with those without prophylaxis. CAPA was defined according the ECMM/ISHAM criteria. Sixty-four SOTRs were admitted to ICU for COVID-19 during the study period. One patient received antifungal prophylaxis with isavuconazole and was excluded from the analysis. Of the remaining 63 SOTRs, nineteen (30.2%) received anti-mold prophylaxis with nebulized amphotericin-B. Ten SOTRs who did not receive prophylaxis developed pulmonary mold infections (nine CAPA and one mucormycosis) compared with one who received nebulized amphotericin-B (22.7% vs 5.3%; risk ratio 0.23; 95%CI 0.032-1.68), but with no differences in survival. No severe adverse events related to nebulized amphotericin-B were recorded. SOTRs admitted to ICU with COVID-19 are at high risk for CAPA. However, nebulized amphotericin-B is safe and might reduce the incidence of CAPA in this high-risk population. A randomized clinical trial to confirm these findings is warranted.AR received a predoctoral research grant from the Instituto de Salud Carlos III, Spanish Ministry of Science, Innovation and Universities, (PFIS grant FI18/00183). This work was supported by the Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Economía, Industria y Competitividad, Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Madrid, Spain. We thank CERCA Programme/Generalitat de Catalunya for institutional support

In Vitro and In Vivo Antimicrobial Activity of Hypochlorous Acid against Drug-Resistant and Biofilm-Producing Strains

Antibiotic lock technique; Biofilms; Catheter-related infectionTécnica de bloqueo antibiótico; Biopelículas; Infección relacionada con el catéterTècnica de bloqueig antibiòtic; Biofilms; Infecció relacionada amb el catèterThe aims of this study were as follows. First, we determined the antimicrobial efficacy of hypochlorous acid (HClO) against bacterial, fungal, and yeast strains growing planktonically and growing in biofilms. Second, we sought to compare the activity of the combination of daptomycin and HClO versus those of the antimicrobial agents alone for the treatment of experimental catheter-related Staphylococcus epidermidis infection (CRI) using the antibiotic lock technique (ALT) in a rabbit model. HClO was generated through direct electric current (DC) shots at determined amperages and times. For planktonic susceptibility studies, 1 to 3 DC shots of 2, 5, and 10 mA from 0 to 300 s were applied. A DC shot of 20 mA from 0 to 20 min was applied to biofilm-producing strains. Central venous catheters were inserted into New Zealand White rabbits, inoculated with an S. epidermidis strain, and treated with saline solution or ALT using daptomycin (50 mg/mL), HClO (20 mA for 45 min), or daptomycin plus HClO. One hundred percent of the planktonic bacterial, fungal, and yeast strains were killed by applying one DC shot of 2, 5, and 10 mA, respectively. One DC shot of 20 mA for 20 min was sufficient to eradicate 100% of the tested biofilm-producing strains. Daptomycin plus HClO lock therapy showed the highest activity for experimental CRI with S. epidermidis. HClO could be an effective strategy for treating infections caused by extensively drug-resistant or multidrug-resistant and biofilm-producing strains in medical devices and chronic wounds. The results of the ALT using daptomycin plus HClO may be promising. IMPORTANCE Currently, drug-resistant infections are increasing and there are fewer antibiotics available to treat them. Therefore, there is an urgent need to find new antibiotics and nonantimicrobial strategies to treat these infections. We present a new nonantibiotic strategy based on hypochlorous acid generation to treat long-term catheter-related and chronic wounds infections.This study was supported by research grants from the Ministerio de Sanidad y Consumo, Instituto de Salud Carlos III (FIS 01162), la Marató TV3 (472/U/2018), and CaixaImpulse Program (Fundació “LaCaixa”) and the Spanish Network for the Research in Infectious Diseases (REIPI RD19/0016)

Antifungal prophylaxis with nebulized amphotericin-B in solid-organ transplant recipients with severe COVID-19: a retrospective observational study

COVID-19-associated pulmonary aspergillosis (CAPA) has emerged as a frequent complication in the intensive care unit (ICU). However, little is known about this life-threatening fungal superinfection in solid organ transplant recipients (SOTRs), including whether targeted anti-mold prophylaxis might be justified in this immunosuppressed population. We performed a multicentric observational retrospective study of all consecutive ICU-admitted COVID-19 SOTRs between August 1, 2020 and December 31, 2021. SOTRs receiving antifungal prophylaxis with nebulized amphotericin-B were compared with those without prophylaxis. CAPA was defined according the ECMM/ISHAM criteria. Sixty-four SOTRs were admitted to ICU for COVID-19 during the study period. One patient received antifungal prophylaxis with isavuconazole and was excluded from the analysis. Of the remaining 63 SOTRs, nineteen (30.2%) received anti-mold prophylaxis with nebulized amphotericin-B. Ten SOTRs who did not receive prophylaxis developed pulmonary mold infections (nine CAPA and one mucormycosis) compared with one who received nebulized amphotericin-B (22.7% vs 5.3%; risk ratio 0.23; 95%CI 0.032-1.68), but with no differences in survival. No severe adverse events related to nebulized amphotericin-B were recorded. SOTRs admitted to ICU with COVID-19 are at high risk for CAPA. However, nebulized amphotericin-B is safe and might reduce the incidence of CAPA in this high-risk population. A randomized clinical trial to confirm these findings is warranted

Case Report: Successful Lung Transplantation from a Donor Seropositive for Trypanosoma cruzi Infection (Chagas Disease) to a Seronegative Recipient

Lung transplantation; Seropositive donor; Trypanosoma cruziTrasplantament de pulmó; Donant seropositiu; Trypanosoma cruziTrasplante de pulmón; Donante seropositivo; Trypanosoma cruziThe increasing shortage of organs for transplantation has prompted transplant programs to investigate the use of extended criteria donors, such as those with transmissible infectious diseases. Successful cases of organ transplantation (mostly kidney and liver) from Trypanosoma cruzi seropositive donors to seronegative recipients have been reported. We present a case of lung transplantation from a donor serologically positive for Chagas disease to a seronegative recipient, and provide a review of the literature. Left single lung transplantation was performed in a 44-year-old Spanish woman presenting with interstitial lung disease in February 2016. The deceased donor was a Colombian immigrant living in Spain who was serologically positive for Chagas disease. Oral administration of 5 mg/kg/day benznidazole divided in three doses for 60 days was given for specific Chagas disease prophylaxis after transplantation. Periodic follow-up with serological reverse transcription polymerase chain reaction to detect T. cruzi DNA were performed until 6 months after the end of treatment. All results were negative, indicating that transmission of T. cruzi had not occurred. In a review of the literature, two similar cases were identified in Argentina and the United States. In both cases T. cruzi infection was detected posttransplant in the recipients, after which they were treated with benznidazole. The course of the patient described herein confirms that lungs from donors with chronic T. cruzi infection can be used successfully as allografts, and that posttransplant prophylaxis with benznidazole may reduce the probability of transmission of T. cruzi to the recipient

Community-acquired pneumonia in hospitalised patients: changes in aetiology, clinical presentation, and severity outcomes in a 10-year period

Staphylococcus aureus; Mortality; VirologyStaphylococcus aureus; Mortalidad; VirologíaStaphylococcus aureus; Mortalitat; VirologiaBackground and objective Community-acquired pneumonia (CAP) is a frequent cause of hospitalisation. Several factors, such as pandemics, vaccines and globalisation may lead to changes in epidemiology, clinical presentation, and outcomes of CAP, which oblige to a constant actualisation. We performed this study to analyse how these factors have evolved over a 10-year period. Materials and methods Patients diagnosed with CAP for two 1-year periods that were 10 years apart (2007–2008 and 2017–2018) were included. We compared microbiological information, clinical data and evolutive outcomes in the two periods. A mortality analysis was performed. Results 1043 patients were included: 452 during the first period (2007- 2008), and 591 during the second period (2017–2018). Bacterial aetiology did not change during the 10-year period, besides a slight increase in Staphylococcus aureus (0.9% vs 2.9%, p = 0.026). There was a decline in the proportion of bacteraemia in the second period (14.8% vs 9.6%, p = 0.012). The incidence of complicated pleural effusion and septic shock declined too (6.4% vs 3.6%, p = 0.04 and 15.5% vs 6.3%, p < 0.001). Respiratory failure and Intensive care unit (ICU) admission were similar in both periods. Variables independently associated with mortality were age and septic shock. Influenza vaccine was a protective factor against mortality in the second period. Conclusions We have not found relevant differences in the bacterial aetiology of CAP over this 10-year period. There has been a decline in septic complications of CAP such as septic shock, bacteraemia, and complicated pleural effusion. Influenza vaccination is an important tool to reduce mortality