Impact of ceftolozane/tazobactam concentrations in continuous infusion against extensively drug-resistant Pseudomonas aeruginosa isolates in a hollow-fiber infection model.

Ceftolozane/tazobactam (C/T) has emerged as a potential agent for the treatment of extensively drug-resistant (XDR) Pseudomonas aeruginosa infections. As it is a time-dependent antimicrobial, prolonged infusion may help achieve pharmacokinetic/pharmacodynamic (PK/PD) targets. To compare alternative steady-state concentrations (Css) of C/T in continuous infusion (CI) against three XDR P. aeruginosa ST175 isolates with C/T minimum inhibitory concentration (MIC) values of 2 to 16 mg/L in a hollow-fiber infection model (HFIM). Duplicate 10-day HFIM assays were performed to evaluate Css of C/T in CI: one compared 20 and 45 mg/L against the C/T-susceptible isolate while the other compared 45 and 80 mg/L against the two C/T-non-susceptible isolates. C/T resistance emerged when C/T-susceptible isolate was treated with C/T in CI at a Css of 20 mg/L; which showed a deletion in the gene encoding AmpC ß-lactamase. The higher dosing regimen (80 mg/L) showed a slight advantage in effectiveness. The higher dosing regimen has the greatest bactericidal effect, regardless of C/T MIC. Exposure to the suboptimal Css of 20 mg/L led to the emergence of C/T resistance in the susceptible isolate. Antimicrobial regimens should be optimized through C/T levels monitoring and dose adjustments to improve clinical management.

Time-Kill Evaluation of Antibiotic Combinations Containing Ceftazidime-Avibactam against Extensively Drug-Resistant Pseudomonas aeruginosa and Their Potential Role against Ceftazidime-Avibactam-Resistant Isolates.

Ceftazidime-avibactam (CZA) has emerged as a promising solution to the lack of new antibiotics against Pseudomonas aeruginosa infections. Data from in vitro assays of CZA combinations, however, are scarce. The objective of our study was to perform a time-kill analysis of the effectiveness of CZA alone and in combination with other antibiotics against a collection of extensively drug-resistant (XDR) P. aeruginosa isolates. Twenty-one previously characterized representative XDR P. aeruginosa isolates were selected. Antibiotic susceptibility was tested by broth microdilution, and results were interpreted using CLSI criteria. The time-kill experiments were performed in duplicate for each isolate. Antibiotics were tested at clinically achievable free-drug concentrations. Different treatment options, including CZA alone and combined with amikacin, aztreonam, meropenem, and colistin, were evaluated to identify the most effective combinations. Seven isolates were resistant to CZA (MIC ≥ 16/4 mg/liter), including four metallo-ß-lactamase (MBL)-carrying isolates and two class A carbapenemases. Five of them were resistant or intermediate to aztreonam (MIC ≥ 16 mg/liter). Three isolates were resistant to amikacin (MIC ≥ 64 mg/liter) and one to colistin (MIC ≥ 4 mg/liter). CZA monotherapy had a bactericidal effect in 100% (14/14) of the CZA-susceptible isolates. Combination therapies achieved a greater overall reduction in bacterial load than monotherapy for the CZA-resistant isolates. CZA plus colistin was additive or synergistic in 100% (7/7) of the CZA-resistant isolates, while CZA plus amikacin and CZA plus aztreonam were additive or synergistic in 85%. CZA combined with colistin, amikacin, or aztreonam was more effective than monotherapy against XDR P. aeruginosa isolates. A CZA combination could be useful for treating XDR P. aeruginosa infections, including those caused by CZA-resistant isolates. IMPORTANCE The emergence of resistance to antibiotics is a serious public health problem worldwide and can be a cause of mortality. For this reason, antibiotic treatment is compromised, and we have few therapeutic options to treat infections. The main goal of our study is to search for new treatment options for infections caused by difficult-to-treat resistant germs. Pseudomonas aeruginosa is a Gram-negative bacterium distributed throughout the world with the ability to become resistant to most available antibiotics. Ceftazidime-avibactam (CZA) emerged as a promising solution to the lack of new antibiotics against infections caused by P. aeruginosa strains. This study intended to analyze the effect of CZA alone or in combination with other available antibiotics against P. aeruginosa strains. The combination of CZA with other antibiotics could be more effective than monotherapy against extensively drug-resistant P. aeruginosa strains.

Sugar Functionalization of Silks with Pathway-Controlled Substitution and Properties.

Silk biomaterials are important for applications in biomedical fields due to their outstanding mechanical properties, biocompatibility, and tunable biodegradation. Chemical functionalization of silk by various chemistries can be leveraged to enhance and tune these features and enable the expansion of silk-based biomaterials into additional fields. Sugars are particularly relevant for intracellular communication, signal transduction events, as well as in hydrated extracellular matrices such as in cartilage, vitreous, and brain tissues. Multiple reaction pathways are demonstrated (carboxylation of serines followed by carbodiimide coupling with glucosamine, carboxylation of tyrosines followed by carbodiimide coupling with glucosamine; direct carbodiimide coupling of the inherent carboxylic acids of silk (aspartic and glutamic acid) with glucosamine) for the covalent conjugation of glucosamine onto silk with characterization by proton nuclear magnetic resonance (1 H-NMR), liquid chromatography tandem mass spectroscopy (LC-MS), water contact angle (WCA), and Fourier transform infrared (FTIR) spectroscopy. The results indicate that different pathways substitute different amounts of glucosamine onto silk chains, with control over resulting material properties, including hydrophobicity/hydrophilicity and biological responses. The aqueous processability of these conjugates into functional material formats (films, sponges) is assessed. These new classes of bio-inspired materials can lead to multifunctional biomaterials for potential applications in different fields of biomedical engineering.

COVID-19 in elderly kidney transplant recipients.

The SARS-Cov-2 infection disease (COVID-19) pandemic has posed at risk the kidney transplant (KT) population, particularly the elderly recipients. From March 12 until April 4, 2020, we diagnosed COVID-19 in 16 of our 324 KT patients aged ≥65 years old (4.9%). Many of them had had contact with healthcare facilities in the month prior to infection. Median time of symptom onset to admission was 7 days. All presented with fever and all but one with pneumonia. Up to 33% showed renal graft dysfunction. At infection diagnosis, mTOR inhibitors or mycophenolate were withdrawn. Tacrolimus was withdrawn in 70%. The main treatment combination was hydroxychloroquine and azithromycin. A subset of patients was treated with anti-retroviral and tocilizumab. Short-term fatality rate was 50% at a median time since admission of 3 days. Those who died were more frequently obese, frail, and had underlying heart disease. Although a higher respiratory rate was observed at admission in nonsurvivors, symptoms at presentation were similar between both groups. Patients who died were more anemic, lymphopenic, and showed higher D-dimer, C-reactive protein, and IL-6 at their first tests. COVID-19 is frequent among the elderly KT population and associates a very early and high mortality rate.

Colistin plus meropenem combination is synergistic in vitro against extensively drug-resistant Pseudomonas aeruginosa, including high-risk clones.

BACKGROUND: Extensively drug-resistant (XDR) Pseudomonas aeruginosa (P. aeruginosa) and particularly P. aeruginosa high-risk clones, are of growing concern because treatment options are limited. For years, colistin monotherapy has been the only available treatment, but is well known that is not an optimal treatment. A combination of colistin with another antibiotic could be a possible therapeutic option. OBJECTIVES: This study aimed to investigate effective antibiotic combinations against 20 XDR P. aeruginosa isolates obtained in a Spanish multicentre study (2015). METHODS: Forty-five checkerboards with six antipseudomonal antibiotics (amikacin, aztreonam, ceftazidime, meropenem, colistin, and ceftolozane/tazobactam) were performed to determine whether combinations were synergic or additive by fractional inhibitory concentration indices. On average, 15 different regimens were evaluated in duplicate against the three most prevalent high-risk clones (ST175, ST235, ST111) by time-kill analyses over 24h. The combination showing synergism in the three high-risk clones was validated in all studied XDR isolates. RESULTS: In time-kill curves, the untreated control failed, as did each study regimen when administered alone. Two combinations were synergistic in the three high-risk clones that were initially studied: amikacin plus ceftazidime and colistin plus meropenem, with the second being the most effective combination. The efficacy of colistin plus meropenem was then tested in all 20 isolates. A synergistic bacterial density reduction for the duration of the study occurred in 80% of the entire XDR collection. CONCLUSIONS: These data suggest that colistin plus meropenem may be a useful combination for the treatment of infections due to XDR P. aeruginosa, including high-risk clones, which warrants evaluation in a clinical trial.

Supervivencia y estado neurológico tras muerte súbita cardiaca extrahospitalaria. Resultados del Registro Andaluz de Parada Cardiorrespiratoria Extrahospitalaria / Survival and neurologic outcome after out-of-hospital cardiac arrest. Results of the andalusian out-of-hospital cardiopulmonary arrest registry

Introducción y objetivos: No hay demasiados datos sobre la muerte súbita prehospitalaria en España. El objetivo es describir su incidencia, las características de los pacientes y los resultados de su atención por un servicio de emergencias extrahospitalario. Métodos: Análisis retrospectivo de un registro prospectivo de parada cardiorrespiratoria atendida por un servicio de emergencias extrahospitalario entre enero de 2008 y diciembre de 2012. Se incluyó a todos los pacientes con estimación de etiología cardiaca como causa de la parada. Se realizó análisis descriptivo de las características generales de los pacientes y de los factores asociados con alta hospitalaria con buen estado neurológico. Resultados: Se incluyó a 4.072 pacientes, con una incidencia estimada de 14,6 eventos por 100.000 habitantes y año, el 72,6% varones. La media de edad era 62,0 ± 15,8 años. El 58,6% de los casos ocurrieron en domicilio. El 25% de los pacientes tenían un ritmo inicial desfibrilable. El 28,8% de los pacientes llegaron con pulso al hospital, el 58,3% del grupo con ritmo desfibrilable. El 10,2% recibió el alta en buen estado neurológico. Las variables asociadas con esta recuperación fueron: parada presenciada (p = 0,04), parada presenciada por el equipo de emergencias (p = 0,005), realización previa de soporte vital (p = 0,04), ritmo inicial desfibrilable (p = 0,0001) y realización de intervencionismo coronario (p = 0,0001). Conclusiones: Más de la mitad de los casos de muerte súbita ocurren en el domicilio. Afectan a una población relativamente joven. Aunque 1 de cada 10 pacientes tuvo una recuperación satisfactoria, la fase previa a la llegada de los equipos de emergencias debe mejorar. El intervencionismo coronario tuvo gran impacto en el pronóstico de los pacientes (AU)

Introduction and objectives: There is a paucity of data on prehospital cardiac arrest in Spain. Our aim was to describe the incidence, patient characteristics, and outcomes of out-of-hospital emergency care for this event. Methods: We conducted a retrospective analysis of a prospective registry of cardiopulmonary arrest handled by an out-of-hospital emergency service between January 2008 and December 2012. The registry included all patients considered to have a cardiac etiology as the cause of arrest, with a descriptive analysis performed of general patient characteristics and factors associated with good neurologic outcome at hospital discharge. Results: A total of 4072 patients were included, with an estimated incidence of 14.6 events per 100 000 inhabitants and year; 72.6% were men. The mean age was 62.0 ± 15.8 years, 58.6% of cases occurred in the home, 25% of patients had initial defibrillable rhythm, 28.8% of patients arrived with a pulse at the hospital (58.3% of the group with defibrillable rhythm), and 10.2% were discharged with good neurologic outcome. The variables associated with this recovery were: witnessed arrest (P = .04), arrest witnessed by emergency team (P = .005), previous life support (P = .04), initial defibrillable rhythm (P = .0001), and performance of a coronary interventional procedure (P = .0001). Conclusions: More than half the cases of sudden cardiac arrest occur at home, and the population was found to be relatively young. Although recovery was satisfactory in 1 out of every 10 patients, there is a need for improvement in the phase prior to emergency team arrival. Coronary interventional procedures had an impact on patient prognosis (AU)

Survival and Neurologic Outcome After Out-of-hospital Cardiac Arrest. Results of the Andalusian Out-of-hospital Cardiopulmonary Arrest Registry.

INTRODUCTION AND OBJECTIVES: There is a paucity of data on prehospital cardiac arrest in Spain. Our aim was to describe the incidence, patient characteristics, and outcomes of out-of-hospital emergency care for this event. METHODS: We conducted a retrospective analysis of a prospective registry of cardiopulmonary arrest handled by an out-of-hospital emergency service between January 2008 and December 2012. The registry included all patients considered to have a cardiac etiology as the cause of arrest, with a descriptive analysis performed of general patient characteristics and factors associated with good neurologic outcome at hospital discharge. RESULTS: A total of 4072 patients were included, with an estimated incidence of 14.6 events per 100000 inhabitants and year; 72.6% were men. The mean age was 62.0 ± 15.8 years, 58.6% of cases occurred in the home, 25% of patients had initial defibrillable rhythm, 28.8% of patients arrived with a pulse at the hospital (58.3% of the group with defibrillable rhythm), and 10.2% were discharged with good neurologic outcome. The variables associated with this recovery were: witnessed arrest (P=.04), arrest witnessed by emergency team (P=.005), previous life support (P=.04), initial defibrillable rhythm (P=.0001), and performance of a coronary interventional procedure (P=.0001). CONCLUSIONS: More than half the cases of sudden cardiac arrest occur at home, and the population was found to be relatively young. Although recovery was satisfactory in 1 out of every 10 patients, there is a need for improvement in the phase prior to emergency team arrival. Coronary interventional procedures had an impact on patient prognosis.

Initial complications and factors related to prehospital mortality in acute myocardial infarction with ST segment elevation.

OBJECTIVE: Hospital mortality in myocardial infarction ST-elevation myocardial infarction has decreased in recent years, in contrast to prehospital mortality. Our objective was to determine initial complications and factors related to prehospital mortality in patients with acute myocardial infarction with ST segment elevation (STEMI). METHODS: Observational study based on a prospective continuous register of patients of any age attended by out-of-hospital emergency teams in Andalusia between January 2006 and June 2009. This includes patients with acute coronary syndrome-like symptoms whose initial ECG showed ST elevation or presumably new left bundle branch block (LBBB). Epidemiological, prehospital data and final diagnostic were recorded. The study included all patients with STEMI on the register, without age restrictions. Forward stepwise logistic regression analysis was performed to control for confounders. RESULTS: A total of 2528 patients were included, 24% were women. Mean age 63.4±13.4 years; 16.7% presented atypical clinical symptoms. Initial complications: ventricular fibrillation (VF) 8.4%, severe bradycardia 5.8%, third-degree atrial-ventricular (AV) block 2.4% and hypotension 13.5%. Fifty-two (2.1%) patients died before reaching hospital. Factors associated with prehospital mortality were female sex (OR 2.36, CI 1.28 to 4.33), atypical clinical picture (OR 2.31, CI 1.21 to 4.41), hypotension (OR 4.95, CI 2.60 to 9.20), LBBB (OR 4.29, CI 1.71 to 10.74), extensive infarction (ST elevation in ≥5 leads) (OR 2.53, CI 1.28 to 5.01) and VF (OR 2.82, CI 1.38 to 5.78). CONCLUSIONS: A significant proportion of patients with STEMI present early complications in the prehospital setting, and some die before reaching hospital. Prehospital mortality was associated with female sex and atypical presentation, as pre-existing conditions, and hypotension, extensive infarction, LBBB and VF on emergency team attendance.