Seroprevalence of SARS-CoV-2 antibody among healthcare workers in a university hospital in Mallorca, Spain, during the first wave of the COVID-19 pandemic.

OBJECTIVE: To estimate the SARS-CoV-2 antibody seroprevalence in healthcare workers (HCWs) at a university hospital in Mallorca, Spain. METHODS: All HCWs received an e-mail inviting them to take part in the study. Participants had a nasopharyngeal swab test performed for reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) and serological tests to detect SARS-CoV-2 antibodies (primary study). Additionally, they were invited to complete a questionnaire on their exposure to COVID-19 individuals and their COVID-19-related symptoms (secondary study). Prevalence of antibodies (IgG, IgM, or both) and 95% confidence intervals (CIs) were calculated. RESULTS: Seventy-nine percent of the hospital's HCWs (N = 2210) took part in the primary study. Antibodies were detected in 61 participants, a prevalence of 2.8% (95% CI: 2.5-3.1). The prevalence was slightly higher in nurses (3.4%), registrars (3.9%), and wardens (3.4%). Thirty-nine percent of the primary study participants completed the secondary study questionnaire. Those with positive antibody test results had closer contact with COVID-19 individuals (60% vs. 92%; p < 0.001). CONCLUSION: After the first wave of the COVID-19 pandemic in Spain, the seroprevalence of SARS-CoV-2 antibodies in our university hospital HCWs was around 2.8%, which is slightly higher than the seroprevalence in the general population in our region. We believe it would be advisable to perform additional seroprevalence studies during the second wave of the epidemic.

Pharmacodynamics of amphotericin B deoxycholate, amphotericin B lipid complex, and liposomal amphotericin B against Aspergillus fumigatus.

Amphotericin B is a first-line agent for the treatment of invasive aspergillosis. However, relatively little is known about the pharmacodynamics of amphotericin B for invasive pulmonary aspergillosis. We studied the pharmacokinetics (PK) and pharmacodynamics (PD) of amphotericin B deoxycholate (DAMB), amphotericin B lipid complex (ABLC), and liposomal amphotericin B (LAMB) by using a neutropenic-rabbit model of invasive pulmonary aspergillosis. The study endpoints were lung weight, infarct score, and levels of circulating galactomannan and (1 → 3)-ß-D-glucan. Mathematical models were used to describe PK-PD relationships. The experimental findings were bridged to humans by Monte Carlo simulation. Each amphotericin B formulation induced a dose-dependent decline in study endpoints. Near-maximal antifungal activity was evident with DAMB at 1 mg/kg/day and ABLC and LAMB at 5 mg/kg/day. The bridging study suggested that the "average" patient receiving LAMB at 3 mg/kg/day was predicted to have complete suppression of galactomannan and (1 → 3)-ß-D-glucan levels, but 20 to 30% of the patients still had a galactomannan index of >1 and (1 → 3)-ß-D-glucan levels of >60 pg/ml. All formulations of amphotericin B induce a dose-dependent reduction in markers of lung injury and circulating fungus-related biomarkers. A clinical dosage of liposomal amphotericin B of 3 mg/kg/day is predicted to cause complete suppression of galactomannan and (1 → 3)-ß-D-glucan levels in the majority of patients.

Are we missing opportunities to confirm the diagnosis of tuberculosis by microbial culture?

SETTING: Tuberculosis (TB) incidence is rising globally, with drug resistance becoming increasingly problematic. Microbiological confirmation ensures correct anti-tuberculous chemotherapy. OBJECTIVE/DESIGN: We retrospectively analysed all TB cases diagnosed in Central Manchester in 2009 investigating how often we are not achieving microbiological diagnosis, factors influencing this and whether opportunities to obtain microbiological samples are missed. RESULTS: 128/156 (82%) cases had samples sent for microbiology. Factors affecting this included disease site, with ocular disease least likely to be sampled (p < 0.0001), and patient age (with children less likely to be sampled p = 0.002). Ethnicity did not affect sampling (n.s.). Overall, 92/156 (59%) cases were culture positive. Negative culture was related to specimen type (p < 0.0001) and patient age (p = 0.019), with children significantly less likely to have a positive culture. Ethnicity and disease site did not affect culture results. There was a trend towards culture positivity being more common in pulmonary (75%) than non-pulmonary (46%) disease (n.s.). In only 7 (4%), could samples have been sent where they were originally absent (3) or further samples obtained where the cultures proved to be negative (4). CONCLUSION: Despite an overall culture positive rate of 59%, opportunities to achieve microbiological confirmation are seldom missed. In our centre, which is typical of UK practice, this lack of capacity to increase microbiological confirmation, particularly in an era of increasing importance of extra-pulmonary TB, is concerning. Improvements in sample acquisition and laboratory methods are urgently required.

Pharmacokinetics and pharmacodynamics of fluconazole for cryptococcal meningoencephalitis: implications for antifungal therapy and in vitro susceptibility breakpoints.

Fluconazole is frequently the only antifungal agent that is available for induction therapy for cryptococcal meningitis. There is relatively little understanding of the pharmacokinetics and pharmacodynamics (PK-PD) of fluconazole in this setting. PK-PD relationships were estimated with 4 clinical isolates of Cryptococcus neoformans. MICs were determined using Clinical and Laboratory Standards Institute (CLSI) methodology. A nonimmunosuppressed murine model of cryptococcal meningitis was used. Mice received two different doses of fluconazole (125 mg/kg of body weight/day and 250 mg/kg of body weight/day) orally for 9 days; a control group of mice was not given fluconazole. Fluconazole concentrations in plasma and in the cerebrum were determined using high-performance liquid chromatography (HPLC). The cryptococcal density in the brain was estimated using quantitative cultures. A mathematical model was fitted to the PK-PD data. The experimental results were extrapolated to humans (bridging study). The PK were linear. A dose-dependent decline in fungal burden was observed, with near-maximal activity evident with dosages of 250 mg/kg/day. The MIC was important for understanding the exposure-response relationships. The mean AUC/MIC ratio associated with stasis was 389. The results of the bridging study suggested that only 66.7% of patients receiving 1,200 mg/kg would achieve or exceed an AUC/MIC ratio of 389. The potential breakpoints for fluconazole against Cryptococcus neoformans follow: susceptible, ≤ 2 mg/liter; resistant, >2 mg/liter. Fluconazole may be an inferior agent for induction therapy because many patients cannot achieve the pharmacodynamic target. Clinical breakpoints are likely to be significantly lower than epidemiological cutoff values. The MIC may guide the appropriate use of fluconazole. If fluconazole is the only option for induction therapy, then the highest possible dose should be used.

Combination of voriconazole and anidulafungin for treatment of triazole-resistant aspergillus fumigatus in an in vitro model of invasive pulmonary aspergillosis.

Voriconazole is a first-line agent for the treatment of invasive pulmonary aspergillosis. Isolates with elevated voriconazole MICs are increasingly being seen, and the optimal treatment regimen is not defined. We investigated whether the combination of voriconazole with anidulafungin may be beneficial for the treatment of A. fumigatus strains with elevated voriconazole MICs. We used an in vitro model of the human alveolus to define the exposure-response relationships for a wild-type strain (voriconazole MIC, 0.5 mg/liter) and strains with defined molecular mechanisms of triazole resistance (MICs, 4 to 16 mg/liter). All strains had anidulafungin minimum effective concentrations (MECs) of 0.0078 mg/liter. Exposure-response relationships were estimated using galactomannan as a biomarker. Concentrations of voriconazole and anidulafungin were measured using high-performance liquid chromatography (HPLC). The interaction of voriconazole and anidulafungin was described using the Greco model. Fungal growth was progressively inhibited with higher drug exposures of voriconazole. Strains with elevated voriconazole MICs required proportionally greater voriconazole exposures to achieve a comparable antifungal effect. Galactomannan concentrations were only marginally reduced by anidulafungin monotherapy. An additive effect between voriconazole and anidulafungin was apparent. In conclusion, the addition of anidulafungin does not markedly alter the exposure-response relationship of voriconazole. A rise in serum galactomannan during combination therapy with voriconazole and anidulafungin should be interpreted as treatment failure and not attributed to a paradoxical reaction related to echinocandin treatment.

Pharmacodynamics of itraconazole against Aspergillus fumigatus in an in vitro model of the human alveolus: perspectives on the treatment of triazole-resistant infection and utility of airway administration.

Itraconazole is used for the prevention and treatment of infections caused by Aspergillus fumigatus. An understanding of the pharmacodynamics of itraconazole against wild-type and triazole-resistant strains provides a basis for innovative therapeutic strategies for treatment of infections. An in vitro model of the human alveolus was used to define the pharmacodynamics of itraconazole. Galactomannan was used as a biomarker. The effect of systemic and airway administration of itraconazole was assessed, as was a combination of itraconazole administered to the airway and systemically administered 5FC. Systemically administered itraconazole against the wild type induced a concentration-dependent decline in galactomannan in the alveolar and endothelial compartments. No exposure-response relationships were apparent for the L98H, M220T, or G138C mutant. The administration of itraconazole to the airway resulted in comparable exposure-response relationships to those observed with systemic therapy. This was achieved without detectable concentrations of drug within the endothelial compartment. The airway administration of itraconazole resulted in a definite but submaximal effect in the endothelial compartment against the L98H mutant. The administration of 5FC resulted in a concentration-dependent decline in galactomannan in both the alveolar and endothelial compartments. The combination of airway administration of itraconazole and systemically administered 5FC was additive. Systemic administration of itraconazole is ineffective against Cyp51 mutants. The airway administration of itraconazole is effective for the treatment of wild-type strains and appears to have some activity against the L98H mutants. Combination with other agents, such as 5FC, may enable the attainment of near-maximal antifungal activity.

Pharmacodynamics of voriconazole in a dynamic in vitro model of invasive pulmonary aspergillosis: implications for in vitro susceptibility breakpoints.

BACKGROUND: Voriconazole is a first-line agent for the treatment of invasive pulmonary aspergillosis (IPA). There are increasing reports of Aspergillus fumigatus isolates with reduced susceptibility to voriconazole. METHODS: An in vitro dynamic model of IPA was developed that enabled simulation of human-like voriconazole pharmacokinetics. Galactomannan was used as a biomarker. The pharmacodynamics of voriconazole against wild-type and 3 resistant strains of A. fumigatus were defined. The results were bridged to humans to provide decision support for setting breakpoints for voriconazole using Clinical Laboratory Standards Institute (CLSI) and European Committee of Antimicrobial Susceptibility Testing (EUCAST) methodologies. RESULTS: Isolates with higher minimum inhibitory concentrations (MICs) required higher area under the concentration time curves (AUCs) to achieve suppression of galactomannan. Using CLSI and EUCAST methodologies, the AUC:MIC values that achieved suppression of galactomannan were 55 and 32.1, respectively. Using CLSI and EUCAST methodologies, the trough concentration:MIC values that achieved suppression of galactomannan were 1.68 and 1, respectively. Potential CLSI breakpoints for voriconazole are ≤ 0.5 mg/L for susceptible and >1 mg/L for resistant. Potential EUCAST breakpoints for voriconazole are ≤1 mg/L for susceptible and >2 mg/L for resistant. CONCLUSIONS: This dynamic model of IPA is a useful tool to address many remaining questions related to antifungal treatment of Aspergillus spp.

Eficiencia del tratamiento antibiótico intravenoso domiciliario en la fibrosis quística / Efficiency of the home intravenous antibiotics treatment in cystic fibrosis

Fundamento y objetivo: El objetivo de nuestro trabajo ha sido estimar el ahorro de costes derivado de la implantación de un programa de tratamiento antibiótico intravenoso domiciliario (TAIVD), frente al esquema terapéutico tradicional (con ingreso hospitalario), en pacientes con fibrosis quística. Pacientes y método: Se incluyó consecutivamente en el estudio a los pacientes pertenecientes a una unidad de adultos de fibrosis quística que recibieron algún día TAIVD durante el período comprendido entre enero de 2002 y diciembre de 2004. Para el análisis de ahorro de costes del TAIVD se calculó la diferencia entre los costes de las estancias brutas evitadas y los generados por el tratamiento domiciliario (fármacos, material fungible) y en el hospital de día, en el caso de que el paciente no hubiese ingresado en el hospital. Todos los pacientes recibieron tratamiento antibiótico intravenoso un mínimo de 14 días. Los datos económicos fueron proporcionados por el Servicio de Contabilidad del hospital con la ayuda del programa de Gestión Clínico-Financiera (GECLIF). Resultados: Durante los 3 años del estudio 22 pacientes con fibrosis quística recibieron 85 ciclos de tratamiento antibiótico intravenoso; 43 fueron íntegramente domiciliarios; 14, hospitalarios y 28, mixtos (hospital y domicilio). Los 71 ciclos de TAIVD (incluidos los 28 mixtos) se desglosaron en 909 días en domicilio, con una media (desviación estándar) de 12,80 (4,18) días y 43 estancias en el hospital de día. Los tratamientos antibióticos que originaron mayor gasto en el domicilio (3.964,34 e) fueron la combinación de meropenem (1 g/6 h) intravenoso con linezolid (600 mg/12 h) por vía oral durante 14 días y, en segundo lugar, la asociación de ceftazidima, tobramicina y linezolid, cuyo gasto en un ciclo de 14 días fue de 2.464,84 e. El ahorro medio en los 3 años de estudio se estimó en 2.647,29 e por cada ciclo de TAIVD, y de forma global, en 197.689,78 e. Conclusiones: La implantación del programa de TAIVD supuso un importante ahorro de costes. Dicho ahorro fue mayor cada año, dado que el coste de la estancia hospitalaria se elevó de forma considerable cada año transcurrido

Background and objective: The objective of our study was to determine the costs saving with the implementing of a home intravenous antibiotic treatment (HIVAT) program for patients with cystic fibrosis and to compare it with the conventional system (inpatient). Patients and method: Consecutive patients in an adults cystic fibrosis unit were selected who received some days of HIVAT, between January 2002 and December 2004. For the analysis of costs saving of the HIVAT, we used the difference between the total costs of the avoided stay days and the costs generated by the domiciliary therapy (drugs, expendable equipment) and by the ambulatory medicine unit in case the patients were not hospitalized. All patients received a therapy with an intravenous antibiotic for a minimum of 14 days. All these data were provided by the accounting service of the hospital with the aid management Clinical Financier Program (GECLIF). Results: 22 patients with cystic fibrosis needed 85 intravenous antibiotics treatments during the 3 years of the study, of which: 43 cycles were completely domiciliary, 14 inpatient and 28 were combined (hospital and home). The 71 cycles of HIVAT originated 909 days at home, with an average (standard deviation) of 12.80 (4.18) days and 43 treatments in ambulatory medicine unit. The home antibiotic treatments that originated greater cost (3,964.34 e) was meropenem (1 g/6 h) i.v. with linezolid (600 mg/12 h) via oral combination during 14 days, and in second place the association of ceftazidime, tobramycine and linezolid, whose cost in cycle of 14 days was of 2464.84 e. The average saving cost in the 3 years of study was of 2,647.29 e by each cycle of HIVAT and global 197,689.78 e. Conclusions: HIVAT obtained important sanitary costs saving and this was greater every year, not due to the increase of days at home, but due to the rising cost per day of hospital stays every new year