Economic impact of managing invasive mold disease with isavuconazole compared with liposomal amphotericin B followed by posaconazole in Spain.

BACKGROUND: Invasive fungal infections (IFI) are associated with significant morbidity and mortality. The objective of this work was to compare the costs per adult patient, associated with intravenous isavuconazole (ISAV) followed by oral ISAV versus the regimen of liposomal amphotericin B followed by posaconazole (L-AMB→POSA) in the treatment of IFI. The comparison was conducted from the perspective of the Spanish National Health System (SNS). METHODS: As indirect comparisons have demonstrated similar efficacy between the comparators, a cost-minimization approach was taken. Drug acquisition, administration, hospitalization, laboratory tests and adverse events costs were evaluated from SNS perspective. Deterministic and probabilistic sensitivity analyzes were performed. RESULTS: Total costs per-patient were €24,715.54 with ISAV versus €29,753.53 with L-AMB→POSA, resulting in cost-savings per patient treated with ISAV of €5,037.99 (-16.9%). Treatment costs of IFI remained lower for ISAV than for L-AMB→POSA across all sensitivity analyses (-7,968.89€ to -326.59€), being treatment duration the most influential parameter. CONCLUSION: According to the present model, the treatment of IFIs with ISAV would generate savings for the SNS compared to L-AMB→POSA. These savings are attributed to the shorter duration of IV treatment, reduced use of healthcare resources and lower costs associated with managing adverse effects when ISAV was employed.

Recommendations on the use of azole antifungals in hematology-oncology patients.

The administration of antifungals for therapeutic and, especially, prophylactic purposes is virtually a constant in patients requiring hematology-oncology treatment. Any attempt to prevent or treat Aspergillus or Mucor infections requires the administration of some drugs in the azole group, which include voriconazole, posaconazole and isavuconazole, noted for their activity against these pathogens. One very relevant aspect is the potential risk of interaction when associated with one of the antineoplastic drugs used to treat hematologic tumors, with serious complications. In this regard, acalabrutinib, bortezomib, bosutinib, carfilzomib, cyclophosphamide, cyclosporine A, dasatinib, duvelisib, gilteritinib, glasdegib, ibrutinib, imatinib, nilotinib, ponatinib, prednisone, ruxolitinib, tacrolimus, all-transretinoic acid, arsenic trioxide, venetoclax, or any of the vinca alkaloids, are very clear examples of risk, in some cases because their clearance is reduced and in others because of increased risk of QTc prolongation, which is particularly evident when the drug of choice is voriconazole or posaconazole.

Interactions listed in the Paxlovid fact sheet, classified according to risks, pharmacological groups, and consequences.

Paxlovid (nirmatrelvir plus ritonavir) is a new oral antiviral therapeutic for the treatment and post-exposure prophylaxis of COVID-19. Nirmatrelvir is an inhibitor of SARS-CoV-2 main protease, while ritonavir is used as a CYP3A inhibitor in low doses to slow the metabolism of nirmatrelvir, thus enhancing their therapeutic effect. The isoenzyme CYP3A4 is responsible for at least part of the oxidative metabolism of approximately 60% of available medications and ritonavir is therefore a significant source of drug interactions. We describe here the drugs that are contraindicated or should be used with or without precautions when Paxlovid (nirmaltrevir plus ritonavir) should be administered according to each fact sheet in force at the Spanish Agency for Medicines and Health Products.

Recommendations for antibiotic selection for severe nosocomial infections.

Severe infection and its evolution to sepsis are becoming more prevalent every day and are among the leading causes of critical illness and mortality. Proper management is crucial to improve prognosis. This document addresses three essential points that have a significant impact on this objective: a) early recognition of patients with sepsis criteria, b) identification of those patients who suffer from an infection and have a high risk of progressing to sepsis, and c) adequate selection and optimization of the initial antimicrobial treatment.

Antibiotic selection in the treatment of acute invasive infections by Pseudomonas aeruginosa: Guidelines by the Spanish Society of Chemotherapy.

Pseudomonas aeruginosa is characterized by a notable intrinsic resistance to antibiotics, mainly mediated by the expression of inducible chromosomic ß-lactamases and the production of constitutive or inducible efflux pumps. Apart from this intrinsic resistance, P. aeruginosa possess an extraordinary ability to develop resistance to nearly all available antimicrobials through selection of mutations. The progressive increase in resistance rates in P. aeruginosa has led to the emergence of strains which, based on their degree of resistance to common antibiotics, have been defined as multidrug resistant, extended-resistant and panresistant strains. These strains are increasingly disseminated worldwide, progressively complicating the treatment of P. aeruginosa infections. In this scenario, the objective of the present guidelines was to review and update published evidence for the treatment of patients with acute, invasive and severe infections caused by P. aeruginosa. To this end, mechanisms of intrinsic resistance, factors favoring development of resistance during antibiotic exposure, prevalence of resistance in Spain, classical and recently appeared new antibiotics active against P. aeruginosa, pharmacodynamic principles predicting efficacy, clinical experience with monotherapy and combination therapy, and principles for antibiotic treatment were reviewed to elaborate recommendations by the panel of experts for empirical and directed treatment of P. aeruginosa invasive infections.

Antifungal prophylaxis with anidulafungin to minimize drug interactions with an antiepileptic treatment in a hematopoietic stem cell transplant recipient.

WHAT IS KNOWN AND OBJECTIVE: Invasive fungal infections are a major cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT). This provides a clear rationale for antifungal prophylaxis in this population. A concern is the potential for drug interactions, given that most of antifungals are metabolized through the P450 cytochrome system. CASE SUMMARY: We present a case of a 33-year-old woman, with a past history of high-risk epilepsy, who underwent allogeneic HSCT for a myelodysplastic syndrome. Anidulafungin was successfully used as antifungal prophylaxis to minimize drug interactions with her antiepileptic treatment. WHAT IS NEW AND CONCLUSION: This is the first reported case of antifungal prophylaxis with this echinocandin in HSCT. Anidulafungin may be an option in transplant recipients with multiple risk factors for drug interactions.

Monoclonal antibodies: pharmacokinetics as a basis for new dosage regimens?

Complete monoclonal IgG antibodies which are in use in clinical practice share some pharmacological properties resulting in high concentrations in plasma. This fact is reflected in their low volumes of distribution, which can also be correlated with a high molecular weight and water solubility. This feature allows a novel approach to be applied to the dosing schedule for this group of drugs with fixed doses being used instead of the initially developed weight- or body surface-adjusted dosing schedules. In addition, the development of a new formulation containing hyaluronidase allows a subcutaneous route of administration to be used, because hyaluronidase creates a space in the subcutaneous tissue that helps antibody absorption. This method requires higher doses, but has allowed testing the feasibility of administering a fixed dose, with no individual dose adjustments based on weight or body surface. Moreover, loading doses are not needed, because the first dose results, within 3 weeks, in minimum concentrations that are higher than effective concentrations.

Daptomycin is safe and effective for the treatment of gram-positive cocci infections in solid organ transplantation.

INTRODUCTION: Infections caused by resistant gram-positive cocci (GPC), especially to glycopeptides, are difficult to treat in solid organ transplant (SOT) recipients as a result of lower effectiveness and high rates of renal impairment. The aim of this study was to evaluate the use of daptomycin in this population. METHODS: Over a 2-year period (March 2008-2010) in 9 Spanish centers, we enrolled all consecutive recipients who received daptomycin to treat GPC infection. The study included 43 patients, mainly liver and kidney transplant recipients. RESULTS: The most frequent infections were catheter-related bacteremia caused by coagulase-negative staphylococci (23.2%), skin infection caused by Staphylococcus aureus (11.5%), and intra-abdominal abscess caused by Enterococcus faecium (20.9%). The daily daptomycin dose was 6 mg/kg in 32 patients (74.4%). On day 7 of daptomycin treatment, median estimated area under the curve was 1251 µg/mL/h. At the end of follow-up, analytical parameters were similar to the values at the start of therapy. No changes were observed in tacrolimus levels. No patient required discontinuation of daptomycin because of adverse effects. Clinical success at treatment completion was achieved in 37 (86%) patients. Three patients died while on treatment with daptomycin. CONCLUSION: In summary, daptomycin was a safe and useful treatment for GPC infection in SOT recipients.

Oral availability of bilastine.

BACKGROUND AND OBJECTIVE: Bilastine (Bilaxten™) is a novel non-sedating H1 receptor antagonist (antihistamine) developed in the dosage form of oral tablets and indicated for the treatment of allergic rhinitis (seasonal and perennial) and urticaria. Several clinical trials have been performed in order to determine the efficacy and safety of bilastine. The aim of this trial was to study the absolute oral bioavailability of bilastine in humans. METHODS: Twelve male and female adults were recruited into a single centre for a randomized, single-dose, open-label, controlled two-arm crossover study with a minimum 14-day washout period between the two single doses. Two single doses of bilastine were administered: a 20-mg oral tablet and a 10-mg intravenous formulation. Blood and urine samples were collected between 0 and 72 h post each administration. The clinical trial was carried out under quality assurance and quality control systems with standard operating procedures to ensure that the study was conducted and data generated in compliance with the protocol, Good Clinical Practice standards, International Conference on Harmonisation and other applicable regulations. RESULTS: Oral bioavailability of bilastine was 60.67 % with a 90 % parametric confidence interval of 53.79-67.56. The maximum bilastine concentration was measured 1.31 h after oral administration. Pharmacokinetic parameters were similar to those observed in previous studies. Tolerance to treatment was good, with no adverse events related to study medication. CONCLUSION: The absorption of bilastine after oral administration to healthy subjects was rapid. The absolute oral bioavailability was moderate.

[Endotoxin adsortion as adjuvant therapy in gram negative severe sepsis]. / La depuración de endotoxina como tratamiento coadyuvante en la sepsis grave por microorganismos gramnegativos.

The mortality rate of severe sepsis and septic shock remains still high. Within the last years a better knowledge of its physiopathology and the implementation of a group of measures addressed to a fast identification and early treatment of the septic patients have proved to reduce mortality rate. Likewise, it continues being investigated in modulating the inflammatory response and limiting the harmful action of the bacterial products on the immune system. As a result of this research some endotoxin adsorber devices have been designed to control one of the most important targets that start the inflammatory cascade when gram negative microorganisms are involved.The usefulness that these endotoxin removal devices might have as adjuvant treatment in the Septic Syndrome and its applicability are reviewed in this paper. Likewise a profile of patient that might be to the benefit of this therapy is suggested according to the current knowledge.

La depuracion de endotoxina como tratamiento coadyuvante en la sepsis grave por microorganismos gramnegativos / Endotoxin adsortion as adjuvant therapy in gramnegative severe sepsis

La sepsis grave y el shock séptico siguen siendo situaciones clínicas con alta mortalidad. En los últimos años, un mejor conocimiento de su fisiopatología y la puesta en marcha de un conjunto de medidas encaminadas a una rápida detección y un inmediato tratamiento de los pacientes sépticos han demostrado que pueden disminuir la mortalidad. Así mismo, se sigue investigando en modular la respuesta inflamatoria y limitar la acción dañina de los productos bacterianos sobre el sistema inmune. Fruto de esta investigación se han desarrollado dispositivos adsorbentes de endotoxina para actuar sobre ella por ser ésta una de las principales dianas que inician la cascada inflamatoria en infecciones causadas por gérmenes gramnegativos. En este artículo se revisa la utilidad y modo de empleo que estos dispositivos de depuración de endotoxinas pueden tener como tratamiento coadyuvante del Síndrome séptico. Así mismo se sugiere, en base a los conocimientos actuales, el perfil de paciente que puede beneficiarse de dicha terapia(AU)

The mortality rate of severe sepsis and septic shock remains still high. Within the last years a better knowledge of its physiopathology and the implementation of a group of measures addressed to a fast identification and early treatment of the septic patients have proved to reduce mortality rate. Likewise, it continues being investigated in modulating the inflammatory response and limiting the harmful action of the bacterial products on the immune system. As a result of this research some endotoxin adsorber devices have been designed to control one of the most important targets that start the inflammatory cascade when gramnegative microorganisms are involved. The usefulness that these endotoxin removal devices might have as adjuvant treatment in the Septic Syndrome and its applicability are reviewed in this paper. Likewise a profile of patient that might be to the benefit of this therapy is suggested according to the current knowledge(AU)

Recomendaciones de tratamiento antifúngico en pacientes con bajo gradode inmunodepresión / Recommendations of antifungal treatment in patients with low grade inmunosuppression

La relevancia que las micosis sistémicas han adquiridoen los pacientes no profundamente inmunodeprimidos, lasdificultades de tratamiento que presentan por el incrementode la especies de Candida no albicans y la necesidad dehacer un mejor uso y más racional de los nuevos antifúngicos(voriconazol, posaconazol, caspofungina, micafungina yanidulafungina) han reunido a un panel de expertos en enfermedadesinfecciosas en representación de la Sociedad Españolade Quimioterapia (SEQ), Sociedad Española de MedicinaInterna (SEMI) y Sociedad Española de Neumología yCirugía Torácica (SEPAR) para hacer unas recomendacionesbasadas en la evidencia científica buscando mejorar la efectividad (AU)

Because of the relevance that the systemic mycoses hasacquired in non-highly immunocompromised patients, thetreatment difficulties they have due to the increase of thenon-albicans Candida species and the need to have a betterand more rational use of the new antifungal agents (voriconazole,posaconazole, caspofungin, anidulafungin and micafungin),an experts' panel on infectious diseases in representationof the Spanish Society of Chemotherapy, SpanishSociety of Internal Medicine, and Spanish Society of Pneumologyand Thoracic Surgery has met in order to make a few recommendations based on the scientific evidence in aneffort to improve their efficiency (AU)

[Recommendations of antifungal treatment in patients with low grade immunosuppression]. / Recomendaciones de tratamiento antifúngico en pacientes con bajo grado de inmunodepresión.

Because of the relevance that the systemic mycoses has acquired in non-highly immunocompromised patients, the treatment difficulties they have due to the increase of the non-albicans Candida species and the need to have a better and more rational use of the new antifungal agents (voriconazole, posaconazole, caspofungin, anidulafungin and micafungin), an experts' panel on infectious diseases in representation of the Spanish Society of Chemotherapy, Spanish Society of Internal Medicine, and Spanish Society of Pneumology and Thoracic Surgery has met in order to make a few recommendations based on the scientific evidence in an effort to improve their efficiency.

Análisis coste-efectividad de la prevención de la reagudización de la esquizofrenia en el estudio longitudinal Ziprasidone Extended Use in Schizophrenia (ZEUS) / Cost-effectiveness analysis of the prevention of relapse of schizophrenia in the longitudinal study Ziprasidone Extended Use in Schizophrenia (ZEUS)

Objetivo. Estimar el coste-efectividad de la prevención de la reagudización de la esquizofrenia en el estudio longitudinal Ziprasidone Extended Use in Schizophrenia Study (ZEUS) en el que se compara ziprasidona con la opción de no tratar. Métodos. Se analizó 1 año de tratamiento usando los datos de un ensayo clínico aleatorizado (estudio ZEUS) con un modelo determinista, del tipo análisis coste-efectividad, realizado desde la perspectiva del Sistema Nacional de Salud (SNS). Resultados. El coste medio anual adicional por reagudización evitada con ziprasidona fue de 186 € para la dosis media, oscilando entre -556 € (ahorro) con la dosis de 80 mg/día y 1.014 € con 160 mg/día, inferiores en todos los casos al coste mínimo de una reagudización (2.830 €), considerado como valor umbral para establecer el coste-efectividad del tratamiento con ziprasidona. Conclusiones. La prevención de la reagudización de la esquizofrenia con ziprasidona a largo plazo es coste-efectiva en comparación con la opción de no tratar. El tratamiento con ziprasidona evita episodios de recidivas a un coste razonable generando ahorros para el SNS

Objective. Estimate the cost-effectiveness of the prevention of relapse of schizophrenia in the ZEUS (Ziprasidone Extended Use in Schizophrenia Study) longitudinal study that compares ziprasidone with the option of not treating. Methods. One year of treatment was analyzed using the randomized clinical trial data (ZEUS study) with a deterministic model, having cost-effectiveness analysis type, conducted from the perspective of the National Health Care System (NHCS). Results. Additional mean yearly cost for worsening avoided with ziprasidone was 186 € for the mean dose, ranging from -556 € (savings) with the 80 mg/day dose and 1,014 € with 160 mg/day, which was always lower than the minimum cost of a relapse (2,830 €), considered as threshold value to establish cost-effectiveness of treatment with ziprasidone. Conclusions. Prevention of relapse of schizophrenia with long-term ziprasidone is cost-effective in comparison with the option of not treating. Treatment with ziprasidone avoids relapse episodes at a reasonable cost, generating savings for the NHCS

Cost-effectiveness analysis of the prevention of relapse of schizophrenia in the longitudinal study Ziprasidone Extended Use in Schizophrenia (ZEUS).

OBJECTIVE: Estimate the cost-effectiveness of the prevention of relapse of schizophrenia in the ZEUS (Ziprasidone Extended Use in Schizophrenia Study) longitudinal study that compares ziprasidone with the option of not treating. METHODS: One year of treatment was analyzed using the randomized clinical trial data (ZEUS study) with a deterministic model, having cost-effectiveness analysis type, conducted from the perspective of the National Health Care System (NHCS). RESULTS: Additional mean yearly cost for worsening avoided with ziprasidone was 186 Pounds for the mean dose, ranging from -556 Pounds (savings) with the 80 mg/day dose and 1,014 Pounds with 160 mg/day, which was always lower than the minimum cost of a relapse (2,830 Pounds), considered as threshold value to establish cost-effectiveness of treatment with ziprasidone. CONCLUSIONS: Prevention of relapse of schizophrenia with long-term ziprasidone is cost-effective in comparison with the option of not treating. Treatment with ziprasidone avoids relapse episodes at a reasonable cost, generating savings for the NHCS.

Pharmacokinetic/pharmacodynamic serum and urine profile of cefditoren following single-dose and multiple twice- and thrice-daily regimens in healthy volunteers: a phase I study.

The objectives of this randomized, double-blind study were to evaluate the pharmacokinetics, and the pharmacodynamic and gastrointestinal (GI) tolerance of cefditoren pivoxil in healthy adult male volunteers when it is administered three times a day. Twenty healthy volunteers were included in the study. On day 1, 10 subjects received a 200-mg single dose of cefditoren pivoxil and 10 received a 400-mg dose. After a washout period of 8 days, eight subjects received cefditoren pivoxil 400 mg b.i.d., eight received 400 mg t.i.d., and four received placebo for 10 days. Medication was taken 30 min after meals. Blood and urine collections were carried out on days 1, 9, 14 and 19. Volunteers were asked about any GI change, especially about bowel habits, nausea, vomiting and abdominal pain. The maximum cefditoren concentration (C(max)) had a mean value of 3.77+/-0.66 mg/l, and was reached between 1.5 and 3 h in the thrice-daily administration. In the twice-daily regimen, the C(max) was 3.27+/-0.64 mg/l. The mean time above breakpoint minumum inhibitory concentration (MIC), calculated with data from each pharmacokinetic profile, was always above 40%, in both the twice- and thrice-daily regimens. The half-life of cefditoren was 1.19+/-0.2 h and 1.36+/-0.2 h in the twice-daily and thrice-daily regimens, respectively. The C(max) of cefditoren in urine was reached between 2 and 4 h postadministration, with a mean value of 154.53 mg/l in the twice-daily regimen, and 186.59 mg/l in the thrice-daily administration. There were no differences between the groups in the incidence of GI adverse events. The present data show that the administration of cefditoren pivoxil 400 mg t.i.d. is possible because it is well tolerated, and it increases the probability of success when the MIC of the causative bacteria is close to the susceptibility breakpoint. The high concentrations of active drug in the urine enable cefditoren to be considered as a useful candidate for the treatment of uncomplicated urinary tract infections (UTIs).

Efficacy and tolerability of prolonged linezolid therapy in the treatment of orthopedic implant infections.

The aim of the study presented here was to assess the efficacy and tolerability of linezolid in the treatment of orthopedic implant infections (OII). Eighty-five patients with an OII treated with linezolid were prospectively followed up for a minimum of 12 months from the end of antibiotic therapy. Outcome was evaluated in relation to the duration and type of symptoms (acute or chronic) and the retention or removal of the implant. For acute and chronic infections, the respective success rates were 100 and 92.3% when the implant was removed and 72.2 and 42.8% when it was not. The median length of linezolid treatment in acute and chronic infections was 47 and 60 days, respectively. Thrombocytopenia was observed in four (4.7%) patients and anemia in five (5.8%). The results suggest oral linezolid is an effective and well-tolerated alternative for treating OII.

[The most common infections in the transplanted patient]. / Infecciones más comunes en el paciente trasplantado.

Organ transplantation has become one of the most important areas of medical research and, at present, is still the only therapeutical tool for several diseases. However, there are a number of factors related to transplantation, like immunosuppression and prolonged neutropenia that affect the incidence of infection. These infections are somehow peculiar to transplant recipients. In fact, there are infectious diseases that only occur in immunodepression situations and, moreover, clinical expression of these infectious diseases can be quite different from that in immunocompetent patients. Besides these aspects, some infections, due to the high prevalence described, must be considered for prevention strategies because they continue to be a principal cause of morbidity and mortality, either due to direct effects or to their implication in the pathogenesis of rejection. These strategies commence before transplantation by active immunization through vaccine administration to the patient and to people in the milieu and continue after transplantation with prophylaxis or pre-emptive therapy. The importance of infectious diseases in the evolution and prognosis of transplant recipients gives a special meaning to the understanding of associated infections, their clinical expression and ways of prevention and treatment.

Nuevas perspectivas del tratamiento inmunosupresor en el trasplante de órganos / New perspectives in immunosuppresion

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Ziprasidona: de la farmacología a la práctica clínica. Un año de experiencia / Ziprasidone: from pharmacology to the clinical practice. One year of experience

Transcurridos más de 2 años desde la comercialización del antipsicótico atípico ziprasidona, los datos procedentes de estudios de investigación y de la práctica clínica han proporcionado abundante información útil para su manejo práctico en el tratamiento de la esquizofrenia. Sus características farmacodinámicas y los resultados de los estudios clínicos con dosis flexible parecen justificar la necesidad de administrar dosis en el rango superior de las inicialmente previstas, con un mínimo inicial de 120 mg/día y una rápida titulación hasta 160 mg/día. Dichas dosis permiten alcanzar concentraciones plasmáticas que permiten ocupar al menos el 60 % de los receptores D2 del que se derivará el efecto antipsicótico. Además, se confirma su actividad antidepresiva y su perfil no sedante, con un posible efecto favorable sobre la atención y otras funciones cognitivas del paciente, en relación con la elevada afinidad frente a receptores 5HT1A y D1 y la inhibición de la recaptación de serotonina y noradrenalina.Por último, la escasa afinidad de este fármaco frente a receptores alpha-adrenérgicos, histamínicos y muscarínicos favorece un buen perfil de tolerabilidad, con un efecto neutro sobre el peso y falta de efectos anticolinérgicos. Los resultados de diversos ensayos clínicos muestran que el uso de dosis en el rango superior se asocia a una mejoría clínica más rápida y pronunciada que dosis inferiores, sin añadir un mayor riesgo de efectos adversos

More than a year after the marketing of the atypical anti-psychotic ziprasidone, data from research studies and clinical practice have provided a fair amount of useful information for its practical use in the treatment of schizophrenia. Its pharmacodynamical characteristics and the results from clinical trials with a flexible dose seem to justify the need to administer doses in a range higher than what was initially foreseen, with an initial minimum of 120 mg per day and a fast titulation up to 160 mg per day. Such doses make it possible to achieve sufficient plasma concentrations to occupy at least 60 % of the D2 receptors from which the anti-psychotic effect derives. Moreover, its anti-depressive activity and its non-sedative profile have been confirmed, with a favorable effect on attention and other cognitive functions of the patient, according to its high affinity for 5HT1A and D1 receptors and the inhibition of serotonin and noradrenaline re-uptake.Finally, the low affinity of this drug for á-adrenergic, histaminergic and muscarinic receptors favors a good tolerability profile, with a neutral effect on weight, and a lack of anti-cholinergic effects. Results from different clinical trials show that the use of doses in the higher range is associated to a faster and more pronounced clinical improvement without adding a higher risk of adverse events