Incidencia de hipopotasemia en pacientes con neutropenia febril que reciben tratamiento con anfotericina B liposomal / Incidence of hypokalemia in patients with febrile neutropenia receiving treatment with liposomal amphotericin B

Objetivos: Describir la incidencia, la gravedad y los factores asociados a la aparición de hipopotasemia en pacientes con neutropenia febril en tratamiento con anfotericina B liposomal.Métodos: Estudio unicéntrico retrospectivo (enero 2010- mayo 2020), que incluyó a aquellos pacientes hematológicos con neutropenia febril que recibieron tratamiento con anfotericina B liposomal durante al menos 72 h. Se evaluó la incidencia de aparición de hipokalemia asociada al empleo del fármaco, la gravedad de la misma, así como el impacto del empleo de una suplementación de potasio sobre la aparición de hipokalemia en este grupo de pacientes.Resultados: Se incluyeron 89 pacientes (50,6% mujeres [n=45]; edad media 63,5 años [20-90]). El 59,6% (n=53) de los pacientes desarrolló hipopotasemia durante el tratamiento con anfotericina B liposomal: leve (52,8%, n=28), moderada (35,8%, n=19) y grave (11,3%, n=6). El empleo de una suplementación de inicio precoz a base de potasio disminuyó la tasa de aparición de hipokalemia en estos pacientes (p=0,001). El periodo entre el inicio del fármaco y el aporte de potasio fue menor en pacientes que no desarrollaron hipokalemia (p<0,001). Asimismo, este grupo de pacientes se benefició de periodos más prolongados de suplementación (p=0,002) y terapia antifúngica (p=0,039).Conclusiones: La hipopotasemia es un efecto adverso muy frecuente en pacientes con neutropenia febril que reciben tratamiento con anfotericina B liposomal, siendo necesario el establecimiento de protocolos de suplementación de potasio que disminuyan el riesgo de aparición de esta reacción adversa. (AU)

Objectives: To describe the incidence, severity and factors associated with the appearance of hypokalemia in patients with febrile neutropenia in treatment with liposomal amphotericin B. Methods: Retrospective unicenter study (January 2010-May 2020), which included those hematological patients with febrile neutropenia who were treated with liposomal amphotericin B for at least 72 h. The incidence of hypokalemia associated with the use of the drug, its severity, and the influence of potassium supplementation on the occurrence of hypokalemia in this group of patients were evaluated. Results: 89 patients were included (50.6% women [n=45]; mean age 63.5 years [20-90]). 59.6% (n=53) of patients developed hypokalemia during treatment with liposomal amphotericin B: mild (52.8%, n=28), moderate (35.8%, n=19) and severe (11.3%, n=6). The use of early-onset potassium-based supplementation decreased the rate of occurrence of hypokalemia in these patients (p=0.001). The period between drug initiation and potassium intake was lower in patients who did not develop hypokalemia (p<0.001). Likewise, this group of patients benefited from longer periods of supplementation (p=0.002) and antifungal therapy (p=0.039).Conclusions: Hypokalemia is a very frequent adverse effect in patients with febrile neutropenia who are treated with liposomal amphotericin B. It is necessary to establish protocols for potassium supplementation to reduce the risk of this adverse reaction. (AU)

[Individualized antifungal therapy in critically ill patients with invasive fungal infection]. / Tratamiento antifúngico individualizado en el paciente crítico con infección fúngica invasora.

Invasive candidiasis (IC) is the most common invasive fungal infection (IFI) affecting critically ill patients, followed by invasive pulmonary aspergillosis (IPA). International guidelines provide different recommendations for a first-line antifungal therapy and, in most of them, echinocandins are considered the first-line treatment for IC, and triazoles are so for the treatment of IPA. However, liposomal amphotericinB (L-AmB) is still considered a second-line therapy for both clinical entities. Although in the last decade the management of IFI has improved, several controversies persist. The antifungal drugs currently available may have a suboptimal activity, or be wrongly used in certain IFI involving critically ill patients. The aim of this review is to analyze when to provide individualized antifungal therapy to critically ill patients suffering from IFI, emphasizing the role of L-AmB. Drug-drug interactions, the clinical status, infectious foci (peritoneal candidiasis is discussed), the fungal species involved, and the need of monitoring the concentration of the antifungal drug in the patient are considered.

[AmBisome, three challenges: Candida auris infection, central nervous system infection, and biofilm-associated infection]. / AmBisome, tres retos: infección por Candida auris, infección del sistema nervioso central e infección asociada a biopelículas.

The treatment of invasive fungal infections remains a challenge, both for the diagnosis and for the need of providing the appropriate antifungal therapy. Candida auris is a pathogenic yeast that is responsible for hospital outbreaks, especially in intensive care units; it is characterized by a high resistance to the antifungal agents and can become multidrug-resistant. At present, the recommended antifungal agents for the invasive infections with this pathogen are echinocandins, always after carrying out an antifungal susceptibility testing. In case of no clinical response or persistent candidemia, the addition of liposomal amphotericin B or isavuconazole may be considered. Both fungal infection of the central nervous system and that associated with biomedical devices remain rare entities affecting mainly immunocompromised patients. However, an increase in their incidence in recent years, along with high morbidity and mortality, has been shown. The treatment of these infections is conditioned by the limited knowledge of the pharmacokinetic properties of antifungals. A better understanding of the pharmacokinetic and pharmacodynamic parameters of the different antifungals is essential to determine the efficacy of the antifungal agents in the treatment of these infections.

[Liposomal amphotericin B: Clinical pharmacology, pharmacokinetics and pharmacodynamics]. / Anfotericina B liposomal: farmacología clínica, farmacocinética y farmacodinamia.

Liposomal amphotericin B is a lipid formulation of the antifungal drug amphotericin B with some distinguishing characteristics in its pharmacological behavior that entail some clinical differences of great interest. The significant improvement in the systemic and renal tolerability is one of them. This fact is related to the great stability of the liposome, promoted by its negative charge, the presence of cholesterol and the remarkable thermo-stability of the remaining lipids that compose it. In this situation, amphotericin B seems to be released from the liposome not spontaneously but when the liposome binds to the ergosterol in the fungal cell membrane. For this reason, there is almost no free amphotericin B in plasma or tissues, although it seems that its availability is greater when there is fungal infection. As a consequence, when the pharmacokinetic behavior is studied, the concentration and availability of liposomal amphotericin B are very high, and its volume of distribution is reduced in comparison with the other formulations.

Mucormicosis rinocerebral: Una revisión bibliográfica a propósito de un caso clínico / Rhinocerebral mucormycosis: A literature review and report of clinical case

RESUMEN La mucormicosis es una infección fúngica oportunista, poco común causada por hongos del orden de los mucorales. Ocurre a una tasa anual de 1.7 casos por cada millón de personas y presenta una tasa de mortalidad alta que oscila desde el 30 hasta el 90% de acuerdo con el estado sistémico del paciente. Los escenarios más complejos se observan en pacientes inmunosuprimidos, mientras que, en pacientes competentes, la invasión fúngica es bien controlada por el sistema inmune del huésped. La infección comienza luego de la ex-posición, inhalación e invasión de esporas dentro de la cavidad oral y nasal desde donde se puede diseminar a otras partes del cuerpo, permitiendo diferentes presentaciones clínicas en pacientes susceptibles. Actualmente, los registros internacionales de mortalidad de mucormicosis en niños con neoplasias van desde 41.3 a 66.6, por lo que el objetivo de este estudio es presentar un caso raro de mu-cormicosis rinocerebral en un paciente masculino de 4 años quien además presentó como enfermedad base una leucemia linfoblástica aguda B común, tratado con anfotericina B liposomal y debridación quirúrgica de las zonas afectadas. Finalmente, se realizó una revisión sistemática de la literatura disponible con el afán de determinar y describir los signos, síntomas, diagnóstico, tratamiento disponible y pronóstico de esta enfermedad.

ABSTRACT Mucormycosis is an uncommon opportunistic fungal infection caused by fungi of the mucoral order. Occurs at an annual rate of 1.7 cas-es per million people. It has a high mortality rate ranging from 30 to 90% according to the patient's systemic status. The most complex scenarios are observed in immunosuppressed patients, whereas, in competent patients, the fungal invasion is well controlled by the host's immune system. The infection begins after exposure, inhalation and invasion of spores into the oral and nasal cavity from where it can spread to other parts of the body, allowing different clinical presentations in susceptible patients. Currently, international records of mortality of mucormycosis in children with neoplasms range from 41.3 to 66.6. The objective of this study is to present a rare case of rhi-nocerebral mucormycosis in a 4-year-old male patient who also presented as a base disease a leukemia acute B-lymphoblastic disease. Our patient was treated with liposomal amphotericin B and surgical debridement of affected areas. In addition, a systematic review of the available literature was carried out with the aim of determining and describing the signs, symptoms, diagnosis, available treatment and prognosis of this disease.

Antifungal stewardship in a tertiary hospital.

BACKGROUND: The inappropriate use of antifungals is an important health problem related to increasing adverse effects, unnecessary cost and promotion of resistant and emerging fungal infections. Despite its relevance, many health institutions assign few resources to improve prescribing practices. AIMS: To evaluate the efficiency of an antifungal stewardship programme (ASP) centered on restricted antifungal agents. METHODS: The main activity during the eight-month study was to perform a programmed review of restricted antifungals (lipid formulations of amphotericin B, echinocandins and voriconazole) prescribed in hospitalized patients. In the case of amendable antifungal treatment, a recommendation was included in the electronic medical record. RESULTS: A total of 280 antifungal prescriptions for 262 patients were revised during the study period. The indications were prophylactic in 85 cases (30.4%), pre-emptive in 10 cases (3.5%), empiric in 122 cases (43.6%), and directed in 63 cases (22.5%). A total of 70 prescriptions (25%) in 61 patients were considered to be amendable. In most of these cases, treatment could have been reduced considering the patient's clinical improvement and microbiological results. The most common advice was antifungals change (70%), antifungal withdrawal (21%), removal of one antifungal drug in cases of combined therapy (7%), and switching to oral route (1%). Proposed recommendations were addressed in 28 cases (40%). There was no significant difference in adherence with respect to the type of recommendation (p=0.554). There was a 42% lower use of antifungals during the period of the study compared to that observed during a similar previous period. Mortality among patients who were treated according to the recommendations of the ASP was 17% and in whom treatment was not modified it was 30% (p=0.393). CONCLUSIONS: ASPs centered on hospitalized patients may be an efficient strategy to ameliorate antifungal use in hospitals.

[Mixed invasive fungal infection due to Rhizomucor pusillus and Aspergillus niger in an immunocompetent patient]. / Infección fúngica invasiva mixta por Rhizomucor pusillus y Aspergillus niger en un paciente inmunocompetente.

BACKGROUND: Mucormycosis infections are rare in immunocompetent patients, and very few cases of mucormycosis associated with aspergillosis in non-haematological patients have been reported. CASE REPORT: A 17-year-old male, immunocompetent and without any previously known risk factors, was admitted to hospital due to a seizure episode 11 days after a motorcycle accident. He had a complicated clinical course as he had a mixed invasive fungal infection with pulmonary involvement due to Aspergillus niger and disseminated mucormycosis due to Rhizomucor pusillus (histopathological and microbiological diagnosis in several non-contiguous sites). He was treated with liposomal amphotericin B for 7 weeks (total cumulative dose >10 g) and required several surgical operations. The patient survived and was discharged from ICU after 5 months and multiple complications. CONCLUSIONS: Treatment with liposomal amphotericin B and aggressive surgical management achieved the eradication of a mixed invasive fungal infection. However, we emphasise the need to maintain a higher level of clinical suspicion and to perform microbiological techniques for early diagnosis of invasive fungal infections in non-immunocompromised patients, in order to prevent spread of the disease and the poor prognosis associated with it.

[Analysis of the use of liposomal amphotericin B]. / Análisis de la utilización de anfotericina B liposomal.

BACKGROUND: The increase in immunosuppressed patients and in the use of cytotoxic and immunosuppressive agents in the last few years has led to a rise in the incidence of invasive fungal infections. AIMS: The objective of this study is to evaluate the use of liposomal amphotericin B according to its indication, dosage, effectiveness and nephrotoxicity. METHODS: This is a retrospective study over a 8 year-period. Indications and dosage described in the Summary of Product Characteristics were taken as reference. Effectiveness was measured in terms of resolution of infection, no recurrence or emergence, survival at 7th day, no discontinuation and no addition of another antifungal. Effectiveness was also analysed in relation to indication, dosage, treatment duration, cumulative dose and comorbidity. Nephrotoxicity was defined as a doubled serum creatinine when compared with basal values. RESULTS: A total of 47 episodes were analysed, with 91.5% of treatments being adequate for the indications. Effectiveness was achieved in 44.7% of cases: 33% in neutropenic patients, 50% of aspergillosis, 60% of candidiasis, and 100% of the leishmaniasis. Response rates in patients treated for 15 days or less and those for more than 15 days were 25 and 56.5% (P=.039), respectively. The main causes of failure were death (23%) and lack of effectiveness (17%), with 9% of patients suffering from nephrotoxicity. CONCLUSIONS: The effectiveness and nephrotoxicity data agree with those obtained in other studies. Liposomal amphotericin B is a safe drug with a moderate effectiveness that is associated with the duration of the treatment.

Zigomicosis cutanea en un paciente de 10 años: primer caso pediátrico en Venezuela: revisión de la literatura / Cutaneous zigomycosis in a 10 year-old patient: first pediatric case in Venezuela: revision of the literature

La zinomicosis es una infección aguda causada por los hongos de la clase Zigomicetos, de la cual no existen casos publicados anteriormente en el área pediátrica en nuestro país. Estos hongos producen una angioinvasión que puede manifestarse de varias formas, siendo la forma mas frecuente la rino-órbito- cerebral. Se describe el caso de un escolar masculino de 10 años que representa politraumatismo con herida muy contaminada en muslo izquierdo. Recibe antibióticos, curas quirúrgicas y dexametasona. En el curso de 13 días presentó una fascitis necrotizante con una zona aterciopelada blanca de la cual se toma muestra, diagnosticándose hongos del tipo Zigomicetos, especie Saksenaea vasiformis. Se desatircula el miembro inferior izquierdo, se le coloca Anfotericina B liposomal y Caspofungina. El paciente falleció luego de 13 días a pesar del tratamiento. La Zigomicosis cutánea severa es una patología de alta mortalidad cuyo pronóstico dependerá de un diagnóstico precoz y un manejo médico y quirúrgico agresivo. El Posaconazol ofrece nuevas perspectivas en el tratamiento de esta enfermedad.

Zygomycosis is an acute micotic infection caused by the Zygomycetes class that has not been previously described in the pediatric area in our country. These fungi produce an angioinvasion with several clinical manifestations, of which the most frequent isthe rhino-orbito-cerebral form. This is a 10 year-old male who presents with multiple injuries and a very contaminated wound in the left thigh. The child receives antibiotics, surgical cleaning, dexametaxone and presents, during the course of 13 days, a necrotizing fasciitis with a velvety white zone from where Zygomycete, specie Saksenaea vasiformis was isolated. The left thigh and leg had to bedis articulated and liposomal Amphotericin B plus Caspofungin was prescribed. In spite of the treatment the patient died 13 days later. Cutaneous Zygomycosis is a severe pathology of high mortality which prognosis will depend on an early diagnosis and aggressive medical and surgical treatment. Posaconazole offers a new perspective in the treatment of this disease.