Impact of an antimicrobial stewardship program on critical haematological patients / Impacto de un programa de optimización de antimicrobianos sobre el paciente crítico hematológico

Objective: Antimicrobial Stewardship Programs (ASPs) have appeared as very useful tools in order to improve the use of antimicrobial agents. The objective of this study is to assess the impact of an ASP on haematological patients hospitalized in an Intensive Care Unit (ICU). Methods: A quasi-experimental pre-post intervention study, which included haematological patients admitted to an ICU and assessed by the ASP program during 3 years. The impact of the program on patient evolution was assessed by comparison between the previous period and the intervention period in terms of mortality, mean stay, number of re-hospitalizations, and duration of mechanical ventilation for intubated patients. Results: The ASP team assessed 324 antimicrobial agents in 169 patients; they recommended 121 modifications, including 55 treatment discontinuations. Compared with the pre-intervention period, there were no significant differences in the variables assessed. No variation was observed in colonization by multi-resistant bacteria. Conclusions: The implementation of an APS on critical haematological patients will lead to a relevant number of treatment modifications, without any impact on the clinical evolution of patients (AU)

Objetivo: Los programas de optimización de antimicrobianos (PROA) han surgido como herramientas de gran utilidad para mejorar el uso de estos. El objetivo del presente estudio es evaluar el impacto de un PROA sobre pacientes hematológicos ingresados en una unidad de pacientes críticos. Métodos: Estudio cuasi-experimental pre-post intervención. Se incluyeron pacientes hematológicos ingresados en una unidad de críticos evaluados por el equipo PROA durante 3 años. El impacto del programa sobre la evolución de los pacientes se evaluó mediante la comparación entre el periodo previo y de intervención de la mortalidad, estancia media, número de reingresos y duración de ventilación mecánica en los pacientes intubados. Resultados: 324 antimicrobianos de 169 pacientes fueron evaluaron por el equipo PROA, recomendando un total de 121 modificaciones, incluyendo 55 suspensiones de tratamiento. Comparados con el periodo pre-intervención, no se observaron diferencias significativas en las variables consideradas. No se observó variación en la colonización por bacterias multirresistentes. Conclusiones: La implantación de un PROA sobre el paciente crítico hematológico conduce a un número relevante de modificaciones en el tratamiento, sin afectar la evolución clínica de los pacientes (AU)

Impact of an antimicrobial stewardship program on critical haematological patients.

OBJECTIVE: Antimicrobial Stewardship Programs (ASPs) have appeared as very useful tools in order to improve the use of antimicrobial agents. The objective of this study is to assess the impact of an ASP on haematological patients hospitalized in an Intensive Care Unit (ICU). METHODS: A quasi-experimental pre-post intervention study, which included haematological patients admitted to an ICU and assessed by the ASP program during 3 years. The impact of the program on patient evolution was assessed by comparison between the previous period and the intervention period in terms of mortality, mean stay, number of re-hospitalizations, and duration of mechanical ventilation for intubated patients. RESULTS: The ASP team assessed 324 antimicrobial agents in 169 patients; they recommended 121 modifications, including 55 treatment discontinuations. Compared with the pre-intervention period, there were no significant differences in the variables assessed. No variation was observed in colonization by multi-resistant bacteria. CONCLUSIONS: The implementation of an APS on critical haematological patients will lead to a relevant number of treatment modifications, without any impact on the clinical evolution of patients.

Introducción: Los programas de optimización de antimicrobianos (PROA) han surgido como herramientas de gran utilidad para mejorar el uso de estos. El objetivo del presente estudio es evaluar el impacto de un PROA sobre pacientes hematológicos ingresados en una unidad de pacientes críticos.Material y métodos: Estudio cuasi-experimental pre-post intervención. Se incluyeron pacientes hematológicos ingresados en una unidad de críticos evaluados por el equipo PROA durante 3 años. El impacto del programa sobre la evolución de los pacientes se evaluó mediante la comparación entre el periodo previo y de intervención de la mortalidad, estancia media, número de reingresos y duración de ventilación mecánica en los pacientes intubados.Resultados: 324 antimicrobianos de 169 pacientes fueron evaluaron por el equipo PROA, recomendando un total de 121 modificaciones, incluyendo 55 suspensiones de tratamiento. Comparados con el periodo pre-intervención, no se observaron diferencias significativas en las variables consideradas. No se observó variación en la colonización por bacterias multirresistentes.Conclusiones: La implantación de un PROA sobre el paciente crítico hematológico conduce a un número relevante de modificaciones en el tratamiento, sin afectar la evolución clínica de los pacientes.

Cost-effectiveness analysis of implementing an antimicrobial stewardship program in critical care units.

AIMS: To evaluate the cost-effectiveness of antimicrobial stewardship (AS) program implementation focused on critical care units based on assumptions for the Spanish setting. MATERIALS AND METHODS: A decision model comparing costs and outcomes of sepsis, community-acquired pneumonia, and nosocomial infections (including catheter-related bacteremia, urinary tract infection, and ventilator-associated pneumonia) in critical care units with or without an AS was designed. Model variables and costs, along with their distributions, were obtained from the literature. The study was performed from the Spanish National Health System (NHS) perspective, including only direct costs. The Incremental Cost-Effectiveness Ratio (ICER) was analysed regarding the ability of the program to reduce multi-drug resistant bacteria. Uncertainty in ICERs was evaluated with probabilistic sensitivity analyses. RESULTS: In the short-term, implementing an AS reduces the consumption of antimicrobials with a net benefit of €71,738. In the long-term, the maintenance of the program involves an additional cost to the system of €107,569. Cost per avoided resistance was €7,342, and cost-per-life-years gained (LYG) was €9,788. Results from the probabilistic sensitivity analysis showed that there was a more than 90% likelihood that an AS would be cost-effective at a level of €8,000 per LYG. LIMITATIONS: Wide variability of economic results obtained from the implementation of this type of AS program and short information on their impact on patient evolution and any resistance avoided. CONCLUSIONS: Implementing an AS focusing on critical care patients is a long-term cost-effective tool. Implementation costs are amortized by reducing antimicrobial consumption to prevent infection by multidrug-resistant pathogens.

Consenso español para la prevención y el tratamiento de la infección bronquial por Pseudomonas aeruginosa en el paciente con fibrosis quística / Spanish Consensus on the Prevention and Treatment of Pseudomonas aeruginosa Bronchial Infections in Cystic Fibrosis Patients

Pseudomonas aeruginosa es el patógeno más importante en la infección broncopulmonar en fibrosis quística (FQ). Solo se erradica en la infección inicial, mientras que la reducción de su carga bacteriana es el objetivo terapéutico en la infección crónica y exacerbaciones. El cribado neonatal y la farmacociné- tica/farmacodinámica han cambiado el manejo del paciente con FQ. Se debe realizar un seguimiento microbiológico en los pacientes sin infección por P. aeruginosa. En la infección inicial se recomienda tratamiento inhalado (28 días) con colistina (0,5-2 MU/8 h), tobramicina (300 mg/12 h) o aztreonam (75 mg/8 h) con o sin ciprofloxacino oral (15-20 mg/kg/12 h, 2-3 semanas). En la infección crónica se recomienda solo vía inhalada en tratamiento continuo con colistina, o en ciclos on-off de 28 días con tobramicina o aztreonam. Durante las exacerbaciones leves-moderadas se recomienda tratamiento oral (ciprofloxacino, 2-3 semanas) y en las graves tratamiento intravenoso (-lactámico asociado a un aminoglicósido o una fluoroquinolona). Estudios futuros sustentarán la rotación y nuevas combinaciones de antimicrobianos. Se deben establecer también medidas epidemiológicas que eviten nuevas infecciones y la transmisión cruzada de P. aeruginosa

Pseudomonas aeruginosa is the main pathogen in bronchopulmonary infections in cystic fibrosis (CF) patients. It can only be eradicated at early infection stages while reduction of its bacterial load is the therapeutic goal during chronic infection or exacerbations. Neonatal screening and pharmacokinetic/pharmacodynamic knowledge has modified the management of CF-patients. A culture based microbiological follow-up should be performed in patients with no infection with P. aeruginosa. At initial infection, inhaled colistin (0,5-2 MU/tid), tobramycin (300 mg/bid) or aztreonam (75 mg/tid) with or without oral ciprofloxacin (15-20 mg/kg/bid, 2-3 weeks) are recommended. In chronic infections, treatment is based on continuous administration of colistin or with a 28-day on-off regimen with tobramycin or aztreonam. During mild-moderate exacerbations oral ciprofloxacin (2-3 weeks) can be administered while serious exacerbations must be treated with intravenous combination therapy (beta-lactam with an aminoglycoside or a fluoroquinolone). Future studies will support antibiotic rotation and/or new combination therapies. Epidemiological measures are also recommended to avoid new P. aeruginosa infections and "patient-to-patient transmission" of this pathogen

Spanish consensus on the prevention and treatment of Pseudomonas aeruginosa bronchial infections in cystic fibrosis patients.

Pseudomonas aeruginosa is the main pathogen in bronchopulmonary infections in cystic fibrosis (CF) patients. It can only be eradicated at early infection stages while reduction of its bacterial load is the therapeutic goal during chronic infection or exacerbations. Neonatal screening and pharmacokinetic/pharmacodynamic knowledge has modified the management of CF-patients. A culture based microbiological follow-up should be performed in patients with no infection with P.aeruginosa. At initial infection, inhaled colistin (0,5-2MU/tid), tobramycin (300mg/bid) or aztreonam (75mg/tid) with or without oral ciprofloxacin (15-20mg/kg/bid, 2-3weeks) are recommended. In chronic infections, treatment is based on continuous administration of colistin or with a 28-day on-off regimen with tobramycin or aztreonam. During mild-moderate exacerbations oral ciprofloxacin (2-3weeks) can be administered while serious exacerbations must be treated with intravenous combination therapy (beta-lactam with an aminoglycoside or a fluoroquinolone). Future studies will support antibiotic rotation and/or new combination therapies. Epidemiological measures are also recommended to avoid new P.aeruginosa infections and "patient-to-patient transmission" of this pathogen.

Paclitaxel and carboplatin treatment for advanced ovarian cancer during pregnancy.

Ovarian carcinoma during pregnancy is a rare event that should be treated. In these cases, due to the lack of information available, doubts about the safety of mother and fetus are present. In this report, a 42-year-old woman who was diagnosed with a stage III ovarian carcinoma received six cycles of chemotherapy with carboplatin and paclitaxel from the 16th until 36th week of gestation. At 38 weeks, a normal male baby was born. There were no abnormalities during birth and during a 2-month follow-up period. This case adds to the available literature and supports the use of these chemotherapy agents during pregnancy, if the risk-benefit balance is appropriate.

Epidemiology and echinocandin susceptibility of Candida parapsilosis sensu lato species isolated from bloodstream infections at a Spanish university hospital.

OBJECTIVES: The aims of this work were to study the epidemiological profiles, differences in echinocandin susceptibilities and clinical relevance of the Candida parapsilosis sensu lato species isolated from proven fungaemia cases at La Fe University Hospital of Valencia (Spain) from 1995 to 2007. RESULTS: The prevalence of these species was: C. parapsilosis sensu stricto, 74.4%; Candida orthopsilosis, 23.54%; and Candida metapsilosis, 2.05%. The incidence of the species complex as agents of fungaemia remained stationary until 2005 and doubled in 2006. The incidence of C. orthopsilosis showed an increasing trend during the study period, while C. parapsilosis sensu stricto incidence diminished. Also, an important epidemiological change was observed starting in 2004, when 86.5% of the C. parapsilosis sensu lato strains were found in adult patients, while before that year only 13.5% of the isolates were found in this population. CONCLUSIONS: Echinocandin drug susceptibility testing using the CLSI M27-A3 document showed a wide range of MIC values (0.015-4 mg/L), with micafungin being the most potent in vitro inhibitor followed by anidulafungin and caspofungin (MIC geometric mean of 0.68, 0.74 and 0.87 mg/L, respectively). C. metapsilosis was the most susceptible species of the complex to anidulafungin and micafungin in vitro (MIC(50) for anidulafungin and micafungin: 0.06 mg/L), while there were no differences between C. parapsilosis sensu lato species when caspofungin MIC(50)s were compared (MIC(50) 1.00 mg/L). Differences in caspofungin in vitro susceptibility were observed between the different clinical service departments of La Fe Hospital.

Assessment of two new molecular methods for identification of Candida parapsilosis sensu lato species.

Candida parapsilosis sensu stricto, C. orthopsilosis, and C. metapsilosis replaced C. parapsilosis groups I, II, and III in 2005. Since then, an increased interest in studying their epidemiology has arisen based on the observed differences in antifungal susceptibilities and virulence the three species. A strict differentiation of these species cannot be achieved by phenotypic methods. We evaluate two new molecular methodologies to differentiate among these species by the use of a collection of 293 bloodstream infection isolates of C. parapsilosis sensu lato. For the first method, the isolates were studied using PCR amplification of a fragment of the C. parapsilosis sensu lato FKS1 gene and a universal primer pair followed by EcoRI enzyme digestion. The other method used the allele discrimination ability of molecular beacons in a multiplex real-time PCR format. Both methods of identification showed 100% concordance with internal transcribed spacer 1 (ITS1)/ITS2 sequencing and proved to be effective for clinical applications, even with mixed-species DNAs.

In utero exposure to mycophenolate mofetil: a characteristic phenotype?

Mycophenolate mofetil (MMF) is a widely prescribed immunosuppressive agent after solid organ transplantation. Potential teratogenic effects after in utero exposure to MMF in experimental studies and clinical observations in humans has been postulated in recent literature. However, a specific pattern of malformation has not been identified yet. We present a newborn patient, born to a recipient of renal transplantation, who became pregnant while taking MMF as immunosuppressive therapy. The newborn exhibited cleft lip and palate, bilateral microtia and atretic external auditory canals, chorioretinal coloboma, hypertelorism, and micrognathia. An extensive review of the literature documented six other cases with similar malformations after in utero exposure to MMF. A consistent pattern of malformations comprising cleft lip and palate, microtia and external auditory canals could be observed in five of the six cases. A different malformative pattern observed in one of the patients could be attributed to a different agent rather than MMF. The possible teratogenic effects of other immunosuppressive drugs, such as tacrolimus and prednisone, to which this patient was also exposed, are discussed herein. In addition, the differential diagnosis with other dysmorphic syndromes that can present with a similar phenotype, such as CHARGE syndrome, 18q deletion and hypertelorism-microtia-clefting (HMC) syndrome, is presented. We conclude that in utero exposure to MMF can cause a characteristic phenotype and propose the existence of a mycophenolate-associated embryopathy whose main features are: cleft lip and palate, microtia with atresia of external auditory canal, micrognathia and hypertelorism. Ocular anomalies, corpus callosum agenesis, heart defects, kidney malformations, and diaphragmatic hernia may be part of the phenotypic spectrum of MMF embryopathy. The human teratogenicity of MMF is reinforced by this report, and the current contraceptive recommendations about its use in fertile women are stressed.

Multidisciplinary approach to the treatment of invasive fungal infections in adult patients. Prophylaxis, empirical, preemptive or targeted therapy, which is the best in the different hosts?

The high morbidity, mortality, and health care costs associated with invasive fungal infections, especially in the critical care setting and immunocompromised host, have made it an excellent target for prophylactic, empiric, and preemptive therapy interventions principally based on early identification of risk factors. Early diagnosis and treatment are associated with a better prognosis. In the last years there have been important developments in antifungal pharmacotherapy. An approach to the new diagnosis tools in the clinical mycology laboratory and an analysis of the use new antifungal agents and its application in different clinical situations has been made. Furthermore, an attempt of developing a state of the art in each clinical scenario (critically ill, hematological, and solid organ transplant patients) has been performed, trying to choose the best strategy for each clinical situation (prophylaxis, pre-emptive, empirical, or targeted therapy). The high mortality rates in these settings make mandatory the application of early de-escalation therapy in critically ill patients with fungal infection. In addition, the possibility of antifungal combination therapy might be considered in solid organ transplant and hematological patients.

Voriconazole in the management of nosocomial invasive fungal infections.

Voriconazole is a new triazole developed for the treatment of life-threatening fungal infections. The drug is available for both oral and intravenous administration; the oral formulation has excellent bioavailability. The side-effect profile of voriconazole presents an acceptable safety and tolerability spectrum: transient visual disturbances, liver enzyme abnormalities, and skin rashes are the most frequently reported side effects but rarely lead to discontinuation. The potential for drug-drug interactions is high, because of its extensive hepatic metabolism. Careful attention to dosage is required, and serum levels and the effects of interacting drugs should be monitored. Review of 25 470 isolates of yeasts and 3216 isolates of filamentous fungi showed voriconazole to have broad-spectrum activity against pathogenic yeasts including intrinsically fluconazole-resistant isolates such as Candida krusei, dimorphic fungi, and opportunistic moulds like Aspergillus spp, amphotericin-B-resistant Aspergillus terreus, Fusarium spp, and Scedosporium apiospermum. It displays excellent clinical efficacy in patients with fluconazole-resistant and -susceptible Candida infections, invasive bone and central nervous system aspergillosis, and various refractory fungal infections. Voriconazole has been approved by the US Food and Drug Administration and by the European Medicines Agency for the treatment of invasive aspergillosis, serious infections caused by Fusarium and S. apiospermum, fluconazole-resistant invasive Candida infections, and candidemia in nonneutropenic patients.

[Role of linezolid in antimicrobial therapy]. / Papel de linezolid en terapéutica antimicrobiana.

The progressive emergence of multi-resistant gram-positive strains has prompted the search for new molecules (quinolones, streptogramins, oxazolidinones, ketolides, glycopeptides, daptomycin) to add to the current therapeutic arsenal. Linezolid, the first commercially available member of the oxazolidinone family, has evidenced activity against multi-resistant gram-positive strains (methicillin-resistant Staphylococcus aureus, S. aureus with decreased glycopeptide sensitivity, vancomycin-resistant Enterococcus spp., Streptococcus pneumoniae with decreased sensitivity to penicillin and cephalosporins), thereby providing a new option for treating infections by these microorganisms. This work reviews the microbiologic and pharmacologic aspects of this agent in order to establish its position among the available options for antimicrobial chemotherapy.

Papel de linezolid en terapéutica antimicrobiana / Role of linezolid in antimicrobial therapy

La aparición progresiva de cepas de microorganismos grampositivos resistentes a los antibacterianos de primera línea ha motivado la búsqueda de nuevas moléculas (quinolonas, estreptograminas, oxazolidinonas, cetólidos, glucopéptidos, daptomicina) que aumenten el arsenal terapéutico disponible. Linezolid es el primer representante comercializado de la familia de las oxazolidinonas, y se ha mostrado efectivo frente a cepas multirresistentes de microorganismos grampositivos (Staphylococcus aureus resistente a meticilina, S. aureus con sensibilidad disminuida a los glucopéptidos, Enterococcus spp. resistente a vancomicina, Streptococcus pneumoniae con sensibilidad disminuida a penicilina y cefalosporinas), por lo que se presenta como una nueva opción para el tratamiento de las infecciones por estos microorganismos. En este trabajo se revisan los aspectos microbiológicos y farmacológicos de este fármaco con el fin de ubicarlo en la terapéutica antimicrobiana (AU)