Evaluating the optimal time for amikacin administration with respect to haemodialysis using an in vitro pharmacodynamic simulation against epidemic nosocomial OXA-48 producing Klebsiella pneumoniae ST405 strains.

OBJECTIVES: Bacterial viability and enrichment of resistance resulting from three different amikacin administration schedules with respect to haemodialysis (HD) were assessed against three OXA-48-producing Klebsiella pneumoniae isolated during an outbreak in a Spanish hospital. METHODS: A previously described two-compartment dynamic system was used. Three possible amikacin administration schedules were simulated: (i) haemodialysis immediately after amikacin infusion (pre-HD); (ii) infusion immediately after haemodialysis (post-HD); and (iii) infusion at 50% interdialytic period. Amikacin standard dose (SD) and double dose (DD) were simulated for each schedule. Values of Cmax/MIC, Cmax/MPC (mutant prevention concentration), AUC0-48h/MIC, AUC0-48h/MPC and %TMSW (percentage of time that the concentration was inside the mutant selection window) were determined with experimental data and were correlated with the area under the bacterial killing curve of the total population and the resistant subpopulation. RESULTS: Both with SD and DD, the pre-HD schedule resulted in increases at 48h in bacterial counts of the total population at the expense of enrichment of pre-existing resistant subpopulations from 12h onwards for all strains. The estimated %TMSW that prevented enrichment of resistant mutants was <61.5%. The AUC0-48h/MPC (with values of ≈40 being associated with countering of increases in resistant subpopulations) was better than the %TMSW as a predictive parameter. CONCLUSION: This study showed that the longest times concentrations were above the MPC (i.e. highest AUC0-48h/MPC, lowest %TMSW), the lowest enrichment of resistant subpopulations. This implies use of the highest possible amikacin dose (limited by toxicity) and post-HD as the best administration schedule.

Factors associated with development of nephrotoxicity in patients treated with vancomycin versus daptomycin for severe Gram-positive infections: A practice-based study / Factores asociados con el desarrollo de nefrotoxicidad en pacientes tratados con vancomicina frente a daptomicina en infecciones graves por grampositivos: Un estudio basado en la práctica clínica

Objectives. To evaluate nephrotoxicity development in patients treated with vancomycin (VAN) and daptomycin (DAP) for proven severe Gram-positive infections in daily practice. Patients and methods. A practice-based, observational, retrospective study (eight Spanish hospitals) was performed including patients ≥18 years with a baseline glomerular filtration rate (GFR)>30 mL/min and/or serum creatinine level<2 mg/dL treated with DAP or VAN for >48h. Nephrotoxicity was considered as a decrease in baseline GRF to <50 mL/min or decrease of >10 mL/min from a baseline GRF<50 mL/min. Multivariate analyses were performed to determine factors associated with 1) treatment selection, 2) nephrotoxicity development, and 3) nephrotoxicity development within each antibiotic group. Results. A total of 133 patients (62 treated with DAP, 71 with VAN) were included. Twenty-one (15.8%) developed nephrotoxicity: 4/62 (6.3%) patients with DAP and 17/71 (23.3%) with VAN (p=0.006). No differences in concomitant administration of aminoglycosides or other potential nephrotoxic drugs were found between groups. Factors associated with DAP treatment were diabetes mellitus with organ lesion (OR=7.81, 95%CI:1.39-4.35) and basal creatinine ≥0.9 mg/dL (OR=2.53, 95%CI:1.15-4.35). Factors associated with VAN treatment were stroke (OR=7.22, 95%CI:1.50-34.67), acute myocardial infarction (OR=6.59, 95%CI:1.51-28.69) and primary bacteremia (OR=5.18, 95%CI:1.03-25.99). Factors associated with nephrotoxicity (R2=0.142; p=0.001) were creatinine clearance<80 mL/min (OR=9.22, 95%CI:1.98-30.93) and VAN treatment (OR=6.07, 95%CI:1.86-19.93). Factors associated with nephrotoxicity within patients treated with VAN (R2=0.232; p=0.018) were congestive heart failure (OR=4.35, 95%CI:1.23-15.37), endocarditis (OR=7.63, 95%CI:1.02-57.31) and basal creatinine clearance<80 mL/min (OR=7.73, 95%CI:1.20-49.71). Conclusions. Nephrotoxicity with VAN was significantly higher than with DAP despite poorer basal renal status in the DAP group

Objectivos: Evaluar el desarrollo de nefrotoxicidad en la práctica clínica diaria en pacientes con infecciones graves probadas por grampositivos, tratados con vancomicina (VAN) y daptomicina (DAP). Pacientes y métodos: Se diseñó un estudio observacional retrospectivo, basado en la práctica clínica diaria (ocho hospitales españoles), en el que se incluyeron pacientes ≥ 18 años con una tasa basal de filtrado glomerular (GFR) > 30 mL/min y/o una creatinina sérica < 2 mg/dl para los pacientes tratados con DAP o vancomicina durante > 48 horas. La nefrotoxicidad fue considerada como una disminución del GRF basal a < 50 mL/min o una disminución de > 10 mL/min desde un GRF basal de < 50 ml/min. Se diseñaron análisis multivariantes para determinar los factores asociados con: 1) la selección del tratamiento, 2) el desarrollo de nefrotoxicidad y 3) el desarrollo de nefrotoxicidad con cada antibiótico. Resultados: Se incluyeron 133 pacientes (62 tratados con DAP, 71 con vancomicina). Veintiuno (15,8%) desarrollaron nefrotoxicidad: 4/62 (6,3%) pacientes con DAP y 17/71 (23,3%) con VAN (p=0,006). No se encontraron diferencias entre los grupos en la administración concomitante de aminoglucósidos u otros fármacos potencialmente nefrotóxicos. Los factores asociados con el tratamiento con DAP fueron diabetes mellitus con lesión orgánica (OR=7,81; IC95%:1,39-4,35) y una creatinina basal ≥0,9 mg/dL (OR=2,53; IC95%:1,15-4,35). Los factores asociados con tratamiento con VAN fueron ictus (OR=7,22; IC95%:1,50-34,67), infarto agudo de miocardio (OR=6,59; IC95%:1,51-28,69) y bacteriemia primaria (OR=5,18, IC95%:1,03-25,99). Los factores asociados con nefrotoxicidad (R2=0,142; p=0,001) fueron aclaramiento de creatinina <80 mL/min (OR=9,22; IC95%:1,98-30,93) y tratamiento con VAN (OR=6,07; IC95%:1,86-19,93). Los factores asociados con nefrotoxicidad en los pacientes tratados con VAN (R2=0,232; p=0,018) fueron insuficiencia cardíaca congestiva (OR=4.35; IC95%:1,23-15,37), endocarditis (OR=7,63; IC95%:1,02-57,31) y una creatinina basal <80 mL/min (OR=7,73; IC95%:1,20-49,71). Conclusiones: La nefrotoxicidad con VAN fue significativamente más alta que la de DAP a pesar del pobre status basal renal del grupo de DAP

Revisiting cefditoren for the treatment of community-acquired infections caused by human-adapted respiratory pathogens in adults.

Fifteen years after its licensure, this revision assesses the role of cefditoren facing the current pharmacoepidemiology of resistances in respiratory human-adapted pathogens (Streptococcus pneumoniae, Streptococcus pyogenes, Haemophilus influenzae and Moraxella catarrhalis). In the era of post- pneumococcal conjugate vaccines and in an environment of increasing diffusion of the ftsI gene among H. influenzae isolates, published studies on the cefditoren in vitro microbiological activity, pharmacokinetic/pharmcodynamic (PK/PD) activity and clinical efficacy are reviewed. Based on published data, an overall analysis is performed for PK/PD susceptibility interpretation. Further translation of PK/PD data into clinical/microbiological outcomes obtained in clinical trials carried out in the respiratory indications approved for cefditoren in adults (tonsillitis, sinusitis, acute exacerbation of chronic bronchitis and community-acquired pneumonia) is commented. Finally, the role of cefditoren within the current antibiotic armamentarium for the treatment of community respiratory tract infections in adults is discussed based on the revised information on its intrinsic activity, pharmacodynamic adequacy and clinical/bacteriological efficacy. Cefditoren remains an option to be taken into account when selecting an oral antibiotic for the empirical treatment of respiratory infections in the community caused by human-adapted pathogens, even when considering changes in the pharmacoepidemiology of resistances over the last two decades.

Risk factors for colonization by carbapenemase-producing enterobacteria at admission to a Surgical ICU: A retrospective study / Factores de riesgo para la colonización por enterobacterias productoras de carbapenemasas en el momento de admisión en una UCI quirúrgica: estudio retrospectivo

Introduction: In 2011, a hospital-wide outbreak of OXA-48 producing Klebsiella pneumoniae occurred in our hospital, an epidemiological setting of high ESBL-producing K. pneumoniae rates. This study identifies risk factors for colonization with carbapenemase-producing enterobacteria (CPE) at Surgical Intensive Care Unit (SICU) admission. Methods: A 2-year retrospective study was performed in all patients admitted to the SICU that following routine had a rectal swab collected upon admission. Results: Of 254 patients admitted, 41 (16.1%) harbored CPE (five showing two carbapenemase-producing isolates). Most frequent carbapenemase-producing isolates and carbapenemases were K. pneumoniae (39/46, 84.8%) and OXA-48 (31/46; 76.1%), respectively. Carriers significantly had higher rates of chronic renal disease, previous digestive/biliary endoscopy, hospitalization, ICU/SICU admission, intraabdominal surgery, and antibiotic intake, as well as higher median values of clinical scores (SOFA, SAPS II and APACHE II). In the multivariate analysis (R2 = 0.309, p < 0.001), CPE carriage was associated with prior administration of 3rd-4th generation cephalosporins (OR = 27.96, 95%CI = 6.88, 113.58, p < 0.001), β -lactam/ β -lactamase inhibitor (OR = 11.71, 95%CI = 4.51, 30.43, p < 0.001), abdominal surgery (OR = 6.33, 95%CI = 2.12, 18.89, p = 0.001), and prior digestive/biliary endoscopy (OR = 3.88, 95%CI = 1.56, 9.67, p = 0.004). Conclusions: A strong association between production of ESBLs and carriage of CPE (mainly OXA-48 producing K. pneumoniae) was found. According to the model, the co-selection of β-lactamases by previous exposure to broad-spectrum cephalosporins and β-lactam/ β -lactamase inhibitors (with lower relative risk), abdominal surgery and prior digestive/biliary endoscopy were factors associated with CPE carriage (AU)

Introducción: En 2011 se produjo un brote epidémico de Klebsiella pneumoniae productor de OXA-48 en nuestro hospital, un entorno epidemiológico de altas tasas de K. pneumoniae productor de BLEE. Este estudio identifica factores de riesgo de colonización por enterobacterias productoras de carbapenemasas (EPC) en el momento del ingreso en la unidad de cuidados críticos quirúrgicos (UCCQ). Métodos: Se realizó un estudio retrospectivo durante 2 años en todos los pacientes ingresados en la UCCQ a los que, siguiendo la rutina habitual, se les tomaba un hisopo rectal en el momento de ingreso. Resultados: De los 254 pacientes ingresados, 41 (16,1%) portaban EPC (5 con 2 aislados productores de carbapenemasas). Los aislados productores de carbapenemasas y las carbapenemasas más frecuentes fueron K. pneumoniae (39/46, 84,8%) y OXA-48 (31/46; 76,1%), respectivamente. Los portadores presentaban de forma significativa mayor frecuencia de insuficiencia renal crónica, historia previa de endoscopia digestiva/biliar, hospitalización, ingreso previo en UCI/UCCQ, cirugía intraabdominal y exposición a antibióticos, así como valores más altos (mediana) de SOFA, SAPS II y APACHE II. En el análisis multivariado (R2 = 0,309; p < 0,001), el estado de portador de EPC se asoció con la administración previa de cefalosporinas de amplio espectro (OR = 27,96; IC 95%: 6,88-113,58; p < 0,001), β-lactámicos/inhibidores de β -lactamasas (OR = 11,71; IC 95%: 4,51-30,43; p < 0,001), cirugía abdominal (OR = 6,33; IC 95%: 2,12- 18,89; p = 0,001) y endoscopia digestiva/biliar previa (OR = 3,88; IC 95%: 1,56-9,67; p = 0,004). Conclusiones: Se encontró una fuerte asociación entre la producción de BLEE y la portación de EPC (fundamentalmente K. pneumoniae productora de OXA-48). De acuerdo con el modelo, la co-selección de β-lactamasas tras exposición previa a cefalosporinas de amplio espectro y en menor medida a β-lactámicos/inhibidores de β-lactamasas, la cirugía abdominal y la endoscopia digestiva/biliar previa fueron factores asociados a la portación de EPC (AU)

Development of Aspergillosis in a cohort of non-neutropenic, non-transplant patients colonised by Aspergillus spp.

BACKGROUND: A previous study explored factors discriminating colonization and true infection among non-transplant, non-neutropenic patients with repeated Aspergillus spp. isolation from lower respiratory samples. The present study explored the evolution of patients with Aspergillus colonization in that study to determine the percentage of cases progressing to aspergillosis and time to development. METHODS: Clinical records were retrospectively reviewed (for each patient from his end date in the past study) and data from all respiratory processes suffered by patients up to April 2015 were recorded. Comparisons of variables were performed between colonized patients that developed aspergillosis and those that did not. A Kaplan-Meier curve was used to describe time to development of aspergillosis in chronic obstructive pulmonary disease (COPD) patients for II-IV stages of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification. RESULTS: Sixty seven colonized patients were followed, 12 of them (17.9%) developed aspergillosis. Diagnoses included six tracheobronchitis (4 invasive, 2 simple tracheobronchitis), four pulmonary disease (2 invasive pulmonary aspergillosis, 2 chronic pulmonary aspergillosis), one allergic bronchopulmonary aspergillosis and one pulmonary aspergilloma. Up to 47 (70.4%) of the study patients presented COPD. Among patients developing aspergillosis COPD was more frequent (100%) than among those that did not develop aspergillosis (35 out of 55; 63.6%) (p = 0.012), as well as GOLD IV patients were more frequent among COPD patients developing aspergillosis than among COPD patients that did not (50.0 vs. 26.1%, p = 0.046). Mean time to development of aspergillosis was 18.4 months (median: 8.5) with a wide range (1-58). Overtime, the percentage of patients developing aspergillosis was significantly higher among GOLD IV patients than among GOLD II-III patients (p = 0.032). CONCLUSIONS: The high percentage of cases progressing to aspergillosis among colonized patients, especially among those with COPD (25.5%), stresses the importance of colonization as risk factor, and creates awareness of the possible change from colonization to invasive disease in GOLD IV patients.

Risk factors for colonization by carbapenemase-producing enterobacteria at admission to a Surgical ICU: A retrospective study.

INTRODUCTION: In 2011, a hospital-wide outbreak of OXA-48 producing Klebsiella pneumoniae occurred in our hospital, an epidemiological setting of high ESBL-producing K. pneumoniae rates. This study identifies risk factors for colonization with carbapenemase-producing enterobacteria (CPE) at Surgical Intensive Care Unit (SICU) admission. METHODS: A 2-year retrospective study was performed in all patients admitted to the SICU that following routine had a rectal swab collected upon admission. RESULTS: Of 254 patients admitted, 41 (16.1%) harbored CPE (five showing two carbapenemase-producing isolates). Most frequent carbapenemase-producing isolates and carbapenemases were K. pneumoniae (39/46, 84.8%) and OXA-48 (31/46; 76.1%), respectively. Carriers significantly had higher rates of chronic renal disease, previous digestive/biliary endoscopy, hospitalization, ICU/SICU admission, intraabdominal surgery, and antibiotic intake, as well as higher median values of clinical scores (SOFA, SAPS II and APACHE II). In the multivariate analysis (R2=0.309, p<0.001), CPE carriage was associated with prior administration of 3rd-4th generation cephalosporins (OR=27.96, 95%CI=6.88, 113.58, p<0.001), ß-lactam/ß-lactamase inhibitor (OR=11.71, 95%CI=4.51, 30.43, p<0.001), abdominal surgery (OR=6.33, 95%CI=2.12, 18.89, p=0.001), and prior digestive/biliary endoscopy (OR=3.88, 95%CI=1.56, 9.67, p=0.004). CONCLUSIONS: A strong association between production of ESBLs and carriage of CPE (mainly OXA-48 producing K. pneumoniae) was found. According to the model, the co-selection of ß-lactamases by previous exposure to broad-spectrum cephalosporins and ß-lactam/ß-lactamase inhibitors (with lower relative risk), abdominal surgery and prior digestive/biliary endoscopy were factors associated with CPE carriage.

Basis for selecting optimum antibiotic regimens for secondary peritonitis.

Adequate management of severely ill patients with secondary peritonitis requires supportive therapy of organ dysfunction, source control of infection and antimicrobial therapy. Since secondary peritonitis is polymicrobial, appropriate empiric therapy requires combination therapy in order to achieve the needed coverage for both common and more unusual organisms. This article reviews etiological agents, resistance mechanisms and their prevalence, how and when to cover them and guidelines for treatment in the literature. Local surveillances are the basis for the selection of compounds in antibiotic regimens, which should be further adapted to the increasing number of patients with risk factors for resistance (clinical setting, comorbidities, previous antibiotic treatments, previous colonization, severity…). Inadequate antimicrobial regimens are strongly associated with unfavorable outcomes. Awareness of resistance epidemiology and of clinical consequences of inadequate therapy against resistant bacteria is crucial for clinicians treating secondary peritonitis, with delicate balance between optimization of empirical therapy (improving outcomes) and antimicrobial overuse (increasing resistance emergence).

Secular trends (1990-2013) in serotypes and associated non-susceptibility of S. pneumoniae isolates causing invasive disease in the pre-/post-era of pneumococcal conjugate vaccines in Spanish regions without universal paediatric pneumococcal vaccination.

This study analyzed temporal trends of non-susceptibility/serotypes in invasive pneumococci from Spanish regions where pneumococcal conjugate vaccines (PCVs) were not included in paediatric immunization programmes. All invasive pneumococcal isolates voluntarily sent to the Spanish Reference Laboratory for Pneumococci (January 1990-December 2013) from hospitals located in target study regions were analyzed by age group. The PCV estimated coverage in children <24 months was correlated with 13-valent PCV (PCV13) serotypes trends. A total of 28,124 invasive isolates were analyzed: 3138 (11.2%) from children <24 months, 2161 (7.7%) from children 24-59 months, 781 (2.8%) from children 5-14 years, and 22,044 (78.4%) from adults. The estimated coverage increased from 17.6% (2002) to around 40% (2010-2013). The percentage of PCV13 serotypes among all isolates over time followed a cubic significant trend (R(2)=0.884), with an increasing trend up to 2001 followed by a decrease (more prominent from 2010 onwards). The estimated PCVs coverage was significantly correlated with the decrease in the percentage of PCV13 isolates in children <24 months (r(2)=0.824) and in adults (r(2)=0.786), mainly due to decreases in serotypes 1 and 7F in adults, and in serogroup 6 and serotypes 7F and 19A in children <24 months. None of the non-PCV13 serotypes stood out with substantial increases in the last period. This study showed that the different serotypes (and its associated non-susceptibility trends) were not equally affected by low PCVs disposition. Lack of impact in certain serotypes as serotype 1 (in children 24-59 months), 6C (in all age groups), and 19A (in adults) suggests the need for increasing vaccine coverage in the target vaccine population to increase direct and indirect protection.

Biomarkers (Procalcitonin, C Reactive Protein, and Lactate) as Predictors of Mortality in Surgical Patients with Complicated Intra-Abdominal Infection.

BACKGROUND: An accurate and readily available biomarker for identifying patients with complicated intra-abdominal infection needing special attention in critical care units because of their greater risk of dying would be of value for intensivists. METHODS: A multi-center, observational, retrospective study explored blood lactate, C-reactive protein (CRP), and procalcitonin (PCT) concentrations, and also Sequential Organ Failure Assessment (SOFA) and Simplified Acute Physiology Score (SAPS II) as mortality predictors in all adult patients with complicated intra-abdominal infection (cIAI) admitted to Surgical Critical Care Units (SCCUs) for ≥48 h in four Spanish hospitals (June 2012-June 2013). Logistic regression models (step-wise procedure) were constructed using as dependent variables "intra-SCCU mortality" or "overall mortality," and variables showing differences (p≤0.1) in bivariate analyses as independent variables. RESULTS: One hundred twenty-one cases were included. Mortality intra-SCCU (R(2)=0.189, p=0.001) was associated with SAPS II (categorized as high if ≥47) (OR=9.55; 95% CI, 1.09-83.85; p=0.042) and 24 h-lactate (≥5.87 categorized as high) (OR=6.90; 95% CI, 1.28-37.08). Overall mortality (R(2)=0.275, p=0.001) was associated with peak PCT (≥100 categorized as high) (OR=11.28; 95% CI, 1.80-70.20), peak lactate (≥1.8 categorized as high) (OR=8.86; 95% CI, 1.51-52.10) and SOFA at admission (≥7 categorized as high) (OR=8.14; 95% CI, 1.69-39.20), but was predicted better (R(2)=0.275, p=0.001) by a single dummy variable (high peak PCT-high peak lactate concentrations) (OR=99.11; 95% CI, 5.21-1885.97; p=0.002). CONCLUSIONS: In the present study, SAPS II and 24 h-lactate concentrations predicted intra-SCCU mortality whereas overall mortality was predicted better by concurrent high PCT and lactate peak concentrations than by clinical scores or by each biomarker separately.

A practice-based observational study identifying factors associated with the use of high-dose tigecycline in the treatment of secondary peritonitis in severely ill patients.

INTRODUCTION: Based on tigecycline linear pharmacokinetic/pharmacodynamics, dose increases have been advocated to maximise activity especially when severe infections with high bacterial load and/or multidrug resistance are suspected. This practice-based observational study explored factors associated with tigecycline administration (100 mg/12h, 200 mg loading dose) in severely ill patients with complicated intra-abdominal infection (cIAI) admitted to four Surgical Critical Care Units (SCCUs). METHODS: Medical records of all consecutive adult patients with cIAI and controlled infection source requiring surgery and admission for ≥ 48 h to SCCU were reviewed and divided into patients treated with a regimen including tigecycline (tigecycline group) and those that not (control group). A logistic regression model was performed using "tigecycline administration" (dependent variable) and variables showing differences (p ≤ 0.1) in bivariate analyses (independent variables). RESULTS: One hundred and twenty one patients were included. In the tigecycline group, higher percentage of patients (vs. controls) presented colon as surgical site (66.7% vs. 41.8%, p = 0.006), nosocomial infection (55.6% vs. 26.9%, p = 0.001), mechanical ventilation (48.1% vs. 28.4%, p = 0.025), chronic renal replacement therapy (40.7% vs. 19.4%, p =0.008), septic shock (72.2% vs. 46.3%, p = 0.004), and higher values of SAPS II (48.0 ± 15.0 vs. 39.6 ± 15.5, p = 0.003), SOFA at admission (7.0 ± 3.3 vs. 5.5 ± 3.7, p = 0.020), lactate-24h (2.5 ± 2.8 vs. 1.6 ± 0.9, p = 0.029) and CRP-72 h (207.4 ± 87.9 vs. 163.7 ± 76.8, p = 0.021). In the multivariate analysis (R2 = 0.187, p < 0.001) nosocomial infection (OR = 7.721; 95%CI = 2.193, 27.179; p = 0.001), colon as infection site (OR = 4.338; 95%CI = 1.432, 13.145; p = 0.009) and CRP-72 h (OR = 1.009 per-unit; 95%CI = 1.002, 1.016; p = 0.012) were associated with tigecycline administration. CONCLUSIONS: In severely ill patients with cIAI, high-dose tigecycline administration was associated with nosocomial origin of cIAI and colon as source infection site.

A practice-based observational study identifying factors associated with the use of high-dose tigecycline in the treatment of secondary peritonitis in severely ill patients

Introducción. Se han postulado incrementos en la dosis de tigeciclina basándose en su farmacocinética/farmacodinamia lineal, especialmente en infecciones graves con sospecha de alta carga bacteriana o/y multirresistencia. El presente estudio observacional basado en la práctica diaria explora los factores asociados con la administración de tigeciclina (100 mg/12h, 200 mg dosis de carga) en pacientes críticos con infección intraabdominal complicada (cIIA) ingresados en 4 Unidades de Cuidados Críticos Quirúrgicos (UCCQ). Métodos. Las historias clínicas de todos los pacientes adultos consecutivos con cIIA y foco de infección controlado que requerían cirugía e ingresaron en UCCQ durante ≥48h fueron revisadas y los pacientes fueron divididos en dos grupos: pacientes tratados con un régimen antibiótico que incluía tigeciclina (grupo tigeciclina) y aquellos que no (grupo control). Se realizó un modelo de regresión logística utilizando como variable dependiente la administración de tigeciclina y como independientes aquellas variables que mostraron diferencias (p≤0,1) en el análisis bivariado realizado. Resultados. Se incluyeron 121 pacientes. En el grupo tigeciclina, un mayor porcentaje de pacientes (vs. control) presentaban el colon como sitio quirúrgico (66,7% vs. 41,8%, p=0,006), infección nosocomial (55,6% vs. 26,9%, p=0,001), ventilación mecánica (48,1% vs. 28,4%, p=0,025), terapia renal sustitutoria (40,7% vs. 19,4%, p=0,008), shock séptico (72,2% vs. 46,3%, p=0,025) y valores más altos de SAPS II (48,0±15,0 vs. 39,6±15,5, p=0,003), SOFA al ingreso (7,0±3,3 vs. 5,5±3,7, p=0,020), lactato-24h (2,5±2,8 vs. 1,6±0,9, p=0,029) y PCR-72h (207,4±87,9 vs. 163,7±76,8, p=0,021). En el análisis multivariado (R2=0,187, p<0,001) la administración de tigeciclina se asoció con infección nosocomial (OR=7,721, 95%IC=2,193-27,179; p=0,001), colon como foco de infección (OR=4,338, 95%IC=1,432-13,145; p=0,009) y PCR-72h (OR=1,009 por unidad, 95%IC=1,002-1,016; p=0,012). Conclusiones. En pacientes críticos con cIIA, la administración de tigeciclina a dosis alta se asoció con el origen nosocomial de la infección y con el colon como foco de la misma (AU)

Introduction. Based on tigecycline linear pharmacokinetic/pharmacodynamics, dose increases have been advocated to maximise activity especially when severe infections with high bacterial load and/or multidrug resistance are suspected. This practice-based observational study explored factors associated with tigecycline administration (100 mg/12h, 200 mg loading dose) in severely ill patients with complicated intra-abdominal infection (cIAI) admitted to four Surgical Critical Care Units (SCCUs). Methods. Medical records of all consecutive adult patients with cIAI and controlled infection source requiring surgery and admission for ≥48h to SCCU were reviewed and divided into patients treated with a regimen including tigecycline (tigecycline group) and those that not (control group). A logistic regression model was performed using 'tigecycline administration' (dependent variable) and variables showing differences (p≤0.1) in bivariate analyses (independent variables). Results. One hundred and twenty one patients were included. In the tigecycline group, higher percentage of patients(vs. controls) presented colon as surgical site (66.7% vs. 41.8%, p=0.006), nosocomial infection (55.6% vs. 26.9%, p=0.001), mechanical ventilation (48.1% vs. 28.4%, p=0.025), chronic renal replacement therapy (40.7% vs. 19.4%, p=0.008), septic shock (72.2% vs. 46.3%, p=0.004), and higher values of SAPS II (48.0±15.0 vs. 39.6±15.5, p=0.003), SOFA at admission (7.0±3.3 vs. 5.5±3.7, p=0.020), lactate-24h (2.5±2.8 vs. 1.6±0.9, p=0.029) and CRP-72h (207.4±87.9 vs. 163.7±76.8, p=0.021). In the multivariate analysis (R2=0.187, p<0.001) nosocomial infection (OR=7.721; 95%CI=2.193, 27.179; p=0.001), colon as infection site (OR=4.338; 95%CI=1.432, 13.145; p=0.009) and CRP-72h (OR=1.009 per-unit; 95%CI=1.002, 1.016; p=0.012) were associated with tigecycline administration. Conclusions. In severely ill patients with cIAI, high-dose tigecycline administration was associated with nosocomial origin of cIAI and colon as source infection site (AU)

Procalcitonin-guided therapy may reduce length of antibiotic treatment in intensive care unit patients with secondary peritonitis: A multicenter retrospective study.

PURPOSE: Because procalcitonin (PCT) might be surrogate for antimicrobial discontinuation in general intensive care units (ICUs), this study explored its use for secondary peritonitis in 4 surgical ICUs (SICUs). METHODS: A retrospective study including all consecutive patients with secondary peritonitis, controlled infection source, requiring surgery, and at least 48-hour SICU admission was performed (June 2012-June 2013). Patients were divided following notations in medical records into PCT-guided (notation of PCT-based antibiotic discontinuation) and non-PCT-guided (no notation) groups. RESULTS: A total of 121 patients (52 PCT-guided, 69 non-PCT-guided) were included. No differences in clinical scores, biomarkers, or septic shock (30 [57.7%] PCT-guided vs 40 [58.0%] non-PCT-guided) were found. Length of intra-SICU (median, 5.0 days; both groups) or in-hospital (median, 20.0 vs 17.5 days) stay, and mortality intra-SICU (9.6% vs 13.0%), 28-day (15.4% vs 20.3%), or in-hospital (19.2% vs 29.0%) were not significantly different (PCT-guided vs non-PCT-guided). In septic shock patients, no mortality differences were found (PCT-guided vs non-PCT-guided): 16.7% vs 22.5% (intra-SICU), 26.7% vs 32.5% (28-day), and 33.3% vs 42.5% (in-hospital). Treatment was shorter in the PCT-guided group (5.1 ±2.1 vs 10.2 ± 3.7 days, P < .001), without differences between patients with and without septic shock. CONCLUSION: Procalcitonin guidance produced 50% reduction in antibiotic duration (P < .001, log-rank test).

Ceftolozane/tazobactam (CXA 201) for the treatment of intra-abdominal infections.

During the mid-nineties, 95-97% of intra-abdominal infection (IAI)- associated microbes were susceptible to commonly used antibiotics. Nowadays, in Gram-negative bacilli, ß-lactam resistance and the associated co-resistance to other antibiotics leading to multidrug resistance is reaching crisis proportions. This is a critical issue in the treatment of IAIs, especially for complicated IAIs and for those of nosocomial origin in severely ill patients. In this setting, this article reviews the place in the therapeutic armamentarium of ceftolozane/tazobactam, a new cephalosporin/ß-lactamase inhibitor with good activity against extended spectrum ß-lactamase producing Enterobacteriaceae, with stability to AmpC ß-lactamases and good anti-pseudomonal activity being stable against the most common resistance mechanisms driven by mutation in Pseudomonas aeruginosa. A profound review of its in vitro activity, in vivo efficacy in animal models, pharmacodynamics, pharmacokinetics, clinical efficacy in clinical trials in complicated IAIs and safety data is performed.

Per-species risk factors and predictors of invasive Candida infections in patients admitted to pediatric intensive care units: development of ERICAP scoring systems.

BACKGROUND: Prediction rules for invasive Candida infection (ICI) are available for adult but not for infants and children managed in pediatric intensive care units (PICU). METHODS: Observational study in 24 PICU with prospective phase (all children admitted during 1 year) and retrospective review of ICI records. Four logistic regression models were performed using ICI by Candida spp., Candida albicans, Candida parapsilosis or Candida tropicalis as dependent variables. Scores were constructed. RESULTS: One hundred and twenty five ICI (47 C. albicans, 37 C. parapsilosis, 19 C. tropicalis and 22 others) and 1022 controls were included. Incidence (cases/100 PICU admissions): 4.22 (all Candida), 2.44 (C. albicans), 1.41 (C. parapsilosis), 0.19 (C. tropicalis). ICI was associated [Area under the receiver operating characteristics curve (AUC) = 0.764, 95% confidence interval (CI) = 0.719-0.809, P < 0.001] with pre-PICU hospitalization ≥ 15 days [odds ratio (OR) = 3.3; score: +3], fever (OR = 2.6; +2), thrombopenia (OR = 2.0; +1) and parenteral nutrition (OR=2.4; +2). Additionally, the following associations were noted: C. albicans ICI (AUC = 0.716, 95% CI = 0.640-0.792, P < 0.001) with chronic metabolic disease (OR = 10.7; score:+4), surgical digestive process (OR = 2.8; +1), fever (OR = 2.8; +1) and parenteral nutrition (OR = 2.3; +1); C. parapsilosis ICI (AUC = 0.808, 95% CI = 0.739-0.877, P < 0.001) with previous colonization (OR = 7.1; score:+3), tracheostomy (OR = 5.1; +2), parenteral nutrition (OR = 4.3; +2), thrombopenia (OR = 3.6; +1) and previous bacterial infection (OR = 3.0; +1) and ICI by C. tropicalis (AUC = 0.941, 95% CI=0.886-0.995, P < 0.001) with thrombopenia (OR = 53.8; score: +10), neutropenia (OR = 7.2; +1), pre-PICU hospitalization ≥ 15 days (OR = 17.2; +3) and hematologic (OR = 22.4; +4) and cardiovascular infectious processes (OR = 5.5; +1). Specificity was >90% for cut offs of 5 (all Candida), 3 (C. albicans), 3 (C. parapsilosis) and 11 (C. tropicalis). CONCLUSIONS: Once validated, these scores may help for identification of ICI by specific species allowing adequate empiric/prophylactic treatment.

C. albicans, C. parapsilosis and C. tropicalis invasive infections in the PICU: clinical features, prognosis and mortality / Infección invasiva por C. albicans, C. parapsilosis y C. tropicalis en la UCI pediátrica: características clínicas, pronóstico y mortalidad

Candida albicans remains the most common agent associated with invasive Candida infection (ICI), but with increasing number of non-albicans species. An epidemiological, observational study exploring host criteria, clinical characteristics and mortality of ICI was performed in 24 pediatric intensive care units (PICU) in Spain. Patients were analyzed in global and distributed by infecting species (for groups with ≥15 patients). A total of 125 ICI were included: 47 by C. albicans, 37 by C. parapsilosis, 19 by C. tropicalis, 4 C. glabrata, and 18 others. Up to 66% of ICI by C. albicans and 75.7% by C. parapsilosis occurred in children ≤24 months, while the percentage of children >60 months was higher in ICI by C. tropicalis. Bloodstream infection was most common among C. tropicalis (78.9%) or C. parapsilosis (83.8%) ICI, but urinary infections were almost as common as bloodstream infections among C. albicans ICI (31.9% and 38.3%, respectively). Fever refractory to antimicrobials was the most frequent host criterion (46.4% patients), but with equal frequency than prolonged neutropenia in C. tropicalis ICI. Thrombopenia was more frequent (p<0.05) in C. parapsilosis (60.7%) or C. tropicalis (66.7%) ICI than in C. albicans ICI (26.5%). Uremia was more frequent (p<0.05) in C. albicans (78.3%) or C. tropicalis (73.3%) than in C. parapsilosis ICI (40.7%). Multiple organ failure and heart insufficiency was higher in C. tropicalis ICI. Short duration (≤7 days) of PICU stay was more frequent in C. albicans ICI. Mortality rates were: 8.5% (C. albicans ICI), 13.5% (C. parapsilosis ICI) and 23.3% (C. tropicalis ICI) (Au)

Candida albicans es el agente más frecuentemente asociado con candidiasis invasiva, pero con un número creciente de casos causados por especies no-albicans. Se realizó un estudio epidemiológico observacional explorando criterios del huésped, características clínicas y mortalidad en 24 unidades de cuidados intensivos pediátricas en España. Se analizó a los pacientes en conjunto y distribuidos por la especie infectante (para aquellos grupos con ≥15 pacientes). Se incluyó un total de 125 candidiasis invasivas: 47 por C. albicans, 37 por C. parapsilosis, 19 por C. tropicalis, 4 por C. glabrata, y 18 casos por otras especies. Hasta un 66% de las candidiasis invasivas por C. albicans y un 75,7% de las causadas por C. parapsilosis ocurrieron en niños ≤24 meses, mientras que el porcentaje de niños con >60 meses fue mayor en el grupo de candidiasis invasiva por C. tropicalis. La candidemia fue la infección más frecuente en el grupo de infecciones por C. tropicalis (78,9%) o C. parapsilosis (83,8%), pero las infecciones del tracto urinario fueron tan frecuentes como la bacteremia entre las infecciones por C. albicans (31,9% y 38,3%, respectivamente). La fiebre refractaria a antimicrobianos fue el criterio de huésped más frecuente (46,4% pacientes), pero con igual frecuencia que la neutropenia prolongada en la candidiasis invasiva por C. tropicalis. La trombopenia fue más frecuente (p<0,05) en las infecciones por C. parapsilosis (60,7%) o C. tropicalis (66,7%) que en las producidas por C. albicans (26,5%). La uremia fue más frecuente (p<0,05) en las infecciones por C. albicans (78,3%) o C .tropicalis (73,3%) que en las producidas por C. parapsilosis (40,7%). El fallo multiorgánico y la insuficiencia cardiaca fueron más frecuentes en el grupo de infecciones por C. tropicalis. La estancia corta (≤7 días) en la unidad fue más frecuente en el caso de infecciones por C.albicans. Las tasas de mortalidad fueron: 8,5% (C. albicans), 13,5% (C. parapsilosis) y 23,3% (C. tropicalis). El análisis de la candidiasis invasiva por las distintas especies de Candida mostró perfiles clínicos diferentes y distintas tasas de mortalidad, haciendo esencial la identificación a nivel especie (AU)

Bugs, hosts and ICU environment: Countering pan-resistance in nosocomial microbiota and treating bacterial infections in the critical care setting / Gérmenes, huéspedes y el entorno de la Unidad de Cuidados Intensivos: contrarrestando la panresistencia en la microbiota nosocomial para tratar las infecciones bacterianas en cuidados críticos

ICUs are areas where resistance problems are the largest, and these constitute a major problem for the intensivist's clinical practice. Main resistance phenotypes among nosocomial microbiota are (I) vancomycin-resistance/heteroresistance and tolerance in grampositives (MRSA, enterococci) and (II) efflux pumps/enzymatic resistance mechanisms (ESBLs, AmpC, metallo-betalactamases) in gramnegatives. These phenotypes are found at different rates in pathogens causing respiratory (nosocomial pneumonia/ventilator-associated pneumonia), bloodstream (primary bacteremia/catheter-associated bacteremia), urinary, intraabdominal and surgical wound infections and endocarditis in the ICU. New antibiotics are available to overcome non-susceptibility in grampositives; however, accumulation of resistance traits in gramnegatives has led to multidrug resistance, a worrisome problem nowadays. This article reviews microorganism/infection risk factors for multidrug resistance, suggesting adequate empirical treatments. Drugs, patient and environmental factors all play a role in the decision to prescribe/recommend antibiotic regimens in the specific ICU patient, implying that intensivists should be familiar with available drugs, environmental epidemiology and patient factors (AU)

UCIs son las áreas donde los problemas de resistencia son los más grandes, y éstos constituyen un problema importante para la práctica clínica de los intensivistas . Fenotipos de resistencia principales entre la microbiota nosocomial son ( I ) vancomycin-resistance/heteroresistance y tolerancia en grampositives ( MRSA, enterococos ) y ( II ) las bombas de flujo / mecanismos enzimáticos de resistencia ( BLEE , AmpC , metalo- betalactamasas ) en gramnegativos . Estos fenotipos se encuentran en diferentes tipos de patógenos causantes de las vías respiratorias (neumonía / pulmonía nosocomial asociada a ventilación mecánica), el torrente sanguíneo ( bacteremia primaria / bacteriemia asociada a catéter ) , urinario, infecciones de las heridas quirúrgicas intraabdominales y endocarditis y en la UCI. Nuevos antibióticos están disponibles para superar la no - susceptibilidad in grampositives, sin embargo, la acumulación de rasgos de resistencia en gramnegativos ha dado lugar a la resistencia a múltiples fármacos, un problema preocupante en la actualidad. Este artículo revisa los factores de riesgo microorganismo / infección de la resistencia a múltiples fármacos, lo que sugiere tratamientos empíricos adecuados. Las drogas, el paciente y los factores ambientales juegan un papel en la decisión de prescribir / recomendar regímenes de antibióticos en el paciente en la UCI específica, lo que implica que los intensivistas deben familiarizarse con los fármacos disponibles, epidemiología ambiental y los factores del paciente (AU)

Micafungin pharmacokinetic/pharmacodynamic adequacy for the treatment of invasive candidiasis in critically ill patients on continuous venovenous haemofiltration.

OBJECTIVES: To explore the pharmacokinetics (PK) and pharmacodynamics (PD) of micafungin in patients undergoing continuous venovenous haemofiltration (CVVH). PATIENTS AND METHODS: Ten patients receiving CVVH treated with 100 mg/day micafungin were included (April-December 2012). CVVH was performed using polyethersulphone or polysulphone haemofilters. Dialysis membranes were not changed on sampling days. On Days 1 and 2, blood samples from arterial pre-filter and venous post-filter ports and ultrafiltrate samples were collected at the start and end of the infusion and at 3, 5, 8, 18 and 24 h. Concentrations were determined using HPLC. Values for the area under the concentration-time curve (AUC0-24) were calculated. Monte Carlo simulations were performed using pre-filter and post-filter AUC0-24/MIC ratios on Days 1 and 2. The probability of target attainment (PTA) was calculated using AUC0-24/MIC cut-offs: 285 (C. parapsilosis), 3000 (all Candida spp.) and 5000 (non-parapsilosis Candida spp.). Cumulative fraction responses (CFRs) were calculated using EUCAST MIC distributions. RESULTS: Mean post-filter AUC0-24 (mg·h/L) values were higher than pre-filter values on Day 1 (83.31 ±â€Š15.87 versus 71.31 ±â€Š14.24; P = 0.008) and Day 2 (119.01 ±â€Š27.20 versus 104.54 ±â€Š21.23; P = 0.005). PTAs were ≥90% for MICs of 0.125 mg/L (cut-off = 285), 0.016 mg/L (cut-off = 3000) and 0.008 mg/L (cut-off = 5000) on Day 1, and for MICs of 0.25 mg/L (cut-off = 285) and 0.016 mg/L (cut-off = 3000 and 5000) on Day 2, without differences between pre- and post-filter values. On Day 2, CFRs >90% were obtained for C. albicans (cut-off = 3000 and 5000) and C. glabrata (cut-off = 3000), but not for C. parapsilosis. CONCLUSIONS: There was no removal of micafungin by CVVH or need for dose adjustment, and there was optimal PK/PD coverage for non-parapsilosis Candida and equivalence of pre- and post-filter PD.

Bugs, hosts and ICU environment: countering pan-resistance in nosocomial microbiota and treating bacterial infections in the critical care setting.

ICUs are areas where resistance problems are the largest, and these constitute a major problem for the intensivist's clinical practice. Main resistance phenotypes among nosocomial microbiota are (i) vancomycin-resistance/heteroresistance and tolerance in grampositives (MRSA, enterococci) and (ii) efflux pumps/enzymatic resistance mechanisms (ESBLs, AmpC, metallo-betalactamases) in gramnegatives. These phenotypes are found at different rates in pathogens causing respiratory (nosocomial pneumonia/ventilator-associated pneumonia), bloodstream (primary bacteremia/catheter-associated bacteremia), urinary, intraabdominal and surgical wound infections and endocarditis in the ICU. New antibiotics are available to overcome non-susceptibility in grampositives; however, accumulation of resistance traits in gramnegatives has led to multidrug resistance, a worrisome problem nowadays. This article reviews microorganism/infection risk factors for multidrug resistance, suggesting adequate empirical treatments. Drugs, patient and environmental factors all play a role in the decision to prescribe/recommend antibiotic regimens in the specific ICU patient, implying that intensivists should be familiar with available drugs, environmental epidemiology and patient factors.

Protection of Enterococcus faecalis in mixed cultures with carbapenemase-producing Escherichia coli and Bacteroide fragilis: effect of the bacterial load.

INTRODUCTION: This study explores effects of pH and inoculum size on imipenem versus tigecycline activity against E. coli, B. fragilis and E. faecalis, both in individual and mixed cultures. METHODS: MIC/MBCs (mg/L) of tigecycline and imipenem were 0.12/≥ 16 and 4/4 for E. coli, 0.12/0.5 and ≥ 16/≥ 16 for B. fragilis, and 0.12/≥ 16 and 2/≥ 16 for E. faecalis, respectively. Killing curves in supplemented Brucella broth were performed at pH 7 or 5.8, with two final inocula (≈ 105 or ≈ 107 cfu/ml) of each isolate (individual cultures) and with 1:1:1 mixed inocula. Tubes were 48 h incubated at 37 ºC in anaerobiosis. Final concentrations (estimated concentrations in colon) were 1.50 mg/L for tigecycline and 26.40 mg/L for imipenem, with antibiotic-free curves as controls. Experiments were performed in triplicate. RESULTS: Imipenem showed inoculum effect against E.coli and B. fragilis, with reductions in initial inocula in experiments with standard inocula contrasting with increases in experiments with high inocula (both individual and mixed cultures). Against E. faecalis no inoculum effect for imipenem was observed in individual cultures, with marked reductions in initial inocula regardless inoculum size. However in mixed experiments the indirect protection of E. faecalis by the two gramnegatives resulted in bacterial regrowth. This protection was inoculum-dependant since it occurred with high but not with standard inocula. Tigecycline reduced initial inocula of the three isolates regardless culture type (individual/mixed) or experimental conditions (pH/inocula size), with lower reductions for the tolerant E. faecalis. CONCLUSION: Carbapenemase activity was inoculum-dependant for self-protection and indirect protection of E. faecalis.