Population pharmacokinetics/pharmacodynamics of micafungin against Candida species in obese, critically ill, and morbidly obese critically ill patients.

BACKGROUND: Dosing in obese critically ill patients is challenging due to pathophysiological changes derived from obesity and/or critical illness, and it remains fully unexplored. This study estimated the micafungin probability of reaching adequate 24-h area under the curve (AUC0-24h)/minimum inhibitory concentration (MIC) values against Candida spp. for an obese/nonobese, critically ill/noncritically ill, large population. METHODS: Blood samples for pharmacokinetic analyses were collected from 10 critically ill nonobese patients, 10 noncritically ill obese patients, and 11 critically ill morbidly obese patients under empirical/directed micafungin treatment. Patients received once daily 100-150 mg micafungin at the discretion of the treating physician following the prescribing information and hospital guidelines. Total micafungin concentrations were determined by high-performance liquid chromatography (HPLC). Monte-Carlo simulations were performed and the probability of target attainment (PTA) was calculated using the AUC0-24/MIC cut-offs 285 (C. parapsilosis), 3000 (all Candida spp.), and 5000 (nonparapsilosis Candida spp.). Intravenous once-daily 100-mg, 150-mg, and 200-mg doses were simulated at different body weights (45, 80, 115, 150, and 185 kg) and age (30, 50, 70 and 90 years old). PTAs ≥ 90% were considered optimal. Fractional target attainment (FTA) was calculated using published MIC distributions. A dosing regimen was considered successful if the FTA was ≥ 90%. RESULTS: Overall, 100 mg of micafungin was once-daily administered for nonobese and obese patients with body mass index (BMI) ≤ 45 kg/m2 and 150 mg for morbidly obese patients with BMI > 45 kg/m2 (except two noncritically ill obese patients with BMI ~ 35 kg/m2 receiving 150 mg, and one critically ill patient with BMI > 45 kg/m2 receiving 100 mg). Micafungin concentrations in plasma were best described using a two-compartment model. Weight and age (but not severity score) were significant covariates and improved the model. FTAs > 90% were obtained against C. albicans with the 200 mg/24 h dose for all body weights (up to 185 kg), and with the 150 mg/24 h for body weights < 115 kg, and against C. glabrata with the 200 mg/24 h dose for body weights < 115 kg. CONCLUSION: The lack of adequacy for the 100 mg/24 h dose suggested the need to increase the dose to 150 mg/24 h for C. albicans infections. Further pharmacokinetic/pharmacodynamic studies should address optimization of micafungin dosing for nonalbicans Candida infections.

A practice-based observational study on the use of micafungin in Surgical Critical Care Units.

INTRODUCTION: Echinocandins are first-line therapy in critically ill patients with invasive Candida infection (ICI). This study describes our experience with micafungin at Surgical Critical Care Units (SCCUs). METHODS: A multicenter, observational, retrospective study was performed (12 SCCUs) by reviewing all adult patients receiving 100 mg/24h micafungin for ≥72h during ad-mission (April 2011-July 2013). Patients were divided by ICI category (possible, probable + proven), 24h-SOFA (<7, ≥7) and outcome. RESULTS: 72 patients were included (29 possible, 13 probable, 30 proven ICI). Forty patients (55.6%) presented SOFA ≥7. Up to 78.0% patients were admitted after urgent surgery (64.3% with SOFA <7 vs. 90.3% with SOFA ≥7, p=0.016), and 84.7% presented septic shock. In 66.7% the site of infection was intraabdominal. Forty-nine isolates were recovered (51.0% C. albicans). Treatment was empirical (59.7%), microbiologically directed (19.4%), rescue therapy (15.3%), or anticipated therapy and prophylaxis (2.8% each). Empirical treatment was more frequent (p<0.001) in possible versus probable + proven ICI (86.2% vs. 41.9%). Treatment (median) was longer (p=0.002) in probable + proven versus possible ICI (13.0 vs. 8.0 days). Favorable response was 86.1%, without differences by group. Age, blood Candida isolation, rescue therapy, final MELD value and %MELD variation were significantly higher in patients with non-favorable response. In the multivariate analysis (R2=0.246, p<0.001) non-favorable response was associated with positive %MELD variations (OR=15.445, 95%CI= 2.529-94.308, p=0.003) and blood Candida isolation (OR=11.409, 95%CI=1.843-70.634, p=0.009). CONCLUSION: High favorable response was obtained, with blood Candida isolation associated with non-favorable response, in this series with high percentage of patients with intraabdominal ICI, septic shock and microbiological criteria for ICI.

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 on the use of micafungin in Surgical Critical Care Units / Estudio observacional basado en la práctica clínica sobre la utilización de micafungina en Unidades de Cuidados Críticos Quirúrgicos

Introducción. Las equinocandinas son tratamiento de primera línea en pacientes críticos con infección invasiva por Candida (IIC). Este estudio describe nuestra experiencia con micafungina en Unidades de Cuidados Críticos Quirúrgicos (UCCQs). Métodos. Se realizó un estudio multicéntrico, observacional y retrospectivo (12 UCCQs) revisando todos los pacientes adultos que recibieron 100 mg/24h micafungina durante ≥72h tras su admisión en la UCCQ (Abril 2011-Julio 2013). Los pacientes se dividieron según la categoría de IIC (posible, probable + probada), valor de SOFA (<7, >=7) y evolución. Resultados. Se incluyeron 72 pacientes (29 posible, 13 probable y 30 IIC probadas). Cuarenta pacientes (55,6%) presentaron SOFA ≥7. Un total de 78,0% pacientes fueron ingresados tras cirugía urgente (64,3% con SOFA <7 vs. 90,3% con SOFA ≥7, p=0,016) y un 84,7% presentó shock séptico. El 66,7% de pacientes presentaban infección intraabdominal. Se recuperaron 49 aislados (51,0% C. albicans). El tratamiento fue empírico (59,7%), dirigido microbiológicamente (19,4%), terapia de rescate (15,3%), o anticipado y profilaxis (2,8% cada uno). El tratamiento empírico fue más frecuente (p<0,001) en IIC posible versus probable + probada (86,2% vs. 41,9%). La duración del tratamiento (mediana) fue mayor (p=0,002) en IIC probable + probada que en IIC posible (13,0% vs. 8,0%). La respuesta clínica fue favorable en el 86,1% sin diferencias por grupo. La edad, el aislamiento de sangre, la terapia de rescate, el valor de MELD final y la variación de MELD fueron significativamente superiores en pacientes con respuesta clínica no favorable. En el análisis multivariado (R2 =0,246, p<0,001) la respuesta no favorable se asoció con variación positiva del MELD (OR=15,445, 95%IC= 2,529-94,308, p=0,003) y aislamiento de Candida en sangre (OR=11,409, 95%IC=1,843-70,634, p=0,009). Conclusión: Se obtuvo una alta tasa de respuesta favorable, con el aislamiento de Candida en sangre asociado con respuesta no favorable en esta serie de pacientes con alto porcentaje de IIC intraabdominal, shock séptico e IIC con criterios microbiológicos (AU)

Introduction. Echinocandins are first-line therapy in critically ill patients with invasive Candida infection (ICI). This study describes our experience with micafungin at Surgical Critical Care Units (SCCUs). Methods. A multicenter, observational, retrospective study was performed (12 SCCUs) by reviewing all adult patients receiving 100 mg/24h micafungin for ≥72h during admission (April 2011-July 2013). Patients were divided by ICI category (possible, probable + proven), 24h-SOFA (<7, ≥7) and outcome. Results. 72 patients were included (29 possible, 13 probable, 30 proven ICI). Forty patients (55.6%) presented SOFA ≥7. Up to 78.0% patients were admitted after urgent surgery (64.3% with SOFA <7 vs. 90.3% with SOFA ≥7, p=0.016), and 84.7% presented septic shock. In 66.7% the site of infection was intraabdominal. Forty-nine isolates were recovered (51.0% C. albicans). Treatment was empirical (59.7%), microbiologically directed (19.4%), rescue therapy (15.3%), or anticipated therapy and prophylaxis (2.8% each). Empirical treatment was more frequent (p<0.001) in possible versus probable + proven ICI (86.2% vs. 41.9%). Treatment (median) was longer (p=0.002) in probable + proven versus possible ICI (13.0 vs. 8.0 days). Favorable response was 86.1%, without differences by group. Age, blood Candida isolation, rescue therapy, final MELD value and %MELD variation were significantly higher in patients with non-favorable response. In the multivariate analysis (R2 =0.246, p<0.001) non-favorable response was associated with positive %MELD variations (OR=15.445, 95%CI= 2.529-94.308, p=0.003) and blood Candida isolation (OR=11.409, 95%CI=1.843-70.634, p=0.009) (AU)

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).