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Patients undergoing elective pelvic exenteration surgery who receive piperacillin/tazobactam as surgical prophylaxis are at risk of suboptimal intraoperative antibiotic exposure. With this work, we aimed to study the plasma pharmacokinetics of piperacillin and tazobactam in this population to provide dosing recommendations that optimize antibiotic exposure. We developed a prospective, observational, pharmacokinetic study of piperacillin/tazobactam in patients undergoing pelvic exenteration. Population pharmacokinetic analysis and Monte Carlo simulations were performed with Monolix and Simulx software. Probabilities of target attainment of different dosing regimens against the minimum inhibitory concentration (MIC) breakpoints (8 and 16 mg/L) were calculated. Twelve patients were included in the study, with a median age of 50.0 years [interquartile interval (45.3-57.5)] and a median weight of 79.0 kg (61.3-88.3). Median surgical time was 10.5 h (9.8-11.7). A two-compartment linear model best fitted piperacillin and tazobactam data (190 plasma samples). Monte Carlo simulations showed that a lower dose of 2 g/0.25 g loading dose followed by 4 g/0.5 g q8h by continuous infusion provided ≥90% probability of target attainment for MIC = 16 mg/L for most of the patients. For non-continuous infusion regimens, only the 2-hourly bolus re-dosing achieved intraoperative concentrations of piperacillin ≥16 mg/L. Patients with weights ≥ 100 kg and glomerular filtration rates ≥ 120 mL/min required 4 g/0.5 g q6h by continuous infusion after a loading dose. In conclusion, continuous infusion of lower doses of piperacillin/tazobactam is as adequate as the 2-hourly re-dosing recommended by the current guidelines for surgical prophylaxis in pelvic exenteration. Patients with higher weights and glomerular filtration rates are at greater risk of inadequate exposure., Competing Interests: The authors declare no conflict of interest.

Objectives: The efficacy of extended infusions (EI) of β-lactam antibiotics for optimising outcomes in febrile neutropenia is unclear. We assessed whether the administration of β-lactams was more effective in EI than in intermittent infusion (II) for the treatment of febrile neutropenia., Methods: We performed a randomized, open-label, superiority clinical trial of patients with febrile neutropenia at four Spanish university hospitals. Patients undergoing haematopoietic stem cell transplantation or with acute leukaemia receiving chemotherapy who required empirical antibiotic treatment for febrile neutropenia were randomly assigned (1:1) to receive EI of β-lactam or II after a first dose in bolus. The choice of antipseudomonal β-lactam was left to the discretion of the attending physician. The primary endpoint was treatment success at day 5, defined as defervescence without modifying the antibiotic treatment. Secondary endpoints included adverse events, attainment of the pharmacokinetic/pharmacodynamic target of 50%, 75%, and 100%ƒ u T  > MIC , and 30-day mortality., Results: From November 19, 2019 to June 22, 2022, 295 patients were screened for eligibility, of whom 150 were randomly assigned to receive EI (n = 77) or II (n = 73) of the antipseudomonal β-lactam of choice. In the intention-to-treat analysis, treatment success at day 5 was achieved in 39/77 patients (50.6%) receiving EI versus 46/73 patients (63.0%) receiving II (risk difference, -12.4%; 95% CI, -29.4 to 4.7; p 0.17). The pharmacokinetic/pharmacodynamic targets of 75% and 100% ƒ u T  > MIC for empirical treatment were achieved more frequently in the EI group. No statistically significant differences were found between groups in terms of adverse events or 30-day mortality., Discussion: Our findings do not support the routine use of empirical EI of β-lactams in febrile neutropenia. Further studies should consider the clinical heterogeneity of febrile neutropenia and focus on patients with sepsis or septic shock and microbiologically documented infections, particularly those with infections caused by microorganisms less susceptible to β-lactams., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: Device-related infections are difficult to treat due to biofilms. In this setting, optimizing antibiotic efficacy is difficult as most pharmacokinetic/pharmacdynamic (PK/PD) studies have been performed on planktonic cells, and therapies are limited when multi-drug-resistant bacteria are involved. This study aimed to analyse the PK/PD indices of meropenem predicting anti-biofilm efficacy against meropenem-susceptible and meropenem-resistant strains of Pseudomonas aeruginosa., Materials and Methods: Pharmacodynamics of meropenem dosages mimicking those of clinical practice (intermittent bolus of 2 g every 8 h; extended infusion of 2 g over 4 h every 8 h), with and without colistin, were evaluated with the CDC Biofilm Reactor in-vitro model for susceptible (PAO1) and extensively-drug-resistant (XDR-HUB3) P. aeruginosa. Efficacy was correlated with the PK/PD indices for meropenem., Results: For PAO1, both meropenem regimens were bactericidal, with higher killing for extended infusion [∆log 10 colony-forming units (CFU)/mL 54-0h=-4.66±0.93 for extended infusion vs ∆log 10 CFU/mL 54-0h=-3.4±0.41 for intermittent bolus; P<0.001]. For XDR-HUB3, the intermittent bolus regimen was non-active, but extended infusion showed bactericidal effect (∆log 10 CFU/mL 54-0h=-3.65±0.29; P<0.001). Time above minimum inhibitory concentration (f%T >MIC ) had the best correlation with efficacy for both strains. The addition of colistin always improved meropenem activity, and resistant strains did not emerge., Conclusion: f%T >MIC was the PK/PD index that best correlated with the anti-biofilm efficacy of meropenem; it was better optimized when using the extended infusion regimen, allowing recovery of bactericidal activity in monotherapy, including activity against meropenem-resistant P. aeruginosa. Combining meropenem by extended infusion with colistin offered the most effective therapy for both strains. Optimizing meropenem dosing by extended infusion should be encouraged when treating biofilm-related infections., (Copyright © 2023 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.)

Infection after spinal instrumentation (IASI) by Cutibacterium spp. is being more frequently reported. The aim of this study was to analyse the incidence, risk factors, clinical characteristics, and outcome of a Cutibacterium spp. IASI (CG) compared with non- Cutibacterium IASI (NCG) infections, with an additional focus on the role of rifampin in the treatment. All patients from a multicentre, retrospective, observational study with a confirmed IASI between January 2010 and December 2016 were divided into two groups: (CG and NCG) IASI. Baseline, medical, surgical, infection treatment, and follow-up data were compared for both groups. In total, 411 patients were included: 27 CG and 384 NCG. The CG patients were significantly younger. They had a longer median time to diagnosis (23 vs. 13 days) ( p = 0.025), although 55.6% debuted within the first month after surgery. Cutibacterium patients were more likely to have the implant removed (29.6% vs. 12.8%; p = 0.014) and received shorter antibiotic regimens ( p = 0.014). In 33% of Cutibacterium cases, rifampin was added to the baseline therapy. None of the 27 infections resulted in treatment failure during follow-up regardless of rifampin use. Cutibacterium spp. is associated with a younger age and may cause both early and late IASIs. In our experience, the use of rifampin to improve the outcome in the treatment of a Cutibacterium spp. IASI is not relevant since, in our series, none of the cases had therapeutic failure regardless of the use of rifampin.

Objectives: The aim of this study was to develop a mechanistic protein-binding model to predict the unbound flucloxacillin concentrations in different patient populations., Methods: A mechanistic protein-binding model was fitted to the data using non-linear mixed-effects modelling. Data were obtained from four datasets, containing 710 paired total and unbound flucloxacillin concentrations from healthy volunteers, non-critically ill and critically ill patients. A fifth dataset with data from hospitalized patients was used for evaluation of our model. The predictive performance of the mechanistic model was evaluated and compared with the calculation of the unbound concentration with a fixed unbound fraction of 5%. Finally, we performed a fit-for-use evaluation, verifying whether the model-predicted unbound flucloxacillin concentrations would lead to clinically incorrect dose adjustments., Results: The mechanistic protein-binding model predicted the unbound flucloxacillin concentrations more accurately than assuming an unbound fraction of 5%. The mean prediction error varied between -26.2% to 27.8% for the mechanistic model and between -30.8% to 83% for calculation with a fixed factor of 5%. The normalized root mean squared error varied between 36.8% and 69% respectively between 57.1% and 134%. Predicting the unbound concentration with the use of the mechanistic model resulted in 6.1% incorrect dose adjustments versus 19.4% if calculated with a fixed unbound fraction of 5%., Conclusions: Estimating the unbound concentration with a mechanistic protein-binding model outperforms the calculation with the use of a fixed protein binding factor of 5%, but neither demonstrates acceptable performance. When performing dose individualization of flucloxacillin, this should be done based on measured unbound concentrations rather than on estimated unbound concentrations from the measured total concentrations. In the absence of an assay for unbound concentrations, the mechanistic binding model should be preferred over assuming a fixed unbound fraction of 5%., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: Ceftriaxone total and unbound pharmacokinetics (PK) can be altered in critically ill patients with septic shock and hypoalbuminemia receiving continuous veno-venous hemodiafiltration (CVVHDF). The objective of this study was to determine the dosing strategy of ceftriaxone that maximizes the probability of maintaining the concentration above the MIC of the susceptible bacteria (≤2 mg/L by the EUCAST) for a 100% of the dosing interval (100% ƒ u T >MIC )., Methods: In a prospective PK study in the intensive care units of two tertiary Spanish hospitals, six timed blood samples were collected per patient; for each sample, ceftriaxone total and unbound concentrations were measured using a liquid chromatography coupled to tandem mass spectrometry method. Population PK analysis and Monte-Carlo simulations were performed using NONMEMv.7.3®., Results: We enrolled 8 critically ill patients that met the inclusion criteria (47 blood samples). Median age (range) was 70 years (47-85), weight 72.5 kg (40-95), albumin concentration 24.2 g/L (22-34), APACHE II score at admission 26 (17-36), and SOFA score on the day of study 12 (9-15). The unbound fraction (ƒ u ) of ceftriaxone was 44%, and total CL was 1.27 L/h, 25-30% higher than the CL reported in septic critically ill patients not receiving renal replacement therapies, and dependent on albumin concentration and weight. Despite this increment in ƒ u and CL, Monte-Carlo simulations showed that a dose of 1 g once-daily ceftriaxone is sufficient to achieve a 100% ƒ u T >MIC for MICs ≤2 mg/L for any range of weight and albumin concentration., Conclusion: Once-daily 1 g ceftriaxone provides optimal exposure in critically ill patients with septic shock and hypoalbuminemia receiving CVVHDF., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

Background: The optimal dosing of antibiotics in critically ill patients receiving renal replacement therapy (RRT) remains unclear. In this study, we describe the variability in RRT techniques and antibiotic dosing in critically ill patients receiving RRT and relate observed trough antibiotic concentrations to optimal targets., Methods: We performed a prospective, observational, multinational, pharmacokinetic study in 29 intensive care units from 14 countries. We collected demographic, clinical, and RRT data. We measured trough antibiotic concentrations of meropenem, piperacillin-tazobactam, and vancomycin and related them to high- and low-target trough concentrations., Results: We studied 381 patients and obtained 508 trough antibiotic concentrations. There was wide variability (4-8-fold) in antibiotic dosing regimens, RRT prescription, and estimated endogenous renal function. The overall median estimated total renal clearance (eTRCL) was 50 mL/minute (interquartile range [IQR], 35-65) and higher eTRCL was associated with lower trough concentrations for all antibiotics (P < .05). The median (IQR) trough concentration for meropenem was 12.1 mg/L (7.9-18.8), piperacillin was 78.6 mg/L (49.5-127.3), tazobactam was 9.5 mg/L (6.3-14.2), and vancomycin was 14.3 mg/L (11.6-21.8). Trough concentrations failed to meet optimal higher limits in 26%, 36%, and 72% and optimal lower limits in 4%, 4%, and 55% of patients for meropenem, piperacillin, and vancomycin, respectively., Conclusions: In critically ill patients treated with RRT, antibiotic dosing regimens, RRT prescription, and eTRCL varied markedly and resulted in highly variable antibiotic concentrations that failed to meet therapeutic targets in many patients., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Daptomycin-induced eosinophilic pneumonia (DEP) is a rare but severe adverse effect and the risk factors are unknown. The aim of this study was to determine risk factors for DEP., Methods: A retrospective cohort study was performed at the Bone and Joint Infection Unit of the Hospital Universitari Bellvitge (January 2014-December 2018). To identify risk factors for DEP, cases were divided into two groups: those who developed DEP and those without DEP., Results: Among the whole cohort ( n = 229) we identified 11 DEP cases (4.8%) and this percentage almost doubled in the subgroup of patients ≥70 years (8.1%). The risk factors for DEP were age ≥70 years (HR 10.19, 95%CI 1.28-80.93), therapy >14 days (7.71, 1.98-30.09) and total cumulative dose of daptomycin ≥10 g (5.30, 1.14-24.66)., Conclusions: Clinicians should monitor cumulative daptomycin dosage to minimize DEP risk, and be cautious particularly in older patients when the total dose of daptomycin exceeds 10 g.

Background and Objectives: Available information about infection after spine instrumentation (IASI) and its management are scarce. We aimed to analyse DAIR (debridement, antibiotics and implant retention) prognosis and evaluate effectiveness of short antibiotic courses on early forms., Methods: Multicentre retrospective study of patients with IASI managed surgically (January 2010-December 2016). Risk factors for failure were analysed by multivariate Cox regression and differences between short and long antibiotic treatment were evaluated with a propensity score-matched analysis., Results: Of the 411 IASI cases, 300 (73%) presented in the first month after surgery, 48 in the second month, 22 in the third and 41 thereafter. Infections within the first 2 months (early cases) occurred mainly to older patients, with local inflammatory signs and predominance of Enterobacteriaceae, unlike those in the later periods. When managed with DAIR, prognosis of early cases was better than later ones (failure rate 10.4% versus 26.1%, respectively; P = 0.02). Risk factors for DAIR failure in early cases were female sex, Charlson Score, large fusions (>6 levels) and polymicrobial infections (adjusted HRs of 2.4, 1.3, 2.6 and 2.26, respectively). Propensity score matching proved shorter courses of antibiotics (4-6 weeks) as effective as longer courses (failure rates 11.4% and 10.5%, respectively; P = 0.870)., Conclusions: IASIs within the first 2 months could be managed effectively with DAIR and shorter antibiotic courses. Clinicians should be cautious when faced with patients with comorbidities, large fusions and/or polymicrobial infections., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Initial appropriate anti-infective therapy is associated with improved outcomes in patients with severe infections. In critically ill patients, altered pharmacokinetic (PK) behaviour is common and known to influence the achievement of PK/pharmacodynamic targets., Objectives: To describe population PK and optimized dosing regimens for flucloxacillin in critically ill patients., Methods: First, we developed a population PK model, estimated between-patient variability (BPV) and identified covariates that could explain BPV through non-linear mixed-effects analysis, using total and unbound concentrations obtained from 35 adult critically ill patients treated with intermittent flucloxacillin. Second, we validated the model using external datasets from two different countries. Finally, frequently prescribed dosing regimens were evaluated using Monte Carlo simulations., Results: A two-compartment model with non-linear protein binding was developed and validated. BPV of the maximum binding capacity decreased from 42.2% to 30.4% and BPV of unbound clearance decreased from 88.1% to 71.6% upon inclusion of serum albumin concentrations and estimated glomerular filtration rate (eGFR; by CKD-EPI equation), respectively. PTA (target of 100%fT>MIC) was 91% for patients with eGFR of 33 mL/min and 1 g q6h, 87% for patients with eGFR of 96 mL/min and 2 g q4h and 71% for patients with eGFR of 153 mL/min and 2 g q4h., Conclusions: For patients with high creatinine clearance who are infected with moderately susceptible pathogens, therapeutic drug monitoring is advised since there is a risk of underexposure to flucloxacillin. Due to the non-linear protein binding of flucloxacillin and the high prevalence of hypoalbuminaemia in critically ill patients, dose adjustments should be based on unbound concentrations., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.)

Background: The coronavirus disease (COVID-19) pandemic has caused an unprecedented worldwide public health crisis that requires new management approaches. COVIDApp is a mobile app that was adapted for the management of institutionalized individuals in long-term care facilities., Objective: The aim of this paper is to report the implementation of this innovative tool for the management of long-term care facility residents as a high-risk population, specifically for early identification and self-isolation of suspected cases, remote monitoring of mild cases, and real-time monitoring of the progression of the infection., Methods: COVIDApp was implemented in 196 care centers in collaboration with 64 primary care teams. The following parameters of COVID-19 were reported daily: signs/symptoms; diagnosis by reverse transcriptase-polymerase chain reaction; absence of symptoms for ≥14 days; total deaths; and number of health care workers isolated with suspected COVID-19. The number of at-risk centers was also described., Results: Data were recorded from 10,347 institutionalized individuals and up to 4000 health care workers between April 1 and 30, 2020. A rapid increase in suspected cases was seen until day 6 but decreased during the last two weeks (from 1084 to 282 cases). The number of confirmed cases increased from 419 (day 6) to 1293 (day 22) and remained stable during the last week. Of the 10,347 institutionalized individuals, 5,090 (49,2%) remained asymptomatic for ≥14 days. A total of 854/10,347 deaths (8.3%) were reported; 383 of these deaths (44.8%) were suspected/confirmed cases. The number of isolated health care workers remained high over the 30 days, while the number of suspected cases decreased during the last 2 weeks. The number of high-risk long-term care facilities decreased from 19/196 (9.5%) to 3/196 (1.5%)., Conclusions: COVIDApp can help clinicians rapidly detect and remotely monitor suspected and confirmed cases of COVID-19 among institutionalized individuals, thus limiting the risk of spreading the virus. The platform shows the progression of infection in real time and can aid in designing new monitoring strategies., (©Patricia Echeverría, Miquel Angel Mas Bergas, Jordi Puig, Mar Isnard, Mireia Massot, Cristina Vedia, Ricardo Peiró, Yolanda Ordorica, Sara Pablo, María Ulldemolins, Mercé Iruela, Dolors Balart, José María Ruiz, Jordi Herms, Bonaventura Clotet Sala, Eugenia Negredo. Originally published in JMIR Public Health and Surveillance (http://publichealth.jmir.org), 17.07.2020.)

Background: Semi-recumbent position is recommended to prevent ventilator-associated pneumonia. Its implementation, however, is below optimal., Objectives: We aimed to assess real semi-recumbent position compliance and the degree of head-of-bed elevation in Spanish intensive care units, along with factors determining compliance and head-of-bed elevation and their relationship with the development of pressure ulcers. Finally, we investigated the impact that might have the diagnosis of pressure ulcers in the attitude toward head-of-bed elevation., Methods: We performed a prospective, multicenter, observational study in 6 intensive care units. Inclusion criteria were patients ≥18 years old and expected to remain under mechanical ventilator for ≥48h. Exclusion criteria were patients with contraindications for semi-recumbent position from admission, mechanical ventilation during the previous 7 days and prehospital intubation. Head-of-bed elevation was measured 3 times/day for a maximum of 28 days using the BOSCH GLM80(®) device. The variables collected related to patient admission, risk of pressure ulcers and the measurements themselves. Bivariate and multivariate analyses were carried out using multiple binary logistic regression and linear regression as appropriate. Statistical significance was set at p<0.05. All analyses were performed with IBM SPSS for Windows Version 20.0., Results: 276 patients were included (6894 measurements). 45.9% of the measurements were <30.0°. The mean head-of-bed elevation was 30.1 (SD 6.7)° and mean patient compliance was 53.6 (SD 26.1)%. The main reasons for non-compliance according to the staff nurses were those related to the patient's care followed by clinical reasons. The factors independently related to semi-recumbent position compliance were intensive care unit, ventilation mode, nurse belonging to the research team, intracranial pressure catheter, beds with head-of-bed elevation device, type of pathology, lateral position, renal replacement therapy, nursing shift, open abdomen, abdominal vacuum therapy and agitation. Twenty-five patients (9.1%) developed a total of 34 pressure ulcers. The diagnosis of pressure ulcers did not affect the head-of-bed elevation. In the multivariate analysis, head-of-bed elevation was not identified as an independent risk factor for pressure ulcers., Conclusions: Semi-recumbent position compliance is below optimal despite the fact that it seems achievable most of the time. Factors that affect semi-recumbent position include the particular intensive care unit, abdominal conditions, renal replacement therapy, agitation and bed type. Head-of-bed elevation was not related to the risk of pressure ulcers. Efforts should be made to clarify semi-recumbent position contraindications and further analysis of its safety profile should be carried out., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Objectives: This multicentre study aimed to describe the pharmacokinetics (PK) of piperacillin in critically ill patients with multiple organ dysfunction syndrome (MODS) receiving continuous venovenous haemodiafiltration (CVVHDF), to identify the sources of PK variability and evaluate different dosing regimens to develop recommendations based on clinical parameters., Patients and Methods: Nineteen patients with MODS and CVVHDF receiving piperacillin/tazobactam were enrolled from three tertiary hospitals (95 plasma samples). Population PK modelling and Monte Carlo simulations were performed using NONMEM v7.3(®)., Results: Patients' median age was 70 years (range 39-82), median weight was 80 kg (45-129), median APACHE II score at admission was 21 (13-33) and median SOFA score on the day of study was 11 (8-21). The final population PK model was characterized by CL (L/h) = 6.11 * [weight (kg)/80](1.39) * CLMEMB. If membrane = 1.5 m(2) AN69ST, CLMEMB = 1; if membrane = 0.9 m(2) AN69, CLMEMB = 0.51. Monte Carlo simulations showed that: (i) to maintain unbound piperacillin concentrations above the MIC for the bacteria for 100% of dosing interval T (100%fuT>MIC), patients receiving CVVHDF with 1.5 m(2) AN69ST membranes required doses of 4000 mg q8h for the treatment of bacteria with a susceptibility to piperacillin close to the clinical breakpoint (MIC = 8-16 mg/L) (2000 mg q8h was sufficient for patients with CVVHDF using 0.9 m(2) AN69 membranes); and (ii) for the treatment of bacteria with high susceptibility to piperacillin (MIC <4 mg/L) or for the attainment of a more traditional pharmacodynamic target (50%fuT>MIC), 2000 mg q8h sufficed regardless of type of membrane and body weight., Conclusions: Our results suggest that type of membrane and body weight should be considered for piperacillin dose titration in critically ill patients with MODS and CVVHDF requirement., (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Meropenem dosing in critically ill patients with septic shock and continuous renal replacement therapy (CRRT) is complex, with the recommended maintenance doses being 500 mg to 1,000 mg every 8 h (q8h) to every 12 h. This multicenter study aimed to describe the pharmacokinetics (PKs) of meropenem in this population to identify the sources of PK variability and to evaluate different dosing regimens to develop recommendations based on clinical parameters. Thirty patients with septic shock and CRRT receiving meropenem were enrolled (153 plasma samples were tested). A population PK model was developed with data from 24 patients and subsequently validated with data from 6 patients using NONMEM software (v.7.3). The final model was characterized by CL = 3.68 + 0.22 · (residual diuresis/100) and V = 33.00 · (weight/73)(2.07), where CL is total body clearance (in liters per hour), residual diuresis is the volume of residual diuresis (in milliliters per 24 h), and V is the apparent volume of distribution (in liters). CRRT intensity was not identified to be a CL modifier. Monte Carlo simulations showed that to maintain concentrations of the unbound fraction (fu ) of drug above the MIC of the bacteria for 40% of dosing interval T (referred to as 40% of the ƒ uT >MIC), a meropenem dose of 500 mg q8h as a bolus over 30 min would be sufficient regardless of the residual diuresis. If 100% of the ƒ uT >MIC was chosen as the target, oligoanuric patients would require 500 mg q8h as a bolus over 30 min for the treatment of susceptible bacteria (MIC < 2 mg/liter), while patients with preserved diuresis would require the same dose given as an infusion over 3 h. If bacteria with MICs close to the resistance breakpoint (2 to 4 mg/liter) were to be treated with meropenem, a dose of 500 mg every 6 h would be necessary: a bolus over 30 min for oligoanuric patients and an infusion over 3 h for patients with preserved diuresis. Our results suggest that residual diuresis may be an easy and inexpensive tool to help with titration of the meropenem dose and infusion time in this challenging population., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

Although early and appropriate antibiotic therapy remains the most important intervention for successful treatment of septic shock, data guiding optimization of beta-lactam prescription in critically ill patients prescribed with continuous renal replacement therapy (CRRT) are still limited. Being small hydrophilic molecules, beta-lactams are likely to be cleared by CRRT to a significant extent. As a result, additional variability may be introduced to the per se variable antibiotic concentrations in critically ill patients. This article aims to describe the current clinical scenario for beta-lactam dosing in critically ill patients with septic shock and CRRT, to highlight the sources of variability among the different studies that reduce extrapolation to clinical practice, and to identify the opportunities for future research and improvement in this field. Three frequently prescribed beta-lactams (meropenem, piperacillin and ceftriaxone) were chosen for review. Our findings showed that present dosing recommendations are based on studies with drawbacks limiting their applicability in the clinical setting. In general, current antibiotic dosing regimens for CRRT follow a one-size-fits-all fashion despite emerging clinical data suggesting that drug clearance is partially dependent on CRRT modality and intensity. Moreover, some studies pool data from heterogeneous populations with CRRT that may exhibit different pharmacokinetics (for example, admission diagnoses different to septic shock, such as trauma), which also limit their extrapolation to critically ill patients with septic shock. Finally, there is still no consensus regarding the %T>MIC (percentage of dosing interval when concentration of the antibiotic is above the minimum inhibitory concentration of the pathogen) value that should be chosen as the pharmacodynamic target for antibiotic therapy in patients with septic shock and CRRT. For empirically optimized dosing, during the first day a loading dose is required to compensate the increased volume of distribution, regardless of impaired organ function. An additional loading dose may be required when CRRT is initiated due to steady-state equilibrium breakage driven by clearance variation. From day 2, dosing must be adjusted to CRRT settings and residual renal function. Therapeutic drug monitoring of beta-lactams may be regarded as a useful tool to daily individualize dosing and to ensure optimal antibiotic exposure.

Despite the importance of early an appropriate therapy for the outcomes of severe infections in critically ill patients, there is still little understanding of dose optimization during the most important phase of the treatment, the initial phase. Disease-driven variations in pharmacokinetics and pharmacokinetics/ pharmacodynamics may compromise the therapeutic success of antibiotic therapy. Therefore, dose adjustments that account for these variations are paramount for improving antibiotic use in critically ill patients. Compelling evidence shows significant increases in the Vd of both hydrophilic and lipophilic drugs in critically ill patients as a consequence of patient pathology and from clinical interventions. These increases in the Vd can lead to lower than expected plasma concentrations during the first day of therapy, which may result in sub-optimal achievement of antibiotic pharmacokinetics/pharmacodynamic targets, resulting in inappropriate treatment. Therefore, loading doses of antibiotic during the first day of therapy that account for the predicted increase in the Vd are required. Further research towards the establishment of new dosing regimens that use loading doses to satisfy such increased volumes of distribution is recommended.

The objectives of this study were to assess the determinants of empirical antibiotic choice, prescription patterns and outcomes in patients with hospital-acquired pneumonia (HAP)/ventilator-associated pneumonia (VAP) in Europe. We performed a prospective, observational cohort study in 27 intensive care units (ICUs) from nine European countries. 100 consecutive patients on mechanical ventilation for HAP, on mechanical ventilation>48 h or with VAP were enrolled per ICU. Admission category, sickness severity and Acinetobacter spp. prevalence>10% in pneumonia episodes determined antibiotic empirical choice. Trauma patients were more often prescribed non-anti-Pseudomonas cephalosporins (OR 2.68, 95% CI 1.50-4.78). Surgical patients received less aminoglycosides (OR 0.26, 95% CI 0.14-0.49). A significant correlation (p<0.01) was found between Simplified Acute Physiology Score II score and carbapenem prescription. Basal Acinetobacter spp. prevalence>10% dramatically increased the prescription of carbapenems (OR 3.5, 95% CI 2.0-6.1) and colistin (OR 115.7, 95% CI 6.9-1,930.9). Appropriate empirical antibiotics decreased ICU length of stay by 6 days (26.3±19.8 days versus 32.8±29.4 days; p=0.04). The antibiotics that were prescribed most were carbapenems, piperacillin/tazobactam and quinolones. Median (interquartile range) duration of antibiotic therapy was 9 (6-12) days. Anti-methicillin-resistant Staphylococcus aureus agents were prescribed in 38.4% of VAP episodes. Admission category, sickness severity and basal Acinetobacter prevalence>10% in pneumonia episodes were the major determinants of antibiotic choice at the bedside. Across Europe, carbapenems were the antibiotic most prescribed for HAP/VAP.

Although early and appropriate antibiotic therapy remains the cornerstone of success for the treatment of septic shock, few data exist to guide antibiotic dose optimization in critically ill patients, particularly those with multiple organ dysfunction syndrome (MODS). It is well known that MODS significantly alters the patient's physiology, but the effects of these variations on pharmacokinetics have not been reviewed concisely. Therefore, the aims of this article are to summarize the disease-driven variations in pharmacokinetics and pharmacodynamics and to provide antibiotic dosing recommendations for critically ill patients with MODS. The main findings of this review are that the two parameters that vary with greatest significance in critically ill patients with MODS are drug volume of distribution and clearance. Disease- and clinician-driven changes lead to an increased volume of distribution and lower-than-expected plasma drug concentrations during the first day of therapy at least. Decreased antibiotic clearance is common and can lead to drug toxicity. In summary, "front-loaded" doses of antibiotic during the first 24 h of therapy should account for the likely increases in the antibiotic volume of distribution. Thereafter, maintenance dosing must be guided by drug clearance and adjusted to the degree of organ dysfunction.

Low serum albumin levels are very common in critically ill patients, with reported incidences as high as 40-50%. This condition appears to be associated with alterations in the degree of protein binding of many highly protein-bound antibacterials, which lead to altered pharmacokinetics and pharmacodynamics, although this topic is infrequently considered in daily clinical practice. The effects of hypoalbuminaemia on pharmacokinetics are driven by the decrease in the extent of antibacterial bound to albumin, which increases the unbound fraction of the drug. Unlike the fraction bound to plasma proteins, the unbound fraction is the only fraction available for distribution and clearance from the plasma (central compartment). Hence, hypoalbuminaemia is likely to increase the apparent total volume of distribution (V(d)) and clearance (CL) of a drug, which would translate to lower antibacterial exposures that might compromise the attainment of pharmacodynamic targets, especially for time-dependent antibacterials. The effect of hypoalbuminaemia on unbound concentrations is also likely to have an important impact on pharmacodynamics, but there is very little information available on this area. The objectives of this review were to identify the original research papers that report variations in the highly protein-bound antibacterial pharmacokinetics (mainly V(d) and CL) in critically ill patients with hypoalbuminaemia and without renal failure, and subsequently to interpret the consequences for antibacterial dosing. All relevant articles that described the pharmacokinetics and/or pharmacodynamics of highly protein-bound antibacterials in critically ill patients with hypoalbuminaemia and conserved renal function were reviewed. We found that decreases in the protein binding of antibacterials in the presence of hypoalbuminaemia are frequently observed in critically ill patients. For example, the V(d) and CL of ceftriaxone (85-95% protein binding) in hypoalbuminaemic critically ill patients were increased 2-fold. A similar phenomenon was reported with ertapenem (85-95% protein binding), which led to failure to attain pharmacodynamic targets (40% time for which the concentration of unbound [free] antibacterial was maintained above the minimal inhibitory concentration [fT>MIC] of the bacteria throughout the dosing interval). The V(d) and CL of other highly protein-bound antibacterials such as teicoplanin, aztreonam, fusidic acid or daptomycin among others were significantly increased in critically ill patients with hypoalbuminaemia compared with healthy subjects. Increased antibacterial V(d) appeared to be the most significant pharmacokinetic effect of decreased albumin binding, together with increased CL. These pharmacokinetic changes may result in decreased achievement of pharmacodynamic targets especially for time-dependent antibacterials, resulting in sub-optimal treatment. The effects on concentration-dependent antibacterial pharmacodynamics are more controversial due to the lack of data on this topic. In conclusion, altered antibacterial-albumin binding in the presence of hypoalbuminaemia is likely to produce significant variations in the pharmacokinetics of many highly protein-bound antibacterials. Dose adjustments of these antibacterials in critically ill patients with hypoalbuminaemia should be regarded as another step for antibacterial dosing optimization. Moreover, some of the new antibacterials in development exhibit a high level of protein binding although hypoalbuminaemia is rarely considered in clinical trials in critically ill patients. Further research that defines dosing regimens that account for such altered pharmacokinetics is recommended.

Ventilator associated pneumonia is the principal infectious complication in the Intensive Care Unit (ICU), and represents the main infectious cause of morbidity and mortality. Its diagnosis and management is complex. Consequently, its prevention becomes a cornerstone in daily clinical practice. Daily interruption of sedation, oral and digestive decontamination, prophylactic administration of systemic and/or inhaled antibiotics, glycemic control, stress ulcer prophylaxis, transfusion policy and timing and adequacy of antibiotic treatment are the main suggested pharmacologic interventions. The aim of this review is to critically describe the principal pharmacologic interventions for the prevention of ventilator associated pneumonia, focusing on the degree of the evidence and the appropriateness for daily clinical practice., (Copyright © 2009 Elsevier España, S.L. All rights reserved.)

Inappropriate empirical antibiotic therapy for severe infections in the intensive care unit is a modifiable prognostic factor that has a great effect on patient outcome and health care resources. Inappropriate treatment is usually associated with microorganisms resistant to the common antibiotics, which must be empirically targeted when risk factors are present. Previous antibiotic exposure, prolonged length of hospital stay, admission category, local susceptibilities, colonization pressure, and the presence of invasive devices increase the likelihood of infection by resistant pathogens. Consideration of issues beyond in vitro susceptibility, such as antibiotic physicochemistry, tissue penetration, and pharmacokinetic/pharmacodynamic-driven dosing, is mandatory for the optimization of antibiotic use., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The extreme pharmacokinetic behaviour of drugs sometimes observed in critically ill patients poses a significant threat to the achievement of optimal antibiotic treatment outcomes. Scant information on beta-lactam antibiotic therapeutic drug monitoring (TDM) is available. The objective of this prospective study was to evaluate the practicality and utility of a beta-lactam TDM programme in critically ill patients. TDM was performed twice weekly on all eligible patients at a 30-bed tertiary referral critical care unit. Blood concentrations were determined by fast-throughput high-performance liquid chromatography (HPLC) assays and were available within 12h of sampling. Dose adjustment was instituted if the trough or steady-state blood concentration was below 4-5x the minimum inhibitory concentration (MIC) or above 10x MIC. A total of 236 patients were subject to TDM over an 11-month period. The mean+/-standard deviation age was 53.5+/-18.3 years. Dose adjustment was required in 175 (74.2%) of the patients, with 119 of these patients (50.4%) requiring dose increases after the first TDM. For outcome of therapy, 206 (87.3%) courses resulted in a positive treatment outcome and there were 30 (12.7%) treatment failures observed including 14 deaths and 15 courses requiring escalation to broader-spectrum agents; 1 course was ceased due to an adverse drug reaction. Using binomial logistic regression, only an elevated Acute Physiology and Chronic Health Evaluation (APACHE) II score (P<0.01) and elevated plasma creatinine concentration (P=0.05) were found to be predictive of mortality. In conclusion, further research is required to determine definitively whether achievement of optimal beta-lactam pharmacodynamic targets improves clinical outcomes., (Copyright 2010 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.)

Ventilator-associated pneumonia (VAP) management depends on the interaction between the infective agent, the host response, and the antimicrobial drug used. After the pathogen reaches the lungs, two outcomes are possible: either the microorganisms are eliminated by the host immune system, or they overcome the immune system and cause pulmonary infection. When a patient is thought to have VAP, two steps are strongly recommended: etiologic diagnostic testing and the immediate initiation of antibiotics. The daily management of VAP remains a challenge for physicians in the ICU. In recent years, a more dynamic approach has evolved, updating local epidemiology, evaluating VAP and diagnostic tools every day, and assessing host response using clinical and biochemical parameters.