Prolonged vs short-term infusion of β-lactam antibiotics for the treatment of febrile neutropenia: A systematic review and meta-analysis

Background: The optimisation of the use of beta-lactam antibiotics (BLA) via prolonged infusions in life-threatening complications such as febrile neutropenia (FN) is still controversial. This systematic review and meta-analysis aim to evaluate the efficacy of this strategy in onco-haematological patients with FN. Methods: A systematic search was performed of PubMed, Web of Science, Cochrane, EMBASE, World Health Organization, and ClinicalTrials.gov, from database inception until December 2022. The search included randomised controlled trials (RCTs) and observational studies that compared prolonged vs short-term infusions of the same BLA. The primary outcome was all-cause mortality. Secondary outcomes were defervescence, requirement of vasoactive drugs, length of hospital stay and adverse events. Pooled risk ratios were calculated using random effects models. Results: Five studies were included, comprising 691 episodes of FN, mainly in haematological patients. Prolonged infusion was not associated with a reduction in all-cause mortality (pRR 0.83; 95% confidence interval 0.47-1.48). Nor differences were found in secondary outcomes. Conclusions: The limited data available did not show significant differences in terms of all-cause mortality or significant secondary outcomes in patients with FN receiving BLA in prolonged vs. short-term infusion. High-quality RCTs are needed to determine whether there are subgroups of FN patients who would benefit from prolonged BLA infusion. (c) 2023 The Author(s). Published by Elsevier Ltd on behalf of The British Infection Association. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Optimization of flucloxacillin dosing regimens in critically ill patients using population pharmacokinetic modelling of total and unbound concentrations

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 serumalbumin 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 33mL/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

Risk Factors of Daptomycin-Induced Eosinophilic Pneumonia in a Population with Osteoarticular Infection

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

A meta-analysis of protein binding of flucloxacillin in healthy volunteers and hospitalized patients

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%

Cutibacterium spp. Infections after Instrumented Spine Surgery Have a Good Prognosis Regardless of Rifampin Use: A Cross-Sectional Study

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

Genealogies. Rescatar penyores

[ca] Com a «penyores»... coneixem aquells objectes que es deixen en poder d’algú, com a prova de retorn o com a promesa de record. Penyores són també aquells estris oblidats en espais en desús, peces descartades, de manera conscient o involuntària —descuidar-se, fugir. Els espais que ens envolten, on diàriament vivim i treballem, acumulen artefactes carregats de vivències, històries i faules de qui abans els ha emprat. Narren èxits, fracassos, formes de viure; si més no, la màgia de la quotidianitat. Independentment de l’estadi vital on s’estigui —joventut o senectut—, s’entén la importància i el potencial de reutilitzar el que s’ha llegat: per acostar-se a la memòria, rellegir-la, fer-ne crida, furgar-hi, reivindicar i, siguin els que siguin, propiciar canvis a situacions actuals. A «Genealogies. Rescatar penyores», artistes novells, artistes convidats i professorat de la Facultat de Belles Arts de la Universitat de Barcelona, amb la complicitat del públic assistent, miren d’aportar noves visions sobre els objectes i els temps pignorats que contenen, com a punt de partida per encetar un diàleg narratiu de tint feminista, econòmic, de cura, de sostenibilitat emocional

Infections after spine instrumentation: effectiveness of short antibiotic treatment in a large multicentre cohort

REIPI (Spanish Network for Research in Infectious Disease)/GEIO–SEIMC (Group for the Study of Osteoarticular Infections – Spanish Society of Infectious Diseases and Clinical Microbiology).[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.E.B. was supported with a grant of the Instituto de Salud Carlos III – Ministry of Science and Innovation (FI 16/00397). This research was carried out as part of our routine work.Peer reviewe

Optimization of meropenem and piperacillin dosing in critically ill patients with septic shock and acute kidney injury requiring continuous renal replacement therapy: a pharmacokinetic and pharmacodynamic study

[eng] BACKGROUND: Early and appropriate antibiotic administration has been shown to be the most effective intervention for reducing mortality in critically ill patients with septic shock and multiple organ dysfunction syndrome (MODS). However, despite its relevance, antibiotic dosing in those patients with MODS including acute kidney injury (AKI) that require continuous renal replacement therapy (CRRT) still represents a major challenge for clinicians. In our environment, the broad[spectrum beta[lactams meropenem and piperacillin (in combination with tazobactam) are the antibiotics most frequently prescribed to these patients with very high levels of sickness severity. The impact of septic shock, AKI and CRRT on these antibiotics’ dose requirements is vital, as medical interventions and the disease itself are likely to produce significant variations in their pharmacokinetics (PK), which may lead to alterations in drug concentrations over time and hence compromise the achievement of drug concentrations within the therapeutic range. However, it is still very complex to individualize piperacillin and meropenem dosing in patients with septic shock and AKI necessitating CRRT. HYPOTHESIS: Meropenem and piperacillin dosing is not optimal in critically ill patients with septic shock and AKI requiring CRRT due to disease and medical[driven variations in antibiotic PK and, therefore, in dose requirements, which may lead to failure in the achievement of therapeutic concentrations. AIMS: 1. To evaluate the suitability of current meropenem and piperacillin dosing recommendations in critically ill patients with septic shock and AKI necessitating CRRT; 2. To identify the sources of variability that compromise optimal drug dosing in this patient population; and 3. To develop new recommendations that allow dose individualization considering these variability sources. METHODS: Three studies have been developed under the study hypothesis and aims. Study 1: Literature review. A systematic literature review and critical evaluation of the available evidence on meropenem and piperacillin dosing in critically ill patients with septic shock and AKI necessitating CRRT has been performed. Studies 2 and 3: Characterization of the PK of meropenem and piperacillin in critically ill patients with septic shock and AKI necessitating CRRT. Two observational, prospective, multicenter, open[label pharmacokinetic studies have been performed in the Intensive Care Units from three Spanish tertiary hospitals. Thirty patients with septic shock and CRRT receiving meropenem and 19 patients receiving piperacillin have been enrolled. Two population PK models have been developed and subsequently validated with data from these patients, and Monte Carlo simulations have been undertaken using NONMEM v.7.3®. RESULTS: The main finding of study 1 is that present “oneTsizeTfitsTall” dosing recommendations for meropenem and piperacillin in critically ill patients with septic shock and AKI requiring CRRT are based on studies with some drawbacks, such as: 1) different sickness severities and levels of renal function, 2) different admission diagnostics (medical versus surgical versus trauma), 3) different clinical managements mainly CRRT settings, 4) heterogeneous PK methodologies, and 5) different PD targets for dosing recommendations. This scenario limits extrapolation of their conclusions to our patient population. Later on, studies 2 and 3 have identified important sources of meropenem and piperacillin PK variability that may assist in dose individualization. For meropenem, the main finding of the population PK analysis is the relationship existing between the 24h urine output and meropenem total clearance (CL). Patients with conserved diuresis (>500mL/24h) exhibit at least a 30% increase in meropenem total CL compared to those patients who are anuric (MIC), oligoanuric patients (residual diuresis 0[500mL/24h) require 500mg/q8h over 30min for the treatment of susceptible bacteria (MIC500 mL/24h) require the same dose over a 3h[infusion. If bacteria with MIC close to the resistance breakpoint (2[4mg/L) are to be treated with meropenem, a dose of 500mg/q6h is necessary: over a 30min[bolus for oligoanuric patients and over a 3h[infusion for patients with preserved diuresis. For the attainment of more conservative PD targets (40% FuT>MIC), 500mg/q8h over a 30min[bolus is sufficient regardless of residual diuresis With regards to piperacillin, the main finding of the population PK analysis is the relationship existing among the type of membrane used for CVVHDF, the patient’s weight and piperacillin total CL; for a body weight of 80kg, piperacillin total CL is doubled when a 1.5m2 AN69 acrylonitrile and sodium methallyl sulfonate copolymer filter pre[ coated with heparin and polyethyleneimine (AN69ST) is used compared to the CL for a 0.9m2 AN69 filter. Subsequent Monte Carlo simulations have shown that for a PD target of 100% FuT>MIC, patients receiving CVVHDF with 1.5m2 AN69ST membranes require doses of 4000mg/q8h for the treatment of bacteria with a susceptibility to piperacillin close to the clinical breakpoint (MIC = 8[16mg/L). In contrast, 2000mg/q8h are sufficient for patients with CVVHDF using 0.9m2AN69 membranes. For the treatment of bacteria with high susceptibility to piperacillin (MIC ≤ 4mg/L) or for the attainment of a more conservative PD target (50% FuT>MIC), 2000mg/q8h are sufficient in all cases. CONCLUSIONS: Due to data heterogeneity, current meropenem and piperacillin dosing recommendations for patients with septic shock and CRRT follow a one[size[fits[all fashion, which often translates into a best[guess dosing at the bedside. In this context, we have shown that identification and consideration of clinical and demographic parameters that influence meropenem and piperacillin PK, such as 24h urine output, patient’s weight and type of CRRT membrane, is advantageous for dose titration. As they are characteristics easy to be measured at the bedside, the implementation of our research findings in the real clinical setting is easy and may be helpful in the complex process of optimization of antibiotic use in the Intensive Care Unit.[spa] L’administració precoç d’antibioteràpia apropiada ha demostrat ser la intervenció més eficaç per reduir la mortalitat en pacients crítics amb xoc sèptic i síndrome de disfunció multiorgànica (SDMO). Malgrat la seva rellevància, però, la dosificació antibiòtica en els pacients amb SDMO incloent insuficiència renal aguda (IRA) que requereixen teràpia continua de suport renal (TCSR) encara representa un repte diari pels professionals de la salut. Al nostre medi, els antibiòtics beta[lactàmics d’ampli espectre meropenem i piperacilelina (en combinació amb tazobactam) són els antibiòtics més prescrits a aquests pacients d’altíssima complexitat i gravetat. L'impacte del xoc sèptic, la IRA i la TCSR en els requeriments de dosis d'aquests fàrmacs és vital, ja que tant la pròpia malaltia com les intervencions mèdiques produeixen alteracions significatives en la seva farmacocinètica (FC), que duen a variacions en els perfils concentració[temps i, conseqüentment, comprometen l'assoliment de concentracions del fàrmac dins del rang terapèutic. No obstant això, individualitzar la dosificació de meropenem i piperacilelina en pacients amb xoc sèptic, IRA i requeriment de TCSR és encara molt complex. HIPÒTESI: La dosificació de meropenem i piperacilelina en pacients crítics amb xoc sèptic i IRA que requereixen TCSR és sub[òptima degut a les variacions en el comportament FC dels fàrmacs produïdes tant per la malaltia com pel maneig mèdic d’aquesta. Aquestes variacions FC poden comprometre l'assoliment de concentracions terapèutiques. OBJECTIUS: 1. Avaluar la idoneïtat de les recomanacions actuals sobre dosificació de meropenem i piperacilelina en pacients crítics amb xoc sèptic i IRA que requereixen TCSR; 2. Identificar les fonts de variabilitat que comprometen l’exposició òptima a aquests antibiòtics en la nostra població de pacients; i 3. Desenvolupar noves recomanacions per individualitzar la dosificació d’aquests antibiòtics tenint en compte aquestes fonts de variabilitat. METODOLOGIA: En base a la hipòtesi i els objectius, s’han desenvolupat els tres estudis següents: Estudi 1: Revisió de la literatura. S’ha realitzat una revisió sistemàtica i avaluació crítica de l'evidència disponible sobre la dosificació de meropenem i piperacilelina en pacients crítics amb xoc sèptic, IRA i requeriment de TCSR. Estudis 2 i 3: Caracterització de la FC de meropenem i piperacilelina en pacients crítics amb xoc sèptic i IRA que requereixen TCSR. S’han realitzat dos estudis farmacocinètics multicèntrics, oberts, prospectius observacionals, a les Unitats de Medicina Intensiva de tres hospitals espanyols de tercer nivell. S’han inclòs a l’estudi 30 pacients amb xoc sèptic, IRA i TCSR que rebien meropenem i 19 pacients que rebien piperacilelina. Amb les dades procedents d’aquests pacients, s’han desenvolupat i validat dos models FC poblacionals, a partir dels quals s’han realitzat simulacions de Monte Carlo de diferents esquemes terapèutics (mitjançant el software NONMEM v.7.3®). RESULTATS: La principal troballa de l'estudi 1 és que les recomanacions actuals de dosificació de meropenem i piperacilelina en pacients crítics amb xoc sèptic i IRA que requereixen TCSR es basen en estudis amb algunes limitacions, com ara: 1) diferents nivells de gravetat de la malaltia i de disfunció renal, 2) diferents diagnòstics d’ingrés (mèdic versus quirúrgic versus trauma), 3) diferents maneigs clínics, principalment referent a les característiques de la TCSR, 4) metodologies heterogènies d’anàlisi FC, i 5) diferents objectius farmacodinàmics (FD) en base als quals es fan les recomanacions de dosificació. Això compromet l'extrapolació dels resultats d’aquests estudis a la nostra població de pacients. Posteriorment, els estudis 2 i 3 han identificat importants fonts de variabilitat en la FC de meropenem i piperacilelina, que si es consideren en el moment de la dosificació poden ser útils per individualitzar el tractament antibiòtic. Pel que fa a meropenem, la principal conclusió de l'anàlisi FC poblacional és la relació existent entre la diüresi acumulada de 24h i l’aclariment total de meropenem (CL). Els pacients amb diüresi conservada (>500ml/24h) presenten un increment d’almenys el 30% sobre el CL total de meropenem en comparació amb aquells pacients anúrics (CMI), els pacients oligo[anúrics (diüresi residual de 0[500mL/24h) requereixen 500mg/q8h administrats en un bolus de 30 minuts per al tractament de microorganismes susceptibles (CMI 500mL/24h) requereixen la mateixa dosi administrada mitjançant una perfusió de 3h. Pel tractament de microorganismes amb una CMI propera al límit de susceptibilitat (2[ 4mg/L) és necessària una dosi de 500mg/q6h: administrada en un bolus de 30 minuts de en pacients oligo[anúrics i mitjançant una perfusió de 3h en pacients amb una diüresi conservada. Si s’escull un objectiu FD més conservador, (40% FuT>CMI), una dosi de 500mg/q8h administrada en un bolus de 30 minuts és suficient amb independència de la diüresi residual. Pel que fa a la piperacilelina, la principal conclusió de l'anàlisi FC poblacional és la relació existent entre el tipus de membrana utilitzada per la TCSR, el pes del pacient i el CL total de piperacilelina; per a un pes de 80 kg, el CL total de piperacilelina es duplica quan es fa servir una membrana d’1,5m2 de copolímer d’acrilonitril i sulfat sòdic de metalelil amb un recobriment d’heparina i polietilenimina (AN69ST) en comparació amb el CL total observat quan es fa servir un filtre AN69 convencional de 0,9m2. Posteriors simulacions de Monte Carlo han demostrat que per a un objectiu FD de 100% FuT>CMI, els pacients que reben TCSR amb membranes AN69ST d’1,5m2 requereixen dosis de 4000mg/q8h per al tractament de microorganismes amb CMI properes al límit de susceptibilitat (CMI = 8[ 16mg/L). Per contra, 2000mg/q8h són suficients per als pacients que reben TCSR amb membranes AN69 de 0,9 m2. Per al tractament de soques d’alta susceptibilitat a la piperacilelina (CMI ≤ 4mg/L), o per l’assoliment d'un objectiu FD més conservador (50% FuT>CMI), 2000mg/q8h són suficients en tots els casos

Meropenem: Focus on its use in serious bacterial infections

Meropenem is an effective broad-spectrum carbapenem antibiotic frequently prescribed for treatment of severe bacterial infections. We conducted a structured review of the published literature to review the microbiology, clinical efficacy and pharmacokinetics, pharmacodynamics and tolerability of meropenem for the treatment of serious bacterial infections. Robust susceptibility data describes the broad spectrum of action of meropenem against many Gram positive and Gram negative organisms as well as stability against ESBL producing organisms. In clinical trials with other antibiotic comparators such as imipenem/cilastatin and cephalosporins (with and without an aminoglycoside), meropenem has been shown to have comparable efficacy for the treatment of different types of serious bacterial infections including severe community acquired pneumonia, complicated intra-abdominal infections, complicated skin and skin structure infections, bacterial meningitis and complicated urinary tract infections. In clinical studies of meropenem versus ceftazidime and an aminoglycoside, meropenem produced superior results for treatment of nosocomial and ventilator associated pneumonia. Meropenem also has a favourable pharmacokinetic profile enabling distribution into many tissue sites whilst maintaining a good safety and tolerability profile in adult and paediatric patients. Like other beta-lactam antibiotics, distribution into peripheral tissue may be impaired in critically ill patients. Administration can occur by either bolus dosing or intermittent infusion, although poor stability at room temperature complicates possible administration by continuous infusion. Such properties make meropenem a useful treatment for serious bacterial infections as either empiric or directed therapy, with administration by extended infusion appropriate for treatment of infections caused by pathogens with reduced susceptibility