Article

Beta-Lactam Infusion in Severe Sepsis (BLISS): a prospective, two-centre, open-labelled randomised controlled trial of continuous versus intermittent beta-lactam infusion in critically ill patients with severe sepsis

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Abstract

Purpose: This study aims to determine if continuous infusion (CI) is associated with better clinical and pharmacokinetic/pharmacodynamic (PK/PD) outcomes compared to intermittent bolus (IB) dosing in critically ill patients with severe sepsis. Methods: This was a two-centre randomised controlled trial of CI versus IB dosing of beta-lactam antibiotics, which enrolled critically ill participants with severe sepsis who were not on renal replacement therapy (RRT). The primary outcome was clinical cure at 14 days after antibiotic cessation. Secondary outcomes were PK/PD target attainment, ICU-free days and ventilator-free days at day 28 post-randomisation, 14- and 30-day survival, and time to white cell count normalisation. Results: A total of 140 participants were enrolled with 70 participants each allocated to CI and IB dosing. CI participants had higher clinical cure rates (56 versus 34 %, p = 0.011) and higher median ventilator-free days (22 versus 14 days, p < 0.043) than IB participants. PK/PD target attainment rates were higher in the CI arm at 100 % fT >MIC than the IB arm on day 1 (97 versus 70 %, p < 0.001) and day 3 (97 versus 68 %, p < 0.001) post-randomisation. There was no difference in 14-day or 30-day survival between the treatment arms. Conclusions: In critically ill patients with severe sepsis not receiving RRT, CI demonstrated higher clinical cure rates and had better PK/PD target attainment compared to IB dosing of beta-lactam antibiotics. Continuous beta-lactam infusion may be mostly advantageous for critically ill patients with high levels of illness severity and not receiving RRT. Malaysian National Medical Research Register ID: NMRR-12-1013-14017.

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... Lorente et al. rapportent ainsi une augmentation de la guérison clinique de 52,3-59,6% à 89,2-90,5% selon les molécules avec le méropénème, la pipéracilline/tazobactam et la ceftazidime (157,167,169). Une mortalité réduite est également rapportée en cas de pneumopathie (177,180), de même qu'une diminution du nombre de jours de ventilation mécanique (165). Les perfusions continues permettent non seulement une meilleure atteinte des concentrations sériques mais aussi tissulaires, avec une cible concentration de ceftazidime à 8 mg/L retrouvée dans le liquide broncho-alvéolaire atteinte deux fois plus fréquemment dans le groupe perfusion continue (181). ...
... Les perfusions continues permettent non seulement une meilleure atteinte des concentrations sériques mais aussi tissulaires, avec une cible concentration de ceftazidime à 8 mg/L retrouvée dans le liquide broncho-alvéolaire atteinte deux fois plus fréquemment dans le groupe perfusion continue (181). Le bénéfice clinique de l'administration de perfusions prolongées/continues est d'autant plus vrai en cas d'infections à bacilles à Gram négatif non fermentants et en cas de germes à CMI élevée, grâce à une meilleure atteinte des PTA autorisant des CMI plus élevées (144,165,180,182). La meilleure atteinte des PTA a été confirmée par des modélisations de Monte-Carlo (183)(184)(185)(186). Il semblerait que les patients les plus graves tirent le plus de bénéfices de ce mode d'administration (8,29,34,177,179). ...
... L'effet inoculum et le faible nombre de patients peuvent également jouer un rôle. De nombreuses études ont néanmoins démontré la supériorité de la perfusion prolongée ou continue notamment pour la pipéracilline/tazobactam(144,(157)(158)(159)(160)(161)(162)(163)(164)(165), la ceftazidime(166,167), le céfépime(168), le méropénème(133,163,164,(169)(170)(171)(172) et l'imipénem(173). L'étude randomisée et contrôlée BLISS portant sur les perfusions continues de BL chez des patients septiques, montre un taux de guérison à J14 de 56% versus 34% en faveur des perfusions continues et une meilleure atteinte de l'objectif PK/PD ciblé dans l'étude, à savoir 100% T > CMI (97% versus 70%)(165). ...
Thesis
Les variations pharmacocinétiques des patients de réanimation surajoutées à celles induites par l’épuration extra-rénale continue soulèvent de nombreuses questions concernant les adaptations posologiques d’antibiotiques. Cette problématique est particulièrement présente dans les pneumopathies, qui représentent les infections les plus fréquentes en réanimation. Les sous-dosages de bêta-lactamines engendrent un risque d’échec thérapeutique tandis que les surdosages exposent à un risque de neurotoxicité. Face au risque très important de sous-dosage et au caractère continu de l’épuration extra-rénale, de nombreux praticiens n’adaptent pas les posologies. Une enquête a été réalisée mettant en évidence de nombreuses divergences de pratique concernant les posologies de bêta-lactamines utilisées chez les patients épurés en continu. Les modalités d’administration des bêta-lactamines ont été revues de façon à privilégier les perfusions prolongées/continues et optimiser l’atteinte des objectifs PK/PD. L’étude BLIPIC est une étude prospective multicentrique non-interventionnelle consistant à réaliser des dosages de bêta-lactamines chez les patients de réanimation atteints de pneumopathie et traités par CVVHD, de façon à refléter l’exposition aux antibiotiques. Les résultats de l’étude préliminaire semblent montrer que les posologies actuellement utilisées sont suffisantes, mais exposent à un risque de surdosage. Les méthodes bayésiennes pourraient permettre une adaptation individualisée des posologies.
... Extended or continuous infusion of beta-lactams increase fT .MIC and may therefore enhance antimicrobial efficacy (55)(56)(57)(58). In critically ill patients with respiratory infections, continuous infusion of beta-lactams was associated with a higher clinical cure rate and a lower 30-day mortality (52,59). In addition to increased clinical efficacy, higher % fT .MIC targets may reduce the emergence of antibiotic resistance during treatment, a common problem encountered in critical care (60). ...
... might be more appropriate for neutropenic patients, immunocompromised patients, patients on cardiocirculatory support, and critically ill patients (33,(49)(50)(51)(52)(53)(54). Continuous infusion of beta-lactams has been shown to increase the clinical cure rate and lower the 30-day mortality (52,59). Furthermore, higher % fT .MIC targets may reduce the emergence of antibiotic resistance during treatment (60). ...
Article
Background: Ceftaroline fosamil, a 5th generation cephalosporin antibiotic with activity against MRSA, is currently approved for the treatment of pneumonia and complicated skin and soft tissue infections. However, pharmacokinetic data on free lung tissue concentrations in critical patient populations are lacking. Objectives: The aim of this study was to evaluate the pharmacokinetics of the high-dose regimen of ceftaroline in plasma and lung tissue in cardiac surgery patients during intermittent and continuous administration. Materials and methods: 9 patients undergoing elective cardiac surgery on cardiopulmonary bypass were included in this study and randomly assigned to intermittent or continuous administration. 1800mg ceftaroline fosamil were administered intravenously as either 600mg over 2h q8h (intermittent group) or 600mg over 2h (loading dose) and 1200mg over 22h (continuous group). Interstitial lung tissue concentrations were measured by in-vivo microdialysis. Relevant pharmacokinetic parameters were calculated for each group. Results: Plasma exposure during intermittent and continuous administration were comparable to previously published studies and did not differ significantly between both groups. In-vivo microdialysis demonstrated reliable and adequate penetration of ceftaroline into lung tissue during intermittent and continuous administration. The AUCSS 0-8 and AUCtissue/plasma ratio were descriptively higher in the continuous group. Continuous administration of ceftaroline fosamil achieved significantly higher fT4x>MIC than intermittent administration for pathogens with a minimal inhibitory concentration of 1mg/L. Conclusion: Ceftaroline showed adequate penetration into interstitial lung tissue of critically ill patients undergoing major cardiothoracic surgery, supporting its use for pneumonia caused by susceptible pathogens.
... There is evidence defining the impact of early and appropriate antibiotic administration on decreased mortality [61,62]. In sepsis studies, interventions aimed at optimizing antibiotic therapy demonstrate the greatest improvements in clinical outcomes [63,64]. Convincing in vitro, animal and clinical data also suggest that microbiological success may be optimal when serum β-lactam concentrations are maintained above 4 × MIC during the entire time frame [65][66][67][68][69]. ...
... The results of the DALI study indeed support the conclusions that better outcomes for critically ill patients can be expected with higher drug exposures [63]. Prolonged infusion schemes increase the fraction of the dose interval in which unbound antibiotic concentrations exceed the MIC of the pathogen (fT > MIC), as compared with standard intermittent infusion [64,[70][71][72][73][74]. A meta-analysis showed that hospital mortality was significantly lower (RR, 0.74; 95% CI, 0.56-1.00; ...
Article
Full-text available
Necrotizing soft tissue infections (NSTIs) are rare life-threatening bacterial infections characterized by an extensive necrosis of skin and subcutaneous tissues. Initial urgent management of NSTIs relies on broad-spectrum antibiotic therapy, rapid surgical debridement of all infected tissues and, when present, treatment of associated organ failures in the intensive care unit. Antibiotic therapy for NSTI patients faces several challenges and should (1) carry broad-spectrum activity against gram-positive and gram-negative pathogens because of frequent polymicrobial infections, considering extended coverage for multidrug resistance in selected cases. In practice, a broad-spectrum beta-lactam antibiotic (e.g., piperacillin-tazobactam) is the mainstay of empirical therapy; (2) decrease toxin production, typically using a clindamycin combination, mainly in proven or suspected group A streptococcus infections; and (3) achieve the best possible tissue diffusion with regards to impaired regional perfusion, tissue necrosis, and pharmacokinetic and pharmacodynamic alterations. The best duration of antibiotic treatment has not been well established and is generally comprised between 7 and 15 days. This article reviews the currently available knowledge regarding antibiotic use in NSTIs.
... In addition, Sumi et al. [30] evaluated intermittent, extended and continuous infusion piperacillin/tazobactam in an in vitro dynamic hollow-fiber infection model against ceftriaxoneresistant Klebsiella pneumoniae. For the Kp69 strain (with an MIC of 1 mg/L), a Cmin/MIC ratio of 1.09 with intermittent infusion was sufficient to avoid resistance development, The ability of prolonged infusion to increase the %f T >MIC has been clearly demonstrated [14,15]. Unfortunately, the benefit of prolonged infusion in terms of reduced mortality is still a matter of debate. ...
... Only two randomized clinical trials (RCTs) have demonstrated a lower mortality rate with a prolonged versus intermittent infusion of beta-lactam antibiotics in critically ill patients [16,17]. Other RCTs have demonstrated improved clinical cure rates [14,18], lower costs [19,20], a faster reduction of the APACHE (Acute Physiology and Chronic Health Evaluation) II score [21], increased microbiological success rates [22] or improved target attainment rates [15,23] with prolonged infusion, albeit without an effect on mortality. Two systematic reviews and one individual patient meta-analysis demonstrated lower mortality rates with prolonged as opposed to intermittent infusion in patients with sepsis and severe sepsis [24][25][26]. ...
Article
Full-text available
The surge in antimicrobial resistance and the limited availability of new antimicrobial drugs has fueled the interest in optimizing antibiotic dosing. An ideal dosing regimen leads to maximal bacterial cell kill, whilst minimizing the risk of toxicity or antimicrobial resistance. For beta-lactam antibiotics specifically, PK/PD-based considerations have led to the widespread adoption of prolonged infusion. The rationale behind prolonged infusion is increasing the percentage of time the beta-lactam antibiotic concentration remains above the minimal inhibitory concentration (%fT>MIC). The ultimate goal of prolonged infusion of beta-lactam antibiotics is to improve the outcome of infectious diseases. However, merely increasing target attainment (or the %fT>MIC) is unlikely to lead to improved clinical outcome for several reasons. First, the PK/PD index and target are dynamic entities. Changing the PK (as is the case if prolonged instead of intermittent infusion is used) will result in different PK/PD targets and even PK/PD indices necessary to obtain the same level of bacterial cell kill. Second, the minimal inhibitory concentration is not a good denominator to describe either the emergence of resistance or toxicity. Therefore, we believe a different approach to antibiotic dosing is necessary. In this perspective, we introduce the concept of the maximum tolerable dose (MTD). This MTD is the highest dose of an antimicrobial drug deemed safe for the patient. The goal of the MTD is to maximize bacterial cell kill and minimize the risk of antimicrobial resistance and toxicity. Unfortunately, data about what beta-lactam antibiotic levels are associated with toxicity and how beta-lactam antibiotic toxicity should be measured are limited. This perspective is, therefore, a plea to invest in research aimed at deciphering the dose–response relationship between beta-lactam antibiotic drug concentrations and toxicity. In this regard, we provide a theoretical approach of how increasing uremic toxin concentrations could be used as a quantifiable marker of beta-lactam antibiotic toxicity.
... The intake, circulation, and modification of the active substance in the human body also depends on the means of administration. In modern clinics and hospitals, preference is given to drugs that can be administered parenterally (especially intravenously or intramuscularly), since this method of administration ensures the greatest bioavailability of the drug, accelerates its entry into the bloodstream and reduces the risk of presystemic biotransformation, or biotransformation of the drug during its "first-pass" through the liver, before entering systemic circulation 16 . Drugs are administered quickly and quickly begin to act. ...
... Table 2 presents combinations of drugs with known positive results that are used in modern practice. In some cases, antibiotics are combined according to the principle of one of the cidalgroup, one or more of the statics, for example, beta-lactams and tetracyclines, beta-lactams and aminoglycosides 16 . This is due to their mechanism of action, the localization of the pathogen (extracellular and intracellular), as well as the cross-resistance of the pathogen if superinfection is suspected. ...
Article
Full-text available
In the modern world, the problem of antibiotic therapy is acute. Despite the diversity of existing antibiotic drugs, their efficacy decreases as new, resistant forms of pathogenic microorganisms emerge. It is extremely difficult to control such processes and even more difficult to treat severe bacterial infections. In such situations, an individual approach to each patient is required and physicians need parameters to estimate the efficacy of antibiotic therapy. This review discusses the significance of monitoring the content of antibiotics in the blood for this purpose, in combination with the content of inflammatory markers, such as C-reactive protein and procalcitonin. The basic principles of antibiotic therapy, and factors in the resistance of microorganisms to antibiotics, are examined. Approaches to assess the efficacy of antibiotic therapy, as well as methods to detect antibiotics and inflammatory markers in the blood of patients, and comparative assessment of their capabilities and limitations, are described.
... Our systematic review and meta-analysis demonstrated that con- Achieving PK/PD targets to maintain %fT > MIC for beta-lactams has been correlated with improved clinical outcomes among the critically ill. 2 Both continuous and extended infusions are established methods that may improve the probability of PK/PD target attainment within the critically ill population. 8 8,9,17,25 In the meta-analysis for the beta-lactam subgroup, a significant decrease in overall mortality was observed in the carbapenem and penicillin or beta-lactamase inhibitor groups, but not in the ceph- In conclusion, our meta-analysis showed an association between CEIs and clinical outcomes such as overall and hospital mortality, clinical cure and length of ICU stay in critically ill patients. ...
... Our systematic review and meta-analysis demonstrated that con- Achieving PK/PD targets to maintain %fT > MIC for beta-lactams has been correlated with improved clinical outcomes among the critically ill. 2 Both continuous and extended infusions are established methods that may improve the probability of PK/PD target attainment within the critically ill population. 8 8,9,17,25 In the meta-analysis for the beta-lactam subgroup, a significant decrease in overall mortality was observed in the carbapenem and penicillin or beta-lactamase inhibitor groups, but not in the ceph- In conclusion, our meta-analysis showed an association between CEIs and clinical outcomes such as overall and hospital mortality, clinical cure and length of ICU stay in critically ill patients. ...
Article
Full-text available
What is known and objective The role of continuous/extended beta‐lactam infusions (CEIs) in improving clinical outcomes among critically ill patients remains controversial. Therefore, we aimed to compare the clinical efficacy of CEI versus intermittent administration (IA) of beta‐lactams by performing a systematic review and meta‐analysis. Methods PubMed, the Cochrane Library and Embase were searched from inception until December 2018 for studies comparing clinical outcomes of CEI versus IA in critically ill patients. The meta‐analysis included 18 randomized controlled trials (RCTs) and 13 non‐RCTs. Results and discussion For CEI versus IA, the summary relative risk (RR) for overall mortality and clinical cure was 0.82 (95% confidence interval [CI]: 0.72–0.94) and 1.31 (95% CI: 1.15–1.49), respectively. Subgroup and meta‐regression analyses of the loading dose revealed a significantly increased clinical cure rate in the loading‐dose group (RR: 1.44, 95% CI: 1.22–1.69), which remained significant after adjustments for beta‐lactam type, and association between clinical cure and loading dose for clinical cure (RR: 1.47, 95% CI: 1.20–1.80; p = .001). Subgroup analysis of administration type indicated that both groups had low mortality and high clinical cure rates; however, the heterogeneity analysis did not support an association across continuous infusion and extended infusion groups. Subgroup analysis of the Acute Physiology and Chronic Health Evaluation (APACHE) score was conducted; according to APACHE scores ≥ 16, overall mortality and clinical cure significantly differed between CEI and IA. What is new and conclusion CEIs with loading‐dose treatment may significantly improve the clinical outcomes in critically ill sepsis or septic shock patients.
... In adult populations, PD modeling and patient-level data support EI dose augmentation, [9][10][11][12][13] prompting many institutions to administer beta-lactam antibiotics via EI as standard of care. [14][15][16] Published benefits of EI or CI in adults include faster time to defervescence, enhanced ...
... cost effectiveness, shorter intensive care unit (ICU) length of stay, higher rate of clinical cure, and decreased mortality. [9][10][11][17][18][19][20][21] This review aims to summarize the available literature for the use of EI and CI beta-lactams in pediatric patients. ...
Article
Intravenous beta-lactam antibiotics are the most prescribed antibiotic class in US hospitalized patients of all ages; therefore, optimizing their dosing is crucial. Bactericidal killing is best predicted by the time in which beta-lactam drug concentrations are maintained above the organism's minimum inhibitory concentration (MIC), rather than achievement of a high peak concentration. As such, administration of beta-lactam antibiotics via extended or continuous infusions over a minimum of 3 hours, rather than standard infusions over approximately 30 minutes, has been associated with improved achievement of pharmacodynamic targets and improved clinical outcomes in adult medical literature. This review summarizes the pediatric medical literature. Applicable studies include pharmacodynamic models, case series, retrospective analyses, and prospective studies on the use of extended infusion and continuous infusion penicillins, cephalosporins, carbapenems, and monobactams in neonates, infants, children, and adolescents. Specialized patient populations with unique pharmacokinetics and high-risk infections (neonates, critically ill, febrile neutropenia, cystic fibrosis) are also reviewed. While more studies are needed to confirm prospective clinical outcomes, the current body of evidence suggests extended and continuous infusions of beta-lactam antibiotics are well tolerated in children and improve achievement of pharmacokineticpharmacodynamic targets with similar or superior clinical outcomes, particularly in infections associated with high MICs.
... Three prospective RCT assessed β-lactams dosing, comparing continuous infusion with intermittent conventional dosing [47,208,209]. In all three RCT, patients receiving RRT were excluded. ...
... In all three RCT, patients receiving RRT were excluded. The first RCT [208] included 140 patients and found a better clinical cure rate in patients receiving continuous infusion β-lactams (56 versus 34 %, p = 0.011), along with higher rates of the intended target (100% free T > MIC) attainment on day 1 (97 versus 70 %, p < 0.001). Nevertheless, there were no differences in 14 or 30-day mortality. ...
Article
Full-text available
A fundamental step in the successful management of sepsis and septic shock is early empiric antimicrobial therapy. However, for this to be effective, several decisions must be addressed simultaneously: (1) antimicrobial choices should be adequate, covering the most probable pathogens; (2) they should be administered in the appropriate dose, (3) by the correct route, and (4) using the correct mode of administration to achieve successful concentration at the infection site. In critically ill patients, antimicrobial dosing is a common challenge and a frequent source of errors, since these patients present deranged pharmacokinetics, namely increased volume of distribution and altered drug clearance, which either increased or decreased. Moreover, the clinical condition of these patients changes markedly over time, either improving or deteriorating. The consequent impact on drug pharmacokinetics further complicates the selection of correct drug schedules and dosing during the course of therapy. In recent years, the knowledge of pharmacokinetics and pharmacodynamics, drug dosing, therapeutic drug monitoring, and antimicrobial resistance in the critically ill patients has greatly improved, fostering strategies to optimize therapeutic efficacy and to reduce toxicity and adverse events. Nonetheless, delivering adequate and appropriate antimicrobial therapy is still a challenge, since pathogen resistance continues to rise, and new therapeutic agents remain scarce. We aim to review the available literature to assess the challenges, impact, and tools to optimize individualization of antimicrobial dosing to maximize exposure and effectiveness in critically ill patients.
... Previous investigations already suggested lower mortality rates and better clinical outcome using extended infusions in adults [23][24][25][34][35][36] and pediatric patients [37]. These effects are attributed to improved PK target attainment during extended infusions [36,[38][39][40]. Critical patients included in the study of Roberts [22] and Abdul-Aziz et al. [23] had median SOFA scores of only 6 (IQR 3-9) and had varying sites of infection. ...
... While PCT is routinely used in abdominal infections its role in guiding therapy is still unclear [47].In what way the gut-lung axis and its role in immunomodulation contributes remains to be investigated [48]. Unlike previous prospective studies [38,39], we included patients on RRT or/and hepatic dysfunction. RRT may have unpredictable effects on serum concentrations of hydrophilic β-lactams and PK target attainment, according to recently published work [36,49]. ...
Article
Full-text available
Septic shock substantially alters the pharmacokinetic properties of β-lactams with a subsequently high risk of insufficiently low serum concentrations and treatment failure. Considering their pharmacokinetic (PK)/pharmacodynamic (PD) index, prolonged infusions (PI) of β-lactams extend the time that the unbound fraction of the drug remains above the minimal inhibitory concentration MIC (ft >MIC) and may improve patient survival. The present study is a monocentric, retrospective before-and-after analysis of septic shock patients treated with β-lactams. Patients of the years 2015-2017 received intermittent bolus application whereas patients of 2017–2020 received PI of β-lactams. The primary outcome was mortality at day 30 and 90 after diagnosis of septic shock. Mortality rates in the PI group were significantly lower on day 30 (PI: 41%, n = 119/290 vs. IB: 54.8%, n = 68/114; p = 0.0097) and day 90 (PI: 47.9%, n = 139/290 vs. IB: 62.9%, n = 78/124; p = 0.005). After propensity-score matching, 30- and 90-day mortality remained lower for the PI group (−10%, p = 0.14). PI was further associated with a reduction in the duration of invasive ventilation and a stronger decrease in SOFA scores within a 14d-observation period. PI of β-lactams was associated with a significant reduction of mortality in patients with septic shock and may have beneficial effects on invasive ventilation and recovery from sepsis-related organ failure.
... Having a perfectly designed randomized controlled study to conclude on CI superiority is complicated as it requires large cohort sizes to reach proper statistical power and the correct clinical outcomes. Although such studies have already been realized in the past, such as the BLING II [71] and BLISS [72] studies, both studies had a different conclusion. Indeed, the BLING II study did not find any difference between CI and intermittent administration [71], whereas the BLISS study reported that CI was beneficial only to a specific kind of patient in the ICU, notably the most severe cases of septic patients who did not receive RRT [72]. ...
... Although such studies have already been realized in the past, such as the BLING II [71] and BLISS [72] studies, both studies had a different conclusion. Indeed, the BLING II study did not find any difference between CI and intermittent administration [71], whereas the BLISS study reported that CI was beneficial only to a specific kind of patient in the ICU, notably the most severe cases of septic patients who did not receive RRT [72]. This could indicate that CI would help only a certain type of patient admitted to the ICU. ...
Article
Piperacillin-tazobactam is a potent β-lactam/β-lactamase inhibitor antibiotic commonly prescribed in the intensive care unit setting. Admitted patients often show large variability in treatment response due to multiple pathophysiological changes present in this population that alter the drug’s pharmacokinetics. This review summarizes the population pharmacokinetic models developed for piperacillin-tazobactam and provides comprehensive data on current dosing strategies while identifying significant covariates in critically ill patients. A literature search on the PubMed database was conducted, from its inception to July 2020. Relevant articles were retained if they met the defined inclusion/exclusion criteria. A total of ten studies, published between 2009 and 2020, were eligible. One- and two-compartment models were used in two and eight studies, respectively. The lowest estimated piperacillin clearance value was 3.12 L/h, and the highest value was 19.9 L/h. The estimations for volume of distribution varied between 11.2 and 41.2 L. Tazobactam clearance values ranged between 5.1 and 6.78 L/h, and tazobactam volume of distribution values ranged between 17.5 and 76.1 L. The most frequent covariates were creatinine clearance and body weight, each present in four studies. Almost all studies used an exponential approach for the interindividual variability. The highest variability was observed in piperacillin central volume of distribution, at a value of 75.0%. Simulations showed that continuous or extended infusion methods performed better than intermittent administration to achieve appropriate pharmacodynamic targets. This review synthesizes important pharmacokinetic elements for piperacillin-tazobactam in an intensive care unit setting. This will help clinicians better understand changes in the drug’s pharmacokinetic parameters in this specific population.
... In 2014, the landmark 'Defining antibiotic levels in intensive care unit patients' (DALI) trial demonstrated that serum concentration goals were reached more often when continuous application was performed [8]. Two years later, the 'Betalactam infusion in severe sepsis' (BLISS) study showed a survival benefit when piperacillin and meropenem were applied continuously in patients with septic shock [9]. Insights gained from recent meta-analyses confirmed positive effects of continuous application of these antibiotics, although a mortality benefit was not consistently seen [10,11]. ...
... As antibiotics constitute the decisive causal treatment in severe infections, several large studies were performed to assess the effects of a continuous infusion of betalactams. Two randomized trials [8,9] elucidated that continuous infusion of meropenem and piperacillin were more likely to reach serum concentration goals in critically ill patients than intermittent infusion, and showed that continuous application was associated with a better clinical outcome [25]. Many of these studies recommended a high beta-lactam exposure well ...
Article
Full-text available
Background Effective antimicrobial treatment is key to reduce mortality associated with bacterial sepsis in patients on intensive care units (ICUs). Dose adjustments are often necessary to account for pathophysiological changes or renal replacement therapy. Extracorporeal membrane oxygenation (ECMO) is increasingly being used for the treatment of respiratory and/or cardiac failure. However, it remains unclear whether dose adjustments are necessary to avoid subtherapeutic drug levels in septic patients on ECMO support. Here, we aimed to evaluate and comparatively assess serum concentrations of continuously applied antibiotics in intensive care patients being treated with and without ECMO. Methods Between October 2018 and December 2019, we prospectively enrolled patients on a pneumological ICU in southwest Germany who received antibiotic treatment with piperacillin/tazobactam, ceftazidime, meropenem, or linezolid. All antibiotics were applied using continuous infusion, and therapeutic drug monitoring of serum concentrations (expressed as mg/L) was carried out using high-performance liquid chromatography. Target concentrations were defined as fourfold above the minimal inhibitory concentration (MIC) of susceptible bacterial isolates, according to EUCAST breakpoints. Results The final cohort comprised 105 ICU patients, of whom 30 were treated with ECMO. ECMO patients were significantly younger (mean age: 47.7 vs. 61.2 years; p < 0.001), required renal replacement therapy more frequently (53.3% vs. 32.0%; p = 0.048) and had an elevated ICU mortality (60.0% vs. 22.7%; p < 0.001). Data on antibiotic serum concentrations derived from 112 measurements among ECMO and 186 measurements from non-ECMO patients showed significantly lower median serum concentrations for piperacillin (32.3 vs. 52.9; p = 0.029) and standard-dose meropenem (15.0 vs. 17.8; p = 0.020) in the ECMO group. We found high rates of insufficient antibiotic serum concentrations below the pre-specified MIC target among ECMO patients (piperacillin: 48% vs. 13% in non-ECMO; linezolid: 35% vs. 15% in non-ECMO), whereas no such difference was observed for ceftazidime and meropenem. Conclusions ECMO treatment was associated with significantly reduced serum concentrations of specific antibiotics. Future studies are needed to assess the pharmacokinetic characteristics of antibiotics in ICU patients on ECMO support.
... Previous investigations already suggested lower mortality rates and better clinical outcome using extended infusions in adults [23][24][25][34][35][36] and pediatric patients [37]. These effects are attributed to improved PK target attainment during extended infusions [36,[38][39][40]. Critical patients included in the study of Roberts [22] and Abdul-Aziz et al. [23] had median SOFA scores of only 6 (IQR 3-9) and had varying sites of infection. ...
... In what way the gut-lung axis and its role in immunomodulation contributes remains to be investigated [47]. Unlike previous prospective studies [38,39], we included patients on RRT or/and hepatic dysfunction. RRT may have unpredictable effects on serum concentrations of hydrophilic ß-lactams and PK target attainment, according to recently published work [36,48]. ...
Preprint
Septic shock substantially alters the pharmacokinetic properties of ß-lactams with a subsequently high risk of insufficiently low serum concentrations and treatment failure. Considering their pharmacokinetic (PK)/pharmacodynamic (PD) index, prolonged infusions (PI) of ß-lactams extend the time that the unbound fraction of the drug remains above the minimal inhibitory concentration MIC (ft >MIC) and may improve patient survival. The present study is a monocentric, retrospective before-and-after analysis of septic shock patients treated with ß-lactams. Patients of the years 2015-2017 received intermittent bolus application whereas patients of 2017-2020 received PI of ß-lactams. The primary outcome was mortality at day 30 and 90 after diagnosis of septic shock. Mortality rates in the PI group were significantly lower on day 30 (PI: 41%, n=119/290 vs. IB: 54.8%, n=68/114; p=0.0097) and day 90 (PI: 47.9%, n=139/290 vs. IB: 62.9%, n=78/124; p=0.005). After propensity-score matching, 30- and 90-day mortality remained lower for the PI group (-10%). PI further reduced duration of invasive ventilation. PI of β-lactam antibiotics led to a stronger decrease in SOFA scores within a 14d-observation period. PI of ß-lactams significantly reduces mortality in patients with septic shock and may have beneficial effects on invasive ventilation and recovery from sepsis-related organ failure.
... [3,6] Pathophysiological changes in volume of distribution, drug clearance, and proteinbinding can be significantly different in critically ill patients compared to what is observed in other patient groups. [3,[7][8][9][10][11][12][13] In COVID-19 patients with sepsis-related multiple organ dysfunction and/or a strong cytokine storm, pathophysiological changes remains poorly defined. It has been suggested, that organotropism might aggravate preexisting conditions. ...
Article
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Pathophysiological changes are important risk factors for critically ill patients with pneumonia manifesting sub-therapeutic antibiotic exposures during empirical treatment. The effect of coronavirus disease 2019 (COVID-19) on antibiotic dosing requirements is uncertain. We aimed to determine the effect of COVID-19 on ß-lactam pharmacokinetics (PK) and PK target attainment in critically ill patients with a personalized dosing strategy.Retrospective, single-center analysis of COVID-19 ± critically ill patients with pneumonia (community-acquired pneumonia or hospital-acquired pneumonia) who received continuous infusion of a ß-lactam antibiotic with dosing personalized through dosing software and therapeutic drug monitoring. A therapeutic exposure was defined as serum concentration between (css) 4 to 8 times the EUCAST non-species related breakpoint).Data from 58 patients with pneumonia was analyzed. Nineteen patients were tested COVID-19-positive before the start of the antibiotic therapy for community-acquired pneumonia or hospital-acquired pneumonia. Therapeutic exposure was achieved in 71% of COVID-19 patients (68% considering all patients). All patients demonstrated css above the non-species-related breakpoint. Twenty percent exceeded css above the target range (24% of all patients). The median ß-lactam clearance was 49% compared to ß-lactam clearance in a standard patient without a significant difference regarding antibiotic, time of sampling or present COVID-19 infection. Median daily doses were 50% lower compared to standard bolus dosing.COVID-19 did not significantly affect ß-lactam pharmacokinetics in critically ill patients. Personalized ß-lactam dosing strategies were safe in critically ill patients and lead to high PK target attainment with less resources.
... A chief contributor to inter-and intraindividual β-lactam-level variability in the ICU is limitation of the existing approach to kidney function assessment (20,23). Existing models use serum creatinine to estimate kidney function and to determine clearance of FEP, MEM, and TZP (24)(25)(26). Creatinine is an insensitive and nonspecific marker of kidney function in the ICU given the many nonrenal factors that alter its production and elimination (27). As the terminal byproduct of skeletal muscle catabolism, creatinine is affected by deconditioning, altered muscle mass, and dietary changes that are incompletely accounted for in creatinine clearance equations and common in the ICU. ...
Article
Background The class of antibiotics known as β-lactams are a commonly used due to their effectiveness and safety. Therapeutic drug monitoring has been proposed but requires an accurate assay along with well-characterized preanalytic stability, as β-lactams are known to be relatively unstable. Methods A high-throughput LC-MS/MS assay validation and stability study was performed for cefepime, meropenem, and piperacillin and tazobactam in serum. Patient samples, standards, and QCs were crashed with acetonitrile containing internal standard. Following centrifugation, an aliquot of the supernatant was diluted with clinical laboratory reagent water and analyzed by LC-MS/MS. Results The assay showed linearity between 0.5 and 60 µg/mL for each analyte. The intra- and interassay reproducibility at 3 different concentrations (approximately 2, 25, and 40 µg/mL) was <5% for each analyte. Accuracy studies for each analyte were compared using linear regression and demonstrated: slope = 1.0 ± 0.1; r2 ≥ 0.980; and y intercept 95% CI that included zero. Minimal ion suppression or enhancement was observed, and no significant carryover was observed up to 500 µg/mL of each analyte. Stability studies demonstrated significant loss in serum for each analyte at ambient and refrigerated temperatures (2–8 °C) and at −20 °C over days or weeks. In contrast, when stored at −80 °C, no significant loss was observed. Conclusions The LC-MS/MS assay showed acceptable performance characteristics for quantitation of β-lactams. With well-characterized stability, this assay can be used with residual specimens for pharmacokinetic modeling, which may lead to individualized dosing and improved patient care.
... Population PK models can be used to simulate multiple dosing regimens and to predict the probability of target attainment in different populations. As an example, PK/PD principles have been applied to defend the use of extended and continuous infusion rather than short infusions of beta-lactams in septic or critically ill patients [9,[112][113][114][115][116][117]. Beta-lactams exhibit a time-dependent antibacterial activity and therefore extending the duration of perfusion increases the probability to attain the PK/PD target. ...
Article
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Pharmacokinetic/pharmacodynamic (PK/PD) analysis has proved to be very useful to establish rational dosage regimens of antimicrobial agents in human and veterinary medicine. Actually, PK/PD studies are included in the European Medicines Agency (EMA) guidelines for the evaluation of medicinal products. The PK/PD approach implies the use of in vitro, ex vivo, and in vivo models, as well as mathematical models to describe the relationship between the kinetics and the dynamic to determine the optimal dosing regimens of antimicrobials, but also to establish susceptibility breakpoints, and prevention of resistance. The final goal is to optimize therapy in order to maximize efficacy and minimize side effects and emergence of resistance. In this review, we revise the PK/PD principles and the models to investigate the relationship between the PK and the PD of antibiotics. Additionally, we highlight the outstanding role of the PK/PD analysis at different levels, from the development and evaluation of new antibiotics to the optimization of the dosage regimens of currently available drugs, both for human and animal use.
... [24,25] Improved clinical outcomes may be seen in critically ill patients utilizing prolonged-infusion, but it is unknown whether this technique is beneficial for all patients. [26,27] Both institutions utilized prolonged infusion in Limitations of this study include the retrospective study design. Specifically, the determination of primary treatment failure relied on documentation in electronic health records. ...
Article
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Background Altered pharmacokinetics in obese patients raise concerns over worse clinical outcomes. This study assessed whether obese patients receiving a beta-lactam (BL) have worse clinical outcomes compared to non-obese patients and to identify if therapeutic drug monitoring (TDM) may be beneficial. Methods This multi-center, retrospective cohort included hospitalized adults admitted from July 2015-July 2017 treated with a BL as definitive monotherapy against a Gram-negative bacilli for ≥72 hours. Patients were excluded if there was lack of source control or if polymicrobial infections required >1 antibiotic for definitive therapy. Patients were classified based on body mass index (BMI): non-obese (BMI ≤29.9 kg/m 2) and obese (BMI ≥30.0 kg/m 2). The primary outcome was clinical treatment failure, and secondary were hospital length of stay (LOS), inpatient all-cause mortality, and 30-day all-cause readmission. Results There were 257 (43.6%) obese patients and 332 (56.4%) non-obese patients included. The most common infections were urinary (50.9%) and respiratory (31.4%). Definitive treatment was driven by 3 rd generation cephalosporins (46.9%) and cefepime (44.7%). Treatment failure occurred in 131 (51%) obese patients and 109 (32.8%) non-obese patients (p<0.001). Obesity and respiratory source were independently associated with increased likelihood of treatment failure. Obese patients were hospitalized longer than non-obese patients (p=0.002), but no differences were found for all-cause mortality (p=0.117) or infection-related readmission (0=0.112). Conclusions Obese patients treated with BLs have higher rates of treatment failure and longer hospitalization periods than non-obese patients. Future studies are needed to assess the impact of TDM and specific dosing recommendations for targeted infection types.
... Due to the variable MIC of Pseudomonas aeruginosa, we chose the theoretical EUCAST cut-off of 2 mg/L as the targeted value [17,21]. Taking into account a cefiderocol proteinbinding of 50% a total C min of 4 mg/L (equals a free fraction of approx. 2 mg/L) would be adequate to maintain a PK/PD target of 100% f T > MIC. ...
Article
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Cefiderocol is a new siderophore-cephalosporin for the treatment of multi-drug resistant Gram-negative pathogens. As a reserve agent, it will and should be used primarily in critically ill patients in the upcoming years. Due to the novelty of the substance little data on the pharmacokinetics in critically ill patients with septic shock and renal failure (including continuous renal replacement therapy and cytokine adsorber therapy) is available. We performed therapeutic drug monitoring in a cohort of five patients treated with cefiderocol, to improve the knowledge on pharmacokinetics in this vulnerable patient population. As expected for a cephalosporin with predominantly renal elimination the maintenance dose could be reduced in patients with renal impairment or on continuous renal replacement therapy. The manufacturer’s dosing instructions were sufficient to achieve a drug level well above the MIC. However, the addition of a cytokine adsorber might reduce serum levels substantially, so that in this context therapeutic drug monitoring and dose adjustment are recommended.
... We hypothesize that one important factor is not only to treat the underlying infection with correct antibiotic/s but to be aggressive and proactive in this strategy using continuous intravenous infusions of beta-lactam/ carbapenem antibiotics with monitoring of targeted plasma concentrations and repeated frequent culturing during ECMO support. 33,34 Other contributing factors are active management of fluid balance/withdrawal using CRRT, plasmapheresis in the patients that cannot be substantially weaned from vasoactive support in the first day of ECMO, and awake ECMO. Start of extracorporeal support may provide secondary changes in milieu interieur when tissue perfusion is restored, leading to tissue lactate, pH, and other metabolic factors to subsequently recover, which may be the major cause of benefit of ECMO in distributive septic shock. ...
Article
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Extracorporeal membrane oxygenation (ECMO) is a rescue treatment used in children and adults with reversible cardiorespiratory failure. The role of ECMO is not fully established in pediatric sepsis. In this retrospective single-center study, we aimed to investigate risk factors and survival in pediatric septic shock supported with peripheral cannulation ECMO. All patients aged 30 days to 18 years treated between 2007 and 2016 with ECMO for septic shock were included. Of 158 screened patients, 31 were enrolled in the study. The P/F ratio was 48 ± 22 mm Hg, b-lactate 8.5 ± 6.6 mmol/L, p-procalcitonin 214 (IQR 19-294) μg/L, and 2 (1-2) vasoactive drugs were infused. The number of organ failures were 3 (3-4). Ten patients were commenced on venovenous and 21 on venoarterial ECMO. Survival from ECMO was 71%, and 68% survived to hospital discharge. Hospital survival was 80% for venovenous ECMO and 62% in venoarterial support (p = 0.43). Factors associated with in-hospital mortality were high b-lactate (p = 0.015) and high creatinine (p = 0.019) at admission. Conversion between modalities was not a risk factor. Sixty percent were alive at long-term follow-up (median 6.5 years). Peripheral cannulation ECMO is feasible in pediatric septic shock. Treatment should be performed at high-volume ECMO centers experienced in sepsis, and central or peripheral type and ECMO modality according to center preference and patient's need.
... 21,22 Despite the challenges of gold-standard trial design for TDM, we applaud that investigators are rising to the challenge of conducting such trials and establishing high levels of evidence, and more high-level evidence will be available soon. 23 Until that time, the best available evidence from b-lactam pre-clinical studies, retrospective reviews and clinical trials [24][25][26][27][28] suggests that precision dosing and optimizing PK/PD benefits some patients. [29][30][31] For vancomycin, clear relationships have been found between exposure, toxicity 17,32 and optimal monitoring strategies 33 in prospective studies. ...
Article
The need for precision dosing has been challenged on the basis of insufficient evidence. Herein, we argue that adequate evidence exists to conduct therapeutic drug monitoring (TDM) and precisely target antibiotic exposures. While achievement of any antibiotic concentration does not guarantee efficacy sans toxicity for any single patient, stochastic control optimizes the probability of achieving favourable responses across patients. We argue that variability in targets (such as the organism’s MIC) can be considered with models. That is, complexity alone does not relegate the decision-making framework to ‘clinician intuition’. We acknowledge the exposure–response relationships are modified by patient-specific factors (other drugs, baseline organ functional status etc.) and describe how precision dosing can inform clinical decision making rather than protocolize it. Finally, we call for randomized, controlled trials; however, we suggest that these trials are not necessary to make TDM standard of care for multiple classes of antibiotics.
... 9,10 Hence, to optimize probability of target attainment (PTA), frequent dosing with prolonged infusions or continuous infusions have been recommended for severely ill patients undergoing β-lactam treatment. [11][12][13] For ceftaroline fosamil, standard doses are given every 8 or 12 hours, with product labeling originally specifying a 1-hour infusion duration. Population PK modeling and Monte Carlo simulations based on patient PK data from the adult and pediatric ceftaroline fosamil clinical development programs have shown that standard ceftaroline fosamil doses administered by 1hour infusion are expected to achieve >90% PTA in adults and pediatric patients aged ≥2 months against target pathogens including S. aureus and S. pneumoniae based on pathogen-specific f T>MIC targets. ...
Article
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The key pharmacokinetic/pharmacodynamic (PK/PD) efficacy index for β-lactam antibiotics is the percentage of time that free drug concentrations exceed the minimum inhibitory concentration (MIC) of bacteria during each dosing interval (fT>MIC). Ceftaroline fosamil, the prodrug of the β-lactam ceftaroline, was initially approved for administration as 60-minute intravenous (IV) infusions. Population PK analyses comparing exposure and PK/PD target attainment for 5-minute and 60-minute IV infusions, described here, have supported ceftaroline fosamil labeling updates to include variable infusion durations of 5 to 60 minutes in adults and children aged ≥2 months. A 2-compartment disposition PK model for ceftaroline fosamil and ceftaroline was used to predict steady-state ceftaroline exposures (maximum plasma concentrations [Cmax,ss ] and area under the plasma concentration-time curve over 24 hours [AUCss,0-24 ]) and probability of target attainment in simulated adult and pediatric patients with various degrees of renal function receiving standard doses of ceftaroline fosamil as 5-minute or 60-minute IV infusions. Across age groups and renal function categories, median ceftaroline AUCss,0-24 values were similar for 5-minute and 60-minute infusions, whereas Cmax,ss was up to 42% higher for 5-minute infusions. Both infusion durations achieved >99% probability of target attainment based on PK/PD targets for Staphylococcus aureus (35% fT>MIC) and Streptococcus pneumoniae (44% fT>MIC) at European Committee on Antimicrobial Susceptibility Testing/Clinical and Laboratory Standards Institute MIC breakpoints (1 mg/L and 0.25/0.5 mg/L, respectively). These findings support administration of standard ceftaroline fosamil doses over 5 to 60 minutes for adults and children aged ≥2 months, providing added flexibility to clinicians and patients.
... The administration of piperacillin by extended infusion, over half the dosing interval (i.e., infused over 4 h, administered q8 h), or after an initial loading dose helped overcome subtherapeutic piperacillin drug exposures in all the simulated scenarios. This has previ-Antibiotics 2021, 10, 348 7 of 12 ously been shown in observational studies as well as randomized controlled trials (RCT) and also correlates with the higher rates of clinical cure in the RCTs [23][24][25]. In our model, we observed a slight benefit with the administration of a loading dose, especially against a piperacillin MIC of 32 mg/L (considered as resistant). ...
Article
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This study analyzes the pharmacokinetic variability of piperacillin in non-critically ill patients with Enterobacteriaceae bloodstream infections (EBSI) and explores predicted clinical outcomes and piperacillin-related neurotoxicity under different renal conditions. Hospitalized, non-critically ill patients treated with piperacillin–tazobactam for EBSI were included. Four serum samples per patient were collected and analyzed. A population pharmacokinetic model was developed using the Pmetrics package for R. Monte Carlo simulations of various dosage regimens of 4 g piperacillin, administered q8 h or q12 h by short (0.5 h) or long (4 h) infusion, following the different glomerular filtration rate (GFR) categories used to classify chronic kidney disease (Kidney Disease: Improving Global Outcomes, KDIGO) to determine the probability of target attainment (PTA) using a free drug concentrations above the minimal inhibitory concentration (fT > MIC) of 50% for efficacy and targets for piperacillin-associated neurotoxicity. Twenty-seven patients (102 samples) were included. Extended piperacillin infusions reached a PTA > 90% (50%fT > MIC) within the susceptibility range, although a loading dose did not greatly improve the expected outcome. Long infusions reduced the expected toxicity in patients with severe renal impairment. The study supports the use of extended infusions of piperacillin in non-critically ill patients with EBSI. No benefits of a loading dose were expected in our population. Finally, extended infusions may reduce the risk of toxicity in patients with severe renal impairment.
... To prevent resistance, a trough-to-MIC ratio of .3.8 was needed (23). Higher targets (i.e., 100% fT .MIC and fT .4ÂMIC ) might be desirable in the clinical setting (24)(25)(26). The differences in favorable targets between the preclinical and clinical studies might be due to the fact that suggested preclinical targets are assumed to be at the site of infection, whereas clinically, plasma concentrations are usually measured, which may not correlate with the concentration at the site of infection. ...
Article
Sepsis causes half of acute kidney injuries in the intensive care unit (ICU). ICU patients may need continuous renal replacement therapy (CRRT) which will affect their antimicrobial exposure. We aim to build a cefepime population pharmacokinetic (PK) model in CRRT ICU patients and perform simulations to assess target attainment. Patients who were ≥18 years old, admitted to the ICU, and received cefepime 2 g every 8 hours as 4-hour infusion while on CRRT were enrolled prospectively. Samples were collected from the predialyzer, postdialyzer ports, and effluent fluid at times 1, 2, 3, 4, and 8 hours after the first dose and at steady state. Age, sex, weight, urine output, and CRRT parameters were recorded. Pmetrics was used for population PK and simulations. The target exposure was 100% f T >MIC . Ten patients were included and their mean age was 53 years and weight 119 kg. Seventy percent were males. Cefepime was described by a five-compartment model. The downtime was applied to the CRRT flow rates which were used to describe the rates of transfer between the compartments. At MIC of ≤8 mg/L, cefepime 2g intermittent infusion every 8 hours achieved good target attainment both early in therapy and at steady state. Only extended and continuous infusion regimens achieved good target attainment at MIC 16 mg/L. In conclusion, cefepime 2g infused over 30 minutes followed by 2g extended infusion every 8 hours achieved good target attainment at MIC ≤16 mg/L with different CRRT flow rates and may be considered in resistant bacterial infections.
... 4-7 PTZ, unlike VNC, has a low toxicity profile and does not require TDM for safety reasons, but it may be of use to achieve improved therapeutic outcomes in critically ill patients. 4,5,8,9 Several recent retrospective studies have suggested that the combination of VNC-PTZ increases the risk of acute kidney injury (AKI) compared to PTZ or VNC treatment alone, with reported rates ranging between 11.8-49.0%, compared to 1.7% and 5.0-8.1% respectively. ...
Article
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Aim: To evaluate the risk of acute kidney injury (AKI) in patients who receive vancomycin (VNC) and piperacillin-tazobactam (PTZ) combination therapy. Method: A single centre, retrospective audit of adult patients treated with VNC alone and in combination with PTZ between 2014-2015. Data was extracted from digital medical records and therapeutic drug monitoring sheets completed by clinical pharmacists. Rates of AKI and duration of combination therapy were analysed by chi-square, with logistic regression analysis completed to control for nephrotoxins, intensive care unit admission, use of inotropes and pre-existing chronic kidney disease. Results: Out of 525 vancomycin courses, that met the inclusion criteria, 211 had PTZ co-prescribed during the study period. Combination therapy was significantly both associated with an increased rate of AKI compared to VNC use alone (17.5% vs 10.5%, P = 0.02). The mean duration of combination therapy was 4 days (1-17 days). Increased duration of exposure to combination therapy was also associated with a higher incidence of AKI (3.8 days vs. 5.2 days, P = 0.014). VNC-TPZ combination was identified to be an independent risk factor for AKI (OR 1.73, 95% CI 1.01-2.96, P = 0.046) after adjusting for other known risk factors for AKI, including vasopressor use and intensive care unit admission. Conclusion: Combined use of VNC-PTZ, as well as the duration of combination therapy are both associated with an increased risk of AKI compared with VNC alone. The results are similar to previous literature reports of AKI from the combination of antibiotics. Healthcare providers need to be vigilant and limit the exposure to this combination as clinically appropriate.
... Unfortunately, the remarkable prevalence of nonsusceptible isolates with high MIC in critical care setting [53], the inaccuracy in MIC determination with automated test [101], and the concomitant existence of PK alterations (i.e. ARC, higher CRRT intensity) may render the achievement of aggressive PK/PD target unpredictable in renal critically ill patients, even when the best altered dosing strategies (namely higher dose and prolonged infusion) have been implemented [100,102]. ...
Article
Introduction: : Several novel beta-lactams (BLs) and/or beta lactams/beta-lactamase inhibitors (BL/BLIs) have been recently developed for the management of multidrug-resistant bacterial infections. Data concerning dose optimization in critically ill patients with altered renal function are scanty. Areas covered: : This article provides a critical reappraisal of pharmacokinetic and clinical issues emerged with novel BLs and/or BL/BLIs in renal critically ill patients. Clinical and pharmacokinetic studies published in English until December 2020 were searched on PubMed-MEDLINE database. Expert opinion: : Several issues emerged with the use of novel BLs and/or BL/BLIs in critically ill renal patients. Suboptimal clinical response rate with ceftazidime-avibactam and ceftolozane-tazobactam was reported in phase II-III trials in patients with moderate kidney injury; data on patients undergoing renal replacement therapy are limited to some case reports; dose adjustment in augmented renal clearance is provided only for cefiderocol. Implementation of altered dosing strategies (prolonged infusion and/or higher dosage) coupled with adaptive real-time therapeutic drug monitoring could represent the most effective approach in warranting optimal pharmacokinetic/pharmacodynamic targets with novel BLs and/or BL/BLIs in challenging scenarios, thus minimizing the risk of clinical failure and/or of resistance selection.
... Previous studies in animal found that for antimicrobial killing effect of β-lactams, the target of 100% T >MIC was unnecessary (Vogelman et al., 1988;Craig, 1995) and bactericidal killing activities of carbapenems were found at the target of 40% T >MIC (Drusano, 2003). Moreover, several clinical studies showed that an extended infusion of β-lactam antibiotics for the treatment of patients with severe infections had lower mortality (Lodise et al., 2007;Shabaan et al., 2017;Vardakas et al., 2018;Yu et al., 2018) and higher rates of clinical improvement (Abdul-Aziz et al., 2016;Shabaan et al., 2017;Yu et al., 2018) and microbiologic eradication (Shabaan et al., 2017) than short-term infusion. Our MCS analysis found that the achievement of the PTAs by the extended infusion of ertapenem were higher compared to the short infusion, findings which were similar to previous studies with other β-lactam antibiotics (Masich et al., 2018;Thabit et al., 2019). ...
... Additionally, such antibiotics often fail in the treatment of biofilm-type infections (8). These scenarios strongly invite the use of phage therapy as alternative or to complement existing cell wall-targeting antibiotics (9), which are the foundation of modern infection therapy (~70% of all prescriptions), including sepsis management (10). ...
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The bacterial L-form is induced by exposure to cell wall targeting antibiotics or innate immune effectors such as lysozyme and is likely to be important in many human infections. Here, we demonstrate that the osmotically fragile L-form is a distinct physiological state in Escherichia coli that is highly tolerant of oxidative stress and resistant to powerful antibiotics and common therapeutic bacteriophages. L-forms quickly revert (<20h) to their cell-walled state after antibiotic withdrawal, with apparently normal physiology and with few or no changes in DNA sequence. T4-like phages that are obligately lytic in cell-walled E. coli preferentially pseudolysogenise their L-forms providing them with transient superinfection immunity. Our data indicate that L-form switching is a common response of pathogenic E. coli strains to cell wall-targeting antibiotics and that the most commonly used lytic bacteriophages are ineffective against them in this state.
... The administration of a loading dose before the initiation of continuous infusion is generally accepted and recommended for beta-lactams 6 . In the majority of studies investigating continuous infusion loading doses were administered, including the large multicenter studies BLISS and BLING II 6,13,14 . This practice is supported by a significant mortality reduction when loading doses are administered compared to no loading doses according to a large meta-analysis by Vardakas et al. 15 . ...
Article
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The aim of this study was to investigate optimal loading doses prior to continuous infusion of meropenem in critically ill patients. A previously published and successfully evaluated pharmacokinetic model of critically ill patients was used for stochastic simulations of virtual patients. Maintenance doses administered as continuous infusion of 1.5–6 g/24 h with preceding loading doses (administered as 30 min infusion) of 0.15–2 g were investigated. In addition to the examination of the influence of individual covariates, a best-case and worst-case scenario were simulated. Dosing regimens were considered adequate if the 5th percentile of the concentration–time profile did not drop at any time below four times the S/I breakpoint (= 2 mg/L) of Pseudomonas aeruginosa according to the EUCAST definition. Low albumin concentrations, high body weight and high creatinine clearances increased the required loading dose. A maximum loading dose of 0.33 g resulted in sufficient plasma concentrations when only one covariate showed extreme values. If all three covariates showed extreme values (= worst-case scenario), a loading dose of 0.5 g was necessary. Higher loading doses did not lead to further improvements of target attainment. We recommend the administration of a loading dose of 0.5 g meropenem over 30 min immediately followed by continuous infusion.
... The results of a systematic review showed that there were 13 RCTs which compared intermittent administration of b-lactams to either its continuous administration or the extension of its administration times among patients with sepsis or septic shock, and a meta-analysis of these RCTs was performed. [175][176][177][178][179][180][181][182][183][184][185][186][187] The estimated value of the effects on mortality (10 RCTs, n = 844) yielded a RD of 69 fewer per 1,000 (95%CI: 135 fewer to 32 more), and the estimated value of the effects on clinical cures (9 RCTs, n = 886) yielded an RD of 113 more per 1,000 (95%CI: 9 more to 241 more). The estimated value of the effects on the incidence of adverse effects (3 RCTs, n = 691) yielded an RD of 0 per 1,000 (95%CI: 41 fewer to 59 more), and no increases in the incidence of adverse effects were found. ...
Article
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The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2020 (J-SSCG 2020), a Japanese-specific set of clinical practice guidelines for sepsis and septic shock created as revised from J-SSCG 2016 jointly by the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine, was first released in September 2020 and published in February 2021. An English-language version of these guidelines was created based on the contents of the original Japanese-language version. The purpose of this guideline is to assist medical staff in making appropriate decisions to improve the prognosis of patients undergoing treatment for sepsis and septic shock. We aimed to provide high-quality guidelines that are easy to use and understand for specialists, general clinicians, and multidisciplinary medical professionals. J-SSCG 2016 took up new subjects that were not present in SSCG 2016 (e.g., ICU-acquired weakness [ICU-AW], post-intensive care syndrome [PICS], and body temperature management). The J-SSCG 2020 covered a total of 22 areas with four additional new areas (patient- and family-centered care, sepsis treatment system, neuro-intensive treatment, and stress ulcers). A total of 118 important clinical issues (clinical questions, CQs) were extracted regardless of the presence or absence of evidence. These CQs also include those that have been given particular focus within Japan. This is a large-scale guideline covering multiple fields; thus, in addition to the 25 committee members, we had the participation and support of a total of 226 members who are professionals (physicians, nurses, physiotherapists, clinical engineers, and pharmacists) and medical workers with a history of sepsis or critical illness. The GRADE method was adopted for making recommendations, and the modified Delphi method was used to determine recommendations by voting from all committee members. As a result, 79 GRADE-based recommendations, 5 Good Practice Statements (GPS), 18 expert consensuses, 27 answers to background questions (BQs), and summaries of definitions and diagnosis of sepsis were created as responses to 118 CQs. We also incorporated visual information for each CQ according to the time course of treatment, and we will also distribute this as an app. The J-SSCG 2020 is expected to be widely used as a useful bedside guideline in the field of sepsis treatment both in Japan and overseas involving multiple disciplines.
... The relative change was not influenced by the dosing regimen (intermittent vs. continuous) in both antibiotics. In general, continuous beta-lactam infusion might be favorable in critically ill patients and is for example recommended by the French Society of Anesthesia and Intensive Care Medicine [16,17,32]. With respect to SLEDD therapy, continuous infusion might be problematic when TDM is not regularly available, as antibiotic levels may be below the target for long periods after the SLEDD interval. ...
Article
Beta-lactam dosing is challenging in critically ill patients with slow extended daily dialysis (SLEDD). This prospective observational study aimed to investigate meropenem and piperacillin concentrations and half-lives during SLEDD and in SLEDD-free intervals. Critically ill patients with SLEDD-therapy and meropenem or piperacillin therapy were included. Breakpoints of target attainment were defined as 2 and 20.8 mg/L for meropenem and piperacillin, respectively. Daily TDM was performed and therapies were adapted based on the measured concentrations. Elimination rate constants were determined by using nonlinear regression analysis. Seventeen patients were included (48 SLEDD intervals; median SLEDD-duration: 7.25 h). The median antibiotic trough concentrations and half-lives were significantly (p < 0.001) lower during and after the SLEDD-therapy compared to SLEDD-free intervals (median meropenem: 22.3 (IQR: 12.8, 25.6) vs. 28.3 mg/L (IQR: 16.9, 37.4); median piperacillin: 55.8 (IQR: 45.1, 84.9) vs. 130 mg/L (IQR: 91.5, 154.5); relative change: −48.0% each, IQR meropenem: −33.3, −58.5%; IQR piperacillin: −36.3, −52.1%). However, none of the measured trough concentrations were subtherapeutic during SLEDD. SLEDD leads to a reduction in meropenem and piperacillin concentrations of approximately 50% independently of the initial concentration. If the concentration is twice as high as the breakpoint of target attainment before SLEDD-therapy, subtherapeutic levels can be avoided.
... For beta-lactam agents, in vitro and clinical studies suggest that maintaining free serum concentrations at least four times as high as the organism's minimum inhibitory concentration (MIC) (fT≥4×MIC) optimizes bactericidal activity and clinical response in critically ill patients compared to less stringent pharmacodynamic targets [11][12][13]. Moreover, clinical outcomes were superior when the PD target maintained free drug concentrations above the 1×MIC (fT≥1×MIC) level for 100% of the dosing interval in critically ill patients [14]. The objective of this post-hoc study was to determine PTA over the first 72 h of commonly prescribed doses of beta-lactams (cefepime, ceftazidime, and piperacillin/tazobactam) and carbapenems (imipenem, meropenem) in different patient weight quartiles using Monte Carlo simulation (MCS) techniques. ...
Article
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(1) Purpose of this study: To determine whether patient weight influences the probability of target attainment (PTA) over 72 h of initial therapy with beta-lactam (cefepime, ceftazidime, piperacillin/tazobactam) and carbapenem (imipenem, ertapenem, meropenem) antibiotics in the critical care setting. This is the first paper to address the question of whether patient size affects antibiotic PTA in the ICU. (2) Methods: We performed a post hoc analysis of Monte Carlo simulations conducted in virtual critically ill patients receiving antibiotics and continuous renal replacement therapy. The PTA was calculated for each antibiotic on the following pharmacodynamic (PD) targets: (a) were above the target organism’s minimum inhibitory concentration (≥%fT≥1×MIC), (b) were above four times the MIC (≥%fT≥4×MIC), and (c) were always above the MIC (≥100%fT≥MIC) for the first 72 h of antibiotic therapy. The PTA was analyzed in patient weight quartiles [Q1 (lightest)-Q4 (heaviest)]. Optimal doses were defined as the lowest dose achieving ≥90% PTA. (3) Results: The PTA for fT≥1×MIC led to similarly high rates regardless of weight quartiles. Yet, patient weight influenced the PTA for higher PD targets (100%fT≥MIC and fT≥4×MIC) with commonly used beta-lactams and carbapenems. Reaching the optimal PTA was more difficult with a PD target of 100%fT≥MIC compared to fT≥4×MIC. (4) Conclusions: The Monte Carlo simulations showed patients in lower weight quartiles tended to achieve higher antibiotic pharmacodynamic target attainment compared to heavier patients.
... Continuous or prolonged (to at least 40-50% of the dosing interval) application of β-lactam antibiotics were reported to cause increased (e.g., 1-4x MIC) and extended (e.g., 100% fT MIC ) blood antimicrobial drug levels compared to intermitted infusion in critically ill patients [20][21][22]. In order to avoid sub-therapeutic antimicrobial levels during a continuous or prolonged dose regime, daily TDM is highly recommended in several guidelines [23,24]. ...
Article
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Therapeutic drug monitoring (TDM) is increasingly relevant for an individualized antibiotic therapy and subsequently a necessary tool to reduce multidrug-resistant pathogens, especially in light of diminishing antimicrobial capabilities. Critical illness is associated with profound pharmacokinetic and pharmacodynamic alterations, which challenge dose finding and the application of particularly hydrophilic drugs such as β-lactam antibiotics. Methods: Implementation strategy, potential benefit, and practicability of the developed standard operating procedures were retrospectively analyzed from January to December 2020. Furthermore, the efficacy of the proposed dosing target of piperacillin in critically ill patients was evaluated. Results: In total, 160 patients received piperacillin/tazobactam therapy and were subsequently included in the study. Of them, 114 patients received piperacillin/tazobactam by continuous infusion and had at least one measurement of piperacillin serum level according to the standard operating procedure. In total, 271 measurements were performed with an average level of 79.0 ± 46.0 mg/L. Seventy-one piperacillin levels exceeded 100 mg/L and six levels were lower than 22.5 mg/L. The high-level and the low-level group differed significantly in infection laboratory parameters (CRP (mg/dL) 20.18 ± 11.71 vs. 5.75 ± 5.33) and renal function [glomerular filtration rate (mL/min/1.75 m2) 40.85 ± 26.74 vs. 120.50 ± 70.48]. Conclusions: Piperacillin levels are unpredictable in critically ill patients. TDM during piperacillin/tazobactam therapy is highly recommended for all patients. Although our implementation strategy was effective, further strategies implemented into the daily clinical workflow might support the health care staff and increase the clinicians’ alertness.
... One possibility is that continuous intravenous infusion (CIV) of CMZ is effectively applied to a greater number of patients with ESBL-EC infections. Abdul-Aziz et al. suggested that maximal β-lactam effects are considered more likely with continuous infusion than with intermittent bolus dosing based on the PK/PD characteristics (28). In addition, CMZ in saline or 5% dextrose solution shows high stability for 24 h (29). ...
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PurposeCefmetazole (CMZ) has received attention as a pharmaceutical intervention for extended-spectrum beta-lactamase-producing Escherichia coli (ESBL-EC) infections. This study aimed to investigate the pharmacokinetics/pharmacodynamics (PK/PD) characteristics of CMZ against ESBL-EC.Methods The susceptibility and time-killing activity of CMZ against clinically isolated ESBL-EC (EC9 and EC19) were determined in vitro. The optimal PK/PD index and its target value were calculated based on the results of a PK study in healthy mice and PD study in neutropenic murine thigh infection model mice.ResultsThe minimum inhibitory concentrations (MICs) of CMZ against EC9 and EC19 were 2.0 and 1.0 µg/mL, respectively. Time–kill studies showed that colony-forming units decreased in a time-dependent manner at CMZ concentrations in the range of 4–64 × MIC. In in vivo PK/PD studies, the antibacterial effect of CMZ showed the better correlation with the time that the free drug concentration remaining above the MIC (fT>MIC), with the target values for a static effect and 1 log10 kill reduction calculated as 57.6% and 69.6%, respectively.ConclusionCMZ possesses time-dependent bactericidal activities against ESBL-EC and is required to achieve “fT>MIC” ≥ 69.6% for the treatment of ESBL-EC infections.
... [4][5][6][7] Although these methods have shown enhanced clinical response rates and improvement in surrogate markers of outcomes in adults, only a small amount of published information has shown similar outcomes in pediatric patients. [8][9][10]22,23,[26][27][28][29][30][31][32][33][34] Unfortunately, because pediatric patients have different pharmacokinetic parameters than adults, the specifics of dosing optimization cannot be simply extrapolated from adult models. Monte Carlo simulations have been recommended as one method to help optimize pediatric antibiotic dosing. ...
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Objective To characterize pharmacodynamic dosing strategies used at children’s hospitals using a national survey. Design Survey. Setting Children’s hospitals. Participants Volunteer sample of antimicrobial stewardship program (ASP) respondents. Methods A nationwide survey was conducted to gain greater insight into the current adoption of nontraditional dosing methods and monitoring of select β-lactam and fluoroquinolone antibiotics used to treat serious gram-negative infections in pediatric populations. The survey was performed through the Sharing Antimicrobial Reports for Pediatric Stewardship (SHARPS) Collaborative. Results Of the 75 children’s hospitals that responded, 68% of programs reported adoption of pharmacodynamically optimized dosing using prolonged β-lactam infusions and 35% using continuous β-lactam infusions, although use was infrequent. Factors including routine MIC monitoring and formal postgraduate training and board certification of ASP pharmacists were associated with increased utilization of pharmacodynamic dosing. In addition, 60% of programs reported using pharmacodynamically optimized ciprofloxacin and 14% reported using pharmacodynamically optimized levofloxacin. Only 20% of programs monitored β-lactam levels; they commonly cited lack of published guidance, practitioner experience, and laboratomory support as reasons for lack of utilization. Less physician time dedicated to ASP programs was associated with lower adoption of optimized dosing. Conclusions Use of pharmacodynamic dosing through prolonged and continuous infusions of β-lactams have not yet been routinely adopted at children’s hospitals. Further guidance from trials and literature are needed to continue to guide pediatric pharmacodynamic dosing efforts. Children’s hospitals should utilize these data to compare practices and to prioritize further research and education efforts.
... To maximize therapeutic effect and for early reduction of bacterial burden, on the one hand it is important to consider starting treatment with a high dose of an antibiotic to achieve high drug concentrations as soon as possible [60]. On the other hand, several studies showed that continuous infusions (over 24 h) or prolonged infusions (over ≥3 h) of β-lactam antibiotics lead to better PK/PD targets attainment rates and patient outcomes than intermittent intravenous bolus administration (over 30-60 min, 1 to 6 times per day), particularly in critically ill patients and in patients with serious infections [61][62][63][64][65]. Administering β-lactams continuously or by prolonged infusion to achieve optimal PK/PD might slow the development of resistance and improve the outcomes of patients with sepsis and septic shock. ...
Article
The incidence of infections caused by bacteria that are resistant to antibiotics is constantly increasing. In Europe alone, it has been estimated that each year about 33′000 deaths are attributable to such infections. One important driver of antimicrobial resistance is the use and abuse of antibiotics in human medicine. Inappropriate prescribing of antibiotics is still very frequent: up to 50% of all antimicrobials prescribed in humans might be unnecessary and several studies show that at least 50% of antibiotic treatments are inadequate, depending on the setting. Possible strategies to optimize antibiotic use in everyday clinical practice and to reduce the risk of inducing bacterial resistance include: the implementation of rapid microbiological diagnostics for identification and antimicrobial susceptibility testing, the use of inflammation markers to guide initiation and duration of therapies, the reduction of standard durations of antibiotic courses, the individualization of antibiotic therapies and dosing considering pharmacokinetics/pharmacodynamics targets, and avoiding antibiotic classes carrying a higher risk for induction of bacterial resistance. Importantly, measures to improve antibiotic prescribing and antibiotic stewardship programs should focus on facilitating clinical reasoning and improving prescribing environment in order to remove any barriers to good prescribing.
... There were no cases of recurrence in the EI or STI group after meropenem treatment. Previously, the effectiveness and safety of EI of meropenem were investigated in adult sepsis, ventilator-associated pneumonia, and severe infections [8][9][10]. In addition, Zhou et al. summarized clinical trials, case reports, and PK evidence on EI of meropenem in children with severe infection [11]. ...
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This single-center historical cohort study investigated the effectiveness and safety of extended infusion (EI) compared with short-term infusion (STI) of meropenem in neonatal sepsis. Patient electronic health records from Peking University Third Hospital (1 December 2011–1 April 2021) were screened. Neonates diagnosed with sepsis and treated with meropenem in the neonatal intensive care unit were included (256 patients) as STI (0.5 h, 129 patients) and EI (2–3 h, 127 patients) groups. Three-day clinical effectiveness and three-day microbial clearance were considered the main outcomes. Univariate and multivariate analyses were performed. Baseline characteristics were similar in both groups. EI of meropenem was associated with a significantly higher 3-day clinical effectiveness rate (0.335 (0.180, 0.623), p = 0.001) and 3-day microbial clearance (4.127 (1.235, 13.784), p = 0.021) than STI, with comparable safety. Subgroup analyses showed that neonates with very low birth weight benefited from EI in terms of 3-day clinical effectiveness rate (75.6% versus 56.6%, p = 0.007), with no significant difference in the 3-day clinical effectiveness (85.1% versus 78.3%, p = 0.325) and microbial clearance (6% versus 5%, p > 0.999) rates between 3 h and 2 h infusions. Thus, EI of meropenem may be associated with better effectiveness and comparable safety in treating neonatal sepsis than STI. Nonetheless, historically analyzed safety evaluation might be biased, and these findings need confirmation in randomized controlled trials of larger sample sizes.
... To facilitate the attainment of these targets, some clinical facilities have opted for the administration of piperacillin by continuous (CI) or extended infusion over the more traditional intermittent bolus method. As a time-dependent antibiotic, continuously administering piperacillin may seem a better method over intermittent administration, where trough concentrations may fall below the target MIC, resulting in suboptimal antimicrobial therapy, but this remains debated [5][6][7]. Furthermore, some societies have recommended the use of therapeutic drug monitoring for β-lactams such as piperacillin to improve target attainment [2,3]. However, a recent study revealed no significant benefit in reducing mortality or Sequential Organ Failure Assessment (SOFA) score in patients with sepsis [8]. ...
Article
BACKGROUND AND OBJECTIVE: Piperacillin is a broad-spectrum β-lactam antibiotic commonly prescribed in intensive care units. Many piperacillin population pharmacokinetic models have been published, but few underwent an external evaluation. External evaluation is an important process to determine a model's capability of being generalized to other hospitals. We aimed to assess the predictive performance of these models with an external validation dataset. Methods: Six models were evaluated with a dataset consisting of 30 critically ill patients (35 samples) receiving piperacillin by continuous infusion. Models were subject to prediction-based (bias and imprecision) and simulation-based evaluations. When a model had an acceptable evaluation, it was used for dosing simulations to evaluate the probability of target attainment. Results: Bias and imprecision ranged from - 35.7 to 295% and from 22.7 to 295%, respectively. The models of Klastrup et al. and of Udy et al. were acceptable according to our criteria and were used for dosing simulations. Simulations showed that a loading dose of 4 g followed by a maintenance dose of 16 g/24 h of piperacillin infused continuously was necessary to remain above a pharmacokinetic-pharmacodynamic target set as a minimal inhibitory concentration of 16 mg/L in 90% of patients, for a median patient with a creatinine clearance of 76 mL/min. Conclusions: Despite the considerable variation in the predictive performance of the models with the external validation dataset, this study was able to validate two of these models and led to the elaboration of a dosing nomogram for piperacillin by continuous infusion that can be used by clinicians in intensive care units.
Article
Purpose of review: Antibiotics are an essential treatment for septic shock. This review provides an overview of the key issues in antimicrobial therapy for septic shock. We include a summary of available evidence with an emphasis on data published in the last few years. Recent findings: We examine apparently contradictory data supporting the importance of minimizing time to antimicrobial therapy in sepsis, discuss approaches to choosing appropriate antibiotics, and review the importance and challenges presented by antimicrobial dosing. Lastly, we evaluate the evolving concepts of de-escalation, and optimization of the duration of antimicrobials. Summary: The topics discussed in this review provide background to key clinical decisions in antimicrobial therapy for septic shock: timing, antibiotic choice, dosage, de-escalation, and duration. Although acknowledging some controversy, antimicrobial therapy in septic shock should be delivered early, be of the adequate spectrum, appropriately and individually dosed, rationalized when possible, and of minimal effective duration.
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Résumé Les modifications pharmacocinétiques des patients de réanimation et celles induites par les thérapeutiques réanimatoires soulèvent de nombreuses questions concernant les adaptations posologiques d’antibiotiques. Les bêta-lactamines sont des anti-infectieux largement utilisés en réanimation. Les fréquents sous-dosages engendrent un risque d’échec thérapeutique potentiellement létal et d’émergence de résistances bactériennes. Les surdosages exposent quant à eux à un risque de neurotoxicité et de néphrotoxicité. Une compréhension des mécanismes pharmacocinétiques à l’origine de ces problématiques apparait alors comme indispensable. Une approche pharmacocinétique/pharmacodynamique globale est requise, intégrant l’utilisation de perfusions prolongées et continues de bêta-lactamines de façon à optimiser les probabilités d’atteinte des objectifs pharmacocinétiques et pharmacodynamiques. Le Suivi Thérapeutique Pharmacologique des bêta-lactamines doit également être considéré. Les experts s’accordent pour cibler une concentration sérique libre de bêta-lactamine d’au moins 4 fois la CMI de la bactérie concernée pendant 100% du temps. Les méthodes bayésiennes pourraient permettre une adaptation individualisée des posologies.
Article
Introduction Intensive Care Units (ICU) are among the hospital wards exhibiting the highest prevalence of antimicrobial resistance (AMR), and resulting impact on patient outcomes. Antimicrobial resistance surveillance and antimicrobial stewardship (AMS) programs play a pivotal role in promoting interventions tailored to optimize infection diagnosis and treatment in the final attempt to limit unnecessary antimicrobial use and development of resistance. Areas covered A narrative review of the literature was carried out to summarize the available evidence and develop a set of actions that should be considered for integration into the ICU stewardship framework. Four questions were addressed: how AMR surveillance can inform antibiotic policy in ICU; whether pharmacokinetic and pharmacodynamic (PK/PD) principles and the use of procalcitonin should be incorporated as a standard practice in ICU AMS programs to optimize antibiotic treatment and to drive antibiotic discontinuation; which criteria should drive treatment duration of ICU-associated infections. Expert opinion In this review we aim to highlight that the ICU must be considered in its own right. Each ICU has its own characteristics depending on the country, on the local antibiotic resistance profile, on the patients feature and the severity of infection.
Article
Pharmacokinetic-pharmacodynamic (PKPD) models have met increasing interest as tools to identify potential efficacious antibiotic dosing regimens in vitro and in vivo. We sought to investigate the impact of diversely shaped clinical pharmacokinetic profiles of meropenem on the growth/killing patterns of Pseudomonas aeruginosa (ARU552, MIC = 16 mg/L) over time using a semi-mechanistic PKPD model and a PK/PD index-based approach. Bacterial growth/killing were driven by the PK profiles of six patient populations (infected adults, burns, critically ill, neurosurgery, obese patients) given varied pathogen features (e.g. EC50, growth rate, inoculum), patient characteristics (e.g. creatinine clearance), and ten dosing regimens (including two dose levels and 0.5-h, 3-h and continuous-infusion regimens). Conclusions regarding the most favourable dosing regimen depended on the assessment of (i) the total bacterial load or fT>MIC (time that unbound concentrations exceed the minimum inhibitory concentration); (ii) the median or P0.95 profile of the population; and (iii) 8 h or 24 h time points. Continuous infusion plus loading dose as well as 3-h infusions (3-h infusions: e.g. for scenarios associated with low meropenem concentrations, P0.95 profiles, and MIC ≥ 16 mg/L) appeared superior to standard 0.5-h infusions at 24 h. The developed platform can serve to identify promising strategies of efficacious dosing for clinical trials.
Article
OBJECTIVES:. Beta-lactam antibiotics exhibit high interindividual variability in drug concentrations in patients with critical illness which led to an interest in the use of therapeutic drug monitoring to improve effectiveness and safety. To implement therapeutic drug monitoring, it is necessary to define the beta-lactam therapeutic range—in essence, what drug concentration would prompt a clinician to make dose adjustments up or down. This objective of this narrative review was to summarize evidence for the “floor” (for effectiveness) and “ceiling” (for toxicity) for the beta-lactam therapeutic range to be used with individualized therapeutic drug monitoring. DATA SOURCES:. Research articles were sourced from PubMed using search term combinations of “pharmacokinetics,” “pharmacodynamics,” “toxicity,” “neurotoxicity,” “therapeutic drug monitoring,” “beta-lactam,” “cefepime,” “meropenem,” “piperacillin/tazobactam,” “ICU,” and “critical illness.” STUDY SELECTION:. Articles were selected if they included preclinical, translational, or clinical data on pharmacokinetic and pharmacodynamic thresholds for effectiveness and safety for beta-lactams in critical illness. DATA SYNTHESIS:. Experimental data indicate a beta-lactam concentration above the minimum inhibitory concentration of the organism for greater than or equal to 40–60% of the dosing interval is needed, but clinical data indicate that higher concentrations may be preferrable. In the first 48 hours of critical illness, a free beta-lactam concentration at or above the susceptibility breakpoint of the most likely pathogen for 100% of the dosing interval would be reasonable (typically based on Pseudomonas aeruginosa). After 48 hours, the lowest acceptable concentration could be tailored to 1–2× the observed minimum inhibitory concentration of the organism for 100% of the dosing interval (often a more susceptible organism). Neurotoxicity is the primary dose-dependent adverse effect of beta-lactams, but the evidence remains insufficient to link a specific drug concentration to greater risk. CONCLUSIONS:. As studies advance the understanding of beta-lactam exposure and response in critically ill patients, it is essential to clearly define the acceptable therapeutic range to guide regimen selection and adjustment.
Article
There is insufficient data on the relationship between antibiotic dosing and plasma concentrations in patients treated with continuous renal replacement therapy (CRRT). In this prospective observational study, we explored the variability in plasma concentrations of meropenem and piperacillin in critically ill patients treated with CRRT and the correlation between concentrations and CRRT intensity. Antibiotic concentrations were measured at the mid and end of the dosing interval and repeated after 2-3 days when feasible. Measured concentrations were compared to the clinical susceptible breakpoints for Pseudomonas aeruginosa, 16 and 2 mg/L for piperacillin and meropenem respectively. CRRT intensity was estimated by delivered, time-averaged, total effluent flow (Qeff), corrected for predilution. Concentrations were also compared between patients with different residual diuresis. We included 140 meropenem concentrations from 98 patients and 47 piperacillin concentrations from 37 patients. Concentrations at the mid of the dosing interval were above target at all occasions for both antibiotics. For meropenem, 6.5% of trough concentrations were below target, for piperacillin 22%. Correlations between Qeff and antibiotic concentrations or concentration T½ were either statistically not significant or weak. Meropenem concentrations and T½ differed between patients with different residual diuresis. Thus, when treating ICU patients with CRRT and recommended doses of meropenem or piperacillin, both low, suboptimal, and unnecessary high, potentially toxic, plasma concentrations are common. Plasma concentrations cannot be predicted from CRRT intensity. Residual diuresis is associated with lower meropenem concentrations, but the correlation is weak. Concentration measurements is likely the most useful approach to avoid suboptimal treatment.
Article
Introduction Ventilator-associated pneumonia (VAP) and hospital-acquired pneumonia (HAP) result in significant morbidity and mortality. The emergence of multi-drug resistant organisms has complicated the matter, as many of these pathogens now represent key causes of VAP and HAP. While a number of new medications have been approved, a comprehensive appreciation of pharmacokinetic and pharmacodynamic principles, which, are often neglected, is key to effective treatment. Areas covered The authors discuss the central pharmacokinetic and pharmacodynamic principles underlying antibiotic utilization, especially as they pertain to the treatment of VAP and HAP. They further address the concept of and implications of augmented renal clearance for the patient with nosocomial pneumonia. Finally, the authors review the evolving data on colistin and inhaled antibiotics in the management of pneumonia. Expert opinion An enhanced understanding of the pharmacokinetic and pharmacodynamic principles along with insight into the concept of augmented renal clearance can help guide drug development and improve the way we currently dose and deliver most antibiotics. There is now mounting data on the limited efficacy and substantial nephrotoxicity of colistin which makes it difficult to justify its continued use. While the concept of inhaled antibiotics is enticing, we lack conclusive data proving efficacy of this paradigm.
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Background and Objectives Morbidity and mortality from serious infections are common in intensive care units (ICUs). The appropriateness of the antibiotic treatment is essential to combat sepsis. We aimed to evaluate pharmacokinetic/pharmacodynamic target attainment of meropenem and piperacillin/tazobactam administered at standard total daily dose as continuous infusion in critically ill patients without renal dysfunction and to identify risk factors of non-pharmacokinetic/pharmacodynamic target attainment.ResultsWe included 118 patients (149 concentrations), 47% had microorganism isolation. Minimum inhibitory concentration (MIC) [median (interquartile range, IQR) values in isolated pathogens were: meropenem: 0.05 (0.02–0.12) mg/l; piperacillin: 3 (1–4) mg/l]. Pharmacokinetic/pharmacodynamic target attainments (100%fCss≥1xMIC, 100%fCss≥4xMIC and 100%fCss ≥ 8xMIC, respectively) were: 100%, 96.15%, 96.15% (meropenem) and 95.56%, 91.11%, 62.22% (piperacillin) for actual MIC; 98.11%, 71.70%, 47.17% (meropenem, MIC 2 mg/l), 95.83%, 44.79%, 6.25% (piperacillin, MIC 8 mg/l), 83.33%, 6.25%, 1.04% (piperacillin, MIC 16 mg/l) for EUCAST breakpoint of Enterobacteriaceae spp. and Pseudomonas spp. Multivariable linear analysis identified creatinine clearance (CrCL) as a predictive factor of free antibiotic concentrations (fCss) of both therapies (meropenem [β = − 0.01 (95% CI − 0.02 to − 0.0; p = 0.043)] and piperacillin [β = − 0.01 (95% CI − 0.02 to 0.01, p < 0.001)]). Neurocritical status was associated with lower piperacillin fCss [β = − 0.36 (95% CI − 0.61 to − 0.11; p = 0.005)].Conclusion Standard total daily dose of meropenem allowed achieving pharmacokinetic/pharmacodynamic target attainments in ICU patients without renal dysfunction. Higher doses of piperacillin/tazobactam would be needed to cover microorganisms with MIC > 8 mg/l. CrCL was the most powerful factor predictive of fCss in both therapies.
Article
Background: In 2017, a national drug shortage of small volume solutions significantly affected the preparation of intravenous antibiotics. In response, a continuous infusion administration protocol for piperacillin/tazobactam (PIP/TAZ) was implemented. Objective: To compare the outcomes of continuous to prolonged infusions of PIP/TAZ in the setting of drug shortages. Methods: This study is a single-center, retrospective cohort study in a community hospital of patients 18 years and older who received intravenous PIP/TAZ through 2 different dosing strategies of intravenous antibiotics from December 2016 to January 2018. Data were collected for 2 months on patients receiving prolonged infusions of PIP/TAZ prior to November 2017 and for 2 months on patients receiving continuous infusions of PIP/TAZ after November 2017. Results: A total of 90 patients who received PIP/TAZ via either prolonged (n = 47) or continuous infusion (n = 43) were evaluated. There were no differences between the groups in mortality (3 vs 2 deaths, P = 1.00), length of therapy (6 ± 4 vs 6 ± 3 days, P = .86), or length of stay (9 ± 7 vs 8 ± 6 days, P = .47). Additionally, no differences were noted between incidences of thrombocytopenia ( P = .41), Clostridioides difficile infection ( P = .48), acute renal failure ( P = 1.00), seizures ( P = 1.0), or 30-day readmission rates ( P = .27). Conclusions: Administration of continuous infusion PIP/TAZ appears to be a viable mitigation strategy during small volume fluid shortages. Future cost-effectiveness studies may provide information on the financial impact of continuous infusions during costly drug shortages.
Chapter
Pharmacokinetic (PK) and pharmacodynamic (PD) properties of antibiotics are useful to guide the design of dosing regimens that maximize patient outcomes. This chapter aims to describe the influence of PK/PD properties on the mode of infusional drug delivery regimens and due considerations for the design and optimization of antibiotic infusions in the critically‐ill. Further, it summarizes the clinical benefit of the different modes of antibiotic infusion. Existing evidence suggests that short intermittent infusion can achieve required exposure for antibiotics with a PK/PD dosing target of maximum concentration to minimum inhibitory concentration ( C max /MIC) ratio. For time‐dependent antibiotics, prolonged infusions achieve better exposure in terms of time the free antibiotic concentration remains above MIC ( f T >MIC ). For specific PK/PD targets of area under the concentration–time curve (AUC) to MIC ratio, loading dose may be required with prolonged infusion in patients with increased volume of distribution. PD consideration such as the extent of post antibiotic effect and altered susceptibility profile can influence the need for prolonged infusion administration. Short intermittent infusions or short duration of prolonged infusion may be adequate when significant post‐antibiotic effect exists. Better patient outcomes may be achieved with extended or continuous infusion regimens for time‐dependent antibiotics such as β‐lactams compared to intermittent infusions that are often sub‐optimal in critically‐ill patients. However, although some existing evidence demonstrate better clinical cure rates with continuous infusion regimens, no study has yet shown a mortality benefit. The ongoing effort to address this knowledge gap in a large randomized controlled trial is highly recommended.
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Introduction: Severe burn injury involves widespread skin and tissue damage leading to systemic inflammation, hypermetabolism and multi-organ failure. The hypermetabolic phase of burn injury has been associated with increased systemic antibiotic clearance; however, critical illness in the absence of burn may also induce similar physiologic changes. Continuous renal replacement therapy (CRRT) is often implemented in critically ill patients and may also affect antibiotic clearance. Although the pharmacokinetics (PK) of meropenem has been described in both the burn and non-burn critically ill populations, direct comparative data is lacking. Methods: For this study, we evaluated PK parameters of meropenem from 23 critically ill patients, burn or non-burn, treated with or without continuous veno-venous haemofiltration (CVVH) to determine the contribution of burn and CVVH to the variability of therapeutic meropenem levels. Results: A two-compartment model best described the data and revealed creatinine clearance (CrCl) and total burn surface area (TBSA) as significant covariates on clearance (CL) and peripheral volume of distribution (Vp), respectively. Of interest, non-burn patients on CVVH displayed an overall lower inherent CL as compared to burn patients on CVVH (6.43 vs. 12.85 L/h). Probability of target attainment (PTA) simulations revealed augmented renal clearance (ARC) may necessitate dose adjustments, but TBSA and CVVH would not. Conclusions: We recommend a standard dose of 1000 mg every 8 hours; however, if ARC is suspected, or the severity of illness requires a more stringent therapeutic target, we recommend a loading dose of 1000-2000 mg infused over 30 minutes to 1 hour followed by continuous infusion (3000-6000 mg over 24 hours), or intermittent infusion of 2000 mg every 8 hours.
Article
Introduction: : In the past 15 years, treatment of VAP caused by carbapenem-resistant Gram-negative bacteria (CR-GNB) has represented an intricate challenge for clinicians. Areas covered: In this perspective article, we discuss the available clinical data about novel agents for the treatment of CR-GNB VAP, together with general PK/PD principles for the treatment of VAP, in the attempt to provide some suggestions for optimizing antimicrobial therapy of CR-GNB VAP in the daily clinical practice. Expert opinion: Recently, novel BL and BL/BLI combinations have become available that have shown potent in vitro activity against CR-GNB and have attracted much interest as novel, less toxic, and possibly more efficacious options for the treatment of CR-GNB VAP compared with previous standard of care. Besides randomized controlled trials, a good solution to enrich our knowledge on how to use these novel agents at best in the near future, while at the same time remaining adherent to current evidence-based guidelines, is to improve our collaboration to conduct larger multinational observational studies to collect sufficiently large populations treated in real life with those novel agents for which guidelines currently do not provide a recommendation (in favor or against) for certain causative organisms.
Article
Antibiotic resistance presents an incessant threat to our drug armamentarium that necessitates novel approaches to therapy. Over the past several decades, investigation of pharmacokinetic and pharmacodynamic (PKPD) principles has substantially improved our understanding of the relationships between the antibiotic, pathogen, and infected patient. However, crucial gaps in our understanding of the pharmacology of antibacterials and their optimal use in the care of patients continue to exist; simply attaining antibiotic exposures that are considered adequate based on traditional targets can still result in treatment being unsuccessful and resistance proliferation for some infections. It is this salient paradox that points to key future directions for research in antibiotic therapeutics. This Personal View discusses six priority areas for antibiotic pharmacology research: (1) antibiotic-pathogen interactions, (2) antibiotic targets for combination therapy, (3) mechanistic models that describe the time-course of treatment response, (4) understanding and modelling of host response to infection, (5) personalised medicine through therapeutic drug management, and (6) application of these principles to support development of novel therapies. Innovative approaches that enhance our understanding of antibiotic pharmacology and facilitate more accurate predictions of treatment success, coupled with traditional pharmacology research, can be applied at the population level and to individual patients to improve outcomes.
Article
Purpose of review: The aim of this review is to discuss the rationale of and current evidence for prolonged beta-lactam infusion in the management of Gram-negative infections. Recent findings: Pharmacokinetic/pharmacodynamic (PK/PD) data from various in-vitro and in-vivo experimental studies conclusively support prolonged infusion over intermittent infusion in terms of achieving effective beta-lactam exposure for maximal bacterial killing. Superior PK/PD target attainment has been demonstrated with prolonged beta-lactam infusion in patient populations that are more likely to have less susceptible Gram-negative infections. These populations include critically ill patients, cystic fibrosis patients and patients with malignant diseases. The clinical impact of prolonged beta-lactam infusion is likely to be the greatest in these patient groups: critically ill patients with a high level of illness severity who are not receiving renal replacement therapy; patients with nonfermenting Gram-negative bacilli infection and patients with respiratory infection. Critically ill patients with augmented renal clearance may not achieve effective beta-lactam exposure even with the use of prolonged infusion. Maximizing the effectiveness of prolonged beta-lactam infusion via therapeutic drug monitoring is becoming a more common strategy in the management of critically ill patients with Gram-negative infection. Summary: Prolonged beta-lactam infusion may not benefit all patients but only for those who are critically ill and/or immunocompromised, who are also more likely to have less susceptible Gram-negative infections.
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A formula has been developed to predict creatinine clearance (Ccr) from serum creatinine (Scr) in adult males: (see article)(15% less in females). Derivation included the relationship found between age and 24-hour creatinine excretion/kg in 249 patients aged 18-92. Values for Ccr were predicted by this formula and four other methods and the results compared with the means of two 24-hour Ccr's measured in 236 patients. The above formula gave a correlation coefficient between predicted and mean measured Ccr's of 0.83; on average, the difference predicted and mean measured values was no greater than that between paired clearances. Factors for age and body weight must be included for reasonable prediction.
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This paper presents the form and validation results of APACHE II, a severity of disease classification system. APACHE II uses a point score based upon initial values of 12 routine physiologic measurements, age, and previous health status to provide a general measure of severity of disease. An increasing score (range 0 to 71) was closely correlated with the subsequent risk of hospital death for 5815 intensive care admissions from 13 hospitals. This relationship was also found for many common diseases.When APACHE II scores are combined with an accurate description of disease, they can prognostically stratify acutely ill patients and assist investigators comparing the success of new or differing forms of therapy. This scoring index can be used to evaluate the use of hospital resources and compare the efficacy of intensive care in different hospitals or over time.
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The recent surge in multidrug-resistant pathogens combined with the diminishing antibiotic pipeline has created a growing need to optimize the use of our existing antibiotic armamentarium, particularly in the management of intensive care unit (ICU) patients. Optimal and timely pharmacokinetic/pharmacodynamic (PK/PD) target attainment has been associated with an increased likelihood of clinical and microbiological success in critically ill patients. Emerging data, mostly from in vitro and in vivo studies, suggest that optimization of antibiotic therapy should not only aim to maximize clinical outcomes but also to include the suppression of resistance. The development of antibiotic dosing regimens that adheres to the PK/PD principles may prolong the clinical lifespan of our existing antibiotics by minimizing the emergence of resistance. This article summarizes the relevance of PK/PD characteristics of different antibiotic classes on the development of antibiotic resistance. On the basis of the available data, we propose dosing recommendations that can be adopted in the clinical setting, to maximize therapeutic success and limit the emergence of resistance in the ICU. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.
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Background. Morbidity and mortality for critically ill patients with infections remains a global healthcare problem. We aimed to determine whether β-lactam antibiotic dosing in critically ill patients achieves concentrations associated with maximal activity and whether antibiotic concentrations affect patient outcome. Methods. This was a prospective, multinational pharmacokinetic point-prevalence study including 8 β-lactam antibiotics. Two blood samples were taken from each patient during a single dosing interval. The primary pharmacokinetic/pharmacodynamic targets were free antibiotic concentrations above the minimum inhibitory concentration (MIC) of the pathogen at both 50% (50% f T>MIC) and 100% (100% f T>MIC) of the dosing interval. We used skewed logistic regression to describe the effect of antibiotic exposure on patient outcome. Results. We included 384 patients (361 evaluable patients) across 68 hospitals. The median age was 61 (interquartile range [IQR], 48–73) years, the median Acute Physiology and Chronic Health Evaluation II score was 18 (IQR, 14–24), and 65% of patients were male. Of the 248 patients treated for infection, 16% did not achieve 50% f T>MIC and these patients were 32% less likely to have a positive clinical outcome (odds ratio [OR], 0.68; P = .009). Positive clinical outcome was associated with increasing 50% f T>MIC and 100% f T>MIC ratios (OR, 1.02 and 1.56, respectively; P < .03), with significant interaction with sickness severity status. Conclusions. Infected critically ill patients may have adverse outcomes as a result of inadeqaute antibiotic exposure; a paradigm change to more personalized antibiotic dosing may be necessary to improve outcomes for these most seriously ill patients.
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Background: Doripenem is the most recently introduced carbapenem, with a broad spectrum of antimicrobial activity. Preliminary data indicated that activity is optimized by maximizing the time that serum concentration remains above the minimum inhibitory concentration; however, limited clinical data are available to support this approach. Objective: To compare clinical outcomes before and after implementation of a hospital-wide initiative extending the duration of infusion for doripenem from 1 hour (standard) to 4 hours (prolonged). Methods: This retrospective, quasi-experimental study compared clinical outcomes associated with doripenem administered as a 1-hour infusion versus a 4-hour infusion for treatment of suspected or documented infections caused by gram-negative organisms. Outcomes were assessed for the entire cohort, as well as for the subpopulation of patients admitted to the intensive care unit. Results: Two hundred patients were included; 106 patients received doripenem via standard infusion and 94 patients via prolonged infusion. No significant differences were noted between the treatment groups in clinical success, length of stay, or duration of treatment when the entire cohort was evaluated. In the critically ill subgroup, pneumonia, standard-infusion doripenem, and concomitant bacteremia were independent predictors of clinical failure (adjusted odds ratio [95% CI] 7.8 [2.4-25.6], 5.5 [1.6-18.7], and 7.0 [1.6-31.3], respectively). Additionally, critically ill patients who received doripenem via standard infusion were significantly more likely to experience recurrence of infection or death within 90 days. No significant differences were noted in length of stay or duration of bacteremia. Conclusions: The duration of infusion did not significantly impact outcomes when the entire cohort was compared; however, prolonged infusion of doripenem was associated with significantly improved clinical outcomes among critically ill patients. These findings support the use of prolonged infusion of doripenem for critically ill patients.
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OBJECTIVE:: To provide an update to the "Surviving Sepsis Campaign Guidelines for Management of Severe Sepsis and Septic Shock," last published in 2008. DESIGN:: A consensus committee of 68 international experts representing 30 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict of interest policy was developed at the onset of the process and enforced throughout. The entire guidelines process was conducted independent of any industry funding. A stand-alone meeting was held for all subgroup heads, co- and vice-chairs, and selected individuals. Teleconferences and electronic-based discussion among subgroups and among the entire committee served as an integral part of the development. METHODS:: The authors were advised to follow the principles of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to guide assessment of quality of evidence from high (A) to very low (D) and to determine the strength of recommendations as strong (1) or weak (2). The potential drawbacks of making strong recommendations in the presence of low-quality evidence were emphasized. Some recommendations were ungraded (UG). Recommendations were classified into three groups: 1) those directly targeting severe sepsis; 2) those targeting general care of the critically ill patient and considered high priority in severe sepsis; and 3) pediatric considerations. RESULTS:: Key recommendations and suggestions, listed by category, include: early quantitative resuscitation of the septic patient during the first 6 hrs after recognition (1C); blood cultures before antibiotic therapy (1C); imaging studies performed promptly to confirm a potential source of infection (UG); administration of broad-spectrum antimicrobials therapy within 1 hr of recognition of septic shock (1B) and severe sepsis without septic shock (1C) as the goal of therapy; reassessment of antimicrobial therapy daily for de-escalation, when appropriate (1B); infection source control with attention to the balance of risks and benefits of the chosen method within 12 hrs of diagnosis (1C); initial fluid resuscitation with crystalloid (1B) and consideration of the addition of albumin in patients who continue to require substantial amounts of crystalloid to maintain adequate mean arterial pressure (2C) and the avoidance of hetastarch formulations (1C); initial fluid challenge in patients with sepsis-induced tissue hypoperfusion and suspicion of hypovolemia to achieve a minimum of 30 mL/kg of crystalloids (more rapid administration and greater amounts of fluid may be needed in some patients) (1C); fluid challenge technique continued as long as hemodynamic improvement, as based on either dynamic or static variables (UG); norepinephrine as the first-choice vasopressor to maintain mean arterial pressure ≥ 65 mm Hg (1B); epinephrine when an additional agent is needed to maintain adequate blood pressure (2B); vasopressin (0.03 U/min) can be added to norepinephrine to either raise mean arterial pressure to target or to decrease norepinephrine dose but should not be used as the initial vasopressor (UG); dopamine is not recommended except in highly selected circumstances (2C); dobutamine infusion administered or added to vasopressor in the presence of a) myocardial dysfunction as suggested by elevated cardiac filling pressures and low cardiac output, or b) ongoing signs of hypoperfusion despite achieving adequate intravascular volume and adequate mean arterial pressure (1C); avoiding use of intravenous hydrocortisone in adult septic shock patients if adequate fluid resuscitation and vasopressor therapy are able to restore hemodynamic stability (2C); hemoglobin target of 7-9 g/dL in the absence of tissue hypoperfusion, ischemic coronary artery disease, or acute hemorrhage (1B); low tidal volume (1A) and limitation of inspiratory plateau pressure (1B) for acute respiratory distress syndrome (ARDS); application of at least a minimal amount of positive end-expiratory pressure (PEEP) in ARDS (1B); higher rather than lower level of PEEP for patients with sepsis-induced moderate or severe ARDS (2C); recruitment maneuvers in sepsis patients with severe refractory hypoxemia due to ARDS (2C); prone positioning in sepsis-induced ARDS patients with a PaO2/FIO2 ratio of ≤ 100 mm Hg in facilities that have experience with such practices (2C); head-of-bed elevation in mechanically ventilated patients unless contraindicated (1B); a conservative fluid strategy for patients with established ARDS who do not have evidence of tissue hypoperfusion (1C); protocols for weaning and sedation (1A); minimizing use of either intermittent bolus sedation or continuous infusion sedation targeting specific titration endpoints (1B); avoidance of neuromuscular blockers if possible in the septic patient without ARDS (1C); a short course of neuromuscular blocker (no longer than 48 hrs) for patients with early ARDS and a Pao2/Fio2 < 150 mm Hg (2C); a protocolized approach to blood glucose management commencing insulin dosing when two consecutive blood glucose levels are > 180 mg/dL, targeting an upper blood glucose ≤ 180 mg/dL (1A); equivalency of continuous veno-venous hemofiltration or intermittent hemodialysis (2B); prophylaxis for deep vein thrombosis (1B); use of stress ulcer prophylaxis to prevent upper gastrointestinal bleeding in patients with bleeding risk factors (1B); oral or enteral (if necessary) feedings, as tolerated, rather than either complete fasting or provision of only intravenous glucose within the first 48 hrs after a diagnosis of severe sepsis/septic shock (2C); and addressing goals of care, including treatment plans and end-of-life planning (as appropriate) (1B), as early as feasible, but within 72 hrs of intensive care unit admission (2C). Recommendations specific to pediatric severe sepsis include: therapy with face mask oxygen, high flow nasal cannula oxygen, or nasopharyngeal continuous PEEP in the presence of respiratory distress and hypoxemia (2C), use of physical examination therapeutic endpoints such as capillary refill (2C); for septic shock associated with hypovolemia, the use of crystalloids or albumin to deliver a bolus of 20 mL/kg of crystalloids (or albumin equivalent) over 5 to 10 mins (2C); more common use of inotropes and vasodilators for low cardiac output septic shock associated with elevated systemic vascular resistance (2C); and use of hydrocortisone only in children with suspected or proven "absolute"' adrenal insufficiency (2C). CONCLUSIONS:: Strong agreement existed among a large cohort of international experts regarding many level 1 recommendations for the best care of patients with severe sepsis. 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There is controversy over whether traditional intermittent bolus dosing or continuous infusion of beta-lactam antibiotics is preferable in critically ill patients. No significant difference between these two dosing strategies in terms of patient outcomes has been shown yet. This is despite compelling in vitro and in vivo pharmacokinetic/pharmacodynamic (PK/PD) data. A lack of significance in clinical outcome studies may be due to several methodological flaws potentially masking the benefits of continuous infusion observed in preclinical studies. In this review, we explore the methodological shortcomings of the published clinical studies and describe the criteria that should be considered for performing a definitive clinical trial. We found that most trials utilized inconsistent antibiotic doses and recruited only small numbers of heterogeneous patient groups. The results of these trials suggest that continuous infusion of beta-lactam antibiotics may have variable efficacy in different patient groups. Patients who may benefit from continuous infusion are critically ill patients with a high level of illness severity. Thus, future trials should test the potential clinical advantages of continuous infusion in this patient population. To further ascertain whether benefits of continuous infusion in critically ill patients do exist, a large-scale, prospective, multinational trial with a robust design is required.
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Introduction Meropenem bactericidal activity depends on the time when the free drug concentrations remain above the minimum inhibitory concentration of pathogens. The goal of this study was to compare clinical and bacteriological efficacy of continuous meropenem infusion versus bolus administration in critically ill patients with severe infection, and to evaluate the safety of both dosing regimens. Methods Patients admitted to the interdisciplinary Intensive Care Unit (ICU) who suffered from severe infections and received meropenem were randomized either in the Infusion group (n = 120) or in the Bolus group (n = 120). Patients in the Infusion group received a loading dose of 2 g of meropenem followed by a continuous infusion of 4 g of meropenem over 24 hours. Patients in the Bolus group were given 2 g of meropenem over 30 minutes every 8 hours. Clinical and microbiological outcome, safety, meropenem-related length of ICU and hospital stay, meropenem-related length of mechanical ventilation, duration of meropenem treatment, total dose of meropenem, and ICU and in-hospital mortality were assessed. Results Clinical cure at the end of meropenem therapy was comparable between both groups (83.0% patients in the Infusion vs. 75.0% patients in the Bolus group; P = 0.180). Microbiological success rate was higher in the Infusion group as opposed to the Bolus group (90.6% vs. 78.4%; P = 0.020). Multivariate logistic regression identified continuous administration of meropenem as an independent predictor of microbiological success (OR = 2.977; 95% CI = 1.050 to 8.443; P = 0.040). Meropenem-related ICU stay was shorter in the Infusion group compared to the Bolus group (10 (7 to 14) days vs. 12 (7 to 19) days; P = 0.044) as well as shorter duration of meropenem therapy (7 (6 to 8) days vs. 8 (7 to 10) days; P = 0.035) and lower total dose of meropenem (24 (21 to 32) grams vs. 48 (42 to 60) grams; P < 0.0001). No severe adverse events related to meropenem administration in either group were observed. Conclusions Continuous infusion of meropenem is safe and, in comparison with higher intermittent dosage, provides equal clinical outcome, generates superior bacteriological efficacy and offers encouraging alternative of antimicrobial therapy in critically ill patients.
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Since the bactericidal effects of beta-lactam antibiotics are time dependent, the optimum strategy for their administration could be continuous infusion. In this prospective, randomised controlled trial to evaluate the clinical efficacy of continuous infusion therapy, we evaluated the outcomes for 40 septic critically ill patients who received piperacillin either continuously (2 g intravenously (i.v.) over 0.5 h as a loading dose followed by 8 g i.v. daily over 24 h (n=20)) or as an intermittent infusion (3 g i.v. every 6h over 0.5 h (n=20)). Results from our study demonstrated that the clinical efficacy of piperacillin as a continuous infusion is superior to intermittent administration in critically ill patients. Change in APACHE II scores from baseline at the end of the second, third and fourth days, respectively, were 4.1, 5.1 and 5.2 for continuous infusion and 2.0, 2.6 and 2.8 for intermittent infusion (P< or =0.04). Considering minimum inhibitory concentrations (MICs) of 16 microg/mL and 32 microg/mL, the percentage of time for which piperacillin plasma concentrations were higher than the MIC (%T>MIC) was calculated for each patient in the two groups. For MICs of 16 microg/mL and 32 microg/mL, %T>MIC in the continuous infusion group was 100% and 65% of the dosing interval, respectively; in the intermittent infusion group, %T>MIC was only 62% and 39% of the dosing interval. There was a significant relationship between clinical results and laboratory data. It was shown that the superiority of the clinical efficacy of continuous infusion could be related to piperacillin pharmacodynamics. Continuous infusion significantly reduced the severity of illness as demonstrated by APACHE II scores during therapy.
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To compare the clinical and bacteriological outcome of critically ill patients with sepsis treated by ceftriaxone administered as a once-a-day intermittent bolus dose or by 24 h continuous infusion. We conducted an open-label, randomized controlled pilot study in 57 patients clinically diagnosed with sepsis (suspected/proven infection and systemic inflammatory response syndrome) in a tertiary level intensive care unit. Patients were randomized to receive 2 g of ceftriaxone administered by once-daily intermittent bolus dosing or by 24 h continuous infusion. Clinical and bacteriological outcomes were assessed by blinded clinicians. Fifty-seven patients were enrolled in the study, 50 of whom fulfilled the a priori definition of treatment for 4 or more days. The infusion (n = 29) and bolus groups (n = 28) were similar in terms of demographics, although the median age of those receiving the infusion was younger. Intention-to-treat analysis found no statistically significant differences in the primary outcomes for clinical response (P = 0.17), clinical cure [infusion n = 13/29 versus bolus n = 5/28; adjusted odds ratio (AOR) = 3.74; 95% confidence interval (95% CI) = 1.11-12.57; P = 0.06], bacteriological response (P = 0.41) and bacteriological cure (infusion n = 18/29 versus bolus 14/28; AOR = 1.64; 95% CI = 0.57-4.70; P = 0.52). However, logistic regression in patients that complied with the a priori definitions who received ceftriaxone by continuous infusion (AOR = 22.8; 95% CI = 2.24-232.3; P = 0.008) or patients with a low Acute Physiology and Chronic Health Evaluation (APACHE) II score (AOR = 0.70; 95% CI = 0.54-0.91; P = 0.008) were associated with an improved clinical outcome when age and Sepsis Organ Failure Assessment (SOFA) score at time of study entry were controlled for. This pilot study suggests clinical and bacteriological advantages of continuous infusion of ceftriaxone over bolus administration in critically ill patients in patients requiring 4 or more days of treatment. This sets the scene for a large multicentre double-blind randomized controlled trial to confirm these findings.
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