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Individualised antibiotic dosing for patients who are critically ill: Challenges and potential solutions
Abstract
Infections in critically ill patients are associated with persistently poor clinical outcomes. These patients have severely altered and variable antibiotic pharmacokinetics and are infected by less susceptible pathogens. Antibiotic dosing that does not account for these features is likely to result in suboptimum outcomes. In this Review, we explore the challenges related to patients and pathogens that contribute to inadequate antibiotic dosing and discuss how to implement a process for individualised antibiotic therapy that increases the accuracy of dosing and optimises care for critically ill patients. To improve antibiotic dosing, any physiological changes in patients that could alter antibiotic concentrations should first be established; such changes include altered fluid status, changes in serum albumin concentrations and renal and hepatic function, and microvascular failure. Second, antibiotic susceptibility of pathogens should be confirmed with microbiological techniques. Data for bacterial susceptibility could then be combined with measured data for antibiotic concentrations (when available) in clinical dosing software, which uses pharmacokinetic/pharmacodynamic derived models from critically ill patients to predict accurately the dosing needs for individual patients. Individualisation of dosing could optimise antibiotic exposure and maximise effectiveness.
... Beta-lactams currently represent a backbone therapy for managing Gram-negative infections in solid organ transplant (SOT) recipients, including OLT [12], and they are the first-line prophylaxis of surgical site infections in OLT recipients [13]. In this scenario, the prompt optimization of beta-lactam exposure may play a key role, given the remarkable pathophysiological alterations that have been commonly observed in critically ill patients, potentially leading to a high risk of changeable exposure [14]. Real-time therapeutic drug monitoring (TDM)-based expert clinical pharmacological advice (ECPA) programs may be helpful for optimizing beta-lactam exposure in OLT recipients according to the so-called antimicrobial therapy puzzle concepts [15]. ...
... The demographics and clinical features of the patients are summarized in Table 1. (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29). In seven cases (9.1%), DCD was implemented. ...
... In this scenario, beta-lactams are first-line treatments [12], and attaining an optimal PK/PD target early may allow for the maximization of clinical efficacy and suppress resistance development with beta-lactams [17,18]. Unfortunately, the complex pathophysiological conditions of OLT patients may deeply alter the pharmacokinetic behavior of hydrophilic agents like the beta-lactams, thus hampering the possibility of attaining adequate PK/PD targets [14,[22][23][24][25][26]. In this regard, a TDM-guided ECPA program may be found to be very useful [27]. ...
(1) Objectives: To describe the attainment of optimal pharmacokinetic/pharmacodynamic (PK/PD) targets in orthotopic liver transplant (OLT) recipients treated with continuous infusion (CI) beta-lactams optimized using a real-time therapeutic drug monitoring (TDM)-guided expert clinical pharmacological advice (ECPA) program during the early post-surgical period. (2) Methods: OLT recipients admitted to the post-transplant intensive care unit over the period of July 2021–September 2023, receiving empirical or targeted therapy with CI meropenem, piperacillin-tazobactam, meropenem-vaborbactam, or ceftazidime-avibactam optimized using a real-time TDM-guided ECPA program, were retrospectively retrieved. Steady-state beta-lactam (BL) and/or beta-lactamase inhibitor (BLI) plasma concentrations (Css) were measured, and the Css/MIC ratio was selected as the best PK/PD target for beta-lactam efficacy. The PK/PD target of meropenem was defined as being optimal when attaining a fCss/MIC ratio > 4. The joint PK/PD target of the BL/BLI combinations (namely piperacillin-tazobactam, ceftazidime-avibactam, and meropenem-vaborbactam) was defined as being optimal when the fCss/MIC ratio > 4 of the BL and the fCss/target concentration (CT) ratio > 1 of tazobactam or avibactam, or the fAUC/CT ratio > 24 of vaborbactam were simultaneously attained. Multivariate logistic regression analysis was performed for testing potential variables that were associated with a failure in attaining early (i.e., at first TDM assessment) optimal PK/PD targets. (3) Results: Overall, 77 critically ill OLT recipients (median age, 57 years; male, 63.6%; median MELD score at transplantation, 17 points) receiving a total of 100 beta-lactam treatment courses, were included. Beta-lactam therapy was targeted in 43% of cases. Beta-lactam dosing adjustments were provided in 76 out of 100 first TDM assessments (76.0%; 69.0% decreases and 7.0% increases), and overall, in 134 out of 245 total ECPAs (54.7%). Optimal PK/PD target was attained early in 88% of treatment courses, and throughout beta-lactam therapy in 89% of cases. Augmented renal clearance (ARC; OR 7.64; 95%CI 1.32–44.13) and MIC values above the EUCAST clinical breakpoint (OR 91.55; 95%CI 7.12–1177.12) emerged as independent predictors of failure in attaining early optimal beta-lactam PK/PD targets. (4) Conclusion: A real-time TDM-guided ECPA program allowed for the attainment of optimal beta-lactam PK/PD targets in approximately 90% of critically ill OLT recipients treated with CI beta-lactams during the early post-transplant period. OLT recipients having ARC or being affected by pathogens with MIC values above the EUCAST clinical breakpoint were at high risk for failure in attaining early optimal beta-lactam PK/PD targets. Larger prospective studies are warranted for confirming our findings.
... Burn injury, particularly when involving more than 20% of total body surface area (TBSA), produces extensive and dynamic pathophysiological changes. These include: dramatic variation of hemodynamic status, altered fluid balance, altered protein homeostasis, evolving changes of volume of distribution (Vd), and increased total and renal clearance (CL T and CL R ); all of these exhibit substantial inter-patient variability [1][2][3][4][5]. Moreover, such burn patients require long hospital stays and need intensive health care support, with a consequent high incidence of hospital-acquired infectious complications. ...
... First, they are the cornerstone of antibiotic treatment in this setting, where MDR gram-negative pathogens are frequent, particularly Pseudomonas aeruginosa, but also MDR Enterobacterales and Acinetobacter baumannii [9,10]. Second, it is known that the PK/PD properties of these agents can significantly change in the population of burn patients [1][2][3]51], making the usual drug regimens potentially inappropriate. ...
Background:
Burn injury causes profound pathophysiological changes in the pharmacokinetic/pharmacodynamic (PK/PD) properties of antibiotics. Infections are among the principal complications after burn injuries, and broad-spectrum beta-lactams are the cornerstone of treatment. The aim of this study was to review the evidence for the best regimens of these antibiotics in the burn patient population.
Methods:
We performed a systematic review of evidence available on MEDLINE (from its inception to 2023) of pharmacology studies that focused on the use of 13 broad-spectrum beta-lactams in burn patients. We extracted and synthetized data on drug regimens and their ability to attain adequate PK/PD targets.
Results:
We selected 35 studies for analysis. Overall, studies showed that both high doses and the continuous infusion (CI) of broad-spectrum beta-lactams were needed to achieve internationally-recognized PK/PD targets, ideally with therapeutic drug monitoring guidance. The most extensive evidence concerned meropenem, but similar conclusions could be drawn about piperacillin-tazobactam, ceftazidime, cefepime, imipenem-clinastatin and aztreonam. Insufficient data were available about new beta-lactam-beta-lactamase inhibitor combinations, ceftaroline, ceftobiprole and cefiderocol.
Conclusions:
Both high doses and CI of broad-spectrum beta-lactams are needed when treating burn patients due to the peculiar changes in the PK/PD of antibiotics in this population. Further studies are needed, particularly about newer antibiotics.
... C ritically ill patients often manifest extreme inter-and intraindividual pharmaco kinetic (PK) variability (1). The use of extracorporeal support devices, namely continuous renal replacement therapy (CRRT) and extracorporeal membrane oxygena tion (ECMO), may exacerbate this PK variability (2). Both devices are frequently used concomitantly in critically ill patients (3) and have different consequences on drug PK depending on drugs' physicochemical properties. ...
... However, ECMO, because of the large volume of fluids (crystalloid, albumin, or exogenous blood) required to prime the ECMO circuit and the circuit's sequestration propensity, can also affect the volume of distribution and clearance of hydrophilic drugs (5,6). Therefore, concomitant use of ECMO and CRRT is thought to lead to unpredictable drug concentrations exposing patients to under-or overdosage of hydrophilic drugs which in the case of antifungals could lead to treatment failure, antifungal resistance, or drug toxicity (2). ...
This multicenter study describes the population pharmacokinetics (PK) of fluconazole in critically ill patients receiving concomitant extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT) and includes an evaluation of different fluconazole dosing regimens for achievement of target exposure associated with maximal efficacy. Serial blood samples were obtained from critically ill patients on ECMO and CRRT receiving fluconazole. Total fluconazole concentrations were measured in plasma using a validated chromatographic assay. A population PK model was developed and Monte Carlo dosing simulations were performed using Pmetrics in R. The probability of target attainment (PTA) of various dosing regimens to achieve fluconazole area under the curve to minimal inhibitory concentration ratio (AUC0-24/MIC) >100 was estimated. Eight critically ill patients receiving concomitant ECMO and CRRT were included. A two-compartment model including total body weight as a covariate on clearance adequately described the data. The mean (±standard deviation, SD) clearance and volume of distribution were 2.87 ± 0.63 L/h and 15.90 ± 13.29 L, respectively. Dosing simulations showed that current guidelines (initial loading dose of 12 mg/kg then 6 mg/kg q24h) achieved >90% of PTA for a MIC up to 1 mg/L. None of the tested dosing regimens achieved 90% of PTA for MIC above 2 mg/L. Current fluconazole dosing regimen guidelines achieved >90% PTA only for Candida species with MIC <1 mg/L and thus should be only used for Candida-documented infections in critically ill patients receiving concomitant ECMO and CRRT. Total body weight should be considered for fluconazole dose.
... The clinical outcome of critically ill patients with infections remains unsatisfactory even with combined and aggressive antibiotic therapy. 1 This may be owing to a pre-existing hazard of death from severe pathological burden, or inadequate antimicrobial effects due to difficultto-achieve pharmacokinetic/pharmacodynamic (PK/PD) target attainment of antibiotics. Appropriate antibiotic dosing to ensure early and sufficient target attainment in patients in the intensive care unit (ICU) is quite challenging. ...
... 5 Last, altered volume of distribution and drug clearance (CL) driven by profound pathophysiological changes or surgery interventions in patients in the ICU may cause substantial PK variability, so that the therapeutic dose for non-critically ill patients may not be suitable for patients in the ICU and a tailored dosing regimen might be needed. 1,6 Because direct measurement and continuous quantification of antimicrobial effects is not feasible in patients in the ICU, clinical PK/PD analysis attempts to identify the breakpoint of a PK/PD index that best separates cure/no cure or mortality/survival subgroups. 7 Although tree-based modeling (e.g., classification and regression tree analysis [CART]) is clinically attractive due to intuitive and understandable decision rules from a heterogeneous group of predictors, such a retrospective time-collapsed approach is questionable in application. ...
Appropriate antibiotic dosing to ensure early and sufficient target attainment is crucial for improving clinical outcome in critically ill patients. Parametric survival analysis is a preferred modeling method to quantify time-varying antibiotic exposure - response effects, whereas bias may be introduced in hazard functions and survival functions when competing events occur. This study investigated predictors of in-hospital mortality in critically ill patients treated with meropenem by pharmacometric multistate modeling. A multistate model comprising five states (ongoing meropenem treatment, other antibiotic treatment, antibiotic treatment termination, discharge, and death) was developed to capture the transitions in a cohort of 577 critically ill patients treated with meropenem. Various factors were investigated as potential predictors of the transitions, including patient demographics, CLCRCG (creatinine clearance calculated by Cockcroft-Gault equation), fT>MIC (time that unbound concentrations exceed the minimum inhibitory concentration), and microbiology-related measures. The probabilities to transit to other states from ongoing meropenem treatment increased over time. A 10 mL/min decrease in CLCRCG was found to elevate the hazard of transitioning from states of ongoing meropenem treatment and antibiotic treatment termination to the death state by 18%. The attainment of 100% fT>MIC significantly increased the transition rate from ongoing meropenem treatment to antibiotic treatment termination (by 9.7%), and was associated with improved survival outcome. The multistate model prospectively assessed predictors of death and can serve as a useful tool for survival analysis in different infection scenarios, particularly when competing risks are present.
... Therapeutic drug monitoring (TDM) of β-lactam antibiotics has been proposed as a promising tool to personalize and optimize antibiotic dosing in critically ill patients in ICUs. 1,2 Because severe infections are a common cause of admission, and at least 70% of all ICU patients receive antibiotic treatment at some point, a more precision-based approach to antibiotic dosing could improve mortality and morbidity in the ICU. 1,3,4 However, it has not been proved that attaining pharmacokinetic (PK)/pharmacodynamic (PD) targets in ICU patients is correlated with lower mortality. ...
... 1,2 Because severe infections are a common cause of admission, and at least 70% of all ICU patients receive antibiotic treatment at some point, a more precision-based approach to antibiotic dosing could improve mortality and morbidity in the ICU. 1,3,4 However, it has not been proved that attaining pharmacokinetic (PK)/pharmacodynamic (PD) targets in ICU patients is correlated with lower mortality. 2,5 One reason could be that the PK/PD target attainment calculation consists of many uncertain elements such as which PK/PD target to use in ICU patients, assessing the correct degree of protein binding when total antibiotic concentrations are measured, the impact of which MIC parameter to use, and the impact of the technical variability of the MIC testing itself. ...
Background
Therapeutic drug monitoring (TDM) has been suggested to optimize antimicrobial target attainment, typically using 100%T>MIC, in β-lactam treatment in the ICU. The MIC parameter used in this equation is mostly the worst case scenario MIC (MICWCS)—the highest MIC the empirical treatment should cover. However, the impact of the MIC parameter used in pharmacokinetic/pharmacodynamic calculations has been poorly investigated.
Objectives
To assess the influence of target attainment rates for two different MIC parameters using actual MICs of the causative pathogens as the primary reference.
Methods
In a Swedish multicentre study of target attainment for 138 ICU patients treated with β-lactams, the causative pathogen was isolated and subjected to reference MIC testing. Whenever the strain belonged to the WT distribution, we assigned it to the category MICECOFF (epidemiological cut-off value). In the calculations we compared the MICECOFF and the MICWCS.
Results
The proportion of patients with target attainment failure for all antibiotics using 100%T>MIC was 45% (95% CI, 37%–53%) for MICWCS and 23% (95% CI, 16%–31%) for MICECOFF. When the target 50%T>4×MIC was used, corresponding attainment failures were 57% (95% CI, 49%–66%) and 25% (95% CI, 17%–32%) for MICWCS and MICECOFF, respectively.
Conclusions
MICWCS can overestimate target attainment failure. The use of MICWCS could be one reason for the difficulties in establishing a relationship between target failure and mortality in other studies. Based on findings herein, the MICECOFF, which is based on the MIC of the causative pathogen, should be considered a more suitable alternative. When no pathogen is detected, the MICECOFF of likely pathogens according to infection type should be used.
... In patients with normal liver and kidney function, hypoalbuminemia can result in elevated levels of unbound drugs, potentially leading to an increased CL, especially in highly protein-bound antibiotics like caspofungin. Additionally, as a hydrophilic drug, caspofungin's V d may increase due to fluid shifts and extensive fluid resuscitation [41,42]. ...
Background: Caspofungin is an echinocandin antifungal agent commonly used as the first-line therapy for invasive candidiasis, salvage therapy for invasive aspergillosis, and empirical therapy for presumed fungal infections. Pharmacokinetic (PK) variabilities and suboptimal exposure have been reported for caspofungin, increasing the risk of insufficient efficacy. Objective: This work aimed to develop a caspofungin population pharmacokinetic (popPK) library and demonstrate its utility by assessing the probability of target attainment across diverse settings. Methods: We established a caspofungin popPK model library following a rigorous literature review, re-implementing selected models in R with rxode2. Quality control procedures included a comparison of different studies and assessing covariate impacts. Model libraries were primarily used to perform Monte Carlo simulations to estimate target attainment and guide personalized dosing in Candida infections. Results: A total of 13 models, one- or two-compartment models, were included. The most significant covariates were body size (weight and body surface area), liver function, and albumin level. The results show that children and adults showed considerable differences in pharmacokinetics. For C. albicans and C. parapsilosis, none of the populations achieved a PTA of ≥90% at their respective susceptible MIC values. In contrast, for C. glabrata, 70% of the adult studies reached a PTA of ≥90%, while all pediatric studies achieved the same PTA level. Conclusion: At the recommended dosage, adult patients showed notably lower exposure to caspofungin compared to pediatric patients. Considering body size, liver function, and serum albumin is crucial when determining caspofungin dosage regimens. Furthermore, further research is required to comprehensively understand the pharmacokinetics of caspofungin in pediatric patients.
... The pathophysiological characteristics of the critically ill population differ from those of the general ward population; therefore, the PK profiles of voriconazole are significantly different in ICU patients [7]. Patients admitted to the ICU often show changes in fluid balance because of fluid therapy, capillary leakage, changes in plasma protein binding caused by hypoalbuminemia, and altered renal and hepatic function [7][8][9]. These changes are often accompanied by complex co-administered medications, systemic inflammation, bleeding, and transfusion, which can impact the drug clearance rate (CL) and apparent volume of distribution (Vd) [10]. ...
Aims: The pharmacokinetic (PK) profiles of voriconazole in intensive care unit (ICU) patients differ from that in other patients. We aimed to develop a population pharmacokinetic (PopPK) model to evaluate the effects of using extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT) and those of various biological covariates on the voriconazole PK profile. Methods: Modeling analyses of the PK parameters were conducted using the nonlinear mixed-effects modeling method (NONMEM) with a two-compartment model. Monte Carlo simulations (MCSs) were performed to observe the probability of target attainment (PTA) when receiving CRRT or not under different dosage regimens, different stratifications of quick C-reactive protein (qCRP), and different minimum inhibitory concentration (MIC) ranges. Results: A total of 408 critically ill patients with 746 voriconazole concentration–time data points were included in this study. A two-compartment population PK model with qCRP, CRRT, creatinine clearance rate (CLCR), platelets (PLT), and prothrombin time (PT) as fixed effects was developed using the NONMEM. Conclusions: We found that qCRP, CRRT, CLCR, PLT, and PT affected the voriconazole clearance. The most commonly used clinical regimen of 200 mg q12h was sufficient for the most common sensitive pathogens (MIC ≤ 0.25 mg/L), regardless of whether CRRT was performed and the level of qCRP. When the MIC was 0.5 mg/L, 200 mg q12h was insufficient only when the qCRP was <40 mg/L and CRRT was performed. When the MIC was ≥2 mg/L, a dose of 300 mg q12h could not achieve ≥ 90% PTA, necessitating the evaluation of a higher dose.
... have altered pharmacokinetics due to profoundly altered pathophysiological processes [3,4]. Routine therapeutic drug monitoring (TDM) of especially antibiotics in ICU patients is recommended to reduce the risk of under-or overdosing, to maximize the efficacy, and to minimize toxicity [5][6][7], hopefully leading to a higher rate of target attainment. Linezolid is regularly used in ICU patients with pneumonia or skin and soft tissue infections caused by gram-positive bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA) or vancomycin-resistant enterococci (VRE) [8]. ...
Background
Therapeutic drug monitoring (TDM) of anti-infectives such as linezolid is routinely performed in blood of intensive care unit (ICU) patients to optimize target attainment. However, the concentration at the site of infection is considered more important for a successful therapy. Until now, bronchoalveolar lavage (BAL) is the gold standard to measure intrapulmonary concentrations of anti-infective agents. However, it is an invasive method and unsuitable for regular TDM. The aim of this proof-of-concept study was to investigate whether it is possible to reliably determine the intrapulmonary concentration of linezolid from endotracheal aspiration (ENTA).
Methods
Intubated ICU patients receiving 600 mg intravenous linezolid twice daily were examined in steady state. First, preliminary experiments were performed in six patients to investigate which patients are suitable for linezolid measurement in ENTA. In a second step, trough and peak linezolid concentrations of plasma and ENTA were determined in nine suitable patients.
Results
Linezolid can validly be detected in ENTA with viscous texture and > 0.5 mL volume. The mean (SD) linezolid trough concentration was 2.02 (1.27) mg/L in plasma and 1.60 (1.36) mg/L in ENTA, resulting in a median lung penetration rate of 104%. The mean (SD) peak concentration in plasma and ENTA was 10.77 (5.93) and 4.74 (2.66) mg/L.
Conclusions
Linezolid can validly be determined in ENTA with an adequate texture and volume. The penetration rate is comparable to already published BAL concentrations. This method might offer a simple and non-invasive method for TDM at the site of infection “lung”. Due to promising results of the feasibility study, comparison of ENTA and BAL in the same patient should be investigated in a further trial.
... infections. [130][131][132] In those with decompensated cirrhosis, meropenem clearance is reduced and drug distribution can be affected by ACLF and higher MELD scores. 133 In addition to Candida, there has been a notable increase in invasive aspergillosis in recent years. ...
Background
The increase in prevalence of liver disease globally will lead to a substantial incremental burden on intensive care requirements. While liver transplantation offers a potential life‐saving intervention, not all patients are eligible due to limitations such as organ availability, resource constraints, ongoing sepsis or multiple organ failures. Consequently, the focus of critical care of patients with advanced and decompensated cirrhosis turns to liver‐centric intensive care protocols, to mitigate the high mortality in such patients.
Aim
Provide an updated and comprehensive understanding of cirrhosis management in critical care, and which includes emergency care, secondary organ failure management (mechanical ventilation, renal replacement therapy, haemodynamic support and intensive care nutrition), use of innovative liver support systems, infection control, liver transplantation and palliative and end‐of life care.
Methods
We conducted a structured bibliographic search on PubMed, sourcing articles published up to 31 March 2024, to cover topics addressed. We considered data from observational studies, recommendations of society guidelines, systematic reviews, and meta‐analyses, randomised controlled trials, and incorporated our clinical expertise in liver critical care.
Results
Critical care management of the patient with cirrhosis has evolved over time while mortality remains high despite aggressive management with liver transplantation serving as a crucial but not universally available resource.
Conclusions
Implementation of organ support therapies, intensive care protocols, nutrition, palliative care and end‐of‐life discussions and decisions are an integral part of critical care of the patient with cirrhosis. A multi‐disciplinary approach towards critical care management is likely to yield better outcomes.
... These pathophysiological shifts arise from the underlying severe acute or chronic conditions as well as the responses to clinical interventions provided. They often coincide with an increase in cardiac output, resulting in increased clearance, inflammatory responses, and capillary leaks that further contribute to excess extravascular fluid [2,3]. These factors significantly impact the pharmacokinetics and pharmacodynamics (PK/PD) properties of antimicrobial drugs, making therapy outcomes unpredictable. ...
Augmented renal clearance (ARC), defined as a creatinine clearance (CrCl) > 130 mL/min/1.73 m², is observed in 30–65% of critically ill patients. When following standard dosage guidelines, patients with ARC often experience subtherapeutic vancomycin levels, resulting in treatment failure due to accelerated drug elimination. This review aims to explore ARC’s impact on vancomycin pharmacokinetics and pharmacodynamics (PK/PD) indices in ARC patients, seeking to identify an accurate dose adjustment method for this patient population. In September 2023, a comprehensive literature search was conducted on the MEDLINE and EMBASE databases to include all available studies providing information on the impact of ARC on vancomycin therapy in critically ill adults. Articles that studied the pediatric population and those with insufficient PK data were excluded. A total of 21 articles met the inclusion criteria. The findings revealed a positive correlation between CrCl and vancomycin clearance, indicating low serum concentrations. Therefore, upward dosing adjustments are necessary to improve treatment success. Younger age consistently emerged as a major contributor to ARC and vancomycin PK/PD alterations. This study summarizes the PK/PD alterations, current dosage recommendations and proposes preliminary recommendations on possible dosing approaches to decrease the risk of subtherapeutic exposure in this patient population.
... A special attention on antibiotic therapy management is therefore essential. Sepsis leads to alterations of antibiotics PK/PD parameters because of renal clearance alteration [78,79] and/or extracorporeal supports [80], may reducing blood concentrations leading to failure, or increasing drug toxicity [81,82], therefore, guidelines recommend optimizing dosing antibiotic therapy based on PK/PD principles and specific drug properties [28]. To avoid the development of antimicrobial resistance, a daily assessment for de-escalation of antimicrobials over using fixed durations of therapy without daily reassessment for de-escalation is recommended [28]. ...
This article describes the structures and processes involved in healthcare delivery for sepsis, from the prehospital setting until rehabilitation. Quality improvement initiatives in sepsis may reduce both morbidity and mortality. Positive outcomes are more likely when the following steps are optimized: early recognition, severity assessment, prehospital emergency medical system activation when available, early therapy (antimicrobials and hemodynamic optimization), early orientation to an adequate facility (emergency room, operating theater or intensive care unit), in-hospital organ failure resuscitation associated with source control, and finally a comprehensive rehabilitation program. Such a trajectory of care dedicated to sepsis amounts to a chain of survival and rehabilitation for sepsis. Implementation of this chain of survival and rehabilitation for sepsis requires full interconnection between each link. To date, despite regular international recommendations updates, the adherence to sepsis guidelines remains low leading to a considerable burden of the disease. Developing and optimizing such an integrated network could significantly reduce sepsis related mortality and morbidity.
... The list of benefits of tracking medication usage has grown to include assessing how effectively drugs are functioning, ensuring patients are taking their prescriptions as directed, averting negative drug interactions, and even determining when to stop using them. It is possible to monitor drug concentrations in plasma independently, which is helpful in some circumstances even if not all medications work with all indications [21][22][23]. On the other hand, measuring plasma levels could be useful. ...
Therapeutic drug monitoring (TDM) has evolved into therapeutic drug management throughout the past three to four decades, becoming a crucial facet of precision medicine. Even though India has one of the fastest-growing economies in the world, TDM is not widely used there. At the moment, it is restricted to a small number of teaching hospitals and academic medical institutes. Other therapeutic domains, such anticancer, antifungal, antibacterial, and antitubercular medications, have shown considerable promise to enhance patient outcomes in Indian settings, aside from immunosuppressive pharmaceuticals. The population of this subcontinent is unique in terms of the importance of TDM due to factors like the higher prevalence of nutritional deficiencies, tropical diseases, the widespread adoption of alternative medicines, unlike pharmacogenomics, and the scarcity of population-specific data on the therapeutic ranges of multiple drugs.TDM has not gotten the interest it merits in India, despite its vast applicability and influence on clinical science. This study aims to present a SWOT (strength, weakness, opportunity, and threats) analysis of TDM in India so that suitable measures for promoting TDM growth can be envisaged. Forming a collaborative group with all the stakeholders-including TDM experts, physicians, and the government-and coming up with a National Action Plan to support TDM are urgent needs. To determine the country's TDM focus areas, nodal TDM facilities should be formed, and pilot programmes should be launched. Capacity development and awareness rising are also important steps towards integrating TDM into traditional clinical practice.
... Furthermore, failure in attaining aggressive PK/PD targets with beta-lactams was independently associated with a significantly higher risk of microbiological failure [31,51]. Unfortunately, the relevant pathophysiological alterations occurring in critically ill patients may affect the likelihood of attaining aggressive betalactam PK/PD targets [5,29,[59][60][61][62]. Consequently, implementing a real-time TDM-guided ECPA program could be helpful in addressing this issue by providing proper dosing adjustments for promptly attaining aggressive PK/PD target [28], as witnessed by our findings. ...
(1) Background: The advantage of using carbapenems over beta-lactam/beta-lactamase inhibitor combinations in critically ill septic patients still remains a debated issue. We aimed to assess the comparative impact of an optimized pharmacokinetic/pharmacodynamic (PK/PD) target attainment of piperacillin-tazobactam vs. meropenem on the trend over time of both Sequential Organ Failure Assessment (SOFA) score and inflammatory biomarkers in critically ill patients receiving continuous infusion (CI) monotherapy with piperacillin-tazobactam or meropenem for treating documented Gram-negative bloodstream infections (BSI) and/or ventilator-associated pneumonia (VAP). (2) Methods: We performed a retrospective observational study comparing critically ill patients receiving targeted treatment with CI meropenem monotherapy for documented Gram-negative BSIs or VAP with a historical cohort of critical patients receiving CI piperacillin-tazobactam monotherapy. Patients included in the two groups were admitted to the general and post-transplant intensive care unit in the period July 2021–September 2023 and fulfilled the same inclusion criteria. The delta values of the SOFA score between the baseline of meropenem or piperacillin-tazobactam treatment and those at 48-h (delta 48-h SOFA score) or at 7-days (delta 7-days SOFA) were selected as primary outcomes. Delta 48-h and 7-days C-reactive protein (CRP) and procalcitonin (PCT), microbiological eradication, resistance occurrence, clinical cure, multi-drug resistant colonization at 90-day, ICU, and 30-day mortality rate were selected as secondary outcomes. Univariate analysis comparing primary and secondary outcomes between critically ill patients receiving CI monotherapy with piperacillin-tazobactam vs. meropenem was carried out. (3) Results: Overall, 32 critically ill patients receiving CI meropenem monotherapy were compared with a historical cohort of 43 cases receiving CI piperacillin-tazobactam monotherapy. No significant differences in terms of demographics and clinical features emerged at baseline between the two groups. Optimal PK/PD target was attained in 83.7% and 100.0% of patients receiving piperacillin-tazobactam and meropenem, respectively. No significant differences were observed between groups in terms of median values of delta 48-h SOFA (0 points vs. 1 point; p = 0.89) and median delta 7-days SOFA (2 points vs. 1 point; p = 0.43). Similarly, no significant differences were found between patients receiving piperacillin-tazobactam vs. meropenem for any of the secondary outcomes. (4) Conclusion: Our findings may support the contention that in critically ill patients with documented Gram-negative BSIs and/or VAP, the decreases in the SOFA score and in the inflammatory biomarkers serum levels achievable with CI piperacillin-tazobactam monotherapy at 48-h and at 7-days may be of similar extent and as effective as to those achievable with CI meropenem monotherapy provided that optimization on real-time by means of a TDM-based expert clinical pharmacological advice program is granted.
... Therefore, the recommended concentration of antibiotics in critically ill patients may not be accurate due to differences in the volume of distribution, clearance and organ function, such as kidney and liver, which are the main organs for metabolising and excreting antibiotics. Various factors, such as serum albumin, fluid status, systemic inflammatory response syndrome, microvascular failure, and changes in renal and hepatic function may change the pharmacokinetics, which can alter the concentration of the antibiotic in critically ill patients (41). Therefore, antibiotics should be individualised in the future. ...
Background
The aim of the study was to determine the predictors of meropenem treatment failure and mortality in the Intensive Care Unit (ICU).
Methods
This was a retrospective study, involving sepsis and septic shock patients who were admitted to the ICU and received intravenous meropenem. Treatment failure is defined as evidence of non-resolved fever, non-reduced total white cell (TWC), non-reduced C-reactive protein (CRP), subsequent culture negative and death in ICU.
Results
An Acute Physiology and Chronic Health Evaluation II (APACHE II) and duration of antibiotic treatment less than 5 days were associated with treatment failure with adjusted OR = 1.24 (95% CI: 1.15, 1.33; P < 0.001), OR = 65.43 (95% CI: 21.70, 197.23; P < 0.001). A higher risk of mortality was observed with higher APACHE and Sequential Organ Failure Assessment (SOFA) scores, initiating antibiotics > 72 h of sepsis, duration of antibiotic treatment less than 5 days and meropenem with renal adjustment dose with an adjusted OR = 1.21 (95% CI: 1.12, 1.30; P < 0.001), adjusted OR = 1.23 (95% CI: 1.08, 1.41; P < 0.001), adjusted OR = 6.38 (95% CI: 1.67, 24.50; P = 0.007), adjusted OR = 0.03 (95% CI: 0.01, 0.14; P < 0.001), adjusted OR = 0.30 (95% CI: 0.14, 0.64; P = 0.002).
Conclusion
A total of 50 (14.12%) patients had a treatment failure with meropenem with 120 (48.02%) ICU mortality. The predictors of meropenem failure are higher APACHE score and shorter duration of meropenem treatment. The high APACHE, high SOFA score, initiating antibiotics more than 72 h of sepsis, shorter duration of treatment and meropenem with renal adjustment dose were predictors of mortality.
... It is generally defined as a coordinated interventions designed to improve and measure the appropriate use of antimicrobials by promoting the selection of the optimal antimicrobial drug regimen, dose, duration of therapy, and route of administration [6]. This issue is even more challenging in critically ill patients, where the occurrence of sepsis-related pathophysiological alterations like increased volume of distribution, augmented renal clearance, need for continuous renal replacement therapy (CRRT), have a strong impact on the pharmacokinetic/pharmacodynamic (PK/PD) behaviour of antimicrobials, increasing the risks of under exposure, mainly for beta lactams (BL) [7,8]. A growing body of evidence shows that early appropriate antibiotic therapy is a cornerstone in the management of septic ICU patients, being associated with a significant decrease in mortality rate [9]. ...
Background
Bloodstream infections (BSIs) by Gram-negative pathogens play a major role in intensive care patients, both in terms of prevalence and severity, especially if multi-drug resistant pathogens are involved. Early appropriate antibiotic therapy is therefore a cornerstone in the management of these patients, and growing evidence shows that implementation of a multidisciplinary team may improve patients’ outcomes. Our aim was to evaluate the clinical and microbiological impact of the application of a multidisciplinary team on critically ill patients.
Methods
Pre-post study enrolling critically ill patients with Gram negative bloodstream infection in intensive care unit. In the pre-intervention phase (from January until December 2018) patients were managed with infectious disease consultation on demand, in the post-intervention phase (from January until December 2022) patients were managed with a daily evaluation by a multidisciplinary team composed of intensivist, infectious disease physician, clinical pharmacologist and microbiologist.
Results
Overall, 135 patients were enrolled during the study period, of them 67 (49.6%) in the pre-intervention phase and 68 (50.4%) in the post-intervention phase. Median age was 67 (58–75) years, sex male was 31.9%. Septic shock, the need for continuous renal replacement therapy and mechanical ventilation at BSI onset were similar in both groups, no difference of multidrug-resistant organisms (MDRO) prevalence was observed. In the post-phase, empirical administration of carbapenems decreased significantly (40.3% vs. 62.7%, p = 0.02) with an increase of appropriate empirical therapy (86.9% vs. 55.2%, p < 0.001) and a decrease of overall antibiotic treatment (12 vs. 16 days, p < 0.001). Despite no differences in delta SOFA and all-cause 30-day mortality, a significant decrease in microbiological failure (10.3% vs. 29.9%, p = 0.005) and a new-onset 30-day MDRO colonization (8.3% vs. 36.6%, p < 0.001) in the post-phase was reported. At multivariable analysis adjusted for main covariates, the institution of a multidisciplinary management team (MMT) was found to be protective both for new MDRO colonization [OR 0.17, 95%CI(0.05–0.67)] and microbiological failure [OR 0.37, 95%CI (0.14–0.98)].
Conclusions
The institution of a MMT allowed for an optimization of antimicrobial treatments, reflecting to a significant decrease in new MDRO colonization and microbiological failure among critically ill patients.
... Most patients requiring SLED reside in an intensive care unit (ICU) and require antimicrobial therapy for the treatment of sepsis, the leading cause of acute kidney injury (AKI) in the critically ill population (3). There is a 50% higher mortality risk in septic patients compared to non-septic patients requiring KRT, a problem potentially related to underdosing of antimicrobials in this population (4). Critically ill patients have significant pharmacokinetic (PK) alterations, decreasing the likelihood of achieving optimal PK and pharmacodynamic targets with antimicrobials (5). ...
Adequate dosing of antimicrobials is paramount for treating infections in critically ill patients undergoing kidney replacement therapy; however, little is known about antimicrobial removal by sustained low-efficiency dialysis (SLED). The objective was to quantify the removal of cefepime, daptomycin, meropenem, piperacillin–tazobactam, and vancomycin in patients undergoing SLED. Adult patients ≥18 years with acute kidney injury (AKI) or end-stage kidney disease receiving one of the select antimicrobials and requiring SLED were included. Blood and dialysate flow rates were maintained at 250 and 100 mL/min, respectively. Simultaneous arterial and venous blood samples for the analysis of antibiotic concentrations were collected hourly for 8 hours during SLED (on-SLED). Arterial samples were collected every 2 hours for up to 6 hours while not receiving SLED (off-SLED) for the calculation of SLED clearance, half-life (t1/2) on-SLED and off-SLED, and the fraction of removal by SLED (fD). Twenty-one patients completed the study: 52% male, mean age (±SD) 53 ± 13 years, and mean weight of 98 ± 30 kg. Eighty-six percent had AKI, and 4 patients were receiving cefepime, 3 daptomycin, 10 meropenem, 6 piperacillin–tazobactam, and 13 vancomycin. The average SLED time was 7.3 ± 1.1 hours, and the mean ultrafiltration rate was 95 ± 52 mL/hour (range 10–211). The t1/2 on-SLED was substantially lower than the off-SLED t1/2 for all antimicrobials, and the SLED fD varied between 44% and 77%. An 8-hour SLED session led to significant elimination of most antimicrobials evaluated. If SLED is performed, modification of the dosing regimen is warranted to avoid subtherapeutic concentrations.
... Pharmacometrics modeling is a powerful tool that can support the development and implementation of personalized dosing by taking patient variability into consideration, 1 as often seen in the field of antiinfective treatment or pediatric treatment. 2,3 Whereas pharmacometric modeling has been widely accepted as a mainstream tool for development of new treatment in optimizing and selecting one-size-fits-all dose on a population level, its application for optimizing treatment on an individual level is still uncommon. 4,5 Model-informed personalized dosing can be especially useful when a new treatment has a narrow therapeutic window on a population level, 6 but advancing it to routine clinical practice requires overcoming numerous barriers, including methodological refinements 7,8 and providing robust evidence to demonstrate improved patient outcomes. ...
Personalized dosing approaches play important roles in clinical practices to improve benefit: risk profiles. Whereas this is also important for drug development, especially in the context of drugs with narrow therapeutic windows, such approaches have not been fully evaluated during clinical development. Fazpilodemab (BFKB8488A) is an agonistic bispecific antibody which was being developed for the treatment of nonalcoholic steatohepatitis. The objective of this study was to characterize the exposure-response relationships of fazpilodemab with the purpose of guiding dose selection for a phase II study, as well as to evaluate various personalized dosing strategies to optimize the treatment benefit. Fazpilodemab exhibited clear exposure-response relationships for a pharmacodynamic (PD) biomarker and gastrointestinal adverse events (GIAEs), such as nausea and vomiting. Static exposure-response analysis, as well as longitudinal adverse event (AE) analysis using discrete-time Markov model, were performed to characterize the observations. Clinical trial simulations were performed based on the developed exposure-response models to evaluate probability of achieving target PD response and the frequency of GIAEs to inform phase II dose selection. Dynamic simulation of personalized dosing strategies demonstrated that the AE-based personalized dosing is the most effective approach for optimizing the benefit-risk profiles. The approach presented here can be a useful framework for quantifying the benefit of personalized dosing for drugs with narrow therapeutic windows.
... The sepsis inflammatory response leads to significant fluid shifts into the interstitial space, an initial high cardiac output, and hypoalbuminaemia, leading to increased volume of distribution (Vd); less antimicrobial is available in plasma and, therefore, at the site of infection [92,94]. For other patients, organ dysfunction with renal or hepatic impairment may require reduced dosing to ensure therapeutic but nontoxic levels [95]. Acute kidney injury requiring CRRT occurs in 15% of septic patients and increases mortality by 50%. ...
Sepsis stands as a formidable global health challenge, with persistently elevated mortality rates in recent decades. Each year, sepsis not only contributes to heightened morbidity but also imposes substantial healthcare costs on survivors. This narrative review aims to highlight the targeted measures that can be instituted to alleviate the incidence and impact of sepsis in intensive care. Here we discuss measures to reduce nosocomial infections and the prevention of equipment and patient colonisation by resilient pathogens. The overarching global crisis of bacterial resistance to newly developed antimicrobial agents intensifies the imperative for antimicrobial stewardship and de-escalation. This urgency has been accentuated in recent years, notably during the COVID-19 pandemic, as high-dose steroids and opportunistic infections presented escalating challenges. Ongoing research into airway colonisation’s role in influencing disease outcomes among critically ill patients underscores the importance of tailoring treatments to disease endotypes within heterogeneous populations, which are important lessons for intensivists in training. Looking ahead, the significance of novel antimicrobial delivery systems and drug monitoring is poised to increase. This narrative review delves into the multifaceted barriers and facilitators inherent in effectively treating critically ill patients vulnerable to nosocomial infections. The future trajectory of intensive care medicine hinges on the meticulous implementation of vigilant stewardship programs, robust infection control measures, and the continued exploration of innovative and efficient technological solutions within this demanding healthcare landscape.
... High variability in PK frequently observed in ICU populations requires more frequent sampling early in the dosing interval. 27 Further challenges with limited sampling strategies for use in population pharmacokinetic models have been thoroughly discussed by Hovd et al. 28 ...
Background
Several studies report lack of meropenem pharmacokinetic/pharmacodynamic (PK/PD) target attainment (TA) and risk of therapeutic failure with intermittent bolus infusions in intensive care unit (ICU) patients. The aim of this study was to describe meropenem TA in an ICU population and the clinical response in the first 72 h after therapy initiation.
Methods
A prospective observational study of ICU patients ≥18 years was conducted from 2014 to 2017. Patients with normal renal clearance (NRC) and augmented renal clearance (ARC) and patients on continuous renal replacement therapy (CRRT) were included. Meropenem was administered as intermittent bolus infusions, mainly at a dose of 1 g q6h. Peak, mid, and trough levels were sampled at 24, 48, and 72 h after therapy initiation. TA was defined as 100% T > 4× MIC or trough concentration above 4× MIC. Meropenem PK was estimated using traditional calculation methods and population pharmacokinetic modeling (P‐metrics®). Clinical response was evaluated by change in C‐reactive protein (CRP), Sequential Organ Failure Assessment (SOFA) score, leukocyte count, and defervescence.
Results
Eighty‐seven patients were included, with a median Simplified Acute Physiology (SAPS) II score 37 and 90 days mortality rate of 32%. Median TA was 100% for all groups except for the ARC group with 45.5%. Median CRP fell from 175 (interquartile range [IQR], 88–257) to 70 (IQR, 30–114) ( p < .001) in the total population. A reduction in SOFA score was observed only in the non‐CRRT groups ( p < .001).
Conclusion
Intermittent meropenem bolus infusion q6h gives satisfactory TA in an ICU population with variable renal function and CRRT modality, except for ARC patients. No consistent relationship between TA and clinical endpoints were observed.
... Best practices have been established to standardize the application of typical in vivo PK/PD models [36][37][38]. The neutropenic murine thigh and lung infection models have demonstrated their ability to predict the clinical exposure targets for multiple established antibiotic classes [39,40], and a positive correlation has been described between clinical cure, mortality, and achievement of exposure targets [41]. It stands to reason that the established translatability across multiple classes of antibiotics, from bacterial load reduction in vivo to positive outcomes in clinical trials, would also hold true for antibiotics acting through a novel Mechanism of Action (MoA). ...
Antibiotic development traditionally involved large Phase 3 programs, preceded by Phase 2 studies. Recognizing the high unmet medical need for new antibiotics and, in some cases, challenges to conducting large clinical trials, regulators created a streamlined clinical development pathway in which a lean clinical efficacy dataset is complemented by nonclinical data as supportive evidence of efficacy. In this context, translational Pharmacokinetic/Pharmacodynamic (PK/PD) plays a key role and is a major contributor to a “robust” nonclinical package. The classical PK/PD index approach, proven successful for established classes of antibiotics, is at the core of recent antibiotic approvals and the current antibacterial PK/PD guidelines by regulators. Nevertheless, in the case of novel antibiotics with a novel Mechanism of Action (MoA), there is no prior experience with the PK/PD index approach as the basis for translating nonclinical efficacy to clinical outcome, and additional nonclinical studies and PK/PD analyses might be considered to increase confidence. In this review, we discuss the value and limitations of the classical PK/PD approach and present potential risk mitigation activities, including the introduction of a semi-mechanism-based PK/PD modeling approach. We propose a general nonclinical PK/PD package from which drug developers might choose the studies most relevant for each individual candidate in order to build up a “robust” nonclinical PK/PD understanding.
... Ceftriaxone clearance is dependent on biliary and renal excretion [8] and has a long halflife due to its high albumin-binding capacity [9]. These pharmacokinetic parameters have been known to change in critically ill patients [10], resulting in abnormal plasma concentrations of ceftriaxone [11]. ...
b> Introduction: We describe a child with meningococcal sepsis who suffered cephalosporin-related neurotoxicity. Case Presentation: A four-year-old girl was treated with intravenous ceftriaxone and supportive therapy. After rapid improvement, inotropic and respiratory support was stopped within 2 days. However, she developed renal failure and, on day four, deteriorated neurologically. Research into the cause of her encephalopathy revealed supra-therapeutic ceftriaxone concentrations with greatly increased unbound fractions leading to the diagnosis of cephalosporin-related neurotoxicity. Ceftriaxone treatment was discontinued, and renal replacement therapy was initiated on day six. With both discontinuation of ceftriaxone and renal replacement therapy, the girl’s condition improved rapidly. Conclusion: We postulate that in the described case both renal impairment and hypoalbuminemia played an important role in the development of high unbound ceftriaxone serum levels. We advocate therapeutic drug monitoring for ceftriaxone in critically ill children with renal failure or hypoalbuminemia.
... Its clinical presentation is often non-speci c, while the processes of pathogen identi cation and susceptibility testing using conventional culture-based methods are time-consuming [5]. Even when pathogen and susceptibility are known, patients in the intensive care unit (ICU) are exposed to subtherapeutic antibiotic exposures as a consequence of the pathophysiological changes that occur in critical illness, and the interventions they require [6,7]. Overcoming these barriers and reducing the time to therapeutic antibiotic exposures is intended to lead to reductions in mortality and length of stay. ...
Purpose
Early recognition and effective treatment of sepsis improves outcomes in critically ill patients. However, antibiotic exposures are frequently suboptimal in the Intensive Care Unit (ICU) setting. We describe the feasibility of the Bayesian dosing software ID-ODS™ to reduce time to effective antibiotic exposure in children and adults in ICU with sepsis.
Methods
A multi-centre prospective, non-randomised interventional trial in three adult ICUs and one paediatric ICU. In a pre-intervention Phase 1, we measured the time to target antibiotic exposure in participants. In Phase 2, antibiotic dosing recommendations were made using ID-ODS™, and time to target antibiotic concentrations compared to patients in Phase 1 (a pre-post design).
Results
175 antibiotic courses (Phase 1 = 123, Phase 2 = 52) were analysed from 156 participants. Across all patients, there was no difference in the time to achieve target exposures (8.7 hours vs 14.3 hours in Phase 1 and Phase 2 respectively, p = 0.45). Sixty-one courses in 54 participants failed to achieve target exposures within 24 hours of antibiotic commencement (n = 36 in Phase 1, n = 18 in Phase 2). In these participants, ID-ODS was associated with a reduction in time to target antibiotic exposure (96.0 vs 36.4 hours in Phase 1 and Phase 2 respectively, p < 0.01). These patients were less likely to exhibit subtherapeutic antibiotic exposures at 96 hours (HR 0.02, 95%CI 0.01–0.05, p < 0.01). There was no difference observed in in-hospital mortality.
Conclusions
Dosing software may reduce the time to achieve target antibiotic exposures with the potential to improve clinical outcomes.
... In a metaanalysis of individual patient data from RCTs, it seemed that patients with an Acute Physiology and Chronic Health Evaluation II (APACHE II) score of 22 or higher benefited more from prolonged infusion than patients with an APACHE II score of less than 22, including hospital mortality, ICU mortality, and clinical cure [31]. This can be explained by the fact that the more severe the disease, the more obvious changes in pharmacokinetic/ pharmacodynamic parameters are due to various reasons [32,33]. In addition, in theory, prolonged infusion is more likely to achieve pharmacokinetic/pharmacodynamic targets than intermittent infusion [8]. ...
Background
The prolonged β-lactam antibiotics infusion has been an attractive strategy in severe infections, because it provides a more stable free drug concentration and a longer duration of free drug concentration above the minimum inhibitory concentration (MIC). We conducted this systematic review of randomized clinical trials (RCTs) with meta-analysis and trial sequential analysis (TSA) to compare the effects of prolonged vs intermittent intravenous infusion of β-lactam antibiotics for patients with sepsis.
Methods
This study was prospectively registered on PROSPERO database (CRD42023447692). We searched EMBASE, PubMed, and Cochrane Library to identify eligible studies (up to July 6, 2023). Any study meeting the inclusion and exclusion criteria would be included. The primary outcome was all-cause mortality within 30 days. Two authors independently screened studies and extracted data. When the I 2 values < 50%, we used fixed-effect mode. Otherwise, the random effects model was used. TSA was also performed to search for the possibility of false-positive (type I error) or false-negative (type II error) results.
Results
A total of 4355 studies were identified in our search, and nine studies with 1762 patients were finally included. The pooled results showed that, compared with intermittent intravenous infusion, prolonged intravenous infusion of beta-lactam antibiotics resulted in a significant reduction in all-cause mortality within 30 days in patients with sepsis (RR 0.82; 95%CI 0.70–0.96; P = 0.01; TSA-adjusted CI 0.62–1.07). However, the certainty of the evidence was rated as low, and the TSA results suggested that more studies were needed to further confirm our conclusion. In addition, it is associated with lower hospital mortality, ICU mortality, and higher clinical cure. No significant reduction in 90-day mortality or the emergence of resistance bacteria was detected between the two groups.
Conclusions
Prolonged intravenous infusion of beta-lactam antibiotics in patients with sepsis was associated with short-term survival benefits and higher clinical cure. However, the TSA results suggested that more studies are needed to reach a definitive conclusion. In terms of long-term survival benefits, we could not show an improvement.
... First, our analysis exclusively considered healthy volunteers without altered pathophysiologic conditions and its results might not necessarily be transferable to infected patients with comorbidities, as suggested by a previous population PK analysis on CPT in patients with CAP, cSSTI and/or renal impairment versus healthy volunteers [17]. Highly variable exposure and faster drug elimination have been shown in infected patients, particularly in severely ill patients and those with augmented renal clearance, implying likely lower target attainment rates than in healthy volunteers [10,31]. Thus, the dosing regimens required to attain specific PK/PD targets might differ between healthy volunteers and severely ill patients. ...
Ceftaroline fosamil is a β-lactam antibiotic approved as a 600 mg twice daily dose (≤1 h infusion, ‘standard dosing’) or a 600 mg thrice daily dose (2 h infusion) to treat complicated skin and soft tissue infections caused by Staphylococcus aureus (minimum inhibitory concentration [MIC] 2–4 mg/L). We sought to systematically evaluate the relative impact of the three key components of the intensified dosing regimen (i.e. shortened dosing interval, prolonged infusion duration and increased total daily dose [TDD]) on the pharmacokinetic/pharmacodynamic (PK/PD) target attainment given different grades of bacterial susceptibility.
A population PK model was developed using data from 12 healthy volunteers (EudraCT-2012-005134-11) receiving standard or intensified dosing. PK/PD target attainment (ƒT>MIC = 35% and 100%) after 24 h was compared following systematically varied combinations of the (1) dosing interval (every 12 h [q12h]→ every 8 h [q8h]); (2) infusion duration (1 h→2 h); and (3) individual and total daily dose (400→900 mg, i.e. TDD 1200→1800 mg), as well as for varying susceptibility of S. aureus (MIC 0.032–8 mg/L).
A two-compartment model with linear elimination adequately described ceftaroline concentrations (n = 274). The relevance of the dosing components dosing interval/infusion duration/TDD for ƒT>MIC systematically changed with pathogen susceptibility. For susceptible pathogens with MIC ≤1 mg/L, shortened dosing intervals appeared as the main driver of the improved target attainment associated with the intensified dosing regimen, followed by increased TDD and infusion duration. For less susceptible pathogens, the advantage of q8h dosing and 2 h infusions declined, and increased TDD improved ƒT>MIC the most.
The analysis calls to mind consideration of dose increases when prolonging the infusion duration in the case of low bacterial susceptibility.
... Antibiotic therapy is a cornerstone in the treatment of sepsis and severe infections, and appropriate antibiotic dosing design based on pharmacokinetics/pharmacodynamics (PK/PD) is necessary [1][2][3][4]. The Surviving Sepsis Campaign suggested that dosing strategies for antimicrobials should be optimized based on PK/PD and specific drug properties as a best practice statement [5]. ...
Background
The efficacy of therapeutic drug monitoring (TDM)-based antimicrobial dosing optimization strategies on pharmacokinetics/pharmacodynamics and specific drug properties for critically ill patients is unclear. Here, we conducted a systematic review and meta-analysis of randomized controlled trials to evaluate the effectiveness of TDM-based regimen in these patients.
Methods
Articles from three databases were systematically retrieved to identify relevant randomized control studies. Version two of the Cochrane tool for assessing risk of bias in randomized trials was used to assess the risk of bias in studies included in the analysis, and quality assessment of evidence was graded using the Grading of Recommendations Assessment, Development, and Evaluation approach. Primary outcome was the 28-day mortality and secondary outcome were in-hospital mortality, clinical cure, length of stay in the intensive care unit (ICU) and target attainment at day 1 and 3.
Results
In total, 5 studies involving 1011 patients were included for meta-analysis of the primary outcome, of which no significant difference was observed between TDM-based regimen and control groups (risk ratio [RR] 0.94, 95% confidence interval [CI]: 0.77–1.14; I ² = 0%). In-hospital mortality (RR 0.96, 95% CI: 0.76–1.20), clinical cure (RR 1.23, 95% CI: 0.91–1.67), length of stay in the ICU (mean difference 0, 95% CI: − 2.18–2.19), and target attainment at day 1 (RR 1.14, 95% CI: 0.88–1.48) and day 3 (RR 1.35, 95% CI: 0.90–2.03) were not significantly different between the two groups, and all evidence for the secondary outcomes had a low or very low level of certainty because the included studies had serious risk of bias, variation of definition for outcomes, and small sample sizes.
Conclusion
TDM-based regimens had no significant efficacy for clinical or pharmacological outcomes. Further studies with other achievable targets and well-defined outcomes are required.
Trial registration : Clinical trial registration; PROSPERO ( https://www.crd.york.ac.uk/prospero/ ), registry number: CRD 42022371959. Registered 24 November 2022.
Background
Daptomycin is widely used in critically ill patients for Gram-positive bacterial infections. Extracorporeal membrane oxygenation (ECMO) is increasingly used in this population and can potentially alter the pharmacokinetic (PK) behaviour of antibiotics. However, the effect of ECMO has not been evaluated in daptomycin. Our study aims to explore the effect of ECMO on daptomycin in critically ill patients through population pharmacokinetic (PopPK) analysis and to determine optimal dosage regimens based on both efficacy and safety considerations.
Methods
A prospective, open-label PK study was carried out in critically ill patients with or without ECMO. The total concentration of daptomycin was determined by UPLC-MS/MS. NONMEM was used for PopPK analysis and Monte Carlo simulations.
Results
Two hundred and ninety-three plasma samples were collected from 36 critically ill patients, 24 of whom received ECMO support. A two-compartment model with first-order elimination can best describe the PK of daptomycin. Creatinine clearance (CLCR) significantly affects the clearance of daptomycin while ECMO has no significant effect on the PK parameters. Monte Carlo simulations showed that, when the MICs for bacteria are ≥1 mg/L, the currently recommended dosage regimen is insufficient for critically ill patients with CLCR > 30 mL/min. Our simulations suggest 10 mg/kg for patients with CLCR between 30 and 90 mL/min, and 12 mg/kg for patients with CLCR higher than 90 mL/min.
Conclusions
This is the first PopPK model of daptomycin in ECMO patients. Optimal dosage regimens considering efficacy, safety, and pathogens were provided for critical patients based on pharmacokinetic-pharmacodynamic analysis.
Background Antimicrobial dosing in critically ill patients is challenging and model-informed precision dosing (MIPD) software may be used to optimize dosing in these patients. However, few intensive care units (ICU) currently adopt MIPD software use.
Objectives To determine the usability of MIPD software perceived by ICU clinicians and identify implementation barriers and enablers of software in the ICU.
Methods Clinicians (pharmacists and medical staff) who participated in a wider multicenter study using MIPD software were invited to participate in this mixed-method study. Participants scored the industry validated Post-study System Usability Questionnaire (PSSUQ, assessing software usability) and Technology Acceptance Model 2 (TAM2, assessing factors impacting software acceptance) survey. Semistructured interviews were used to explore survey responses. The framework approach was used to identify factors influencing software usability and integration into the ICU from the survey and interview data.
Results Seven of the eight eligible clinicians agreed to participate in the study. The PSSUQ usability scores ranked poorer than the reference norms (2.95 vs. 2.62). The TAM2 survey favorably ranked acceptance in all domains, except image. Qualitatively, key enablers to workflow integration included clear and accessible data entry, visual representation of recommendations, involvement of specialist clinicians, and local governance of software use. Barriers included rigid data entry systems and nonconformity of recommendations to local practices.
Conclusion Participants scored the MIPD software below the threshold that implies good usability. Factors such as availability of software support by specialist clinicians was important to participants while rigid data entry was found to be a deterrent.
Patients undergoing extracorporeal membrane oxygenation (ECMO) often require therapy with anti-infective drugs. The pharmacokinetics of these drugs may be altered during ECMO treatment due to pathophysiological changes in the drug metabolism of the critically ill and/or the ECMO therapy itself. This study investigates the latter aspect for commonly used anti-infective drugs in an ex vivo setting. A fully functional ECMO device circulated an albumin–electrolyte solution through the ECMO tubes and oxygenator. The antibiotic agents cefazolin, cefuroxim, cefepime, cefiderocol, linezolid and daptomycin and the antifungal agent anidulafungin were added. Blood samples were taken over a period of four hours and drug concentrations were measured via high-pressure liquid chromatography (HPLC) with UV detection. Subsequently, the study analyzed the time course of anti-infective concentrations. The results showed no significant changes in the concentration of any tested anti-infectives throughout the study period. This ex vivo study demonstrates that the ECMO device itself has no impact on the concentration of commonly used anti-infectives. These findings suggest that ECMO therapy does not contribute to alterations in the concentrations of anti-infective medications in severely ill patients.
Background
Extracorporeal membrane oxygenation (ECMO) is a life-saving modality but has the potential to alter the pharmacokinetics (PK) of antimicrobials. Imipenem/cilastatin/relebactam is an antibiotic with utility in treating certain multi-drug resistant Gram-negative infections. Herein, we describe the population pharmacokinetics of imipenem and relebactam in critically ill patients supported on ECMO.
Methods
Patients with infection supported on ECMO received 4–6 doses of imipenem/cilastatin/relebactam per current prescribing information based on estimated creatinine clearance. Blood samples were collected following the final dose of the antibiotic. Concentrations were determined via LC–MS/MS. Population PK models were fit with and without covariates using Pmetrics. Monte Carlo simulations of 1000 patients assessed joint PTA of fAUC0–24/MIC ≥ 8 for relebactam, and ≥40% fT > MIC for imipenem for each approved dosing regimen.
Results
Seven patients supported on ECMO were included in PK analyses. A two-compartment model with creatinine clearance as a covariate on clearance for both imipenem and relebactam fitted the data best. The mean ± standard deviation parameters were: CL0, 15.21 ± 6.52 L/h; Vc, 10.13 ± 2.26 L; K12, 2.45 ± 1.16 h−1 and K21, 1.76 ± 0.49 h−1 for imipenem, and 6.95 ± 1.34 L/h, 9.81 ± 2.69 L, 2.43 ± 1.13 h−1 and 1.52 ± 0.67 h−1 for relebactam. Simulating each approved dose of imipenem/cilastatin/relebactam according to creatinine clearance yielded PTAs of ≥90% up to an MIC of 2 mg/L.
Conclusions
Imipenem/cilastatin/relebactam dosed according to package insert in patients supported on ECMO is predicted to achieve exposures sufficient to treat susceptible Gram-negative isolates, including Pseudomonas aeruginosa.
Early recognition and effective treatment of sepsis improves outcomes in critically ill patients. However, antibiotic exposures are frequently suboptimal in the intensive care unit (ICU) setting. We describe the feasibility of the Bayesian dosing software Individually Designed Optimum Dosing Strategies (ID-ODS™), to reduce time to effective antibiotic exposure in children and adults with sepsis in ICU.
A multi-centre prospective, non-randomised interventional trial in three adult ICUs and one paediatric ICU. In a pre-intervention Phase 1, we measured the time to target antibiotic exposure in participants. In Phase 2, antibiotic dosing recommendations were made using ID-ODS™, and time to target antibiotic concentrations were compared to patients in Phase 1 (a pre–post-design).
175 antibiotic courses (Phase 1 = 123, Phase 2 = 52) were analysed from 156 participants. Across all patients, there was no difference in the time to achieve target exposures (8.7 h vs 14.3 h in Phase 1 and Phase 2, respectively, p = 0.45). Sixty-one courses in 54 participants failed to achieve target exposures within 24 h of antibiotic commencement (n = 36 in Phase 1, n = 18 in Phase 2). In these participants, ID-ODS™ was associated with a reduction in time to target antibiotic exposure (96 vs 36.4 h in Phase 1 and Phase 2, respectively, p < 0.01). These patients were less likely to exhibit subtherapeutic antibiotic exposures at 96 h (hazard ratio (HR) 0.02, 95% confidence interval (CI) 0.01–0.05, p < 0.01). There was no difference observed in in-hospital mortality.
Dosing software may reduce the time to achieve target antibiotic exposures. It should be evaluated further in trials to establish its impact on clinical outcomes.
Meticulous antimicrobial management is essential among critically ill patients with acute kidney injury, particularly if renal replacement therapy is needed. Many factors affect drug removal in patients undergoing continuous renal replacement therapy CRRT. In this study, we aimed to compare current databases that are frequently used to adjust CRRT dosages of antimicrobial drugs with the gold standard. The dosage recommendations from various databases for antimicrobial drugs eliminated by CRRT were investigated. The book 'Renal Pharmacotherapy: Dosage Adjustment of Medications Eliminated by the Kidneys' was chosen as the gold standard. There were variations in the databases. Micromedex, UpToDate, and Sanford had similar rates to the gold standard of 45%, 35%, and 30%, respectively. The Micromedex database shows the most similar results to the gold standard source. In addition, a consensus was reached as a result of the expert panel meetings established to discuss the different antimicrobial dose recommendations of the databases.
Keywords: CRRT; antimicrobial dosing; antimicrobial stewardship; databases; gold standard; pharmacokinetics; sepsis.
Introduction
Antibiotic concentration target attainment is known to be poor in critically ill patients. Dose adjustment is recommended in patients with altered clearance, obesity and those with bacterial species with intermediate susceptibility. The aim of this study was to investigate the variation of antibiotic concentration in critically ill patients with standard or adjusted dosing regimens.
Methods
The concentration of three beta‐lactam antibiotics used in the intensive care unit (ICU) setting, cefotaxime, piperacillin/tazobactam, and meropenem, was measured in patients with confirmed or suspected infection. Mid‐dose and trough values were collected during a single dosing interval. The pharmacokinetic endpoints were a free antibiotic concentration that, during the whole dosing interval, was above MIC (100% ƒT > MIC, primary endpoint) or above four times MIC (100% ƒT > 4MIC, secondary endpoint). Non‐species related MIC breakpoints were used (1 mg/L for cefotaxime, 8 mg/L for piperacillin/tazobactam, and 2 mg/L for meropenem).
Results
We included 102 patients (38 cefotaxime, 30 piperacillin/tazobactam, and 34 meropenem) at a single ICU, with a median age of 66 years. In total, 73% were males, 40% were obese (BMI ≥30) and the median SAPS 3 score was 63 points. Of all patients, 78 patients (76%) reached the primary endpoint (100%ƒT > MIC), with 74% for cefotaxime, 67% for piperacillin/tazobactam and 88% for meropenem. Target attainment for 100% ƒT > 4MIC was achieved in 40 (39%) patients, overall, with 34% for cefotaxime, 30% for piperacillin/tazobactam and 53% for meropenem. In patients with standard dose 71% attained 100%ƒT > MIC and 37% for 100%ƒT > 4MIC. All patients with reduced dose attained 100%ƒT > MIC and 27% attained 100% ƒT > 4MIC. In patients with increased dose 79% attained 100%ƒT > MIC and 48% 100%ƒT > 4MIC respectively.
Conclusions
Beta‐lactam antibiotics concentration vary widely in critically ill patients. The current standard dosing regimens employed during the study were not sufficient to reach 100% ƒT > MIC in approximately a quarter of the patients. In patients where dose adjustment was performed, the group with increased dose also had low target attainment, as opposed to patients with dose reduction, who all reached target. This suggests the need for further individualization of dosing where therapeutic drug monitoring can be an alternative to further increase target attainment.
Eravacycline (ERC) was approved for clinical use in 2018. It is more potent than other tetracyclines and can overcome resistance, making it an attractive option for combating multidrug-resistant bacterial infections. Intensive pharmacokinetic (PK) studies are currently being conducted to ensure the effectiveness and safety of ERC in various groups of patients, including those undergoing extracorporeal therapies. This study is the first attempt to develop a simple, efficient, and high-throughput immunoassay for quantifying ERC in human or animal serum. BSA-ERC conjugate as immunogen elicited antibody production in rabbits. Monitoring of the immune response and comparison of homologous and heterologous coating antigens allowed selection of immunoreagents and development of an assay that was selective for ERC possessing sensitivity (IC50), dynamic range (IC20-IC80) and detection limit equal to 3.3 ng/mL, 0.27–54 ng/mL and 0.09 ng/mL, respectively. The developed ELISA showed acceptable recovery of ERC (85–105 %) from rabbit and human serum in the clinically relevant concentration range of 0.1–3.0 mg/L. The method was used to quantify serum ERC concentration in the pilot PK study in Soviet chinchilla rabbits. The results were confirmed by HPLC-MS/MS.
Sepsis is life-threatening organ dysfunction due to a dysregulated host response to an underlying acute infection. Sepsis is a major worldwide healthcare problem. An annual estimated 48.9 million incident cases of sepsis is reported, with 11 million (20%) sepsis-related deaths. Administration of appropriate antimicrobials is one of the most effective therapeutic interventions to reduce mortality. The severity of illness informs the urgency of antimicrobial administration. Nevertheless, even used properly, they cause adverse effects and contribute to the development of antibiotic resistance. Both inadequate and unnecessarily broad empiric antibiotics are associated with higher mortality and also select for antibiotic-resistant germs. In this narrative review, we will first discuss important factors and potential confounders which may influence the occurrence of surgical site infection (SSI) and which should be considered in the provision of perioperative antibiotic prophylaxis (PAP). Then, we will summarize recent advances and perspectives to optimize antibiotic therapy in the intensive care unit (ICU). Finally, the major role of the microbiota and the impact of antimicrobials on it will be discussed. While expert recommendations help guide daily practice in the operating theatre and ICU, a thorough knowledge of pharmacokinetic/pharmacodynamic (PK/PD) rules is critical to optimize the management of complex patients and minimize the emergence of multidrug-resistant organisms.
Objectives
The purpose of this study was to develop a physiologically based pharmacokinetic/pharmacodynamic model (PBPK/PD) of meropenem for critically ill patients.
Methods
A PBPK model of meropenem in healthy adults was established using PK-Sim® software and subsequently extrapolated to critically ill patients based on anatomic and physiological parameters. The mean fold error (MFE) and geometric mean fold error (GMFE) method were used to compare the differences between predicted and observed values of pharmacokinetic parameters Cmax, AUC0−∞, CL to evaluate the accuracy of PBPK model. The model was verified by using meropenem plasma samples obtained from the ICU patients, which were determined by HPLC-MS/MS. The PBPK model was thereafter combined with a PKPD model, developed based on f%T > MIC. Monte Carlo simulation was utilized to calculate the probability of target attainment (PTA) in patients.
Results
The developed PBPK model successfully predicted the meropenem disposition in critically ill patients, wherein the MFE average and GMFE of all predicted PK parameters were within 1.25-fold error range. The therapeutic drug monitoring (TDM) of meropenem was conducted 92 blood samples from 31 ICU patients, of which 71 (77.17%) blood samples were consistent with the simulated value. The TDM results showed that we may not need age-specific dose adjustment of meropenem in critically ill patients. Monte Carlo simulations showed that continuous infusion and frequent administration were necessary to achieve curative effect for critically ill patients, whereas excessive infusion time (> 4h) was not necessary.
Conclusion
The PBPK/PD modelling incorporating literature data and prospective study data is able to correctly predict meropenem pharmacokinetics in critically ill patients. Our study provides a reference for realizing clinical personalized medication for critically ill patients.
(1) Background: Piperacillin-tazobactam represents the first-line option for treating infections caused by full- or multi-susceptible Enterobacterales and/or Pseudomonas aeruginosa in critically ill patients. Several studies reported that attaining aggressive pharmacokinetic/pharmacodynamic (PK/PD) targets with beta-lactams is associated with an improved microbiological/clinical outcome. We aimed to assess the relationship between the joint PK/PD target attainment of continuous infusion (CI) piperacillin-tazobactam and the microbiological/clinical outcome of documented Gram-negative bloodstream infections (BSI) and/or ventilator-associated pneumonia (VAP) of critically ill patients treated with CI piperacillin-tazobactam monotherapy. (2) Methods: Critically ill patients admitted to the general and post-transplant intensive care unit in the period July 2021–September 2023 treated with CI piperacillin-tazobactam monotherapy optimized by means of a real-time therapeutic drug monitoring (TDM)-guided expert clinical pharmacological advice (ECPA) program for documented Gram-negative BSIs and/or VAP were retrospectively retrieved. Steady-state plasma concentrations (Css) of piperacillin and of tazobactam were measured, and the free fractions (f) were calculated according to respective plasma protein binding. The joint PK/PD target was defined as optimal whenever both the piperacillin fCss/MIC ratio was >4 and the tazobactam fCss/target concentration (CT) ratio was > 1 (quasi-optimal or suboptimal whenever only one or none of the two weas achieved, respectively). Multivariate logistic regression analysis was performed for testing variables potentially associated with microbiological outcome. (3) Results: Overall, 43 critically ill patients (median age 69 years; male 58.1%; median SOFA score at baseline 8) treated with CI piperacillin-tazobactam monotherapy were included. Optimal joint PK/PD target was attained in 36 cases (83.7%). At multivariate analysis, optimal attaining of joint PK/PD target was protective against microbiological failure (OR 0.03; 95%CI 0.003–0.27; p = 0.002), whereas quasi-optimal/suboptimal emerged as the only independent predictor of microbiological failure (OR 37.2; 95%CI 3.66–377.86; p = 0.002). (4) Conclusion: Optimized joint PK/PD target attainment of CI piperacillin-tazobactam could represent a valuable strategy for maximizing microbiological outcome in critically ill patients with documented Gram-negative BSI and/or VAP, even when sustained by extended-spectrum beta-lactamase (ESBL)-producing Enterobacterales. In this scenario, implementing a real-time TDM-guided ECPA program may be helpful in preventing failure in attaining optimal joint PK/PD targets among critically ill patients. Larger prospective studies are warranted to confirm our findings.
Antimicrobial resistance is a matter of rising concern, especially in fungal diseases. Multiple reports all over the world are highlighting a worrisome increase in azole- and echinocandin-resistance among fungal pathogens, especially in Candida species, as reported in the recently published fungal pathogens priority list made by WHO. Despite continuous efforts and advances in infection control, development of new antifungal molecules, and research on molecular mechanisms of antifungal resistance made by the scientific community, trends in invasive fungal diseases and associated antifungal resistance are on the rise, hindering therapeutic options and clinical cures. In this context, in vitro susceptibility testing aimed at evaluating minimum inhibitory concentrations, is still a milestone in the management of fungal diseases. However, such testing is not the only type at a microbiologist’s disposal. There are other adjunctive in vitro tests aimed at evaluating fungicidal activity of antifungal molecules and also exploring tolerance to antifungals. This plethora of in vitro tests are still left behind and performed only for research purposes, but their role in the context of invasive fungal diseases associated with antifungal resistance might add resourceful information to the clinical management of patients. The aim of this review was therefore to revise and explore all other in vitro tests that could be potentially implemented in current clinical practice in resistant and difficult-to-treat cases.
Purpose of review
The early recognition of acute bacterial skin infections (ABSIs) and their swift and adequate care are the major determinants of success. The features that can hamper or delay surgical and medical management can lead to ‘difficult-to-treat’ ABSIs.
Recent findings
Delayed diagnosis and belated management are the key obstacles to be overcome. Clinicians should be careful about underestimating the severity of ABSIs and overlooking comorbidities, especially immunosuppression. Many conditions can lead to delayed source control, including a misdiagnosis, interhospital transfers, delayed re-exploration, or extensive injuries. Difficult therapeutic issues can occur, including rapidly destructive infections from highly pathogenic microorganisms (Group-A-streptococci, Vibrio spp., Clostridium spp. and Staphylococcus aureus ) or inadequate antibiotic therapy resulting from multidrug-resistant bacteria. Impaired pharmacokinetic capacities of antibiotic agents should also be considered as a source of clinical failure due to insufficient antimicrobial activity at the site of infection.
Summary
Microbiological samples should be used for guiding antimicrobial therapy. Risk factors for multidrug-resistant bacteria should be considered, including local epidemiology and comorbidities. The optimization of antibiotic therapy should be achieved. Optimized care should be achieved through multidisciplinary management involving professionals with sufficient and appropriate training.
Background: Volumetric absorptive microsamples (VAMS) can support pharmacokinetic / pharmacodynamic studies. We present the bioanalytical method development for the simultaneous quantification of ampicillin, cefepime, ceftriaxone, meropenem, piperacillin, tazobactam, and vancomycin from VAMS. Methods & results: Optimal extraction, chromatographic, and mass spectrometry conditions were identified. Maximum extraction recoveries included 100 μl of water for rehydration and methanol for protein precipitation. Chromatographic separation used Phenomenex Kinetex ™ Polar C18 column with a mobile phase comprising water/acetonitrile with formic acid and was fully validated. Hematocrit effects were only observed for vancomycin. Samples were stable for 90 days at -80°C except for meropenem, which was stable for 60 days. Conclusion: Multiple antibiotics can be assayed from a single VAMS sample to facilitate pharmacokinetic/pharmacodynamic studies.
Certain classes of antibiotics show “concentration dependent” antimicrobial activity; higher concentrations result in increased bacterial killing rates, in contrast to “time dependent antibiotics”, which show antimicrobial activity that depends on the time that antibiotic concentrations remain above the MIC. Aminoglycosides and fluoroquinolones are still widely used concentration-dependent antibiotics. These antibiotics are not hydrolyzed by beta-lactamases and are less sensitive to the inoculum effect, which can be defined as an increased MIC for the antibiotic in the presence of a relatively higher bacterial load (inoculum). In addition, they possess a relatively long Post-Antibiotic Effect (PAE), which can be defined as the absence of bacterial growth when antibiotic concentrations fall below the MIC. These characteristics make them interesting complementary antibiotics in the management of Multi-Drug Resistant (MDR) bacteria and/or (neutropenic) patients with severe sepsis. Global surveillance studies have shown that up to 90% of MDR Gram-negative bacteria still remain susceptible to aminoglycosides, depending on the susceptibility breakpoint (e.g., CLSI or EUCAST) being applied. This percentage is notably lower for fluoroquinolones but depends on the region, type of organism, and mechanism of resistance involved. Daily (high-dose) dosing of aminoglycosides for less than one week has been associated with significantly less nephro/oto toxicity and improved target attainment. Furthermore, higher-than-conventional dosing of fluoroquinolones has been linked to improved clinical outcomes. Beta-lactam antibiotics are the recommended backbone of therapy for severe sepsis. Since these antibiotics are time-dependent, the addition of a second concentration-dependent antibiotic could serve to quickly lower the bacterial inoculum, create PAE, and reduce Penicillin-Binding Protein (PBP) expression. Inadequate antibiotic levels at the site of infection, especially in the presence of high inoculum infections, have been shown to be important risk factors for inadequate resistance suppression and therapeutic failure. Therefore, in the early phase of severe sepsis, effort should be made to optimize the dose and quickly lower the inoculum. In this article, the authors propose a novel concept of “Inoculum Based Dosing” in which the decision for antibiotic dosing regimens and/or combination therapy is not only based on the PK parameters of the patient, but also on the presumed inoculum size. Once the inoculum has been lowered, indirectly reflected by clinical improvement, treatment simplification should be considered to further treat the infection.
In this report, we describe a case of brain abscess due to inadequate treatment based on initial blood culture results because emergency surgical treatment of a severe cerebral hemorrhage was given priority. This case emphasizes the importance of first recognizing bacteremia based on culture results, and if bacteremia is determined to be present, of selecting appropriate antimicrobial agents and ensuring an adequate treatment period.
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.
The use of therapeutic drug monitoring (TDM) to optimize beta-lactam dosing in critically ill patients is growing in popularity, although there is limited data describing the potential impact of altered protein binding on achievement of target concentrations. The aim of this study was to compare the measured unbound concentration with the unbound concentration predicted from published protein binding values for seven beta-lactams using data from blood samples obtained from critically ill patients. From 161 eligible patients, we obtained 228 and 221 plasma samples at mid-dosing interval and trough respectively for ceftriaxone, cefazolin, meropenem, piperacillin, ampicillin, benzylpenicillin, and flucloxacillin. The total and unbound beta-lactam concentrations were measured using validated methods. Variability in both unbound and total concentrations were marked for all antibiotics, with significant differences present between measured and predicted unbound concentrations for ceftriaxone, and for flucloxacillin at mid-dosing interval (p<0.05). The predictive performance for calculating unbound concentrations using published protein binding values was poor with bias for over-prediction of unbound concentrations for ceftriaxone (83.3%), flucloxacillin (56.8%), and benzylpenicillin (25%) and under-prediction for meropenem (12.1%). Linear correlations between the measured total and unbound concentrations were observed for all beta-lactams (R(2) = 0.81 - 1.00, p<0.05) except ceftriaxone and flucloxacillin. The percentage protein binding of flucloxacillin and plasma albumin concentration were also found to be linearly correlated (R(2) = 0.776, p<0.01). In conclusion, significant differences between measured and predicted unbound drug concentrations were found only for the highly protein bound beta-lactams ceftriaxone and flucloxacillin. However, direct measurement of unbound drug in research and clinical practice is suggested for selected beta-lactams.
Monte Carlo Simulation (MCS) of antimicrobial dosage regimens during drug development to derive predicted target attainment values is frequently used to choose the optimal dose for the treatment of patients in phase 2 and 3 studies. A criticism is that pharmacokinetic parameter estimates and variability in healthy volunteers is smaller from those in patients. In this study the initial estimates of exposure from MCS were compared with actual exposure data in patients treated with ceftobiprole in a phase 3 nosocomial pneumonia study (NTC00210964). Results of MCS using population PK data from ceftobiprole derived from 12 healthy volunteers were used (Mouton et al. AAC, 2004 48:1713). Actual individual exposures in patients were derived after building a population pharmacokinetic model and used to calculate the individual exposure to ceftobiprole (percentage of time the unbound concentration exceeds the MIC, %fT>MIC) for a range of MIC-values. For the ranges of %fTMIC used to determine the dosage schedule in the phase 3 NP study, the MCS using data from one single phase 1 study in healthy volunteers well predicted the actual clinical exposure to ceftobiprole. The difference at 50%fT>MIC at an MIC of 4 mg/L was 3.5% for PK sampled patients. For higher values of %fTMIC and MICs, the MCS slightly underestimated the target attainment, probably due to extreme values in the PK-profile distribution used in the simulations. The probability of target attainment based on MCS in healthy volunteers adequately predicted the actual exposures in a patient population, including severely ill patients.
The efficacy of voriconazole is potentially compromised by considerable pharmacokinetic variability. There are increasing insights into voriconazole concentrations that are safe and effective for treatment of invasive fungal infections. Therapeutic drug monitoring is increasingly advocated. Software to aid in the individualisation of dosing would be an extremely useful clinical tool. We developed software to enable the individualisation of voriconazole dosing to attain predefined serum concentration targets. The process of individualised voriconazole therapy was based on concepts of Bayesian stochastic adaptive control. Multiple model dosage design with feedback control was used to calculate dosages that achieved desired concentration targets with maximum precision. The performance of the software program was assessed using the data from 10 recipients of an allogeneic HSCT receiving i.v. voriconazole. The program was able to model the plasma concentrations with a high level of precision, despite the wide range of concentration trajectories and inter-individual pharmacokinetic variability. The voriconazole concentrations predicted after the last dosages were largely concordant with those actually measured. Simulations provided an illustration of the way in which the software can be used to adjust dosages of patients falling outside desired concentration targets. This software appears to be an extremely useful tool to further optimise voriconazole therapy and aid in therapeutic drug monitoring. Further prospective studies are now required to define the utility of the controller in daily clinical practice.
Background:
ß-Lactam antibiotics demonstrate time-dependent killing. Prolonged infusion of these agents is commonly performed to optimize the time the unbound concentration of an antibiotic remains greater than the minimum inhibitory concentration and decrease costs, despite limited evidence suggesting improved clinical results.
Objective:
To determine whether prolonged infusion of ß-lactam antibiotics improves outcomes in critically ill patients with suspected gram-negative infection.
Methods:
We conducted a single-center, before-after, comparative effectiveness trial between January 2010 and January 2011 in the intensive care units at Barnes-Jewish Hospital, an urban teaching hospital affiliated with the Washington University School of Medicine in St. Louis, MO. Outcomes were compared between patients who received standardized dosing of meropenem, piperacillin-tazobactam, or cefepime as an intermittent infusion over 30 minutes (January 1, 2010, to June 30, 2010) and patients who received prolonged infusion over 3 hours (August 1, 2010, to January 31, 2011).
Results:
A total of 503 patients (intermittent infusion, n = 242; prolonged infusion, n = 261) treated for gram-negative infection were included in the clinically evaluable population. Approximately 50% of patients in each group received cefepime and 20% received piperacillin-tazobactam. More patients in the intermittent infusion group received meropenem (35.5% vs 24.5%; p = 0.007). Baseline characteristics were similar between groups, with the exception of a greater occurrence of chronic obstructive pulmonary disease (COPD) in the intermittent infusion group. Treatment success rates in the clinically evaluable group were 56.6% for intermittent infusion and 51.0% for prolonged infusion (p = 0.204), and in the microbiologically evaluable population, 55.2% for intermittent infusion and 49.5% for prolonged infusion (p = 0.486). Fourteen-day, 30-day, and inhospital mortality rates in the clinically evaluable population for the intermittent and prolonged infusion groups were 13.2% versus 18.0% (p = 0.141), 23.6% versus 25.7% (p = 0.582), and 19.4% versus 23.0% (p = 0.329).
Conclusions:
Routine use of prolonged infusion of time-dependent antibiotics for the empiric treatment of gram-negative bacterial infections offers no advantage over intermittent infusion antibiotic therapy with regard to treatment success, mortality, or hospital length of stay. These results were confirmed after controlling for potential confounders in a multivariate analysis.
Background:
Colistin often remains the only active agent against multidrug-resistant Gram-negative pathogens. The aim of the study was to assess efficacy of nebulized colistin for treating ventilator-associated pneumonia (VAP) caused by multidrug-resistant Pseudomonas aeruginosa and Acinetobacter baumannii.
Methods:
One hundred and sixty-five patients with VAP caused by P. aeruginosa and A. baumannii were enrolled in a prospective, observational, and comparative study. The sensitive strain group included 122 patients with VAP caused by P. aeruginosa and A. baumannii susceptible to β-lactams, aminoglycosides, or quinolones and treated with intravenous antibiotics for 14 days. The multidrug-resistant strain group included 43 patients with VAP caused by multidrug-resistant P. aeruginosa and A. baumannii and treated with nebulized colistin (5 million international units every 8 h) either in monotherapy (n=28) or combined to a 3-day intravenous aminoglycosides for 7-19 days. The primary endpoint was clinical cure rate. Aerosol was delivered using vibrating plate nebulizer.
Results:
After treatment, clinical cure rate was 66% in sensitive strain group and 67% in multidrug-resistant strain group (difference -1%, lower limit of 95% CI for difference -12.6%). Mortality was not different between groups (23 vs. 16%). Among 16 patients with persisting or recurrent P. aeruginosa infection, colistin minimum inhibitory concentration increased in two patients.
Conclusion:
Nebulization of high-dose colistin was effective to treat VAP caused by multidrug-resistant P. aeruginosa or A. baumannii. Its therapeutic effect was noninferior to intravenous β-lactams associated with aminoglycosides or quinolones for treating VAP caused by susceptible P. aeruginosa and A. baumannii.
Background:
Beta-lactam antibiotics are a commonly used treatment for severe sepsis, with intermittent bolus dosing standard therapy, despite a strong theoretical rationale for continuous administration. The aim of this trial was to determine the clinical and pharmacokinetic differences between continuous and intermittent dosing in patients with severe sepsis.
Methods:
This was a prospective, double-blind, randomized controlled trial of continuous infusion versus intermittent bolus dosing of piperacillin-tazobactam, meropenem, and ticarcillin-clavulanate conducted in 5 intensive care units across Australia and Hong Kong. The primary pharmacokinetic outcome on treatment analysis was plasma antibiotic concentration above the minimum inhibitory concentration (MIC) on days 3 and 4. The assessed clinical outcomes were clinical response 7-14 days after study drug cessation, ICU-free days at day 28 and hospital survival.
Results:
Sixty patients were enrolled with 30 patients each allocated to the intervention and control groups. Plasma antibiotic concentrations exceeded the MIC in 82% of patients (18 of 22) in the continuous arm versus 29% (6 of 21) in the intermittent arm (P = .001). Clinical cure was higher in the continuous group (70% vs 43%; P = .037), but ICU-free days (19.5 vs 17 days; P = .14) did not significantly differ between groups. Survival to hospital discharge was 90% in the continuous group versus 80% in the intermittent group (P = .47).
Conclusions:
Continuous administration of beta-lactam antibiotics achieved higher plasma antibiotic concentrations than intermittent administration with improvement in clinical cure. This study provides a strong rationale for further multicenter trials with sufficient power to identify differences in patient-centered endpoints.
The worrisome increase in Gram-negative bacteria with borderline susceptibility to carbapenems and of carbapenemase-producing
Enterobacteriaceae has significantly undermined their efficacy. Continuous infusion may be the best way to maximize the time-dependent activity
of meropenem. The aim of this study was to create dosing nomograms in relation to different creatinine clearance (CLCr) estimates for use in daily clinical practice to target the steady-state concentrations (Csss) of meropenem during continuous infusion at 8 to 16 mg/liter (after the administration of an initial loading dose of 1 to
2 g over 30 min). The correlation between meropenem clearance (CLm) and CLCr was retrospectively assessed in a cohort of critically ill patients (group 1, n = 67) to create a formula for dosage calculation to target Css. The performance of this formula was validated in a similar cohort (group 2, n = 56) by comparison of the observed and the predicted Csss. A significant relationship between CLm and CLCr was observed in group 1 (r = 0.72, P < 0.001). The application of the formula to meropenem dosing in group 2, infusion rate (g/24 h) = [0.078 × CLCr (ml/min) + 2.85] × target Css × (24/1,000), led to a significant correlation between the observed and the predicted Csss (r = 0.92, P < 0.001). Dosing nomograms based on CLCr were created to target the meropenem Css at 8, 12, and 16 mg/liter in critically ill patients. These nomograms could be helpful in improving the treatment of severe
Gram-negative infections with meropenem, especially in the presence of borderline susceptible pathogens or even of carbapenemase
producers and/or of pathophysiological conditions which may enhance meropenem clearance.
The pharmacokinetics of beta-lactam antibiotics in intensive care patients may be profoundly altered due to the dynamic, unpredictable pathophysiological changes that occur in critical illness. For many drugs, significant increases in the volume of distribution and/or variability in drug clearance are common. When "standard" beta-lactam doses are used, such pharmacokinetic changes can result in subtherapeutic plasma concentrations, treatment failure, and the development of antibiotic resistance. Emerging data support the use of beta-lactam therapeutic drug monitoring (TDM) and individualized dosing to ensure the achievement of pharmacodynamic targets associated with rapid bacterial killing and optimal clinical outcomes. The purpose of this work was to describe the pharmacokinetic variability of beta-lactams in the critically ill and to discuss the potential utility of TDM to optimize antibiotic therapy through a structured literature review of all relevant publications between 1946 and October 2011. Only a few studies have reported the utility of TDM as a tool to improve beta-lactam dosing in critically ill patients. Moreover, there is little agreement between studies on the pharmacodynamic targets required to optimize antibiotic therapy. The impact of TDM on important clinical outcomes also remains to be established. Whereas TDM may be theoretically rational, clinical studies to assess utility in the clinical setting are urgently required.
Background
The clinical effects of varying pharmacokinetic exposures of antibiotics (antibacterials and antifungals) on outcome in infected critically ill patients are poorly described. A large-scale multi-centre study (DALI Study) is currently underway describing the clinical outcomes of patients achieving pre-defined antibiotic exposures. This report describes the protocol.
Methods
DALI will recruit over 500 patients administered a wide range of either beta-lactam or glycopeptide antibiotics or triazole or echinocandin antifungals in a pharmacokinetic point-prevalence study. It is anticipated that over 60 European intensive care units (ICUs) will participate. The primary aim will be to determine whether contemporary antibiotic dosing for critically ill patients achieves plasma concentrations associated with maximal activity. Secondary aims will compare antibiotic pharmacokinetic exposures with patient outcome and will describe the population pharmacokinetics of the antibiotics included. Various subgroup analyses will be conducted to determine patient groups that may be at risk of very low or very high concentrations of antibiotics.
Discussion
The DALI study should inform clinicians of the potential clinical advantages of achieving certain antibiotic pharmacokinetic exposures in infected critically ill patients.
There have been conflicting reports on the efficacy of recombinant human activated protein C, or drotrecogin alfa (activated) (DrotAA), for the treatment of patients with septic shock.
In this randomized, double-blind, placebo-controlled, multicenter trial, we assigned 1697 patients with infection, systemic inflammation, and shock who were receiving fluids and vasopressors above a threshold dose for 4 hours to receive either DrotAA (at a dose of 24 μg per kilogram of body weight per hour) or placebo for 96 hours. The primary outcome was death from any cause 28 days after randomization.
At 28 days, 223 of 846 patients (26.4%) in the DrotAA group and 202 of 834 (24.2%) in the placebo group had died (relative risk in the DrotAA group, 1.09; 95% confidence interval [CI], 0.92 to 1.28; P=0.31). At 90 days, 287 of 842 patients (34.1%) in the DrotAA group and 269 of 822 (32.7%) in the placebo group had died (relative risk, 1.04; 95% CI, 0.90 to 1.19; P=0.56). Among patients with severe protein C deficiency at baseline, 98 of 342 (28.7%) in the DrotAA group had died at 28 days, as compared with 102 of 331 (30.8%) in the placebo group (risk ratio, 0.93; 95% CI, 0.74 to 1.17; P=0.54). Similarly, rates of death at 28 and 90 days were not significantly different in other predefined subgroups, including patients at increased risk for death. Serious bleeding during the treatment period occurred in 10 patients in the DrotAA group and 8 in the placebo group (P=0.81).
DrotAA did not significantly reduce mortality at 28 or 90 days, as compared with placebo, in patients with septic shock. (Funded by Eli Lilly; PROWESS-SHOCK ClinicalTrials.gov number, NCT00604214.).
Pharmacokinetic and clinical data from tigecycline-treated patients with hospital-acquired pneumonia (HAP) who were enrolled
in a phase 3 clinical trial were integrated in order to evaluate pharmacokinetic-pharmacodynamic (PK-PD) relationships for
efficacy. Univariable and multivariable analyses were conducted to identify factors associated with clinical and microbiological
responses, based on data from 61 evaluable HAP patients who received tigecycline intravenously as a 100-mg loading dose followed
by 50 mg every 12 h for a minimum of 7 days and for whom there were adequate clinical, pharmacokinetic, and response data.
The final multivariable logistic regression model for clinical response contained albumin and the ratio of the free-drug area
under the concentration-time curve from 0 to 24 h (fAUC0–24) to the MIC (fAUC0–24:MIC ratio). The odds of clinical success were 13.0 times higher for every 1-g/dl increase in albumin (P < 0.001) and 8.42 times higher for patients with fAUC0–24:MIC ratios of ≥0.9 compared to patients with fAUC0–24:MIC ratios of <0.9 (P = 0.008). Average model-estimated probabilities of clinical success for the albumin/fAUC0–24:MIC ratio combinations of <2.6/<0.9, <2.6/≥0.9, ≥2.6/<0.9, and ≥2.6/≥0.9 were 0.21, 0.57, 0.64, and 0.93, respectively. For
microbiological response, the final model contained albumin and ventilator-associated pneumonia (VAP) status. The odds of
microbiological success were 21.0 times higher for every 1-g/dl increase in albumin (P < 0.001) and 8.59 times higher for patients without VAP compared to those with VAP (P = 0.003). Among the remaining variables evaluated, the MIC had the greatest statistical significance, an observation which
was not surprising given the differences in MIC distributions between VAP and non-VAP patients (MIC50and MIC90 values of 0.5 and 0.25 mg/liter versus 16 and 1 mg/liter for VAP versus non-VAP patients, respectively; P = 0.006). These findings demonstrated the impact of pharmacological and patient-specific factors on the clinical and microbiological
responses.
Exposure-response analyses for efficacy and safety were performed for tigecycline-treated patients suffering from community-acquired
pneumonia. Data were collected from two randomized, controlled clinical trials in which patients were administered a 100-mg
loading dose followed by 50 mg of tigecycline every 12 h. A categorical endpoint, success or failure, 7 to 23 days after the
end of therapy (test of cure) and a continuous endpoint, time to fever resolution, were evaluated for exposure-response analyses
for efficacy. Nausea/vomiting, diarrhea, headache, and changes in blood urea nitrogen concentration (BUN) and total bilirubin
were evaluated for exposure-response analyses for safety. For efficacy, ratios of the free-drug area under the concentration-time
curve at 24 h to the MIC of the pathogen (fAUC0-24:MIC) of ≥12.8 were associated with a faster time to fever resolution; patients with lower drug exposures had a slower time
to fever resolution (P = 0.05). For safety, a multivariable logistic regression model demonstrated that a tigecycline AUC above a threshold of 6.87
mg · hr/liter (P = 0.004) and female sex were predictive of the occurrence of nausea and/or vomiting (P = 0.004). Although statistically significant, the linear relationship between tigecycline exposure and maximum change from
baseline in total bilirubin is unlikely to be clinically significant.
Several reports have shown marked heterogeneity of antibiotic pharmacokinetics (PK) in patients admitted to ICUs, which might potentially affect outcomes. Therefore, the pharmacodynamic (PD) parameter of the efficacy of β-lactam antibiotics, that is, the time that its concentration is above the bacteria minimal inhibitory concentration (T > MIC), cannot be safely extrapolated from data derived from the PK of healthy volunteers.
We performed a full review of published studies addressing the PK of intravenous β-lactam antibiotics given to infected ICU patients. Study selection comprised a comprehensive bibliographic search of the PubMed database and bibliographic references in relevant reviews from January 1966 to December 2010. We selected only English-language articles reporting studies addressing β-lactam antibiotics that had been described in at least five previously published studies. Studies of the PK of patients undergoing renal replacement therapy were excluded.
A total of 57 studies addressing six different β-lactam antibiotics (meropenem, imipenem, piperacillin, cefpirome, cefepime and ceftazidime) were selected. Significant PK heterogeneity was noted, with a broad, more than twofold variation both of volume of distribution and of drug clearance (Cl). The correlation of antibiotic Cl with creatinine clearance was usually reported. Consequently, in ICU patients, β-lactam antibiotic half-life and T > MIC were virtually unpredictable, especially in those patients with normal renal function. A better PD profile was usually obtained by prolonged or even continuous infusion. Tissue penetration was also found to be compromised in critically ill patients with septic shock.
The PK of β-lactam antibiotics are heterogeneous and largely unpredictable in ICU patients. Consequently, the dosing of antibiotics should be supported by PK concepts, including data derived from studies of the PK of ICU patients and therapeutic drug monitoring.
The increasing prevalence of antimicrobial resistant bacteria has become a serious worldwide problem. The aim of this study was to analyze antimicrobial resistance data generated in 2009 by hospitals and commercial laboratories participating in the Korean Nationwide Surveillance of Antimicrobial Resistance program.
Susceptibility data were collected from 24 hospitals and two commercial laboratories. In the analysis, resistance did not include intermediate susceptibility. Duplicate isolates were excluded from the analysis of hospital isolates, but not from the commercial laboratory isolates.
Among the hospital isolates, methicillin-resistant Staphylococcus aureus, penicillin G-nonsusceptible Streptococcus pneumoniae based on meningitis breakpoint, and ampicillin- resistant Enterococcus faecium remained highly prevalent. The proportion of vancomycin-resistant E. faecium gradually increased to 29%. Ceftazidime-resistant Escherichia coli and Klebsiella pneumoniae increased to 17% and 33%, respectively, and fluoroquinolone-resistant K. pneumoniae, Acinetobacter spp. and Pseudomonas aeruginosa increased to 33%, 67% and 39%, respectively. Amikacin-resistant Acinetobacter spp. increased to 48%. Imipenem-resistant Acinetobacter spp. and P. aeruginosa increased to 51% and 26%, respectively. Higher resistance rates were observed in intensive care unit (ICU) isolates than in non-ICU isolates among the isolates from hospitals. Resistance rates were higher in hospital isolates than in clinic isolates among the isolates from commercial laboratories.
Among the hospital isolates, ceftazidime-resistant K. pneumoniae and fluoroquinolone- resistant K. pneumoniae, Acinetobacter spp., and P. aeruginosa further increased. The increase in imipenem resistance was slight in P. aeruginosa, but drastic in Acinetobacter spp. The problematic antimicrobial-organism combinations were much more prevalent among ICU isolates.
We evaluated the pharmacokinetic profile of ciprofloxacin and its penetration into bronchial secretions of critically ill patients with chronic obstructive pulmonary disease (COPD). Twenty-five mechanically ventilated patients with severe COPD who were suffering from an acute, infectious exacerbation were included in this prospective, open-label study. All subjects received a 1-hour intravenous infusion of 400 mg ciprofloxacin every 8 h. Serial blood and bronchial secretion samples were obtained at steady state, and concentrations were determined using high-performance liquid chromatography. The pharmacodynamic parameters that are associated with the efficacy of fluoroquinolones against Gram-negative pathogens were also calculated. The mean peak (maximum) concentration (C(max)) and trough (minimum) concentration in plasma were 5.37 ± 1.57 and 1 ± 0.53 mg/liter, respectively. Mean values for volume of distribution, clearance, half-life, and area under the curve from 0 to 24 h (AUC(0-24)) were 169.87 ± 84.11 liters, 26.96 ± 8.86 liters/h, 5.35 ± 2.21 h, and 47.41 ± 17.02 mg · h/liter, respectively. In bronchial secretions, a mean C(max) of 3.08 ± 1.21 mg/liter was achieved in 3.12 ± 1.01 h, and the penetration ratio was 1.16 ± 0.59. The target of AUC(0-24)/MIC of ≥125 was attained in all patients, in the majority of them (76%), and in none at MICs of 0.125, 0.25, and 1 μg/ml, respectively. Slightly better results were obtained for the ratio C(max)/MIC of ≥10. In conclusion, ciprofloxacin demonstrates excellent penetration into bronchial secretions. There is wide interindividual variability in its pharmacokinetic parameters in critically ill COPD patients and inadequate pharmacodynamic exposure against bacteria with MICs of ≥0.5 μg/ml.
Sepsis is responsible for important alterations in the pharmacokinetics of antibiotics. Continuous renal replacement therapy (CRRT), which is commonly used in septic patients, may further contribute to pharmacokinetic changes. Current recommendations for antibiotic doses during CRRT combine data obtained from heterogeneous patient populations in which different CRRT devices and techniques have been used. We studied whether these recommendations met optimal pharmacokinetic criteria for broad-spectrum antibiotic levels in septic shock patients undergoing CRRT.
This open, prospective study enrolled consecutive patients treated with CRRT and receiving either meropenem (MEM), piperacillin-tazobactam (TZP), cefepime (FEP) or ceftazidime (CAZ). Serum concentrations of these antibiotics were determined by high-performance liquid chromatography from samples taken before (t = 0) and 1, 2, 5, and 6 or 12 hours (depending on the β-lactam regimen) after the administration of each antibiotic. Series of measurements were separated into those taken during the early phase (< 48 hours from the first dose) of therapy and those taken later (> 48 hours).
A total of 69 series of serum samples were obtained in 53 patients (MEM, n = 17; TZP, n = 16; FEP, n = 8; CAZ, n = 12). Serum concentrations remained above four times the minimal inhibitory concentration for Pseudomonas spp. for the recommended time in 81% of patients treated with MEM, in 71% with TZP, in 53% with CAZ and in 0% with FEP. Accumulation after 48 hours of treatment was significant only for MEM.
In septic patients receiving CRRT, recommended doses of β-lactams for Pseudomonas aeruginosa are adequate for MEM but not for TZP, FEP and CAZ; for these latter drugs, higher doses and/or extended infusions should be used to optimise serum concentrations.
Although early and appropriate antibiotic therapy remains the cornerstone of success for the treatment of septic shock, few data exist to guide antibiotic dose optimization in critically ill patients, particularly those with multiple organ dysfunction syndrome (MODS). It is well known that MODS significantly alters the patient's physiology, but the effects of these variations on pharmacokinetics have not been reviewed concisely. Therefore, the aims of this article are to summarize the disease-driven variations in pharmacokinetics and pharmacodynamics and to provide antibiotic dosing recommendations for critically ill patients with MODS. The main findings of this review are that the two parameters that vary with greatest significance in critically ill patients with MODS are drug volume of distribution and clearance. Disease- and clinician-driven changes lead to an increased volume of distribution and lower-than-expected plasma drug concentrations during the first day of therapy at least. Decreased antibiotic clearance is common and can lead to drug toxicity. In summary, "front-loaded" doses of antibiotic during the first 24 h of therapy should account for the likely increases in the antibiotic volume of distribution. Thereafter, maintenance dosing must be guided by drug clearance and adjusted to the degree of organ dysfunction.
Despite the development of novel antibiotics active against Gram-positive bacteria, vancomycin generally remains the first treatment, although rapidly achieving concentrations associated with maximal efficacy provides an unresolved challenge. The objective of this study was to conduct a population pharmacokinetic analysis of vancomycin in a large population of critically ill patients. This was a retrospective data collection of 206 adult septic critically ill patients who were administered vancomycin as a loading dose followed by continuous infusion. The concentration-versus-time data for vancomycin in serum was analyzed by a nonlinear mixed-effects modeling approach using NONMEM. Monte Carlo simulations were performed using the final covariate model. We found that the best population pharmacokinetic model consisted of a one-compartment linear model with combined proportional and additive residual unknown variability. The volume of distribution of vancomycin (1.5 liters/kg) was described by total body weight and clearance (4.6 liters/h) by 24-hour urinary creatinine clearance (CrCl), normalized to body surface area. Simulation data showed that a 35-mg/kg loading dose was necessary to rapidly achieve vancomycin concentrations of 20 mg/liter. Daily vancomycin requirements were dependent on CrCl, such that a patient with a CrCl of 100 ml/min/1.73 m² would require at least 35 mg/kg per day by continuous infusion to maintain target concentrations. In conclusion, we have found that higher-than-recommended loading and daily doses of vancomycin seem to be necessary to rapidly achieve therapeutic serum concentrations in these patients.
Antibiotic penetration to the infection site is critical for obtaining a good clinical outcome in patients with ventilator-associated
pneumonia (VAP). Surprisingly few studies have quantified the penetration of β-lactam agents into the lung, as measured by
the ratio of area under the concentration-time curve (AUC) in epithelial lining fluid (ELF) to AUC in plasma (AUCELF/AUCplasma ratio). These have typically involved noninfected patients. This study examines the penetration and pharmacodynamics of meropenem
in the ELF among patients with VAP. Meropenem plasma and ELF concentration-time data were obtained from patients in a multicenter
clinical trial. Concentration-time profiles in plasma and ELF were simultaneously modeled using a three-compartment model
with zero-order infusion and first-order elimination and transfer (big nonparametric adaptive grid [BigNPAG]). A Monte Carlo
simulation was performed to estimate the range of ELF/plasma penetration ratios one would expect to observe in patients with
VAP, as measured by the AUCELF/AUCplasma ratio. The range of AUCELF/AUCplasma penetration ratios predicted by the Monte Carlo simulation was large. The 10th percentile of lung penetration was 3.7%, while
the 90th percentile of penetration was 178%. The variability of ELF penetration is such that if relatively high ELF exposure
targets are required to attain multilog kill or resistance suppression for bacteria like Pseudomonas aeruginosa, then even receiving the largest licensed dose of meropenem with an optimal prolonged infusion may not result in target attainment
for a substantial fraction of the population.
In critically ill patients with acute kidney injury, high intensity continuous renal replacement therapy (CRRT) (effluent flow rate >25mL/kg/h) shows no benefit on 90-day mortality and is associated with more hypophosphataemia.
Investigations over the past 20 years have demonstrated that antibacterials can vary markedly in the time course of antimicrobial activity. These differences in pharmacodynamic activity have implications for optimal dosage regimens. The results of more recent studies suggest that the magnitude of the pharmacokinetic/pharmacodynamic parameters required for efficacy are relatively similar in animal infection models and in human infections. However, there is still much to learn. Additional studies are needed to further correlate pharmacokinetic/ pharmacodynamic parameters for many antibacterials with therapeutic efficacy in a variety of animal infection models and in human infections. The potential value of using pharmacokinetic/pharmacodynamic parameters as guides for establishing optimal dosing regimens for new and old drugs and for new emerging pathogens and resistant organisms, for setting susceptibility break points, and for reducing the cost of drug development should make the continuing search for the therapeutic rationale of antibacterial dosing of mice and men worthwhile.
Background The optimal intensity of continuous renal-replacement therapy remains unclear. We conducted a multicenter, randomized trial to compare the effect of this therapy, delivered at two different levels of intensity, on 90-day mortality among critically ill patients with acute kidney injury. Methods We randomly assigned critically ill adults with acute kidney injury to continuous renal-replacement therapy in the form of postdilution continuous venovenous hemodiafiltration with an effluent flow of either 40 ml per kilogram of body weight per hour (higher intensity) or 25 ml per kilogram per hour (lower intensity). The primary outcome measure was death within 90 days after randomization. Results Of the 1508 enrolled patients, 747 were randomly assigned to higher-intensity therapy, and 761 to lower-intensity therapy with continuous venovenous hemodiafiltration. Data on primary outcomes were available for 1464 patients (97.1%): 721 in the higher-intensity group and 743 in the lower-intensity group. The two study groups had similar baseline characteristics and received the study treatment for an average of 6.3 and 5.9 days, respectively (P = 0.35). At 90 days after randomization, 322 deaths had occurred in the higher-intensity group and 332 deaths in the lower-intensity group, for a mortality of 44.7% in each group (odds ratio, 1.00; 95% confidence interval [CI], 0.81 to 1.23; P = 0.99). At 90 days, 6.8% of survivors in the higher-intensity group (27 of 399), as compared with 4.4% of survivors in the lower-intensity group (18 of 411), were still receiving renal-replacement therapy (odds ratio, 1.59; 95% CI, 0.86 to 2.92; P = 0.14). Hypophosphatemia was more common in the higher-intensity group than in the lower-intensity group (65% vs. 54%, P< 0.001). Conclusions In critically ill patients with acute kidney injury, treatment with higher-intensity continuous renal-replacement therapy did not reduce mortality at 90 days. (ClinicalTrials.gov number, NCT00221013.)
Context.— One purpose of early clinical trials is to establish the appropriate
dose of an antibiotic for phase 3 trials. Development of a relationship between
the ratio of drug exposure to organism minimum inhibitory concentration (MIC)
and therapeutic response early in the development process would allow an optimal
choice of dose to maximize response.
Objective.— To prospectively quantitate the relationship between plasma levels of
levofloxacin and successful clinical and/or microbiological outcomes and occurrence
of adverse events in infected patients.
Design.— Multicenter open-label trial.
Setting.— Twenty-two enrolling university-affiliated medical centers.
Patients.— A total of 313 patients with clinical signs and symptoms of bacterial
infections of the respiratory tract, skin, or urinary tract.
Main Outcome Measures.— Clinical response and microbiological eradication of pathogenic organisms.
Results.— Of 313 patients, 272 had plasma concentration-time data obtained. Of
these, 134 patients had a pathogen recovered from the primary infection site
and had an MIC of the pathogen to levofloxacin determined. These patients
constituted the primary analysis group for clinical outcome. Groups of 116
and 272 patients, respectively, were analyzed for microbiological outcome
and incidence of adverse events. In a logistic regression analysis, the clinical
outcome was predicted by the ratio of peak plasma concentration to MIC (Peak/MIC)
and site of infection (P<.001). Microbiological
eradication was predicted by the Peak/MIC ratio (P<.001).
Both clinical and microbiological outcomes were most likely to be favorable
if the Peak/MIC ratio was at least 12.2.
Conclusions.— Levofloxacin generated clinical and microbiological response rates of
95% and 96%, respectively. These response rates included fluoroquinolone "problem
pathogens," such as Streptococcus pneumoniae and Staphylococcus aureus. Exposure to levofloxacin was significantly
associated with successful clinical and microbiological outcomes. The principles
used in these analyses can be applied to other classes of drugs to develop
similar relationships between exposure and outcome. This pharmacokinetic modeling
could be used to determine optimal treatment dose in clinical trials in a
shorter time frame with fewer patients. This modeling also should be evaluated
for its potential to improve outcomes (maximizing therapeutic response, preventing
emergence of resistance, and minimizing adverse events) of patients treated
with this drug.
Study objective
To evaluate the relationship between inadequate antimicrobial treatment of infections (both community-acquired and nosocomial infections) and hospital mortality for patients requiring ICU admission.
Design
Prospective cohort study.
Setting
Barnes-Jewish Hospital, a university-affiliated urban teaching hospital.
Patients
Two thousand consecutive patients requiring admission to the medical or surgical ICU.
Interventions
Prospective patient surveillance and data collection.
Measurements and results
One hundred sixty-nine (8.5%) infected patients received inadequate antimicrobial treatment of their infections. This represented 25.8% of the 655 patients assessed to have either community-acquired or nosocomial infections. The occurrence of inadequate antimicrobial treatment of infection was most common among patients with nosocomial infections, which developed after treatment of a community-acquired infection (45.2%), followed by patients with nosocomial infections alone (34.3%) and patients with community-acquired infections alone (17.1%) (p < 0.001). Multiple logistic regression analysis, using only the cohort of infected patients (n = 655), demonstrated that the prior administration of antibiotics (adjusted odds ratio [OR], 3.39; 95% confidence interval [CI], 2.88 to 4.23; p < 0.001), presence of a bloodstream infection (adjusted OR, 1.88; 95% CI, 1.52 to 2.32; p = 0.003), increasing acute physiology and chronic health evaluation (APACHE) II scores (adjusted OR, 1.04; 95% CI, 1.03 to 1.05; p = 0.002), and decreasing patient age (adjusted OR, 1.01; 95% CI, 1.01 to 1.02; p = 0.012) were independently associated with the administration of inadequate antimicrobial treatment. The hospital mortality rate of infected patients receiving inadequate antimicrobial treatment (52.1%) was statistically greater than the hospital mortality rate of the remaining patients in the cohort (n = 1,831) without this risk factor (12.2%) (relative risk [RR], 4.26; 95% CI, 3.52 to 5.15; p < 0.001). Similarly, the infection-related mortality rate for infected patients receiving inadequate antimicrobial treatment (42.0%) was significantly greater than the infection-related mortality rate of infected patients receiving adequate antimicrobial treatment (17.7%) (RR, 2.37; 95% CI, 1.83 to 3.08; p < 0.001). Using a logistic regression model, inadequate antimicrobial treatment of infection was found to be the most important independent determinant of hospital mortality for the entire patient cohort (adjusted OR, 4.27; 95% CI, 3.35 to 5.44; p < 0.001). The other identified independent determinants of hospital mortality included the number of acquired organ system derangements, use of vasopressor agents, the presence of an underlying malignancy, increasing APACHE II scores, increasing age, and having a nonsurgical diagnosis at the time of ICU admission.
Conclusions
Inadequate treatment of infections among patients requiring ICU admission appears to be an important determinant of hospital mortality. These data suggest that clinical efforts aimed at reducing the occurrence of inadequate antimicrobial treatment could improve the outcomes of critically ill patients. Additionally, prior antimicrobial therapy should be recognized as an important risk factor for the administration of inadequate antimicrobial treatment among ICU patients with clinically suspected infections.
We conducted a prospective, open-label study to delineate a relationship between exposure and outcomes in 36 patients treated with cefepime. Twenty patients had documented Gram-negative infections. Timed blood and urine samples were obtained at steady state to determine pharmacokinetic and pharmacodynamic parameters. Microbiological success was significantly correlated with the proportion of the dosing interval that cefepime concentrations exceeded 4.3 x MIC. Our results support in vitro data that suggest bactericidal activity of β-lactams is optimized at concentrations ∼4 × MIC. These results should be validated by large prospective clinical trials.
Several lower respiratory tract infection (LRTI) trials have documented a correlation between clinical response and area under the inhibitory curve (24 h AUC/MIC; AUIC). The AUIC values in these studies were based on measured MICs and measured serum concentrations. This study evaluates AUIC estimates made using population pharmacokinetic parameters, and MICs from an automated microbiological susceptibility testing system. A computer database review over 2 years yielded 81 patients at Millard Fillmore Hospital with a culture-documented Gramnegative LRTI who had been treated with piperacillin and an aminoglycosid e, ceftazidime, ciprofloxacin or imipenem. Their AUIC values were estimated using renal function, drug dosages and MIC values. Outcome groups (clinical and microbiological cures and failures) were related to the AUIC values using Kruskal‐Wallis ANOVA, linear regression and classification and regression tree (CART) analysis. A significant breakpoint for clinical cures was an AUIC value at least 72 SIT ‐1 ·24 h (inverse serum inhibitory titre integrated over time). All antibiotics performed significantly better above this value than below it. Clinical cure was well described by a Hill-type equation. Within the piperacillin/aminoglycoside regimen, most of the activity came from the piperacillin, which had a higher overall AUIC value than the aminoglycoside. AUIC estimations based upon MIC values derived from the automated susceptibility testing method differed from NCCLS breakpoint data and from tube dilution derived values in this hospital by as much as three tube dilutions. These automated methods probably overestimated the MIC values of extremely susceptible organisms. The lack of precise MIC estimates in automated clinical microbiology methods impairs the use of AUIC to prospectively optimize microbiological outcome. Even ignoring this limitation and using the values as they are reported, the results of this analysis suggest that AUIC targets between 72 and 275 SIT ‐1 ·24 h are useful in predicting clinical outcome.
• Fifty patients with gram-negative lower respiratory tract infections were treated with intravenous ciprofloxacin to evaluate efficacy and safety. Relationships between individual pharmacokinetics and clinical and bacteriologic outcome were studied. Ciprofloxacin concentrations in plasma were determined by high-performance liquid chromatography. Respiratory secretion cultures were obtained daily to determine the eradication day of the infecting organism. Susceptibility (minimum inhibitory concentration) to ciprofloxacin and other antimicrobials was determined using standard microdilution techniques. The mean age of the patients was 70 years. They had multiple underlying diseases, and two thirds of them were ventilator dependent at entry. Approximately 50% of the patients had failed previous treatment for the same infections. Patients infected with Enterobacteriaceae or Haemophilus influenzae with minimum inhibitory concentrations of less than 0.25 mg/L responded well to intravenous ciprofloxacin therapy (200 mg every 12 hours). The organisms were eradicated from sputum cultures usually within 1 day after ciprofloxacin therapy was started. Most clinical failures occurred in patients who were infected with Pseudomonas aeruginosa and had multiple underlying diseases. Pseudomonas aeruginosa was isolated from 10 patients with pneumonia, 2 patients with lung abscess, and 1 patient with bronchiectasis. The Pseudomonas isolate acquired resistance during ciprofloxacin treatment in 7 patients with pneumonia and in all of the remaining 3 patients. We conclude that ciprofloxacin is safe and effective at a dosage of 200 mg administered intravenously every 12 hours for nosocomial lower respiratory tract infections caused by Enterobacteriaceae or Haemophilus species. Many patients who had failed previous antibiotic treatment for Enterobacteriaceae infections had good clinical response to ciprofloxacin therapy. Studies using either higher dosages of ciprofloxacin or combination therapy should be conducted to determine if acquired resistance can be avoided in Pseudomonas infections.
(Arch Intern Med. 1989;149:2269-2273)
Current guidelines for adjusting antimicrobial therapy regimens commonly are based on drug concentrations measured in plasma. In septic patients, however, the interstitial space of soft tissues in addition to the central compartment represents the target site of infection. We thus hypothesized that one explanation for therapeutic failure during antibiotic treatment might be the inability to achieve effective antimicrobial concentrations in the interstitial space fluid of soft tissues. This is corroborated by the fact that piperacillin, a frequently administered beta-lactam antibiotic, often fails to be effective despite documented susceptibility of the causative pathogen in vitro.
Prospective comparative study of two groups.
The intensive care unit and research ward of an university hospital.
Six patients with septic shock and a control group of six gender- and age-matched healthy volunteers.
To measure piperacillin penetration into the interstitial space fluid of skeletal muscle and subcutaneous adipose tissue, we employed microdialysis after a single intravenous administration of 4.0 g of piperacillin to patients and healthy volunteers. Piperacillin concentrations were assayed by using reversed-phase high-pressure liquid chromatography.
In septic shock patients, interstitial piperacillin concentrations in skeletal muscle and subcutaneous adipose tissue were five- to ten-fold lower than corresponding free plasma concentrations (p <.03). Mean piperacillin concentrations in subcutaneous adipose tissue never exceeded 11 microg/mL, which is below the minimal inhibitory concentration for a range of relevant pathogens in patients with septic shock.
The results of the present study demonstrate that in septic shock patients, piperacillin concentrations in the interstitial space may be subinhibitory, even though effective concentrations are attained in plasma. The lack of success of antimicrobial therapy in these patients thus might be attributable to inadequate target site penetration of antibiotics.
Three hundred and forty eight critically-ill patients with a documented Gram-negative infection were randomized to receive
amikacin once- (od) or twice-daily (bd). The amikacin was given by slow intravenous injection in a daily dose of 20 mg/kg
in patients under the age of one year (paediatric group) and 15 mg/kg in patients over the age of one year (adult group).
Paediatric and adult patients on the od regimen received a loading dose of 25 and 20 mg/kg respectively. The dosages were
subsequently adjusted to achieve desirable blood levels. Patients received other antibiotics as clinically indicated. Forty-eight
patients were withdrawn from the study due to death or azotaemia occurring in the first 72 h. One hundred and fifty five patients
(76 paediatric) received an od dose and 145 (65 paediatric) received a bd dose. The clinical cure rate was 83% in the od group
compared to 66% in the bd group (P = 0·001). The bacteriological cure rate was 81% in the od group compared to 58% in the bd group (P = 0·005). In the paediatric sub-group the cure rate was higher with the od regimen (P = 0·002) but this difference was not statistically significant in the adult patients (P = 0·1). The serum creatinine rose in 35% of patients in the bd group compared to 21% in the od group (P = 0·05). Although audiometry was not performed there was no clinical evidence of ototoxkaty in any of the patients. In conclusion
od amikacin dosing resulted in a higher cure and less nephrotoxicity than conventional bd dosing.
Given the lack of clinical data to guide optimal dosing of vancomycin in critically ill patients with life-threatening infections, the objective was to characterise vancomycin pharmacodynamics in MRSA-associated septic shock. Cases were extracted from an observational, multicentre study in Canadian Intensive Care Units and included 35 adult patients with MRSA-associated septic shock who received vancomycin and had a measured serum concentration within the first 72h of therapy. Univariate and multivariate analyses were used to assess variables predictive of in-hospital mortality. Patients who survived were significantly younger and had better renal function, lower probability of chronic obstructive pulmonary disease, higher probability of intravenous drug use, lower probability of healthcare-associated infection and lower APACHE II score. Survivors also received higher vancomycin doses and had higher serum troughs and AUC(24)/MIC values. The survival rate was 2.5-fold greater in patients who had vancomycin troughs ≥15mg/L [70.6% (12/17) vs. 27.8% (5/18); P=0.001]. Two significant AUC(24)/MIC thresholds for survival, ≥451 (P=0.006) and ≥578 (P=0.012), were identified by CART analysis. Only younger age (P=0.028) and higher vancomycin AUC(24)/MIC (P=0.045) were significant in multivariate analyses of survival. This study of vancomycin in critically ill patients supports the current recommendation for serum troughs of at least 15mg/L and, in patients with septic shock, an AUC(24)/MIC threshold higher than the conventional 400. Improved survival was observed with the attainment of these pharmacodynamic targets.
Objective:
Doripenem is a valuable broad-spectrum antibiotic for empirical therapy in critically ill patients, although little data exist to guide effective dosing. We sought to describe the population pharmacokinetics of doripenem in critically ill patients with nosocomial pneumonia and then to use Monte Carlo dosing simulations to procure clinically relevant dosing recommendations for that population.
Design:
Pharmacokinetic analysis of Phase III Trial data.
Setting:
Critical care units at multiple centers.
Patients:
Thirty-one critically ill adult patients with nosocomial pneumonia.
Interventions:
Serial blood samples were taken on day 2 or 3 of treatment and used for population pharmacokinetic analysis with nonlinear mixed effects modelling and Monte Carlo simulation.
Measurements and main results:
A two-compartment linear model was most appropriate. The mean values for doripenem clearance (20.4 ± 14.2 L/hr) and volume of distribution (45.9 ± 36.3 L) were larger than that observed in previous studies in noncritically ill patients. Doripenem clearance was correlated with creatinine clearance and peripheral volume of distribution with patient body weight. Administration by extended infusion negated much of the pharmacokinetic variability caused by different patient body weight and renal function and enabled achievement of concentrations associated with maximal bacterial killing.
Conclusion:
: This is the first article describing the pharmacokinetics/pharmacodynamics of doripenem solely in critically ill patients and emphasizes the effect of patient weight and creatinine clearance on pharmacokinetics. Use of extended infusions with this antibiotic should be encouraged as it maximizes the likelihood of achieving target blood concentrations.
Therapeutic drug monitoring (TDM) aims to optimize treatments by individualizing dosage regimens based on the measurement of blood concentrations. Dosage individualization to maintain concentrations within a target range requires pharmacokinetic and clinical capabilities. Bayesian calculations currently represent the gold standard TDM approach but require computation assistance. In recent decades computer programs have been developed to assist clinicians in this assignment. The aim of this survey was to assess and compare computer tools designed to support TDM clinical activities. The literature and the Internet were searched to identify software. All programs were tested on personal computers. Each program was scored against a standardized grid covering pharmacokinetic relevance, user friendliness, computing aspects, interfacing and storage. A weighting factor was applied to each criterion of the grid to account for its relative importance. To assess the robustness of the software, six representative clinical vignettes were processed through each of them. Altogether, 12 software tools were identified, tested and ranked, representing a comprehensive review of the available software. Numbers of drugs handled by the software vary widely (from two to 180), and eight programs offer users the possibility of adding new drug models based on population pharmacokinetic analyses. Bayesian computation to predict dosage adaptation from blood concentration (a posteriori adjustment) is performed by ten tools, while nine are also able to propose a priori dosage regimens, based only on individual patient covariates such as age, sex and bodyweight. Among those applying Bayesian calculation, MM-USC*PACK© uses the non-parametric approach. The top two programs emerging from this benchmark were MwPharm© and TCIWorks. Most other programs evaluated had good potential while being less sophisticated or less user friendly. Programs vary in complexity and might not fit all healthcare settings. Each software tool must therefore be regarded with respect to the individual needs of hospitals or clinicians. Programs should be easy and fast for routine activities, including for non-experienced users. Computer-assisted TDM is gaining growing interest and should further improve, especially in terms of information system interfacing, user friendliness, data storage capability and report generation.
Objectives:
The %fT>MIC of ceftazidime has been shown to correlate with microbiological outcome of Gram-negative bacteria (GNB) in preclinical studies. However, clinical data are still lacking. We explored the relationship of ceftazidime exposure and outcome in patients with nosocomial pneumonia using data from a recent randomized, double-blind Phase 3 clinical trial.
Patients and methods:
Pharmacokinetic (PK) and demographic data from three clinical trials were used to construct a population PK model using non-linear mixed-effects modelling. Individual concentration-time curves and PK/pharmacodynamic indices were determined for individual patients. The MICs used in the analyses were the highest MICs for any GNB cultured at baseline or end of therapy.
Results:
A two-compartment model best fit the data, with creatinine clearance as covariate on clearance and age on the central compartment. Classification and regression tree analysis showed a breakpoint value of 44.9% (P<0.0001) for GNB in 154 patients. The Emax model showed a good fit (R(2) =0.93). The benefit of adequate treatment increased from an eradication rate of 0.4848 at %fT>MIC of 0% to 0.9971 at 100%. The EC50 was 46.8% and the EC90 was 95.5% for %fT>MIC. Exposure correlated significantly with both microbiological and clinical outcome at test-of-cure.
Conclusions:
We conclude that exposures to ceftazidime predict microbiological as well as clinical outcome, and the %fT>MIC required to result in a likely favourable outcome is >45% of the dosing interval. This value is similar to that observed in animal models and underscores the principle that adequate dosing can be predicted and is beneficial to patient care.
Controversy reigns as to how protein binding changes alter the time course of unbound drug concentrations in patients. Given that the unbound concentration is responsible for drug efficacy and potential drug toxicity, this area is of significant interest to clinicians and academics worldwide. The present uncertainty means that many questions relating to this area exist, including "How important is protein binding?", "Is protein binding always constant?", "Do pH and temperature changes alter binding?" and "How do protein binding changes affect dosing requirements?". In this paper, we seek to address these questions and consider the data associated with altered pharmacokinetics in the presence of changes in protein binding and the clinical consequences that these may have on therapy, using examples from the critical care area. The published literature consistently indicates that a change in the protein binding and unbound concentrations of some drugs are common in certain specific patient groups such as the critically ill. Changes in pharmacokinetic parameters, including clearance and apparent volume of distribution (V(d)), may be dramatic. Drugs with high protein binding, high intrinsic clearance (e.g. clearance by glomerular filtration) and where dosing is not titrated to effect are most likely to be affected in a clinical context. Drugs such as highly protein bound antibacterials with multiple half-lives within a dosing interval and that have some level of renal clearance, such as ertapenem, teicoplanin, ceftriaxone and flucloxacillin, are commonly affected. In response to these challenges, clinicians need to adapt dosing regimens rationally based on the pharmacokinetic/pharmacodynamic characteristics of the drug. We propose that further pharmacokinetic modelling-based research is required to enable the design of robust dosing regimens for drugs affected by altered protein binding.
Antibiotic dosing for critically ill patients that is derived from other patient groups is likely to be suboptimal because of significant antibiotic pharmacokinetic changes, particularly in terms of drug volume of distribution and clearance. Organ support techniques including renal replacement therapy (RRT) and extracorporeal membrane oxygenation (ECMO) increase the pharmacokinetic variability. This article reviews the recently published antibiotic pharmacokinetic data associated with burns patients, those receiving continuous RRT (CRRT), sustained low-efficiency dialysis (SLED) and ECMO.
These groups develop increases in volume of distribution that necessitate the use of higher initial doses to rapidly achieve therapeutic antibiotic concentrations. Burns patients have supranormal drug clearances requiring more frequent administration of antibiotics. Patients receiving CRRT or SLED have variable drug clearances related to different equipment and RRT settings at different institutions. ECMO presents a different challenge because there is such a dearth of data with higher than standard doses potentially required, even in the presence of end-organ failure.
In the context of such variable pharmacokinetics, a guideline approach to dosing remains elusive because of insufficient available data and, therefore, use of therapeutic drug monitoring should be considered advantageous where possible.
In critically ill patients receiving continuous renal replacement therapy, we aimed to assess the variability of antibiotic trough concentrations, the influence of effluent flow rates on such concentrations, and the incidence of suboptimal antibiotic dosage.
Prospective, observational, multicenter, pharmacokinetic study.
Four tertiary intensive care units within the multicenter RENAL randomized controlled trial of continuous renal replacement therapy intensity.
Twenty-four critically ill adult patients with acute kidney injury receiving ciprofloxacin, meropenem, piperacillin/tazobactam, or vancomycin during continuous renal replacement therapy.
We obtained trough blood samples and measured antibiotic concentrations.
We obtained data from 40 dosing intervals and observed wide variability in trough concentrations (6.7-fold for meropenem, 3.8-fold for piperacillin, 10.5-fold for tazobactam, 1.9-fold for vancomycin, and 3.9-fold for ciprofloxacin). The median (interquartile range) trough concentrations (mg/L) for meropenem was 12.1 (7.8-18.4), 105.0 (74.4-204.0)/3.8 (3.4-21.8) for piperacillin/tazobactam, 12.0 (9.8-16.0) for vancomycin, and 3.7 (3.0-5.6) for ciprofloxacin. Overall, 15% of dosing intervals did not meet predetermined minimum therapeutic target concentrations, 40% did not achieve the higher target concentration, and, during 10% of dosing intervals, antibiotic concentrations were excessive. No difference, however, was found between patients on the basis of the intensity of continuous renal replacement therapy; this effect may have been obscured by differences in dosing regimens, time off the filter, or altered pharmacokinetics.
There is significant variability in antibiotic trough concentrations in critically ill patients receiving continuous renal replacement therapy, which did not only appear to be influenced by effluent flow rate. Here, empirical dosing of antibiotics failed to achieve the target trough antibiotic concentration during 25% of the dosing intervals.
The aim of this study was to determine the current susceptibility of hospital isolates of contemporary Gram-negative pathogens to the carbapenems doripenem, imipenem and meropenem. Between May and October 2008, seven centres in Germany were invited to collect and submit Pseudomonas aeruginosa, Enterobacteriaceae and other Gram-negative bacterial Intensive Care Unit (ICU)/non-ICU isolates from patients with complicated intra-abdominal infections (cIAIs), bloodstream infections (BSIs) or nosocomial pneumonia (NP). Susceptibility was determined at each centre by Etest. A central laboratory performed species confirmation as well as limited susceptibility and quality control testing. In total, 363 isolates were collected, comprising 46.0% Enterobacteriaceae, 45.2% P. aeruginosa, 4.7% Acinetobacter spp. and 4.1% other Gram-negatives. Most isolates (47.9%) were collected from NP, 32.8% were from cIAIs and 19.3% from BSIs; 57.3% were obtained from ICU patients. The MIC(90) values (minimum inhibitory concentration for 90% of the isolates) for doripenem, meropenem and imipenem were, respectively, 4, 16 and 32 mg/L against P. aeruginosa, 0.06, 0.06 and 0.5mg/L against Enterobacteriaceae and ≥ 64 mg/L for each carbapenem against other Gram-negative isolates. Using European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints, 81.1%, 75.6% and 79.3% of P. aeruginosa were susceptible to doripenem, imipenem and meropenem, respectively. Against all pathogens combined, MIC(90) values for ICU versus non-ICU isolates, respectively, were 4 mg/L vs. 1mg/L for doripenem, 8 mg/L vs. 1mg/L for meropenem and ≥ 64 mg/L vs. 8 mg/L for imipenem. Doripenem showed comparable activity against P. aeruginosa from patients with BSIs, cIAIs or NP. Similar findings were observed for Enterobacteriaceae and other Gram-negatives, including Acinetobacter spp. Doripenem generally showed similar or slightly better activity than meropenem and better activity than imipenem against Gram-negative pathogens collected in Germany.
β-Lactams are routinely used as empirical therapy in critical illness, with extended concentrations above the minimum inhibitory concentration (MIC) of the infecting organism required for effective treatment. Changes in renal function in this setting can significantly impact the probability of achieving such targets.
Analysis was made of trough plasma drug concentrations obtained via therapeutic drug monitoring, compared with renal function, in critically ill patients receiving empirical β-lactam therapy. Drug concentrations were measured by means of high-performance liquid chromatography and corrected for protein binding. Therapeutic levels were defined as greater than or equal to MIC and greater than or equal to four times MIC (maximum bacterial eradication), respectively. Renal function was assessed by means of an 8-h creatinine clearance (CLCR).
Fifty-two concurrent trough concentrations and CLCR measures were used in analysis. Piperacillin was the most frequent β-lactam prescribed (48%), whereas empirical cover and Staphylococcus species were the most common indications for therapy (62%). Most patients were mechanically ventilated on the day of study (85%), although only 25% were receiving vasopressors. In only 58% (n = 30) was the trough drug concentration greater than or equal to MIC, falling to 31% (n = 16) when using four times MIC as the target. CLCR values ≥ 130 mL/min/1.73 m2 were associated with trough concentrations less than MIC in 82% (P < .001) and less than four times MIC in 72% (P < .001). CLCR remained a significant predictor of subtherapeutic concentrations in multivariate analysis.
Elevated CLCR appears to be an important predictor of subtherapeutic β-lactam concentrations and suggests an important role in identifying such patients in the ICU.
Early, appropriate antibacterial therapy is a key factor in effectively managing septic critically ill patients ¹ . The prescriber must not only employ an agent of appropriate spectrum, but also in an adequate dose to achieve bacterial eradication at the site of infection. However, the relationship between drug administration and therapeutic success is complex in the critically ill, such that a patient's physiology heavily influences the way drugs distribute into tissue and are eliminated. This represents a significant challenge to the emergency or intensive care physician, and in this manner, personalising therapy, through a greater understanding of how a drug will behave in an individual patient, is likely to lead to improved outcomes.
The exposure-response relationship of anti-infective agents at the site of infection is currently being re-examined. Epithelial lining fluid (ELF) has been suggested as the site (compartment) of antimicrobial activity against lung infections caused by extracellular pathogens. There have been an extensive number of studies conducted during the past 20 years to determine drug penetration into ELF and to compare plasma and ELF concentrations of anti-infective agents. The majority of these studies estimated ELF drug concentrations by the method of urea dilution and involved either healthy adult subjects or patients undergoing diagnostic bronchoscopy. Antibacterial agents such as macrolides, ketolides, newer fluoroquinolones and oxazolidinones have ELF to plasma concentration ratios of >1. In comparison, β-lactams, aminoglycosides and glycopeptides have ELF to plasma concentration ratios of ≤1. Potential explanations (e.g. drug transporters, overestimation of the ELF volume, lysis of cells) for why these differences in ELF penetration occur among antibacterial classes need further investigation. The relationship between ELF concentrations and clinical outcomes has been under-studied. In vitro pharmacodynamic models, using simulated ELF and plasma concentrations, have been used to examine the eradication rates of resistant and susceptible pathogens and to explain why selected anti-infective agents (e.g. those with ELF to plasma concentration ratios of >1) are less likely to be associated with clinical treatment failures. Population pharmacokinetic modelling and Monte Carlo simulations have recently been used and permit ELF and plasma concentrations to be evaluated with regard to achievement of target attainment rates. These mathematical modelling techniques have also allowed further examination of drug doses and differences in the time courses of ELF and plasma concentrations as potential explanations for clinical and microbiological effects seen in clinical trials. Further studies are warranted in patients with lower respiratory tract infections to confirm and explore the relationships between ELF concentrations, clinical and microbiological outcomes, and pharmacodynamic parameters.
Optimizing the prescription of antimicrobials is required to improve clinical outcome from infections and to reduce the development of antimicrobial resistance. One such method to improve antimicrobial dosing in individual patients is through application of therapeutic drug monitoring (TDM). The aim of this manuscript is to review the place of TDM in the dosing of antimicrobial agents, specifically the importance of pharmacokinetics (PK) and pharmacodynamics (PD) to define the antimicrobial exposures necessary for maximizing killing or inhibition of bacterial growth. In this context, there are robust data for some antimicrobials, including the ratio of a PK parameter (e.g. peak concentration) to the minimal inhibitory concentration of the bacteria associated with maximal antimicrobial effect. Blood sampling of an individual patient can then further define the relevant PK parameter value in that patient and, if necessary, antimicrobial dosing can be adjusted to enable achievement of the target PK/PD ratio. To date, the clinical outcome benefits of a systematic TDM programme for antimicrobials have only been demonstrated for aminoglycosides, although the decreasing susceptibility of bacteria to available antimicrobials and the increasing costs of pharmaceuticals, as well as emerging data on pharmacokinetic variability, suggest that benefits are likely.
Critically ill patients can display markedly abnormal physiological parameters compared with those in ward-based or ambulatory settings. As a function of both the underlying inflammatory state and the interventions provided, these patients manifest substantial changes in their cardiovascular and renal function that are not always immediately discernable using standard diagnostic tests. Impaired renal function is well documented among such individuals; however, even patients with normal serum creatinine concentrations might display elevated glomerular filtration rates, a phenomenon we have termed augmented renal clearance (ARC). This finding has important ramifications for the accurate dosing of renally eliminated drugs, given that most pharmaceutical dosing regimens were validated outside the critical care environment. Empirical approaches to dosing are unlikely to achieve therapeutic drug concentrations in patients with ARC, placing them at risk of suboptimal drug exposure and potential treatment failure. With an increasing appreciation of this phenomenon, alternative dosing strategies will need to be investigated.