Objective To evaluate whether individualized dosage regimen based on therapeutic drug monitoring (TDM) is beneficial for improving the rate of pharmacokinetics/pharmacodynamics (PK/PD) reaching the standard and anti-infection efficacy. Methods Totally, 36 cases in the intensive care unit (ICU) of Nanjing Drum Tower Hospital using meropenem during January 2015 to December 2015 were collected, and divided into intervention group and control group. Results On the fourth day of administration, meropenem concentration in intervention group was significantly higher than that of the control group (22.5 μg·mL-1 and 17.5 μg·mL-1, respectively, P=0.007).With minimal inhibitory concentration (Cmin) >8 μg·mL-1 serving as target, the rate of reaching the standard was both 22.2% on day 2, 100.0% and 72.2% on day 4 in intervention group and control group, respectively (P=0.015). With minimal inhibitory concentration (Cmin) >32 μg·mL-1 serving as target, the rate of reaching the standard was both 0 on day 2, 38.9% and 5.5% on day 4 in intervention group and control group, respectively (P=0.015). The clinical curative rate of the intervention group and control group was 83.3% and 72.2%, respectively (P=0.437), and the failure rate was 16.7% and 27.8%, respectively.Bacteria clearance rate was 88.9% and 55.5% in the intervention group and control group, respectively(P<0.05). Conclusion Individualized dosage regimen based on TDM in ICU patients is beneficial to improving the rate of PK/PD reaching the standard and anti-infection efficacy.
治疗药物监测(therapeutic drug monitoring,TDM)常用来针对那些治疗指数窄的药物,从而减少毒副作用的发生或增强疗效。同时,用来优化给药方案以应对患者间个体差异较大导致的药物PK参数变化。多年来,临床上已对万古霉素、抗癫痫药、抗精神病药等常规进行血药浓度监测。因此,笔者在本研究设计了临床队列研究,考察基于TDM的个体化给药方案是否有利于增加重症患者美罗培南的PK/PD靶目标达标率,以及是否有助于提高抗感染治疗的效果。
BOUSSEKEYN,CANTRELJ,DORCHIN DL,et al.Epide-miology,prognosis,and evolution of management of septic shock in a French intensive care unit:a five years survey[J].,2010,2010:436427.
Purpose. To evaluate the epidemiology, prognosis, and management of septic shock patients hospitalized in our intensive care unit (ICU). Materiel and Methods. Five-year monocenter observational study including 320 patients. Results. ICU mortality was 54.4%. Independent mortality risk factors were mechanical ventilation ( O R = 4 . 9 7 ), Simplify Acute Physiology Score (SAPS) II > 60 ( O R = 4 . 2 8 ), chronic alcoholism ( O R = 3 . 3 8 ), age >65 years ( O R = 2 . 6 5 ), prothrombin ratio <40% ( O R = 2 . 3 7 ), and P a O 2 / F i O 2 ratio <150 ( O R = 1 . 9 1 ). These six mortality risk factors recovered allow screening immediately septic shock patients with a high mortality risk. Morbidity improved with time (diminution of septic shock complications, increase of the number of days alive free from mechanical ventilation and vasopressors on day 28), concomitant to an evolution of the management (earlier institution of all replacement and medical therapies and more initial volume expansion). There was no difference in mortality. Conclusion. Our study confirms a high mortality rate in septic shock patients despite a new approach of treatment.
MELAMEDA,SORVILLO FJ.The burden of sepsis-assoc-iated mortality in the United States from 1999 to 2005:an analysis of multiple-cause-of-death data[J].,2009,13(1):R28.
Introduction Sepsis is the 10th leading cause of death in the United States. The National Center for Health Statistics ' multiple-cause-of-death (MCOD) dataset is a large, publicly available, population-based source of information on disease burden in the United States. We have analysed MCOD data from 1999 to 2005 to investigate trends, assess disparities and provide population-based estimates of sepsis-associated mortality during this period. Methods Sepsis-associated deaths occurring in the United States from 1999 to 2005 were identified in MCOD data using International Classification of Disease , 10th Revision ( ICD-10 ) codes. Population-based mortality rates were calculated using bridged-race population estimates from the National Center for Health Statistics . Comparisons across age, sex and racial/ethnic groups were achieved by calculating mortality rate ratios. Results From 1999 to 2005 there were 16,948,482 deaths in the United States. Of these, 1,017,616 were associated with sepsis (6.0% of all deaths). The age-adjusted rate of sepsis-associated mortality was 50.37 deaths per 100,000 (95% confidence interval (CI) = 50.28 to 50.47). There were significant disparities in sepsis-associated mortality in race/ethnicity and sex groups ( P < 0.0001). After controlling for age, Asians were less likely than whites to experience sepsis-related death (rate ratio (RR) = 0.78, 95% CI = 0.77 to 0.78), while Blacks (RR = 2.24, 95% CI = 2.23 to 2.24), American Indians/Alaska Natives (RR = 1.24, 95% CI = 1.24 to 1.25) and Hispanics (RR = 1.14, 95% CI = 1.13 to 1.14) were more likely than whites to experience sepsis-related death. Men were at increased risk for sepsis-associated death in all race/ethnicity categories (RR = 1.27, 95% CI = 1.27 to 1.28), but the degree of increased susceptibility associated with being male differed among racial/ethnic groups ( P < 0.0001). Although crude sepsis-associated mortality increased by 0.67% per year during the study period ( P < 0.0001), the age-adjusted mortality rate decreased by 0.18% per year ( P < 0.01). Conclusions The rapid rise in sepsis mortality seen in previous decades has slowed, but population ageing continues to drive the growth of sepsis-associated mortality in the United States. Disparities in sepsis-associated mortality mirror those previously reported for sepsis incidence. Sepsis in Asians, Hispanics and American Indian/Alaska Natives should be studied separately because aggregate measures may obscure important differences among these groups.
ROBERTS JA,PAUL SK,AKOVAM,et al.DALI:defini-ng antibiotic levels in intensive care unit patients:are current beta-lactam antibiotic doses sufficient for critically ill patients?[J].,2014,58(8):1072-1083.
This was a multinational study to determine the appropriateness of 0205-lactam antibiotic dosing in critically ill patients. Of patients treated for infection, 16% did not achieve minimum concentrations targets and these patients were 32% less likely to have a positive clinical outcome.Background. Morbidity and mortality for critically ill patients with infections remains a global healthcare problem. We aimed to determine whether 0205-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 0205-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], 4809“73) years, the median Acute Physiology and Chronic Health Evaluation II score was 18 (IQR, 1409“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.
ROBERTS JA,ABDUL-AZIZ M H,LIPMAN J,et al.Indi-vidualised antibiotic dosing for patients who are critically ill:challenges and potential solutions[J].,2014,14(6):498-509.
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.
DRUSANO GL.Antimicrobial pharmacodynamics:critical interactions of 'bug and drug'[J].,2004,2(4):289-300.
ABSTRACT Antimicrobial pharmacodynamics is the discipline that integrates microbiology and pharmacology, with the aim of linking a measure of drug exposure, relative to a measure of drug potency for the pathogen in question, to the microbiological or clinical effect achieved. The delineation of such relationships allows the drug dose to be chosen in a rational manner, so that the desired effect (for example, the maximal bactericidal effect) can be achieved in a large proportion of the intended patient population. Ultimately, the goal of any anti-infective therapy is to administer a dose of drug that has an acceptably high probability of achieving the desired therapeutic effect balanced with an acceptably low probability of toxicity. Appropriate use of the latest pharmacodynamic modelling approaches can minimize the emergence of resistance and optimize the outcome for patients.
ROBERTS JA,NORRISR,PATERSON DL,et al.Thera-peutic drug monitoring of antimicrobials[J].,2012,73(1):27-36.
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.
HAYASHIY,LIPMANJ,UDY AA,et al.Beta-lactam thera-peutic drug monitoring in the critically ill:optimising drug exposure in patients with fluctuating renal function and hypoalbuminaemia[J].,2013,41(2):162-166.
β-Lactams are routinely prescribed in the treatment of serious infections. Empirical dosing schedules are typically derived from studies in healthy volunteers and largely fail to consider the significant changes in antibacterial pharmacokinetics often encountered in the critically ill. These changes are primarily driven by the underlying pathophysiology and the interventions provided, leading to altered protein binding, poor tissue penetration, and fluctuations in the volume of distribution and drug clearance. Each separately, and in combination, is likely to complicate successful β-lactam administration in this setting. Although antibacterial therapeutic drug monitoring (TDM) has traditionally been employed to minimise drug toxicity, the challenges to achieving 'optimal' drug concentrations in the critically ill suggest β-lactam TDM as an attractive means to optimise drug exposure. Whilst there is currently little evidence to support routine widespread application of such a service, β-lactam TDM may still have a role in select patients where difficulty in establishing therapeutic concentrations can be illustrated. This series utilises three representative cases from a β-lactam TDM service that highlight the utility of this intervention in optimising antibacterial dosing. These preliminary data support an expanding role for β-lactam TDM in select critically ill patients and provide insight into the subpopulations most at risk of suboptimal drug exposure. Future studies investigating the clinical outcome benefits of β-lactam TDM in these patient groups are now warranted.
UDY AA,PUTT MT,SHANMUGATHASANS,et al.Augmented renal clearance in the intensive care unit:an illustrative case series[J].,2010,35(6):606-608.
The substantial underlying disease burden, in combination with the therapeutic interventions provided, can result in significantly altered end-organ function in the critically ill. These changes can in turn affect key pharmacokinetic (PK) indices for many antibiotics, including drug clearance, promoting potentially subtherapeutic concentrations for lengthy periods of the dosing interval, therapeutic failure or the selection of resistant organisms. This paper presents three instructional cases from our tertiary-level Intensive Care Unit, where established antibiotic dosing regimens failed to achieve predefined PK targets for optimal bacterial killing. Using therapeutic drug monitoring (TDM), significant dose modification was subsequently undertaken. We propose augmented renal clearance as a possible mechanism underlying this phenomenon, particularly in young post-operative, burns or head-injured patients with normal serum creatinine concentrations. TDM, or at least a measured creatinine clearance, should be considered early in this setting to allow the optimisation of antibiotic exposure.
A patient with septic shock due to extensively drug resistant (XDR) Pseudomonas aeruginosa was cured by optimizing the meropenem (MEM) regimen to obtain at least 40% of the time between two administrations in which drug levels were four times higher than the MIC of the pathogen. As the standard drug dose did not achieve these optimal concentrations, the MEM regimen was progressively increased up to 12 g/day (3 g every 6 h in a 3-h extended infusion), which eventually resulted in sepsis resolution. High MEM dosage may represent a valuable therapeutic option for infection due to multidrug-resistant (MDR) strains, and drug monitoring would allow rapid regimen adjustment in clinical practice.
Beta-lactam thera-peutic drug monitoring in the critically ill:optimising drug exposure in patients with fluctuating renal function and hypoalbuminaemia