How could we reduce antibiotic use in critically ill patients?

The role of antibiotic pressure in the selection of antibiotic-resistant bacteria is still under debate in the scientific community and often confounded by scarce data on antibiotic usage. Several studies demonstrated that prior antibiotic exposure is likely to increase patient's colonization and infection by antimicrobial-resistant bacteria. Of even more concern is the significant mortality associated with these infections, in particular in critically ill patients. Therefore, the control of antibiotic usage in intensive care units (ICUs) is of paramount importance. Antibiotic stewardship programmes (ASP) have been demonstrated to represent a useful intervention to reduce the inappropriate antibiotic usage in hospitalized patients. A few trials were performed in ICU population with positive results. The major risk we foresee for the implementation of ASP for ICU patients is the lack of consideration of local ecology and strict quality indicators. The development of new pattern of antimicrobial resistance might be ascribed to an inappropriate ASP. European networks to define best strategies and antibiotic-care bundles need to be supported at national and international level. To optimize antibiotic use in the ICU and to fight against the spread of resistance, it is extremely important to adopt a multifaceted approach including ASP.     

How to measure pharmacokinetics in critically ill patients?

There is pressing need to better understand pharmacokinetics in critically ill patients. This will aid clinicians in selecting optimal dosing regimens. Pharmacokinetic studies are difficult in this population due to the heterogeneity of the patients and the practical issues of research involving critically ill patients. Therapeutic drug monitoring is routinely performed to guide dosing for aminoglycoside and glycopeptide antibiotics. Expanding its use to other drug classes could provide new therapeutic advantages. Plasma concentration may not always reflect tissue distribution in critically ill patients. Microdialysis is a technique that can be applied in the Intensive Care Unit to measure tissue concentrations and provide further insights to antimicrobial therapy for critically ill patients. Finally, the application of population pharmacokinetic analysis in studies in critically ill patients may identify factors affecting pharmacokinetics and enhance drug dosing regimens for varied patient groups.     

Vancomycin therapy in critically ill patients on continuous renal replacement therapy; are we doing enough?

Background

Recommendations regarding vancomycin dosing and monitoring in critically ill patients on continuous renal replacement therapy (CRRT) are limited. This is a retrospective study to assess the adequacy of current vancomycin dosing and monitoring practice for patients on CRRT in a tertiary hospital in Riyadh, Saudi Arabia.

Methods

A retrospective chart review of adult patients admitted between 1 April 2011 and 30 March 2013 to critical care and received intravenous vancomycin therapy whilst on CRRT was performed.

Results

A total of 68 patients received intravenous vancomycin therapy whilst on CRRT, of which 32 met the inclusion criteria. Fifty-one percent were males and median (range) age was 62.5 (19 – 90) years. Median APACHE II score was 33.5 (22–43) and median Charlson Comorbidity Score was 4 (0–8). The mean (± standard deviation) dose of vancomycin was 879.9 mg (± 281.2 mg) for an average duration of 5.9 days (± 3.7 days). All patients received continuous veno-venous haemofiltration (CVVH). A total of 55 vancomycin level readings were available from the study population, ranging from 6.6 to 41.3, with wide variations within the same sampling time frames. Vancomycin levels of > 15 mg/L or were achieved at least once in 24 patients (75.0%), but only 11 patients (34.3%) had 2 or more serum vancomycin level readings of 15 mg/L or more.

Conclusion

Therapeutic vancomycin levels are difficult to maintain in critically ill patients who are receiving IV vancomycin therapy whilst on CRRT. Aggressive dosing schedules and frequent monitoring are required to ensure adequate vancomycin therapy in this setting.     

Does consistent piperacillin dosing result in consistent therapeutic concentrations in critically ill patients? A longitudinal study over an entire antibiotic course

Piperacillin plasma concentrations are known to vary between critically ill patients. However, there are no comprehensive data on the variability of antibiotic concentrations within the same patient. The purpose of this study was to investigate the adequacy of dosing during an entire 7-day antibiotic course and to investigate the variability in antibiotic trough concentrations both between patients and within the same patient. Piperacillin trough concentrations were measured daily in critically ill patients with normal renal function. The drug assay was performed using UPLC–MS/MS. The pharmacokinetic/pharmacodynamic target was 100% fT_>MIC of the Pseudomonas aeruginosa EUCAST breakpoint. Within- and between-patient variability were calculated as percent coefficient of variation (CV). Eleven patients treated for pneumonia were included in this nested prospective observational cohort study. The median (range) age was 67 (18–79) years, weight was 75 (57–90) kg and BMI was 23.5 (22.3–26.4). The median (range) creatinine clearance on Day 1 of antibiotic treatment was 102 (62–154) mL/min. Trough concentrations were variable, ranging from 4.9 mg/L to 98.0 mg/L. A median CV of 40% for within-patient variability and 57% for between-patient variability was found. Within-patient variability was inversely correlated with SOFA score (R = 0.65, P = 0.027) and APACHE II score on admission (R = 0.73, P = 0.009). In conclusion, piperacillin concentrations varied widely both between patients and within the same patient. Within-patient variability was inversely correlated with disease severity. Consistent dosing of piperacillin/tazobactam does not result in consistent piperacillin concentrations throughout the entire treatment period.     

To what extent are biomonitoring data available in chemical risk assessment?

1. Chemical risk assessment integrates the identification of hazards and the human exposure levels which can be established from external and/or internal exposure data. 2. The availability of biomonitoring and metabolism animal data, the skin penetration ability, and the existence of atmospheric threshold limit values were examined for twelve substances of the European first list of priority existing substances. This investigation was focused on workplace exposures and on urinary biomarkers of exposure. Appropriate biomonitoring data appeared to be available for two substances: styrene and trichloroethylene. Some biomonitoring research has been conducted on acrylonitrile, buta-1,3-diene, cyclohexane, 1,4-dichlorobenzene, hydrogen fluoride, 2-(2-methoxyethoxy)ethanol, however additional studies could be usefully carried out. No biomonitoring data are available for alkanes, C10-13, chloro; benzene, C10-13-alkyl derivatives; bis(pentabromophenyl)ether; diphenylether, octabromo-derivative. 3. It was concluded that in some cases, biomonitoring data are either lacking or scarce. This is rather surprising since the selection of the substances of the priority list was based on high tonnage, widespread use, extent of human exposure, and toxicological concern. The development of biomonitoring information could be helpful in assessing individual or population chemical exposure whatever the source and route, and would result in both more realistic and more accurate risk assessments.     

Thymosin α1 therapy in critically ill patients with COVID-19: A multicenter retrospective cohort study

BackgroundCOVID-19 characterized by refractory hypoxemia increases patient mortality because of immunosuppression effects. This study aimed to evaluate the efficacy of immunomodulatory with thymosin α1 for critical COVID-19 patients.MethodsThis multicenter retrospective cohort study was performed in 8 government-designated treatment centers for COVID-19 patients in China from Dec. 2019 to Mar. 2020. Thymosin α1 was administrated with 1.6 mg qd or q12 h for >5 days. The primary outcomes were the 28-day and 60-day mortality, the secondary outcomes were hospital length of stay and the total duration of the disease. Subgroup analysis was carried out according to clinical classification.ResultsOf the 334 enrolled COVID-19 patients, 42 (12.6%) died within 28 days, and 55 (16.5%) died within 60 days of hospitalization. There was a significant difference in the 28-day mortality between the thymosin α1 and non-thymosin α1-treated groups in adjusted model (P = 0.016), without obvious differences in the 60-day mortality and survival time in the overall cohort (P > 0.05). In the subgroup analysis, it was found that thymosin α1 therapy significantly reduced 28-day mortality (Hazards Ratios HR, 0.11, 95% confidence interval CI 0.02–0.63, P=0.013) via improvement of Pa0₂/FiO₂ (P = 0.036) and prolonged the hospital length of stay (P = 0.024) as well as the total duration of the disease (P=0.001) in the critical type patients, especially those aged over 64 years, with white blood cell >6.8×10⁹/L, neutrophil >5.3×10⁹/L, lymphocyte < 0.73 × 10⁹/L, PaO₂/FiO₂ < 196, SOFA > 3, and acute physiology and chronic health evaluation (APACHE) II > 7.ConclusionThese results suggest that treatment with thymosin α1 can markedly decrease 28-day mortality and attenuate acute lung injury in critical type COVID-19 patients.     

β-Lactam pharmacokinetics and pharmacodynamics in critically ill patients and strategies for dose optimization: a structured review

1. Infections and related sepsis are two of the most prevalent issues in the care of critically ill patients, with mortality as high as 70%. Appropriate antibiotic selection, as well as adequate dosing, is important to improve the clinical outcome for these patients. 2. β-Lactams are the most common antibiotic class used in critically ill sepsis patients because of their broad spectrum of activity and high tolerability. β-Lactams exhibit time-dependent antibacterial activity. Therefore, concentrations need to be maintained above the minimum inhibitory concentration (MIC) of pathogenic bacteria. β-Lactams are hydrophilic antibiotics with small distribution volumes similar to extracellular water and are predominantly excreted through the renal system. 3. Critically ill patients experience a myriad of physiological changes that result in changes in the pharmacokinetics (PK) of hydrophilic drugs such as β-lactams. A different approach to dosing with β-lactams may increase the likelihood of positive outcomes considering the pharmacodynamics (PD) of β-lactams, as well as the changes in PK in critically ill patients. 4. The present review describes the strategies for dose optimization of β-lactams in critically ill patients in line with the PK and PD of these drugs.     

To what extent are key services offered in treatment programs for special populations?

Many substance abuse treatment (SAT) facilities offer programs designed specifically for special populations such as women, adolescents, gays/lesbians and others. Previous research shows that there are specific services that are integral to the successful treatment of these populations (e.g., family therapy for adolescents, childcare and transportation assistance for women, and HIV testing and counseling for gays/lesbians). This study examines whether facilities that self-report having programs for special populations actually offer the recommended services. The data come from the 2000 National Survey of Substance Abuse Treatment Services, which contains information on service offerings, special programs and other characteristics for all SAT facilities in the USA. The results indicate that facilities with special programs are more likely to offer the recommended key services. However, often less than half of these facilities provide the key services. There are consistent differences by ownership status, with for-profit facilities less likely to offer many of the key services.     

To what extent is intoxication associated with aggression in bars? A multilevel analysis

OBJECTIVE: The purpose of this study was to assess the relationship between level of intoxication and the frequency and severity of aggression at the person, incident, visit, and bar level for aggressive incidents observed in bars or clubs. METHOD: Hierarchical Linear Modeling (HLM) analysis of 1025 incidents of aggression documented by trained observers during 1334 nights of observation in 118 bars and clubs in Toronto, Canada, was conducted. RESULTS: Both level of intoxication of the crowd during the visit as well as mean level of intoxication at the bar level significantly predicted frequency of aggression. There was a positive association between level of intoxication and severity of aggression at both the incident and person level except for the highest level of intoxication at the person level, where severity of aggression was less than for moderate intoxication. A person-incident level interaction between intoxication and severity of aggression was also found. CONCLUSIONS: These results suggest that prevention efforts should focus on both identifying bars that typically have more intoxicated patrons and reducing the intoxication levels of patrons across bars generally. The results also showed a strong positive relationship between level of intoxication and severity of aggression (except at the highest levels), indicating that intoxication increases risk in terms of both frequency and severity of aggression. The significant interaction between person- and visit-level intoxication suggests that greater attention needs to be paid to group dynamics in alcohol-related aggression.     

Supraventricular tachycardia in fetus: how can we treat ?

The normal fetal cardiac rhythm is characterized by a regular heart rate ranging between 100 and 160 -180 beats/min with a normal 1: 1 atrioventricular electromechanical relationship during each cardiac cycle. Fetal tachycardia occurring in approximately 0.5% of all pregnancies and it is an important cause of fetal morbidity and mortality. A fetal tachycardic heart is at risk for developing low cardiac output, hydrops and ultimately fetal death or significant neurological morbidity. Different conditions can play a role to determine the natural history of tachycardic fetus as gestational age, underlying pathophysiology of the arrhythmia, fetal heart rate, duration of the tachyarrhythmia, and presence or absence of cardiac dysfunction. Reliable diagnosis in utero of fetal arrhythmia is possible by ultrasound examination of the fetal heart. In fact pulsed wave Doppler guided by two-dimensional echocardiography provided important information on cardiac rhythm as it study the blood flow from different chambers. With the introduction of the latest myocardial deformation methodology, the fetal tachyarrhythmias can be diagnosed more accu notrately. Precise diagnosis of cardiac arrhythmias in the fetus is crucial for a managed therapeutic approach. The choice of management is correlated to many factors: gestational age, underlying pathophysiology of the arrhythmia, fetal heart rate, duration of the tachyarrhythmia, and presence or absence of cardiac dysfunction. A large review of fetal arrhythmias was been reported in our work.     

To what extent do the PANSS and CGI-S overlap?

BACKGROUND: The Positive and Negative Symptom Scale (PANSS) and Clinical Global Impression (CGI-S) item for severity are used together to measure severity of psychotic illness. PANSS is the "gold standard" measure of efficacy, but it is not always feasible to use, yet the CGI-S requires validation. OBJECTIVES: To examine the overlap between PANSS and CGI-S. METHODS: The overlap of the PANSS and CGI-S were examined using data from 7 large antipsychotic clinical trials (n = 4287). RESULTS: Regression analysis identified 21% to 60% overlap of the measures depending on the trial and measurement point. The pooled study mean PANSS value corresponding with a CGI-S of 2, 3, and 4 were 67.1 (n = 799), 79.6 (n = 1645), and 92.4 (n = 1056), respectively. A decrease of 1 on the CGI-S corresponded to a 20% decline on the PANSS. Of the 37 planned comparisons in these studies, there was an agreement between the PANSS and CGI-S on change from baseline to end point on 32 comparisons and on dichotomized change variables (PANSS > or =-20% and CGI-S > or =-1 point) on 31 comparisons. The differences in the remaining comparisons would not have changed the conclusions of the studies. The positive and disorganized PANSS scales were the most closely related to the CGI-S, followed by hostility and negative scale with almost no association with anxiety/depression. CONCLUSIONS: The CGI-S and PANSS are correlated but are not synonymous. Both measures, however, show substantial agreement in detecting change, and the CGI-S shows overlap with the core symptoms of schizophrenia.