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Abstract Background This study analyzed the relationship between vancomycin area under the concentration-time curve (AUC) and acute kidney injury (AKI) reported across recent studies. Methods A systematic review of PubMed, Medline, Scopus, and compiled references was conducted. We included randomized cohort and case-control studies that reported vancomycin AUCs and risk of AKI (from 1990 to 2018). The primary outcome was AKI, defined as an increase in serum creatinine of ≥0.5 mg/L or a 50% increase from baseline on ≥2 consecutive measurements. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Primary analyses compared the impact of AUC cutpoint (greater than ~650 mg × hour/L) and AKI. Additional analysis compared AUC vs trough-guided monitoring on AKI incidence. Results Eight observational studies met inclusion/exclusion criteria with data for 2491 patients. Five studies reported first-24-hour AUCs (AUC0-24) and AKI, 2 studies reported 24- to 48-hour AUCs (AUC24-48) and AKI, and 2 studies reported AKI associated with AUC- vs trough-guided monitoring. AUC less than approximately 650 mg × hour/L was associated with decreased AKI for AUC0-24 (OR, 0.36 [95% CI, .23–.56]) as well as AUC24-48 (OR, 0.45 [95% CI, .27–.75]). AKI associated with the AUC monitoring strategy was significantly lower than trough-guided monitoring (OR, 0.68 [95% CI, .46–.99]). Conclusions AUCs measured in the first or second 24 hours and lower than approximately 650 mg × hour/L may result in a decreased risk of AKI. Vancomycin AUC monitoring strategy may result in less vancomycin-associated AKI. Additional investigations are warranted. This meta-analysis identifies a clear exposure–response relationship (ie, area under the curve threshold greater than ~650 mg × hour/L) for vancomycin and acute kidney injury (AKI). It also suggests that area under the concentration-time curve monitoring strategies can potentially decrease the risk of AKI.

Background In recent years, numerous dosing studies have been conducted to optimize therapeutic antibiotic exposures in patients with serious infections. These studies have led to the inclusion of dose optimization recommendations in international clinical practice guidelines. The last international survey describing dosing, administration and monitoring of commonly prescribed antibiotics for critically ill patients was published in 2015 (ADMIN-ICU 2015). This study aimed to describe the evolution of practice since this time. Methods A cross-sectional international survey distributed through professional societies and networks was used to obtain information on practices used in the dosing, administration and monitoring of vancomycin, piperacillin/tazobactam, meropenem and aminoglycosides. Results A total of 538 respondents (71% physicians and 29% pharmacists) from 409 hospitals in 45 countries completed the survey. Vancomycin was mostly administered as an intermittent infusion, and loading doses were used by 74% of respondents with 25 mg/kg and 20 mg/kg the most favoured doses for intermittent and continuous infusions, respectively. Piperacillin/tazobactam and meropenem were most frequently administered as an extended infusion (42% and 51%, respectively). Therapeutic drug monitoring was undertaken by 90%, 82%, 43%, and 39% of respondents for vancomycin, aminoglycosides, piperacillin/tazobactam, and meropenem, respectively, and was more frequently performed in high-income countries. Respondents rarely used dosing software to guide therapy in clinical practice and was most frequently used with vancomycin (11%). Conclusions We observed numerous changes in practice since the ADMIN-ICU 2015 survey was conducted. Beta-lactams are more commonly administered as extended infusions, and therapeutic drug monitoring use has increased, which align with emerging evidence.

Polymyxin B remains an antibiotic of last resort because of its toxicities. Although newer therapies are becoming available, it is anticipated that resistance to these agents will continue to emerge, and understanding the safest and most efficacious manner to deliver polymyxin B will remain highly important. Recent data have demonstrated that polymyxin B may be less nephrotoxic than colistin. Pharmacokinetically, polymyxin B is primarily eliminated via non-renal pathways, and most do not recommend adjusting the dose for renal impairment. However, some recent studies suggest a weak relationship between polymyxin B clearance and patient creatinine clearance. This review article will describe the clinical pharmacokinetics of polymyxin B and address relevant issues in chemistry and assays available.

Three years after SARS-CoV-2 emerged as a global infectious threat, the virus has become endemic. The neurological complications such as depression, anxiety, and other CNS complications after COVID-19 disease are increasing. The brain, and CSF have been shown as viral reservoirs for SARS-CoV-2, yielding a potential hypothesis for CNS effects. Thus, we investigated the CNS pharmacology of orally dosed nirmatrelvir/ritonavir (NMR/RTV). Using both an in vitro and an in vivo rodent model, we investigated CNS penetration and potential pharmacodynamic activity of NMR. Through pharmacokinetic modeling, we estimated the median CSF penetration of NMR to be low at 18.11% of plasma with very low accumulation in rodent brain tissue. Based on the multiples of the 90% maximal effective concentration (EC 90 ) for SARS-CoV-2, NMR concentrations in the CSF and brain do not achieve an exposure level similar to that of plasma. A median of only 16% of all the predicted CSF concentrations in rats were > 3xEC 90 (unadjusted for protein binding). This may have implications for viral persistence and neurologic post-acute sequelae of COVID-19 if increased NMR penetration in the CNS leads to decreased CNS viral loads and decreased CNS inflammation.

Vancomycin is a commonly used antibiotic in hospital settings, especially against Methicillin-resistant staphylococcus aureus (MRSA). One of the major adverse events of vancomycin use in adults is kidney injury. The drug concentration, specifically the area under the concentration curve, predicts kidney injury in adults receiving vancomycin. To attempt to reduce vancomycin-induced nephrotoxicity, we have successfully encapsulated vancomycin in polyethylene glycol-coated liposomes (PEG-VANCO-lipo). We have previously carried out in vitro cytotoxicity studies on kidney cells using PEG-VANCO-lipo and found it to be minimally toxic compared to the standard vancomycin. In this study, we have dosed male adult rats with PEG-VANCO-lipo or vancomycin HCl and compared plasma vancomycin concentrations and KIM-1 as an injury biomarker in rat urine. Male Sprague Dawley rats (350 ± 10 g) were administered vancomycin (n = 6) or PEG-VANCO-lipo (n = 6) 150 mg/kg/day for three days using an IV infusion in the left jugular vein catheter. Blood was collected for plasma at 15, 30, 60, 120, 240, and 1440 min after the first and the last IV dose. Urine was collected 0–2, 2–4, 4–8, and 8–24 h after the first and the last IV infusions using metabolic cages. The animals were observed for three days after the last compound administration. Vancomycin was quantified in plasma by LC-MS/MS. Urinary KIM-1 analysis was done by using an ELISA kit. Three days after the last dose, under terminal anesthesia with IP ketamine (65–100 mg/kg) and xylazine (7–10 mg/kg), rats were euthanized. Vancomycin urine and kidney concentrations and KIM-1 were lower on day three in the PEG-Vanco-lipo group compared to the vancomycin group (p < 0.05, ANOVA and/or t-test). There was a significant reduction in plasma vancomycin concentration on day one and day three (p < 0.05, t-test) in the vancomycin group compared to the PEG-VANCO-lipo group. Vancomycin-loaded PEGylated liposomes resulted in lower levels of kidney injury, as noted by a decrease in KIM-1 values. Moreover, longer circulation in plasma with increased concentration in plasma as opposed to the kidney was observed with the PEG-VANCO-lipo group. The results indicate the high potential of PEG-VANCO-lipo in decreasing the nephrotoxicity of vancomycin clinically.

Background Clinical risk factors for nephrotoxicity in Staphylococcus aureus bacteraemia remain largely undetermined, despite its common occurrence and clinical significance. In an international, multicentre, prospective clinical trial (CAMERA2), which compared standard therapy (vancomycin monotherapy) to combination therapy (adding an anti-staphylococcal beta-lactam) for methicillin-resistant S. aureus bacteraemia, significantly more people in the combination therapy arm experienced acute kidney injury compared with those in the monotherapy arm (23% vs 6%). Objective The aim of this post hoc analysis was to explore in greater depth the risk factors for acute kidney injury from the CAMERA2 trial. Methods Among participants of the CAMERA2 trial, demographic-related, infection-related and treatment-related risk factors were assessed for their relationship with acute kidney injury by univariable and multivariable logistic regression. Acute kidney injury was defined by a modified-KDIGO (Kidney Disease: Improving Global Outcomes) criteria (not including urinary output). Results Of the 266 participants included, age ( p = 0.04), randomisation to combination therapy ( p = 0.002), vancomycin area under the concentration–time curve ( p = 0.03) and receipt of (flu)cloxacillin as the companion beta-lactam ( p < 0.001) were significantly associated with acute kidney injury. On a multivariable analysis, concurrent use of (flu)cloxacillin increased the risk of acute kidney injury over four times compared with the use of cefazolin or no beta-lactam. The association of vancomycin area under the concentration–time curve with acute kidney injury also persisted in the multivariable model. Conclusions For participants receiving vancomycin for S. aureus bacteraemia, use of (flu)cloxacillin and increased vancomycin area under the concentration–time curve were risk factors for acute kidney injury. These represent potentially modifiable risk factors for nephrotoxicity and highlight the importance of avoiding the use of concurrent nephrotoxins.

The aim of the present article was to briefly summarize current knowledge about the immunomodulatory effects of general anesthetics and the possible clinical effects of this immunomodulation in patients with COVID-19. The PubMed, Scopus, and Google Scholar databases were comprehensively searched for relevant studies. The novel coronavirus causes a wide spectrum of clinical manifestations, with a large absolute number of patients experiencing severe pneumonia and rapid progression to acute respiratory distress syndrome and multiple organ failure. In these patients, the equilibrium of the inflammatory response is a major determinant of survival. The impact of anesthetics on immune-system modulation may vary and includes both pro-inflammatory and anti-inflammatory effects. Inhibition of the development of severe inflammation and/or the enhancement of inflammation resolution by anesthetics may limit organ damage and improve outcomes in patients with COVID-19. Potent effects of etomidate in patients with COVID-19. ∗Patients intubated without the use of etomidate are anticipated to maintain the pre-induction inflammatory status for the subsequent 24–72 h. ARDS = acute respiratory distress syndrome; MODS = multiple organ dysfunction syndrome; RSI = rapid sequence induction. [Display omitted]

Polymyxin B (PMB) has reemerged as a last‐line therapy for infections caused by multidrug‐resistant gram‐negative pathogens, but dosing is challenging because of its narrow therapeutic window and pharmacokinetic (PK) variability. Population PK (POPPK) models based on suitably powered clinical studies with appropriate sampling strategies that take variability into consideration can inform PMB dosing to maximize efficacy and minimize toxicity and resistance. Here we reviewed published PMB POPPK models and evaluated them using an external validation data set (EVD) of patients who are critically ill and enrolled in an ongoing clinical study to assess their utility. Seven published POPPK models were employed using the reported model equations, parameter values, covariate relationships, interpatient variability, parameter covariance, and unexplained residual variability in NONMEM (Version 7.4.3). The predictive ability of the models was assessed using prediction‐based and simulation‐based diagnostics. Patient characteristics and treatment information were comparable across studies and with the EVD (n = 40), but the sampling strategy was a main source of PK variability across studies. All models visually and statistically underpredicted EVD plasma concentrations, but the two‐compartment models more accurately described the external data set. As current POPPK models were inadequately predictive of the EVD, creation of a new POPPK model based on an appropriately powered clinical study with an informed PK sampling strategy would be expected to improve characterization of PMB PK and identify covariates to explain interpatient variability. Such a model would support model‐informed precision dosing frameworks, which are urgently needed to improve PMB treatment efficacy, limit resistance, and reduce toxicity in patients who are critically ill.

During the periarrest period, intestinal ischemia may result in barrier dysfunction and bacterial translocation, which has clear mechanistic links to inflammation and cascade stimulation, especially in patients who are treated with therapeutic hypothermia. Despite optimal management, periarrest bacterial translocation may worsen the outcome of cardiac arrest victims.

Background We evaluated the effectiveness of targeted antimicrobial prophylaxis in transrectal ultrasound guided prostate biopsy (TRUSP). Methods A prospective, non-randomized cohort study was conducted. Rectal swab cultures plated on non-selective blood agar and on selective MacConkey agar supplemented with ciprofloxacin identified ciprofloxacin-susceptible and –resistant gram-negative bacteria (CS-GNB and CR-GNB). Patients with CS-GNB received ciprofloxacin while those with CR-GNB received directed prophylaxis. Infectious complications were defined clinically and microbiologically within 30 days after TRUSP. Data were derived at 7 and 30 days post procedure by questionnaires and electronic medical records. We hypothesized that there would be no difference in the infectious outcomes among the CS and CR groups. Results From November 1, 2012 to March 31, 2015, 510 men completed the study; 430 (84.3%) had CS-GNB and 80 (15.7%) had CR-GNB. 484 (94.9%) completed the study per protocol, while 26 (5.1%) had an intention-to-treat (ITT) analysis. Of the 484, 475 (98.1%) had no infections, nine (1.9%) had infections, six of which (1.2%) were culture-proven (CP). The nine infections were as follows: five (1.0%) uncomplicated UTIs, one (0.2%) complicated UTI, and three (0.6%) urosepsis. One case of uncomplicated UTI and two cases of urosepsis were not CP, but were diagnosed clinically. ITT outcomes were similar. The infection rates were not statistically different between the CS-and CR-GNB patients ( p -value = 0.314; 95% CI 0.8–3.3). The four patients with complicated UTIs or sepsis were hospitalized for a mean of 2.6 days and discharged without sequelae. Of the nine infections, three were antimicrobial prophylaxis failures (two ciprofloxacin and one amikacin); three were likely due to failure of the collection or processing of the rectal swab or increasing bacterial resistance between the time of swab collection and biopsy, and three developed clinical infections with no isolate recovered. Conclusions Targeted antimicrobial prophylaxis follows the principles of antimicrobial stewardship and achieved a low rate of infectious complications with limited morbidity and no sequelae. This individualized method of prophylaxis may be widely applied. Further studies are needed to explore reasons for targeted prophylaxis failure and to determine comparative efficacy of non-ciprofloxacin-containing targeted prophylaxis regimens. Trial registration ClinicalTrials.gov. NCT01659866 . Registered 9 July 2012. First patient enrolled 1 November 2012.