Liposomal Amphotericin B Induced Acute Reactions

Three formulations of amphotericin B are available: liposomal, lipid complex and conventional. The liposomal amphotericin B is more preferred agent than other formulations because of its tolerability, safety and potent antifungal activity. However, the liposomal amphotericin B can cause infusion-related reactions. In this case report, we aimed to report a patient who developed infusion-related reactions during the treatment with the liposomal amphotericin B but eventually tolerated the prolonged infusion. In this case report, we present a patient who developed an infusion-related reaction during The liposomal amphotericin B treatment. A 26-year-old male patient with acute promyelocytic leukemia was hospitalized for the third course of chemotherapy. Due to the invasive fungal infection history in previous hospitalizations, the liposomal amphotericin B 400 mg (IV, 5 mg/kg) once daily was initiated as secondary antifungal prophylaxis. Swelling in infusion site and chest pain were reported within 10 minutes of the liposomal amphotericin B administration, and the infusion rate was slowed down to 400 mg/6 hours from 400 mg/2 hours. All these reactions disappeared with prolonged infusion time. The patient received a total of 7 liposomal amphotericin B doses subsequently without any reaction during the chemotherapy cycle. In our experience, the liposomal amphotericin B-induced infusion-related reactions can be resolved by prolonging the infusion time.

Population Pharmacokinetics of Meropenem in Critically Ill Korean Patients and Effects of Extracorporeal Membrane Oxygenation

Limited studies have investigated population pharmacokinetic (PK) models and optimal dosage regimens of meropenem for critically ill adult patients using the probability of target attainment, including patients receiving extracorporeal membrane oxygenation (ECMO). A population PK analysis was conducted using non-linear mixed-effect modeling. Monte Carlo simulation was used to determine for how long the free drug concentration was above the minimum inhibitory concentration (MIC) at steady state conditions in patients with various degrees of renal function. Meropenem PK in critically ill patients was described using a two-compartment model, in which glomerular filtration rate was identified as a covariate for clearance. ECMO did not affect meropenem PK. The simulation results showed that the current meropenem dosing regimen would be sufficient for attaining 40%fT>MIC for Pseudomonas aeruginosa at MIC ≤ 4 mg/L. Prolonged infusion over 3 h or a high-dosage regimen of 2 g/8 h was needed for MIC > 2 mg/L or in patients with augmented renal clearance, for a target of 100%fT>MIC or 100%fT>4XMIC. Our study suggests that clinicians should consider prolonged infusion or a high-dosage regimen of meropenem, particularly when treating critically ill patients with augmented renal clearance or those infected with pathogens with decreased in vitro susceptibility, regardless of ECMO support.

Does prolonged infusion time really improve the efficacy of meropenem therapy? A prospective study in critically ill patients

Background: Meropenem is a carbapenem antibiotic that has demonstrated excellent in vitro activity against gram-negative clinical isolates and is commonly used in critically ill patients. This study aimed to find the pharmacokinetic/ pharmacodynamic of meropenem in critically ill patients and whether prolonged injection duration is really beneficial to meropenem therapy. Method: We included 209 samples in 64 patients in this prospective study. PPK analysis and Monte Carlo dosing simulations were developed using Phoenix.Results: A two-compartment model described the data adequately. Clearance (CL), volume (V), clearance of peripheral compartment (CL2), volume of peripheral compartment (V2) were 6.15 L/h, 2.83 L/h, 17.40L, and 17.48L, respectively. Creatinine clearance and uric acid were significant covariates. Patients with creatinine clearance of 60 ml/min or less and uric acid greater than 400 μmol/l could achieve the target > 90% under the minimum inhibitory concentration (MIC) of 8 mg/L, even with the administration dose of 500 mg/8 h with a 2-h infusion. Prolonging the infusion time significantly improved the therapeutic effect when MIC＜4. However, for the pharmacodynamic (PD) effects of 100% fT > MIC and 100% fT > 4MIC, no significant statistical difference was observed in critically ill patients.Conclusions: Critically ill patients with lower creatinine clearance and higher uric acid levels were likely to need a lower dosage of meropenem. Prolonged infusion time were not always beneficial for those who need a higher therapeutic target (100% fT > MIC,100% fT > 4 MIC) or with MIC 4mg/L. Increasing dose or alternative therapeutic strategies may be required for critically ill patients with drug-resistant or severe infections. The study is of great significance to guide the rational use of meropenem in critically ill patients.Trial registration: The trial was registered in the China Clinical Trial (ChiCTR1900020672). Registered on 12 January 2019.

Sedation of children in the intensive care unit: what’s new in the field?

Background. The purpose of sedation is to reduce anxiety, create amnesia, reduce motor activity when performing invasive procedures, and provide the synchronization with the respirator. The ideal sedative drug should be characterized by minimal toxicity and minimal depressant effects on the cardiovascular system, the possibility of rapid awakening, the absence of withdrawal syndrome. Objective. To describe the sedation of children in the intensive care unit. Materials and methods. Analysis of literature sources on this topic. Results and discussion. A meta-analysis of 25 studies found that sedation is often suboptimal and rarely regularly evaluated. Excessive sedation can increase the duration of hospitalization, cause tolerance and withdrawal syndrome (Nienke J. Vet et al., 2013). In turn, insufficient sedation increases distress and the frequency of complications, including infectious ones. Frequent problems of sedation also include the choice of suboptimal drug, prolonged infusion, limited use of propofol and dexmedetomidine, lack of routine practice of earplugs and face masks, insufficient frequency of delirium assessment. In a significant proportion of cases, benzodiazepines, primarily midazolam, are used for sedation. In hepatic insufficiency, lorazepam is preferred. Disadvantages of benzodiazepines are respiratory depression, vasoplegia, cardiopression, withdrawal syndrome. Midazolam is often combined with fentanyl or morphine, however, there is little evidence of such a combination. Propofol infusions can cause metabolic acidosis, hyperkalemia, hyperlipidemia, rhabdomyolysis, and even heart failure. The so-called propofol infusion syndrome develops at a dose >4 mg/kg/h in case of infusion for >48 hours. Analysis of sedation with propofol (at a dose 0.3-6.5 g/kg/h) in 174 children aged from 2 months to 16 years revealed that 8 children exceeded the threshold level of lactate; one child died (Svensson M., Lindberg L., 2012). According to the authors of another study, propofol is safe at a dose of 1-4 mg/kg/h. Clonidine and dexmedetomidine are centrally acting α2a-agonists that exert their effects in the locus coeruleus of the brainstem. Dexmedetomidine does not cause respiratory depression and withdrawal syndrome. Children receiving dexmedetomidine required significantly less morphine than ones receiving midazolam. Dexmedetomidine has been shown to reduce the number of inadequately sedated patients (Tobias J.D. et al., 2004). The pharmacokinetics of this drug in children older than 4 years corresponds to the pharmacokinetics in adults. At a dose of 0.1-0.25 μg/kg/h dexmedetomidine reduces the need for benzodiazepines and opioids, as a monosedation at a dose 0.25 μg/kg/h it is comparable to midazolam, and at a dose of 0.5 μg/kg/h – exceeds the latter in efficiency. Meta-analysis of M. Plambech and A. Afshari (2014) found that dexmedetomidine is convenient and safe for use in children with various pathological conditions. In order to prevent complications, non-pharmacological techniques should be used (reduction of light and sound stress, formation of normal biorhythms, swaddling of young children) and switch to oral forms of necessary drugs as soon as possible. Conclusions. 1. Frequent problems of sedation include insufficient/excessive sedation, choice of suboptimal drugs, prolonged infusion, limited use of propofol and dexmedetomidine, lack of routine practice of earplugs and face masks, insufficient frequency of delirium assessment. 2. It is necessary to form sedation protocols in children. 3. For optimal sedation, it is important to implement modern techniques and drugs, regularly assess the level of sedation and treat the underlying pathological condition.

Emergence of resistance in Klebsiella aerogenes to piperacillin-tazobactam and ceftriaxone

We examined the effects of piperacillin-tazobactam (TZP) concentration and bacteria inoculum on in vitro killing and the emergence of resistance in Klebsiella aerogenes. Fifteen clinical respiratory isolates had MICs determined by broth microdilution for TZP and Etest for ceftriaxone (CRO) and cefepime (FEP). The presence of resistance in TZP-susceptible isolates (n=10) was determined by serial passes over increasing concentrations of TZP-containing and CRO-containing agar plates. Isolates with growth on TZP 16/4 μg/mL and CRO 8 μg/mL plates (n=5) were tested in high- (HI; 7.0 log10 CFU/mL) and low-inoculum (LI; 5.0 log10 CFU/mL) time-kill studies. Antibiotic concentrations were selected to approximate TZP 3.375 g q8h via 4 h prolonged-infusion free peak concentration (40 μg/mL; TZP40), peak epithelial lining fluid (ELF) concentrations and average AUC0-24 of TZP (20 μg/mL; TZP20 and 10 μg/mL; TZP10, respectively); ELF FEP concentration (14 μg/mL); and average AUC0-24 CRO concentration (6 μg/mL). At HI, FEP-exposure significantly reduced 24 h inocula against all comparators (p≤0.05) with reduction of 4.93 ± 0.64 log10 CFU/mL. Exposure to TZP40, TZP20, and TZP10 reduced inocula by 0.81 ± 0.43, 0.21 ± 0.18, and 0.05 ± 0.16 log10 CFU/mL, respectively. CRO-exposed isolates demonstrated an increase of 0.42 ± 0.39 log10 CFU/mL compared to the starting inocula, with four of five CRO-exposed isolates demonstrating TZP-non-susceptibility. At LI after 24 hours of exposure to TZP20 and TZP10, the starting inoculum decreased by an average of 2.24 ± 1.98 and 2.91 ± 0.50 log10 CFU/mL, respectively. TZP demonstrated significant inoculum-dependent killing, warranting dose optimization studies.

Prolonged versus intermittent β-lactam antibiotics intravenous infusion strategy in sepsis or septic shock patients: a systematic review with meta-analysis and trial sequential analysis of randomized trials

Background The prolonged β-lactam infusion strategy has emerged as the standard treatment for sepsis or septic shock despite its unknown efficacy. This study aimed to assess the efficacy of prolonged versus intermittent β-lactam antibiotics infusion on outcomes in sepsis or septic shock patients by conducting a systematic review and meta-analysis. Methods A thorough search was conducted on MEDLINE, the Cochrane Central Register of Controlled Trials, and the Igaku Chuo Zasshi databases. Randomized controlled trials (RCTs) comparing mortality between prolonged and intermittent infusion in adult patients with sepsis or septic shock were included. The primary outcome was hospital mortality. The secondary outcomes were the attainment of the target plasma concentration, clinical cure, adverse events, and occurrence of antibiotic-resistant bacteria. We performed a subgroup analysis stratified according to the year of publication before or after 2015 and a trial sequential analysis (TSA). The Der Simonian–Laird random-effects models were subsequently used to report the pooled risk ratios (RR) with confidence intervals (CI). Results We identified 2869 studies from the 3 databases, and 13 studies were included in the meta-analysis. Hospital mortality did not decrease (RR 0.69 [95%CI 0.47–1.02]) in the prolonged infusion group. The attainment of the target plasma concentration and clinical cure significantly improved (RR 0.40 [95%CI 0.21–0.75] and RR 0.84 [95%CI 0.73–0.97], respectively) in the prolonged infusion group. There were, however, no significant differences in the adverse events and the occurrence of antibiotic-resistant bacteria between the groups (RR 1.01 (95%CI 0.95–1.06) and RR 0.53 [95%CI 0.10–2.83], respectively). For the subgroup analysis, a significant improvement in hospital mortality or clinical cure was reported in studies published in or after 2015 (RR 0.66 [95%CI 0.44–0.98] and RR 0.67 [95%CI 0.50–0.90], respectively). The results of the TSA indicated an insufficient number of studies for a definitive analysis. Conclusions The prolonged infusion of β-lactam antibiotics significantly improved upon attaining the target plasma concentration and clinical cure without increasing the adverse event or the occurrence of antibiotic-resistant bacteria. Prolonged infusion could not improve hospital mortality although an improvement was shown for studies published in or after 2015. Further studies are warranted as suggested by our TSA results.