Investigation of pharmacokinetic and clinical outcomes of various meropenem regimens in patients with ventilator-associated pneumonia and augmented renal clearance.

INTRODUCTION: Augmented renal clearance (ARC) defined as creatinine clearance (Clcr) above 130 mL/min/1.73m2 may lead to suboptimal antibacterial treatment. The aim of this study was to determine a strategy for meropenem administration to achieve both pharmacodynamic-pharmacokinetic (PK-PD) target (50%fT > MIC) and better clinical outcomes in patients with VAP and ARC. MATERIALS AND METHODS: In this randomized clinical trial, patients with VAP and high risk for ARC were recruited. An 8-h urine collection was performed on the 1st, 3rd, and 5th days of study to measure Clcr. Included patients were divided into three groups: (1) 1 g meropenem, 3-h infusion, (2) 2 g meropenem, 3-h infusion, (3) 1 g meropenem, 6-h infusion. On the 2nd, 3rd, and 5th days of treatment, peak and trough blood samples were collected to undergo HPLC assay. MICs were assessed using microdilution method. Patients were also clinically monitored for 14 days. RESULTS: Forty-five patients were included. Group 3 showed significanty higher rate of patients achieving fT > MIC > 50% (100% for group 3 versus 40% for group 2 and 13% for group 1; p = 0.0001). Mean fT > MIC% was significantly higher in group 3 (78.77 ± 5.87 for group 3 versus 49.6 ± 7.38 for group 2 and 43.2 ± 7.98 for group 1; p = 0.0001). Statistical analysis showed no significant differences among groups regarding clinical improvement. CONCLUSION: According to the findings of this trial, prolonged meropenem infusion is an appropriate strategy compared to dose elevation among ARC patients.

Evaluation of the prophylactic effect of hydroxychloroquine on people in close-contact with patients with COVID-19.

INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic has caused significant mortality worldwide. The disease attacks the lung tissue and may lead to acute respiratory distress syndrome. An in vitro study showed that hydroxychloroquine (HCQ) has a prophylactic effect against COVID-19 due to its anti-inflammatory effects. The present study aimed to evaluate the prophylactic effect of HCQ on individuals in close contact with patients with COVID-19. METHOD: In this quasi-trial study, we prescribed HCQ for 7 days to all people who had close contact with a patient with COVID-19. All contacts underwent a nasal swab in two steps, and those positive for COVID-19 were excluded from the study. After 14 days of follow-up, the clinical and laboratory manifestations of COVID-19 were evaluated. RESULTS: A total of 113 participants completed the study. The HCQ group comprised 51 (45.13%) contacts, and 62 (54.86%) contacts were allocated to the control group. According to the results of clinical examination and real-time polymerase chain reaction test, 8 (12.90%) contacts in the control group were reported to have contracted COVID-19. In the HCQ group, 7 (13.72%) contacts were confirmed to have contracted COVID-19. There was no relationship between HCQ use and age, sex, underlying disorders, and laboratory data (all p > 0.05). In terms of HCQ side effects, five participants experienced gastrointestinal and cutaneous side effects that subsided on discontinuation of HCQ. CONCLUSION: The current study showed that HCQ had no prophylactic effect with regard to COVID-19 prevention.

The effects of vitamin E on colistin-induced nephrotoxicity in treatment of drug-resistant gram-negative bacterial infections: A randomized clinical trial.

INTRODUCTION: Nephrotoxicity remains a major long-standing concern for colistin, and it is critical to find agents that can prevent it. The present study aims to investigate the effect of vitamin E on the prevention of colistin-induced nephrotoxicity based on its antioxidant and free radical scavenging properties. METHODS: A randomized clinical trial was designed for 52 patients taking colistin. These patients were categorized into two groups of equal size, receiving colistin or colistin plus vitamin E (α-Tocopherol). Vitamin E with doses of 400 units was administrated daily either orally or by a nasogastric tube if needed. The incidence of Acute Kidney Injury (AKI) and its duration was recorded based on RIFLE criteria. RESULTS: The Incidence of AKI based on RIFLE criteria was 42.3% and 46.2% in intervention and control groups, respectively. The analysis showed no significant difference in the prevalence of AKI for the two groups (P = 0.78). There was no significant difference in the duration of AKI neither (P = 0.83). CONCLUSION: Although vitamin E is a powerful biological antioxidant, the effects of Vitamin E prophylaxis on colistin-induced nephrotoxicity was not taken into consideration in this study.

Coenzyme Q10 supplementation in acute ischemic stroke: Is it beneficial in short-term administration?

Backgrounds and aims: Clinical studies demonstrated that the efficacy of Coenzyme Q10 (CoQ10) as an adjuvant therapeutic agent in several neurological diseases such as Parkinson disease (PD), Huntington disease (HD), and migraine. The purpose of this study is to investigate oxidative stress effects, antioxidant enzymes activity, neuroinflammatory markers levels, and neurological outcome in acute ischemic stroke (AIS) patients following administration of CoQ10 (300 mg/day). Methods: Patients with AIS (n = 60) were randomly assigned to a placebo group (wheat starch, n = 30) or CoQ10-supplemented group (300 mg/day, n = 30). The intervention was administered for 4 weeks. Serum CoQ10 concentration, malondialdehyde (MDA), superoxide dismutase (SOD) activity, glial fibrillary acidic protein (GFAP) levels as primary outcomes and National Institute of Health Stroke Scale (NIHSS), Modified Ranking Scale (MRS), and Mini-Mental State Examination (MMSE) as secondary outcome were measured at the both beginning and end of the study. Results: Forty-four subjects with AIS completed the intervention study. A significant increase in CoQ10 level was observed in the supplement-treated group compared with placebo group (mean difference = 26.05 ± 26.63 ng/ml, 14.12 ± 14.69 ng/ml, respectively; P = 0.01), moreover CoQ10 supplementation improved NIHSS and MMSE scores significantly (P = 0.05, P = 0.03 respectively). but there were no statistically significant differences in MRS score, MDA, SOD, and GFAP levels between the two groups. Conclusions: CoQ10 probably due to low dose and short duration of supplementation, no favorable effects on MDA level, SOD activity and GFAP level.

N-acetylcysteine decreases urinary level of neutrophil gelatinase-associated lipocalin in deceased-donor renal transplant recipients: a randomized clinical trial.

CONTEXT: Acute kidney injury (AKI) is a common complication after kidney transplantation (KT), especially in recipients from deceased donors. Urinary neutrophil gelatinase-associated lipocalin (u-NGAL) is an early and sensitive marker of AKI after transplantation. OBJECTIVES: We assessed the renoprotective effect of N-acetylcysteine (NAC) on u-NGAL levels as an early prognostic marker of graft function immediately after transplantation. MATERIALS AND METHODS: A double-blind, randomized, placebo-controlled trial was conducted on 70 deceased-donor KT recipients ( www.irct.ir , trial registration number: IRCT2014090214693N4). Patients received 600 mg oral NAC or placebo twice daily from day 0 to 5 and urine samples were taken before, and on the first and fifth days after transplantation. U-NGAL and early graft function were compared between the two groups. RESULTS: NAC significantly reduced u-NGAL levels compared to placebo (p value = 0.02), while improvement in early graft function with NAC did not reach statistical significance. CONCLUSIONS: This study showed that NAC administration in deceased-donor KT recipients can reduce tubular kidney injury, evidenced by u-NGAL measurements. Improvement in early graft function needs a larger sample size to reach a statistical conclusion.

Erythema Multiforme Associated With Misoprostol: A Case Report.

A 33-year-old healthy woman at 6 weeks of gestation without any underlying disease developed erythema multiforme (EM) after misoprostol. She had no history of herpes simplex virus infection and drug allergy to nonsteroidal anti-inflammatory drugs and antibiotic agents. Medical abortion was performed at 6 weeks' gestation. Later day, the patient developed oral lesions as several white bullae lesions in her buccal mucosa and hyperkeratotic lip plaques with mild pain. Then, lesions resolved within approximately 3 weeks. Microscopic finding of oral biopsy from beneath the tongue and lesions was performed. The result was consistent with erosive mucosa with granulation tissue formation and acute inflammation in favor of EM. This is the case report of probable misoprostol-induced EM. Because EM may produce in skin as a Stevens-Johnson syndrome in subsequent attack, monitoring of this adverse drug reaction should be considered for proper management and follow-up.

Assessment of Depression Prevalence and Its Relation With Interleukin 18 One Year After Renal Transplantation.

Renal transplantation is the treatment of choice for many patients with end-stage renal disease. Because there is little information about depression after kidney transplantation, we investigated frequency and determinant factors of depression and also its association with interleukin (IL)-18. Kidney transplant recipients were investigated between January 2011 and February 2013. Depression was assessed using the Beck Depression Inventory (BDI, BDI-II). We investigated the relationship between 1-year posttransplantation depression and all-cause mortality, acute kidney injury, and serum creatinine 1, 3, and 12 months after transplantation. Furthermore, the association of depression with IL-18 biomarker was recorded 1 year after transplantation. A total of 74 patients (age: 37.06 ± 16.2 years; 59.5% male) were enrolled in this study 1 year after transplantation. Nineteen (25.6%), 2 (2.7%), and 1 (1.3%) of them experienced mild, moderate, and severe depression, respectively. IL-18 biomarker (independent variable) was significantly associated with depression 1 year after transplantation. Our data suggested that IL-18 level increased significantly in renal transplant patients with depression.

A review on colistin nephrotoxicity.

PURPOSE: Colistin is an antibiotic that was introduced many years ago and was withdrawn because of its nephrotoxicity. Nowadays, reemergence of this antibiotic for multi-drug resistant Gram-negative infections, and a new high dosing regimen recommendation increases concern about its nephrotoxicity. This review attempts to give a view on colistin nephrotoxicity, its prevalence especially in high doses, the mechanism of injury, risk factors, and prevention of this kidney injury. METHOD: The data collection was done in PubMed, Scopus and Cochrane databases. The keywords for search terms were "colistin", "nephrotoxicity", "toxicity", "renal failure", "high dose", and "risk factor". Randomized clinical trials and prospective or retrospective observational animal and human studies were included. In all, 60 articles have been reviewed. RESULT AND CONCLUSION: Colistin is a nephrotoxic antibiotic; a worldwide increase in nosocomial infections has led to an increase in its usage. Nephrotoxicity is the concerning adverse effect of this drug. The mechanism of nephrotoxicity is via an increase in tubular epithelial cell membrane permeability, which results in cation, anion and water influx leading to cell swelling and cell lysis. There are also some oxidative and inflammatory pathways that seem to be involved in colistin nephrotoxicity. Risk factors of colistin nephrotoxicity can be categorized as dose and duration of colistin therapy, co-administration of other nephrotoxic drugs, and patient-related factors such as age, sex, hypoalbuminemia, hyperbilirubinemia, underlying disease and severity of patient illness.

The Efficacy of High-Dose Pulse Therapy vs. Low-Dose Intravenous Methylprednisolone on Severe to Critical COVID-19 Clinical Outcomes: A Randomized Clinical Trial.

Background: It remains unclear which formulation of the corticosteroid regimen has the optimum efficacies on COVID-19 pneumonia. Objectives: The aim of this study was to compare the clinical outcomes of 2 different regimens in the treatment of acute respiratory distress syndrome (ARDS) caused by COVID-19: Methylprednisolone at a dose of 1 mg/kg every 12 hours (low-dose group) and 1000 mg/day pulse therapy for 3 days following 1 mg/kg methylprednisolone every 12 hours (high-dose group). Methods: In this randomized clinical trial, patients with mild to moderate ARDS due to COVID-19 were randomly assigned to receive either low-dose (n = 47) or high-dose (n = 48) intravenous methylprednisolone regimens. Two groups were matched for age, gender, body mass index (BMI), comorbidities, leukocytes, lymphocytes, neutrophil/lymphocyte, platelet, hemoglobin, and inflammatory markers (erythrocyte sedimentation rate [ESR], C-reactive protein [CRP], and ferritin). Both regimens were initiated upon admission and continued for 10 days. The clinical outcome and secondary complications were evaluated. Results: Evaluating in-hospital outcomes, no difference was revealed in the duration of intensive care unit (ICU) stays (5.4 ± 4.6 vs. 4.5 ± 4.9; P = 0.35), total hospital stays (8 ± 3.1 vs. 6.9 ± 3.4; P = 0.1), requirement rate for invasive ventilation (29.2% vs. 36.2%; P = 0.4) or non-invasive ventilation (16.6% vs 23.4%; P = 0.4), and hemoperfusion (16.6% vs 11.3%; P = 0.3) between the low- and high-dose groups. There was no significant difference in fatality due to ARDS (29.2% vs. 38.3%; P = 0.3) and septic shock (4.2% vs. 6.4%; P = 0.3) between the low- and high-dose groups. Patients in the high-dose group had significantly higher bacterial pneumonia co-infection events compared with those in the low-dose group (18.7% vs 10.6%; P = 0.01). Conclusions: The use of adjuvant pulse therapy with intravenous methylprednisolone did not result in improved in-hospital clinical outcomes among patients with mild to moderate ARDS due to COVID-19. A higher risk of bacterial pneumonia should be considered in such cases as receiving a higher dose of steroids.

Sputnik-V vaccine-induced panniculitis as a local reactions.

Here, a case of Sputnik-V vaccine-induced panniculitis was reported. The patient developed erythema, induration, and local tenderness at the injection site after 13 days of the injection. Ultra-sonography imaging showed inflammation in subcutaneous layers including fat tissue compatible with panniculitis. She received ibuprofen and warm compress, and all symptoms resolved.

Efficacy and Safety of Two Different Enoxaparin Doses for Thromboprophylaxis in Non-critically Ill Patients: A Randomized Controlled Trial.

Background: Recently, a few studies based on anti-factor Xa activity levels have propounded doubtful and sub-prophylactic levels by the usual dose of enoxaparin in surgical and critically ill patients. In this study, we assessed two doses of enoxaparin in adult non-critically ill patients. Methods: Patients were randomly assigned into two groups of intervention and control. While the intervention group received enoxaparin with a daily dose of 60 mg, the control group received enoxaparin 40 mg. Anti-factor Xa activity was measured based on the peak steady-state levels. The level of 0.2 to 0.4 IU/mL was considered as a prophylactic goal. All individuals were followed for bleeding or thromboembolic events during admission. Results: The mean levels of anti-factor Xa were 0.29 ± 0.13 IU/mL in the control group (n = 31) and 0.44 ± 0.19 IU/mL in the intervention group (n = 29). More patients in the control group had an optimal level of anti-factor Xa compared to the patients in the intervention group (62.1% vs. 29%). No adverse outcomes were detected in any of the groups. Conclusions: Enoxaparin dose of 60 mg daily provided anti-factor Xa level higher than desired in most patients. In non-critically ill patients, the dose of 40 mg is the proper dose for thromboprophylaxis.

Datura poisoning in a family: Case series and literature review.

Datura spp. is a potentially poisonous plant that is widely spread and is simply accessible, which can yield poisoning with a central and peripheral anticholinergic effect. We reported cases of family poisoning caused by the herbal tea with refreshing effects that were identified as Datura spp.

Serotonin syndrome due to concomitant use of linezolid and methadone.

Serotonin syndrome is a potentially life-threatening adverse drug reaction typically caused by a single or combination of two or more medications with serotonergic properties due to increased serotonin release. Our case is a 60-year-old drug-addict man who was admitted to the poisoning department of Loghman hospital with methadone poisoning. On the fifth day of hospitalization and after initiating the linezolid treatment for VAP, the patient began to run a fever with agitation, tremor, spontaneous clonus movement in the hands, and tachycardia. Due to patients' manifestations and after ruling out other diagnoses, serotonin syndrome was confirmed with the possibility of concomitant use of linezolid and methadone. Linezolid administration was promptly discontinued, and vancomycin therapy was initiated (1000 mg twice a day intravenously). Supportive therapies were performed. Finally, tremor, rigidity, and clonus movement disappeared within 48 h.

Evaluation of vancomycin pharmacokinetics in patients with augmented renal clearances: A randomized clinical trial.

Purpose: Vancomycin is a narrow therapeutic window glycopeptide antibiotic that acts against Gram-positive bacteria. As it is renally eliminated, therapeutic drug monitoring is recommended for vancomycin, especially in case of kidney function alteration. Augmented renal clearance (ARC), defined as a creatinine clearance of more than 130 ml/min, is a risk factor for sub-therapeutic concentrations of vancomycin. This study aimed to evaluate the vancomycin pharmacokinetics following the administration of two different regimens in ARC patients. Methods: A randomized clinical trial (IRCT20180802040665N1) was conducted on patients in need of vancomycin therapy. Eight hours of urine was collected and 56 patients divided into two groups with creatinine clearance of more than 130 ml/min were included in the study. The first group received 15 mg/kg of vancomycin every 12 h and the second group 15 mg/kg every 8 h. After four doses, the peak and trough concentrations were measured from two blood samples. The primary outcome was the percentage of patients who attainted AUC more than 400. The occurrence of acute kidney injury also was evaluated after seven days. Results: The mean age of patients in the every 12 h and every 8 h groups was 44.04 ± 16.55 and 42.86 ± 11.83 years, respectively. While neurosurgical issues were the most common causes of hospitalization, central nervous infections were the most common indications for vancomycin initiation. Urinary creatinine clearance was 166.94 ± 41.32 ml/min in the every 12 h group and 171.78 ± 48.56 ml/min in the every 8 h group. 46.42% of patients in the every 12 h group and 82.14% of patients in the every 8 h group attained AUC/MIC of more than 400 mg × hr/L. None of the patients in the every 12 h group reached more than 15 mcg/ml concentration. At the 7-day follow-up, 10.7% patients in the BD group and 28.6% patients in the TDS group developed acute kidney injury (p = 0.089). Conclusion: Administration of vancomycin at a dose of 15 mg/kg every 8 h is associated with higher pharmacokinetic attainment in ARC patients. The occurrence of acute kidney injury also was not significantly higher in this therapeutic regimen. AUC/MIC monitoring is necessary in this population.

Study of the Effects of N-acetylcysteine on Inflammatory Biomarkers and Disease Activity Score in Patients with Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is considered as an autoimmune-related condition in which the overproduction of pro-inflammatory cytokines leads to an inflammatory cascade. N-acetylcysteine (NAC) is a potent anti-inflammatory and anti-oxidant agent. We aimed to explore the impact of oral NAC on cytokines activities and clinical indicators in RA patients. In this placebo-controlled randomized double-blind clinical trial, 41 active RA patients were allocated in either NAC (600 mg, twice a day) or placebo group, as add-on therapy to the routine regimen, for 8 weeks. Disease activity score with an erythrocyte sedimentation rate (DAS28-ESR), and serum concentrations of interleukin (IL)-1ß and IL-17 were assessed at baseline and end of the trial for all participants in the test and control groups. The reduction of the DAS28-ESR was higher considerably in the NAC group compared to that of the control group. No statistically significant differences were seen in the reduction of IL-1ß and IL-17 cytokines between the NAC and control groups. In addition, improvements in the patient global assessment, number of tender joints, number of swollen joints, and the ESR rates were in favor of the NAC group. Our findings reveal that NAC may have a beneficial effect on all of the clinical features of RA. However, non-significant variations in the IL-1ß and IL-17 levels suggest an alternative way of NAC effectiveness without influencing the measured cytokines. Nevertheless, these results need to be confirmed by further investigations.

Evaluating the elimination status of medications used for COVID-19 during hemoperfusion and therapeutic plasma exchange: A review.

Since late 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, better known as COVID-19) has rapidly spread worldwide. The primary pathophysiology by which COVID-19 leads to severe lung damage is cytokine releasing syndrome (CRS), which can cause death. Therefore, removing cytokines via therapeutic plasma exchange or hemoperfusion could be a therapeutic approach to treat CRS. However, hemoperfusion or therapeutic plasma exchange could alter the effectiveness of concomitant medications. Thus, concomitant medication doses might need to be adjusted to prevent their elimination via therapeutic plasma exchange or hemoperfusion, thus ensuring that these medications remain effective. This narrative review investigates the elimination status of current medications used to manage COVID-19 during hemoperfusion and therapeutic plasma exchange, with a focus on their pharmacokinetic profiles.

Early Graft Function in Deceased Donor Renal Recipients: Role of N-Acetylcysteine.

Reduced graft function (RGF) in donor renal transplant recipients is caused by oxidative damage due to extensive ischemia-reperfusion (I/R) injury during transplantation. Neutrophil gelatinase-associated lipocalin (NGAL) is a promising biomarker to detect tubular injury early after renal transplantation. N-acetylcysteine (NAC) is a potent antioxidant that can reduce I/R injury by improving oxidative damage. The aim of the present study is to assess the efficacy of NAC in improving graft function and reducing renal tubular injury in deceased donor renal transplant recipients. A double-blind, randomized clinical trial was conducted on 50 deceased donor renal transplant recipients. The patients were randomized into two groups, receiving either 600 mg NAC twice daily, or placebo (days 0 to 5). Results were assessed based on the rate of RGF, levels of plasma NGAL (p-NGAL) and the estimated glomerular filtration rate (eGFR). The rate of RGF was significantly lower in the patients receiving NAC vs. placebo (21.4% vs. 50%). The measurement of p-NGAL levels showed that the patients in the NAC group had significantly greater reduction of p-NGAL by both days 1 and 5 post-transplantation than those in the placebo group. A near steady-state eGFR level was reached by week 1 in the NAC group, however, the improvement of eGFR was significantly slower in the placebo group and a near steady-state was only achieved by week 4. NAC has promising potential in reducing tubular injury and improving graft function, evidenced by significant reduction in the rate of RGF and levels of p-NGAL.

Blood Glucose Control and Opportunities for Clinical Pharmacists in Infectious Diseases Ward.

OBJECTIVE: Increased risk of infection following hyperglycemia has been reported in hospitalized patients. Sliding-scale insulin protocol is an out-of-date method; therefore, it is necessary to examine new approaches in this regard. This study aimed to evaluate the efficacy of sliding-scale protocol versus basal-bolus insulin protocol, which supervised by clinical pharmacists in an infectious disease ward. METHODS: In this prospective randomized clinical trial, 90 hyperglycemic patients who hospitalized in Loghman Hakim Hospital Infectious Disease Ward (Tehran, Iran) were randomized into two groups: sliding-scale insulin protocol (the control group) and the basal-bolus protocol groups that were under supervision clinical pharmacists. Some demographic, laboratory, and clinical variables, as well as patient's blood glucose were measured four times daily. FINDINGS: The results indicated significant improvement among the patients in the intervention group. General indicators including fever, blood glucose level, the duration of hospitalization, incidence of hypoglycemia, days to achieve normal blood glucose, and leukocyte count improved in intervention group. CONCLUSION: According to this study, basal-bolus insulin protocol, which supervised by clinical pharmacy service, showed better blood glucose control and infection remission compared to the sliding-scale protocol.

The study of vitamin D administration effect on CRP and Interleukin-6 as prognostic biomarkers of ventilator associated pneumonia.

PURPOSE: In regard with the effect of immune-stimulants in the treatment of infectious diseases, the effect of vitamin D administration on the outcome of patients with Ventilator-Associated Pneumonia (VAP) with a high rate of mortality, was studied. MATERIAL AND METHOD: In this trial, 46 adult patients suffering from VAP and vitamin D deficiency were enrolled. The first group of patients received single intramuscular injection of vitamin D (300000Unit), while the other group were given the placebo. RESULTS: Administration of vitamin D significantly enhanced its levels (P<0.0001) in the treated patients (12.28±8.26) in comparison with placebo group (1.15±1.50). Serum Interleukin-6 levels were significantly reduced in the treated group compared to placebo (P=0.01). Although C-Reactive protein (CRP) levels showed an improving trend in the vitamin D group, no significant difference between groups (P=0.12) was found. Interestingly, the mortality rate of patients that treated with vitamin D (5/24) was significantly lower (p=0.04) than that of the placebo group (11/22). CONCLUSION: Our results indicate that vitamin D administration can significantly reduce the IL-6 as prognostic marker in VAP patients, and must be considered as adjunct option in the treatment of VAP patients.