Tocilizumab Failed to Reduce Mortality in Severe COVID-19 Patients: Results from a Randomized Controlled Clinical Trial.

The severe coronavirus disease 2019 (COVID-19) is associated with increased levels of blood interleukin (IL)-6. Therefore, it is hypothesized that modulating the levels or effects of IL-6  could diminish airway inflammation and alter the course of COVID-19. We conducted a controlled, randomized, double-blind clinical trial on hospitalized patients with severe COVID-19 in Iran. The patients were randomly distributed by block randomization to take either standard-of-care (SOC) plus 1 or 2 doses of tocilizumab 8 mg/kg or SOC alone. The endpoint was defined by clinical improvement and discharge. We enrolled 40 patients (20 patients in each group) from 10 July to 10 December 2020. After randomization, 1 patient in the SOC arm and 3 patients in the tocilizumab arm refused to participate and were eliminated from the study. The mean age of participants was 59.62±15.80 in the tocilizumab group (8 women and 9 men) and 63.52±12.83 years old in the SOC group (9 women and 10 men) groups. The number of patients who recovered did not differ significantly between the tocilizumab and SOC groups (12 [70.6%][70.6%] vs. 15 [78.9%]), respectively). Hospitalization rates were also similar between the groups (Log-rank test, p=0.615; hazard ratio, 0.83; 95% C I [0. 39-1.78]). The results show that tocilizumab could not be a beneficial agent for treating severe cases of COVID-19 patients and would not significantly improve clinical outcomes.

Population pharmacokinetics of vancomycin in patients with diabetic foot infection: a comparison of five models.

Purpose: This study aimed to compare individual pharmacokinetic (PK) parameters of vancomycin with predicted values from five population PK models in patients with diabetic foot infections (DFIs). Methods: Patients with a diagnosis of DFI and an estimated glomerular filtration rate (eGFR) ≥ 30 mL/min were included in the study. Individual PK data was carried on by collecting three vancomycin serum concentrations in a steady-state condition. Five published population-based nomograms were assumed to predict PK parameters. Optimal vancomycin exposure was considered as a trough level of 15-20 mg/L or the area under the curve over 24 h/minimum inhibitory concentration (AUC24/MIC) ≥ 400. Results: A total of 48 samples from 16 patients were analyzed. There was a statistically significant difference between the volume of distribution (Vd) obtained from population methods and the individual estimations (P ≤ 0.001 in Ambrose and Burton, P = 0.010 and 0.006 in Bauer and Burton revised models, respectively). AUC/MIC ≥ 400 was achieved in 68.7% of patients while 50% had a trough level of less than 15 mg/L. Conclusions: Vancomycin PK parameters, particularly individualized Vd, may not be predictable by population nomograms in patients with DFI and stable renal function. Moreover, the weak correlation between AUC24 values and trough concentrations underlines the starting practice of vancomycin AUC24-based monitoring and dosing in the clinical setting.

Who is the convict; COVID-19 or corticosteroid? Late onset avascular necrosis of hips after COVID-19. A case report with literature review.

AIM: Avascular necrosis (AVN) or osteonecrosis is characterized by death of bone tissue due to endothelial damage and vascular abnormality. Coronavirus can induce endothelial damage and abnormal blood clotting, so that COVID-19 is known as a vascular disease. We aim to evaluate the relationship between AVN and COVID-19. CASE: Here we present a 39-year old man with severe COVID-19 and corticosteroid consumption who developed late onset AVN of both hips 20 month after COVID-19. CONCLUSION: An awareness of the possible osteonecrosis for all physicians dealing with patients with musculoskeletal problems following COVID-19 is necessary.

Adherence to practice guidelines for the management of febrile neutropenia in patients undergoing hematopoietic stem cell transplantation: An observational study in a referral center in Iran.

INTRODUCTION: Patients undergoing hematopoietic stem cell transplantation (HSCT) are suspected to develop febrile neutropenia (FN) and severe infections. Therefore, appropriate prescription of antibiotics in these patients is crucial to reduce the rates of morbidity, mortality, and antimicrobial resistance. The present study aimed to evaluate the physicians' prescription and adherence to the FN clinical guidelines among patients undergoing HSCT. METHODS: This prospective observational single-center study was conducted during a 15-month period in a tertiary referral hospital in Iran. The patients with at least one episode of FN following HSCT were included in the current study. The physicians' adherence to the Infectious Diseases Society of America (IDSA) and National Comprehensive Cancer Network (NCCN) clinical guidelines for the management of FN was evaluated using prescription data and medical record reviews. RESULTS: Two hundred and fifteen patients with 297 FN episodes were evaluated. The timing of antibiotics and the selection of the initial regimen were considered guideline-based therapy. However, antibiotic dosing and initial regimen modification were not followed in terms of the guideline recommendations in 58.1% of the patients. In particular, vancomycin was inappropriately given in 83.1% of patients. The overall adherence of physicians to the guidelines was 35.8%. CONCLUSION: Non-adherence to clinical guidelines is high particularly in initial regimen modification and administration of vancomycin, which affects hospital stay and patient's outcome. Implementation of guideline-review sessions to raise the awareness of the physicians and to improve the rational use of antimicrobial agents may be crucial.

The effects of a combination oral spray (Mucosamin®) for the prevention of oral mucositis in pediatric patients undergoing hematopoietic stem cell transplantation: a double blind randomized clinical trial.

PURPOSE: Oral mucositis (OM) is a frequent complication of conditioning regimens for hematopoietic stem cell transplantation (HSCT). Damage to the nuclear and non-nuclear materials of the mucosal cells by the production of Reactive Oxygen Species (ROS) and proinflammatory cytokines could result to development and progression of OM. Previous studies have shown the effectiveness of Mucosamin® oral spray in the management of pain and acceleration of OM healing. The aims of the current study were to evaluate prophylactic effects of Mucosamin® oral spray in reducing the incidence and severity of OM in pediatric patients undergoing allogeneic HSCT. METHOD: The current study was designed as a double-blind, placebo-controlled randomized clinical trial. Sixty patients were enrolled in the study and received placebo or Mucosamin® spray. Patients in both groups used sprays 4 times daily. Product application was begun at the time of initiation of conditioning regimen and was continued for 14 days. RESULTS: Mucosamin® significantly reduced incidence and severity of OM compared to the placebo (P values: 0.027 and 0.035, respectively). This product could also decrease OM duration and delay OM onset (P values: 0.007 and 0.006, respectively). CONCLUSION: Mucosamin® could effectively reduce incidence, severity, and duration of OM and delay OM onset in pediatric patients undergoing allogeneic HSCT. TRIAL REGISTRATION: The study protocol was registered in the Iranian Registry of Clinical Trials under the registry number IRCT20190917044805N1.

Identification of drug-related problems followed by clinical pharmacist interventions in an outpatient pharmacotherapy clinic.

WHAT IS KNOWN AND OBJECTIVE: Pharmacotherapy is an essential strategy for the treatment of many medical conditions especially chronic disease and often involves multiple medications being used simultaneously. Increasing the use of medications may pose some challenges to safe and effective drug therapy and if not identified and prevented by the pharmacists eventually can lead to drug-related problems (DRPs). The present study aimed to examine the incidence of DRPs in Iranian patients and to evaluate patients' adherence to the clinical pharmacist interventions as well as the physicians' acceptance of these recommendations. METHODS: This study was conducted in a university-affiliated outpatient pharmacotherapy clinic over a 22-month period. Patients aged 18 years and older with at least one chronic disease receiving at least four medications were included in the study. The patients were interviewed by a clinical pharmacist for comprehensive medication review. DRPs were identified using the DOCUMENT classification system. Recommendations were provided by the clinical pharmacist including interventions involving patient and/or physician to resolve DRPs. The patients were followed up after 2 weeks to evaluate their compliance and physician acceptance of clinical pharmacist recommendations. RESULTS AND DISCUSSION: Two hundred patients were included in this study. Overall, 875 DRPs were identified with an average of 4.37 per patient. The most prevalent DRPs were related to patient education or information (22.8%), undertreated indications (17.4%) and patient compliance (17.2%). The most common drugs associated with DRPs were alimentary and metabolism (22.2% of DRPs) followed by the cardiovascular system (19.2%) and nervous system (9.6%) medications. The DRP incidence correlated with gender only and was higher in females (p = 0.019). The clinical pharmacist provided 912 interventions with an average of 4.56 and 1.04 interventions per patient and per DRPs respectively. Patient education (41.3%), medication initiation or discontinuation (24.5%), and non-pharmacological interventions (12.9%) were the most common clinical pharmacist interventions. Out of 912 interventions, 665 were followed up, out of which 427 were patient dependent and 228 involved physicians. The patient's compliance with clinical pharmacist recommendations was 81.2%. The physician acceptance rate of the recommendations was 44.1%. WHAT IS NEW AND CONCLUSION: The study shows that especially designed services such as pharmacotherapy clinics running by clinical pharmacists are necessary to detect and resolve DRPs in an effective way. The high compliance rate of the patients indicates patients' confidence in the clinical pharmacist services provided in the pharmacotherapy clinic. The low acceptance rate of the physicians highlights the need to improve interprofessional collaboration between clinical pharmacists and physicians in an outpatient setting.

High-dose Intravenous Vitamin C in Early Stages of Severe Acute Respiratory Syndrome Coronavirus 2 Infection: A Double-blind, Randomized, Controlled Clinical Trial.

Objective: Based on previous studies in the sepsis population, Vitamin C could prevent injuries when administered in high doses and before the damage is established. This study aimed to evaluate the protective potentials of high-dose Vitamin C in the progression of coronavirus disease 2019 (COVID-19). Methods: A double-blind, placebo-controlled clinical trial was conducted. Patients with moderate-to-severe disease severity based on the World Health Organization definition were enrolled and received 12 g/d Vitamin C (high-dose intravenous Vitamin C [HDIVC]) or placebo for 4 days. Sequential Organ Failure Assessment (SOFA) score as a primary outcome, National Early Warning Score, Ordinal Scale of Clinical Improvement, and cytokine storm biomarkers were recorded on days 0, 3, and 5. Survival was also assessed on day 28 after enrollment. Findings: Seventy-four patients (37 patients in each group) were enrolled from April 5, 2020, to November 19, 2020, and all patients completed follow-up. A lower increase in SOFA score during the first 3 days of treatment (+0.026 vs. +0.204) and a higher decrease in this parameter in the last 2 days (-0.462 vs. -0.036) were observed in the treatment group. However, these differences did not reach a significance level (P = 0.57 and 0.12, respectively). Other indices of clinical and biological improvement, length of hospitalization, and intensive care unit admission days were the same between the two groups. Treatment did not affect the 28-day mortality. Conclusion: Among patients with moderate-to-severe disease of COVID-19, the use of HDIVC plus standard care resulted in no significant difference in SOFA score or 28-day mortality compared to the standard care alone.

Detection of subclinical nephrotoxicity induced by aminoglycosides in critically ill elderly patients using trough levels and urinary neutrophil gelatinase-associated lipocalin.

OBJECTIVES: Early detection of aminoglycoside-induced acute kidney injury (AKI) is crucial in intensive care unit (ICU) patients, but it is not adequately reflected by serum creatinine (SrCr) levels. This study proposed investigating the relationship between amikacin trough levels and the development of nephrotoxicity using both conventional markers and a new biomarker of renal function in critically ill elderly patients. METHODS: Thirty-three critically ill patients aged ≥65 years with normal SrCr who received once-daily amikacin were evaluated. Trough levels of amikacin, creatinine clearance (CrCL) and urinary neutrophil gelatinase-associated lipocalin (uNGAL) were measured during the 10-day study period. The patients were divided into three groups and were compared based on the trough levels on both day 3 and day 7: <3 µg/mL (low trough (LT)), 3-6 µg/mL (moderate trough (MT)) and >6 µg/mL (high trough (HT)). RESULTS: In the LT group, neither CrCL nor uNGAL levels significantly changed from baseline (p=0.364 and p=0.562, respectively). In the MT group, the CrCL level altered significantly over time from baseline (p=0.007), but the uNGAL level did not change significantly over the study period (p=0.916). In the HT group, both CrCL and uNGAL levels significantly changed from baseline during the study period (p=0.002 and p=0.046, respectively). CONCLUSIONS: In critically ill elderly patients with MT, the mean uNGAL level changed at least 4 days earlier than the SrCr level. Instead, the trough level of amikacin demonstrated a potential value for predicting subclinical AKI for implementing necessary interventions. Amikacin trough levels <3 µg/mL in the once-daily dosing regimen appeared safe, even in geriatric patients. Further studies are needed to confirm this finding.

Vancomycin pharmacokinetic parameters in patients undergoing hematopoietic stem cell transplantation.

INTRODUCTION: Current guidelines on vancomycin dosing lack specific recommendations about its dosing in hematopoietic stem cell transplant (HSCT) patients, the objective of the current study was to compare vancomycin pharmacokinetic variables in this population with those of general population. METHODS: A prospective study was designed and the calculated parameters of vancomycin pharmacokinetic were compared with individualized parameters. Two trough levels before 4th and 5th doses and a peak level after the 4th dose, were taken. All patients received a dose of 15 mg/kg of vancomycin two or three times a day. Pharmacokinetic parameters were calculated using a one compartmental model. The association between different variables and of acute kidney injury (AKI) development and achievement of target levels were also evaluated. RESULTS: A significant difference was observed between population Volume of distribution (Vd) and individualized Vd (mean 57.33 L vs 162.86 L, p value 0.019) and trough and peak levels (p values 0.0001 and 0.001; for mean trough and peak levels respectively). The achievement of the recommended trough levels and area under the concentration time curve per minimum inhibitory concentration (AUC24/MIC) was very low (5/71 and 24/71 patients respectively). No significant differences were observed between population and individualized clearance and rate of elimination of vancomycin (p values of 0.092 and 0.55 respectively). Concomitant receipt of cyclosporine was significantly related with development of AKI (p value 0.046). CONCLUSION: The dosing methods which use population-based pharmacokinetic variables does not result in desired therapeutic levels in HSCT patients, mainly because of larger vancomycin volume of distribution.

Efficacy and Safety of Different Dosage of Recombinant Tissue-type Plasminogen Activator (rt-PA) in the Treatment of Acute Pulmonary Embolism: A Systematic Review and Meta-analysis.

Reperfusion therapies are recommended for patients with hemodynamic instability or high-risk acute pulmonary embolism (PE). Lower doses of tissue plasminogen activator (rt-PA) could be considered to improve bleeding complications. The aim of this study was to evaluate the efficacy and safety of a reduced dose of rt-PA for the treatment of acute PE, compared with anticoagulation and standard dose. PubMed Central, Scopus, Web of Science and Embase were searched for all relevant randomized studies and prospective observational studies that compared reduced dose of rt-PA with anticoagulation alone or standard dose of rt-PA in patients with acute PE. The risk ratios (RR, with 95% CI) were calculated according to the value of I2. Outcomes were described as bleeding events, all-cause death, and recurrence of PE. Thirteen articles, including four observational studies (4223 patients) and nine RCTs (780 patients), were included. In comparing reduced dose of rt-PA with anticoagulant, a greater incidence of total bleeding events in low dose was showed (RR, 5.08 (95% CI, (1.39-18.6), I2 = 0.0%). In the standard dose rt-PA vs. reduced dose, there was a greater incidence of total bleeding events in the standard dose of rt-PA, RR 1.48 (95% CI, (1.00-2.19), I2 = 0.0%) was shown. There were no statistical differences in recurrent PE or all-cause mortality. It concluded that in the absence of the benefit of a standard dose of rt-PA in comparison with dose reduction, a reduced dose of rt-PA showed a lower rate of total bleeding events and similar efficacy regarding mortality and PE recurrence rate.

Two seriously ill neonates born to mothers with COVID-19 pneumonia- a case report.

BACKGROUND: Coronavirus disease 2019 (COVID-19), a highly contagious viral disease has spread from Wuhan, Hubei Province, China to all over the world from its first recognition on December 2019. To date, only a few neonatal early-onset sepsis by SARS-COV-2 has been reported worldwide. CASE PRESENTATION: In this report, we present two seriously ill neonates who were born from mothers with stablished COVID-19 pneumonia. Laboratory tests showed lymphopenia with high LDH and hypocalcemia right after the birth. They had fever for days without responding to antibiotics and despite ruling out other potential causes. Both patients had positive RTPCR for SARS-COV-2 in the second round of testing but the first assay tested was negative. Hydroxychloroquine was used to treat both patients; the first patient was treated with it over a period of 14 days before showing signs of improvement. The second patient responded to the treatment over a period of 5 days. CONCLUSION: Although based on the available evidences, vertical transmission of COVID-19 is less likely, many aspects of pathogenesis and transmission of this novel virus are still unclear. Therefore we cannot rule out the vertical transmission totally. Further investigations are warranted to determine the exact mechanisms and routes of transmission.

Evaluation of Amikacin Pharmacokinetics in Critically Ill Patients with Intra-abdominal Sepsis.

Purpose: Although the current widespread use of amikacin is in intra-abdominal sepsis treatment, its pharmacokinetic changes in the present setting are not yet well known. This study was aimed to evaluate the amikacin pharmacokinetic profile in critically ill patients with intraabdominal sepsis compared to pneumosepsis. Methods: Adult septic patients received amikacin therapy were studied. Patients with intraabdominal sepsis were enrolled in group 1 (n=16), and patients with pneumosepsis were enrolled in group 2 (n=13). The amikacin serum concentrations were evaluated in the first, second, fourth and sixth hours after initiating 30-minute infusion. The pharmacokinetic parameters were calculated for each patient. Results: There was no significant difference in the volume of distribution between the two groups (0.33±0.08 vs. 0.28±0.10 L/kg, P=0.193). The amikacin clearance was significantly lower in group 1 compared to group 2 (58.5±21.7 vs. 83.9±37.0 mL/min, P=0.029). There was no significant correlation between amikacin clearance and creatinine clearance estimated by Cockcroft-Gault formula in all patients (P=0.206). The half-life was significantly longer in group 1 compared to group 2 (5.3±2.8 vs. 3.4±3.2 hours, P=0.015). Conclusion: Pathophysiologic changes following intra-abdominal sepsis can affect amikacin pharmacokinetics behavior. The clearance and half-life may change, but the alteration of the volume of distribution is not significantly different in comparison with pneumosepsis. Further studies are required to evaluate the pharmacokinetic variables of amikacin in critically ill patients with intra-abdominal sepsis.

Successful switch to oral tacrolimus in a patient with hypersensitivity reaction to parenteral vitamin K, cyclosporine, and tacrolimus: A case report.

INTRODUCTION: Calcineurin inhibitors are widely used for the prevention and treatment of graft versus host disease in patients undergoing allogeneic hematopoietic stem cell transplantation, and successful treatment with calcineurin inhibitors is very important for the management of these cases. CASE REPORT: A 19-year-old man with thalassemia major experienced hypersensitivity reaction to parenteral vitamin K, cyclosporine, and tacrolimus before hematopoietic stem cell transplantation. All three episodes of reaction appeared a few minutes after administration of offended drugs and cause systemic signs and symptoms of anaphylaxis, i.e. itching, flushing, difficulty in breathing, and hypotension. MANAGEMENT AND OUTCOME: Hypersensitivity reaction was fully controlled by immediately discontinuing the drug and administering hydrocortisone, chlorpheniramine, epinephrine, and intravenous fluids. During hospitalization, the patient tolerated oral tacrolimus without any complication. DISCUSSION: It appears that Cremophor EL (polyoxyethylated castor oil) which acts as a carrier, solubilizer, and emulsifier in intravenous calcineurin inhibitors is responsible for the occurrence of anaphylactic reaction (anaphylaxis); therefore, it is suggested that the administration of cremophor-containing drug should be avoided in patients with a previous history of hypersensitivity reaction to one of these drugs.

A Cost-effectiveness Analysis of Albumin in Septic Shock: A Patient-level Data Analysis.

PURPOSE: Albumin-based fluid therapy in septic shock is a matter of debate and criticism. The aim of this study was to assess the cost-effectiveness of albumin therapy in patients with septic shock. METHODS: A retrospective cohort study was conducted in Imam Khomeini, Sina, and Shariati hospitals on patients with septic shock admitted to intensive care units from March 31, 2016 to September 22, 2017. Data sources were the health information system database and patient medical records. The patients with potential septic shock were identified based on norepinephrine use. Septic shock was confirmed after medical record review based on systemic inflammatory response syndrome criteria, antibiotic use, and fluid therapy. Patients who received albumin in the fluid therapy were compared with patients treated without albumin. The 28-day mortality, life-year gain, and cost-effectiveness were evaluated. FINDINGS: The addition of albumin had no significant increase in life-year gain (mean difference = 0.67; 95% CI, -2.25 to 3.58). However, the addition of albumin increased the total cost of treatment by US $3846.07 (95% CI, US $2093.46-US $5598.98). The incremental cost-effectiveness ratio calculated based on the mean life-years gained was US$5740.40 per a life-year gained. The net monetary benefit was negative (-355.4; 95% CI, -15,387.61 to 14,676.81), and the probability that the addition of albumin will be cost-effective at a gross domestic product per capita was 40.0%. IMPLICATIONS: Albumin-based fluid therapy does not improve the 28-day mortality of patients with septic shock. The addition of albumin in the fluid therapy of patients with septic shock was not cost-effective. Both the observational and retrospective nature of the study was expected to introduce bias. We recommend a cost-effectiveness analysis combined with clinical trials to settle the debate once and for all.

Is Albumin-based Resuscitation in Severe Sepsis and Septic Shock Justifiable? An Evidence from a Cost-effectiveness Evaluation.

BACKGROUND: Fluid and antimicrobial therapy are the essential parts of sepsis management. The type of fluid to resuscitate with is an unsettled issue in the treatment of severe sepsis and septic shock. The objective of this study was to evaluate the cost-effectiveness of albumin-based resuscitation over crystalloids. METHODS: A cost-effectiveness analysis was conducted by extracting data from a database of Sina Hospital, Islamic Republic of Iran. A decision tree was constructed by using Tree Age Pro 2011. The patients were grouped based on the types of fluids used for resuscitation into crystalloid alone or crystalloid + albumin groups at the initial decision node. The patients were followed from the onset of severe sepsis and septic shock upto 28 days. The healthcare payers' perspective was considered in constructing the model. The cost was measured in US dollars and the effectiveness was measured by life years gained. RESULTS: The addition of albumin during resuscitation of patients with severe sepsis and septic shock has an effectiveness gain of 0.09 life years and cost increment of 495.00 USD. The estimated ICER for this analysis was 5500.00 USD per life year gained. The probability that albumin is cost-effective at one GDP per capita is 49.5%. CONCLUSION: Albumin-based resuscitation is not cost-effective in Iran when a GDP per capita was considered for a life year gain. The cost-effectiveness was insensitive to the cost of standard care. We recomend the caustious use albumin as per the Surviving Sepsis Campaign guideline.

High-dose amikacin for achieving serum target levels in critically ill elderly patients.

INTRODUCTION: To achieve target concentrations, the application of higher-than-standard doses of amikacin is proposed for the treatment of sepsis due to an increase in volume of distribution and clearance, but little data are available on aminoglycoside administration in critically ill elderly patients. PATIENTS AND METHODS: Forty critically ill elderly patients (aged over 65 years) who required amikacin therapy due to severe documented, or suspected gram-negative infections, were randomly assigned to two treatment groups. Group A (20 patients) received 15 mg/kg amikacin and Group B (20 patients) received 25 mg/kg amikacin per day as a single daily dose. All the patients were monitored for renal damage by the daily monitoring of serum creatinine. The amikacin peak (Cmax) and trough (Cmin) serum concentrations were measured on Days 3 and 7 postadministration. RESULTS: Data from 18 patients in Group A and 15 patients in Group B were finally analyzed. On Day 3, the amikacin mean Cmax levels in the standard and high-dose treatment groups were 30.4±11 and 52.3±16.1 µg/mL (P<0.001), and the Cmin levels were 3.2±2.1 and 5.2±2.8 µg/mL, respectively (P=0.035). On Day 7, the Cmax levels in the standard and high-dose groups were 33±7.3 and 60.0±17.6 µg/mL (P=0.001), and the Cmin levels were 3.2±2.9 and 9.3±5.6 µg/mL, respectively (P=0.002). In only six (40%) of the patients in the high-dose groups and none of the patients in the standard-dose group, amikacin Cmax reached the target levels (>64 µg/mL), whereas the amikacin mean Cmin levels in the high-dose group were above the threshold of toxicity (5 µg/mL). CONCLUSION: Our results suggest that the optimum dose of amikacin should be determined for elderly critically ill patients. It seems that higher-than-standard doses of amikacin with more extended intervals might be more appropriate than standard once-daily dosing in the elderly critically ill patients.

Achievement of Vancomycin Therapeutic Goals in Critically Ill Patients: Early Individualization May Be Beneficial.

Objective. The aim of our study was to assess and validate the effectiveness of early dose adjustment of vancomycin based on first dose monitoring in achieving target recommended goal in critically ill patients. Methods. Twenty critically ill patients with sepsis received loading dose of 25 mg/kg of vancomycin and then were randomly assigned to 2 groups. Group 1 received maximum empirical doses of vancomycin of 15 mg/kg every 8 hrs. In group 2, the doses were individualized based on serum concentrations of vancomycin. First dose nonsteady state sampling was used to calculate pharmacokinetic parameters of the patients within 24 hours. Results. Steady state trough serum concentrations were significantly higher in group 2 in comparison with group 1 (19.4 ± 4.4 mg/L versus 14.4 ± 4.3 mg/L) (P = 0.03). Steady state AUCs were significantly higher in group 2 compared with group 1 (665.9 ± 136.5 mg·hr/L versus 490.7 ± 101.1 mg·hr/L) (P = 0.008). Conclusions. With early individualized dosing regimen, significantly more patients achieved peak and trough steady state concentrations. In the context of pharmacokinetic/pharmacodynamic goal of area under the time concentration curve to minimum inhibitory concentration (AUC/MIC) ≥400 and also to obtain trough serum concentration of vancomycin of ≥15 mg/L, it is necessary to individualize doses of vancomycin in critically ill patients.

Randomized Trial of the Effect of Magnesium Sulfate Continuous Infusion on IL-6 and CRP Serum Levels Following Abdominal Aortic Aneurysm Surgery.

Abdominal aortic aneurysm (AAA) is widely considered as the disease of elderly white men. Inflammation is one of the most well-known mechanisms involved in the pathogenesis of AAA. Magnesium is one of the most important minerals in the body with established anti-inflammatory effects. In this study, we aimed to investigate the impact of Mg loading following AAA surgery on two inflammation markers, IL-6 and CRP, as well as patient's outcome. This study was conducted as a randomized clinical trial on 18 patients (divided into two groups) after surgical correction of Acute Aortic Aneurysm (AAA). All the patients admitted in ICU ward of Sina Hospital. In intervention group, 10 g of MgSO4 has been infused through 12 h. The control group has not received the intervention. IL-6 and CRP were measured and compared at times 0, 12, 24 and 36 h. The patients were monitored for 36 h. After intervention, the differences of heart rate and APACHE II score were not statistically significant between intervention and control groups (P = 0.097 and P = 0.472, respectively). IL-6 levels decreased consistently in both groups after inclusion in the study. However, IL-6 level was significantly less in intervention group early after the end of MgSO4 infusion comparing with control group (P = 0.01). Likewise, the CRP level decreased significantly after inclusion in the study (P = 0.005). However, these changes were not significant between intervention and control groups (P = 0.297). According to the results of this study, continuous infusion of MgSO4 after AAA surgery may provide IL-6 suppression.

Administration of higher doses of amikacin in early stages of sepsis in critically ill patients.

High-dose extended-interval dosage (HDED) regimen of aminoglycosides is now considered as the standard dosage strategy in sepsis. Although safety and efficacy of this dosing regimen is well studied, but new experiments show increased the risk of resistance development associated with %T>MIC less than 60% of the dosing interval following extended interval dosing. Moreover, limited information is available about safety of more frequent administration of high dose aminoglycosides. Authors studied nephrotoxicity following seven days' exposure to more frequent administration of higher doses of amikacin comparing with HDED regimen. In addition to Serum Creatinine (SrCr) and estimated glomerular filtration rate (eGFR), nephrotoxicity was studied with Neutrophil gelatinase-associated lipocalin (NGAL), a direct marker of tubular injury. A total of 40 patients with sepsis were quasi-randomized in two groups. Seven days' course of treatment with a moderate dose of amikacin (12.5 mg/Kg) was administered every 12 hours, known as the moderate-dose non-liberal-interval dosage (MDNLD) regimen compared with the high-dose extended-interval dosage (HDED) regimen (25 mg/Kg every 24 hours). The pharmacokinetic/pharmacodynamic (PK/PD) goal of the MDNLD regimen was the Cmax>40 and the %T>MIC more than 60% during the PK/PD goal for the HDED regimen was the Cmax>60. The eGFR change from the baseline was the primary outcome of the study with a minimum clinical significance of 20 ml/min (estimated SD of 20, Power>90%, P<0.05). No difference was observed between groups for the values of eGFR change and the SrCr percent change from the baseline (P=0.359 and P=0.114, respectively). Frequency of acute kidney injury also did not differ between groups (P=0.342). Serum NGAL level values' change from the baseline was more in the HDED regimen in comparison with the MDNLD regimen at third day and fifth day of the treatment (P=0.001 and P =0.002, respectively). This indicates a safer pattern of moderate doses with more frequent administration of amikacin at the tubular injury level. Higher doses of amikacin could be safely administered to achieve PK/PD goal of Cmax>40 and %T>MIC more than 60% of the dosing interval. This dosing regimen would be considered as an alternative to minimize the resistance development associated with the extended-interval dosing in septic patients with multi-drug resistant gram-negative organisms.

Increasing the number of adverse drug reactions reporting: the role of clinical pharmacy residents.

Detection of adverse drug reactions (ADRs) in hospitals provides an important measure of the burden of drug related morbidity on the healthcare system. Spontaneous reporting of ADRs is scare and several obstacles to such reporting have been identified formerly. This study aimed to determine the role of clinical pharmacy residents in ADR reporting within a hospital setting. Clinical pharmacy residents were trained to report all suspected ADRs through ADR-reporting yellow cards. The incidence, pattern, seriousness, and preventability of the reported ADRs were analyzed. During the period of 12 months, for 8559 patients, 202 ADR reports were received. The most frequently reported reactions were due to anti-infective agents (38.38%). Rifampin accounted for the highest number of the reported ADRs among anti-infective agents. The gastro-intestinal system was the most frequently affected system (21.56%) of all reactions. Fifty four of the ADRs were reported as serious reactions. Eighteen of the ADRs were classified as preventable. Clinical pharmacy residents' involvement in the ADR reporting program could improve the ADR reporting system.