Oral regimen for high dose methotrexate urine alkalinization: a systematic review and meta-analysis.

OBJECTIVE: Urine alkalinization prevents nephrotoxicity in patients receiving high-dose methotrexate (HDMTX). While the standard approach involves IV sodium bicarbonate, alternative oral bicarbonate regimens are crucial in drug shortages and outpatient settings. This study aims to review the efficacy and safety of such regimens. METHODS: PubMed, WOS, and Scopus were systematically searched using the PRISMA protocol for relevant studies involving human subjects, including randomized clinical trials, retrospective, prospective, cohort, case reports, and case series studies. There were no restrictions on language, time, or age group. Qualified and eligible papers were used to extract data on efficacy and safety indicators, and the final relevant records were assessed for quality using the Risk of Bias in Non-Randomized Studies-of Interventions (ROBINS-I) assessment tool. RESULTS: 12 studies with 1212 participants were included in the systematic review, with pooled data from 8 studies used for meta-analysis. No significant differences in mean differences (MDs) or odds ratio (OR) were found after the oral bicarbonate regimen, except for when urine pH fell to < 7 (MD: 0.91, 95% CI: 0.32, 1.5, P < 0.05) and the incidence of diarrhea (OR: 2.92, 95% CI: 1.69, 5.05, P < 0.05). CONCLUSION: An oral bicarbonate regimen is a safe and effective way to alkalize HDMTX urine, providing a viable and cost-effective alternative to IV protocols. Further prospective multicenter studies are necessary. Systematic review registration identifier: CRD42023379666.

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.

Vincristine-Induced Seizure from Drug Interactions: A Case Report and Review of Literature.

Vincristine (VCR) as a key drug for the treatment of acute lymphoblastic leukemia (ALL) is associated with neurotoxicity. We present a young man with a history of controlled childhood seizures who was diagnosed with pre-B-cell ALL and developed generalized tonic-clonic seizures following the Cancer and Leukemia Group B (CALGB) 8811 regimen. The patient also received oral itraconazole to prevent fungal infection initiated by chemotherapy. Possible causes of seizure, including electrolyte abnormalities, hypoglycemia, central nervous system infection or inflammation, were ruled out. According to the Naranjo Adverse Drug Reaction Scale, the patient's seizure had been attributed to VCR, possibly secondary to concomitant use of itraconazole and doxorubicin. The patient successfully recovered after discontinuation of VCR and supportive care. Clinicians should be aware of the possibility of vincristine-induced seizure in adult patients, especially with the concomitant use of drugs known to have potential drug-drug interactions.

Current and Novel Emerging Medical Therapies for Peripheral Artery Disease: A Literature Review.

Despite the improvements in endovascular techniques during the last decades, there is still an increase in the prevalence of peripheral artery disease (PAD) with limited practical treatment, which timeline impact of any intervention for critical limb ischemia (CLI) is poor. Most common treatments are not suitable for many patients due to their underlying diseases, including aging and diabetes. On the one hand, there are limitations for current therapies due to the contraindications of some individuals, and on the other hand, there are many side effects caused by common medications, for instance, anticoagulants. Therefore, novel treatment strategies like regenerative medicine, cell-based therapies, Nano-therapy, gene therapy, and targeted therapy, besides other traditional drugs combination therapy for PAD, are newly considered promising therapy. Genetic material encoding for specific proteins concludes with a potential future for developed treatments. Novel approaches for therapeutic angiogenesis directly used the angiogenetic factors originating from key biomolecules such as genes, proteins, or cell-based therapy to induce blood vessel formation in adult tissues to initiate the recovery process in the ischemic limb. As PAD is associated with high mortality and morbidity of patients causing disability, considering the limited treatment choices for these patients, developing new treatment strategies to prevent PAD progression and extending life expectancy, and preventing threatening complications is urgently needed. This review aims to introduce the current and the novel strategies for PAD treatment that lead to new challenges for relief the patient's suffered from the disorder.

Optimal regimen of levetiracetam for prevention of busulfan-induced seizure in patients undergoing hematopoietic stem cell transplantation: A review of available evidence.

OBJECTIVE: This review aimed to summarize the available data and offer a practical recommendation regarding the optimal regimen of levetiracetam (LEV) for the prevention of busulfan-induced seizure (BIS) in patients undergoing hematopoietic stem cell transplantation (HSCT). DATA SOURCES: Published articles by searching databases (PubMed, Google Scholar, Cochrane Library, ScienceDirect) were reviewed. All types of original studies performed in pediatric and adult populations have been investigated and required data was extracted. DATA SUMMARY: Eleven articles were eligible to be included in this review. A loading dose was not used in any of the studies. LEV had been started from 6 to 48 h before busulfan (Bu) initiation and continued up to 24 to 48 h after its termination. The dose range of LEV was 10 to 20 mg/kg/day divided every 12 h in pediatrics and 500 to 1000 mg twice daily in adults. Both oral and intravenous (IV) routes of administration were used. Except for three studies, no seizure had occurred in patients who had received LEV. CONCLUSIONS: Considering the available evidence, LEV with the dose range from 500 to 1000 mg twice daily in adults and 10 mg/kg twice daily (20 mg/kg/day in 2 divided doses) in children orally or IV started from 6 to 24 h before Bu initiation up to 24 to 48 h after the last dose of Bu seems to prevent BIS appropriately. More prospective clinical trials with a larger population are needed to validate the optimal dosing of LEV for BIS prophylaxis in patients undergoing HSCT.

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.

Pharmacokinetic study of high-dose oral rifampicin in critically Ill patients with multidrug-resistant Acinetobacter baumannii infection.

PURPOSE: Although rifampicin (RIF) is used as a synergistic agent for multidrug-resistant Acinetobacter baumannii (MDR-AB) infection, the optimal pharmacokinetic (PK) indices of this medication have not been studied in the intensive care unit (ICU) settings. This study aimed to evaluate the PK of high dose oral RIF following fasting versus fed conditions in terms of achieving the therapeutic goals in critically ill patients with MDR-AB infections. METHODS: 29 critically ill patients were included in this study. Under fasting and non-fasting conditions, RIF was given at 1200 mg once daily through a nasogastric tube. Blood samples were obtained at seven time points: exactly before administration of the drug, and at 1, 2, 4, 8, 12, and 24 h after RIF ingestion. To quantify RIF in serum samples, high-performance liquid chromatography (HPLC) was used. The MONOLIX Software and the Monte Carlo simulations were employed to estimate the PK parameters and describe the population PK model. RESULTS: The mean area under the curve over the last 24-h (AUC0-24) value and accuracy (mean ± standard deviation) in the fasting and fed states were 220.24 ± 119.15 and 290.55 ± 276.20 µg × h/mL, respectively. There was no significant difference among AUCs following fasting and non-fasting conditions (P > 0.05). The probability of reaching the therapeutic goals at the minimum inhibitory concentration (MIC) of 4 mg/L, was only 1.6%. CONCLUSION: In critically ill patients with MDR-AB infections, neither fasting nor non-fasting administrations of high-dose oral RIF achieve the therapeutic aims. More research is needed in larger populations and with measuring the amount of protein-unbound RIF levels.

Remdesivir Administration in COVID-19 Patients With Renal Impairment: A Systematic Review.

BACKGROUND: Remdesivir (RDV) is the main antiviral for the treatment of moderate to severe forms of Coronavirus disease 2019 (COVID-19). Several studies revealed a shortening time to clinical improvement of COVID-19 and mortality benefits in patients receiving RDV. The patients with renal disease were excluded from large clinical trials of RDV, and the probable nephrotoxicity of the drug, its metabolites, and the vehicle (sulfobutylether-ß-cyclodextrin) have led to the recommendation against using RDV in patients with an estimated glomerular filtration rate of <30 mL/min. AREAS OF UNCERTAINTY: This systematic review aimed to collect data about the necessity and safety administration of RDV in the setting of renal impairment. DATA SOURCES: Search through databases including MEDLINE, ScienceDirect, Cochrane Library, and PubMed was performed. The studies were carried out in adults and enrolled patients with different types of renal impairment (ie, acute kidney injury, chronic kidney disease, kidney transplant, and renal replacement therapy) were included. Eligible studies were assessed, and required data were extracted. RESULTS: Twenty-two cross-sectional studies, cohorts, case reports, and case series were included in this review. The mortality rate was between 7.3% and 50%, and various severity of COVID-19 was included in the studies. None of them reported an increase in adverse effects attributed to RDV administration. A decrease in inflammatory mediators and other benefits were obvious. CONCLUSIONS: Although the manufacturer's labeling does not recommend RDV administration in patients with severe renal impairment, it seems that nephrotoxicity is less concerning in the population of these patients. Moreover, RDV may be helpful in acute kidney injury induced by the viral invasion of COVID-19. To the best of our knowledge, this is the first systematic review of the use of RDV in kidney failure. Larger, well-designed, and pharmacokinetic studies are required to have a safe and logical recommendation about the use of RDV in patients with renal disorders.

LipoxinA4 as a Potential Prognostic Marker of COVID-19.

This pilot study aimed to determine early changes of LXA4 levels among the hospitalized patients confirmed as COVID-19 cases following the clinical management and its correlation with commonly used inflammatory markers, including erythrocyte sedimentation rate (ESR), c-reactive protein (CRP), and ferritin. Thirty-one adult hospitalized patients infected with the non-severe COVID-19 were included. LXA4 levels were measured at the baseline and 48-72 hours after hospitalization. Accordingly, ESR and CRP levels were collected on the first day of hospitalization. Moreover, the maximum serum ferritin levels were determined during the five days. LXA4 levels significantly increased at 48-72 hours compared to the baseline. ESR, CRP, and ferritin levels were positively correlated with the increased LXA4. In contrast, aging was shown to negatively correlate with the increased LXA4 levels. LXA4 may be known as a valuable marker to assess the treatment response among non-elderly patients with non-severe COVID-19. Furthermore, LXA4 could be considered as a potential treatment option under inflammatory conditions. Further studies are necessary to clarify LXA4 role in COVID-19 pathogenesis, as well as the balance between such pro-resolving mediators and inflammatory parameters.

Management of a critically ill patient with COVID-19-related fulminant myocarditis: A case report.

A 78-year-old man with COVID-19 infection was admitted. Initial echocardiography indicated left ventricular ejection fraction (LVEF) of 15%, high pulmonary arterial pressure, severe left ventricular dysfunction, mild diastolic dysfunction, mild regurgitation mitral valve, and normal septal thickness. Considering the probable diagnosis of COVID-19-related myocarditis, the patient was early managed with the antivirals, immunomodulatory agents, a high dose of ascorbic acid, melatonin, and immunoglobulin therapy. His clinical condition was improved and his last echocardiography revealed LVEF of 40% and improvement in systolic and diastolic dysfunction. The clinicians should be aware of the potentially lethal cardiac complication of COVID-19, especially in geriatrics.

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.

Evaluation of amikacin dosing schedule in critically ill elderly patients with different stages of renal dysfunction.

OBJECTIVES: Amikacin is still a widely used aminoglycoside for the treatment of life-threatening infections. The pharmacokinetic parameters of this antibiotic may be altered in critically ill conditions. Moreover, in the elderly population, pathophysiological changes affect these pharmacokinetic variables, making it difficult to predict the appropriate dose and dosing schedule for amikacin. This study aimed to characterise the pharmacokinetics of amikacin in critically ill elderly patients with renal dysfunction, and to evaluate if the available dose adjustment schedules dependent on renal function would be appropriate for empirical dosing. METHODS: Critically ill patients aged >60 years with a creatinine clearance of >20 mL/min in need of treatment with amikacin were randomly enrolled. All the patients received approximately 25 mg/kg amikacin. The patients were then divided into three groups according to the stages of their renal dysfunction based on creatinine clearance, and the optimum time to re-dosing was calculated for each group. The pharmacokinetic parameters of the patients were calculated and estimated as population pharmacokinetic data. RESULTS: Of 30 patients, only 20% attained the target peak levels of amikacin of >64 mg/L. In addition, the mean volume of distribution was 0.47 L/kg. There was a poor correlation between amikacin clearance and creatinine clearance. The difference in amikacin half-life was not statistically significant among any of the stages of renal impairment. CONCLUSIONS: The initial dosing of amikacin in critically ill elderly patients should not be reduced, even in the context of renal impairment. Regarding the dose adjustment in renal impairment, dosing intervals estimation, no decision can be made based on the creatinine clearance and the first dose individualisation method in terms of the two-sample measurements may be considered as an appropriate strategy.

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.

Relationship between amikacin pharmacokinetics and biological parameters associated with organ dysfunction: a case series study of critically ill patients with intra-abdominal sepsis.

OBJECTIVES: This study aimed to evaluate the relationship between amikacin pharmacokinetics and the biomarkers associated with organ dysfunction in critically ill patients with intra-abdominal sepsis. METHODS: A case series involving critically ill patients with intra-abdominal sepsis who received an amikacin loading dose of 20-25 mg/kg intravenous infusion was studied. The 1-, 2-, 4-, 6- and 24-hour amikacin serum concentrations were measured to calculate the pharmacokinetic parameters. The Sequential Organ Failure Assessment (SOFA) score, white blood cells, neutrophil to lymphocyte ratio, platelet count, serum creatinine, creatinine clearance, bilirubin, partial pressure of oxygen to fraction of inspired oxygen ratio, serum albumin, procalcitonin, lactate level, erythrocyte sedimentation rate (ESR) and C-reactive protein were recorded. A linear regression analysis was performed to examine the relationship between the amikacin pharmacokinetics and the biological parameters. RESULTS: Twenty-one patients were studied. A significant correlation was found between the volume of distribution and ESR (p<0.05, r=0.844). Moreover, drug clearance had a significant inverse correlation with serum lactate (p<0.05, r=-0.603). No other significant correlations were found. CONCLUSIONS: ESR and serum lactate were identified as useful predictors of amikacin pharmacokinetics in critically ill patients with intra-abdominal sepsis and may help guide the selection of appropriate empirical dosing.

Antibiotic therapy in sepsis: No next time for a second chance!

WHAT IS KNOWN AND OBJECTIVE: Sepsis is a life-threatening organ dysfunction associated with a high rate of morbidity and mortality. Appropriate antibiotic therapy remains the cornerstone of sepsis and septic shock management. COMMENT: Although the early initiation of antimicrobial agents in the treatment of sepsis is widely acknowledged, the selection and adjustment to optimal dosage can be equally important. Since significant pathophysiological changes in the critically ill patients lead to altered pharmacokinetics of antibiotics, early consideration of pharmacokinetic/pharmacodynamic (PK/PD) properties is necessary for optimal antibiotic dosing in sepsis and should be integrated in practice. WHAT IS NEW AND CONCLUSION: Where possible, an individualized antibiotic dosing approach through the application of therapeutic drug monitoring (TDM) service should replace the conventional dosing in critically ill patients with sepsis. Finally, antimicrobial stewardship can help improve clinical outcomes.

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.

Area under the Curve-Based Dosing of Vancomycin in Critically Ill Patients Using 6-Hour Urine Creatinine Clearance Measurement.

BACKGROUND: The area under the curve- (AUC-) guided vancomycin dosing is the best strategy for individualized therapy in critical illnesses. Since AUC can be calculated directly using drug clearance (CLvan), any parameter estimating CLvan will be able to achieve the goal of 24-hour AUC (AUC24 h). The present study was aimed to determine CLvan based on 6-hour urine creatinine clearance measurement in critically ill patients with normal renal function. METHOD: 23 adult critically ill patients with an estimated glomerular filtration rate (eGFR) ≥60 mL/min who received vancomycin infusion were enrolled in this pilot study. Vancomycin pharmacokinetic parameters were determined for each patient using serum concentration data and a one-compartment model provided by MONOLIX software using stochastic approximation expectation-maximization (SAEM) algorithm. Correlation of CLvan with the measured creatinine clearance in 6-hour urine collection (CL6 h) and estimated creatinine clearance by the Cockcroft-Gault formula (CLCG) was investigated. RESULTS: Data analysis revealed that CL6 h had a stronger correlation with CLvan rather than CLCG (r = 0.823 vs. 0.594; p < 0.001 vs. 0.003). The relationship between CLvan and CL6 h was utilized to develop the following equation for estimating CLvan: CLvan (mL/min) = ─137.4 + CL6 h (mL/min) + 2.5 IBW (kg) (R 2 = 0.826, p < 0.001). Regarding the described model, the following equation can be used to calculate the empirical dose of vancomycin for achieving the therapeutic goals in critically ill patients without renal impairment: total daily dose of vancomycin (mg) = (─137.4CL6-h (mL/min) + 2.5 IBW (kg)) × 0.06 AUC24 h (mg.hr/L). CONCLUSION: For AUC estimation, CLvan can be obtained by collecting urine in a 6-hour period with good approximation in critically ill patients with normal renal function.

Evaluation of Epithelial Lining Fluid Concentration of Amikacin in Critically Ill Patients With Ventilator-Associated Pneumonia.

INTRODUCTION: Classically, aminoglycosides are known to have low penetration into the lung tissue. So far, no study has been conducted on human adult patients to evaluate amikacin concentration in epithelial lining fluid (ELF) of the alveoli. Therefore, convincing data are not available from the perspective of pharmacokinetics to support the fact that a dosage of 20 mg/kg of amikacin is sufficient to treat patients with ventilator-associated pneumonia (VAP). METHOD: This was a pilot study of amikacin concentration measurement in the alveolar site of action in critically ill adult patients with VAP who required aminoglycoside therapy. A dose of 20 mg/kg of amikacin was administered over a 30-minute infusion. The serum concentrations of amikacin were evaluated in the first, second, fourth, and sixth hours. However, the ELF concentration of amikacin was evaluated in the second hour with the help of bronchoalveolar lavage sampling technique. RESULTS: A total number of 8 patients was included in the study. The mean (SD) administered dose was 20 (0.9) mg/kg. The mean (SD) peak plasma concentration of amikacin was 59.6 (23) mg/L, with the volume of distribution of 0.36 (0.13)L/kg. The amikacin concentration in ELF was successfully measured in 7 patients (6.3) mg/L. The lung tissue penetration of the drug was described as alveolar percentage, proportional to both the first- and second-hour plasma concentrations, with a mean (SD) of 10.1% (8.4%) and 18% (16.7%), respectively. CONCLUSION: To our knowledge, the current study is the first that investigates whether standard doses of amikacin may lead to sufficient alveolar concentration of the drug. The results show that administration of amikacin in doses of 20 mg/kg in critically ill patients with VAP may not provide sufficient concentrations in ELF.