Diuretic, natriuretic, and chloride-regaining effects of oral acetazolamide as an add-on therapy for acute heart failure with volume overload: a single-center, prospective, randomized study.

INTRODUCTION: Decongestion is a therapeutic target in acute heart failure (AHF). Acetazolamide is a diuretic that decreases proximal tubular sodium reabsorption, and may also reverse hypochloremia Objectives: We assessed the decongestive, natriuretic, and chloride­regaining effects as well as the renal safety profile of oral acetazolamide (250 mg) used as an add­on therapy in patients with AHF. PATIENTS AND METHODS: This prospective, randomized study was conducted at the Institute of Heart Diseases in Wroclaw, Poland. It involved patients with AHF who were randomly assigned to receive either 250 mg of oral acetazolamide or standard care, and who underwent clinical and laboratory follow­up for 3 consecutive days since the beginning of the treatment and at discharge. RESULTS: The study population comprised 61 patients (71% men), of whom 31 (51%) were included in the acetazolamide group. The mean (SD) age of the patients was 68 (13) years. In comparison with the controls, the acetazolamide group demonstrated significantly higher cumulative diuresis after 48 and 72 hours since treatment implementation, negative fluid balance, weight loss after 48 hours of treatment, weight loss throughout the hospitalization, natriuresis, and serum chloride concentration. In terms of the renal safety profile, no increase in the creatinine concentration and urinary renal biomarker levels was noted. CONCLUSIONS: Oral acetazolamide seems to be a valuable add­on therapy that helps achieve comprehensive decongestion in patients with AHF.

The blunted loop diuretic response in acute heart failure is driven by reduced tubular responsiveness rather than insufficient tubular delivery. The role of furosemide urine excretion on diuretic and natriuretic response in acute heart failure.

AIMS: Diuretic response in heart failure is blunted when compared to healthy individuals, but the pathophysiology underlying this phenomenon is unclear. We aimed to investigate whether the diuretic resistance mechanism is related to insufficient furosemide tubular delivery or low tubular responsiveness. METHODS AND RESULTS: We conducted a prospective, observational study of 50 patients with acute heart failure patients divided into two groups based on previous furosemide use (furosemide naïve: n = 28 [56%] and chronic furosemide users: n = 22 [44%]). Each patient received a protocol-derived, standardized furosemide dose based on body weight. We measured diuretic response and urine furosemide concentrations. The furosemide naïve group had significantly higher urine volumes and natriuresis when compared to chronic users at all timepoints (all p < 0.05). Urine furosemide delivery was similar in furosemide naïve versus chronic users after accounting for differences in estimated glomerular filtration rate (28.02 [21.03-35.89] vs. 29.70 [18.19-34.71] mg, p = 0.87). However, the tubular response to delivered diuretic was dramatically higher in naïve versus chronic users, that is the urine volume per 1 µg/ml of urine furosemide at 2 h was 148.6 ± 136.1 versus 50.6 ± 56.1 ml (p = 0.005). CONCLUSIONS: Patients naïve to furosemide have significantly better diuresis and natriuresis when compared to chronic furosemide users. The blunted diuretic response in patients with chronic loop diuretic exposure is driven by decreased tubular responsiveness rather than insufficient furosemide tubular delivery.

Relationship of Vascular Endothelial Growth Factor C, a Lymphangiogenesis Modulator, With Edema Formation, Congestion and Outcomes in Acute Heart Failure.

BACKGROUND: Although vascular endothelial growth factor C (VEGF-C) is a known lymphangiogenesis modulator, its relationship with congestion formation and outcomes in acute heart failure (AHF) is unknown. METHODS: Serum VEGF-C levels were measured in 237 patients hospitalized for AHF. The population was stratified by VEGF-C levels and linked with clinical signs of congestion and outcomes. RESULTS: The study's population was divided in VEGF-C tertiles: low (median [Q25-Q75]: 33 [15-175]), medium (606 [468-741]) and high (1141 [968-1442] pg/mL). The group with low VEGF-C on admission presented with the highest prevalence of severe lower-extremity edema (low VEGF-C vs medium VEGF-C vs high VEGF-C): 30% vs 13% vs 20%; P = 0.02); the highest percentage of patients with ascites: 22% vs 9% vs 6%; P = 0.006; and the lowest proportion of patients with pulmonary congestion: 22% vs 30% vs 46%; P = 0.004. The 1-year mortality rate was the highest in the low VEGF-C tertile: 35% vs 28% vs 18%, respectively; P = 0.049. The same pattern was observed for the composite endpoint (death and AHF rehospitalization): 45% vs 43% vs 26%; P = 0.029. The risks of death at 1-year follow-up and composite endpoint were significantly lower in the high VEGF-C group. CONCLUSIONS: Low VEGF-C was associated with more severe signs of congestion (signs of fluid accumulation) and adverse clinical outcomes.

Serum Osmolarity and Vasopressin Concentration in Acute Heart Failure-Influence on Clinical Course and Outcome.

Neurohormone activation plays an important role in Acute Heart Failure (AHF) pathophysiology. Serum osmolarity can affect this activation causing vasopressin excretion. The role of serum osmolarity and vasopressin concentration and its interaction remain still unexplored in AHF. The objective of our study was to evaluate the relationship of serum osmolarity with clinical parameters, vasopressin concentration, in-hospital course, and outcomes in AHF patients. The study group consisted of 338 AHF patients (male (76.3%), mean age of 68 ± 13 years) with serum osmolarity calculated by the equation: 1.86 × sodium [mmol/L] + (glucose [mg/dL]/18) + (urea [mg/dL]/2.8) + 9 and divided into osmolarity quartiles marked as: low: <287 mOsm/L, intermediate low: 287−294 mOsm/L, intermediate high: 295−304 mOsm/L, and high: >304 mOsm/L. There was an increasing age gradient in the groups and patients differed in the occurrence of comorbidities and baseline clinical and laboratory parameters. Importantly, analysis revealed that vasopressin presented a linear correlation with osmolarity (r = −0.221, p = 0.003) and its concentration decreased with quartiles (61.6 [44.0−81.0] vs. 57.8 [50.0−77.3] vs. 52.7 [43.1−69.2] vs. 45.0 [30.7−60.7] pg/mL, respectively, p = 0.034). This association across quartiles was observed among de novo AHF (63.6 [55.3−94.5] vs. 58.0 [50.7−78.6] vs. 52.0 [46.0−58.0] vs. 38.0 [27.0−57.0] pg/mL, respectively, p = 0.022) and was not statistically significant in patients with acute decompensated heart failure (ADHF) (59.5 [37.4−80.0] vs. 52.0 [38.0−74.5] vs. 57.0 [38.0−79.0] vs. 50.0 [33.0−84.0] pg/mL, respectively, p = 0.849). The worsening of renal function episodes were more frequent in quartiles with higher osmolarity (4 vs. 2 vs. 13 vs. 11%, respectively, p = 0.018) and patients that belonged to the quartiles with low and high osmolarity were characterized more often by incidence of worsening heart failure (20 vs. 9 vs. 10 vs. 22%, respectively, p = 0.032). There was also a U-shape distribution in relation to one-year mortality (31 vs. 19 vs. 23 vs. 37%, respectively, p = 0.022). In conclusion, there was an association of serum osmolarity with clinical status and both in-hospital and out-of-hospital outcomes. Moreover, the linear dependence between vasopressin concentration and serum osmolarity in the AHF population was identified and was driven mainly by patients with de novo AHF which suggests different pathophysiological paths in ADHF and AHF de novo.

Are in clinical practice measurements of concentrations and the calculation of mycophenolate mofetil pharmacokinetic parameters needed for optimizing therapy in patients with renal diseases or kidney transplantation?

BACKGROUND: Modern pharmacotherapy requires an individual approach to patients, taking into account changes in pharmacokinetics in pathological states and between-subject variability. This procedure is of particular importance in immunosuppressive drug therapy. In recent years, the attention has been paid to the usefulness of calculating the kinetic parameters of the drug in the optimization of the immunosuppressive treatment. OBJECTIVES: To assess the possibility of using mycophenolic acid (MPA) concentration measurements in order to optimize pharmacotherapy in patients with kidney diseases or after kidney transplantation. MATERIAL AND METHODS: The study included 103 patients with renal diseases (group 1) and after kidney transplantation (group 2), treated at the Department of Nephrology and Transplantation Medicine at the University Clinical Hospital, Wroclaw, Poland. The concentrations of MPA were measured using Enzyme Multiplied Immunoassay Technique (EMIT®) method. A total of 193 pharmacokinetic profiles were performed. RESULTS: The median of initial (C0) concentration for all patients was 2.09 mg/L, in group 1 - 2.06 mg/L and in group 2 - 2.11 mg/L. The median concentration at 30 min after drug administration (C30) was 11.72 mg/L in the whole study group, in group 1 - 11.52 mg/L and in group 2 - 12.72 mg/L. The median concentration at 120 min after the drug administration (C120) was 4.73 mg/L, 4.45 mg/L and 5.57 mg/L, respectively. The median area under the curve from C0 to C120 (AUC)0-120 was 15.77 h × mg/L for the entire study group, in group 1 - 15.46 h × mg/L and in group 2 - 16.78 h × mg/L. Using the Spearman's rank correlation coefficient for both groups, statistically significant (p < 0.05) correlations were found between 1) C0 and C30, 2) C0 and C120, 3) C0 and AUC0-120, 4) C0 and the daily dose, 5) C30 and AUC0-120, and 6) C30 and the morning dose. There were also statistically significant correlations between C120 and AUC0-120. Moreover, in group 1, a statistically significant correlation (p < 0.05) was found between 1) C120 and the daily dose, 2) C120 and albumin, 3) C120 and C30, and 4) C120 and AUC0-120. In the group 2, a statistically significant correlation was found between C120 and the morning dose. CONCLUSIONS: Measurements of MPA concentrations are useful for optimizing immunosuppression in patients requiring an individualized treatment.

Cardiorenal syndrome: Decongestion in heart failure across wide spectrum of kidney pathophysiology.

Heart failure (HF) is a pathophysiologically complex disease that is exceptionally heterogeneous in terms of its etiology. It is associated with unsatisfactorily high mortality, both in-hospital and post-discharge, as well as with very frequent rehospitalizations. High phenotypic variability, coexistence of various hemodynamic disorders (such as changes in systemic and pulmonary vascular resistance, increased central venous pressure, impaired heart cardiac output, and fluid overload) and coexisting metabolic and neurohormonal disorders may eventually lead to impaired systemic perfusion. Congestion that impairs renal perfusion has a significant impact on both glomerular filtration and the renal tubular function. This review article discusses the importance of changes caused by HF in various nephron segments, phenotyping of cardiorenal syndromes, the role of effective natriuresis in decongestion, and the importance of known and new diagnostic biomarkers in predicting renal dysfunction. A better understanding of cardiac and renal interactions may help in selecting an effective, efficient and nephroprotective strategy of treatment for patients with HF.

Antibiotics and the Nervous System-Which Face of Antibiotic Therapy Is Real, Dr. Jekyll (Neurotoxicity) or Mr. Hyde (Neuroprotection)?

Antibiotics as antibacterial drugs have saved many lives, but have also become a victim of their own success. Their widespread abuse reduces their anti-infective effectiveness and causes the development of bacterial resistance. Moreover, irrational antibiotic therapy contributes to gastrointestinal dysbiosis, that increases the risk of the development of many diseases, including neurological and psychiatric. One of the potential options for restoring homeostasis is the use of oral antibiotics that are poorly absorbed from the gastrointestinal tract (e.g., rifaximin alfa). Thus, antibiotic therapy may exert neurological or psychiatric adverse drug reactions which are often considered to be overlooked and undervalued issues. Drug-induced neurotoxicity is mostly observed after beta-lactams and quinolones. Penicillin may produce a wide range of neurological dysfunctions, including encephalopathy, behavioral changes, myoclonus or seizures. Their pathomechanism results from the disturbances of gamma-aminobutyric acid-GABA transmission (due to the molecular similarities between the structure of the ß-lactam ring and GABA molecule) and impairment of the functioning of benzodiazepine receptors (BZD). However, on the other hand, antibiotics have also been studied for their neuroprotective properties in the treatment of neurodegenerative and neuroinflammatory processes (e.g., Alzheimer's or Parkinson's diseases). Antibiotics may, therefore, become promising elements of multi-targeted therapy for these entities.

Differences in the Biomarker Profile of De Novo Acute Heart Failure versus Decompensation of Chronic Heart Failure.

The perception of acute heart failure (AHF) as a single entity is increasingly outdated, as distinct patient profiles can be discerned. Key heart failure (HF) studies have previously highlighted the difference in both the course and prognosis of de novo AHF and acute decompensated chronic HF (ADHF). Accordingly, distinct AHF profiles with differing underlying pathophysiologies of disease progression can be shown. We compared a range of selected biomarkers in order to better describe the profile of de novo AHF and ADHF, including the inter alia-serum lactate, bilirubin, matrix metallopeptidase 9 (MMP-9), follistatin, intercellular adhesion molecule 1 (ICAM-1), lipocalin and galectin-3. The study comprised 248 AHF patients (de novo = 104), who were followed up for one year. The biomarker data of the de novo AHF and ADHF profiles was then compared in order to link biomarkers to their prognosis. Our study demonstrated that, although there are similarities between each patient profile, key biomarker differences do exist-predominantly in terms of NTproBNP, serum lactate, bilirubin, ICAM-1, follistatin, ferritin and sTfR (soluble transferrin receptor). ADHF tended to have compromised organ function and higher risks of both one-year mortality and composite endpoint (one-year mortality or rehospitalization for heart failure) hazard ratios (HR) (95% CI): 3.4 (1.8-6.3) and 2.8 (1.6-4.6), respectively, both p < 0.0001. Among the biomarkers of interest: sTfR HR (95% CI): 1.4 (1.04-1.8), NGAL(log) (neutrophil gelatinase-associated lipocalin) HR (95% CI): 2.0 (1.3-3.1) and GDF-15(log) (growth/differentiation factor-15) HR (95% CI): 4.0 (1.2-13.0) significantly impacted the one-year survival, all p < 0.05.

Role of resistin in cardiovascular diseases: Implications for prevention and treatment.

Cardiovascular diseases (CVDs) are associated with socioeconomic and, most importantly, with clinical problems. Accordingly, the identification of early and specific biomarkers indicating metabolic changes that underlie disease development and/or progression is important and may improve preventive and treatment strategies. A recently discovered protein - resistin (ADSF, FIZZ3) - whose expression is increased in carbohydrate metabolism and adipose tissue disorders, seems to be worth of interest in this context. The current publication was based on a detailed review of available literature, including Medline, EBSCO, Scopus, and Cochrane Library databases. The search period was between January 1, 2001 and December 20, 2020. The following keywords were used: "resistin", "resistin AND cardiology" and "resistin AND cardiosurgery". Our review covered a total of 4476 records, 594 of which were review publications. The presented article summarizes the current knowledge on the role of resistin in prevention and treatment of CVDs. Available literature shows that resistin may be a predictor for various pathological states; however, data from some studies on the pathophysiological mechanisms of action are contradictory. There is a need for further investigations to explore the exact role of resistin in CVDs.

Individualization of treatment with gentamicin in neonates based on drug concentration in the blood serum.

OBJECTIVE: Aim: To evaluate how useful it is to make measurements of gentamicin concentrations in newborns' blood in order to optimize antibiotic therapy. PATIENTS AND METHODS: Material and methods: 73 newborns empirically treated with gentamicin, in doses consistent with the Neofax® guidelines. There were 152 measurements of maximum and minimum serum gentamicin concentrations. Samples were determined based on the chemiluminescence technique on the Siemens Advia Centaur analyzer. The concentrations of gentamicin that were measured were compared with various therapeutic ranges used in the literature. RESULTS: Results: According to the standards adopted in the University Hospital in Wroclaw, the maximum concentration was reached in 38.16% of all the children, while the minimum in 26.32%. In other children the concentrations were below or above the therapeutic range. According to the Neofax® guidelines, the intended maximum concentration was observed in 71.05% of the newborns, and the minimum in 32.89%. The minimum concentration of <2 mg/L was found in 93.42% of the newborns, while >2 mg/L was determined in 33.33%, despite a 48-hour dosing interval. These were premature babies (<28th week of gestational age) and 55.56% of them reached a maximum concentration of 5-12 mg/L. There was no significant correlation between maximum or minimum concentration and gestational age or body weight. CONCLUSION: Conclusions: 1. The dosage of gentamicin in newborns according to the Neofax® recommendations does not ensure achieving the intended serum antibiotic concentrations. 2. In order to optimize gentamicin therapy in newborns it is necessary to individualize the dose based on measurements of drug concentrations in the blood and pharmacokinetic calculations.

Pharmacokinetics of free and total mycophenolic acid in adult lupus nephritis patients-implications for therapeutic drug monitoring.

PURPOSE: To evaluate the relationship between total and free MPA pharmacokinetic (PK) parameters and renal outcome markers, and to verify whether conducting therapeutic drug monitoring (TDM) in lupus nephritis (LN) patients would be of value in routine clinical practice. METHODS: Eighty-four samples were collected from sixteen LN patients. Total and free MPA concentrations were measured at predose, 0.5 and 2 h after mycophenolate mofetil (MMF) intake. Area under the concentration time curve from 0 to 2 h (AUC0-2) and free fraction were calculated. RESULTS: High between-patient variability was observed (CV% of 53.5% for dose-normalized total MPA AUC0-2). A significant but weak correlation between dose-normalized total C0 and AUC0-2 was noted (r = 0.5699). Dose-normalized total C0 above 2.76 µg/mL·g may indicate patients with eGFR < 81 mL/min with sensitivity of 83.3% and specificity of 75.0%. Hypoalbuminemic LN patients demonstrated significantly elevated MPA free fraction when compared with patients with serum albumin concentration ≥ 3.5 g/dL (1.49 ± 0.64% vs 1.08 ± 0.75%). CONCLUSION: This study examined relationship between free and total pharmacokinetic MPA parameters as well as the effect of hypoalbuminemia on MPA plasma protein binding in adult LN patients. The study results suggest that TDM of MPA in LN seems to be a more reasonable approach than the fixed-dose protocol. Moreover, predose total MPA concentration may be a possible estimation of MPA exposure, while monitoring free rather than total MPA may be more beneficial in hypoalbuminemic patients.

CYP2D6 basic genotyping as a potential tool to improve the antiemetic efficacy of ondansetron in prophylaxis of postoperative nausea and vomiting.

BACKGROUND: Postoperative nausea and vomiting (PONV) is a common complication after anesthesia and surgery. Ondansetron is one of the most widely used drugs in the prophylaxis of PONV and is extensively metabolized in humans. In vitro metabolism studies have shown that ondansetron is a substrate for human hepatic cytochrome P450 enzymes. The cytochrome P450 (human hepatic cytochrome [CYP]) 2D6 inhibitor quinidine reduced in vitro hydroxylation of ondansetron, which indicates the important role of CYP2D6 in ondansetron metabolism. Genotyping these alleles allows the prediction of the extensive metabolizer (EM) and poor metabolizer (PM) phenotypes with approx. 90-96% accuracy. OBJECTIVES: The aim of our study was to evaluate whether the pharmacological prevention of PONV with ondansetron depends on the most common CYP2D6 alleles (CYP2D6*1, *3, *4, *5, and NxN [multiplication gene]). MATERIAL AND METHODS: Genotyping for the defective CYP2D6*3, CYP2D6*4 and CYP2D6*5 alleles among 93 surgical female patients was performed by polymerase chain reaction amplification and restriction fragment length polymorphism (PCR-RFLP). RESULTS: The genetically defined EMs and ultrarapid metabolizers (UMs) of CYP2D6 had a statistically significant (p < 0.02) higher frequency of nausea and vomiting after strumectomy (33.3%) than intermediate metabolizers (IMs) (10.3%) and PMs (0%). The relative risk (odds ratio [OR]) of PONV occurrence was 5 times higher for EMs/UMs than IMs/PMs. CONCLUSIONS: Our results suggest that PONV treatment with ondansetron could be improved by basic, widely available and inexpensive PCR-RFLP genetic tests.

Frequency of isolation and drug susceptibility of bacterial strains isolated from child oncohematological patients 2011-2014: A single center study.

BACKGROUND: Infections in pediatric patients with oncohematological diseases pose a huge therapeutic and diagnostic problem. OBJECTIVES: The aim of the study was to investigate the etiology of bacteremia and the antibiotic susceptibility of pathogenic and colonizing bacterial strains in pediatric oncohematological patients. MATERIAL AND METHODS: In the period 2011-2014, 17,209 positive test results, including 1,129 positive blood cultures, were subjected to a detailed analysis. The assessment of drug susceptibility was conducted in accordance with the CLSI (American), EUCAST (European), and KORLD (Polish) recommendations. RESULTS: A high percentage (86-91%) of negative blood culture results was demonstrated. A predominance of Gram-positive bacteria was seen in all years (60-70%) in contrast to Gram-negative strains (30-40%). Coagulase-negative staphylococci (CNS) were the strains most frequently isolated from blood (41-47%) among all bacterial strains. Susceptibility to linezolid and vancomycin was 96-100%, and to teicoplanin 82-96%. Methicyllin-resistant coagulase-negative Staphylococcus (MRCNS) were isolated in 77-86%. All Staphylococcus aureus (S. aureus) strains were susceptible to glycopeptides and linezolid, while Enterococcus spp. was susceptible to linezolid. Apart from the year 2014, no methicillin-resistant S. aureus (MRSA) were isolated. Enterobacteriaceae (EN) were the most susceptible to imipenem and meropenem (91-100%) as well as to amikacin (77-93%). From 2013 to 2014, non-fermentative rods (NF) isolated from blood were less susceptible to imipenem and meropenem (71% and 67-71%, respectively) than to other antibiotics. It has been shown that strains isolated from blood have a statistically significantly different susceptibility to antibiotics (CNS and EN are less and NF is more susceptible) than those existing as colonizing flora. CONCLUSIONS: Our results show that choosing appropriate antibiotics for treating infection in children with oncohematological diseases based on antibiograms for colonizing flora may be difficult because they may not take into account the more resistant strains. According to the antibiotic susceptibility of the strains isolated from blood in our center, the most viable active empirical and carbapenem-saving therapy could be conducted with piperacillin/tazobactam or cefepime.

Influence of CYP2C19 Genotypes on the Occurrence of Adverse Drug Reactions of Voriconazole among Hematological Patients after Allo-HSCT.

The aim of this study was to determine the influence of different CYP2C19 genotypes on selected liver function parameters, and ADR occurrence during VCZ prophylaxis in adult patients after allo-HSCT (allogeneic hematopoietic stem cell transplantation). CYP2C19 mutations were determined in a cohort of 30 adults using PCR-RFLP methods established by Sim et al. and Goldstein and Blaisdell. The patients' protocol included biometrical and biochemical data, information on the underlying disease, chemotherapy, molds infections occurring during VCZ treatment, adverse drug reactions typical for the use of voriconazole, and probable drug - drug interactions. The observation and reporting of ADR took place from the -1 until the +20th day of VCZ therapy. For statistical analysis the χ2 test was used (p < 0.05). Among the examined patients 23 suffered from at least one side effect during VCZ therapy. Most frequent ADR were gastrointestinal disturbances (n = 15), nervous system (n = 11) and skin (n = 7) disorders. Patients with at least one loss of function allele (*2) were more likely to experience adverse drug reactions than those, with different genotypes. Due to the limited number of patients the result could not be proven with a statistical significance. Previous determination of CYP2C19 genotype may be a useful tool for prevention of adverse drug reactions during VCZ prophylaxis among patients after allo-HSCT.

[Measurements of vancomycin concentrations in the blood - a method of personalization the antibiotic therapy in patients with chronic kidney disease]. / Pomiary stezen wankomycyny we krwi ­ metoda personalizacji antybiotykoterapii u chorych na przewlekla chorobe nerek.

Therapeutic Drug Monitoring is a recognized method of personalizing treatment, having particular application in patients with chronic kidney disease who have frequent infections, requiring administration of vancomycin. International guidelines indicate the need to adjust the dose of the drug to the state of renal function. The recommended therapeutic ranges of minimum and maximum levels should be achieved in order to increase the effectiveness and safety of treatment. AIM: The aim of this study was to evaluate the usefulness of measuring the concentration of vancomycin in patients with chronic kidney disease due to bacterial infection. MATERIALS AND METHODS: The study included 96 adult patients with chronic kidney disease of varying severity treated with vancomycin Patients were divided into 3 groups: treated by haemodialysis (hd), after renal transplantations (ktx), do not require renal replacement therapy (nef). In subjects were examined the minimum and maximum concentrations of vancomycin in steady-state and were compared with recommended therapeutic ranges. RESULTS: Statistically significant decrease of inflammatory markers was observed only in patients treated with dialysis. In the other groups not significant changes in values of inflammatory parameters were confirmed. Trough concentrations of vancomycin marked in patients were consistent with the recommendation of EUCAST, but exceeded the value recommended by the manufacturers of the drug. Considering absolute values of the minimum concentrations, only about 50% of patients achieved the therapeutic range (58% for recommendation EUCAST and 36% for the manufacturer's instructions). Peak concentration values indicated in dialyzed patients were below the prescribed range of 20-50 mg/l and averaged 17.7 mg / l. In the other subgroups they were correct. The rating of the absolute values of the peak concentrations of vancomycin also showed that only 46% (64% in the ktx, 30% - hd and 53% - nef) was within the recommended range, while 50% were classified as concentrations of sub-therapeutic (36% in the ktx, 42% of the nef group and 65% in hd). CONCLUSIONS: Vancomycin concentrations measured in patients with chronic kidney disease, both minimum and maximum, were not fully comply with the recommended therapeutic ranges, despite the use of doses determined based on a calculation of glomerular filtration rate. This points to the need for particularly careful monitoring of therapy and analysis of antibiotic concentrations to improve the effectiveness and reduce the incidence of undesirable consequences of treatment.

Continuous vs. intermittent vancomycin therapy for Gram-positive infections not caused by methicillin-resistant Staphylococcus aureus.

BACKGROUND: The aim of this study was to evaluate the effects of vancomycin pharmacokinetics (PKs) on effectiveness and safety in the treatment of Gram-positive infections due to pathogens other than methicillin-resistant Staphylococcus aureus (MRSA). METHODS: Prospective study including septic patients received either continuous (N.=21) or intermittent (N.=21) infusions of vancomycin; the target drug concentration was 15-20 mg/L and target area under the curve of vancomycin concentrations over the minimum inhibitory concentration of the pathogen on day 1 (AUC24/MIC) >400. Clinical and microbiological responses, the development of acute kidney injury (AKI) and therapy costs were recorded. RESULTS: The median AUC24/MIC was 195(133-343) vs. 189(136-328) mg/L*h in the continuous and intermittent infusion groups. Target drug concentrations were achieved in 15/21 vs. 9/21 (P=0.12) patients and AUC24/MIC>400 in only 5/21 vs. 3/21 (P=0.35) patients of continuous and intermittent groups, respectively. High clinical cure (17/21 for continuous vs. 17/21 for intermittent, P=1.00) and microbiological eradication (17/21 vs. 15/21, P=0.47) were observed in both groups and not associated with drug concentrations or with AUC24/MIC. AKI was diagnosed during therapy in 5/21 patients in the continuous group and 8/21 in the intermittent group (P=0.32). The median total therapy costs were lower in the continuous than in the intermittent group (377 [304-485] vs. 552 [371-644] €, P=0.04). CONCLUSIONS: Vancomycin resulted in high clinical response during non-MRSA Gram-positive infections treatment even at drug concentrations lower than those for MRSA. A continuous infusion of vancomycin was associated with a significant reduction in therapy costs compared to intermittent infusions.

Genetic polymorphism of ABCB1 gene (C3435T) in patients with inflammatory bowel diseases. Is there any gender dependency?

BACKGROUND: In recent years, an increasing incidence of inflammatory bowel disease (IBD) has been reported, mainly as Crohn's disease (CD) and ulcerative colitis (UC). The individual susceptibility, the disease's course and response to the applied therapy is likely due to genetic factors such as ABCB1 gene mutations, exemplified by C3435T polymorphism. The aim of the study was to evaluate the distribution of C3435T polymorphism regarding the gender in IBD patients and control subjects from Lower Silesia region and its possible association with IBD susceptibility. METHODS: The research was conducted in groups of 61 IBD patients and 101 healthy subjects from the Lower Silesia region. Polymorphism of C3435T was determined using PCR-RFLP method. RESULTS: Frequency distributions of C3435T genotype and of 3435T or 3435C gene alleles of IBD, CD or UC patients were compared to control group; each treated as a whole or split further by gender. The statistically significant correlation was discovered between gender and C3435T genotype both for IBD and CD patients, with 3435CT heterozygote prevailing in IBD and CD males. Odds ratio calculations revealed statistically significant difference for the 3435CT genotype between control and: IBD group considered as a whole; IBD males; CD males; and for 3435TT variant between control and IBD males. Conclusions. The 3435CT genotype could be a risk factor for IBD and CD in men. The 3435TT genotype in males seems to be associated with the lower chance of IBD presence.

[Welfare as the goal of the analgesic pharmacotherapy accompanying biological treatment in patients with rheumatoid arthritis and ankylosing spondylitis]. / Dobrostan jako cel dzialania farmakoterapii przeciwbólowej towarzyszacej leczeniu biologicznemu u chorych na reumatoidalne zapalenie stawów oraz zesztywniajace zapalenie stawów kregoslupa.

Therapy of chronic rheumatic diseases, such as rheumatoid arthritis (RA) and ankylosing spondylitis (AS) needs a comprehensive approach to the patient, based on the control of pain and improvement in overall condition, which affects the quality-of-life. This requires optimizing the treatment with non-steroidal anti-inflammatory drugs (NSAIDs) or analgesics and control of adverse drug reactions. The aim of the study was to evaluate the efficacy and safety of pain pharmacotherapy in patients with rheumatoid arthritis and ankylosing spondylitis treated as the basic pharmacotherapy-biological drugs, the analysis of awareness of pharmacovigilance and evaluation of analgesic treatment costs. Material and methods. Examined group consisted of 102 people with RA or AS received biological therapy. Test method was questionnaire with closed and open questions. Results. 86.2% of respondents used a pain medication (41%--an ad hoc basis, but 23%--at least once a day), while 79.4%--NSAIDs (33%--an ad hoc basis and 17%--at least once a day). In 85.3% of those not observed adverse effects of pain pharmacotherapy. 5 persons declared abdominal pain. Most of the patients complied with the recommendations of the doctor in the pain treatment. For the third respondents the cost of pharmacotherapy of pain was monthly 1-10 zl, but 6% of patients paying for drugs from 50-60 and above 60 zl monthly. Conclusions. Biological treatment in RA and AS is effective but requires additional analgesic therapy. Adverse effects seen during pharmacological treatment of chronic pain in rheumatic diseases are, in practice sporadic. Therapeutic patient education with chronic diseases is proper. Costs borne by the patient's pain relief in this group are not too high.

Therapeutic drug monitoring of amikacin in septic patients.

INTRODUCTION: Use of higher than standard doses of amikacin (AMK) has been proposed during sepsis, especially to treat less susceptible bacterial strains. However, few data are available on drug concentrations during prolonged therapy and on potential adverse events related to this strategy. METHODS: Sixty-three critically ill patients who required AMK administration for the treatment of severe infection were included in this study. After a loading dose (LD, 18 to 30 mg/kg), the daily regimen was adapted using therapeutic drug monitoring (TDM) of both peak (Cpeak) and trough (Cmin) concentrations. Target concentrations had to give a ratio of at least 8 between Cpeak and the minimal inhibitory concentration (MIC) of the isolated pathogen. A Cmin >5 mg/L was considered as potentially nephrotoxic. We recorded clinical and microbiological responses, the development of acute kidney injury (AKI) during therapy and ICU mortality. RESULTS: The median AMK LD was 1500 (750 to 2400) mg, which resulted in a Cpeak/MIC ≥8 in 40 (63%) patients. Increasing the dose in the 23 patients with a Cpeak/MIC <8 resulted in optimal Cpeak/MIC in 15 of these patients (79%). In 23 patients (37%), Cmin was >5 mg/L after the LD, notably in the presence of altered renal function at the onset of therapy, needing prolongation of drug administration. Overall, only 11 patients (17%) required no dose or interval adjustment during AMK therapy. Clinical cure (32/37 (86%) vs. 16/23 (70%), P = 0.18)) and microbiological eradication (29/35 (83%) vs. 14/23 (61%), P = 0.07) were higher in patients with an initial optimal Cpeak/MIC than in the other patients. The proportion of patients with clinical cure significantly improved as the Cpeak/MIC increased (P = 0.006). Also, increased time to optimal Cpeak was associated with worse microbiological and clinical results. AKI was identified in 15 patients (24%) during AMK therapy; 12 of these patients already had altered renal function before drug administration. Survivors (n = 47) had similar initial Cpeak/MIC ratios but lower Cmin values compared to nonsurvivors. CONCLUSIONS: TDM resulted in adjustment of AMK therapy in most of our septic patients. Early achievement of an optimal Cpeak/MIC ratio may have an impact on clinical and microbiological responses, but not on outcome. In patients with impaired renal function prior to treatment, AMK therapy may be associated with a further decline in renal function.

Continuous infusion of piperacillin/tazobactam in ventilator-associated pneumonia: a pilot study on efficacy and costs.

Ventilator-associated pneumonia (VAP) occurs in nearly one-third of mechanically ventilated patients in the Intensive Care Unit. Piperacillin/tazobactam (TZP) is currently recommended in the empirical treatment of VAP, but intermittent dosing may result in inadequate serum concentrations. The efficacy and costs of continuous infusion (CI) of TZP, using therapeutic drug monitoring for real-time dose adjustment, was assessed in a prospective pilot study of 16 patients with VAP. TZP was given as a loading dose of 2.0/0.25 g followed by a CI of 10.0/1.25g daily. Rapid antimicrobial susceptibility testing was used to determine the minimum inhibitory concentration (MIC) of the pathogens. TZP concentrations were determined by high-pressure liquid chromatography before and at 1, 6, 12, 24, 48, 72 and 96 h after the onset of administration. Dosages were adjusted to maintain piperacillin concentrations four-fold above the MIC (T>4 × MIC) of the pathogen, with a maximum dose of 16.0/2.0 g. The cost of the total TZP administered was compared with the cost of a standard TZP regimen (16.0/2.0 g) if given over the same period of time. The median MIC for TZP was 1 µg/mL (range 0.025-32 µg/mL). TZP concentrations were adequate for 71% of pathogens on the first day of therapy. Clinical cure was achieved in 9/10 patients who had adequate drug concentrations and in 3/6 patients with insufficient levels. The daily dose of TZP received by CI was 37.5% less than that of a standard regimen, which corresponds to a saving of €15 on daily therapy costs compared with the standard regimen. In conclusion, CI of TZP achieved optimal drug concentrations in most patients with VAP, with a favourable impact on costs. Adequate drug concentrations were achieved for MIC ≤ 4 µg/mL, but higher dosages should be considered for the treatment of pathogens with low susceptibility thresholds.