Magdalena Hurkacz

Therapeutic drug monitoring of amikacin in septic patients.

IntroductionUse 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.MethodsSixty-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.ResultsThe 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 >5mg/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.ConclusionsTDM 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.

CYP2D6 extensive, intermediate, and poor phenotypes and genotypes in a Polish population

Abstract Objective. This study investigated the distribution of the CYP2D6 genotypes and phenotypes in a Polish population and compared the concordance of the two methods. Methods. Six hundred unrelated healthy individuals from southwestern Poland were studied. The CYP2D6 phenotype was analyzed in 300 individuals using sparteine as a model drug. The CYP2D6 genotype was analyzed in 300 individuals by polymerase chain reaction amplification and restriction fragment length polymorphism techniques for the CYP2D6*1, CYP2D6*3, and CYP2D6*4 alleles. Additionally, in 60 randomly selected healthy individuals both the CYP2D6 phenotype and genotype was assessed to determine accordance between the methods. Results. Of 300 participants in the study 25 (8.3%) were classified as poor metabolizers, 44 (14.7%) as intermediate metabolizers, and 231 (77%) as extensive metabolizers of sparteine. The frequency of CYP2D6*1, CYP2D6*3, and CYP2D6*4 alleles among the genotyped 300 persons was 75.7%, 1.3%, and 23.0%, respectively. The frequency of CYP2D6 deficient genotypes in a Polish population (8.0%) was similar to phenotyping results. The comparison of phenotype and genotype in 60 randomly selected individuals showed a good concordance of the obtained results. Conclusions. The frequencies of poor metabolizers for CYP2D6 phenotype (8.3%) and genotype (8.0%) in a Polish population from the southwestern region are in concordance and compare well with most results of poor oxidation metabolizers in other white populations.

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.

Optimization of lidocaine application in tumescent local anesthesia

Tumescent local anesthesia is based upon the infusion of large volumes of neutralized anesthetic solutions, mainly lidocaine, at very low concentrations. This results in the paralysis of sensory nerve endings and minute nerve twigs, leading to a reduction in pain. The aim of this study was to assess the safety of lidocaine application in tumescent local anesthesia on different regions of patients bodies. Measures of safety included the analysis of lidocaine concentrations and its pharmacokinetic parameters. In total, 48 patients were infused with tumescent anesthesia in the hypogastrium, buttocks and thighs, axillae, breasts, trunk, and face and neck areas. Lidocaine was infused in doses ranging from 5.2-40 mg/kg b.w., and in concentrations of 0.05% (hypogastrium, buttocks, thighs) or 0.1-0.15% (axillae, breasts, trunk, face, neck), using a total amount of 300-3200 mg. As the peak lidocaine concentration did not exceed 5 microg/ml (commonly known as the toxic threshold), the results of our study indicate that the doses used (not exceeding 40 mg/kg b.w.) are completely safe for patients undergoing tumescent anesthesia in different body areas. The observation of statistically significant correlations between both the dose and the total amount of lidocaine administered and its peak plasma concentration, together with the lack of correlations between the dose and the amount and the time taken to reach peak concentration, allows the safety of each anesthetic dose to be predicted. An analysis of the heterogeneous dynamics of lidocaine plasma concentration changes in tumescent anesthesia in different body areas indicates that both the rates and the degrees of absorption and elimination depend on the area of infiltration; this is in turn related to the vascularization of any given area. The study of lidocaine concentration and pharmacokinetic parameters also showed that there may potentially be a higher risk of a large anesthetic concentration developing within a short period of time during anesthesia of the upper parts of the body. During tumescent anesthesia, significantly higher plasma concentrations of lidocaine were observed in the face and neck than in the hypogastrium, buttocks and thighs, axillae, breast and trunk 0.5 to 4 h after its infusion. This indicates the need for carefully conducted patient observations immediately after infiltration into the aforementioned areas.

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 Crohns disease (CD) and ulcerative colitis (UC). The individual susceptibility, the diseases 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.

CYP2D6 basic genotyping as a potential tool to improve 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 isolatedfrom 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.