[Therapeutic drug monitoring of beta-lactam antibiotics].

Therapeutic drug monitoring (TDM) is a dosage individualization strategy that helps to minimize toxicity whilst maximizing the efficacy of an agent. For many years, beta-lactam antibiotics were not considered ideal candidates for TDM due to their wide therapeutic range. Profound and difficult to predict beta-lactam pharmacokinetic variability in specific patient populations and increasing bacterial resistance suggest that reaching optimal exposures can be challenging in some clinical settings. The aims are to review the role of beta-lactam TDM, identify patients that would most likely benefit from it, summarize methods used to measure beta-lactam concentrations and outline their limitations, discuss the concentration-effect relationship and therapeutic targets and finally describe dosage adjustment strategies.

Is continuous infusion of imipenem always the best choice?

Monte Carlo simulations allow prediction and comparison of concentration-time profiles arising from different dosing regimens in a defined population, provided a population pharmacokinetic model has been established. The aims of this study were to evaluate the population pharmacokinetics of imipenem in critically ill patients with hospital-acquired pneumonia (HAP) and to assess the probability of target attainment (PTA) and cumulative fraction of response (CFR) using EUCAST data. A two-compartment model based on a data set of 19 subjects was employed. Various dosage regimens at 0.5-h and 3-h infusion rates and as continuous infusion were evaluated against the pharmacodynamic targets of 20%fT>MIC, 40%fT>MIC and 100%fT>MIC. For the target of 40%fT>MIC, all 0.5-h infusion regimens achieved optimal exposures (CFR ≥ 90%) against Escherichia coli and Staphylococcus aureus, with nearly optimal exposure against Klebsiella pneumoniae (CFR ≥ 89.4%). The 3-h infusions and continuous infusion exceeded 97% CFR against all pathogens with the exception of Pseudomonas aeruginosa and Acinetobacter spp., where the maximum CFRs were 85.5% and 88.4%, respectively. For the 100%fT>MIC target, only continuous infusion was associated with nearly optimal exposures. Higher PTAs for the targets of 40%fT>MIC and 100%fT>MIC were achieved with 3-h infusions and continuous infusion in comparison with 0.5-h infusions; however, continuous infusion carries a risk of not reaching the MIC of less susceptible pathogens in a higher proportion of patients. In critically ill patients with HAP with risk factors for Gram-negative non-fermenting bacteria, maximum doses administered as extended infusions may be necessary.

Pharmacokinetics of imipenem in critically ill patients during empirical treatment of nosocomial pneumonia: a comparison of 0.5-h and 3-h infusions.

In critically ill patients, pathophysiological changes alter the pharmacokinetics of antibiotics. Imipenem exhibits primarily time-dependent killing. Its administration by prolonged infusion may increase the time for which its plasma concentration exceeds the minimum inhibitory concentrations (MICs) of suspected pathogens. The objectives of this study were to compare the pharmacokinetic parameters of imipenem administered by standard short infusion (1g imipenem/1g cilastatin over 30min three times daily) and by extended infusion with a reduced total dose (0.5g imipenem/0.5g cilastatin over 3h four times daily) and to compare the target pharmacokinetic/pharmacodynamic indices, namely percentage of the dosing interval for which the free plasma concentration of imipenem exceeds the MIC and 4× MIC (%fT>MIC and %fT>4×MIC) of 0.5, 1, 2 and 4mg/L, for these two regimens in critically ill adult patients with nosocomial pneumonia on Day 2 of empirical antibiotic therapy. The study included 22 patients. Whilst no significant differences were found between both groups for %fT>MIC, %fT>4×MIC was 87.4±12.19%, 68.6±15.08%, 47.31±6.64% and 27.81±9.52% of the 8-h interval in the short infusion group for MICs of 0.5, 1, 2 and 4mg/L, respectively, and 85.15±17.57%, 53.14±27.27%, 13.55±24.47% and 0±0% of the 6-h interval for the extended infusion group. In conclusion, administration of 0.5g of imipenem by a 3-h infusion every 6h does not provide sufficient drug concentrations to treat infections caused by pathogens with a MIC of ≥2mg/L.

Antibiotic consumption and its influence on the resistance in Enterobacteriaceae.

BACKGROUND: Increasing bacterial resistance to antibiotics is one of the most serious problems in current medicine. An important factor contributing to the growing prevalence of multiresistant bacteria is application of antibiotics. This study aimed at analyzing the development of resistance of Enterobacteriaceae to selected beta-lactam, fluoroquinolone and aminoglycoside antibiotics in the University Hospital Olomouc and assessing the effect of selection pressure of these antibiotics. METHODS: For the period between 1 January 2000 and 31 December 2011, resistance of Klebsiella pneumoniae, Escherichia coli, Enterobacter cloacae and Proteus mirabilis to third- and fourth-generation cephalosporins, meropenem, piperacillin/tazobactam, fluoroquinolones and aminoglycosides was retrospectively studied. For the assessment of selection pressure of antibiotics, a parameter of defined daily dose in absolute annual consumption (DDDatb) based on the ATC/DDD classification and in relative annual consumption (RDDDatb) as the number of defined daily doses per 100 bed-days was used. The relationship between frequency of strains resistant to a particular antibiotic and antibiotic consumption was assessed by linear regression analysis using Spearman's correlation. The level of statistical significance was set at p < 0.05. RESULTS: A total of 113,027 isolates from the Enterobacteriaceae family were analyzed. There was a significant effect of selection pressure of the primary antibiotic in the following cases: piperacillin/tazobactam in Klebsiella pneumoniae, gentamicin in Klebsiella pneumoniae and Escherichia coli and amikacin in Escherichia coli and Enterobacter cloacae. Also, there was significant correlation between resistance to ceftazidime and consumption of piperacillin/tazobactam in Klebsiella pneumoniae and Escherichia coli. No relationship was found between consumption of third- and fourth-generation cephalosporins and resistance to ceftazidime or between fluoroquinolone consumption and resistance to ciprofloxacin. CONCLUSION: The study showed the effects of both direct and indirect selection pressure on increasing resistance to gentamicin, amikacin, piperacillin/tazobactam and ceftazidime. Given the fact that no correlation was found between resistance to fluoroquinolones and consumption of either primary or secondary antibiotics, we assume that the increasing resistance to fluoroquinolones is probably due to circulation of resistance genes in the bacterial population and that this resistance was not affected by reduced use of these antibiotics.

[Effect of colistin consumption and prevalence of colistin-resistant bacteria]. / Vliv spotreby kolistinu na vyskyt kolistin-rezistentnich bakterii.

OBJECTIVE: Recently, there has been a renaissance of the use of the antibiotic colistin resulting from increasing resistance of bacterial pathogens, particularly in intensive care patients. The study aimed at assessing the impact of colistin consumption on the prevalence of colistin-resistant bacteria in the University Hospital Olomouc (UHO). METHODS: A laboratory database was retrospectively searched to identify all clinically significant colistin-resistant bacterial strains isolated between 2007 and 2011. These data were compared with colistin consumption over the same period and the results were statistically processed. RESULTS: Over the study period, a total of 6 338 clinically significant colistin-resistant strains were detected in the UHO (Acinetobacter spp., Burkholderia cepacia complex, Citrobacter spp., Enterobacter spp., Escherichia coli, Klebsiella spp., Morganella morganii, Proteus spp., Providencia spp., Pseudomonas spp., Serratia marcesces and Stenotrophomonas maltophilia). Over the same period, the consumption of colistin increased nearly 10-fold. With the increasing colistin consumption, the numbers of colistin-resistant strains of Pseudomonas aeruginosa and Acinetobacter spp. decreased over that period of time. By contrast, there was an increase in the rates of naturally Burkholderia cepacia complex strains naturally resistant to colistin. An alarming finding is that the prevalence of colistin-resistant strains of Klebsiella pneumoniae increased in the last years of the study period, especially in intensive care patients. CONCLUSIONS: In the UHO, higher consumption of colistin was accompanied by increased numbers of colistin-resistant strains. There was a marked increase of Burkholderia cepacia complex strains and, recently, a statistically insignificant but alarming increase in colistin-resistant Klebsiella pneumoniae strains.

[Influence of carbapenem selection pressure on bacterial resistance]. / Vliv selekcního tlaku karbapenemu na bakteriální rezistenci.

As a result of high resistance of bacterial pathogens to broad-spectrum penicillins and cephalosporins, carbapenems have been increa-singly used recently. The presented study aimed at analyzing the association between carbapenem consumption and resistance of selected Gramnegative pathogens to meropenem. Using linear regression analysis, a statistically significant association was found between carbapenem consumption and resistance of Pseudomonas aeruginosa.

[Pharmacological characteristics of ertapenem]. / Farmakologické vlastnosti ertapenemu.

Ertapenem is a broad-spectrum bactericidal carbapenem antibiotic. It differs from the other substances of this group by the absence of action against Gram-negative non-fermenting bacilli and by a long elimination half-life, which allows once-daily administration. It is administered once daily in a dose of 1 gram intravenously. Ertapenem is generally well-tolerated, with the most common side effects being diarrhea and phlebitis at the injection site. It is used for the treatment of community-acquired pneumonia, intra-abdominal and gynecological infections, and skin and soft tissue infections, including diabetic foot.