Acute drug intoxication in childhood: a 10-year retrospective observational single-centre study and case reports.

BACKGROUND: Medication poisoning in children is a severe condition that can endanger a child's life. Although drug intoxications are easily preventable, awareness of the proper handling of drugs and their safe storage out of the reach of children is not widespread among the general public. In this work, we investigated the demographic and clinical data of children admitted to the Department of Pediatrics of the University Hospital Olomouc for acute drug-induced intoxication. We also selected several case reports to illustrate the wide range of both presentations and outcomes in individual patients. METHOD: Cases of drug-induced intoxications were selected from a group of patients under the age of 19 years admitted to the hospital for poisoning between January 1, 2010, and December 31, 2019. Medical records of these patients were prospectively evaluated, and overview tables and graphs of predefined research objectives were created. RESULTS: During the given time period, 162 children with suspected drug intoxications were hospitalized at the Department of Pediatrics, University Hospital Olomouc. Of these, 108 cases were reported in girls and 54 in boys (66.7% vs. 33.3%). In 16 cases (9.9%), there was a severe intoxication requiring follow-up intensive care. There was also one case of fatal accidental intoxication. Most poisonings were seen in toddlers (65; 40.1%). Intoxication with suicidal ideation was found in 44 cases (27.2%), with a higher incidence of suicide attempts in girls (40 vs. 4). Repeated intoxication was recorded in nine cases. Analgesics were the most common drug group (61; 37.7%), with paracetamol (28; 17.3%) being the leading drug. In 154 cases (95.1%), the drugs were taken orally, most often in the form of tablets. CONCLUSION: Accidental drug intoxications most frequently occurred in the age group from one to three years old. The second highest incidence was among adolescents most of which were suicide attempts. Analgesics and psychoactive agents accounted for the majority of cases. Medications should be kept in places where children cannot reach them.

Changes of colistin pharmacokinetics in critically ill patients due to the extracorporeal membrane oxygenation: protocol for the COL-ECMO2022 trial - a prospective, non-randomised, open-label phase IV pharmacokinetic clinical trial.

INTRODUCTION: Colistin is a lipopeptide antibiotic administered as an inactive prodrug-colistin methanesulfonate (CMS). Colistin is a drug with a narrow therapeutic window; the limiting factors are mainly nephrotoxicity and neurotoxicity, dependent on plasma concentrations. The number of patients with infections caused by multidrug-resistant Gram-negative bacteria sensitive only to colistin and the number of patients requiring extracorporeal membrane oxygenation (ECMO) support for severe respiratory failure increased significantly in association with COVID-19-induced infections. ECMO can generally affect the pharmacokinetics of drugs by creating a new compartment. METHODS AND ANALYSIS: The COL-ECMO2022 study is a prospective, non-randomised, single-centre, phase IV pharmacokinetic clinical trial designed to assess the influence of ECMO on the pharmacokinetics of colistin and CMS. Up to 30 patients treated with colistin will be included in the study and assigned to one of two arms, depending on the presence/absence of ECMO. All study participants will receive standard CMS dose intravenously. The plasma concentrations of colistin and CMS taken at defined intervals will be assessed by high-performance liquid chromatography-mass spectrometry. Patients will participate in the clinical trial for a maximum of three monitored dosing intervals. A population pharmacokinetic model will be developed to assess the influence of ECMO on pharmacokinetics. A difference greater than 25% is considered clinically significant. ETHICS AND DISSEMINATION: The study has been approved by the Ethics Committee of St. Anne's University Hospital Brno (Number 10ML/2022-AM). Related manuscripts will be submitted to peer-review journals. TRIAL REGISTRATION NUMBERS: EudraCT Number 2022-000291-19; NCT05542446.

Challenges of Colistin Use in ICU and Therapeutic Drug Monitoring: A Literature Review.

The emerging resistance of Gram-negative bacteria is a growing problem worldwide. Together with the financial cost, limited efficacy, and local unavailability of newer antibiotics or their combinations, it has led to the reintroduction of colistin as a therapeutic alternative. Despite its protracted development and availability on the market, there is now a complex maze of questions surrounding colistin with a more or less straightforward relationship to its safety and efficacy. This review aims to offer a way to navigate this maze. We focus on summarizing the available literature regarding the use of colistin in critically ill patients, particularly on stability, pharmacokinetics, methods for determining plasma concentrations, and therapeutic drug monitoring benefits and limitations. Based on these data, we then highlight the main gaps in the available information and help define directions for future research on this drug. The first gap is the lack of data on the stability of intravenous and nebulization solutions at clinically relevant concentrations and under external conditions corresponding to clinical practice. Furthermore, pharmacokinetic-pharmacodynamic parameters should be validated using standardized dosing, including a loading dose. Based on the pharmacokinetic data obtained, a population model for critically ill patients should be developed. Finally, the interference of colistin with extracorporeal methods should be quantified.

Population pharmacokinetic model-based dosing proposal for ampicillin prophylaxis in cardiac surgery patients with cardiopulmonary bypass.

The aim of this study was to describe and quantify pharmacokinetics of ampicillin used prophylactically in cardiac surgery both with and without cardiopulmonary bypass (CPB) using population pharmacokinetic analysis in order to propose an optimal dosing strategy. Adult patients undergoing cardiac surgery and treated with prophylactic dose of 2 g ampicillin were enrolled to this prospective study. Blood samples were collected according to the study protocol and ampicillin plasma concentrations were measured using HPLC/UV system. A three-stage population pharmacokinetic model using nonlinear mixed-effects modelling approach was developed. Totally 273 blood samples obtained from 20 patients undergoing cardiac surgery with the use of the CPB and 20 patients without CPB use were analyzed. Two-comparmental model best fits ampicillin concentration-time data. Mean ± SD body weight-normalized ampicillin central and peripheral volume of distribution was 0.12 ± 0.02 L/kg and 0.15 ± 0.03 L/kg, respectively, while mean ± SD ampicillin clearance in typical patient with eGFR of 1.5 mL/s/1.73 m2 was 1.17 ± 0.05 L/h. The use of CPB did not significantly affect the pharmacokinetics of ampicillin. When administering 2 g of ampicillin before surgery, an additional dose should be administered to reach the PK/PD target of fT > MIC = 50% if the operation lasts longer than 430 min in patients with moderate to severe renal impairment, 320 min in patients with mild renal impairment, 220 min in patients with normal renal function status or 140 min in patients with an augmented renal clearance.

Population pharmacokinetics of three alternative prophylactic antibiotics during cardiac surgery with extracorporeal circulation.

AIMS: The aim of this pharmacokinetic study was to describe and quantify population pharmacokinetics of three antibiotics, cefazolin, ampicillin, and ciprofloxacin, used as antibacterial prophylaxis during cardiovascular surgery with the use of extracorporeal circulation (ECC). METHODS: Adult patients undergoing cardiac surgery with ECC were enrolled to this prospective, pharmacokinetic study. An intravenous bolus of 2 g of ampicillin, 2 g of cefazolin or 400 mg of ciprofloxacin was administered 60-30 min before surgery. Blood samples were collected at 15, 30, 45, 60, 120 and 180 min after the administration and at the end of the surgery. Plasma concentrations of the antibiotics were measured using HPLC methods. Serum concentration-time profiles were analyzed using nonlinear mixed-effects modeling approach. RESULTS: A total of 54 patients were enrolled into the study, 20 with ampicillin, 25 cefazolin and 9 ciprofloxacin. For all antibiotics, population pharmacokinetic models have been successfully developed. CONCLUSION: We identified estimated glomerular filtration rate (eGFR) as the main factor determining the achievement of the pharmacokinetic/pharmacodynamic (PK/PD) target in ampicillin or cefazolin and body weight in ciprofloxacin prophylaxis during cardiac surgery with ECC support.

Population Pharmacokinetics of Prophylactic Cefazolin in Cardiac Surgery with Standard and Minimally Invasive Extracorporeal Circulation.

The objectives of this study were to develop a population pharmacokinetic model of prophylactically administered cefazolin in patients undergoing cardiac surgery with and without the use of the cardiopulmonary bypass of both existing types-standard (ECC) and minimallyu invasive extracorporeal circulation (MiECC)-and to propose cefazoline dosing optimization based on this model. A total of 65 adult patients undergoing cardiac surgery were recruited to this clinical trial. A prophylactic cefazolin dose of 2 g was intravenously administered before surgery. Blood samples were collected using a rich sampling design and cefazolin serum concentrations were measured using the HPLC/UV method. The pharmacokinetic population model was calculated using a nonlinear mixed-effects modeling approach, and the Monte Carlo simulation was used to evaluate the PK/PD target attainment. The population cefazolin central volume of distribution (Vd) of 4.91 L increased by 0.51 L with each 1 m2 of BSA, peripheral Vd of 22.07 L was reduced by 0.77 L or 0.79 L when using ECC or MiECC support, respectively, while clearance started at 0.045 L/h and increased by 0.49 L/h with each 1 mL/min/1.73 m2 of eGFR. ECC/MiECC was shown to be covariate of cefazolin Vd, but without relevance to clinical practice, while eGFR was most influential for the PK/PD target attainment. The standard dose of 2 g was sufficient for PK/PD target attainment throughout surgery in patients with normal renal status or with renal impairment. In patients with augmented renal clearance, an additive cefazolin dose should be administered 215, 245, 288 and 318 min after the first dose at MIC of 4, 3, 2 and 1.5 mg/L, respectively.

Bacterial Resistance to Antibiotics and Clonal Spread in COVID-19-Positive Patients on a Tertiary Hospital Intensive Care Unit, Czech Republic.

This observational retrospective study aimed to analyze whether/how the spectrum of bacterial pathogens and their resistance to antibiotics changed during the worst part of the COVID-19 pandemic (1 November 2020 to 30 April 2021) among intensive care patients in University Hospital Olomouc, Czech Republic, as compared with the pre-pandemic period (1 November 2018 to 30 April 2019). A total of 789 clinically important bacterial isolates from 189 patients were cultured during the pre-COVID-19 period. The most frequent etiologic agents causing nosocomial infections were strains of Klebsiella pneumoniae (17%), Pseudomonas aeruginosa (11%), Escherichia coli (10%), coagulase-negative staphylococci (9%), Burkholderia multivorans (8%), Enterococcus faecium (6%), Enterococcus faecalis (5%), Proteus mirabilis (5%) and Staphylococcus aureus (5%). Over the comparable COVID-19 period, a total of 1500 bacterial isolates from 372 SARS-CoV-2-positive patients were assessed. While the percentage of etiological agents causing nosocomial infections increased in Enterococcus faecium (from 6% to 19%, p < 0.0001), Klebsiella variicola (from 1% to 6%, p = 0.0004) and Serratia marcescens (from 1% to 8%, p < 0.0001), there were significant decreases in Escherichia coli (from 10% to 3%, p < 0.0001), Proteus mirabilis (from 5% to 2%, p = 0.004) and Staphylococcus aureus (from 5% to 2%, p = 0.004). The study demonstrated that the changes in bacterial resistance to antibiotics are ambiguous. An increase in the frequency of ESBL-positive strains of some species (Serratia marcescens and Enterobacter cloacae) was confirmed; on the other hand, resistance decreased (Escherichia coli, Acinetobacter baumannii) or the proportion of resistant strains remained unchanged over both periods (Klebsiella pneumoniae, Enterococcus faecium). Changes in pathogen distribution and resistance were caused partly due to antibiotic selection pressure (cefotaxime consumption increased significantly in the COVID-19 period), but mainly due to clonal spread of identical bacterial isolates from patient to patient, which was confirmed by the pulse field gel electrophoresis methodology. In addition to the above shown results, the importance of infection prevention and control in healthcare facilities is discussed, not only for dealing with SARS-CoV-2 but also for limiting the spread of bacteria.

Implementation of Antibiotic Stewardship in a University Hospital Setting.

The article describes activities of an antibiotic center at a university hospital in the Czech Republic and presents the results of antibiotic stewardship program implementation over a period of 10 years. It provides data on the development of resistance of Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Staphylococcus aureus to selected antibiotic agents as well as consumption data for various antibiotic classes. The genetic basis of resistance to beta-lactam antibiotics and its clonal spread were also assessed. The study showed significant correlations between aminoglycoside consumption and resistance of Escherichia coli and Klebsiella pneumoniae to gentamicin (r = 0.712, r = 0.869), fluoroquinolone consumption and resistance of Klebsiella pneumoniae to ciprofloxacin (r = 0.896), aminoglycoside consumption and resistance of Pseudomonas aeruginosa to amikacin (r = 0.716), as well as carbapenem consumption and resistance of Pseudomonas aeruginosa to meropenem (r = 0.855). Genotyping of ESBL- positive isolates of Klebsiella pneumoniae and Escherichia coli showed a predominance of CTX-M-type; in AmpC-positive strains, DHA, EBC and CIT enzymes prevailed. Of 19 meropenem-resistant strains of Klebsiella pneumoniae, two were identified as NDM-positive. Clonal spread of these strains was not detected. The results suggest that comprehensive antibiotic stewardship implementation in a healthcare facility may help to maintain the effectiveness of antibiotics against bacterial pathogens. Particularly beneficial is the work of clinical microbiologists who, among other things, approve administration of antibiotics to patients with bacterial infections and directly participate in their antibiotic therapy.

[Ciprofloxacin: pharmacokinetics and a potential for therapeutic monitoring].

Ciprofloxacin is a broad-spectrum bactericidal antibiotic with a concentration-dependent antimicrobial effect. Ciprofloxacin penetrates well into tissues, providing good efficacy against many Gram-negative microorganisms. Due to its good antibacterial efficacy and tolerability, it is often used in the treatment of critically ill. However, high interindividual variability in pharmacokinetics is reported in this population, especially in volume of distribution, clearance, and elimination half-life. Interindividual variability across patient groups results in difficult achievement of the therapeutic goal, mostly described as AUC/MIC ≥ 125. The usual dosing is 400 mg after 8-12 hours intravenously for one hour. In critically ill patients, the lower dose proved to be insufficient. In these patients, doses of at least 1 200 mg/day are required. An initial dose of 800 mg increases the probability of achieving the therapeutic goal by 35-45 %. Although many authors mention the possibility of using therapeutic drug monitoring to achieve the therapeutic goal, there are only few trials describing its benefits.

Low-loss GaOx-core/SiO2-cladding planar waveguides on Si substrate.

The unique properties of gallium oxide (GaOx) have drawn increasing interest as a material suitable for high-power electronic and optical applications. Herein, we report the demonstration of low-loss GaOx-core/SiO2-cladding waveguides on Si substrate. We present the fabrication process and annealing treatments of the waveguide devices, and we characterize the corresponding effects on optical transmission for 3 common wavelengths: 633 nm, 1064 nm, and 1550 nm. The best propagation loss achieved for these wavelengths is measured to be -0.4±0.1dB/cm, -0.3±0.2dB/cm, and -2.4±0.5dB/cm, respectively. We discuss the major waveguide loss mechanisms, followed by results of pump and probe experiments using visible/IR wavelengths for waveguides treated under various post-fabrication annealing conditions. We also show nonlinear measurements for a 250 fs laser beam to offer additional insights into the loss mechanisms, which are consistent with the linear optical transmission performances. High waveguide laser-induced damage threshold (LIDT) of >2.5J/cm2 is measured at this pulse width, making GaOx a potential candidate for high-power integrated photonic devices.

Efficacy and analgesic use during the therapy of iatrogenic pneumothorax using Pleuralvent™ and Chest Tube (ASPIRATE): A randomised controlled trial protocol.

BACKGROUND: Iatrogenic pneumothorax is a common complication of various diagnostic and therapeutic procedures such as transbronchial lung biopsies. The classical mode of treatment is chest tube insertion. Pneumothorax devices are now available on the market but there is a dearth of data on their efficacy to treat iatrogenic pneumothorax. It is important to provide such data as the pathophysiology of iatrogenic pneumothorax is different in comparison with spontaneous pneumothorax for which some data is available. METHODS: This is a randomized, non-blinded, actively controlled trial of effectivity of iatrogenic pneumothorax treatment using the Pleuralvent™ device and chest tube insertion (16F). The secondary aim is to compare the overall pain level and the need for analgesic treatment in both treatment arms. We are planning to enrol 126 patients (63 in each treatment arm). DISCUSSION: Preliminary results showed similar effectivity of the Pleuralvent™ system compared to large bore chest tube insertion. This randomized clinical trial should confirm these results and prove that the Pleuralvent™ system is an effective way of treatment of patients with iatrogenic pneumothorax. If Pleuralvent™ proves to have the same level of efficacy, it may become the standard of care of patients with iatrogenic pneumothorax. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03700554.

[Pharmacokinetics and therapeutic monitoring of piperacillin/tazobactam].

Given their wide therapeutic index, beta-lactam antibiotics are commonly used to treat critically ill patients. It is in these patients that significant heterogeneity in pharmacokinetics was noted, compared to the population average, especially in the volume of distribution, drug clearance and biological half-life, with values increasing as much as two-fold or, in the case of biological half-life, as much as four-fold. Significant pharmacokinetic changes also occur in cases of morbid obesity or renal insufficiency and when complex surgical techniques such as extracorporeal circulation are used. Therapeutic monitoring of piperacillin/tazobactam is a way to personalize and optimize therapy for these groups of patients. Preclinical data show a correlation between the probability of therapeutic success and concentrations of the unbound fraction of an antibiotic exceeding the minimum inhibitory concentration (MIC) for 40-50 % of the dosing interval. This time appears to be the preferred pharmacodynamic target for beta-lactam antibiotics. In critically ill patients, however, an even higher target may be required, ideally 100 % fT > 4xMIC. A better pharmacodynamic profile can be obtained using prolonged or continuous infusion. The biggest obstacle to routine TDM in ß-lactams is the speed of quality sample determination. Currently, the most widely used method of measuring plasma concentrations is liquid chromatography coupled with UV or MS detection.

Silicon nitride waveguide as a power delivery component for on-chip dielectric laser accelerators.

We study the weakly guided silicon nitride waveguide as an on-chip power delivery solution for dielectric laser accelerators (DLAs). We focus on the two main limiting factors on the waveguide network for DLAs: the optical damage and nonlinear characteristics. The typical delivered fluence at the onset of optical damage is measured to be ∼0.19 J/cm2 at a 2 µm central wavelength and 250 fs pulse width. This damage fluence is lower than that of the bulk Si3N4 (∼0.65 J/cm2), but higher than that of bulk silicon (∼0.17 J/cm2). We also report the nonlinearity-induced spectrum and phase variance of the output pulse at this pulse duration. We find that a total waveguide length within 3 mm is sufficient to avoid significant self-phase modulation effects when operating slightly below the damage threshold. We also estimate that one SiNx waveguide can power 70 µm silicon dual pillar DLAs from a single side, based on the results from the recent free-space DLA experiment.

Phase-dependent laser acceleration of electrons with symmetrically driven silicon dual pillar gratings.

We present the demonstration of phase-dependent laser acceleration and deflection of electrons using a symmetrically driven silicon dual pillar grating structure. We show that exciting an evanescent inverse Smith-Purcell mode on each side of a dual pillar grating can produce hyperbolic cosine acceleration and hyperbolic sine deflection modes, depending on the relative excitation phase of each side. Our devices accelerate sub-relativistic 99.0 keV kinetic energy electrons by 3.0 keV over a 15 µm distance with accelerating gradients of 200 MeV/m with 40 nJ, 300 fs, 1940 nm pulses from an optical parametric amplifier. These results represent a significant step towards making practical dielectric laser accelerators for ultrafast, medical, and high-energy applications.

Simple, picojoule-sensitive ultraviolet autocorrelator based on two-photon conductivity in sapphire.

We present a simple autocorrelator for ultraviolet pulses based on two-photon conductivity in a bench-top fabricatable sapphire sensor. We perform measurements on femtosecond 226-278 nm ultraviolet pulses from the third and fourth harmonics of a standard 76 MHz titanium sapphire oscillator and picosecond 266 nm pulses from the fourth harmonic of a 1064 nm 50 MHz neodymium vanadate oscillator. Our device is sensitive to 2.6 pJ ultraviolet pulses with peak powers below 20 W. These results represent the lowest measured autocorrelation peak powers by over one order of magnitude for a system with no reference pulse in the deep ultraviolet (<300 nm). The autocorrelator can potentially support UV pulse lengths from 50 fs-10s of picoseconds.

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.

[Antibiotic therapy of hospital-acquired pneumonia and its pharmacoeconomics].

BACKGROUND: Important hospital-acquired infections include pneumonia, mainly because of the increasing resistance of bacterial pathogens to antimicrobials and the associated potential failure of antibiotic therapy. The present study aimed at determining the most frequent etiological agents of hospital-acquired pneumonia (HAP) and assessing the relationship between 30-day mortality and adequacy of antibiotic therapy. Based on the obtained information, optimal patterns of antibiotic therapy were to be defined, including a pharmacoeconomic perspective. METHODS: In patients with clinically confirmed HAP, bacterial etiological agents were identified, their susceptibility to antimicrobials was determined and statistical methods were used to assess the relationship between adequacy of antibiotic therapy and 30-day mortality. RESULTS: The study comprised 68 patients with clinically confirmed HAP. The most common etiological agents were strains of Pseudomonas aeruginosa (30.8 %), Klebsiella pneumoniae (23.1 %) and Burkholderia cepacia complex (15.4 %). Gram-negative bacteria accounted for 86.5 % of all bacterial pathogens. The overall mortality reached 42.5 %. In the subgroup of patients with inadequate antibiotic therapy, 30-day mortality was significantly higher (83.3 %) than in the subgroup with adequate therapy (30.0 %; p = 0.002). The risk for 30-day mortality was 2.78 times higher in case of inadequate antibiotic therapy (95%CI: 1.52-5.07). The proportion of Pseudomonas aeruginosa strains was significantly higher in the subgroup of patients with inadequate antibiotic therapy than in those with adequate therapy (67 % vs. 27 %; p = 0.032). CONCLUSION: Results of the present study suggest a significant relationship between mortality of patients with HAP and ineffective antibiotic therapy due to resistance of the bacterial pathogen. Thus, it is clear that initial antibiotic therapy must be based on qualified assumption of sufficient activity against the most common bacterial pathogens and results of surveillance of bacterial resistance in the relevant epidemiological unit. At the same time, however, it must be stressed that it is impossible to cover all potential variants of the etiological agents and their resistance phenotypes.

Specific features of pharmacokinetics in children.

Human growth and development consist of a continuum of biological events. The impact of these developmental changes in drug disposition is largely related to changes in the body composition (e.g. body water content, plasma protein concentrations) and in the function of organs important in metabolism (e.g. the liver) and excretion (e.g. the kidney). The gastric emptying time during the neonatal period is prolonged, as well as intestinal motility. The ratio of body surface area to body weight is higher in children than in adults, which results in higher absorption of locally applied corticosteroids. Lower plasma protein levels and a higher body water content compared to adults may lead to diminished drug distribution. Phase I drug metabolizing system develops quickly and reaches adult levels between the third and sixth year of age. In newborns up to 3 months, the sulphotransferase activity is more developed than glucuronidation. Glomerular filtration, normalized to body surface area, approaches adult levels by 6 months of age. During the first decade of life, these changes are dynamic and can be non-linear and discordant, making standardized dosing inadequate. During rapid phases of growth/development, drug disposition and response may be altered. The main goal is to optimize drug therapy in children. This can be achieved through a fundamental understanding of how ontogeny influences pharmacokinetics.

Acute pancreatitis as the first manifestation of duodenal MALT lymphoma.

BACKGROUND: Possibly any tumor that can cause mechanical obstruction of the distal bile duct can induce acute pancreatitis. However, acute pancreatitis as the first clinical manifestation of duodenal lymphoma is extremely rare. OBJECTIVE: To report the case of a patient with acute pancreatitis as an extremely rare first manifestation of duodenal MALT lymphoma and possible association with erythema nodosum. METHODS: Case report of a 66-year-old woman who was diagnosed with acute pancreatitis caused by infiltration with duodenal lymphoma. RESULTS: Acute pancreatitis was confirmed by CT imaging. Detailed investigation revealed a duodenal mass causing pancreatic injury. Histological analysis established the diagnosis of MALT lymphoma. The patient's medical history also included erythema nodosum. Complete remission of the malignancy was achieved with chemotherapy. CONCLUSION: This is the first published case report of acute pancreatitis caused by the growth of duodenal MALT lymphoma. An association with erythema nodosum is possible.

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.