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.

• MeSH
• antibakteriální látky krev   MeSH
• beta-laktamy krev   MeSH
• lidé MeSH
• monitorování léčiv * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antibakteriální látky MeSH
• beta-laktamy MeSH

BACKGROUND: Antibiotic resistance stands as a critical medical concern, notably evident in commonly prescribed beta-lactam antibiotics. The imperative need for expeditious and precise early detection methods underscores their role in facilitating timely intervention, curbing the propagation of antibiotic resistance, and enhancing patient outcomes. RESULTS: This study introduces the utilization of surface-enhanced Raman spectroscopy (SERS) in tandem with machine learning (ML) for the sensitive detection of characteristic gene fragments responsible for antibiotic resistance appearance and spreading. To make the detection procedure close to the real case, we used bacterial plasmids as starting biological objects, containing or not the characteristic gene fragment (up to 1:10 ratio), encoding beta-lactam antibiotics resistance. The plasmids were subjected to enzymatic digestion and without preliminary purification or isolation the created fragments were captured by functional SERS substrates. Based on subsequent SERS measurements, a database was created for the training and validation of ML. Method validation was performed using separately measured spectra, which did not overlap with the database used for ML training. To check the efficiency of recognising the target fragment, control experiments involved bacterial plasmids containing different resistance genes, the use of inappropriate enzymes, or the absence of plasmid. SIGNIFICANCE: SERS-ML allowed express detection of bacterial plasmids containing a characteristic gene fragment up to the 10-7 concentration of the initial plasmid, despite the complex composition of the biological sample, including the presence of interfering plasmids. Our approach offers a promising alternative to existing methods for monitoring antibiotic-resistant bacteria, characterized by its simplicity, low detection limit, and the potential for rapid and straightforward analysis.

• Klíčová slova
• Bacterial plasmid, Beta-lactam antibiotics resistance, Detection, Logistic regression, Machine learning, SERS,
• MeSH
• antibakteriální látky farmakologie   MeSH
• beta-laktamová antibiotika MeSH
• beta-laktamová rezistence genetika   MeSH
• beta-laktamy farmakologie   MeSH
• Escherichia coli genetika   účinky léků   izolace a purifikace   MeSH
• plazmidy * genetika   MeSH
• povrchové vlastnosti MeSH
• Ramanova spektroskopie * metody   MeSH
• strojové učení * MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antibakteriální látky MeSH
• beta-laktamová antibiotika MeSH
• beta-laktamy MeSH

A series of experiments were performed with P. aeruginosa to demonstrate which of the biochemical mechanisms are responsible for the resistance to the beta-lactam antibiotics. The constitutive beta-lactamase was isolated and characterized for the strain used as type OXA whose pI was 7.1, with a molar mass of 49 kg/mol. The strain was also submitted to a series of treatments with Tris and Tris-EDTA to disrupt the outer membrane. The treated cells demonstrated a ten-fold reduction in the MIC with cloxacillin, six-fold with penicillin, and five-fold with oxacillin. At least two different biochemical mechanisms were responsible for the resistance to the beta-lactams studied which could be important in the prevalence of P. aeruginosa in nosocomial infections.

• MeSH
• antibakteriální látky metabolismus   farmakologie   MeSH
• antibiotická rezistence MeSH
• bakteriální proteiny analýza   MeSH
• beta-laktamasy analýza   MeSH
• beta-laktamy MeSH
• buněčná membrána metabolismus   MeSH
• permeabilita buněčné membrány MeSH
• Pseudomonas aeruginosa účinky léků   metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antibakteriální látky MeSH
• bakteriální proteiny MeSH
• beta-laktamasy MeSH
• beta-laktamy MeSH

Beta-lactam antibiotics remain one of the most preferred groups of antibiotics in critical care due to their excellent safety profiles and their activity against a wide spectrum of pathogens. The cornerstone of appropriate therapy with beta-lactams is to achieve an adequate plasmatic concentration of a given antibiotic, which is derived primarily from the minimum inhibitory concentration (MIC) of the specific pathogen. In a critically ill patient, the plasmatic levels of drugs could be affected by many significant changes in the patient's physiology, such as hypoalbuminemia, endothelial dysfunction with the leakage of intravascular fluid into interstitial space and acute kidney injury. Predicting antibiotic concentration from models based on non-critically ill populations may be misleading. Therapeutic drug monitoring (TDM) has been shown to be effective in achieving adequate concentrations of many drugs, including beta-lactam antibiotics. Reliable methods, such as high-performance liquid chromatography, provide the accurate testing of a wide range of beta-lactam antibiotics. Long turnaround times remain the main drawback limiting their widespread use, although progress has been made recently in the implementation of different novel methods of antibiotic testing. However, whether the TDM approach can effectively improve clinically relevant patient outcomes must be proved in future clinical trials.

• Klíčová slova
• bacterial susceptibility, beta-lactam antibiotics, critically ill, high-performance liquid chromatography, pharmacokinetics–pharmacodynamics, therapeutic drug monitoring,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Of 50 Salmonella species isolated from pigs, 30 were resistant to cadmium and 18 of these also to azlocillin. The azlocillin-resistant isolates were resistant to cadmium at 80-500 mg/L CdSO4. A broader spectrum of resistance to azlocillin, ampicillin and cephazolin was found in strains resistant to < 200 mg/L CdSO4. Resistance to silver, mercury, chloramphenicol and streptomycin was independent of the resistance to beta-lactam antibiotics and Cd2+. Production and levels of beta-lactamase do not correlate with the spectrum of resistance.

• MeSH
• antibakteriální látky farmakologie   MeSH
• antibiotická rezistence MeSH
• bakteriální proteiny metabolismus   MeSH
• beta-laktamasy metabolismus   MeSH
• beta-laktamy MeSH
• kadmium farmakologie   MeSH
• nemoci prasat mikrobiologie   MeSH
• prasata MeSH
• rtuť farmakologie   MeSH
• Salmonella účinky léků   izolace a purifikace   MeSH
• salmonelová infekce u zvířat mikrobiologie   MeSH
• stříbro farmakologie   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH
• Názvy látek
• antibakteriální látky MeSH
• bakteriální proteiny MeSH
• beta-laktamasy MeSH
• beta-laktamy MeSH
• kadmium MeSH
• rtuť MeSH
• stříbro MeSH

Susceptibility in vitro and trends in resistance to antimicrobials were determined by a dilution micromethod in a group of Actinobacillus pleuropneumoniae, Pasteurella multocida, Mannheimia haemolytica and Escherichia coli isolates from clinical cases of cattle and swine diseases in the Czech Republic from 2007 to 2011. A high susceptibility of pig and cattle respiratory pathogens to antimicrobials was found, with the exception of the moderate prevalence of M. haemolytica resistance to ampicillin. In contrast to respiratory pathogens, low susceptibility of E. coli of pig and cattle isolates to ampicillin and amoxicillin/clavulanic acid was noted. Regarding resistance trends, an increase in levels of resistance among E. coli isolates to ampicillin and amoxicillin/clavulanic acid was identified, but the resistance of respiratory isolates was low, with the exception of M. haemolytica. For the period of 2007-2011, there was a significant and almost continuous increase in sales (compared with population correction unit) of ceftiofur, cefquinome and other beta lactams for pigs. Consumption peaked in 2010. In the case of amoxicillin in combination with clavulanic acid, data showed a significant decrease in sales from 2007 to 2008, followed by a period of fluctuation. In cattle, within the groups of 3rd and 4th generation cephalosporins and for the whole group of other betalactams for the period of 2007-2011, there was a significant and almost continuous increase in sales (compared with population correction unit). Consumption peaked in 2010. In the case of ceftiofur, there was a huge increase noted from 2010. In the case of amoxicillin in combination with betalactamase inhibitor (clavulanic acid) data shows a significant decrease from 2007 to 2008, followed by a period of fluctuation in sales.

• Klíčová slova
• Cattle, Pigs, Resistance, Sales of antimicrobials, Trends,
• MeSH
• Actinobacillus pleuropneumoniae účinky léků   MeSH
• bakteriální léková rezistence genetika   MeSH
• beta-laktamy metabolismus   MeSH
• Escherichia coli účinky léků   MeSH
• infekce bakteriemi čeledi Pasteurellaceae epidemiologie   veterinární   MeSH
• infekce vyvolané Escherichia coli epidemiologie   veterinární   MeSH
• inhibitory beta-laktamasy farmakologie   MeSH
• Mannheimia haemolytica účinky léků   MeSH
• mikrobiální testy citlivosti veterinární   MeSH
• nemoci prasat epidemiologie   mikrobiologie   MeSH
• nemoci skotu epidemiologie   mikrobiologie   MeSH
• Pasteurella multocida účinky léků   MeSH
• prasata MeSH
• prevalence MeSH
• skot MeSH
• zvířata MeSH
• Check Tag
• skot MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika epidemiologie   MeSH
• Názvy látek
• beta-laktamy MeSH
• inhibitory beta-laktamasy MeSH

Early and appropriate antibiotic therapy remains the key intervention for successful treatment of infection in critically ill patients, particularly in the current era of increasing antibiotic resistance. Optimization of the antimicrobial dosing regimens to achieve therapeutic plasma concentrations and concentrations at the site of infection is crucial for maximizing the therapeutic response and minimizing the risk of organ toxicity and is also an important tool to avoid the resistance emergence. Beta-lactam antibiotics have been considered relatively safe and, as opposed to aminoglycosides, therapeutic drug monitoring as a tool conventionally used primarily to minimize toxicity in drugs with narrow therapeutic window or complex pharmacokinetics, has not been provided routinely yet. However, emerging data suggest that optimal antibiotic exposure may not be achieved with traditional dosing strategies in a significant number of critically ill patients and, on the contrary, concerns about insufficient plasma concentrations leading to microbiological and clinical failure are warranted. The treatment of infections in the intensive care unit (ICU) patients is often challenging because of disease complexity, pathophysiologic alterations they undergo and reduced susceptibility of nosocomial pathogens. Therefore, it is of paramount importance to update current recommendations on dosing of beta-lactam antibiotics in severe infections and therapeutic drug monitoring may be regarded as the only exact method to ensure pharmacodynamics target achievement. Na Homolce Hospital is one of the first medical institutions in the Czech Republic where the practice of routine TDM of beta-lactam antibiotics in ICU-patients has been established. In this paper, we introduce our experience and first case reports.

• Klíčová slova
• beta-lactam antibiotics, dose optimization, intensive care unit (ICU), pathophysiologic changes, pharmacokinetics, therapeutic drug monitoring (TDM),
• MeSH
• antibakteriální látky farmakokinetika   MeSH
• bakteriální infekce farmakoterapie   MeSH
• beta-laktamy farmakokinetika   MeSH
• jednotky intenzivní péče * MeSH
• kritický stav MeSH
• lidé MeSH
• monitorování léčiv MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• antibakteriální látky MeSH
• beta-laktamy MeSH

This work monitored the effect of a municipal and a village wastewater treatment plant (WWTP) technology on the fate of beta-lactam resistance genes in bacterial populations in different phases of the wastewater treatment process. In case of the municipal WWTP1, the bacteria possessing a high ampicillin resistance (minimal inhibitory concentration (MIC) values of 20 mg/mL) accumulated in the sedimentation tank, which was accompanied with a higher concentration of ampicillin in the wastewater samples (28.09 ng/L) and an increase in the relative abundance of the blaTEM gene in the bacterial population. However, an opposite trend was revealed with the blaNDM-1 gene, making the sedimentation processes of WWTP1 crucial only for the accumulation of the blaTEM gene. Similarly, the comparison with the WWTP2 showed that the accumulation of the ampicillin resistance in bacterial population probably depended on the WWTP technology and wastewater composition. Out of the four tested resistance genes (blaTEM, blaKPC, blaNDM-1, and blaOXA-48), blaTEM and blaNDM-1 genes were the only two detected in this study. According to NGS analysis of bacterial 16 S rRNA gene, Gammaproteobacteria dominated the ampicillin-resistant bacteria of the WWTP sedimentation tanks. Their relative abundance in the bacterial population also increased during the sedimentation processes in WWTP1. It could indicate the role of the bacterial taxon in ampicillin resistance accumulation in this WWTP and show that only 9.29% of the original bacterial population from the nitrification tank is involved in the documented shifts in beta-lactam resistance of the bacterial population.

• Klíčová slova
• Antibiotic resistance, Beta-lactam resistance genes, Wastewater treatment plant, blaNDM-1, blaTEM,
• MeSH
• antibakteriální látky * farmakologie   MeSH
• bakteriální geny MeSH
• beta-laktamová rezistence MeSH
• čištění vody * MeSH
• odpadní voda analýza   MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antibakteriální látky * MeSH
• odpadní voda MeSH

Beta-lactams are considered to be very important drugs used in the therapy of many serious bacterial infections. In the last few years, the number of isolated clinical strains from the Enterobacteriaceae family, mainly Enterobacter and Klebsiella spp. resistant to 3rd generation cephalosporins, rapidly increased. Resistance can be located on chromosomes or be determined by plasmids and transposons. The production of beta-lactamases is the most frequent manifestation of beta-lactam resistance. Spread of such resistance, especially plasmid-encoded, is believed to be a serious risk factor. Therefore the study of the resistance mechanism is Gram-negative bacilli to beta-lactams not only indicates the present situation, but also trends in future medical therapy.

• MeSH
• antibakteriální látky farmakologie   MeSH
• beta-laktamasy genetika   metabolismus   MeSH
• beta-laktamová rezistence MeSH
• beta-laktamy MeSH
• Enterobacteriaceae účinky léků   genetika   MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• antibakteriální látky MeSH
• beta-laktamasy MeSH
• beta-laktamy MeSH

AIMS: Critically ill patients undergoing aggressive fluid resuscitation and treated empirically with hydrosoluble time-dependent beta-lactam antibiotics are at risk for sub-therapeutic plasma concentrations. The aim of this study was to assess the impact of two covariates - creatinine clearance (Clcr) and cumulative fluid balance (CFB) on pharmacokinetics/pharmacodynamics (PK/PD) target attainment within a week of treatment with meropenem (ME) or piperacillin/tazobactam (PIP/TZB). METHODS: In this prospective observational pharmacokinetic (PK) study, 18 critically ill patients admitted to a surgical Intensive Care Unit (ICU) were enrolled. The primary PK/PD target was free antibiotic concentrations above MIC at 100% of the dosing interval (100%fT>MIC) to obtain maximum bactericidal activity. Drug concentration was measured using liquid chromatography-tandem mass spectrometry. RESULTS: The treatment of both 8 septic patients with IV extended ME dosing 2 g/3 h q8 h and 10 polytraumatized patients with IV intermittent PIP/TZB dosing 4.0/0.5 g q8 h was monitored. 8/18 patients (44%) manifested augmented renal clearence (ARC) where Clcr ≥130 mL/min/1.73 m2. Maximum changes were reported on days 2-3: the median positive CFB followed by the large median volume of distribution: Vdme=70.3 L (41.9-101.5), Vdpip = 46.8 L (39.7-60.0). 100%fTme>MIC was achieved in all patients on ME (aged ≥60 years), and only in two patients (non-ARC, aged ≥65 years) out of 10 on PIP/TZB. A mixed model analysis revealed positive relationship of CFBpip with Vdpip (P=0.021). CONCLUSION: Assuming that the positive correlation between CFB and Vd exists for piperacillin in the setting of the pathological state, then CFB should predict Vdpip across subjects at each and every time point.

• Klíčová slova
• beta-lactam antibiotics, critically ill patient, meropenem, pharmacokinetics/pharmacodynamics target, piperacillin,
• MeSH
• antibakteriální látky aplikace a dávkování   farmakokinetika   farmakologie   MeSH
• beta-laktamy aplikace a dávkování   farmakokinetika   farmakologie   MeSH
• dospělí MeSH
• kritický stav terapie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• meropenem aplikace a dávkování   farmakokinetika   farmakologie   MeSH
• mladiství MeSH
• mladý dospělý MeSH
• peritonitida komplikace   farmakoterapie   MeSH
• piperacilin aplikace a dávkování   farmakokinetika   farmakologie   MeSH
• polytrauma komplikace   farmakoterapie   MeSH
• prospektivní studie MeSH
• rozvrh dávkování léků MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• sepse farmakoterapie   MeSH
• septický šok farmakoterapie   MeSH
• syndrom systémové zánětlivé reakce farmakoterapie   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• pozorovací studie MeSH
• Názvy látek
• antibakteriální látky MeSH
• beta-laktamy MeSH
• meropenem MeSH
• piperacilin MeSH