Methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa are major causes of hospital-acquired infections and sepsis. Due to increasing antibiotic resistance, new treatments are needed. Mesenchymal stem cells (MSCs) have antimicrobial effects, which can be enhanced by preconditioning with antibiotics. This study investigated using antibiotics to strengthen MSCs against MRSA and P. aeruginosa. MSCs were preconditioned with linezolid, vancomycin, meropenem, or cephalosporin. Optimal antibiotic concentrations were determined by assessing MSC survival. Antimicrobial effects were measured by minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), and antimicrobial peptide (AMP) gene expression. Optimal antibiotic concentrations for preconditioning MSCs without reducing viability were 1 μg/mL for linezolid, meropenem, and cephalosporin and 2 μg/mL for vancomycin. In MIC assays, MSCs preconditioned with linezolid, vancomycin, meropenem, or cephalosporin inhibited MRSA or P. aeruginosa growth at lower concentrations than non-preconditioned MSCs (p ≤ 0.001). In MBC assays, preconditioned MSCs showed enhanced bacterial clearance compared to non-preconditioned MSCs, especially when linezolid and vancomycin were used against MRSA (p ≤ 0.05). Preconditioned MSCs showed increased expression of genes encoding the antimicrobial peptide genes hepcidin and LL-37 compared to non-preconditioned MSCs. The highest hepcidin expression was seen with linezolid and vancomycin preconditioning (p ≤ 0.001). The highest LL-37 expression was with linezolid preconditioning (p ≤ 0.001). MSCs' preconditioning with linezolid, vancomycin, meropenem, or cephalosporin at optimal concentrations enhances their antimicrobial effects against MRSA and P. aeruginosa without compromising viability. This suggests preconditioned MSCs could be an effective adjuvant treatment for antibiotic-resistant infections. The mechanism may involve upregulation of AMP genes.

• MeSH
• antibakteriální látky farmakologie   terapeutické užití   MeSH
• antimikrobiální peptidy MeSH
• cefalosporiny farmakologie   MeSH
• hepcidiny farmakologie   terapeutické užití   MeSH
• lidé MeSH
• linezolid farmakologie   terapeutické užití   MeSH
• meropenem farmakologie   terapeutické užití   MeSH
• methicilin rezistentní Staphylococcus aureus * MeSH
• mezenchymální kmenové buňky * MeSH
• mikrobiální testy citlivosti MeSH
• Pseudomonas aeruginosa genetika   MeSH
• stafylokokové infekce * mikrobiologie   MeSH
• vankomycin MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

OBJECTIVES: The objective of this study was to develop a population pharmacokinetic model of meropenem in a heterogeneous population of patients with a serious bacterial infection in order to propose dosing optimisation leading to improved achievement of the pharmacokinetic/pharmacodynamic (PK/PD) target. METHODS: A total of 174 meropenem serum levels obtained from 144 patients during therapeutic drug monitoring were analysed using a non-linear mixed-effects modelling approach and Monte Carlo simulation was then used to compare various dosing regimens in order to optimise PK/PD target attainment. RESULTS: The meropenem volume of distribution of the patient population was 54.95 L, while clearance started at 3.27 L/hour and increased by 0.91 L/hour with each 1 mL/s/1.73 m2 of estimated glomerular filtration rate. Meropenem clearance was also 0.31 L/hour higher in postoperative patients with central nervous system infection. Meropenem administration by continuous infusion showed a significantly higher probability of attaining the PK/PD target than a standard 30 min infusion (95.3% vs 49.5%). CONCLUSIONS: A daily meropenem dose of 3 g, 6 g and 10.5 g administered by continuous infusion was shown to be accurate for patients with moderate to severe renal impairment, normal renal function to mild renal impairment and augmented renal clearance, respectively.

• MeSH
• antibakteriální látky * farmakokinetika   aplikace a dávkování   MeSH
• bakteriální infekce * farmakoterapie   MeSH
• biologické modely * MeSH
• dospělí MeSH
• intravenózní infuze MeSH
• lidé středního věku MeSH
• lidé MeSH
• meropenem * farmakokinetika   aplikace a dávkování   MeSH
• metoda Monte Carlo MeSH
• monitorování léčiv metody   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Delftia acidovorans je gramnegatívna aeróbna tyčinkovitá baktéria. Ochorenia u ľudí vyvoláva len raritne. Spôsobuje predovšetkým nozokomiálne nákazy, opisované častejšie u imunokompromitovaných pacientov v rámci všetkých vekových skupín. V odbornej literatúre bolo v posledných rokoch publikovaných niekoľko prípadov, v rámci ktorých sa uplatnila pri vzniku infekcií postihujúcich rôzne orgánové systémy. S ohľadom na častú rezistenciu voči aminoglykozidom a polymyxínom, ktoré mnohokrát slúžia ako záchranné liečivá pri komplikovaných infekciách gramnegatívnymi baktériami, nastáva nevyhnutne potreba jej rýchlej identifikácie s následne správne zvolenou liečbou. V kazuistike opisujeme prípad pacientky s rozsiahlym fluidothoraxom hrudníka v dôsledku infekcie baktériou Delftia acidovorans a sumarizujeme aktuálne dostupné informácie o infekciách spôsobených týmto zriedkavým patogénom.

Delftia acidovorans is a Gram-negative, aerobic, rod-shaped bacterium which causes infections in humans only rarely. It causes mostly nosocomial infections, described more frequently in immunocompromised patients across all age groups. In recent years, several cases involving this bacterium in infections affecting various organ systems have been published in the literature. With regard to its common resistance to aminoglycosides and polymyxins, which oftentimes serve as salvage therapy for complicated Gram-negative bacterial infections, there is inevitably a need for its quick identification followed by a correctly chosen treatment. This article describes a case of a patient with extensive pleural effusion due to Delftia acidovorans infection and also summarizes the currently available information on infections caused by this rare pathogen.

• MeSH
• Delftia acidovorans izolace a purifikace   MeSH
• empyém pleurální * diagnóza   etiologie   terapie   MeSH
• komorbidita MeSH
• lidé středního věku MeSH
• lidé MeSH
• meropenem aplikace a dávkování   terapeutické užití   MeSH
• mikrobiologické techniky metody   MeSH
• pleurální výpotek diagnóza   terapie   MeSH
• počítačová rentgenová tomografie metody   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

The resistance to carbapenems is usually mediated by enzymes hydrolyzing β-lactam ring. Recently, an alternative way of the modification of the antibiotic, a β-lactone formation by OXA-48-like enzymes, in some carbapenems was identified. We focused our study on a deep analysis of OXA-48-like-producing Enterobacterales, especially strains showing poor hydrolytic activity. In this study, well characterized 74 isolates of Enterobacterales resistant to carbapenems were used. Carbapenemase activity was determined by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), liquid chromatography/mass spectrometry (LC-MS), Carba-NP test and modified Carbapenem Inactivation Method (mCIM). As meropenem-derived β-lactone possesses the same molecular weight as native meropenem (MW 383.46 g/mol), β-lactonization cannot be directly detected by MALDI-TOF MS. In the spectra, however, the peaks of m/z = 340.5 and 362.5 representing decarboxylated β-lactone and its sodium adduct were detected in 25 out of 35 OXA-48-like producers. In the rest 10 isolates, decarboxylated hydrolytic product (m/z = 358.5) and its sodium adduct (m/z = 380.5) have been detected. The peak of m/z = 362.5 was detected in 3 strains co-producing OXA-48-like and NDM-1 carbapenemases. The respective signal was identified in no strain producing class A or class B carbapenemase alone showing its specificity for OXA-48-like carbapenemases. Using LC-MS, we were able to identify meropenem-derived β-lactone directly according to the different retention time. All strains with a predominant β-lactone production showed negative results of Carba NP test. In this study, we have demonstrated that the strains producing OXA-48-like carbapenemases showing false-negative results using Carba NP test and MALDI-TOF MS preferentially produced meropenem-derived β-lactone. We also identified β-lactone-specific peak in MALDI-TOF MS spectra and demonstrated the ability of LC-MS to detect meropenem-derived β-lactone.

• MeSH
• antibakteriální látky farmakologie   MeSH
• bakteriální proteiny * analýza   MeSH
• beta-laktamasy analýza   MeSH
• Enterobacteriaceae * MeSH
• karbapenemy farmakologie   MeSH
• meropenem farmakologie   MeSH
• mikrobiální testy citlivosti MeSH
• spektrometrie hmotnostní - ionizace laserem za účasti matrice metody   MeSH
• Publikační typ
• časopisecké články MeSH

Carbapenem resistance observed in Klebsiella pneumoniae strains limits treatment options. Therefore, use of antibiotics combined with bioactive compounds may be an important strategy to control K. pneumoniae. The purpose of this study was to evaluate the activity of combination of carvacrol and meropenem on carbapenem-resistant K. pneumoniae (CRKP) strains. The presence of blaOXA-48 carbapenemase in all 25 CRKP strains was identified using the PCR technique. The combination of carvacrol and meropenem was tested for antimicrobial activity on CRKP strains. The minimum inhibitory concentrations of carvacrol and meropenem were detected within a range of 32-128 μg/mL using the broth microdilution method. Synergy between carvacrol and meropenem was observed on 8 of the 25 CRKP strains by checkerboard assay (FICI = 0.5) and confirmed by time-kill assay. According to the live-dead test results, the viability percentage of the cells exposed to synergistic combination was 35.47% at the end of 24 h. The membrane damage caused by the synergistic combination was spectrophotometrically measured (A = 0.21) and further confirmed by SEM analysis. According to the MTT assay, both carvacrol and meropenem did not show any statistically significant cytotoxic effect on Vero cells (p > 0.05). In conclusion, the results suggest that carvacrol and meropenem can act synergistically to inhibit the growth of CRKP.

• MeSH
• antibakteriální látky farmakologie   MeSH
• beta-laktamasy * genetika   MeSH
• Cercopithecus aethiops MeSH
• cymeny MeSH
• karbapenemy farmakologie   MeSH
• Klebsiella pneumoniae * MeSH
• meropenem farmakologie   MeSH
• mikrobiální testy citlivosti MeSH
• synergismus léků MeSH
• Vero buňky MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Antimicrobial susceptibility of clinical isolates collected from sites in central Europe in 2019 was tested by CLSI broth microdilution method and EUCAST breakpoints. Most active were amikacin, ceftazidime-avibactam and colistin; respectively, susceptibility rates among P. aeruginosa (n = 701) were 89.2%, 92.2% and 99.9%; difficult-to-treat (DTR) isolates, 62.5%, 37.5% and 100%; multidrug-resistant (MDR) isolates, 68.3%, 72.9% and 99.5%; meropenem-resistant (MEM-R), metallo-β-lactamase-negative (MBL-negative) isolates, 72.8%, 78.6% and 100%. Among Enterobacterales (n = 1639), susceptibility to ceftazidime-avibactam, colistin and tigecycline was ≥ 97.9%; MDR Enterobacterales, 96.8%, 94.4% and 100%, respectively; DTR isolates, ≥ 76.2% to ceftazidime-avibactam and colistin; MEM-R, MBL-negative isolates, ≥ 90.0% to ceftazidime-avibactam and colistin.

• MeSH
• antibakteriální látky farmakologie   terapeutické užití   MeSH
• azabicyklické sloučeniny MeSH
• ceftazidim farmakologie   MeSH
• Enterobacteriaceae MeSH
• fixní kombinace léků MeSH
• kolistin * farmakologie   MeSH
• lidé MeSH
• meropenem MeSH
• mikrobiální testy citlivosti MeSH
• Pseudomonas aeruginosa * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika MeSH
• Chorvatsko MeSH
• Litva MeSH
• Lotyšsko MeSH
• Maďarsko MeSH
• Polsko MeSH

OBJECTIVES: In the ASPECT-NP trial, ceftolozane/tazobactam was non-inferior to meropenem for treating nosocomial pneumonia; efficacy outcomes by causative pathogen were to be evaluated. METHODS: Mechanically ventilated participants with hospital-acquired/ventilator-associated bacterial pneumonia were randomized to 3 g ceftolozane/tazobactam (2 g ceftolozane/1 g tazobactam) q8h or 1 g meropenem q8h. Lower respiratory tract (LRT) cultures were obtained ≤36 h before first dose; pathogen identification and susceptibility were confirmed at a central laboratory. Prospective secondary per-pathogen endpoints included 28 day all-cause mortality (ACM), and clinical and microbiological response at test of cure (7-14 days after the end of therapy) in the microbiological ITT (mITT) population. RESULTS: The mITT population comprised 511 participants (264 ceftolozane/tazobactam, 247 meropenem). Baseline LRT pathogens included Klebsiella pneumoniae (34.6%), Pseudomonas aeruginosa (25.0%) and Escherichia coli (18.2%). Among baseline Enterobacterales isolates, 171/456 (37.5%) were ESBL positive. For Gram-negative baseline LRT pathogens, susceptibility rates were 87.0% for ceftolozane/tazobactam and 93.3% for meropenem. For Gram-negative pathogens, 28 day ACM [52/259 (20.1%) and 62/240 (25.8%)], clinical cure rates [157/259 (60.6%) and 137/240 (57.1%)] and microbiological eradication rates [189/259 (73.0%) and 163/240 (67.9%)] were comparable with ceftolozane/tazobactam and meropenem, respectively. Per-pathogen microbiological eradication for Enterobacterales [145/195 (74.4%) and 129/185 (69.7%); 95% CI: -4.37 to 13.58], ESBL-producing Enterobacterales [56/84 (66.7%) and 52/73 (71.2%); 95% CI: -18.56 to 9.93] and P. aeruginosa [47/63 (74.6%) and 41/65 (63.1%); 95% CI: -4.51 to 19.38], respectively, were also comparable. CONCLUSIONS: In mechanically ventilated participants with nosocomial pneumonia owing to Gram-negative pathogens, ceftolozane/tazobactam was comparable with meropenem for per-pathogen 28 day ACM and clinical and microbiological response.

• MeSH
• antibakteriální látky * terapeutické užití   MeSH
• bakteriální pneumonie * farmakoterapie   MeSH
• cefalosporiny terapeutické užití   MeSH
• lidé MeSH
• mechanické ventilátory MeSH
• meropenem terapeutické užití   MeSH
• mikrobiální testy citlivosti MeSH
• nemocnice MeSH
• prospektivní studie MeSH
• Pseudomonas aeruginosa MeSH
• tazobaktam terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH

• MeSH
• Acinetobacter baumannii patogenita   MeSH
• acitretin aplikace a dávkování   MeSH
• acyklovir terapeutické užití   MeSH
• biopsie MeSH
• Corynebacterium patogenita   MeSH
• Darierova nemoc * diagnóza   komplikace   patologie   MeSH
• erytém etiologie   MeSH
• foskarnet aplikace a dávkování   MeSH
• horečka etiologie   MeSH
• hydrokortison aplikace a dávkování   MeSH
• Kaposiho erupce variceliformní etiologie   farmakoterapie   patologie   virologie   MeSH
• Klebsiella pneumoniae patogenita   MeSH
• kombinace léků piperacilin a tazobactam terapeutické užití   MeSH
• léková rezistence MeSH
• lidé středního věku MeSH
• lidé MeSH
• lidský herpesvirus 1 patogenita   MeSH
• meropenem aplikace a dávkování   MeSH
• neúspěšná terapie MeSH
• oxacilin terapeutické užití   MeSH
• pneumonie etiologie   komplikace   virologie   MeSH
• progrese nemoci MeSH
• umělé dýchání MeSH
• výsledek terapie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

BACKGROUND: Ceftolozane/tazobactam is approved for treatment of hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP) at double the dose approved for other infection sites. Among nosocomial pneumonia subtypes, ventilated HABP (vHABP) is associated with the lowest survival. In the ASPECT-NP randomized, controlled trial, participants with vHABP treated with ceftolozane/tazobactam had lower 28-day all-cause mortality (ACM) than those receiving meropenem. We conducted a series of post hoc analyses to explore the clinical significance of this finding. METHODS: ASPECT-NP was a multinational, phase 3, noninferiority trial comparing ceftolozane/tazobactam with meropenem for treating vHABP and VABP; study design, efficacy, and safety results have been reported previously. The primary endpoint was 28-day ACM. The key secondary endpoint was clinical response at test-of-cure. Participants with vHABP were a prospectively defined subgroup, but subgroup analyses were not powered for noninferiority testing. We compared baseline and treatment factors, efficacy, and safety between ceftolozane/tazobactam and meropenem in participants with vHABP. We also conducted a retrospective multivariable logistic regression analysis in this subgroup to determine the impact of treatment arm on mortality when adjusted for significant prognostic factors. RESULTS: Overall, 99 participants in the ceftolozane/tazobactam and 108 in the meropenem arm had vHABP. 28-day ACM was 24.2% and 37.0%, respectively, in the intention-to-treat population (95% confidence interval [CI] for difference: 0.2, 24.8) and 18.2% and 36.6%, respectively, in the microbiologic intention-to-treat population (95% CI 2.5, 32.5). Clinical cure rates in the intention-to-treat population were 50.5% and 44.4%, respectively (95% CI - 7.4, 19.3). Baseline clinical, baseline microbiologic, and treatment factors were comparable between treatment arms. Multivariable regression identified concomitant vasopressor use and baseline bacteremia as significantly impacting ACM in ASPECT-NP; adjusting for these two factors, the odds of dying by day 28 were 2.3-fold greater when participants received meropenem instead of ceftolozane/tazobactam. CONCLUSIONS: There were no underlying differences between treatment arms expected to have biased the observed survival advantage with ceftolozane/tazobactam in the vHABP subgroup. After adjusting for clinically relevant factors found to impact ACM significantly in this trial, the mortality risk in participants with vHABP was over twice as high when treated with meropenem compared with ceftolozane/tazobactam. TRIAL REGISTRATION: clinicaltrials.gov, NCT02070757. Registered 25 February, 2014, clinicaltrials.gov/ct2/show/NCT02070757.

• MeSH
• antibakteriální látky farmakologie   normy   terapeutické užití   MeSH
• bakteriální pneumonie farmakoterapie   MeSH
• cefalosporiny farmakologie   normy   terapeutické užití   MeSH
• dvojitá slepá metoda MeSH
• hodnocení ekvivalence jako téma MeSH
• lidé středního věku MeSH
• lidé MeSH
• logistické modely MeSH
• meropenem farmakologie   normy   terapeutické užití   MeSH
• nozokomiální pneumonie farmakoterapie   MeSH
• retrospektivní studie MeSH
• senioři MeSH
• tazobaktam farmakologie   normy   terapeutické užití   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH

BACKGROUND: Meropenem dosing for septic critically patients is difficult due to pathophysiological changes associated with sepsis as well as supportive symptomatic therapies. A prospective single-center study assessed whether fluid retention alters meropenem pharmacokinetics and the achievement of the pharmacokinetic/pharmacodynamic (PK/PD) targets for efficacy. METHODS: Twenty-five septic ICU patients (19 m, 6f) aged 32-86 years with the mean APACHE II score of 20.2 (range 11-33), suffering mainly from perioperative intra-abdominal or respiratory infections and septic shock (n = 18), were investigated over three days after the start of extended 3-h i.v. infusions of meropenem q8h. Urinary creatinine clearance (CLcr) and cumulative fluid balance (CFB) were measured daily. Plasma meropenem was measured, and Bayesian estimates of PK parameters were calculated. RESULTS: Eleven patients (9 with peritonitis) were classified as fluid overload (FO) based on a positive day 1 CFB of more than 10% body weight. Compared to NoFO patients (n = 14, 11 with pneumonia), the FO patients had a lower meropenem clearance (CLme 8.5 ± 3.2 vs 11.5 ± 3.5 L/h), higher volume of distribution (V1 14.9 ± 3.5 vs 13.5 ± 4.1 L) and longer half-life (t1/2 1.4 ± 0.63 vs 0.92 ± 0.54 h) (p < 0.05). Over three days, the CFB of the FO patients decreased (11.7 ± 3.3 vs 6.7 ± 4.3 L, p < 0.05) and the PK parameters reached the values comparable with NoFO patients (CLme 12.4 ± 3.8 vs 11.5 ± 2.0 L/h, V1 13.7 ± 2.0 vs 14.0 ± 5.1 L, t1/2 0.81 ± 0.23 vs 0.87 ± 0.40 h). The CLcr and Cockroft-Gault CLcr were stable in time and comparable. The correlation with CLme was weak to moderate (CLcr, day 3 CGCLcr) or absent (day 1 and 2 CGCLcr). Dosing with 2 g meropenem q8h ensured adequate concentrations to treat infections with sensitive pathogens (MIC 2 mg/L). The proportion of pre-dose concentrations exceeding the MIC 8 mg/L and the fraction time with a target-exceeding concentration were higher in the FO group (day 1-3 f Cmin > MIC: 67 vs 27%, p < 0.001; day 1%f T > MIC: 79 ± 17 vs 58 ± 17, p < 0.05). CONCLUSIONS: These findings emphasize the importance of TDM and a cautious approach to augmented maintenance dosing of meropenem to patients with FO infected with less susceptible pathogens, if guided by population covariate relationships between CLme and creatinine clearance.

• MeSH
• antibakteriální látky metabolismus   farmakokinetika   MeSH
• APACHE MeSH
• Bayesova věta MeSH
• dospělí MeSH
• farmakokinetika * MeSH
• jednotky intenzivní péče organizace a řízení   statistika a číselné údaje   MeSH
• kritický stav terapie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• meropenem metabolismus   farmakokinetika   MeSH
• prospektivní studie MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• sepse farmakoterapie   patofyziologie   MeSH
• vodní a elektrolytová rovnováha účinky léků   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH