The emergence of biofilm-induced drug tolerance poses a critical challenge to public healthcare management. Pseudomonas aeruginosa, a gram-negative opportunistic bacterium, is involved in various biofilm-associated infections in human hosts. Towards this direction, in the present study, a combinatorial approach has been explored as it is a demonstrably effective strategy for managing microbial infections. Thus, P. aeruginosa has been treated with cuminaldehyde (a naturally occurring phytochemical) and gentamicin (an aminoglycoside antibiotic) in connection to the effective management of the biofilm challenges. It was also observed that the test molecules could show increased antimicrobial activity against P. aeruginosa. A fractional inhibitory concentration index (FICI) of 0.65 suggested an additive interaction between cuminaldehyde and gentamicin. Besides, a series of experiments such as crystal violet assay, estimation of extracellular polymeric substance (EPS), and microscopic images indicated that an enhanced antibiofilm activity was obtained when the selected compounds were applied together on P. aeruginosa. Furthermore, the combination of the selected compounds was found to reduce the secretion of virulence factors from P. aeruginosa. Taken together, this study suggested that the combinatorial application of cuminaldehyde and gentamicin could be considered an effective approach towards the control of biofilm-linked infections caused by P. aeruginosa.
- MeSH
- Anti-Bacterial Agents * pharmacology MeSH
- Benzaldehydes * pharmacology MeSH
- Biofilms * drug effects MeSH
- Cymenes pharmacology MeSH
- Virulence Factors MeSH
- Gentamicins * pharmacology MeSH
- Humans MeSH
- Microbial Sensitivity Tests * MeSH
- Pseudomonas aeruginosa * drug effects physiology MeSH
- Drug Synergism MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
BACKGROUND: Systemically administered antibiotics are thought to penetrate the wounds more effectively during negative pressure wound therapy (NPWT).To test this hypothesis total and free antibiotic concentrations were quantified in serum and wound exudate. METHODS: UHPLC-MS/MS methods were developed and validated for the determination of ceftazidime, cefepime, cefotaxime, cefuroxime, cefazolin, meropenem, oxacillin, piperacillin with tazobactam, clindamycin, ciprofloxacin, sulfamethoxazole/trimethoprim (cotrimoxazole), gentamicin, vancomycin, and linezolid. The unbound antibiotic fraction was obtained by ultrafiltration using a Millipore Microcon-30kda Centrifugal Filter Unit. Analysis was performed on a 1.7-μm Acquity UPLC BEH C18 2.1 × 100-mm column with a gradient elution. RESULTS: The validation was performed for serum, exudates and free fractions. For all matrices, requirements were met regarding linearity, precision, accuracy, limit of quantitation, and matrix effect. The coefficient of variation was in the range of 1.2-13.6%.and the recovery 87.6-115.6%, respectively. Among the 29 applications of antibiotics thus far, including vancomycin, clindamycin, ciprofloxacin, oxacillin, cefepime, cefotaxime, cotrimoxazole, and gentamicin, total and free antibiotic concentrations in serum and exudate were correlated. CONCLUSION: This method can accurately quantify the total and free concentrations of 16 antibiotics. Comparison of concentration ratios between serum and exudates allows for monitoring individual antibiotics' penetration capacity in patients receiving NPWT.
- MeSH
- Anti-Bacterial Agents MeSH
- Cefepime MeSH
- Cefotaxime MeSH
- Chromatography, Liquid methods MeSH
- Ciprofloxacin MeSH
- Exudates and Transudates MeSH
- Gentamicins MeSH
- Wound Infection * MeSH
- Clindamycin MeSH
- Trimethoprim, Sulfamethoxazole Drug Combination MeSH
- Humans MeSH
- Oxacillin MeSH
- Sternotomy MeSH
- Tandem Mass Spectrometry methods MeSH
- Negative-Pressure Wound Therapy * MeSH
- Vancomycin MeSH
- Chromatography, High Pressure Liquid methods MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
Although progress is evident in the effective treatment of joint replacement-related infections, it still remains a serious issue in orthopedics. As an example, the local application of antibiotics-impregnated bone grafts supplies the high drug levels without systemic side effects. However, antibiotics in the powder or solution form could be a risk for local toxicity and do not allow sustained drug release. The present study evaluated the use of an antibiotic gel, a water-in-oil emulsion, and a PLGA microparticulate solid dispersion as depot delivery systems impregnating bone grafts for the treatment of joint replacement-related infections. The results of rheological and bioadhesive tests revealed the suitability of these formulations for the impregnation of bone grafts. Moreover, no negative effect on proliferation and viability of bone marrow mesenchymal stem cells was detected. An ex vivo dissolution test of vancomycin hydrochloride and gentamicin sulphate from the impregnated bone grafts showed a reduced burst and prolonged drug release. The PLGA-based formulation proved to be particularly promising, as one-day burst release drugs was only 15% followed with sustained antibiotics release with zero-order kinetics. The results of this study will be the basis for the development of a new product in the Tissue Section of the University Hospital for the treatment of bone defects and infections of joint replacements.
- MeSH
- Anti-Bacterial Agents pharmacology therapeutic use MeSH
- Arthroplasty, Replacement * MeSH
- Emulsions MeSH
- Gentamicins MeSH
- Drug Delivery Systems MeSH
- Humans MeSH
- Powders MeSH
- Hematopoietic Stem Cell Transplantation * MeSH
- Vancomycin MeSH
- Water MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
Enteric bacteria have to adapt to environmental stresses in the human gastrointestinal tract such as acid and nutrient stress, oxygen limitation and exposure to antibiotics. Membrane lipid composition has recently emerged as a key factor for stress adaptation. The E. coli ravA-viaA operon is essential for aminoglycoside bactericidal activity under anaerobiosis but its mechanism of action is unclear. Here we characterise the VWA domain-protein ViaA and its interaction with the AAA+ ATPase RavA, and find that both proteins localise at the inner cell membrane. We demonstrate that RavA and ViaA target specific phospholipids and subsequently identify their lipid-binding sites. We further show that mutations abolishing interaction with lipids restore induced changes in cell membrane morphology and lipid composition. Finally we reveal that these mutations render E. coli gentamicin-resistant under fumarate respiration conditions. Our work thus uncovers a ravA-viaA-based pathway which is mobilised in response to aminoglycosides under anaerobiosis and engaged in cell membrane regulation.
- MeSH
- Adenosine Triphosphatases * metabolism MeSH
- Aminoglycosides * pharmacology MeSH
- Anti-Bacterial Agents pharmacology MeSH
- ATPases Associated with Diverse Cellular Activities metabolism MeSH
- Escherichia coli * drug effects enzymology MeSH
- Phospholipids MeSH
- Fumarates MeSH
- Gentamicins MeSH
- Oxygen metabolism MeSH
- Membrane Lipids MeSH
- Escherichia coli Proteins * metabolism MeSH
- Publication type
- Journal Article MeSH
The number of antibiotic-resistant bacterial strains is increasing due to the excessive and inappropriate use of antibiotics, which are therefore becoming ineffective. Here, we report an effective way of enhancing and restoring the antibacterial activity of inactive antibiotics by applying them together with a cyanographene/Ag nanohybrid, a nanomaterial that is applied for the first time for restoring the antibacterial activity of antibiotics. The cyanographene/Ag nanohybrid was synthesized by chemical reduction of a precursor material in which silver cations are coordinated on a cyanographene sheet. The antibacterial efficiency of the combined treatment was evaluated by determining fractional inhibitory concentrations (FIC) for antibiotics with different modes of action (gentamicin, ceftazidime, ciprofloxacin, and colistin) against the strains Escherichia coli, Pseudomonas aeruginosa, and Enterobacter kobei with different resistance mechanisms. Synergistic and partial synergistic effects against multiresistant strains were demonstrated for all of these antibiotics except ciprofloxacin, which exhibited an additive effect. The lowest average FICs equal to 0.29 and 0.39 were obtained for colistin against E. kobei and for gentamicin against E. coli, respectively. More importantly, we have experimentally confirmed for the first time, that interaction between the antibiotic's mode of action and the mechanism of bacterial resistance strongly influenced the combined treatment's efficacy.
- MeSH
- Anti-Bacterial Agents * chemistry pharmacology MeSH
- Ciprofloxacin pharmacology MeSH
- Escherichia coli MeSH
- Gentamicins pharmacology MeSH
- Colistin * pharmacology MeSH
- Microbial Sensitivity Tests MeSH
- Pseudomonas aeruginosa MeSH
- Drug Synergism MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
BACKGROUND: Through regulation of signaling pathways, microRNAs (miRNAs) can be involved in sepsis and associated organ dysfunction. The aims of this study were to track the 7-day time course of blood miRNAs in patients with sepsis treated with vancomycin, gentamicin, or a non-nephrotoxic antibiotic and miRNA associations with neutrophil gelatinase-associated lipokalin (NGAL), creatinine, procalcitonin, interleukin-6, and acute kidney injury (AKI) stage. METHODS: Of 46 adult patients, 7 were on vancomycin, 20 on gentamicin, and 19 on another antibiotic. Blood samples were collected on days 1, 4, and 7 of treatment, and miRNAs were identified using quantitative reverse transcription PCR. RESULTS: The results showed no relationship between miRNA levels and biochemical variables on day 1. By day 7 of gentamicin treatment miR-15a-5p provided good discrimination between AKI and non-AKI (area under curve, 0.828). In patients taking vancomycin, miR-155-5p and miR-192-5p positively correlated with creatinine and NGAL values, and miR-192-5p and miR-423-5p positively correlated with procalcitonin and interleukin-6 in patients treated with a non-nephrotoxic antibiotic. In patients together we found positive correlation between miR-155-5p and miR-423-5p and all biochemical markers. CONCLUSION: The results suggest that these four miRNAs may serve as diagnostic or therapeutic tool in sepsis, renal injury and nephrotoxic treatment. TRIAL REGISTRATION: ClinicalTrials.gov , ID: NCT04991376 . Registered on 27 July 2021.
- MeSH
- Acute Kidney Injury * complications MeSH
- Anti-Bacterial Agents therapeutic use MeSH
- Circulating MicroRNA * MeSH
- Adult MeSH
- Gentamicins MeSH
- Interleukin-6 metabolism MeSH
- Creatinine MeSH
- Humans MeSH
- Lipocalin-2 MeSH
- MicroRNAs * genetics MeSH
- Procalcitonin MeSH
- Sepsis * complications MeSH
- Vancomycin therapeutic use MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Clinical Study MeSH
- Research Support, Non-U.S. Gov't MeSH
S narůstající bakteriální rezistencí ubývají možnosti standardní léčby pneumonie. Slibným rozšířením terapie je inhalační aplikace antibiotik. Pomocí rešerše dostupné literatury jsou v tomto článku navrženy indikace a omezení inhalačních antibiotik v off-label terapii těžké pneumonie u pacientů bez cystické fibrózy, popsány optimální způsoby podání a rizika této léčby. Teoretické předpoklady a omezená data ze studií naznačují možný příznivý účinek inhalačního podání antibiotik u pacientů s multirezistentní gramnegativní pneumonií. Jde o antibiotika s omezeným průnikem do plicních struktur a zároveň významnou systémovou toxicitou limitující jejich dávkování: polymyxiny a aminoglykosidy. Doporučení odborných společností a souhrnné práce většinově podporují jejich použití u infekcí patogeny citlivými pouze k těmto antibiotikům. Způsob podání může ovlivnit depozici antibiotik v dýchacích cestách, a tím jejich účinek. Vhodné je předléčit pacienta bronchodilatanciem a v případě umělé plicní ventilace použít doporučené nastavení. Podle okolností může být použita pouze inhalační léčba, či současné podání stejného či jiného antibiotika intravenózně. V případě rizika významných systémových koncentrací podávaného antibiotika je důležité jejich monitorování. Inhalační antibiotická terapie by neměla být podána u pacientů s těžkou hypoxemií nebo rizikem bronchospasmu. Inhalační podání antibiotik je v terapii pneumonie pacientů v prostředí intenzivní péče celosvětově využívaným postupem. Jde o neschválenou terapii s omezenou oporou v literatuře a mělo by se k ní přistupovat pouze u pacientů s limitovanými možnostmi léčby po pečlivém individuálním zvážení prospěchu a rizika.
- MeSH
- Amikacin administration & dosage pharmacology therapeutic use MeSH
- Anti-Bacterial Agents administration & dosage pharmacology therapeutic use MeSH
- Administration, Inhalation MeSH
- Gentamicins administration & dosage pharmacology therapeutic use MeSH
- Colistin administration & dosage pharmacology therapeutic use MeSH
- Humans MeSH
- Pneumonia * drug therapy MeSH
- Check Tag
- Humans MeSH
- Publication type
- Review MeSH
BACKGROUND: Total gentamicin is a sum of five congeners C1, C1a, C2, C2a and minor C2b, which differ from each other in their methylation on the purpurosamine ring. Liquid chromatography with mass detection (LC-MS/MS) and specified calibration material enables the concentration of total gentamicin and its individual congeners to be analysed. METHODS: 50 µL serum was precipitated with acetonitrile in the presence of 0.5 mol/L formic acid. A RP BEH C18 1.7 µm 2.1x50 mm column maintained at 30 °C and tobramicin as the internal standard were used. Mass detection was performed in positive electrospray. The gentamicin results were compared with fluorescence polarization immunoassay (FPIA) and chemiluminiscent microparticle immunoassay (CMIA). Passing-Bablock regression analysis and Bland-Altman analysis were used. RESULTS: Calibration curves for individual gentamicin congeners were linear with correlation coefficients between 0.997 and 0.998. Recovery was 91.6-102.0% and the coefficients of variation 1.4-8.4%. The total gentamicin concentration was compared with immunoassay FPIA (LC-MSgen = 0.9798xPFIAgen) and CMIA (LC MSgen = 0.9835xCMIAgen) both with significant correlation (p < 0.001). CONCLUSION: The LC-MS/MS method is fast and precise and can be applied to routine TDM in patients. Comparing it to immunoassays makes it possible to measure concentration of gentamicin congeners, which may be important in the case of their different pharmacokinetics.
AIMS: Preoperative chemical vestibular ablation can reduce vestibular symptoms in patients who have gone through vestibular schwannoma resection. The goal of this study was to determine whether chemical vestibular prehabituation influences the patients' post-operative perception of visual stimulation, mental status and quality of life. We also tried to find out whether increases of optokinetic nystagmus, measured by routine electronystagmography, correlate with subjective symptoms. METHODS: We preoperatively administered (2 months prior to surgery) 0.5 - 1.0 mL of 40 mg/mL nonbuffered gentamicin in three intratympanic instillations in 11 patients. Head impulse and caloric tests confirmed reduction of vestibular function in all patients. The control group consisted of 21 patients. Quality of life in both groups was evaluated using the Glasgow Benefit Inventory, the Glasgow Health Status Inventory and the Dizziness Handicap Inventory questionnaires. Visual symptoms and optokinetic sensation were evaluated using a specific questionnaire developed by our team and by measuring gains preoperatively and postoperatively in both groups using routine electronystagmography. The psychological profile was evaluated using the Zung Self-Rating Depression Scale and the Generalised Anxiety Disorder Assessment questionnaires. RESULTS: There were no statistically significant differences between both groups with regards to the results of the questionnaires. Patients who received preoperative gentamicin were less sensitive to visual stimulation (P<0.10) and many of them had a significantly higher gain in the optokinetic nystagmus than the control group in the preoperative stage. CONCLUSION: Pre-treatment with gentamicin helps to lower anxiety levels in patients and improves their general postoperative status. Pre-treated patients are also less sensitive to optokinetic stimulation. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03638310.
- MeSH
- Anti-Bacterial Agents administration & dosage MeSH
- Sensation physiology MeSH
- Adult MeSH
- Gentamicins administration & dosage MeSH
- Quality of Life psychology MeSH
- Middle Aged MeSH
- Humans MeSH
- Young Adult MeSH
- Postoperative Period MeSH
- Preoperative Care * MeSH
- Surveys and Questionnaires MeSH
- Aged MeSH
- Vestibule, Labyrinth surgery MeSH
- Neuroma, Acoustic surgery MeSH
- Visual Acuity physiology MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Young Adult MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
Acute kidney injury is a common complication in critically ill patients with sepsis and/or septic shock. Further, some essential antimicrobial treatment drugs are themselves nephrotoxic. For this reason, timely diagnosis and adequate therapeutic management are paramount. Of potential acute kidney injury (AKI) biomarkers, non-protein-coding RNAs are a subject of ongoing research. This review covers the pathophysiology of vancomycin and gentamicin nephrotoxicity in particular, septic AKI and the microRNAs involved in the pathophysiology of both syndromes. PubMED, UptoDate, MEDLINE and Cochrane databases were searched, using the terms: biomarkers, acute kidney injury, antibiotic nephrotoxicity, sepsis, miRNA and nephrotoxicity. A comprehensive review describing pathophysiology and potential biomarkers of septic and toxic acute kidney injury in septic patients was conducted. In addition, five miRNAs: miR-15a-5p, miR-192-5p, miR-155-5p, miR-486-5p and miR-423-5p specific to septic and toxic acute kidney injury in septic patients, treated by nephrotoxic antibiotic agents (vancomycin and gentamicin) were identified. However, while these are at the stage of clinical testing, preclinical and clinical trials are needed before they can be considered useful biomarkers or therapeutic targets of AKI in the context of antibiotic nephrotoxicity or septic injury.
- MeSH
- Acute Kidney Injury chemically induced diagnosis etiology physiopathology MeSH
- Anti-Bacterial Agents adverse effects therapeutic use MeSH
- Biomarkers analysis MeSH
- Gentamicins adverse effects therapeutic use MeSH
- Kidney drug effects physiopathology MeSH
- Humans MeSH
- MicroRNAs analysis MeSH
- Sepsis complications diagnosis drug therapy physiopathology MeSH
- Vancomycin adverse effects therapeutic use MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
