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The Journal of Antibiotics Jul 1976A sisomicin fermentation carried out in the presence of (methyl-14C)-L-methionine resulted in a crude mixture, composed of methyl-14C-labeled sisomicin as a major...
A sisomicin fermentation carried out in the presence of (methyl-14C)-L-methionine resulted in a crude mixture, composed of methyl-14C-labeled sisomicin as a major component; and two 4''-C-desmethylsisomicin (66-40B and 66-40D) isomer-like components, an unidentified component and a gentamicin A-like antibiotic as minor components. When (methyl-14C)-L-methionine was added in an early stage of the fermentation (24 hours), incorporation of methyl-14C-label into polar components (e.g., gentamicin A-like antibiotic) preceded that into sisomicin. Chromatographic evidence for the bioconversion of (methyl-14C)-gentamicin A to a radioactive sisomicin-like product (possibly (3''-N-methyl-14C)-sisomicin) was seen, when a Micromonospora blocked mutant was incubated in the presence of the former antibiotic.
Topics: Anti-Bacterial Agents; Biotransformation; Fermentation; Gentamicins; Methionine; Micromonospora; Sisomicin; Time Factors
PubMed: 956052
DOI: 10.7164/antibiotics.29.677 -
BMJ Open Dec 2021Gentamicin is the aminoglycoside antibiotic of choice in the UK. It has a narrow therapeutic index: underdosing results in inefficacy while overdosing is characterised...
OBJECTIVES
Gentamicin is the aminoglycoside antibiotic of choice in the UK. It has a narrow therapeutic index: underdosing results in inefficacy while overdosing is characterised by nephrotoxicity and ototoxicity. To improve patient safety, hospitals have protocols for the prescription of gentamicin, which vary in complexity and approach. This study aimed to explore two distinct protocols for prescribing gentamicin in hospital settings, in order to understand the mechanisms they trigger and the outcomes they achieve.
SETTING
A mixed-methods realist evaluation explored gentamicin prescribing protocols in two hospital surgical admissions units in South West England between January and August 2018. Site 1 had a traditional, complex protocol, while site 2 took a simplified protocol.
PARTICIPANTS
Testing the initial programme theory (IPT) involved semi-structured audio-recorded interviews of a volunteer sample of healthcare professionals (HCPs) involved in the prescribing and administering process, alongside a clinical audit reviewing accuracy of gentamicin prescribing.
OUTCOME MEASURES
Three sequential phases were used to identify factors in a successful protocol: IPT generation; testing; refinement of the IPT. The IPT was generated by literature search and analysis of existing protocols of sites 1 and 2. Refinement of the IPT synthesised the results of the quantitative and qualitative research to identify the key characteristics of a successful protocol.
RESULTS
One hundred gentamicin prescriptions were reviewed, with a mean accuracy of gentamicin prescribing at site 1 of 65.67% and at site 2 of 78.79% (p<0.01). Thirty HCPs were interviewed. Key contexts were identified including prescriptiveness, experience and availability of patient information. These triggered hidden mechanisms including uncertainty, fear, confidence and frustration leading to both intended outcomes but also unintended outcomes such as deviation from protocol and unnecessary gentamicin levels.
CONCLUSIONS
A simplified prescribing protocol for gentamicin is better accepted by prescribers, leading to better adherence to protocol and more accurate prescribing.
Topics: Gentamicins; Health Personnel; Hospitals; Humans; Qualitative Research; United Kingdom
PubMed: 34949620
DOI: 10.1136/bmjopen-2021-052697 -
Microbiology Spectrum Aug 2023Enterococcus faecalis is a hospital-associated opportunistic pathogen that can cause infections with high mortality, such as infective endocarditis. With an increasing...
Enterococcus faecalis is a hospital-associated opportunistic pathogen that can cause infections with high mortality, such as infective endocarditis. With an increasing occurrence of multidrug-resistant enterococci, there is a need for alternative strategies to treat enterococcal infections. We isolated a gentamicin-hypersusceptible E. faecalis strain from a patient with infective endocarditis that carried a mutation in the alpha-carbonic anhydrase (α-CA) and investigated how disruption of α-CA sensitized E. faecalis to killing with gentamicin. The gentamicin-hypersusceptible α-CA mutant strain showed increased intracellular gentamicin uptake in comparison to an isogenic strain encoding full-length, wild-type α-CA. We hypothesized that increased gentamicin uptake could be due to increased proton motive force (PMF), increased membrane permeability, or both. We observed increased intracellular ATP production in the α-CA mutant strain, suggesting increased PMF-driven gentamicin uptake contributed to the strain's gentamicin susceptibility. We also analyzed the membrane permeability and fatty acid composition of isogenic wild-type and α-CA mutant strains and found that the mutant displayed a membrane composition that was consistent with increased membrane permeability. Finally, we observed that exposure to the FDA-approved α-CA inhibitor acetazolamide lowered the gentamicin MIC of eight genetically diverse E. faecalis strains with intact α-CA but did not change the MIC of the α-CA mutant strain. These results suggest that α-CA mutation or inhibition increases PMF and alters membrane permeability, leading to increased uptake of gentamicin into E. faecalis. This connection could be exploited clinically to provide new combination therapies for patients with enterococcal infections. Enterococcal infections can be difficult to treat, and new therapeutic approaches are needed. In studying an E. faecalis clinical strain from an infected patient, we found that the bacteria were rendered hypersusceptible to aminoglycoside antibiotics through a mutation that disrupted the α-CA. Our follow-on work suggested two different ways that α-CA disruption causes increased gentamicin accumulation in E. faecalis: increased proton motive force-powered uptake and increased membrane permeability. We also found that a mammalian CA inhibitor could sensitize a variety of E. faecalis strains to killing with gentamicin. Given that mammalian CA inhibitors are frequently used to treat conditions such as glaucoma, hypertension, and epilepsy, our findings suggest that these "off-the-shelf" inhibitors could also be useful partner antibiotics for the treatment of E. faecalis infections.
Topics: Animals; Humans; Enterococcus; Carbonic Anhydrases; Microbial Sensitivity Tests; Anti-Bacterial Agents; Gentamicins; Endocarditis, Bacterial; Gram-Positive Bacterial Infections; Mammals
PubMed: 37260400
DOI: 10.1128/spectrum.03963-22 -
The Journal of Antimicrobial... Sep 2012The aim of this study was to investigate different hydrophobic gentamicin formulations [gentamicin-bis(2-ethylhexyl) sulfosuccinate (GEN-AOT), microstructured GEN-AOT...
OBJECTIVES
The aim of this study was to investigate different hydrophobic gentamicin formulations [gentamicin-bis(2-ethylhexyl) sulfosuccinate (GEN-AOT), microstructured GEN-AOT (PCA GEN-AOT) and GEN-AOT-loaded poly(lactide-co-glycolide) acid (PLGA) nanoparticles (NPs)] in view of improving its therapeutic index against intracellular bacteria. The intracellular accumulation, subcellular distribution and intracellular activity of GEN-AOT and NPs in different monocytic-macrophagic cell lines were studied.
METHODS
Human THP-1 and murine J774 phagocytic cells were incubated with GEN-AOT formulations at relevant extracellular concentrations [from 1× MIC to 18 mg/L (human C(max))], and their intracellular accumulation, subcellular distribution and toxicity were evaluated and compared with those of conventional unmodified gentamicin. Intracellular activity of the formulations was determined against bacteria showing different subcellular localizations, namely Staphylococcus aureus (phagolysosomes) and Listeria monocytogenes (cytosol).
RESULTS
GEN-AOT formulations accumulated 2-fold (GEN-AOT) to 8-fold (GEN-AOT NPs) more than gentamicin in phagocytic cells, with a predominant subcellular localization in the soluble fraction (cytosol) and with no significant cellular toxicity. NP formulations allowed gentamicin to exert its intracellular activity after shorter incubation times and/or at lower concentrations. With an extracellular concentration of 10× MIC, a 1 log(10) decrease in S. aureus intracellular inoculum was obtained after 12 h instead of 24 h for NPs versus free gentamicin, and a static effect was observed against L. monocytogenes at 24 h with NPs, while free gentamicin was ineffective.
CONCLUSIONS
GEN-AOT formulations yielded a high cellular accumulation, especially in the cytosol, which resulted in improved efficacy against both intracellular S. aureus and L. monocytogenes.
Topics: Animals; Anti-Bacterial Agents; Cell Line; Gentamicins; Humans; Listeria monocytogenes; Macrophages; Mice; Microbial Sensitivity Tests; Nanoparticles; Staphylococcus aureus
PubMed: 22615297
DOI: 10.1093/jac/dks172 -
BioMed Research International 2018Copal® spacem is a new PMMA bone cement for fabricating spacers. This study compares elution of gentamicin, elution of vancomycin, and compressive strength of Copal®... (Comparative Study)
Comparative Study
Comparison of Elution Characteristics and Compressive Strength of Biantibiotic-Loaded PMMA Bone Cement for Spacers: Copal® Spacem with Gentamicin and Vancomycin versus Palacos® R+G with Vancomycin.
PURPOSE
Copal® spacem is a new PMMA bone cement for fabricating spacers. This study compares elution of gentamicin, elution of vancomycin, and compressive strength of Copal® spacem and of Palacos® R+G at different vancomycin loadings in the powder of the cements. We hypothesized that antibiotic elution of Copal® spacem is superior at comparable compressive strength.
METHODS
Compression test specimens were fabricated using Copal® spacem manually loaded with 0.5 g gentamicin and additionally 2 g, 4 g, and 6 g of vancomycin per 40 g of cement powder (COP specimens) and using 0.5 g gentamicin premixed Palacos® R+G manually loaded with 2 g, 4 g, and 6 g of vancomycin per 40 g of cement powder (PAL specimens). These specimens were used for determination of gentamicin and vancomycin elution (in fetal calf serum, at 22°C) and for determination of compressive strength both prior and following the elution tests.
RESULTS
Cumulative gentamicin concentrations (p < 0.005) and gentamicin concentration after 28 days (p ≤ 0.043) were significantly lower for COP specimens compared to PAL specimens. Cumulative vancomycin concentrations were significantly higher (p ≤ 0.043) for COP specimens after the second day. Vancomycin concentrations after 28 days were not significantly higher for the Copal specimens loaded with 2 g and 4 g of vancomycin. Compressive strength was not significantly different between COP specimens and PAL specimens before elution tests. Compressive strength after the elution tests was significantly lower (p = 0.005) for COP specimens loaded with 2 g of vancomycin.
CONCLUSION
We could not demonstrate consistent superior antibiotic elution from Copal® spacem compared to Palacos® R+G for fabricating gentamicin and vancomycin loaded spacers. The results do not favor Copal® spacem over Palacos® R+G for the use as a gentamicin and vancomycin biantibiotic-loaded spacer.
Topics: Acrylic Resins; Bone Cements; Compressive Strength; Gentamicins; Materials Testing; Polymethyl Methacrylate; Vancomycin
PubMed: 30410931
DOI: 10.1155/2018/4323518 -
BMC Nephrology Dec 2014The purpose of this study was to evaluate the feasibility of utilizing an in-vitro, closed loop hemodialysis system as a method to assess drug clearance. Secondarily,...
BACKGROUND
The purpose of this study was to evaluate the feasibility of utilizing an in-vitro, closed loop hemodialysis system as a method to assess drug clearance. Secondarily, this study tested the influence of variables (blood flow rate, dialysate flow rate, and type of filter) in the hemodialysis procedure on the clearance of vancomycin and gentamicin.
METHODS
An in-vitro, closed loop hemodialysis system was constructed. The vancomycin (30 mg/L) and gentamicin (25 mg/L) were added to a simulated blood system (SBS). Four conditions (C1-C4) were tested by defining the filter (Polyflux 170H or F180) and the blood and dialysate flow rates (BFR and DFR). All hemodialysis sessions were 3 hours in length and each condition was completed in duplicate. Dialysate effluent was collected in a 50 gallon polyethylene drum. Samples were collected (in duplicate) from the SBS and the dialysate effluent at baseline and at the end of the hemodialysis session. Samples were analyzed for vancomycin and gentamicin with an ultrahigh performance liquid chromatography/tandem mass spectrometry method.
RESULTS
A total of eight 3-hour hemodialysis sessions were conducted. For all tested conditions (C1-C4), vancomycin was undetectable in the SBS at the end of dialysis. However, total vancomycin recovery in the dialysis effluent was 85±18%, suggesting that up to 15% may have adsorbed to the dialysis filter or tubing. Gentamicin clearance from SBS was >98% in all tested conditions. Average gentamicin recovery in the dialysate effluent was 99±15%.
CONCLUSION
Both vancomycin and gentamicin were readily removed by high-flux hemodialysis under all conditions studied. No significant differences in drug clearance were observed between conditions used in this in vitro study. The clinical implications of changing these hemodialysis parameters are unknown.
Topics: Dialysis Solutions; Filtration; Gentamicins; Humans; In Vitro Techniques; Metabolic Clearance Rate; Renal Dialysis; Vancomycin
PubMed: 25526750
DOI: 10.1186/1471-2369-15-204 -
Journal of the Association For Research... Dec 2007Intratympanic (IT) gentamicin injections are effective in the control of episodic vertigo due to Ménière's disease. Histological studies in animals have found that the...
Intratympanic (IT) gentamicin injections are effective in the control of episodic vertigo due to Ménière's disease. Histological studies in animals have found that the loss of type I vestibular hair cells far exceeds that of type II cells after IT gentamicin treatment. The objective of this study was to determine whether this selective toxicity for type I hair cells might be due to selective concentration of the drug by these cells. Gentamicin was localized within the vestibular epithelium by both direct and indirect methods. Gentamicin conjugated to Texas Red(R) was used as a direct tracer, and anti-gentamicin antibody provided an indirect means of localization. Conjugated or unconjugated gentamicin was injected into the left tympanic space of chinchillas. The animals were killed and fixed 1 or 3 weeks post-treatment. Confocal fluorescence microscopy was used to determine the localization of gentamicin in semicircular canal cristae. Results from the animals killed within 1 week of administration showed that numerous type I hair cells still remained throughout the epithelium. The mean intensity in grayscale units (0-255) of anti-gentamicin labeling for type I hair cells was 28.14 (95% CI 24.60-31.69), for type II hair cells was 17.09 (14.99-19.20), and for support cells was 5.35 (5.34-5.46; p < 0.001, ANOVA). Anti-gentamicin antibody labeling appeared in the majority of type I hair cells throughout their cytoplasm, but with greater intensity at the apex (p < 0.001). Intensity of fluorescence with Texas-Red conjugated gentamicin was 25.38 (22.83-27.94) in type I hair cells, 15.60 (14.73-16.48) in type II cells, and 12.62 (12.06-13.17) in support cells (p < 0.001, ANOVA). These results suggest that type I hair cells are more susceptible to gentamicin because they more avidly take up or retain the drug in the early period after administration.
Topics: Animals; Anti-Bacterial Agents; Chinchilla; Gentamicins; Hair Cells, Vestibular; Humans; Immunohistochemistry; Tympanic Membrane; Xanthenes
PubMed: 17899270
DOI: 10.1007/s10162-007-0093-8 -
Journal of Materials Science. Materials... Mar 2022Vascular graft infections (VGI) are severe complications in prosthetic vascular surgery with an incidence ranging from 1 to 6%. In these cases, synthetic grafts are...
Vascular graft infections (VGI) are severe complications in prosthetic vascular surgery with an incidence ranging from 1 to 6%. In these cases, synthetic grafts are commonly used in combination with antimicrobial agents. Expanded polytetrafluoroethylene (ePTFE) is in clinical use as a synthetic graft material and shows promising results by influencing bacterial adhesion. However, the literature on antibiotic-bound ePTFE grafts is scarce. Gentamicin is a frequently used antibiotic for local treatment of surgical site infections, but has not been evaluated as antimicrobial agent on ePTFE grafts. In this study, we examine the antimicrobial efficacy and biocompatibility of novel types of gentamicin-coated ePTFE grafts in vitro. ePTFE grafts coated with gentamicin salt formulations with covalently-bound palmitate were evaluated in two drug concentrations (GP1.75% and GP3.5%). To investigate effects from types of formulations, also suspensions of gentamicin in palmitate as well as polylactide were used at comparable levels (GS + PA and GS + R203). Antibacterial efficacies were estimated by employing a zone of inhibition, growth inhibition and bacterial adhesion assay against Staphylococcus aureus (SA). Cytotoxicity was determined with murine fibroblasts according to the ISO standard 10993-5. Gentamicin-coated ePTFE grafts show low bacterial adherence and strong antibacterial properties in vitro against SA. Bactericidal inhibition lasted until day 11. Highest biocompatibility was achieved using gentamicin palmitate GP1.75% coated ePTFE grafts. ePTFE grafts with gentamicin-coating are effective in vitro against SA growth and adherence. Most promising results regarding antimicrobial properties and biocompatibility were shown with chemically bounded gentamicin palmitate GP1.75% coatings. Graphical abstract.
Topics: Animals; Anti-Bacterial Agents; Blood Vessel Prosthesis; Coated Materials, Biocompatible; Gentamicins; Mice; Polytetrafluoroethylene
PubMed: 35267117
DOI: 10.1007/s10856-022-06650-x -
Amikacin and gentamicin accumulation pharmacokinetics and nephrotoxicity in critically ill patients.Antimicrobial Agents and Chemotherapy Jan 1981Twenty-five critically ill adults receiving blood level-adjusted doses of amikacin were prospectively studied with serum, urine, and, when possible, tissue amikacin...
Twenty-five critically ill adults receiving blood level-adjusted doses of amikacin were prospectively studied with serum, urine, and, when possible, tissue amikacin concentrations. These data were fitted to a two-compartment pharmacokinetic model. Prolonged urine collections or postmortem tissues (or both) were used to confirm predicted tissue accumulation. Nephrotoxicity was also investigated. Patients were defined as having renal damage if they showed an increase in serum creatinine of greater than 0.5 mg/100 ml, an increase in urine beta 2-microglobulin of greater than 50 mg/day, and presence of urinary casts of greater than 500/ml. Renal damage was attributed to amikacin if there was, in addition to the above, tissue accumulation of amikacin of greater than 600 mg. These patients were matched with 25 patients treated with gentamicin during the same time period. There were no statistical differences between the gentamicin- and amikacin-treated patients in age, sex, weight, base-line creatinine clearance, concurrent cephalosporins or diuretics, treatment duration, site of infection, normalized (amikacin/gentamicin dosing ratio of 3:1) total dose, mortality, or tissue accumulation. More amikacin-treated patients (19 of 25) than gentamicin-treated patients (9 of 25) received prior aminoglycosides (P less than 0.01). The only pharmacokinetic parameter that differed between amikacin and gentamicin was a greater K21 for gentamicin. Nephrotoxicity was observed in 4 gentamicin was a greater K21 for gentamicin. Nephrotoxicity was observed in 4 gentamicin-treated patients (16%) and 5 amikacin-treated patients (20%). At a 3:1 dosing ratio, there were no significant differences between amikacin and gentamicin two-compartment pharmacokinetics and nephrotoxic potential in matched critically ill patients, but the trend of these data showed greater amikacin tissue accumulation. However, at an amikacin/gentamicin dosing ratio of 4:1, their tissue accumulation potential appeared to be almost identical.
Topics: Amikacin; Critical Care; Gentamicins; Half-Life; Humans; Kanamycin; Kidney; Kinetics; Tissue Distribution
PubMed: 7247354
DOI: 10.1128/AAC.19.1.147 -
American Journal of Veterinary Research Oct 2000To compare concentrations of gentamicin in serum and bronchial lavage fluid after IV and aerosol administration of gentamicin to horses. (Clinical Trial)
Clinical Trial Randomized Controlled Trial
OBJECTIVE
To compare concentrations of gentamicin in serum and bronchial lavage fluid after IV and aerosol administration of gentamicin to horses.
ANIMALS
9 healthy adult horses.
PROCEDURE
Gentamicin was administered by aerosolization (20 ml of gentamicin solution [50 mg/ml]) and IV injection (6.6 mg of gentamicin/kg of body weight) to each horse, with a minimum of 2 weeks between treatments. Samples of pulmonary epithelial lining fluid were collected by small volume (30 ml) bronchial lavage 0.5, 4, 8, and 24 hours after gentamicin administration. Serum samples were obtained at the same times. All samples were analyzed for gentamicin concentration, and cytologic examinations were performed on aliquots of bronchial lavage fluid collected at 0.5, 8, and 24 hours.
RESULTS
Gentamicin concentrations in bronchial lavage fluid were significantly greater 0.5, 4, and 8 hours after aerosol administration, whereas serum concentrations were significantly less at all times after aerosol administration, compared with IV administration. Neutrophil counts in bronchial lavage fluid increased from 0.5 to 24 hours, regardless of route of gentamicin administration.
CONCLUSIONS AND CLINICAL RELEVANCE
Aerosol administration of gentamicin to healthy horses resulted in gentamicin concentrations in bronchial fluid that were significantly greater than those obtained after IV administration. A mild inflammatory cell response was associated with aerosol delivery of gentamicin and repeated bronchial lavage. Aerosol administration of gentamicin may have clinical use in the treatment of bacterial bronchopneumonia in horses.
Topics: Administration, Inhalation; Animals; Anti-Bacterial Agents; Bronchoalveolar Lavage Fluid; Cross-Over Studies; Female; Gentamicins; Horses; Injections, Intravenous; Male
PubMed: 11039545
DOI: 10.2460/ajvr.2000.61.1185