scholarly journals Colistin Methanesulfonate Is an Inactive Prodrug of Colistin against Pseudomonas aeruginosa

2006 ◽  
Vol 50 (6) ◽  
pp. 1953-1958 ◽  
Author(s):  
Phillip J. Bergen ◽  
Jian Li ◽  
Craig R. Rayner ◽  
Roger L. Nation
Keyword(s):  
Pseudomonas Aeruginosa ◽  
High Performance ◽  
Time Course ◽  
Antimicrobial Activities ◽  
Killing Effect ◽  
Time Profiles ◽  
Concentration Time ◽  
Colistin Methanesulfonate ◽  
Kinetics Of ◽  
Hydrolysis Of

ABSTRACT There is a dearth of information on the pharmacodynamics of “colistin,” despite its increasing use as a last line of defense for treatment of infections caused by multidrug-resistant gram-negative organisms. The antimicrobial activities of colistin and colistin methanesulfonate (CMS) were investigated by studying the time-kill kinetics of each against a type culture of Pseudomonas aeruginosa in cation-adjusted Mueller-Hinton broth. The appearance of colistin from CMS spiked at 8.0 and 32 mg/liter was measured by high-performance liquid chromatography, which generated colistin concentration-time profiles. These concentration-time profiles were subsequently mimicked in other incubations, independent of CMS, by incrementally spiking colistin. When the cultures were spiked with CMS at either concentration, there was a substantial delay in the onset of the killing effect which was not evident until the concentrations of colistin generated from the hydrolysis of CMS had reached approximately 0.5 to 1 mg/liter (i.e., ∼0.5 to 1 times the MIC for colistin). The time course of the killing effect was similar when colistin was added incrementally to achieve the same colistin concentration-time course observed from the hydrolysis of CMS. Given that the killing kinetics of CMS can be accounted for by the appearance of colistin, CMS is an inactive prodrug of colistin with activity against P. aeruginosa. This is the first study to demonstrate the formation of colistin in microbiological media containing CMS and to demonstrate that CMS is an inactive prodrug of colistin. These findings have important implications for susceptibility testing involving “colistin,” in particular, for MIC measurement and for microbiological assays and pharmacokinetic and pharmacodynamic studies.

scholarly journals Meropenem Combined with Ciprofloxacin Combats Hypermutable Pseudomonas aeruginosa from Respiratory Infections of Cystic Fibrosis Patients

2018 ◽  
Vol 62 (11) ◽  
Author(s):  
Vanessa E. Rees ◽  
Rajbharan Yadav ◽  
Kate E. Rogers ◽  
Jürgen B. Bulitta ◽  
Veronika Wirth ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Time Course ◽  
Respiratory Infections ◽  
Resistant Bacteria ◽  
Infection Model ◽  
Time Curve ◽  
Bacterial Killing ◽  
Content Type ◽  
Concentration Time

ABSTRACT Hypermutable Pseudomonas aeruginosa organisms are prevalent in chronic respiratory infections and have been associated with reduced lung function in cystic fibrosis (CF); these isolates can become resistant to all antibiotics in monotherapy. This study aimed to evaluate the time course of bacterial killing and resistance of meropenem and ciprofloxacin in combination against hypermutable and nonhypermutable P. aeruginosa. Static concentration time-kill experiments over 72 h assessed meropenem and ciprofloxacin in mono- and combination therapies against PAO1 (nonhypermutable), PAOΔmutS (hypermutable), and hypermutable isolates CW8, CW35, and CW44 obtained from CF patients with chronic respiratory infections. Meropenem (1 or 2 g every 8 h [q8h] as 3-h infusions and 3 g/day as a continuous infusion) and ciprofloxacin (400 mg q8h as 1-h infusions) in monotherapies and combinations were further evaluated in an 8-day hollow-fiber infection model study (HFIM) against CW44. Concentration-time profiles in lung epithelial lining fluid reflecting the pharmacokinetics in CF patients were simulated and counts of total and resistant bacteria determined. All data were analyzed by mechanism-based modeling (MBM). In the HFIM, all monotherapies resulted in rapid regrowth with resistance at 48 h. The maximum daily doses of 6 g meropenem (T>MIC of 80% to 88%) and 1.2 g ciprofloxacin (area under the concentration-time curve over 24 h in the steady state divided by the MIC [AUC/MIC], 176), both given intermittently, in monotherapy failed to suppress regrowth and resulted in substantial emergence of resistance (≥7.6 log10 CFU/ml resistant populations). The combination of these regimens achieved synergistic killing and suppressed resistance. MBM with subpopulation and mechanistic synergy yielded unbiased and precise curve fits. Thus, the combination of 6 g/day meropenem plus ciprofloxacin holds promise for future clinical evaluation against infections by susceptible hypermutable P. aeruginosa.

scholarly journals Evaluation of Tobramycin and Ciprofloxacin as a Synergistic Combination Against Hypermutable Pseudomonas Aeruginosa Strains via Mechanism-Based Modelling

Pharmaceutics ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 470 ◽  
Author(s):  
Vanessa E. Rees ◽  
Jürgen B. Bulitta ◽  
Antonio Oliver ◽  
Roger L. Nation ◽  
Cornelia B. Landersdorfer
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Time Course ◽  
Respiratory Infections ◽  
Resistant Bacteria ◽  
Bacterial Killing ◽  
Concentration Time ◽  
Colony Forming Units ◽  
Static Concentration ◽  
Susceptible Populations ◽  
Time Kill

Hypermutable Pseudomonas aeruginosa strains have a greatly increased mutation rate and are prevalent in chronic respiratory infections. Initially, we systematically evaluated the time-course of total and resistant populations of hypermutable (PAO∆mutS) and non-hypermutable (PAO1) P. aeruginosa strains in 48-h static concentration time-kill studies with two inocula. Both strains were exposed to clinically relevant concentrations of important antibiotics (aztreonam, ceftazidime, imipenem, meropenem, tobramycin, and ciprofloxacin) in monotherapy. The combination of tobramycin and ciprofloxacin was subsequently assessed in 48-h static concentration time-kill studies against PAO1, PAO∆mutS, and two hypermutable clinical P. aeruginosa strains. Mechanism-based mathematical modelling was conducted to describe the time-course of total and resistant bacteria for all four strains exposed to the combination. With all monotherapies, bacterial regrowth and resistant populations were overall more pronounced for PAO∆mutS compared to PAO1. The combination of tobramycin and ciprofloxacin was synergistic, with up to 106.1 colony forming units (CFU)/mL more bacterial killing than the most active monotherapy for all strains, and largely suppressed less-susceptible populations. This work indicates that monotherapies against hypermutable P. aeruginosa strains are not a viable option. Tobramycin with ciprofloxacin was identified as a promising and tangible option to combat hypermutable P. aeruginosa strains.

scholarly journals Kill kinetics and regrowth patterns of Pseudomonas aeruginosa exposed to concentration-time profiles of tobramycin simulating in vivo infusion and bolus dosing.

1996 ◽  
Vol 40 (5) ◽  
pp. 1321-1324
Author(s):  
P J Wood ◽  
L L Ioannides-Demos ◽  
E B Bastone ◽  
W J Spicer ◽  
A J McLean
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Peak Concentration ◽  
Bacteriostatic Activity ◽  
Antibiotic Concentration ◽  
Initial Profile ◽  
Time Curve ◽  
Time Profiles ◽  
Concentration Time

Pseudomonas aeruginosa ATCC 27853 was exposed to tobramycin concentration-time profiles modelling in vivo bolus and infusion dosing. Dependence of bactericidal and bacteriostatic activity on the initial profile of peak concentration (bolus effect > infusion) and area under the antibiotic concentration-time curve was observed at peak concentration/MIC ratios of 10 or below.

Inhibition of the elastase of Pseudomonas aeruginosa by N.alpha.-phosphoryl dipeptides and kinetics of spontaneous hydrolysis of the inhibitors

Biochemistry ◽  
1984 ◽  
Vol 23 (12) ◽  
pp. 2766-2772 ◽  
Author(s):  
Louis Poncz ◽  
Thomas A. Gerken ◽  
Dorr G. Dearborn ◽  
Damian Grobelny ◽  
Richard E. Galardy
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Spontaneous Hydrolysis ◽  
Kinetics Of ◽  
Hydrolysis Of

Ceftazidime kinetics of diffusion in inoculated agar plates.

1996 ◽  
Vol 40 (5) ◽  
pp. 1280-1281 ◽  
Author(s):  
C Arcelloni ◽  
R Paroni ◽  
M Basile ◽  
P A Bonini ◽  
R Vaiani
Keyword(s):  
Pseudomonas Aeruginosa ◽  
High Performance Liquid Chromatography ◽  
Liquid Chromatography ◽  
Fixed Points ◽  
High Performance ◽  
Statistical Difference ◽  
Disk Center ◽  
Beta Lactamase ◽  
Fixed Times ◽  
Kinetics Of

The ceftazidime concentration in agar plates inoculated with Pseudomonas aeruginosa was determined by high-performance liquid chromatography at fixed points (3, 6, 9, 12, and 15 mm) from the disk center and at fixed times (2, 4, 6, 16, and 24 h) to study the antibiotic kinetics of diffusion. A statistical difference between the concentrations determined in the presence of microorganisms and in uninoculated plates after 16 and 24 h was evidenced and was probably ascribable to the drug hydrolysis carried out by the induced beta-lactamase.

Screening of endophytic fungal metabolites from Cola nitida leaves for antimicrobial activities against clinical isolates of Pseudomonas aeruginosa

2020 ◽  
Vol 4 (3) ◽  
pp. 161-166
Author(s):  
David C. Nwobodo ◽  
Chibueze P. Ihekwereme ◽  
Festus B. C. Okoye
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Endophytic Fungi ◽  
Bacterial Infections ◽  
High Performance ◽  
Antimicrobial Activities ◽  
Diffusion Method ◽  
Array Detector ◽  
Mortality And Morbidity ◽  
Cola Nitida ◽  
Fungal Extracts

AbstractEndophytic fungi of selected Nigerian plants are important sources of bioactive products with enormous potentials for the discovery of new drug molecules for drug development. Pseudomonas aeruginosa is one of the major causes of healthcare-associated bacterial infections, leading to increased mortality and morbidity. In this study, isolated endophytic fungi from Cola nitida were screened for anti-pseudomonas properties. Endophytic fungi associated with healthy leaves of C. nitida were isolated using standard methods. Fungi were identified through their morphological, cultural and microscopic characteristics. The fungi were subjected to solid-state fermentation and secondary metabolites extracted using ethyl acetate and concentrated under vacuum. The crude extracts were screened for antimicrobial activity against clinical and laboratory strains of Pseudomonas aeruginosa using the agar diffusion method. The bioactive components of the fungal extracts were identified using High-Performance Liquid Chromatography-Diode Array Detector (HPLC-DAD) analysis. Three endophytic fungi; Acremonium sp., Aspergillus sp. and Trichophyton sp. were isolated. At 1 mg/ml, extracts of the three fungi displayed antipseudomonal activity with inhibition zone diameter ranging from 6 - 4 mm. HPLC-DAD analysis revealed the presence of compounds, such as 4-hydroxyphenyl acetate. indole-3-acetic acid, and protocatechuic acid among others in the fungal extracts. The findings in this study reveal that endophytic fungi associated with C. nitida possess promising antipseudomonal properties. This finding can open new doors for the discovery of new agents against P. aeruginosa.

scholarly journals Evaluation of the extent of the binding site in human tissue kallikrein by synthetic substrates with sequences of human kininogen fragments

1995 ◽  
Vol 312 (1) ◽  
pp. 233-238 ◽  
Author(s):  
E Del Nery ◽  
J R Chagas ◽  
M A Juliano ◽  
E S Prado ◽  
L Juliano
Keyword(s):  
Human Tissue ◽  
Kinetic Data ◽  
Time Course ◽  
Tissue Kallikrein ◽  
Hydrolysis Time ◽  
Porcine Tissue ◽  
Enzyme Substrate ◽  
Substrate Side ◽  
Kinetics Of ◽  
Hydrolysis Of

We have synthesized internally quenched peptides spanning the Met379-Lys380 or Arg389-Ser390 bonds of human kininogen (hkng) that flank lysyl-bradykinin and have studied the kinetics of their hydrolysis by human tissue kallikrein. The kinetic data for the hydrolysis of the Met-Lys bond in substrates with an N-terminal extension showed that interactions up to position residue P10 contribute to the efficiency of cleavage. In contrast, there were no significant variations in the kinetic data for the hydrolysis of substrates with C-terminal extensions at sites P′4 to P′11. A similar pattern was observed for the cleavage of substrates containing an Arg-Ser bond because substrates extended up to residue P6 were hydrolysed with the highest kcat/Km values in the series, whereas those extended to P′11 on the C-terminal side had a lower susceptibility to hydrolysis. Time-course studies of hydrolysis by human and porcine tissue kallikreins of a Leu373 to Ile393 human kininogen fragment containing omicron-aminobenzoic acid (Abz) at the N-terminus and an amidated C-terminal carboxyl group Abz-Leu-Gly-Met-Ile-Ser-Leu-Met-Lys-Arg- Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg-Ser-Ser-Arg-Ile-NH2 (Abz-[Leu373-Ile393]-hkng-NH2) indicated that the cleavage of Met-Lys and Arg-Ser bonds in the same molecule occurs via the formation of independent enzyme-substrate complexes. The hydrolysis of Abz-F-R-S-S-R-Q-EDDnp [where EDDnp is N-(2,4-dinitrophenyl)ethylenediamine] and Abz-M-I-S-L-M-K-R-P-Q-EDDnp by human tissue kallikrein had maximal kcat/Km values at pH 9-9.5 for both substrates. The pH-dependent variations in this kinetic parameter were almost exclusively due to variations in kcat. A significant decrease in kcat/Km values was observed for the hydrolysis of Arg-Ser and Met-Lys bonds in the presence of 0.1 M NaCl. Because this effect was closely related to an increase in Km, it is likely that sodium competes with the positive charges of the substrate side chains for the same enzyme subsites.

scholarly journals Pharmacokinetics/Pharmacodynamics of Colistin and Imipenem on Mucoid and Nonmucoid Pseudomonas aeruginosa Biofilms

2011 ◽  
Vol 55 (9) ◽  
pp. 4469-4474 ◽  
Author(s):  
Wang Hengzhuang ◽  
Hong Wu ◽  
Oana Ciofu ◽  
Zhijun Song ◽  
Niels Høiby
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Time Course ◽  
Time Dependent ◽  
Content Type ◽  
Planktonic Bacteria ◽  
Kinetics Of ◽  
Higher Doses

ABSTRACTThe time course of activity of colistin and imipenem against mucoid and nonmucoidPseudomonas aeruginosagrowing in a biofilm showed that compared with those for planktonic bacteria, the kinetics of colistin and imipenem retained the concentration- and time-dependent killing, respectively, but higher doses of antibiotics and longer dosing periods were required for biofilm eradication. Biofilms of mucoidP. aeruginosawere more difficult to eradicate than nonmucoid biofilms.

scholarly journals Characteristics of bilirubin photochemical changes under green light-emitting diodes in humans compared with animal species

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kohichiroh Nii ◽  
Hitoshi Okada ◽  
Susumu Itoh ◽  
Takashi Kusaka
Keyword(s):  
Production Rate ◽  
High Performance ◽  
Time Course ◽  
Light Emitting Diodes ◽  
Green Light ◽  
Light Sources ◽  
Light Emitting ◽  
Course Changes ◽  
Complex Solutions ◽  
Kinetics Of

AbstractPhototherapy using light-emitting diodes (LEDs) centered on the green spectrum, which has a high cyclobilirubin production rate, was as effective as that centered on the blue spectrum for neonatal hyperbilirubinemia. There are no reports of species differences in bilirubin photochemical changes in this spectrum, and the characteristics of bilirubin photochemical changes in humans must be elucidated to proceed with the development of new light sources that include these spectra. This report describes the characteristic photochemical kinetics of bilirubin under green-spectrum LEDs in human, rat, rabbit, dog, pig, sheep, bovine and chicken serum albumin and rhesus monkey serum. These albumin-bilirubin complex solutions were irradiated by green LEDs, and the time-course changes in bilirubin photoisomers were measured by high-performance liquid chromatography. The cyclobilirubin production rates in humans, pigs, and monkeys were significantly higher than those in other species. The rate constant of (EZ)-cyclobilirubin production from (EZ)-bilirubin ‘k’ was significantly higher in humans and monkeys than in other species. In conclusion, bilirubin photochemical kinetics under green spectrum LEDs in humans were characterized by a high cyclobilirubin production rate at a low substrate concentration. The bilirubin photochemical kinetics in monkeys were similar to those in humans.

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