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Scientific Reports Sep 2022Persister cell (PC) is dormant, tolerant to antibiotics, and a transient reversible phenotype. These phenotypes are observed in P. aeruginosa and cause bacterial...
Persister cell (PC) is dormant, tolerant to antibiotics, and a transient reversible phenotype. These phenotypes are observed in P. aeruginosa and cause bacterial chronic infection as well as recurrence of biofilm-mediated infection. PC formation requires stringent response and toxin-antitoxin (TA) modules. This study shows the P. aeruginosa PC formation in planktonic and biofilm stages on ceftazidime, gentamicin, and ciprofloxacin treatments. The PC formation was studied using persister assay, flow cytometry using Redox Sensor Green, fluorescence as well as Confocal Laser Scanning Microscopy, and gene expression of stringent response and TA genes. In the planktonic stage, ceftazidime showed a high survival fraction, high redox activity, and elongation of cells was observed followed by ciprofloxacin and gentamicin treatment having redox activity and rod-shaped cells. The gene expression of stringent response and TA genes were upregulated on gentamicin followed by ceftazidime treatment and varied among the isolates. In the biofilm stage, gentamicin and ciprofloxacin showed the biphasic killing pattern, redox activity, gene expression level of stringent response and TA varied across the isolates. Ceftazidime treatment showed higher persister cells in planktonic growth while all three antibiotics were able to induce persister cell formation in the biofilm stage.
Topics: Anti-Bacterial Agents; Antitoxins; Bacterial Infections; Biofilms; Ceftazidime; Ciprofloxacin; Gentamicins; Humans; Microbial Sensitivity Tests; Plankton; Pseudomonas aeruginosa
PubMed: 36168027
DOI: 10.1038/s41598-022-20323-3 -
Journal of Medical Case Reports May 2019Fluoroquinolones have been associated with hypoglycemia in patients taking diabetic medications, most commonly due to drug-drug interactions and other associated risk...
BACKGROUND
Fluoroquinolones have been associated with hypoglycemia in patients taking diabetic medications, most commonly due to drug-drug interactions and other associated risk factors. Except for four published case reports, there are no studies that have found positive associations between ciprofloxacin and hypoglycemia. In all but one of the cases, ciprofloxacin was taken with other hypoglycemic drugs. Recently, the Eritrean National Pharmacovigilance Centre received a serious case of hypoglycemia with recurrent episodes in a young and healthy patient without diabetes following use of oral ciprofloxacin. The aim of the present study is therefore to assess the causal relationship between ciprofloxacin and hypoglycemia in patients without diabetes using the World Health Organization-Uppsala Monitoring Centre global adverse drug reaction database (VigiBase®).
METHODS
A search was made on the World Health Organization global adverse drug reaction database (August 15, 2018) using "ciprofloxacin" as the drug substance and "hypoglycemia" as the reaction term. Cases that used hypoglycemic drugs (patients with diabetes) concurrently with ciprofloxacin and those with a completeness score below 50% were excluded to control for confounders and to improve the strength of the data. Hill criteria were used to assess causation.
RESULTS
A total of 35 cases of hypoglycemia reported since 1989 from 17 countries in patients without diabetes associated with ciprofloxacin use with a median time to onset of 4 days were retrieved. The cases have a median age of 64 years (interquartile range, 50-85) with a similar male-to-female ratio. Ciprofloxacin was the only suspect and the sole drug administered in 48.5% of the cases. In ten cases, hypoglycemia abated following withdrawal of ciprofloxacin, and reaction recurred in one case on the subsequent rechallenge. Hypoglycemia was marked as "serious" in 20 cases, and the outcome was fatal in two cases.
CONCLUSIONS
This assessment found a suggestive causal link between use of ciprofloxacin and hypoglycemia in patients without diabetes.
Topics: Adult; Blood Glucose; Ciprofloxacin; Humans; Hypoglycemia; Male; Urinary Tract Infections
PubMed: 31078137
DOI: 10.1186/s13256-019-2083-y -
European Journal of Clinical... Jul 2020To develop and validate a population pharmacokinetic model of ciprofloxacin intravenously in critically ill patients, and determine target attainment to provide guidance... (Clinical Trial)
Clinical Trial
PURPOSE
To develop and validate a population pharmacokinetic model of ciprofloxacin intravenously in critically ill patients, and determine target attainment to provide guidance for more effective regimens.
METHODS
Non-linear mixed-effects modelling was used for the model development and covariate analysis. Target attainment of an ƒAUC/MIC ≥ 100 for different MICs was calculated for standard dosing regimens. Monte Carlo simulations were performed to define the probability of target attainment (PTA) of several dosing regimens.
RESULTS
A total of 204 blood samples were collected from 42 ICU patients treated with ciprofloxacin 400-1200 mg/day, with median values for age of 66 years, APACHE II score of 22, BMI of 26 kg/m, and eGFR of 58.5 mL/min/1.73 m. The median ƒAUC and ƒC were 29.9 mg•h/L and 3.1 mg/L, respectively. Ciprofloxacin pharmacokinetics were best described by a two-compartment model. We did not find any significant covariate to add to the structural model. The proportion of patients achieving the target ƒAUC/MIC ≥ 100 were 61.9% and 16.7% with MICs of 0.25 and 0.5 mg/L, respectively. Results of the PTA simulations suggest that a dose of ≥ 1200 mg/day is needed to achieve sufficient ƒAUC/MIC ratios.
CONCLUSIONS
The model described the pharmacokinetics of ciprofloxacin in ICU patients adequately. No significant covariates were found and high inter-individual variability of ciprofloxacin pharmacokinetics in ICU patients was observed. The poor target attainment supports the use of higher doses such as 1200 mg/day in critically ill patients, while the variability of inter-individual pharmacokinetics parameters emphasizes the need for therapeutic drug monitoring to ensure optimal exposure.
Topics: Administration, Intravenous; Aged; Anti-Bacterial Agents; Ciprofloxacin; Computer Simulation; Critical Illness; Female; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Models, Biological; Monte Carlo Method; Pseudomonas aeruginosa
PubMed: 32307575
DOI: 10.1007/s00228-020-02873-5 -
Molecular Diversity Aug 2023A series of N-4 piperazinyl ciprofloxacin derivatives as urea-tethered ciprofloxacin-chalcone hybrids 2a-j and thioacetyl-linked ciprofloxacin-pyrimidine hybrids 5a-i...
A series of N-4 piperazinyl ciprofloxacin derivatives as urea-tethered ciprofloxacin-chalcone hybrids 2a-j and thioacetyl-linked ciprofloxacin-pyrimidine hybrids 5a-i were synthesized. The target compounds were investigated for their antibacterial activity against S. aureus, P. aeruginosa, E. coli, and C. albicans strains, respectively. Ciprofloxacin derivatives 2a-j and 5a-i revealed broad antibacterial activity against either Gram positive or Gram negative strains, with MIC range of 0.06-42.23 µg/mL compared to ciprofloxacin with an MIC range of 0.15-3.25 µg/mL. Among the tested compounds, hybrids 2b, 2c, 5a, 5b, 5h, and 5i exhibited remarkable antibacterial activity with MIC range of 0.06-1.53 µg/mL against the tested bacterial strains. On the other hand, compounds 2c, 2e, 5c, and 5e showed comparable antifungal activity to ketoconazole against candida albicans with MIC range of 2.03-3.89 µg/mL and 2.6 µg/mL, respectively. Further investigations showed that some ciprofloxacin hybrids have inhibitory activity against DNA gyrase as potential molecular target compared to ciprofloxacin with IC range of 0.231 ± 0.01-7.592 ± 0.40 µM and 0.323 ± 0.02 µM, respectively. Docking studies of compounds 2b, 2c, 5b, 5c, 5e, 5h, and 5i on the active site of DNA gyrase (PDB: 2XCT) confirmed their ability to form stable complex with the target enzyme like that of ciprofloxacin.
Topics: Ciprofloxacin; Topoisomerase II Inhibitors; Molecular Docking Simulation; DNA Gyrase; Escherichia coli; Staphylococcus aureus; Anti-Infective Agents; Anti-Bacterial Agents; Microbial Sensitivity Tests; Structure-Activity Relationship; Molecular Structure
PubMed: 36152132
DOI: 10.1007/s11030-022-10528-z -
Molecules (Basel, Switzerland) Aug 2023With the overuse and misuse of antimicrobial drugs, antibacterial resistance is becoming a critical global health problem. New antibacterial agents are effective...
With the overuse and misuse of antimicrobial drugs, antibacterial resistance is becoming a critical global health problem. New antibacterial agents are effective measures for overcoming the crisis of drug resistance. In this paper, a novel set of ciprofloxacin-indole/acetophenone hybrids was designed, synthesized, and structurally elucidated with the help of NMR and high-resolution mass spectrometry. The in vitro antibacterial activities of these hybrids against gram-positive and gram-negative pathogens, including four multidrug-resistant clinical isolates, were evaluated and compared with those of the parent drug ciprofloxacin (CIP). All the target compounds (MIC = 0.0625-32 μg/mL) exhibited excellent inhibitory activity against the strains tested. Among them, (MIC = 0.25-8 μg/mL) showed comparable or slightly less potent activity than CIP. The most active hybrid, (MIC = 0.0626-1 μg/mL), showed equal or higher activity than CIP. Moreover, compound showed superior bactericidal capability to CIP, with undetectably low resistance frequencies. Furthermore, molecular docking studies conducted showed that and CIP had a similar binding mode to DNA gyrase (). Thus, hybrids and could act as a platform for further investigations.
Topics: Ciprofloxacin; Molecular Docking Simulation; Anti-Bacterial Agents; DNA Gyrase; Indoles
PubMed: 37687154
DOI: 10.3390/molecules28176325 -
Molecules (Basel, Switzerland) Jun 2022Screening of a library of novel -hydroxylactams amenable by the Castagnoli-Cushman reaction identified four lead compounds that facilitated Fe transport into cells (one...
Screening of a library of novel -hydroxylactams amenable by the Castagnoli-Cushman reaction identified four lead compounds that facilitated Fe transport into cells (one of these synthetic siderophores was found to be as efficient at promoting iron uptake as the natural siderophores pyoverdine, pyochelin or enterobactin). Conjugates of the four lead siderophores with ciprofloxacin were tested for antibacterial activity against POA1 (wild type) and the mutant strain. The antibacterial activity was found to be pronounced against the mutant strain grown in CAA medium but not for the POA1 strain. This may be indicative of these compounds being 'Trojan horse' antibiotics. Further scrutiny of the mechanism of the antibacterial action of the newly developed conjugates is warranted.
Topics: Anti-Bacterial Agents; Ciprofloxacin; Iron; Pseudomonas aeruginosa; Siderophores
PubMed: 35745033
DOI: 10.3390/molecules27123910 -
Molecules (Basel, Switzerland) Nov 2020The research was focused on developing a potentially antibacterial wound dressing made of polyurethane foam and loaded with bismuth-ciprofloxacin (Cip-Bi). The Cip-Bi...
The research was focused on developing a potentially antibacterial wound dressing made of polyurethane foam and loaded with bismuth-ciprofloxacin (Cip-Bi). The Cip-Bi chemical structure was confirmed by Fourier transform infrared spectroscopic (FTIR) analysis. The sought after antibacterial wound dressing was obtained by modification of the raw dressing with an iodine or bromine solution and subsequently with a Cip-Bi hydrogel. The amount of Cip-Bi loaded into the dressing matrix was determined indirectly on the basis of the differences in Cip-Bi concentrations, before and after the modification process, and the determination was performed with the HPLC (high-performance liquid chromatography) method. The modified dressing was found to have a two-step release of Cip-Bi, a feature helpful in the treatment of locally infected wounds and prevention of secondary bacterial infection. The zone of inhibition test against the selected Gram-positive and Gram-negative bacteria confirmed the antibacterial activity of the Cip-Bi-modified dressing. Preliminary tests conducted so far have been indicative of the Cip-Bi dressing's relatively high activity against the tested organisms.
Topics: Anti-Bacterial Agents; Bandages; Bismuth; Ciprofloxacin; Escherichia coli; Humans; Microbial Sensitivity Tests; Staphylococcus aureus
PubMed: 33153027
DOI: 10.3390/molecules25215096 -
American Journal of Veterinary Research Jul 2012To determine the pharmacokinetics of ciprofloxacin in dogs, including oral absorption following administration of generic ciprofloxacin tablets.
OBJECTIVE
To determine the pharmacokinetics of ciprofloxacin in dogs, including oral absorption following administration of generic ciprofloxacin tablets.
ANIMALS
6 healthy Beagles.
PROCEDURES
In a crossover study design, ciprofloxacin was administered as a generic tablet (250 mg, PO; mean dose, 23 mg/kg) and solution (10 mg/kg, IV) to 6 dogs. In a separate experiment, 4 of the dogs received ciprofloxacin solution (10 mg/mL) PO via stomach tube (total dose, 250 mg). Blood samples were collected before (time 0) and for 24 hours after each dose. Plasma concentrations were analyzed with high-pressure liquid chromatography. Pharmacokinetic analysis was performed by means of compartmental modeling.
RESULTS
When ciprofloxacin was administered as tablets PO, peak plasma concentration was 4.4 μg/mL (coefficient of variation [CV], 55.9%), terminal half-life (t(1/2)) was 2.6 hours (CV, 10.8%), area under the time-concentration curve was 22.5 μg•h/mL (CV, 62.3%), and systemic absorption was 58.4% (CV, 45.4%). For the dose administered IV, t(1/2) was 3.7 hours (CV, 52.3%), clearance was 0.588 L/kg/h (CV, 33.9%), and volume of distribution was 2.39 L/kg (CV, 23.7%). After PO administration as a solution versus IV administration, plasma concentrations were more uniform and consistent among dogs, with absorption of 71% (CV, 7.3%), t(1/2) of 3.1 hours (CV, 18.6%), and peak plasma concentration of 4.67 μg/mL (CV, 17.6%).
CONCLUSIONS AND CLINICAL RELEVANCE
Inconsistent oral absorption of ciprofloxacin in some dogs may be formulation dependent and affected by tablet dissolution in the small intestine. Because of the wide range in oral absorption of tablets, the dose needed to reach the pharmacokinetic-pharmacodynamic target concentration in this study ranged from 12 to 52 mg/kg (CV, 102%), with a mean dose of 25 mg/kg, once daily, for bacteria with a minimum inhibitory concentration ≤ 0.25 μg/mL.
Topics: Administration, Oral; Animals; Anti-Infective Agents; Area Under Curve; Biological Availability; Ciprofloxacin; Cross-Over Studies; Dogs; Drugs, Generic; Half-Life; Random Allocation; Tablets
PubMed: 22738062
DOI: 10.2460/ajvr.73.7.1085 -
Photodegradation of Ciprofloxacin, Clarithromycin and Trimethoprim: Influence of pH and Humic Acids.Molecules (Basel, Switzerland) May 2021In view of the rising relevance of emerging pollutants in the environment, this work studies the photodegradation of three antibiotics, evaluating the effects of the pH...
In view of the rising relevance of emerging pollutants in the environment, this work studies the photodegradation of three antibiotics, evaluating the effects of the pH of the medium and the concentration of dissolved organic matter. Simulated light (with a spectrum similar to that of natural sunlight) was applied to the antibiotics Ciprofloxacin (Cip), Clarithromycin (Cla) and Trimethoprim (Tri), at three different pH, and in the presence of different concentrations of humic acids. The sensitivity to light followed the sequence: Cip > Cla > Tri, which was inverse for the half-life (Tri > Cla > Cip). As the pH increased, the half-life generally decreased, except for Cla. Regarding the kinetic constant k, in the case of Cip and Tri it increased with the rise of pH, while decreased for Cla. The results corresponding to total organic carbon (TOC) indicate that the complete mineralization of the antibiotics was not achieved. The effect of humic acids was not marked, slightly increasing the degradation of Cip, and slightly decreasing it for Tri, while no effect was detected for Cla. These results may be relevant in terms of understanding the evolution of these antibiotics, especially when they reach different environmental compartments and receive sunlight radiation.
Topics: Anti-Bacterial Agents; Ciprofloxacin; Clarithromycin; Darkness; Half-Life; Humic Substances; Hydrogen-Ion Concentration; Kinetics; Light; Trimethoprim
PubMed: 34064068
DOI: 10.3390/molecules26113080 -
Environment International Dec 2021Although nanoplastics/microplastics (NPs/MPs) may interact with co-contaminants (e.g. antibiotics) in aquatic systems, little is known about their combined toxicity....
Although nanoplastics/microplastics (NPs/MPs) may interact with co-contaminants (e.g. antibiotics) in aquatic systems, little is known about their combined toxicity. Here, we compared the individual toxicity of NPs/MPs or ciprofloxacin (CIP, a very commonly detected antibiotic) and their combined toxicity toward a unicellular cyanobacterium Synechocystis sp. in terms of the cellular responses and metabolomic analysis. We found that CIP exhibited an antagonistic effect with NPs/MPs due to its adsorption onto the surface of NPs/MPs. Particle size-dependent toxic effects of NPs/MPs were observed. Reactive oxygen species (ROS) was verified as an important factor for NPs/MPs to inhibit cell growth, other than for CIP. Metabolomics further revealed that Synechocystis sp. up-regulated glycerophospholipids, amino acids, nucleotides, and carbohydrates to tolerate CIP pressure. NPs/MPs downregulated the TCA cycle and glycerophospholipids metabolism and impaired the primary production and membrane integrity via adhesion with Synechocystis sp.. Additionally, the toxicity of NPs/MPs throughout ten growth cycles at a sublethal concentration unveiled its potential risks in interfering with metabolism. Collectively, our findings provide insights into the joint ecotoxicity of NPs/MPs and antibiotics, and highlight the potential risks of co-pollutants at environmental relevant concentrations.
Topics: Ciprofloxacin; Microplastics; Plastics; Synechocystis; Water Pollutants, Chemical
PubMed: 34438231
DOI: 10.1016/j.envint.2021.106842