scholarly journals Fluoroquinolone antimicrobial agents.

1989 ◽  
Vol 2 (4) ◽  
pp. 378-424 ◽  
Author(s):  
J S Wolfson ◽  
D C Hooper
Keyword(s):  
Bacterial Infections ◽  
Deoxyribonucleic Acid ◽  
Bacterial Resistance ◽  
Antimicrobial Agents ◽  
Beta Lactam ◽  
Double Blind ◽  
Gram Negative ◽  
Cutaneous Infections ◽  
Tract Infections

The fluoroquinolones, a new class of potent orally absorbed antimicrobial agents, are reviewed, considering structure, mechanisms of action and resistance, spectrum, variables affecting activity in vitro, pharmacokinetic properties, clinical efficacy, emergence of resistance, and tolerability. The primary bacterial target is the enzyme deoxyribonucleic acid gyrase. Bacterial resistance occurs by chromosomal mutations altering deoxyribonucleic acid gyrase and decreasing drug permeation. The drugs are bactericidal and potent in vitro against members of the family Enterobacteriaceae, Haemophilus spp., and Neisseria spp., have good activity against Pseudomonas aeruginosa and staphylococci, and (with several exceptions) are less potent against streptococci and have fair to poor activity against anaerobic species. Potency in vitro decreases in the presence of low pH, magnesium ions, or urine but is little affected by different media, increased inoculum, or serum. The effects of the drugs in combination with a beta-lactam or aminoglycoside are often additive, occasionally synergistic, and rarely antagonistic. The agents are orally absorbed, require at most twice-daily dosing, and achieve high concentrations in urine, feces, and kidney and good concentrations in lung, bone, prostate, and other tissues. The drugs are efficacious in treatment of a variety of bacterial infections, including uncomplicated and complicated urinary tract infections, bacterial gastroenteritis, and gonorrhea, and show promise for therapy of prostatitis, respiratory tract infections, osteomyelitis, and cutaneous infections, particularly when caused by aerobic gram-negative bacilli. Fluoroquinolones have also proved to be efficacious for prophylaxis against travelers' diarrhea and infection with gram-negative bacilli in neutropenic patients. The drugs are effective in eliminating carriage of Neisseria meningitidis. Patient tolerability appears acceptable, with gastrointestinal or central nervous system toxicities occurring most commonly, but only rarely necessitating discontinuance of therapy. In 17 of 18 prospective, randomized, double-blind comparisons with another agent or placebo, fluoroquinolones were tolerated as well as or better than the comparison regimen. Bacterial resistance has been uncommonly documented but occurs, most notably with P. aeruginosa and Staphylococcus aureus and occasionally other species for which the therapeutic ratio is less favorable. Fluoroquinolones offer an efficacious, well-tolerated, and cost-effective alternative to parenteral therapies of selected infections.

Synthesis, In Vitro and In Silico Studies of Indolequinone Derivatives against Clinically Relevant Bacterial Pathogens

2020 ◽  
Vol 20 (3) ◽  
pp. 192-208 ◽  
Author(s):  
Talita Odriane Custodio Leite ◽  
Juliana Silva Novais ◽  
Beatriz Lima Cosenza de Carvalho ◽  
Vitor Francisco Ferreira ◽  
Leonardo Alves Miceli ◽  
...  
Keyword(s):  
In Silico ◽  
Bacterial Infections ◽  
Antimicrobial Agents ◽  
Mass Spectrometry Analysis ◽  
World Health ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Dione Derivative ◽  
In Silico Studies

Background: According to the World Health Organization, antimicrobial resistance is one of the most important public health threats of the 21st century. Therefore, there is an urgent need for the development of antimicrobial agents with new mechanism of action, especially those capable of evading known resistance mechanisms. Objective: We described the synthesis, in vitro antimicrobial evaluation, and in silico analysis of a series of 1H-indole-4,7-dione derivatives. Methods: The new series of 1H-indole-4,7-diones was prepared with good yield by using a copper(II)- mediated reaction between bromoquinone and β-enamino ketones bearing alkyl or phenyl groups attached to the nitrogen atom. The antimicrobial potential of indole derivatives was assessed. Molecular docking studies were also performed using AutoDock 4.2 for Windows. Characterization of all compounds was confirmed by one- and two-dimensional NMR techniques 1H and 13C NMR spectra [1H, 13C – APT, 1H x 1H – COSY, HSQC and HMBC], IR and mass spectrometry analysis. Results: Several indolequinone compounds showed effective antimicrobial profile against Grampositive (MIC = 16 µg.mL-1) and Gram-negative bacteria (MIC = 8 µg.mL-1) similar to antimicrobials current on the market. The 3-acetyl-1-(2,5-dimethylphenyl)-1H-indole-4,7-dione derivative exhibited an important effect against different biofilm stages formed by a serious hospital life-threatening resistant strain of Methicillin-Resistant Staphylococcus aureus (MRSA). A hemocompatibility profile analysis based on in vitro hemolysis assays revealed the low toxicity effects of this new series. Indeed, in silico studies showed a good pharmacokinetics and toxicological profiles for all indolequinone derivatives, reinforcing their feasibility to display a promising oral bioavailability. An elucidation of the promising indolequinone derivatives binding mode was achieved, showing interactions with important sites to biological activity of S. aureus DNA gyrase. These results highlighted 3-acetyl-1-(2-hydroxyethyl)-1Hindole- 4,7-dione derivative as broad-spectrum antimicrobial prototype to be further explored for treating bacterial infections. Conclusion: The highly substituted indolequinones were obtained in moderate to good yields. The pharmacological study indicated that these compounds should be exploited in the search for a leading substance in a project aimed at obtaining new antimicrobials effective against Gram-negative bacteria.

scholarly journals Urinary infection in dogs with chronic kidney disease: aetiology and resistance

2019 ◽  
Vol 40 (6Supl3) ◽  
pp. 3741
Author(s):  
Ariane Martins Fernandes ◽  
Alessandra Tammy Hayakawa Ito de Sousa ◽  
Luciana Auxiliadora Viebrantz da Conceição ◽  
Felipe Gomes da Silva ◽  
Mayara Aparecida Araújo Cayuela ◽  
...  
Keyword(s):  
Urinary Tract ◽  
Bacterial Resistance ◽  
Antimicrobial Agents ◽  
Urine Culture ◽  
Urinary Infection ◽  
Clinical Routine ◽  
Disease Aetiology ◽  
Tract Infections ◽  
And Control

Infections of the genitourinary system are among the most frequent in the clinical routine of small animals. Treatment with the most appropriate antimicrobial therapy, according to the uropathogen susceptibility test, can avoid the spread of bacterial resistance to antimicrobials. A clinical study was performed in 32 canines, of both sexes and differing ages, who attended the Veterinary Teaching Hospital. Urine samples underwent culture, with the objective of evaluating urinary tract infection in dogs with renal disease, identifying the associated bacterial pathogens, and verifying their antimicrobial susceptibility in vitro. Urine culture was positive in 10 dogs, mostly males, with no predisposition for breed, and a mean age of 8.28 years. Most of the urinary tract infections (UTIs) were monobacterial, with the most common microorganisms being Pseudomonas sp. and Staphylococcus sp. The antimicrobials imipenem and meropenem had the best overall sensitivity profile, and ampicillin showed the highest resistance. The variation in epidemiological profiles, and susceptibility to uropathogens, reinforces the importance of the veterinarian in the prevention and control of infection, in addition to the need for further research to identify new antimicrobial agents.

scholarly journals In Vitro and In Vivo Characterization of Tebipenem, an Oral Carbapenem

2020 ◽  
Vol 64 (8) ◽  
Author(s):  
Nicole Cotroneo ◽  
Aileen Rubio ◽  
Ian A. Critchley ◽  
Chris Pillar ◽  
Michael J. Pucci
Keyword(s):  
Bacterial Resistance ◽  
Unmet Need ◽  
Multidrug Resistant ◽  
Oral Agent ◽  
Gram Negative ◽  
Improved Stability ◽  
Tebipenem Pivoxil ◽  
Tract Infections

ABSTRACT The continued evolution of bacterial resistance to the β-lactam class of antibiotics has necessitated countermeasures to ensure continued effectiveness in the treatment of infections caused by bacterial pathogens. One relatively successful approach has been the development of new β-lactam analogs with advantages over prior compounds in this class. The carbapenems are an example of such β-lactam analogs possessing improved stability against β-lactamase enzymes and, therefore, a wider spectrum of activity. However, all carbapenems currently marketed for adult patients are intravenous agents, and there is an unmet need for an oral agent to treat patients that otherwise do not require hospitalization. Tebipenem pivoxil hydrobromide (tebipenem-PI-HBr or SPR994) is an orally available prodrug of tebipenem, a carbapenem with activity versus multidrug-resistant (MDR) Gram-negative pathogens, including quinolone-resistant and extended-spectrum-β-lactamase-producing Enterobacterales. Tebipenem-PI-HBr is currently in development for the treatment of complicated urinary tract infections (cUTI). Microbiological data are presented here that demonstrate equivalency of tebipenem with intravenous carbapenems such as meropenem and support its use in infections in which the potency and spectrum of a carbapenem are desired. The results from standard in vitro microbiology assays as well as efficacy in several in vivo mouse infection models suggest that tebipenem-PI-HBr could be a valuable oral agent available to physicians for the treatment of infections, particularly those caused by antibiotic-resistant Gram-negative pathogens.

Resistenze antibiotiche e nuove molecole: qual è lo scenario attuale?

2018 ◽  
Vol 85 (1_suppl) ◽  
pp. S5-S13 ◽  
Author(s):  
Andrea Novelli
Keyword(s):  
Bacterial Resistance ◽  
Antimicrobial Agents ◽  
Treatment Options ◽  
Public Health Problem ◽  
New Drugs ◽  
Beta Lactam ◽  
Important Public Health Problem ◽  
Extended Spectrum Beta Lactamase ◽  
First Choice ◽  
Tract Infections

Antibiotic resistance and new drugs in urologic setting: what we need to know? Urinary tract infections (UTIs) are among the most frequent infectious diseases, and represent an important public health problem with a substantial economic burden. In recent years the chemoresistance of the main uropathogens has significantly increased worldwide. Extended spectrum beta-lactamase (ESBL) production and multi-drug resistant (MDR) clones of Escherichia coli and Klebsiella pneumoniae are limiting available treatment options. Carbapenems and aminoglycosides are still effective in complicated UTI. New beta-lactam combinations such as ceftolozane-tazobactam and ceftazidime-avibactam may be highly useful in treating severe infections while contributing to the carbapenem sparing strategy. For uncomplicated UTI, within older antibiotics, fosfomycin trometamol may be considered a first-choice drug since it is still retaining a good activity against MDR uropathogens. On the other hand, there are extensive data showing that the administration of antimicrobials according to pharmacokinetic/pharmacodynamic (PK/PD) parameters improves the possibility of a positive clinical outcome, particularly in severely ill patients. Evidence is growing that when PK/PD parameters are used to target not only clinical cure. This article discusses the PK/PD characteristics of antimicrobial agents for the treatment of UTIs, and the pharmacological and therapeutic strategies for limiting or preventing bacterial resistance.

scholarly journals Multiple Mechanisms of the Synthesized Antimicrobial Peptide TS against Gram-Negative Bacteria for High Efficacy Antibacterial Action In Vivo

Molecules ◽  
2020 ◽  
Vol 26 (1) ◽  
pp. 60
Author(s):  
Rui Zhang ◽  
Xiaobo Fan ◽  
Xinglu Jiang ◽  
Mingyuan Zou ◽  
Han Xiao ◽  
...  
Keyword(s):  
Antimicrobial Peptide ◽  
Bacterial Infections ◽  
Bacterial Resistance ◽  
Divalent Cations ◽  
Resistant Bacteria ◽  
Antibacterial Drug ◽  
Gram Negative Bacteria ◽  
Gram Negative

The emergence of drug-resistant bacteria emphasizes the urgent need for novel antibiotics. The antimicrobial peptide TS shows extensive antibacterial activity in vitro and in vivo, especially in gram-negative bacteria; however, its antibacterial mechanism is unclear. Here, we find that TS without hemolytic activity disrupts the integrity of the outer bacterial cell membrane by displacing divalent cations and competitively binding lipopolysaccharides. In addition, the antimicrobial peptide TS can inhibit and kill E. coli by disintegrating the bacteria from within by interacting with bacterial DNA. Thus, antimicrobial peptide TS’s multiple antibacterial mechanisms may not easily induce bacterial resistance, suggesting use as an antibacterial drug to be for combating bacterial infections in the future.

Bacterial Communications in Implant Infections: A Target for an Intelligence War

2007 ◽  
Vol 30 (9) ◽  
pp. 757-763 ◽  
Author(s):  
J.W. Costerton ◽  
L. Montanaro ◽  
C.r. Arciola
Keyword(s):  
Quorum Sensing ◽  
Bacterial Infections ◽  
Bacterial Resistance ◽  
Homoserine Lactone ◽  
Bacterial Virulence ◽  
Gram Positive ◽  
Gram Negative ◽  
Gram Positive Bacteria ◽  
Sensing Systems

The status of population density is communicated among bacteria by specific secreted molecules, called pheromones or autoinducers, and the control mechanism is called “quorum-sensing”. Quorum-sensing systems regulate the expression of a panel of genes, allowing bacteria to adapt to modified environmental conditions at a high density of population. The two known different quorum systems are described as the LuxR-LuxI system in gram-negative bacteria, which uses an N-acyl-homoserine lactone (AHL) as signal, and the agr system in gram-positive bacteria, which uses a peptide-tiolactone as signal and the RNAIII as effector molecules. Both in gram-negative and in gram-positive bacteria, quorum-sensing systems regulate the expression of adhesion mechanisms (biofilm and adhesins) and virulence factors (toxins and exoenzymes) depending on population cell density. In gram-negative Pseudomonas aeruginosa, analogs of signaling molecules such as furanone analogs, are effective in attenuating bacterial virulence and controlling bacterial infections. In gram-positive Staphylococcus aureus, the quorum-sensing RNAIII-inhibiting peptide (RIP), tested in vitro and in animal infection models, has been proved to inhibit virulence and prevent infections. Attenuation of bacterial virulence by quorum-sensing inhibitors, rather than by bactericidal or bacteriostatic drugs, is a highly attractive concept because these antibacterial agents are less likely to induce the development of bacterial resistance.

scholarly journals Bacterial Infections in the Elderly Patient: Focus on Sitafloxacin

2012 ◽  
Vol 4 ◽  
pp. CMT.S7435 ◽  
Author(s):  
Beniam Ghebremedhin
Keyword(s):  
Bacterial Infections ◽  
Randomized Clinical Trials ◽  
Bacterial Pathogens ◽  
Anaerobic Bacteria ◽  
The Elderly ◽  
Gram Positive ◽  
Double Blind ◽  
Odontogenic Infections ◽  
Tract Infections

Sitafloxacin (DU-6859a) is a new-generation oral fluoroquinolone with in vitro activity against a broad range of Gram-positive and -negative bacteria, including anaerobic bacteria, as well as against atypical bacterial pathogens. Particularly in Japan this antibiotic was approved in 2008 for treatment of a number of bacterial infections caused by Gram-positive cocci and Gram-negative cocci and rods, including anaerobia atypical bacterial pathogens. As compared to oral levofloxacin sitafloxacin was non-inferior in the treatment of community-acquired pneumonia and non-inferior in the treatment of complicated urinary tract infections, according to the results of randomized, double-blind, multicentre, non-inferiority trials. Non-comparative studies demonstrated the efficacy of oral sitafloxacin in otorhinolaryngological infections, urethritis in men, cervicitis in women and odontogenic infections. Most common adverse reactions were gastrointestinal disorders and laboratory abnormalities in patients receiving oral sitafloxacin; diarrhea and liver enzyme elevations were among the common. In the Japanese population sitafloxacin covers broad spectrum of bacteria as compared to carbapenems, whereas in the Caucasians its use is currently limited due to the potential for ultraviolet A phototoxicity. Sitafloxacin is a promising therapeutic agent which merits further investigation in randomized clinical trials of elderly patients.

scholarly journals Antibiotic Susceptibility Patterns of Uropathogens Isolated from Female Patients with Urinary Tract Infection in Duhok Province, Iraq

2020 ◽  
Vol 12 (3) ◽  
Author(s):  
Ibrahim A Naqid ◽  
Nawfal R Hussein ◽  
Amer Balatay ◽  
Kurdistan A Saeed ◽  
Hiba A Ahmed
Keyword(s):  
Antibiotic Resistance ◽  
Urinary Tract ◽  
Bacterial Infections ◽  
Antimicrobial Agents ◽  
Empirical Therapy ◽  
Urine Samples ◽  
Gram Positive ◽  
Gram Negative ◽  
Female Patients ◽  
Tract Infections

Background: Urinary Tract Infections (UTIs) are one of the most common bacterial infections worldwide. The study of bacterial uropathogens in a local area and their susceptibility to antimicrobial agents is required to determine empirical therapy. Objectives: This study aimed to assess the profile and antibiotic resistance patterns of bacteria, causing urinary infections isolated from female patients in Duhok province, Iraq. Methods: A total of 530 urine samples were collected from females clinically suspected of UTIs over three years between January 2017 and February 2020. The samples were inoculated directly on MacConkey and Blood agar media and then incubated aerobically for 24 h at 37°C. Samples that gave up colony counts of ≥ 105 CFU/mL were considered as positive growth. Purified colonies were identified through standard bacteriological tests, and their susceptibility to different antibiotics was determined using the Vitek-2 system. Results: Out of 530 urine samples, 450 (84.9%) contained Gram-negative bacteria, while the other 80 (15.1%) harbored Gram-positive bacteria. Escherichia coli was the most common uropathogenic isolate (58.5%), followed by K. pneumoniae (14.3%), Staphylococcus spp. (8.9%), P. mirabilis (6.6%), E. faecalis (3.2%), and S. agalactiae (3.02%). The majority of Gram-negative uropathogens were resistant to ampicillin, aztreonam, ceftriaxone, and cefepime and around 95% were sensitive to ertapenem and imipenem. Most Gram-positive isolates showed high resistance to benzylpenicillin, oxacillin, gentamicin, and erythromycin, and high susceptibility to linezolid, tigecycline, and nitrofurantoin. Conclusions: It was concluded from this study that E. coli is the predominant pathogen causing UTIs in female patients in Duhok province, Iraq. There were increasing antibiotic resistance rates, particularly to ampicillin, aztreonam, ceftriaxone, benzylpenicillin, and erythromycin. Therefore, empirical antibiotic therapy should be based on local sensitivity patterns rather than international guidelines.

scholarly journals 2477. Antimicrobial Resistance patterns of Enterobacteriaceae and Pseudomonas aeruginosa from Colombian clinical isolates. 2017–2018

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S858-S858
Author(s):  
Monica Maria Rojas Rojas ◽  
Catalina López ◽  
Jaime Ruiz ◽  
Jacquleine Pavía ◽  
Jose Oñate ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Antimicrobial Resistance ◽  
Antimicrobial Agents ◽  
Clinical Isolates ◽  
In Vitro Susceptibility ◽  
Gram Negative ◽  
Guidelines Development ◽  
Resistance Patterns ◽  
Tract Infections

Abstract Background The Study for Monitoring Antimicrobial Resistance Trends (SMART) is a worldwide initiative to monitor in vitro susceptibility of clinical Gram-negative isolates to several antimicrobial agents. Surveillance initiatives are essential to provide real-world evidence to support local guidelines development. Colombia has participated since 2012 with isolates from complicated intrabdominal infections (cIAI), complicated urinary tract infections (cUTI) and respiratory tract infections (RTI). This study describes resistant patterns of Escherichia coli (Eco), Klebsiella pneumoniae (Kpn) and Pseudomonas aeruginosa (Pae) clinical isolates collected in Colombian hospitals in a 2 years period (2017–2018). Methods Isolates from patients with cIAI, cUTI and RTI were collected. Identification confirmation was done in central laboratory. Minimum inhibitory concentrations (MIC) were performed by broth microdilution and interpreted according to 2018 CLSI guidelines, same criteria for Extended-spectrum β-lactamase (ESBL) classification. The antimicrobial activity was evaluated for aztreonam (ATM), ceftolozane/tazobactam (C/T), ceftazidime (CAZ), colistin (COL), ertapenem (ETP), cefepime (FEP), imipenem (IMP), meropenem (MEM) and piperacillin–tazobactam (TZP). Results During 2017–2018, 1492 isolates were collected. The main organism was Eco (51%) followed by Kpn (29%) and Pae (20%). In vitro susceptibility activity is presented in Table 1. COL, C/T, ETP, MEM and IPM exhibited over 95% susceptibility in Eco. ESBL prevalence was 18% for Eco (53/314) and 22% for Kpn (36/165). COL and C/T were the most active agents against Pae isolates. For Kpn, MIC50/90 values were: MEM (0.12 / 8), C/T (0.5 / 8) and for TZP (8 / > 64), meanwhile for Pae were MEM (0.5 / 32), C/T (0.5 / 32) and for TZP (8 / > 64). Conclusion Continued antimicrobial resistance surveillance initiatives are critical to guide the empiric treatments decision in a multidrug resistance era. This study shows that Ceftolozane/Tazobactam, MEM and COL have the best susceptibility profile against Eco, Kpn and Pae of cIAI, cUTI and RTI cases in Colombia. The C/T susceptibility rates and low MIC distribution provide evidence to support its use as a non-carbapenem therapeutic alternative for Gram-negative infections. Disclosures All authors: No reported disclosures.

scholarly journals Bacteriophages targeting Acinetobacter baumannii capsule induce antimicrobial resensitization

2020 ◽  
Author(s):  
Fernando Gordillo Altamirano ◽  
John H. Forsyth ◽  
Ruzeen Patwa ◽  
Xenia Kostoulias ◽  
Michael Trim ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Bacterial Resistance ◽  
Antimicrobial Agents ◽  
Phage Therapy ◽  
Loss Of Function ◽  
Beta Lactam ◽  
Bacterial Capsule ◽  
Capsule Production ◽  
Bacterial Mutants

AbstractCarbapenem-resistant Acinetobacter baumannii is responsible for frequent, hard-to-treat and often fatal healthcare-associated infections. Phage therapy, the use of viruses that infect and kill bacteria, is an approach gaining significant clinical interest to combat antibiotic-resistant infections. However, a major limitation is that bacteria can develop resistance against phages. Here, we isolated phages with activity against a panel of A. baumannii strains and focused on clinical isolates AB900 and A9844 and their phages for detailed characterization. As expected, coincubation of the phages with their hosts in vitro resulted in the emergence of phage-resistant bacterial mutants. Genome sequence analysis revealed that phage-resistant mutants harbored loss-of-function mutations in genes from the K locus, responsible for the biosynthesis of the bacterial capsule. Using molecular biology techniques, phage adsorption assays, and quantitative evaluation of capsule production, we established that the bacterial capsule serves as the primary receptor for these phages. As a collateral phenotype of impaired capsule production, the phage-resistant strains could not form biofilms, became fully sensitized to the human complement system, showed increased susceptibility to beta-lactam antibiotics, and became vulnerable to additional phages. Finally, in a murine model of bacteremia, the phage-resistant A. baumannii demonstrated a diminished capacity to colonize blood and solid tissues. This study demonstrates that phages can be used not only for their lytic activity but, if combined with a posteriori knowledge of their receptors and the mechanism of bacterial resistance, for their potential synergy with other antimicrobial agents, thus providing even broader clinical options for phage therapy.

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