Fucoidan from Sargassum hemiphyllum inhibits infection and inflammation of Helicobacter pylori

Having infected by Helicobacter pylori, the infection often leads to gastritis, gastric ulcer, or even gastric cancer. The disease is typically treated with antibiotics as they used to effectively inhibit or kill H. pylori, thus reducing the incidence of gastric adenoma and cancer to significant extent. H. pylori, however, has developed drug resistance to many clinically used antibiotics over the years, highlighting the crisis of antibiotic failure during the H. pylori treatment. We report here that the fucoidan from Sargassum hemiphyllum can significantly reduce the infection of H. pylori without developing to drug resistance. Fucoidan appears to be a strong anti-inflammation agent as manifested by the RAW264.7 cell model examination. Fucoidan can prohibit H. pylori adhesion to host cells, thereby reducing the infection rate by 60%, especially in post treatment in the AGS cell model assay. Mechanistically, fucoidan intervenes the adhesion of BabA and AlpA of H. pylori significantly lowering the total count of H. pylori and the level of IL-6 and TNF-α in vivo. These results all converge on the same fact that fucoidan is an effective agent in a position to protect the stomach from the H. pylori infection by reducing both the total count and induced inflammation.

Antibiotic Treatment, Mechanisms for Failure, and Adjunctive Therapies for Infections by Group A Streptococcus

Group A Streptococcus (GAS; Streptococcus pyogenes) is a nearly ubiquitous human pathogen responsible for a significant global disease burden. No vaccine exists, so antibiotics are essential for effective treatment. Despite a lower incidence of antimicrobial resistance than many pathogens, GAS is still a top 10 cause of death due to infections worldwide. The morbidity and mortality are primarily a consequence of the immune sequelae and invasive infections that are difficult to treat with antibiotics. GAS has remained susceptible to penicillin and other β-lactams, despite their widespread use for 80 years. However, the failure of treatment for invasive infections with penicillin has been consistently reported since the introduction of antibiotics, and strains with reduced susceptibility to β-lactams have emerged. Furthermore, isolates responsible for outbreaks of severe infections are increasingly resistant to other antibiotics of choice, such as clindamycin and macrolides. This review focuses on the challenges in the treatment of GAS infection, the mechanisms that contribute to antibiotic failure, and adjunctive therapeutics. Further understanding of these processes will be necessary for improving the treatment of high-risk GAS infections and surveillance for non-susceptible or resistant isolates. These insights will also help guide treatments against other leading pathogens for which conventional antibiotic strategies are increasingly failing.

Phage Therapy for Antibiotic-Resistant Bacterial Infections

Antibiotic resistance in bacterial pathogens presents a substantial threat to the control of infectious diseases. Development of new classes of antibiotics has slowed in recent years due to pressures of cost and market profitability, and there is a strong need for new antimicrobial therapies. The therapeutic use of bacteriophages has long been considered, with numerous anecdotal reports of success. Interest in phage therapy has been renewed by recent clinical successes in case studies with personalized phage cocktails, and several clinical trials are in progress. We discuss recent progress in the therapeutic use of phages and contemplate the key factors influencing the opportunities and challenges. With strong safety profiles, the main challenges of phage therapeutics involve strain variation among clinical isolates of many pathogens, battling phage resistance, and the potential limitations of host immune responses. However, the opportunities are considerable, with the potential to enhance current antibiotic efficacy, protect newly developed antibiotics, and provide a last resort in response to complete antibiotic failure. Expected final online publication date for the Annual Review of Medicine, Volume 73 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Antibiotic treatment failure

This review presents information on cases of antibiotic failure (insufficient effect) in the global population over the past three years. We analyzed scientific papers, clinical trial data, and the WHO Program for International Drug Monitoring (VigiBase) data from 2018 to 2020. The values of global success and safety rates of antibacterial drugs for medical use are presented. The findings may be of practical interest to physicians, researchers, developers, and healthcare regulators.

Shooting yourself in the foot: How immune cells induce antibiotic tolerance in microbial pathogens

Antibiotic treatment failure of infection is common and frequently occurs in the absence of genetically encoded antibiotic resistance mechanisms. In such scenarios, the ability of bacteria to enter a phenotypic state that renders them tolerant to the killing activity of multiple antibiotic classes is thought to contribute to antibiotic failure. Phagocytic cells, which specialize in engulfing and destroying invading pathogens, may paradoxically contribute to antibiotic tolerance and treatment failure. Macrophages act as reservoirs for some pathogens and impede penetration of certain classes of antibiotics. In addition, increasing evidence suggests that subpopulations of bacteria can survive inside these cells and are coerced into an antibiotic-tolerant state by host cell activity. Uncovering the mechanisms that drive immune-mediated antibiotic tolerance may present novel strategies to improving antibiotic therapy.

Macrophage-produced peroxynitrite induces antibiotic tolerance and supersedes intrinsic mechanisms of persister formation

Staphylococcus aureus is a leading human pathogen that frequently causes chronic and relapsing infections. Antibiotic tolerant persister cells contribute to frequent antibiotic failure in patients. Macrophages represent an important niche during S. aureus bacteremia and recent work has identified a role for oxidative burst in the formation of antibiotic tolerant S. aureus . We find that host-derived peroxynitrite, the reaction product of superoxide and nitric oxide, is the main mediator of antibiotic tolerance in macrophages. Using a collection of S. aureus clinical isolates, we find that, despite significant variation in persister formation in pure culture, all strains were similarly enriched for antibiotic tolerance following internalization by activated macrophages. Our findings suggest that host interaction strongly induces antibiotic tolerance and may negate bacterial mechanisms of persister formation, established in pure culture. These findings emphasize the importance of studying antibiotic tolerance in the context of bacterial interaction with the host suggest that modulation of the host response may represent a viable therapeutic strategy to sensitize S. aureus to antibiotics.

Macrophage-produced peroxynitrite induces antibiotic tolerance and supersedes intrinsic mechanisms of persister formation

Staphylococcus aureus is a leading human pathogen that frequently causes chronic and relapsing infections. Antibiotic tolerant persister cells contribute to frequent antibiotic failure in patients. Macrophages represent an important niche during S. aureus bacteremia and recent work has identified a role for oxidative burst in the formation of antibiotic tolerant S. aureus. We find that host-derived peroxynitrite, the reaction product of superoxide and nitric oxide, is the main mediator of antibiotic tolerance in macrophages. Using a collection of S. aureus clinical isolates, we find that, despite significant variation in persister formation in pure culture, all strains were similarly enriched for antibiotic tolerance following internalization by activated macrophages. Our findings suggest that host interaction strongly induces antibiotic tolerance and may negate bacterial mechanisms of persister formation, established in pure culture. These findings emphasize the importance of studying antibiotic tolerance in the context of bacterial interaction with the host suggest that modulation of the host response may represent a viable therapeutic strategy to sensitize S. aureus to antibiotics.

Development of Antibiotic Resistance, Suggestion For The Safety of Our Future Generation

Background: Rising of multidrug resistance among uropathogenic bacteria is leading our future generation to a crisis. Nevertheless, the era of antibiotic failure due to bacterial resistance has brought interest to other medical science like Traditional Medicine, alternative medicine. Objectives: This study was undertaken to determine the current antibiotic resistance situation among common bacterial uropathogens and suggesting prevention measure. Materials and Methods: A total of 212 patients male 132,female 80 selected. Mid-urine samples were collected. Isolated organisms were identified by conventional methods. Then different antibiotics representing different families of antibiotics were tested on isolated organisms. Results: The most frequently isolated gram negative bacteria was E.Coli (92%) followed by Staphylococcus(7.07%),Klebsiella(7%), Pseudomonas(4.25%). Resistance to Amoxicilline, Ciprofloxacin, Cefixim, Ceftriaxone, Cefuroxim, Cefradin, Cefotaxim was more than 70% of all isolates of E.Coli stains. There was relatively low resistance rate to Nitrofurantoin, Gentamycin,Imipenem, Meropenem, Amikacin, Ceftazidim . However, there was emerging resistance to Ciprofloxacin, specially for common bacteria. Conclusion: It is urgent need to make a policy for antibiotics use . We suggest all health care professional of traditional medicine and modern medicine to combat against antibiotics resistance. KYAMC Journal.2021;12(1): 32-35

Development and Preclinical Evaluation of New Inhaled Lipoglycopeptides for the Treatment of Persistent Pulmonary MRSA Infections

Chronic pulmonary MRSA disease in cystic fibrosis (CF) has a high probably of recurrence following treatment with standard-of-care antibiotics and represents an area of unmet need associated with reduced life expectancy. We developed a lipoglycopeptide therapy customized for pulmonary delivery that not only demonstrates potent activity against planktonic MRSA but also against protected colonies of MRSA both in biofilms and within cells, the latter of which have been linked to clinical antibiotic failure. A library of next-generation potent lipoglycopeptides were synthesized with an emphasis on attaining superior pharmacokinetics (PK) and pharmacodynamics to similar compounds of their class. Our strategy focused on hydrophobic modification of vancomycin where ester and amide functionality were included with carbonyl configuration and alkyl length as key variables. Candidates representative of each carbonyl attachment chemistry demonstrated potent activity in vitro with several compounds being 30-60 times more potent than vancomycin. Several compounds were advanced into in vivo nose-only inhalation PK evaluations in rats where RV94, a potent lipoglycopeptide that utilizes an inverted amide linker to attach a 10-carbon chain to vancomycin, demonstrated the most favorable lung residence time after inhalation. Further in vitro evaluation of RV94 showed superior activity to vancomycin against an expanded panel of gram-positive organisms, cellular accumulation and efficacy against intracellular MRSA, and MRSA biofilm killing. Moreover, in vivo efficacy of inhaled nebulized RV94 in a 48-h acute model of pulmonary MRSA (USA300) infection in neutropenic rats demonstrated statistically significant antibacterial activity that was superior to inhaled vancomycin.

Immunosuppression broadens evolutionary pathways to treatment failure during Acinetobacter baumannii pneumonia

Acinetobacter baumannii is increasingly refractory to antibiotic treatment in healthcare settings. As is true of most human pathogens, the genetic path to antimicrobial resistance (AMR) and the role that the immune system plays in modulating AMR during disease are poorly understood. Here we reproduced several routes to fluoroquinolone resistance, performing evolution experiments using sequential lung infections in mice that are replete or depleted of neutrophils, providing two key insights into the evolution of drug resistance. First, neutropenic hosts were demonstrated to act as reservoirs for the accumulation of drug resistance. Selection for variants with altered drug sensitivity profiles arose readily in the absence of neutrophils, while immunocompetent animals restricted the appearance of these variants. Secondly, antibiotic treatment failure was shown to occur without clinically defined resistance, an unexpected result that provides a model for how antibiotic failure occurs clinically in the absence of AMR. The genetic mechanism underlying both these results is initiated by mutations activating the drug egress pump regulator AdeL, which drives persistence in the presence of the antibiotic. Therefore, antibiotic persistence mutations are demonstrated to present a two-pronged risk during disease, causing drug treatment failure in the immunocompromised host while simultaneously increasing the likelihood of high-level AMR acquisition.