Need For Effective Antibiotics Research Articles

Screening of the Pandemic Response Box library identified promising compound candidate drug combinations against extensively drug-resistant Acinetobacter baumannii

Infections caused by antimicrobial-resistant Acinetobacter baumannii pose a significant threat to human health, particularly in the context of hospital-acquired infections. As existing antibiotics lose efficacy against Acinetobacter isolates, there is an urgent need for the development of novel antimicrobial agents. In this study, we assessed 400 structurally diverse compounds from the Medicines for Malaria Pandemic Response Box for their activity against two clinical isolates of A. baumannii: A. baumannii 5075, known for its extensive drug resistance, and A. baumannii QS17-1084, obtained from an infected wound in a Thai patient. Among the compounds tested, seven from the Pathogen box exhibited inhibitory effects on the in vitro growth of A. baumannii isolates, with IC50s ≤ 48 µM for A. baumannii QS17-1084 and IC50s ≤ 17 µM for A. baumannii 5075. Notably, two of these compounds, MUT056399 and MMV1580854, shared chemical scaffolds resembling triclosan. Further investigations involving drug combinations identified five synergistic drug combinations, suggesting potential avenues for therapeutic development. The combination of MUT056399 and brilacidin against A. baumannii QS17-1084 and that of MUT056399 and eravacycline against A. baumannii 5075 showed bactericidal activity. These combinations significantly inhibited biofilm formation produced by both A. baumannii strains. Our findings highlight the drug combinations as promising candidates for further evaluation in murine wound infection models against multidrug-resistant A. baumannii. These compounds hold potential for addressing the critical need for effective antibiotics in the face of rising antimicrobial resistance.

Landscape of Push Funding in Antibiotic Research: Current Status and Way Forward.

The growing need for effective antibiotics is attributed to the intrinsic ability of bacteria to develop survival mechanisms. The speed at which pathogens develop resistance is at par or even faster than the discovery of newer agents. Due to the enormous cost of developing an antibiotic and poor return on investment, big pharmaceutical companies are stepping out of the antibiotic research field, and the world is now heading towards the silent pandemic of antibiotic resistance. Lack of investment in research has further led to the anemic antibiotic pipeline. To overcome these challenges, various organizations have come forward with push funding to financially assist antibiotic developers. Although push funding has somewhat reinvigorated the dwindled field of antibiotic development by bearing the financial risks of failure, the landscape is still large and staggered. Most of the funding is funneled towards the early stages; however, to carry the promising compounds forward, equal or more funding is required formid- and late-stage research. To some extent, the complexity associated with accessing the funding mechanisms has led to their underutilization. In the present review, we discuss several major push funding mechanisms, issues in their effective utilization, recent strategies adopted, and a way forward to streamline funding in antibiotic research.

A New Era of Antibiotics: The Clinical Potential of Antimicrobial Peptides.

Antimicrobial resistance is a multifaceted crisis, imposing a serious threat to global health. The traditional antibiotic pipeline has been exhausted, prompting research into alternate antimicrobial strategies. Inspired by nature, antimicrobial peptides are rapidly gaining attention for their clinical potential as they present distinct advantages over traditional antibiotics. Antimicrobial peptides are found in all forms of life and demonstrate a pivotal role in the innate immune system. Many antimicrobial peptides are evolutionarily conserved, with limited propensity for resistance. Additionally, chemical modifications to the peptide backbone can be used to improve biological activity and stability and reduce toxicity. This review details the therapeutic potential of peptide-based antimicrobials, as well as the challenges needed to overcome in order for clinical translation. We explore the proposed mechanisms of activity, design of synthetic biomimics, and how this novel class of antimicrobial compound may address the need for effective antibiotics. Finally, we discuss commercially available peptide-based antimicrobials and antimicrobial peptides in clinical trials.

The global need for effective antibiotics—Moving towards concerted action

Antibiotic resistance has emerged as one of the greatest global health challenges to be addressed in the 21st Century. The risk of widespread antibiotic resistance threatens to mitigate the positive changes made in modernizing healthcare systems; therefore, fresh approaches are essential, as well as new and effective antibacterial drugs. In a globalized world, a spectrum of different interventions and health technologies must be employed to contain antibiotic resistance. Finding ways of accelerating the development of new drugs and diagnostic tools is one strategy, as is better surveillance of antibiotic resistance and ways of improving use of existing antibiotics. Moreover, a framework to regulate use is called for to avoid that potential new antibiotics are squandered. Finally, the ongoing pandemic spread of resistant bacteria illustrates that the problem can only be addressed through international cooperation and thus that any new strategy to manage antibiotic resistance must take into consideration issues of global access and affordability.

The global need for effective antibiotics—A summary of plenary presentations

To highlight the global need for effective antibiotics and explore possible concerted actions for change, cross-cutting plenary sessions served to frame the program of the conference. These sessions contained presentations on the present state of antibacterial resistance and the availability, the use and misuse of antibiotics. A number of possible actions were discussed, such as rational use of and access to antibiotics from various perspectives. The roles of vaccines and diagnostics were touched upon and followed by in depth discussions on supply-side bottlenecks with their scientific, regulatory and financial challenges. The value chain for research and development (R&D) of antibiotics has to be reengineered if we are to realize the development of much needed new antibiotics. This challenge will require a multitude of actions, some of which are related to changing the financial realities of antibiotics and interventions by global and regional institutions.

Conserving antibiotics for the future: New ways to use old and new drugs from a pharmacokinetic and pharmacodynamic perspective

There is a growing need to optimize the use of old and new antibiotics to treat serious as well as less serious infections. The topic of how to use pharmacokinetic and pharmacodynamic (PK/PD) knowledge to conserve antibiotics for the future was elaborated on in a workshop of the conference (The conference "The Global Need for Effective Antibiotics - moving towards concerted action", ReAct, Uppsala, Sweden, 2010). The optimization of dosing regimens is accomplished by choosing the dose and schedule that results in the antimicrobial exposure that will achieve the microbiological and clinical outcome desired while simultaneously suppressing emergence of resistance. PK/PD of antimicrobial agents describe how the therapeutic drug effect is dependent on the potency of a drug against a microorganism and the exposure (the concentration of antimicrobial available for effect over time). The description and modeling of these relationships quantitatively then allow for a rational approach to dose optimization and several strategies to that purpose are described. These strategies include not only the dosing regimen itself but also the duration of therapy, preventing collateral damage through inappropriate use and the application of PK/PD in drug development. Furthermore, PK/PD relationships of older antibiotics need to be urgently established. The need for global harmonization of breakpoints is also suggested and would add efficacy to antibiotic therapy. For each of the strategies, a number of priority actions are provided.

The Oxazolidinones.

The need for effective antibiotics to manage the ever increasing frequency of antibiotic-resistant gram-positive infections in much of the developed world has led to the clinical development of the first oxazolidinone antibiotic, linezolid. Linezolid possesses bacteriostatic activity against both antibiotic-susceptible and resistant strains of staphylococci, enterococci, and streptococci of relevance to human infection. Clinical trials have confirmed its effectiveness in the treatment of serious infections of skin and soft tissue and the lower respiratory tract. Linezolid has also provided improved outcomes in the treatment of serious vancomycin-resistant enterococci and methicillin-resistant Staphylococcus aureus infections in a compassionate use program. Emergence of linezolid-resistant gram-positive cocci during clinical use has recently been described, suggesting that its present role in therapy should be reserved for the treatment of antibiotic-resistant gram-positive infections.

A Comparison of Single-Dose Cefixime with Ceftriaxone as Treatment for Uncomplicated Gonorrhea

Because of the widespread existence of Neisseria gonorrhoeae resistant to penicillin or tetracycline, ceftriaxone is now recommended for the treatment of gonorrhea. There is, however, a need for effective antibiotics that can be administered orally as an alternative to ceftriaxone, which requires intramuscular administration. Cefixime is an orally absorbed cephalosporin that is active against resistant gonococci and has pharmacokinetic activity suitable for single-dose administration. In a randomized, unblinded multicenter study of 209 men and 124 women with uncomplicated gonorrhea, we compared three single-dose treatment regimens: 400 mg or 800 mg of cefixime, administered orally, and 250 mg of ceftriaxone administered intramuscularly. The overall cure rates were 96 percent for the 400-mg dose of cefixime (89 of 93 patients) (95 percent confidence interval, 93.5 percent to 97.8 percent); 98 percent for the 800-mg dose of cefixime (86 of 88 patients) (95 percent confidence interval, 94.6 percent to 100 percent); and 98 percent for ceftriaxone (92 of 94 patients) (95 percent confidence interval, 94.9 to 100 percent). The cure rates were similar in men and women, and pharyngeal infection was eradicated in 20 of 22 patients (91 percent). Thirty-nine percent of 303 pretreatment gonococcal isolates had one or more types of antimicrobial resistance; the efficacy of all three regimens was independent of the resistance pattern. Chlamydia trachomatis infection persisted in at least half the patients infected in each treatment group. All three regimens were well tolerated. In the treatment of uncomplicated gonorrhea, a single dose of cefixime (400 or 800 mg) given orally appears to be as effective as the currently recommended regimen of ceftriaxone (250 mg given intramuscularly).