Antibiotic Pipeline Research Articles

Antibiotics Clinical Development and Pipeline.

There is a constant need for resupply with resistance-breaking antibiotics. Governmental programs and updated regulatory guidance have incentivized mainly small- and medium-sized biopharmaceutical companies to develop novel antibiotics up to market licensure, while major pharma players, with exceptions, have abandoned the space for a perceived lack of a return on their investment. The portfolio of approved drugs has improved over recent years for gram-positive infections, including infections caused by methicillin-resistant Staphylococcus aureus. On the other hand, unmet medical need has surfaced in indications dominated by gram-negative pathogens including complicated intra-abdominal and bloodstream infections as well as hospital-acquired and ventilator-associated pneumonia. Few if any treatment options are left for extended-spectrum beta-lactamase- and carbapenemase-producing Enterobacteriaceae, e.g., Klebsiella pneumoniae, and the multi-drug-resistant non-fermenting gram-negative bacteria Pseudomonas aeruginosa and Acinetobacter baumannii. The present paper summarizes and reviews the clinical pipeline of novel antibiotics by clinical indication and identifies the unmet medical need in the space.

Federal Officials, Congress Seek Ways To Stimulate Antibiotic Development

The President's Council of Advisors on Science and Technology (PCAST) last September released a report, “Combating Antibiotic Resistance,” along with a strategy for dealing with this public health problem. In addition, the White House issued an Executive Order emphasizing the importance of addressing this challenge (Microbe, November 2014, p. 432). “Even with improved stewardship and surveillance, it is critical to develop new antibiotics, diagnostics, vaccines, and other interventions at a rate that outpaces the emergence of resistant microbes,” PCAST members noted. “A robust antibiotic pipeline is essential for creating new antibiotics to replace those being steadily lost to antibiotic resistance. Establishing this pipeline and successfully addressing the rise in antibiotic resistant bacteria will require coordination across governmental, academic, health-related, agricultural, and private sectors.”

Battling Drug-Resistant Bacteria

The Obama Administration is ramping up the federal fight against antibiotic-resistant bacteria. These so-called superbugs are linked to an estimated 23,000 deaths and 2 million infections in people each year in the U.S., according to the Centers for Disease Control & Prevention (CDC). White House officials say the situation is a “growing crisis,” threatening national security and the economy. The new efforts, announced in mid-September, include a national strategy to address antibiotic resistance, a directive to federal agencies, and a $20 million prize. Recommendations for addressing the rise of antibiotic resistance from a high-level White House advisory group were also unveiled at the same time. The actions aim to show that the Obama Administration is serious about curbing the rise of deadly antibiotic-resistant bacteria and beefing up the pipeline of new antibiotics and diagnostics. But some public health advocates say the measures do not go far enough, particularly with respect ...

Antibiotic resistance: Are we really to blame?

Nurse PrescribingVol. 12, No. 8 NewsAntibiotic resistance: Are we really to blame?Maria AnguitaMaria AnguitaSearch for more papers by this authorMaria AnguitaPublished Online:6 Aug 2014https://doi.org/10.12968/npre.2014.12.8.370AboutSectionsView articleView Full TextPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareShare onFacebookTwitterLinked InEmail View article References Department of Health (2013) UK 5 Year Antimicrobial Resistance Strategy 2013 to 2018. DH, London. www.gov.uk/government/uploads/system/uploads/attachmentdata/file/244058/20130902_UK_5_year_AMR_strategy.pdf (accessed 15 July 2014) Google ScholarPlumridge H (2014) Drug makers tiptoe back into antibiotic R&D. Wall Street Journal, New York. http://online.wsj.com/news/articles/SB10001424052702303465004579322601579895822 (accessed 10 July 2014) Google ScholarStanton T (2013) A call for antibiotic alternatives research. Trends Microbiol 21(3): 111–3 doi: https://doi.org/10.1016/j.tim.2012.11.002 Google ScholarWise J (2010) Call for global action on antibiotic resistance. BMj 341: C4957 Crossref, Google ScholarWorld Health Organization (2014) Antimicrobial resistance: global report on surveillance. WHO, Geneva, www.who.int/mediacentre/news/releases/2014/amr-report/en/ (accessed 10 July 2014) Google Scholar FiguresReferencesRelatedDetails 2 August 2014Volume 12Issue 8ISSN (print): 1479-9189ISSN (online): 2052-2924 Metrics History Published online 6 August 2014 Published in print 2 August 2014 Information© MA Healthcare LimitedPDF download

New antibiotics for skin and skin-structure infections

On April, 2014, WHO published a report showing the present situation of antimicrobial resistance in many regions of the world and underlining the risk of a global post-antibiotic era in which even common infections can be lethal.1,2 Even more concerning is that the burden of these infections includes high mortality and hospital costs.3,4 Prevention relies mainly on infection control and antimicrobial stewardship, but the pipeline for antibiotics is almost empty. Bacterial skin and skin-structure infections are amongst the most common indications for antibiotic treatment.

The challenge of antimicrobial resistance: new regulatory tools to support product development.

The antibiotic pipeline is thin and lacks diversity, particularly for agents targeting Gram-negative pathogens. The reasons for our anemic global development pipeline are often summarized as (i) discovery of new antibiotics is difficult, (ii) clinical development of new antibiotics is difficult, and (iii) the economics for new antibiotics are unfavorable for the developer. Here, we review recent efforts directed at the second of these challenges.

Superbugs: A Challenge for Scientific Research

Infections caused by multi-drug-resistant bacteria and especially carbapenem-resistant Enterobacteriaceae (CRE) are associated with thousands of deaths each year [1] raising significantly the hospitalization costs in many countries such as the US, India, China, Greece and Israel. The problem is obviously multi-factorial and seems difficult to be addressed. Bacteria possess an extremely versatile genetic armamentarium, being able to acquire genes horizontally, mutate swiftly and accumulate the necessary mechanisms for their survival under evolutionary pressure [2]. Humans however, seem to be much more responsible for the emergence of antibiotic resistance. Immoderate antibiotic prescription, uncontrolled public access to antibiotics in some countries and the use of sub therapeutic doses for the promotion of animal growth in the agricultural sector are only some of the main contributing factors. Moreover, the limited flow through the pipeline of novel antibiotics and the problems that big pharmaceutical companies are facing for the development, license and commercial use of these compounds are leading the less optimistic to talk about future apocalyptic scenarios.

The evolution of the regulatory framework for antibacterial agents.

The rising tide of antibacterial resistance and the lack of a diverse, vibrant pipeline of novel antibacterial agents is a global crisis that impairs our ability to treat life-threatening infections. The recent introduction of a tiered approach to the regulatory framework in this area offers one path to resolving some of the challenges. By drawing heavily on the predictive power of the related sciences of pharmacokinetics and pharmacodynamics, smaller, focused clinical trial programs have become possible for agents that might not otherwise have been possible to progress. There are limitations to these pathways, and they are not easy to implement, but making reliable noninferiority-based approaches available is critical to reinvigorating the global antibiotic pipeline. With the recognition of these ideas by key regulatory authorities in recent guidance, the next challenges in this area will focus on interpretive breakpoints, the extent of data in the prescribing information, ensuring that multiple agents can be progressed, and the challenge of the antibiotic business model.

Overcoming the current deadlock in antibiotic research

Antibiotic-resistant bacteria are on the rise, making it harder to treat bacterial infections. The situation is aggravated by the shrinking of the antibiotic development pipeline. To finance urgently needed incentives for antibiotic research, creative financing solutions are needed. Public-private partnerships (PPPs) are a successful model for moving forward.

Antibiotic Judo

Antibiotic Judo

Dry antibiotic pipeline: Regulatory bottlenecks and regulatory reforms.

Dry antibiotic pipeline: Regulatory bottlenecks and regulatory reforms.

Repurposing of gallium‐based drugs for antibacterial therapy

While the occurrence and spread of antibiotic resistance in bacterial pathogens is vanishing current anti-infective therapies, the antibiotic discovery pipeline is drying up. In the last years, the repurposing of existing drugs for new clinical applications has become a major research area in drug discovery, also in the field of anti-infectives. This review discusses the potential of repurposing previously approved gallium formulations in antibacterial chemotherapy. Gallium has no proven function in biological systems, but it can act as an iron-mimetic in both prokaryotic and eukaryotic cells. The activity of gallium mostly relies on its ability to replace iron in redox enzymes, thus impairing their function and ultimately hampering cell growth. Cancer cells and bacteria are preferential gallium targets due to their active metabolism and fast growth. The wealth of knowledge on the pharmacological properties of gallium has opened the door to the repurposing of gallium-based drugs for the treatment of infections sustained by antibiotic-resistant bacterial pathogens, such as Acinetobacter baumannii or Pseudomonas aeruginosa, and for suppression of Mycobacterium tuberculosis growth. The promising antibacterial activity of gallium both in vitro and in different animal models of infection raises the hope that gallium will confirm its efficacy in clinical trials, and will become a valuable therapeutic option to cure otherwise untreatable bacterial infections.

A novel modified acrylic bone cement matrix. A step forward on antibiotic delivery against multiresistant bacteria responsible for prosthetic joint infections

Currently the safe and responsible use of antibiotics is a world-wide concern as it promotes prevention of the increasing emergence of multiresistant bacterial strains. Considering that there is a noticeable decline of the available antibiotic pipeline able to combat emerging resistance in serious infection a major concern grows around the prosthetic joint infections once the available commercial antibiotic loaded polymethylmethacrylate bone cements (BC) are inadequate for local antibiotic treatment, especially against MRSA, the most commonly isolated and antibiotic-resistant pathogen in bone infections. In this paper a novel modified BC matrix loaded with minocycline is proposed. A renewed interest in this tetracycline arises due to its broad-spectrum of activity against the main organisms responsible for prosthetic joint infections, especially against MRSA. The modified BC matrices were evaluated concerning minocycline release profile, biomechanical properties, solid-state characterization, antimicrobial stability and biocompatibility under in vitro conditions. BC matrix loaded with 2.5% (w/wBC) of minocycline and 10.0% (w/wBC) of lactose presented the best properties since it completely released the loaded minocycline, maintained the mechanical properties and the antimicrobial activity against representative strains of orthopedic infections. In vitro biocompatibility was assessed for the elected matrix and neither minocycline nor lactose loading enhanced BC cytotoxicity.

Call for a Dedicated European Legal Framework for Bacteriophage Therapy

The worldwide emergence of antibiotic resistances and the drying up of the antibiotic pipeline have spurred a search for alternative or complementary antibacterial therapies. Bacteriophages are bacterial viruses that have been used for almost a century to combat bacterial infections, particularly in Poland and the former Soviet Union. The antibiotic crisis has triggered a renewed clinical and agricultural interest in bacteriophages. This, combined with new scientific insights, has pushed bacteriophages to the forefront of the search for new approaches to fighting bacterial infections. But before bacteriophage therapy can be introduced into clinical practice in the European Union, several challenges must be overcome. One of these is the conceptualization and classification of bacteriophage therapy itself and the extent to which it constitutes a human medicinal product regulated under the European Human Code for Medicines (Directive 2001/83/EC). Can therapeutic products containing natural bacteriophages be categorized under the current European regulatory framework, or should this framework be adapted? Various actors in the field have discussed the need for an adapted (or entirely new) regulatory framework for the reintroduction of bacteriophage therapy in Europe. This led to the identification of several characteristics specific to natural bacteriophages that should be taken into consideration by regulators when evaluating bacteriophage therapy. One important consideration is whether bacteriophage therapy development occurs on an industrial scale or a hospital-based, patient-specific scale. More suitable regulatory standards may create opportunities to improve insights into this promising therapeutic approach. In light of this, we argue for the creation of a new, dedicated European regulatory framework for bacteriophage therapy.

Development of antibiotic resistance in Gram negative bacilli: An eye opener

<b>Context:</b> Antibiotic resistance is a global problem. Organisms are showing resistance to not only the conventional antibiotics but also to the higher generation drugs. This enormous amount of resistance faced is a serious threat to mankind and this is further accentuated by the fact that the antibiotic pipeline is fast drying up. We are now left with only a handful of antibiotics to deal with all infections - serious or otherwise. The present paper highlights the current scenario of drug resistance especially in nosocomial settings. <b>Aims and Objectives:</b> To determine the distribution of bacterial pathogens causing nosocomial infections and their antibiogram, a surveillance data from January to December 2011 was collected in Mohan Dai Oswal Hospital. A total of 1800 samples were taken of which maximum samples were urine (766) followed by blood (428) and pus (216), and so on. <b>Settings and Design:</b> This observational study was conducted in the microbiology department of a multispeciality hospital during January-December 2011. <b>Materials and Methods:</b> A total of 1800 samples from different sources were included in the study like pus, blood, urine, sputum, etc., which were taken from patients admitted in the hospital for more than a week. Gram negative bacilli were isolated, identified, and subjected to antibiotic sensitivity test. <b>Statistical Analysis Used:</b> Descriptive statistics using percentages. <b>Results:</b> Out of the total 1800 samples included, maximum positivity was found in the pus samples (70%). Extended-spectrum beta-lactamase (ESBL) positivity was also maximum in the pus samples (90%). These ESBL positive organisms were further subjected to antibiotic sensitivity tests and huge amounts of resistance was noted to the conventional drugs including the higher end agents like Carbapenems. In light of this, newer drugs like Tigecycline, Colistin, and Polymyxin B were also tested. Barring Tigecycline, none showed favorable results. A noteworthy finding was the sensitivity of the urinary ESBL isolates to Nitrofurantoin. <b>Conclusions:</b> The situation is quite dangerous. The time is not far when we will be back in the dark ages of the preantibiotic era. The need of the hour is to be alert of the gravity of this situation and take necessary measures to halt its progress.

Pipeline of Known Chemical Classes of Antibiotics.

Many approaches are used to discover new antibiotic compounds, one of the most widespread being the chemical modification of known antibiotics. This type of discovery has been so important in the development of new antibiotics that most antibiotics used today belong to the same chemical classes as antibiotics discovered in the 1950s and 1960s. Even though the discovery of new classes of antibiotics is urgently needed, the chemical modification of antibiotics in known classes is still widely used to discover new antibiotics, resulting in a great number of compounds in the discovery and clinical pipeline that belong to existing classes. In this scenario, the present article presents an overview of the R&D pipeline of new antibiotics in known classes of antibiotics, from discovery to clinical trial, in order to map out the technological trends in this type of antibiotic R&D, aiming to identify the chemical classes attracting most interest, their spectrum of activity, and the new subclasses under development. The result of the study shows that the new antibiotics in the pipeline belong to the following chemical classes: quinolones, aminoglycosides, macrolides, oxazolidinones, tetracyclines, pleuromutilins, beta-lactams, lipoglycopeptides, polymyxins and cyclic lipopeptides.

New Cephalosporin Shows Promise in Drug-Resistant Pneumonia

New Cephalosporin Shows Promise in Drug-Resistant Pneumonia

Avoiding the doomsday predictions: The dual crises of antibiotic resistance and the failing antibiotic pipeline

Avoiding the doomsday predictions: The dual crises of antibiotic resistance and the failing antibiotic pipeline

Prolonging β-lactam infusion: A review of the rationale and evidence, and guidance for implementation

Given the sparse antibiotic pipeline and the increasing prevalence of resistant organisms, efforts should be made to optimise the pharmacodynamic exposure of currently available agents. Prolonging the infusion duration is a strategy used to increase the percentage of the dosing interval that free drug concentrations remain above the minimum inhibitory concentration (fT>MIC), the pharmacodynamic efficacy driver for time-dependent antibiotics such as β-lactams. β-Lactams, the most commonly prescribed class of antibiotics owing to their efficacy and safety profile, have been the mainstay of therapy since the discovery of penicillin over 60 years ago. Mounting evidence, including the use of population pharmacokinetic modelling and Monte Carlo simulation, suggests that prolonging the infusion time of β-lactam antibiotics may have advantages over standard infusion techniques, including an enhanced probability of achieving requisite fT>MIC exposures, lower mortality and potentially reductions in infection/antibiotic-related costs. As a result of these favourable attributes, clinical practice guidelines support the use of prolonged-infusion β-lactams in the treatment of many severe infections. This article discusses the rationale and evidence for prolonging the infusion of β-lactam antibiotics and provides guidance for the implementation of a prolonged-infusion programme.

Small-Molecule Quorum Quenchers to Prevent Staphylococcus Aureus Infection

Antibiotic-resistant bacteria are one of the most significant current threats to human health. The diminishing antibiotic development pipeline coupled with the propensity for bacterial pathogens to evolve resistance represents an ongoing crisis that needs to be addressed [1] . Resistance development has long been a major concern with Staphylococcus aureus , a notorious bacterial pathogen that causes a wide spectrum of acute and chronic disease. The incidence of methicillin-resistant S. aureus (MRSA) infections in both hospital and community settings continues to rise [2] , and healthcare-associated infections due to MRSA cost more and lead to longer hospital stays than those caused by any other bacterial pathogen [3] . Antibiotic stewardship to preserve the most efficacious treatments for severe bacterial infections needs to be at the forefront of strategies designed to address growing resistance challenges. How can these principles be applied to managing S. aureus disease burden? When considering the breadth of infections caused by S. aureus , the majority are skin and soft tissue infections (SSTIs), resulting in 11.6 million ambulatory care visits per year [4] . In emergency departments, 76% of S. aureus cases are SSTIs and 59% of these are MRSA [5] . Many of these SSTIs would be considered uncomplicated and treated with straightforward courses of antibiotics. Considering these points, the load of antibiotic therapy being directed toward S. aureus SSTIs is significant, and it seems probable that this is contributing to resistance development. What if innovative countermeasures for SSTIs that do not drive resistance could be translated into approved therapies? Such a strategy could help preserve the most effective antibiotics for the severe, deep-seated S. aureus infections and enable uncomplicated infections to be treated more rapidly and effectively.