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Antibacterial Agents in the Pipeline: The future for antibiotics

General | May 14, 2015 | Author: The Super Pharmacist

general

Antibacterial Agents in the Pipeline: The future for antibiotics

Antibacterial agents are drugs or other compounds that are developed and marketed to kill harmful bacteria or otherwise inhibit their proliferation in human tissue. Bacteria are a huge phylum (evolutionary tree) of single-celled organisms. They are associated with a wide range of diseases and disorders that affect infected individuals, including typhoid, tuberculosis, cholera and common food poisoning (i.e. enteric E. coli infections). The mortality and disease burden associated with these conditions has been effectively reduced through improvements in sanitation and public hygiene in many parts of the world. This decrease is also due to antibacterial products, or agents, most notably antibiotics. These drugs cause damage to or attack bacterial cells in various ways to eradicate colonies in patients. For example, some antibiotics disrupt the cell wall of bacteria, causing the contents of the cell to 'spill out' and thus the death of the individual bacterium.

However, bacteria adapt quickly to hostile factors such as antibacterial drugs, and many strains (subtypes of species) have evolved biochemical strategies to avoid susceptibility to antibiotics. This is known as antibiotic resistance. A bacterial strain can develop resistance very rapidly, so that the same antibiotic will not work on the same cause of infection twice. Antibiotic resistance is an important factor of antibiotic failure. Some strains of bacteria are resistant to many different agents. These are known as multidrug-resistant (MDR) strains, such as MDR Salmonella typhi and Staphylococcus aureus. This type of S. aureus, also sometimes known as MDR-SA, is prevalent as a hospital-acquired infection and has become very difficult to eradicate. It may cause gastrointestinal disturbances, but may also be associated with deteriorations and further complications in open wounds, if it is allowed to infiltrate these. Another major factor in antibiotic treatment failure is the relative lack of recent innovation and development in antibacterial agents. There have been few new classes (or types based on function or chemical structure) of antibiotics tested and marketed, particularly in the years between 1970 and 1990. However, the meteoric rise of prevalence in antibiotic-resistant bacteria, particularly MRSA, has demonstrated the immediate need of new forms of antibiotics and other agents, which may improve the current epidemic of hospital-acquired infections and other drug-resistant bacterial conditions worldwide. The use of new agents, whether at the clinical trial or marketing stages, is proving to be promising and cost-effective. This may be due to the reduced need of repeat treatments for recurrent infections. Examples of next-generation antibacterial agents, or antibacterial treatment strategies, include:

Fidaxomicin

This 'next-generation' antibiotic was released into the market in 2011. It is in the macrolide class of antibiotics that has shown efficacy against Clostridium difficle infections. C. difficle is associated with high rates of diarrhoea. It is the most prominent cause of this condition in the United States. However, antibiotics administered to treat C. difficle conditions may also kill the pre-existing 'friendly' bacteria in the gut. These have a range of beneficial effects when present in the body, including the prevention of harmful bacteria proliferating and forming colonies in the gastrointestinal tract. Fidaxomicin is associated with effects on C. difficle that are comparable to the older antibiotic vancomycin, but with reduced effects on 'friendly' bacteria. It is also reported to be associated with a reduced incidence of adverse effects. Treatment with vancomycin (and metronidazole, another conventional antibiotic) is also associated with high rates of recurrent infections.

A trial randomly assigned 548 patients with C. difficle infections to 125 mg vancomycin four times daily or 200mg fidaxomicin twice daily. The rates of eradication were similar in both groups, but the rates of recurrence were significantly lower in the fidaxomicin group. Another trial with a similar protocol including 509 patients reported similar results, although this study did not include data on recurrence. Both trials reported a similar rate of adverse events for both antibiotics.

Bedaquiline

This is another new antibiotic product launched in 2012. It has been found to be effective against MDR Mycobacterium tuberculosis. However, bedaquiline is also linked to an increased mortality rate, and is regarded as a treatment of last resort for drug-resistant tuberculosis9. This may be due to its relatively long half-life (up to six months) in the body. A phase 2 trial randomized 47 patients with newly-diagnosed MDR tuberculosis to a standard treatment regimen and 400 mg bedaquiline daily for two weeks followed by 200 mg three times a week for six more weeks, or the standard treatment with an identical placebo regimen. The time before producing M. tuberculosis-negative samples was significantly lower in the 'bedaquiline' group compared to the 'placebo' group. The adverse events were reported as mostly mild or moderate, although nausea was more frequent among those in the 'bedaquiline' group.

Natural Agents and their Derivatives

Many antibiotics were discovered in plants, fungi or other organisms (including bacteria) that have evolved the ability to produce these chemicals to prevent their own bacterial infections (or to compete with other bacteria by releasing them to kill opposing colonies). Examples of 'natural' antibiotics include erythromycin, vancomycin, streptomycin and penicillin. Other novel antibacterial agents may be derived from plants. An extract of Camellia sinensis showed efficacy against MDR Salmonella typhi in a recent in vitro trial. Other emerging natural antibiotics may include abyssomycins, which are derived from a marine bacterium.

Abyssomycins

These are antibiotics that act in a similar way to the traditional antibiotic class of the sulphonamides. Some abyssomycins (e.g. abyssomycin C) have shown efficacy against MDR-SA in some in vitro trials.

Taxanes

These are a new class of chemicals that interfere with the functions of a protein (FtsZ) involved in cell division. As this protein shows little evolutionary variation in bacteria, it is a possible point of weakness; a bacterium with inactive FtsZ is less likely to be able to replicate itself (i.e. to reproduce properly). This could be a target for novel antibacterial treatment. Therefore, taxanes are a potential new class of antibiotic. Taxanes have been reported as having significant effects against M. tuberculosis in in vitro studies.

Synergistic Combined Antibacterial Agents

These are treatments that contain two or more ingredients that attack bacteria in different, but complementary, ways2. For example, an in vitro study claimed that the combination of antibacterial plant (Juglans regia) extracts and oxacillin could inhibit oxacillin-resistant S. aureus. Beta-lactams are another class of antibiotics (e.g. carbapenems) that can be resisted through the evolution of bacterial beta-lactamase, an enzyme that breaks down the structure of these chemicals. However, combinations of these and new-generation beta-lactamase inhibitors (such as avibactam and relebactam) may be promising emerging treatments that can replace older beta-lactamase inhibitors and products that combine these with beta-lactams.

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