ANTIBIOTIC RESISTANCE

Yehuda Carmeli MD, MPH

Delivering the event’s keynote address to a full auditorium at the 7th International Conference on Ocular Infections in Barcelona, Spain, Yehuda Carmeli MD, MPH, Professor of Internal Medicine and Infectious Diseases at Tel Aviv University, Israel, began his presentation with a photo of the now-famous petri dish of penicillium inhibiting the growth of bacterial colonies.

That was in 1928, nearly a century ago, and many millions of lives have since been improved and even saved due to treatment with penicillin. However, the development of antibiotic resistance rapidly became a problem. This was first seen in hospitals, followed later by the development of resistance in the community.

“Resistance represents a mismatch between treatment and susceptibility, leading to increased cost, morbidity and a two-fold increase in mortality as compared to infection with a susceptible strain. It causes a delay in adequate therapy, and the use of clinically less effective agents leads to worse outcomes,” said Dr Carmeli.

WHAT CAN BE DONE?

“It is widely known that there is a strong correlation between indiscriminate antibiotic use and microbial resistance, with countries like The Netherlands at the forefront of careful and disciplined antibiotic policy,” said Dr Carmeli.

Striking graphs demonstrated the differences between countries regarding total antibiotic use and penicillin-nonsusceptible S. pneumoniae.

Changes can be made. Requiring prior authorisation for selected antimicrobials impedes their indiscriminate use, decreasing resistance rates. Decreasing veterinary medicine use on farms might do the same, as might screening patients from high prevalence areas so that they may be treated before getting the chance to infect others.

With the knowledge that β-lactamase enzymes are the main mechanism of resistance to penicillin, via their hydrolysis of antibiotic molecules, nearly a thousand variants have been identified, with the goal of developing new drugs that avoid this enzymatic destruction.

Dr Carmeli also discussed the changing epidemiology of resistance throughout the world, tracking the rapid spread of resistant strains between countries. Besides well-known organisms like MRSA, others were mentioned: multi-drug resistant enterobacteriaceae and bacteremia due to extended-spectrum β-lactamase (ESBL)-producing Escherichia coli, and carbapenem-resistant Klebsiella pneumoniae and Acinetobacter baumannii. Outcomes for those infected are not good. These so-called “superbugs” have even made it into the news media.

A ray of hope was provided at the end of Dr Carmeli’s presentation. Nationwide interventions can help decrease the incidence of infections with resistant strains, particularly those of nosocomial origin. Countering this good news is the fact that pharmaceutical companies have been decreasing their involvement in antibacterial development.

“There was a steady rise of active corporate antibacterial programmes between the 1940s and the late 1980s. But since then, and especially over the past 15 years, there has been a steady decline. Since 1996, only 14 companies have entered the market while 36 have exited, leading to a significant net decrease in the efforts to develop new and innovative antibiotics,” noted Dr Carmeli.

Solutions must involve enhanced infection control, antibiotic stewardship and sustained focus on drug development, Dr Carmeli concluded.

“But what about ophthalmic drugs?” asked David G Hwang MD, FACS, Professor and Vice Chair of Ophthalmology at the University of California, San Francisco, USA, who spoke next on the topic of ophthalmic drug development.

“Ophthalmic drug development has been dominated by two decades of fluoroquinolone development. Azithromycin is the only other non-fluoroquinolone to gain FDA approval in the past 20 years, and besifloxacin was the last non-combination antimicrobial to be approved, in 2009. This represents a complete drug development void since 2009,” he emphasised.

There are several major unmet needs in ophthalmology, he stressed. These include treatment for fluoroquinolone-resistant strains; antibiotics for methicillin-resistant staphylococci; and formulations of existing antimicrobials intended specifically for topical, intracameral and intravitreal use.

But development hurdles continue to hamper progress.

“The small size of the ophthalmic antibiotic market relative to development costs is a big problem, as are ocular toxicity testing requirements and ophthalmic formulation issues. For example, a number of antimicrobials designed to be reconstituted for immediate parenteral use cannot be used for commercial ophthalmic preparations, because when stored in aqueous solution at room temperature, they are relatively unstable over weeks to months of shelf life. Further, many newly developed antibiotic agents are narrow, second- or third-line agents created for specific, non-ocular targets,” said Dr Hwang.

Dr Hwang remained hopeful, however, because of the recent incentivisation of drug development. The Generating Antibiotics Incentives Now (GAIN) Act of the US Congress (2012) has called for an accelerated FDA approval process for new drugs and a five-year extension of patents for so-called qualified infectious disease products. This has already led to FDA approval of eight new antimicrobials since 2010, although none has yet been developed for ophthalmic use.

“Can we incentivise ophthalmic drug development similarly?” asked Dr Hwang. He stressed the need for a better development path for prophylaxis indications, as these are more commonly needed in ophthalmology than treatment indications. Another suggestion is the granting of an extension of patent exclusivity to the parent compound for approval of non-systemic (in this case, ophthalmic) formulations.

“We need integrated antimicrobial management policies if we are to avoid a dystopian future of massive antibiotic resistance,” concluded Dr Hwang.

Yehuda Carmeli: yehudac@tlvmc.gov.il

David G Hwang: david.hwang@ucsf.edu