Solutions for Antibiotic Needs

IDSA and the African Union talk about ongoing antibiotic needs - Here are some positive steps to address them.

Two recent new articles on antibiotics caught my attention. One was from the Infectious Diseases Society of America on the need for (and dearth of) orally available antibiotics to treat resistant infections.  The other was from the African Union AMR Landmark Report decrying the toll of illness and death from antibiotic resistant infections on the continent.  There are already potential solutions to address both problems. Sadly, they have been inadequately applied.

The IDSA article focuses on infections caused by carbapenem-resistant Gram-negatives and the lack of well-established oral alternatives to IV therapy. Oral antibiotic therapy is important to avoid hospitalization altogether for some patients and to allow for earlier discharge of others. The use of trimethoprim-sulfamethoxazole and fluoroquinolones is cited as possible treatment. But the article notes the lack of clear clinical evidence favoring these regimes. Some propose clinical trials of such treatments in the setting of resistant infections.  I think that is an unnecessary, expensive and potentially infeasible burden. Trials using patients with usually resistant infections combined with a strong PK/PD component should suffice and may not even be necessary depending on prior trial data for these already-approved antibiotics.

What is not mentioned is the antibiotic pipeline where several promising orally available B-lactam-B-lactamase inhibitor combinations along with a very few other oral candidates are in clinical trials for Gram-negative infections. The problem here is that the development of these compounds has been extraordinarily slow.  That, in turn, is almost certainly related, at least in part, to the poor financial performance of new antibiotics and the pessimism by companies and investors that they will ever make a reasonable return on these new antibiotics.

The solution, once again, is a market intervention like the subscription plan already implemented in the UK and, more importantly, the PASTEUR Act proposed here in the US. Having a significant market delinked from use, as this legislation proposes, would be a giant step forward in accelerating and expanding our pipeline of oral antibiotics for resistant infections.  All we must do is act.

The report from the African Union notes -

Although AMR affects populations in both high- and low-income

countries (LMIC’s), the Global Research on Antimicrobial Resistance

(GRAM) study identified the highest burden in low-resource

settings, which face the greatest burden of infectious diseases and

have weaker health systems. In 2019, Sub-Saharan Africa (SSA)

experienced the highest rate of AMR burden, with 23.7 deaths per

100,000 people and 255,000 deaths attributed to AMR, surpassing

mortality from Malaria and HIV/AIDS.

For the problem in Africa, one key element is the lack of access to new antibiotics already approved and marketed in the developed world.

The pervasive lack of access to

common antibiotics, has led to an over-reliance

on a few available drugs, even when they are not

the primary choice for treatment.

Patents and manufacturing controlled by pharmaceutical companies represent a key hurdle to access in Africa and low to middle income countries in general. From the company point of view, the market is already too fragile to lose patent protection and control of manufacturing in LMICs.  But, again, a solution is not only available but has already been implemented by Shionogi for their antibiotic, cefiderocol. To achieve this, Shionogi licensed rights for cefiderocol use in LMICs to GARDP and CHAI (Clinton Health Access Initiative).  Shionogi also hopes to assure local manufacture capability as well. This is a model that is available to any pharmaceutical company, large or small, to help improve access in LMICs. As Shionogi explained to me, this kind of partnership might be more difficult for very large pharma companies and for small biotechs. But, as a model, the Shionogi effort should provide at least an inspiration if not a road map to go forward. Again, all we must do is act.