The positive identification of a bacterial isolate resistant to colistin, an antibiotic of last resort, from a patient in Pennsylvania last April has stirred public concern over the spread of superbugs (i.e., bacterial pathogens resistant to all available antibiotics). Although other bacterial strains resistant to polymyxins, the antibiotic class that includes colistin, have previously been isolated from US patients, what is notable and potentially impactful about this recent finding is the mobile nature of mcr-1 – the gene conferring resistance to colistin in this isolate. This is a plasmid-borne colistin-resistance gene, which is very rare and very concerning. First identified in China, bacteria bearing this gene have now been isolated in multiple continents, including Africa, Europe, Asia and now North America. Unlike genes that reside in the larger bacterial chromosome, genes/traits carried by plasmids – small self-replicating circular DNA molecules – can be more easily transmitted, and the encoded resistance traits can be readily disseminated between bacterial cells.
Some experts believe that, if left unchecked, the spread of colistin resistance could ultimately signal the beginning of an apocalyptic post-antibiotic era, where even relatively simple infections could easily turn deadly. For example, even simple trauma-induced, or surgical wounds could become lead to mortality if an infection took hold and no antibiotic treatment options were available. The post-antibiotic antibiotic era would very much resemble the pre-antibiotic era, when a skin infection or pneumonia led to much higher rates of morbidity and mortality than today. Aside from the impact on public health and quality of life, lack of effective antibiotics would put a tremendous burden on the healthcare systems, resulting not just in deterioration in outcomes for patients with bacterial infections, but also greatly increasing associated hospitalization costs, as well as impact areas of medicine that currently rely on the availability of effective antibacterials, such as elective surgery. As such, this new drug-resistant strain highlights the important need for new antibiotics and classes of antibiotics, which can undoubtedly translate to commercial opportunity for drug developers willing to enter into this space.
The antibiotics market has struggled to retain interest from major pharmaceutical companies. Overall, the antibiotics market is dominated by relatively effective, inexpensive and generically available agents for the treatment of acute infections. Therefore, the commercial attractiveness of the antibiotics market pales in comparison to markets for chronic conditions, and those with fewer generic competitors. In addition, new premium-priced antibiotics are often relegated to patient subpopulations with more difficult-to-treat infections, or for whom cheaper alternatives are contraindicated, further limiting uptake of new market entrants. Such agents are additionally safeguarded to limit the emergence of drug resistance to these therapies, which are generally more potent against drug-resistant isolates. However, advocates for reinvigorating the antibiotics pipeline warn that unless we keep a continuous supply of new antibiotics, we may not have enough new agents to keep up with the waning efficacy of currently available options. As it stands now, nearly a fifth of all urinary tract infections treated in the hospital are caused by pathogens resistant to at least two classes of antibiotics (Decision Resources, Epidemiology for Hospital-Treated Infections, 2015). Further, although it was approved over forty years ago, colistin usage has increased in the past few years in response to the growing prevalence of multi-drug resistant bacteria, particularly bacteria resistant to carbapenems, a powerful and generally safe class of antibiotics. Therefore, although the market seems currently saturated with lower-cost and relatively effective options, this is unlikely to be the case in the next decade unless new drugs come to market.
The resurgence of colistin use in hospitals for bacterial infections underscores how desperate physicians have become when treating deadly and highly drug-resistant infections. Although polymyxins are readily used as components of topical antibacterial creams (e.g., Neosporin®), and their inhaled formulations for lung infections in patients with cystic fibrosis, systemic administration of these agents is reserved for last-line therapy, since at high doses or following prolonged treatment polymyxins can cause severe renal and neurologic toxicities. In some extreme cases, polymyxins can lead to permanent loss of renal function, requiring the patient begin life-long dialysis treatment. Therefore, even though prescribing physicians hope to avoid use of colistin in their patients, one concern with the spread of colistin resistance is that patients with minimal choices will be ultimately left with none. Unfortunately, hospitalized patients will be at the highest risk of developing infections caused by superbugs, as the concentrated usage of colistin and other powerful agents, like carbapenems, in the hospital setting (e.g., ICUs) provides a rich breeding ground for drug-resistant bacteria.
There are promising drugs are on the horizon, however. In recent news, The Medicines Company announced positive top-line results from a Phase 3 clinical trials for their late-stage antibiotic, Carbavance (meropenem/vaborbactam), in the treatment of complicated urinary tract infections – meeting both FDA and EMA primary efficacy end points (www.themedicinescompany.com/investors/news/medicines-company-announces-positive-top-line-results-phase-3-tango-1-clinical-trial). And although this particular clinical trial was not designed to test the combination agent’s efficacy against drug-resistant infections, the company is conducting a second, smaller clinical trial enrolling patients with infections caused by carbapenem-resistant organisms (CROs). Carbavance has adopted a common trend for combating drug resistance, where antimicrobial agents are coupled with inhibitors of beta-lacatamases – enzymes that break down several classes of antibiotics, including penicillins, cephalosporins, and carbapenems. Therefore, although meropenem belongs to the carbapenem class, and by definition is not active against CROs, vabrobactam is an inhibitor of certain carbapenemases (carbapenem-targeting beta-lactamases), and can restore meropenem’s antimicrobial activity against CROs. Assuming Carbavance enters the market in late 2017 or early 2018, it will be the first antibiotic to be developed in a program specifically targeting CROs. And although there are a handful of agents currently available that have activity against CROs, including colistin, the unfavorable safety and tolerability profile of these drugs creates an unmet need that could be addressed by an agent like Carbavance. Other agents, such as Merck’s combination of imipenem (carbapenem) with relebactam (carbapenemase inhibitor) and Achaogen’s plazomicin (aminoglycoside), are also in development for infections caused by CROs.
The identification of a strain bearing the mcr-1 gene on US soil is a reminder that pathogens easily cross national and continental borders. In the age of seamless transportation across the globe, pathogens can move unimpeded between countries, despite best clinical practices that help reduce local spread. In that way, antimicrobial resistance is truly a global problem, and it is not surprising that international agencies are ramping up their efforts to stem back the inappropriate usage of antibiotics that can drive drug resistance, such as reducing use of antibiotics in animal farming. Only when there is a global, concerted effort to both reduce the emergence of drug resistance and increase antibiotic development, will we truly allay both the public’s and physicians’ fears of superbugs.