PLEASE NOTE: The Viewpoints on our website are to be read and freely shared by all. If they are republished, the following text should be used: “This Viewpoint was originally published on the REVIVE website revive.gardp.org, an activity of the Global Antibiotic Research & Development Partnership (GARDP).”

The success of modern medicine relies upon access to effective antibacterial drugs. However, the continued threat of antibiotic resistance has resulted in an urgent need for new antibacterial treatments. In the USA, an estimated 2.8 million patients each year develop infections caused by drug-resistant bacterial pathogens, leading to approximately 35,000 deaths¹. In spite of this need, the antibiotic market is languishing, and several newly approved drugs have not been widely prescribed. This has led to two of the companies that developed new agents for the global market which were approved by the United States of America’s Food and Drug Administration (FDA) and the European Medicines Agency (EMA), but not launched outside the US, going out of business; Achaogen (plazomicin) in 2019 and Tetraphase (eravacycline) in 2020. In a recent GARDP Antimicrobial Viewpoint article, Ryan Cirz and Kevin Krause highlighted the plight of new antibacterial research and development and offered two ideas to help solve the costs required to bring a new antibiotic to market². However, they did not delve into the details as to why physicians do not choose to use new antibacterials. The answer to this question is probably multifactorial and may include some of the following rationales.

1. Not enough clinical information because of a reduced number of labeling claims

In the past, antibiotics were developed for the broadest possible usage based on the spectrum of activity of the drug. For example, an antibiotic directed against Gram-negative bacterial pathogens could be developed for the following indications: complicated urinary tract infections (cUTI), complicated intra-abdominal infections (cIAI) and hospital-associated and ventilator-associated pneumonia (HAP/VAP) where Enterobacterales and non-fermenters are commonly found. Traditionally, each indication required two independently powered phase 3 clinical trials, with several follow-on studies for additional indications. These trials enrolled thousands of patients over several years with considerable costs for each study. The result was that antibiotics were approved with very broad labels, including a multitude of bacterial species that are associated with each of these infection types.

The general consensus for people working in infectious diseases is that the problem of antimicrobial resistance is increasing and there is a dire need for new agents but is that really true on a global level?

In recent years, there has been a trend toward a “leaner and meaner” development pathway for antibiotics with the hopes of reducing development costs and bringing important medicines to patients faster. Several of the newest antibiotics, including plazomicin and meropenem-vaborbactam, have been approved with only one traditional phase 3 study for cUTI together with a second smaller study focused on including patients with some drug-resistant bacterial pathogens. Another new drug, eravacycline was approved following two cIAI studies. The consequence for all three of these examples is a very narrow label with a single indication for cUTI (plazomicin and meropenem-vaborbactam) or cIAI (eravacycline) and only a handful of bacterial species for which there is sufficient clinical evidence to get a labeling claim. All three of these drugs were developed with the hope of being used to treat serious infections caused by carbapenem-resistant Gram-negative bacterial pathogens. Unfortunately, each of these trials enrolled very few patients with infections caused by these organisms. Although off-label use does occur, there is currently little evidence to guide therapy for infections caused by drug-resistant pathogens. The result is that most physicians do not have any information on how and when they should use new antibiotics in infections such as HAP/VAP where these infecting drug-resistant bacteria most often occur or if a bloodstream infection or sepsis develops.

2. Low prevalence of resistant bacteria in the USA and other high-income countries

The general consensus for people working in infectious diseases is that the problem of antimicrobial resistance is increasing and there is a dire need for new agents but is that really true on a global level? The incidence of these drug-resistant pathogens can vary widely by country or region. For example, recent surveillance data from Pfizer’s Atlas program shows the percentage of carbapenem-resistance among clinical isolates of Acinetobacter baumannii to be 89.5% in Greece, 34.2% in the USA and 20.5% in the UK. In addition to the lower percentages in the USA and UK, the low incidence of this organism as an infecting bacterial pathogen translates into an overall incidence of only 75,000 cases annually in developed countries globally. K. pneumoniae is a much more prevalent pathogen; however, the incidence of carbapenem-resistance in this organism is only 4.1 and 2.7% for the USA and UK, respectively. Although the consequences of having one of these resistant bacteria can be substantial for the individual patient, the probability that any given patient needs a new agent that can empirically treat carbapenem-resistant A. baumannii or K. pneumoniae is very low in most institutions in North America and Europe. Therefore, these new drugs are something that most treating physicians view as something they might like to know is available but do not see much need for in their current patient population.

3. High cost of new therapies compared to generic medications

Informal surveys of clinicians and hospital-based infectious disease pharmacists cite the cost of new antibiotics as the number one reason that they are not selected to treat a patient with a drug-resistant infection. There is data to support this in that the inexpensive antibiotics colistin and polymyxin are used at much higher rates for patients with carbapenem-resistant Enterobacteriaceae (CRE) than any of the new drugs approved to treat these infections. This is despite a general acknowledgement that colistin and polymyxin do not work very well and also have significant toxicities. It should be noted that the cost of a course for one of these life-saving new agents is significantly less than the cost of new oncologic chemotherapy drugs that may only prolong life for a few months³.

In the USA, an estimated 2.8 million patients each year develop infections caused by drug-resistant bacterial pathogens, leading to approximately 35,000 deaths¹. In spite of this need, the antibiotic market is languishing, and several newly approved drugs have not been widely prescribed.

A recent evaluation of investigational new drug applications (INDs) submitted to the US FDA for the antibacterial pipeline showed that there was a trend toward fewer antibacterial drug candidates, longer drug development timelines, and fewer products achieving marketing approval in the last decade⁴. This is likely to be directly linked to the poor economic realities in antibiotic development. The longer timelines may be related to the work now being conducted by smaller companies that have to rely on outsourcing the majority of their work. It is unclear whether or not the increase in non-approvals is related to the trending towards smaller, abbreviated development programs that are inherently riskier.

Antibiotic stewardship is a major economic hurdle for newly approved antimicrobials

In a recent commentary, it was noted that the need for antibacterial stewardship of new products has contributed to a crippled economic model in higher-income countries (HICs), in that the economics of antibiotics do not recognize their value in acknowledging and preventing the worsening of the drug-resistance crisis⁵. This is highlighted by the simple math of the development costs of new antibiotics compared to revenue generated after launch. Achaogen invested $560M into the development of plazomicin with an additional $100M required for post-approval commitments such as the pediatric plan. However, plazomicin generated only $0.8M of sales in 2018⁵. At this rate, it would take the company over 650 years to recoup their investment^3,6.

New funding opportunities such as the newly announced AMR Action Fund will hopefully support some of the late-stage development costs. However, this effort will still not address the lack of usage of new antibacterial products by healthcare professionals in HICs. There are several efforts to delink antibiotic sales from reimbursement, with the UK and Sweden currently exploring new models. In addition, the US PASTEUR act, which has recently been proposed in the US, is a subscription model that would provide federal payment to companies that develop antibiotics⁷. More initiatives like these are needed to salvage and reinvigorate antibiotic research and development.

References:

1. Centers for Disease Control and Prevention (US). 2019. Antibiotic resistance threats in the United States.
2. Cirz R, Krause KM. 2020. The antibiotics marketplace collapse: It’s just math, and it’s a solvable equation. 
3. Carr A & Stringer J. 2019. Biotechnology. Antibiotic R&D Update 20 Review of the Antibiotic Space. 
4. Dheman N, Mahoney N, Cox EM, Farley JJ, Amini T, Lanthier ML. 2020. An Analysis of Antibacterial Drug Development Trends in the US, 1980 – 2019. Clinical Infectious Diseases ciaa859 doi:10.1093/cid/ciaa859.
5. Rex JH, Outterson K. 2020. Antibacterial R&D at a crossroads: We’ve pushed as hard as we can … now we need to start pulling! Clinical Infectious Diseases doi:10.1093/cid/ciaa852.
6. GlobeNewsWire. 2020. Achaogen Reports Fourth Quarter and Full Year 2018 Financial Results and Provides Corporate Update. 
7. The Infectious Diseases Society of America. 2020. PASTEUR Act Will Build Antibiotic Arsenal, Protect Existing Medicines.