“Unfortunately, it seems like we’re running out of antibiotic options to treat this infection.”
I’ve reported this news to numerous patients and families over the past few years, informed by extensive red text on microbiologic sensitivity reports indicating resistance. So how do we get to this point? Certainly there are many factors at play that impact the microbiomes of our patients, most apparently in a patient’s exposures and risk factors. Over the past few months, however, I’ve been reflecting on how these conversations are also shaped by events in the antibiotic economy.
Over the past year, popular media has covered stories about shortages of commonly prescribed antibiotics, including amoxicillin powder and benzathine penicillin. The shortages of these specific medications are due, in part, to the complicated economics of generic antibiotic production, which makes them available for a low price to payers. For the pharmaceutical companies producing these medications, however, such low costs disincentivize their production, as companies sometimes lose money on the production of these generic antibiotics. Furthermore, demand is limited both by course duration and by decreased infection transmission with adequate treatment of some infection, a positive externality that should in fact decrease demand — and profits from that particular medication. While appropriate antibiotic prescribing is best for the health of the patient and the public, the relatively low demand for antibiotics impacts the pharmaceutical companies that produce them. Manufacturers report profit losses related to production of generic antibiotics, which has resulted in many pharmaceutical companies ceasing antibiotic production in the past decade. These factors contribute to decreased production and drug shortages.
Antibiotic shortages challenge antimicrobial stewardship capabilities, as an appropriately narrow antibiotic may not be available to treat an infection. Over the past year, some states have even provided guidance on treating syphilis in non-pregnant adult patients with doxycycline as upfront therapy, in order to ensure that benzathine penicillin is available for priority populations requiring first line treatment. Additionally, in light of powdered amoxicillin shortages, children with otitis media have been prescribed broader spectrum antibiotics than would be necessary to treat their infections, with increased rates of amoxicillin-clavulanate and cefdinir prescriptions during shortage. Exposure to non-first line treatments may further contribute to resistance concerns, and put patients at risk for microbiome disruption leading to complications including Clostridiodes difficile infections.
Beyond inappropriate broad-spectrum exposure and its potential for worsening antimicrobial resistance, attention to resistant bacteria and the limited treatments available are also critical considerations in the antibiotic economy. A pathogen’s resistance patterns limit treatment options, and for extensively resistant infections, there may be few — if any — treatment options available. For example, for patients with vancomycin resistant enterococcus (VRE) infections that may include endovascular grafts or hardware, no current oral suppressive options exist in light of the shortage of tedizolid. Without adequate suppression options for patients infected with VRE, reinfection at the site of foreign material is likely and could lead to death. It is also critical to note that antibiotics are the class of medication to which patients have the most reported allergies or adverse effects, which may further limit options available for treatment. Increased diversification of the market with more antibiotic options may help ensure that there is a possible treatment available for management of complex infections in multimorbid patients.
Market diversification and further development of new antibiotics is critical to treatment of infections caused by resistant bacteria. Despite resistant bacteria being recognized as an ongoing threat to public health globally, development of new antibiotics continues to lag behind identified needs for targets against priority pathogens, similarly limited by financial concerns from pharmaceutical companies and research institutions. Ultimately, macroeconomic complexities of antimicrobial demand shape drug availability, and in turn, the microbiota of our patients.
In an effort to address the complexities of the antibiotic economy, a 2012 law called Generating Antibiotic Incentives Now (GAIN) provided five years of investment into antibiotic production and development. While GAIN did lead to increased approval of new medications available to treat priority pathogens, the medications it helped to create are often not readily accessible. GAIN granted an exclusivity extension for companies producing these new antibiotics, which has often translated into limited use of these new medications due to their high cost. While the restricted use of new medications may slow antimicrobial resistance to these agents, arduous authorizations can also create barriers to use when needed.
It is clear that more work needs to be done to ensure improved access to a stable and appropriate supply of antimicrobials. A new bill to address ongoing concerns about sustainable sources of priority antibiotics was introduced last year. The Pioneering Antimicrobial Subscriptions to End Upsurging Resistance (or aptly, the PASTEUR) Act seeks to approve “subscription contracts” for pharmaceutical companies producing or investigating “critical need” antimicrobials. The PASTEUR Act’s subscription model would ensure that some degree of funding remains available to the pharmaceutical company regardless of the amount of antibiotic that is purchased — not unlike how a Netflix subscription is charged monthly, without variation based on the number of shows or movies that a consumer watches. A similar model has existed in the United Kingdom since 2019.
When considering cost and effectiveness of medical treatments, I admit to some frustration when less optimal treatment options are considered for a specific patient-pathogen pair due to factors that are primarily financial. In the grand scheme of drug cost, pressure for cost saving related to antibiotic use seems to be emphasized disproportionately when treating infections compared to treating other life-threatening diseases. I often gripe to an oncologist friend of mine about cost: while certain cancer directed therapies may cost hundreds of thousands of dollars for one treatment, a full course of a long-half life lipoglycopeptide antibiotic costs less than ten thousand dollars.
As an aspiring infectious disease physician, I know that conversations regarding options for treating resistant infections will be a common theme in my career. I am hopeful that improved availability of appropriate antibiotics and development of new antimicrobial therapies will help to reduce some of the pressures that contribute to ever-growing resistance. It is critical to have a stable antibiotic supply of medications with both narrow and broad spectrum activity. I admire the strong advocacy that has been so central to the work of infectious disease physicians in the past, and hope to continue to advance that tradition as policies are considered to secure our antibiotic supply today.
Dr. Michaela C. Barry is a third-year internal medicine resident and aspiring infectious disease fellow currently living in Pennsylvania. She credits her medical school and residency communities for helping develop the thoughts she shares here. Dr. Barry is a 2023–2024 Doximity Op-Med Fellow. She also extends her thanks to the Cornell University Department of Science & Technology Studies for introducing her to these concepts and for multidisciplinary insight into this problem from friends including Nicole Mensa, MS; Jasmine Daniel, JD; Vaishnavi Ganesan, MD, and Sarbajeet Nagdas MD, PhD.
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