Shortages of antibiotics have become a global problem that also affect countries with robust healthcare and regulatory systems. The causes are several, sometimes difficult to oversee, and the solutions are not as easy to implement as they are to conceptualize. Shortages of medicines in general cause patients to lose access to important treatments and, as such, lead to increased costs, morbidity and even mortality. But shortages of antibiotics may also lead to increases in antibiotic resistance.
Shortages of antibiotics became the talk of the day in 2017, when an explosion in a manufacturing plant led to a global shortage of piperacillin-tazobactam. After that event, shortages caused by vulnerabilities in manufacturing and supply chains have drawn more attention in high-income countries.
Perhaps the first thing that comes to mind when thinking about antibiotic shortages is that people die or suffer from complications from an infection that cannot be treated. This is of course true – published estimates say the lack of access to antibiotics leads to 450,000 avoidable deaths annually by pneumonia in children under five. But aside from not being able to treat infections, there are consequences that are more subtle but may accelerate the development of antibiotic resistance. Here are four of these.
1. Patients are prescribed a suboptimal antibiotic
If the first-choice antibiotic is not available, physicians will naturally turn to second- or third- choice antibiotics to threat the infection, provided that they are available. While these antibiotics will probably cure the patient, there is a reason why they are not first choices. They may have poorer effect, higher risk of adverse reactions or be more prone to resistance development. These properties may also cause physicians to deviate from the treatment guidelines and prescribe either higher or lower doses, based on perceptions of effectiveness or toxicity.
2. Patients are prescribed a broader spectrum antibiotic
If a narrower spectrum antibiotic is not available, an antibiotic with a broader spectrum than necessary may be used. Broad spectrum antibiotics are active against a larger variety of bacteria, and as such exert a wider selective pressure to develop antibiotic resistance. Broad spectrum antibiotics have also been shown to cause more severe adverse reactions in patients’ microbiomes, resulting in for example diarrhea. Infections with Clostridioides difficile are also more common after use of broad spectrum antibiotics. To add insult to injury, newer studies on the adverse effects of antibiotic use indicate that broad spectrum antibiotics are more commonly associated with elevated risk for non-communicable diseases like obesity, cardiovascular disease and asthma.
3. Patients are prescribed an antibiotic on higher tiers in the AWaRe classification
When the first-choice antibiotic for a given infection is not available, there is a risk that the second or third choices are in the higher tiers of the Access, Watch and Reserve classification, or on the complementary list that generally require specialized capacity. As an example of this, in 2015, piperacillin/tazobactam suffered from a global shortage of the antibiotic. Around the world, piperacillin/tazobactam was substituted with meropenem, causing a significant increase of meropenem use. For example at a hospital in the US, meropenem use doubled during the shortage. Meropenem is otherwise on the complementary list of the Watch category, and is commonly restricted for use only against serious infections.
4. Substandard and falsified antibiotics get a market opportunity
Given that the need for, and thus market demand of, antibiotics does not decrease, shortages cause a market void for the antibiotic. This void can then be unscrupulously exploited by insincere actors that remarket expired antibiotics or distribute substandard or falsified medicines. Poor quality antibiotics can in turn lead to treatment failure, adverse reactions and increased development of antibiotic resistance, depending on the actual content of the products. Reports from the WHO Global Surveillance and Monitoring System for Substandard and Falsified Drugs have shown that no part of the world is left unaffected.
WHO AWaRe classification of antibiotics
WHO adopted a three-tier classification of antibiotics in 2017.
ACCESS: Drugs that are active against a range of common pathogens and have a lower risk for resistance development. The group currently includes 48 antibiotics, 19 of which are on the Essential Medicines List.
WATCH: Drugs that have a higher risk for resistance development and most of the drugs on the Critically Important Antimicrobials for Human Medicine list. The use of these 110 antibiotics, 11 of which are on the Essential Medicines List, should be subject to antibiotic stewardship programs and used with care.
RESERVE: Drugs that should be seen as last resort options. While they should be accessible, the use should be confined to specific patients where other options are not suitable. 11 antibiotics are found in this category and seven of them are on the Essential Medicines List.
The Essential Medicines List further classifies drugs into core medicines that are the most effective, safe and cost-effective for a basic healthcare system, and a complementary list of drugs requiring specialized diagnostics, monitoring or specialist facilities or training. Reserve group antibiotics are all on the complementary list.
A global systems perspective needed
Drug shortages are a result of dysfunctional supply systems, and have therefore not been a big problem in high-income countries where both regulatory and supply systems have been strong for the past decades. Today, the consequences may be relatively mild, and can be absorbed by the systems in place. However, with increasing resistance to antibiotics, the problems can be expected to grow.
Many low- and middle-income countries struggle with these problems on a daily basis – even when production and distribution of antibiotics run smoothly from a global perspective. Underdeveloped health systems and lack of finances lead to constant restrictions in access to effective antibiotics, leading to human suffering and acceleration of resistance development. Let the current shortages in high-income countries serve as a reminder that action is needed also to ensure access to those less fortunate.
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