Clinical, economic and societal impact of antibiotic resistance

Abstract

The concern over antibiotic resistance has been voiced since the discovery of modern antibiotics > 75 years ago. The concerns have only increased with time, with efforts to control resistance caused by widespread overuse of antibiotics in human medicine and far more than appreciated use in the feeding of animals for human consumption to promote growth. The problem is worldwide, but certain regions and selected health care institutions report far more resistance, including strains of Gram-negative bacteria that are susceptible only to the once discarded drugs polymyxin B or colistin, and pan-resistant strains are on the rise. One of the central efforts to control resistance, apart from antimicrobial stewardship, is the development of new antimicrobial agents. This has lagged significantly over the past 10 – 15 years, for a variety of reasons; but promising new agents are being developed, unfortunately none thus far addressing all potentially resistant strains. There is the unlikely, but not unreal, possibility that we could return to a pre-antibiotic era, where morbidity and mortality rates have risen dramatically and routine surgical procedures are not performed for fear of post-operative infections. The onus of control of resistance is a moral imperative that falls on the shoulders of all.

Keywords:

• antibiotics
• antibiotics in animal feed
• misuse of antibiotics
• resistance

One of the earliest warnings regarding the clinical and societal impact of antibiotic resistance was sounded by Alexander Fleming in his 1945 Nobel lecture ‘Penicillin’, as follows:

The time may come when penicillin can be bought by anyone in the shops. Then there is the danger that the ignorant man may easily under dose himself and by exposing his microbes to non-lethal quantities of the drug make them resistant. Here is a hypothetical illustration. Mr. X. has a sore throat. He buys some penicillin and gives himself, not enough to kill the streptococci but enough to educate them to resist penicillin. He then infects his wife. Mrs. X gets pneumonia and is treated with penicillin. As the streptococci are now resistant to penicillin the treatment fails. Mrs. X dies. Who is primarily responsible for Mrs. X’s death? [1].

The answer to Fleming’s question is that no one was guilty in the scenario described. However, the modern extension of the example to the widespread use, and often misuse, of antibiotics in clinical medicine and veterinary medicine is now the guilty party. The growing prevalence and incidence of infections due to multi-drug resistant (MDR) pathogens is epitomized by the increasing number of familiar acronyms used to describe the causative agents and sometimes the infection; of these, Methicillin-resistant Staphylococcus aureus (MRSA) is probably the most well-known among several, but the list keeps growing. Among the most recent are extended spectrum β-lactamase-producing (ESBL) Klebsiella and Escherichia coli, carbapenem-resistant Enterobacteriaceae (CRE) especially those containing the New Delhi metallo-β-lactamase (NDM-1) and multidrug-resistant Acinetobacter baumannii (MRAB). The latter two are particularly dangerous as they are resistant to all or nearly all available antibiotics. Often, the only available agents are the once-discarded polymyxin B or colistin [2]. Nosocomial infections overwhelmingly dominate cases where MDR pathogens are implicated, but drug-resistant infections are increasingly becoming common in the community. This has been especially true with the emergence of community-acquired MRSA [3].

The increasing prevalence of antibiotic-resistant bacterial infections seen in clinical practice stems from antibiotic use both within human medicine and veterinary medicine. In human medicine, the major problem contributing to the emergence of resistant bacteria is the misuse and overuse of antibiotics [4]. One key intervention is to improve public awareness and education that the common cold is caused by a virus, and that taking antibiotics does not treat a cold, but promotes bacterial resistance in normal bacterial flora. One good consequence of the media’s dramatization of the emergence of ‘superbugs’ is that the public is becoming more aware of this concept. This practice is even more problematic in some countries where antibiotics are sold over the counter without a prescription (as feared by Dr. Fleming).

Animal health practices contributing to resistance include antibiotic use in livestock feed to promote faster growth [5]. A recent case-controlled study of livestock operations in northeastern Pennsylvania and community-acquired cases of MRSA infection revealed that the application of swine manure to crop fields and proximity to livestock operations each was associated with increased incidences of MRSA and skin and soft-tissue infections [6]. Of antibiotics used in the U.S. in 1997, half were used in humans and half in animals [7]. More recently, although difficult to quantify, the proportion is estimated to be as high as 70% in animals [8]. Numerous classes of antibiotics are used in subtherapeutic doses and have been linked to vancomycin resistance (e.g., vancomycin-resistant enterococci) and the aforementioned CRE [9,10].

The costs in terms of morbidity and mortality in the infected, the resources for appropriate infection control programs, and the discovery and development of new antimicrobials active against drug-resistant pathogens are all of great importance. In 2003, Cosgrove and Carmeli authored an excellent paper in Clinical Infectious Diseases that provided an overview of the problem and methods to appropriately assess the economic and health impact of resistance [11]. They reviewed how antimicrobial resistance can affect patient outcomes by enhancing virulence, causing a delay in the administration of appropriate therapy and limiting available therapy. Very importantly, they considered methodological issues in designing and assessing studies that address the clinical outcomes for patients infected or colonized with resistant pathogens, including adjustment for important confounding variables, control group selection and the quantification of economic outcomes.

Since then, several studies have been published that carefully evaluated the economic and clinical outcomes of bacterial resistance. Using methods as described above, Roberts et al. performed an elegant single-hospital evaluation of the economic and health outcomes of antimicrobial resistance [12]. This group found the costs were considerable. In a sample of nearly 1400 patients, 188 (13.5%) had antimicrobial-resistant infection. The attributable medical costs ranged from $18,588 to $29,069 per patient in their sensitivity analysis. Excess duration of hospital stay was 6.4 – 12.7 days and attributable mortality was 6.5%. The societal costs were $10.7 – $15.0 million. Using the lowest estimates from their sensitivity analysis resulted in a total cost of $13.35 million in 2008 dollars in this single-hospital patient cohort. The total costs are staggering when these findings are coupled with the Centers for Disease Control and Prevention (CDC) estimates that each year in the U.S., at least 2 million people become infected with bacteria that are resistant to antibiotics and at least 23,000 people die each year as a direct result of these infections [13].

Yet, even these estimates are likely too low. Smith and Coast [14] took the perspective of a world without antibiotics (i.e., a return to the pre-antibiotic era), a not unlikely scenario given the specter of the emergence of all of the varied resistance phenotypes described above. As an example, they used antibiotic prophylaxis for total hip arthroplasty. Given that surgical prophylaxis (the administration of a brief course of antibiotics perioperatively to prevent infection) is standard practice, and infection rates are about 0.5 – 2%, most patients recover without infection, and those who become infected usually have it successfully treated. They estimated that without antimicrobials, the rate of postoperative infection would be 40 – 50% and about 30% of those with an infection would die. Thus, removal of antibiotics would increase postoperative infection by up to 50% and deaths by as much as 30%. Furthermore, if antibiotics became useless, an additional incalculable consequence would be that patients and physicians would not undertake the high risk of most non-emergency surgeries without the benefit of antibiotic prophylaxis, and therefore, their quality of life would be significantly impacted (e.g., without a hip replacement).

The authors acknowledged this is a simplistic analysis. There are several other factors that contribute to the prevention of infections such as control of underlying conditions (e.g., diabetes), proper hygienic measures (hand washing), and awareness of colonization of the patient by potential pathogens (e.g., MRSA) and decontamination measures. However, the scenario above is presented to illustrate and provoke: to emphasize the point that very high post-operative infection rates and their consequences in terms of costs and human health would be intolerable in modern society.

Expert opinion

In a 2010 letter to the editor, authors of a new Infectious Diseases Society of America (IDSA) initiative to develop new antimicrobials [15] responded to questions about the program: “….we hold closely the principles that antibiotics are a gift to us from prior generations and that we have a moral obligation to ensure that this global treasure is available for our children and future generations” [16]. This moral obligation challenges not only the health care system, but also those of us in the pharmaceutical industry who discover, develop and commercialize antimicrobials. The relative dearth of new antimicrobials approved in the past 15 years has been well chronicled, but there are promising newer agents available for the treatment of multi-resistant Gram-positive infections, and there are several drugs currently in development or under regulatory review that address some (but, regrettably, not all) of the Gram-negative resistance issues [17]. Examples include ceftolozane/tazobactam, ceftazidime/avibactam and plazomicin [17]. In addition, older drugs, heretofore not available in the U.S. such as fosfomycin, are being resurrected. Importantly, critical initiatives such as well-conducted and reported surveillance of resistant pathogens, good antimicrobial stewardship and, of course, infection control measures should never be forgotten [15,17].

On World Health Day 2011, The IDSA issued a policy statement titled “Combating Antimicrobial Resistance: Policy Recommendations to Save Lives,” which provides clear suggestions for addressing the ‘synergistic crises’ of increasing antimicrobial resistance and decreasing availability of new antimicrobial therapies [18]. IDSA continues to work with Congress, the US FDA, the US National Institutes of Health, the CDC and other stakeholder groups, including biotechnology and pharmaceutical manufacturers, to ensure that the focus on the problem will not waver. The scope of the problem of antimicrobial resistance and its impact on society, the health care system as well as individual patients is enormous, incalculable perhaps. It is only with the participation of all stakeholders that we will even begin to tackle the problem.

From human medicine to veterinary medicine, from the FDA to the USDA, from the IDSA to the United States Cattlemen’s Association, the Biotechnology Industry Organization and the Pharmaceutical Research and Manufacturers of America, the moral imperative falls on all of us.

Declaration of interest

SL Barriere is an employee of Theravance Biopharma, Inc. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.