Elsevier

Archives of Medical Research

Volume 36, Issue 6, November–December 2005, Pages 697-705
Archives of Medical Research

Review article
Resistance to Antibiotics: Are We in the Post-Antibiotic Era?

https://doi.org/10.1016/j.arcmed.2005.06.009Get rights and content

Serious infections caused by bacteria that have become resistant to commonly used antibiotics have become a major global healthcare problem in the 21st century. They not only are more severe and require longer and more complex treatments, but they are also significantly more expensive to diagnose and to treat. Antibiotic resistance, initially a problem of the hospital setting associated with an increased number of hospital-acquired infections usually in critically ill and immunosuppressed patients, has now extended into the community causing severe infections difficult to diagnose and treat. The molecular mechanisms by which bacteria have become resistant to antibiotics are diverse and complex. Bacteria have developed resistance to all different classes of antibiotics discovered to date. The most frequent type of resistance is acquired and transmitted horizontally via the conjugation of a plasmid. In recent times new mechanisms of resistance have resulted in the simultaneous development of resistance to several antibiotic classes creating very dangerous multidrug-resistant (MDR) bacterial strains, some also known as “superbugs”. The indiscriminate and inappropriate use of antibiotics in outpatient clinics, hospitalized patients and in the food industry is the single largest factor leading to antibiotic resistance. In recent years, the number of new antibiotics licensed for human use in different parts of the world has been lower than in the recent past. In addition, there has been less innovation in the field of antimicrobial discovery research and development. The pharmaceutical industry, large academic institutions or the government are not investing the necessary resources to produce the next generation of newer safe and effective antimicrobial drugs. In many cases, large pharmaceutical companies have terminated their anti-infective research programs altogether due to economic reasons. The potential negative consequences of all these events are relevant because they put society at risk for the spread of potentially serious MDR bacterial infections.

Introduction

In the last 60 years, major improvements in the early recognition and the treatment of infectious diseases have resulted in an extraordinary reduction in the morbidity and mortality associated with these illnesses. This has been due, in part, to our better understanding of the fine molecular biological mechanisms of these diseases and to our improved understanding of their pathophysiology and their epidemiology but, most notably, to the rapid development of safe and effective new antimicrobial treatments that have been able to attack the specific agent causing the infection, thus helping the infected host to eliminate the infection being treated.

Seen initially as truly miraculous drugs, access to the first available systemic antibiotics (sulfonamides and penicillin) was not immediately available for the general public. In fact, these drugs were scarce and very expensive and were initially reserved for use by the military during World War II (1).

As more antibiotics were discovered, manufacturing processes were simplified, and newer formulations developed, access to antibiotics eased considerably and their use became widespread. Antibiotics had truly become the “panacea” of medicine and were being used to treat even the most common and trivial types of infections, many of these non-bacterial in nature.

Based on the work that he had done in his research laboratory, in an interview with The New York Times in 1945, Sir Alexander Fleming warned that the inappropriate use of penicillin could lead to the selection of resistant “mutant forms” of Staphylococcus aureus that could cause more serious infections in the host or in other people that the host was in contact with and thus could pass the resistant microbe (2). He was right and within 1 year of the widespread use of this drug a significant number of strains of this bacterium had become resistant to penicillin. Only a few years later over 50% were no longer susceptible to this new drug (2).

Unfortunately, things have not improved in the recent past. In fact, every day more common and uncommon bacteria, previously susceptible to common antimicrobials, are reported to have developed resistance to different antibiotics. Although these bacteria initially caused significant nosocomial infections and were the cause of major morbidity and mortality in hospitalized patients, more recently they have spread to the community, causing severe illnesses in previously healthy and otherwise non-vulnerable patients.

This review tries to provide an overview of the serious problem of antibiotic resistance in the 21st century and to begin to open a new window into the complex challenge of new antibiotic development in the future. For this reason, the scope of the article will focus on the problem of bacterial resistance and will not discuss viral, fungal or parasitic resistance. Excellent reviews related on the development and management of resistance of these other microorganisms can be found elsewhere 3, 4, 5, 6, 7.

Section snippets

Antibiotic Resistance: A Long-Term, Serious Problem…Getting Worse

In order to be fit to survive, all living organisms strive to adapt to their environment. Part of this adaptation process includes adjusting to weather conditions, to food, water and in many cases to oxygen availability and also to the presence of potentially dangerous or even lethal external agents. It is no secret that many insects have adapted remarkably well to their environment and so have microorganisms. Thus it should not be surprising to us that bacteria have shown a remarkable ability

Mechanisms of Antibiotic Resistance

At least 17 different classes of antibiotics have been produced to date (Table 1). Unfortunately, for each one of these classes at least one mechanism of resistance (and many times more than one) has developed over the years. In fact, in some cases these bacteria have been able to develop simultaneous resistance to two or more antibiotic classes, making the treatment of infections caused by these microorganisms extremely difficult, very costly and in many instances associated with high

What Leads to the Development of Antibiotic Resistance?

Different factors play a role in the development of antibiotic resistance but what exactly determines that some bacteria become resistant to a specific drug and not to others and what is the specific role and the “relative weight” of each one of these factors in this process remains to be defined (Table 2).

Our understanding of how bacteria adapt to their environment and how this process may culminate in the development of resistance against one or more antibiotics is, at best, incomplete. We

Abuse in the Use of Antibiotics in Clinical Practice Results in “Selective Pressure”

The use of antibiotics in humans results in “selective pressure” in the host receiving the antibiotic. The broader the spectrum of activity, the higher chances for bacteria to develop resistance 57, 58. Third-generation cephalosporins, fluoroquinolones and more recently azithromycin have been linked to these problems (58). The net result is that after the administration of the antibiotic, most susceptible bacteria in the host, the majority of which are part of the normal saprophytic bacteria

Agricultural and Animal Use of Antibiotics

Antibiotics are frequently used in animals as part of the process used to manufacture food, especially meats. This is a non-therapeutic use of very valuable drugs and for this reason they should be preserved for use under very special circumstance only 28, 29.

Recent interactions between regulatory authorities and the food-producing industry in the U.S. are resulting in commitments to reduce and eventually eliminate the use of common antibiotics for non-therapeutic use.

Looking at the Future: Is This the Post-Antibiotic Era?

The problem of the explosive growth in the development of antimicrobial resistance in the last two decades has only been made worse by a significant and steady decrease in the number of approvals of new antibacterials in the last 10–15 years (Figure 1) (64).

The different forces contributing to this major paucity in the pace of antibiotic innovation are multiple, very complex and interlinked, and much has been written about these in recent times 64, 65, 66, 67, 68, 69, 70, 71, 72, 73. When

Tradeoffs Have Been Made within Anti-Infectives Therapeutic Class

The emergence of new, life-threatening infectious diseases, especially AIDS, has created significant and unexpected needs for the discovery and development of new safe and effective anti-HIV drugs that are capable of prolonging and improving the life of those infected with the virus and of containing the spread of this global disease. Research in this area has taken place in record time and new targets have been unfolded quite rapidly. The result of this has been the discovery and the

New Molecular Targets Equal New Drugs

As our knowledge of the pathophysiology and the molecular biology of several diseases has expanded, so has the number of targets amenable to interact with new chemical entities and the business opportunities for the pharmaceutical industry. Thus, in recent years pharmaceutical companies have engaged in the development of new treatments for many common, debilitating, chronic diseases not previously treated (such as osteoporosis) or even for diseases that, while not life-threatening and perceived

Conclusions

In the final analysis, however, the problem of antibiotic resistance will not be solved with the creation of many more, or stronger, bactericidal antimicrobials. If past history is in any way a good predictor of future history, microorganisms will consistently continue to adapt to their environment by developing resistance to newer antibiotics and serious infections caused by these bacteria will continue to pose a major challenge to the practicing clinician.

It will take a collaborative effort

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    Statement of potential conflict of interest: Dr. Alanis is an employee of and is an owner of shares of Eli Lilly and Company.

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