Antibiotic resistance: an escalating threat

Improving the working relationships between infectious disease specialists and other doctors could lead to more judicious use of antibiotics.

In recent years, prominent infectious disease specialists and leaders of major medical associations have been warning both health care professionals and the general public about the looming potential perils associated with antibiotic resistance. Experts worry that since antibiotic resistance is increasing and the number of new antibiotics in development is limited, a situation may be approaching where health care professionals will not have appropriate medications to effectively treat all patients who develop infections.

“We may be heading, from many directions, toward the inability to treat some patients,” said Thomas O’Brien, MD, associate professor of medicine and a medical director of the microbiology laboratory at Brigham and Women’s Hospital in Boston and vice president of the Alliance for the Prudent Use of Antibiotics. “This is especially problematic because infections are more diverse now than they have been at many times in the past. At the same time, the pace of development of new antibiotics now does not compare with earlier eras; the rate of discovery of new classes of antibiotics has slowed down.”

There are several other factors contributing to the growing sense of alarm among experts who are paying close attention to this issue. In addition to the escalating rates of antibiotic resistance and the reduced progress in the development of new antibiotics, infectious diseases are now spreading throughout the world with greater rapidity, fueled by globalization and increased international travel. It is becoming less frequent for infectious diseases to be limited to one geographic area.

James Hughes, MD, professor of medicine and public health at Emory University in Atlanta and a member of the Infectious Disease News editorial board, said human behavior is also playing a significant role in furthering the problem of antibiotic resistance.

“In addition to the evolution of the organisms in response to selective pressure from antimicrobials in their environment, other contributing factors include changes in human demographics and behavior – particularly inappropriate use of antimicrobial agents by physicians and veterinarians,” Hughes said. “There are many other contributing factors, including increasing international travel and commerce facilitating dissemination of resistant organisms; increases in human susceptibility to infection, poverty and social inequality; breakdown of public health measures; and lack of political will to address these contributing factors.”

At the same time, there are an increasing number of patients who are at a higher risk for infection. Conditions such as cancer, diabetes and, in particular, HIV/AIDS further compromise patients’ immune systems.

“We now have health care settings with a high percentage of people at risk for infection,” said John McGowan Jr., MD, at the department of epidemiology at the Rollins School of Public Health at Emory University in Atlanta. “For various reasons, there are a number of patients whose immune systems cannot respond to infections the way we would like to see. These patients are more susceptible to infections. Yet, we are losing the ability to treat them with antibiotics.”

The role of ID specialists

Victor Yu, MD, professor of medicine at the University of Pittsburgh, said he believes infectious disease specialists need to become more proactive in working with other specialists to help reduce the excessive and unnecessary use of antibiotics. He said that academic infectious disease specialists, who were once the thought/opinion leaders in antibiotic prescription issues, have lost influence among general physicians, surgeons and critical care specialists.

“Infectious disease specialists are united on the issue of fighting antibiotic resistance – and yet this problem has occurred under our watch,” Yu said. “In earlier eras, infectious disease specialists in the medical schools and tertiary care centers saw more patients directly with prescribing physicians and spent more time on individual consults. Today, those at the top of the academic pyramid are spending more time on grant writing and lab research with less teaching of junior physicians and minimal patient care.”

Yu said improving the working relationships between infectious disease specialists and other doctors could lead to more judicious use of antibiotics.

“Infectious disease specialists are often exasperated about the extensive and unnecessary use of empiric broad-spectrum antibiotics by their colleagues, yet are often powerless to persuade them to modify their practices,” Yu said. “The loss of a closer working relationship between infectious diseases specialists and physician prescribers renders the written chart recommendations of the infectious disease specialist ineffective. What has emerged is an administrative solution, not a knowledge-based solution: pharmacy departments are playing an activist role with restriction of antibiotics or requiring infectious disease physician approval for expensive antibiotics.”

Improving diagnostics

Improving diagnostics may be a key step in fighting antibiotic resistance and preventing infections. Several experts contacted for this article said that physicians often prescribe an antibiotic before determining which organism is causing the infection – or whether the patient even has an infection.

“It is often challenging to separate viral from bacterial disease on clinical grounds alone, based on signs and symptoms,” said John H. Powers III, MD, assistant clinical professor of medicine at George Washington University School of Medicine. “Therefore, clinicians often prescribe antibiotics ‘just is case’ and to be ‘safe.’ But is it really being safe if this causes more harm than good to both individuals and society? More accurate point of care diagnostics that would give a rapid answer to the question of whether the person has a disease that might respond to treatment would help decrease inappropriate usage. The diagnostic tests should evaluate the person’s immune response to the disease as well as presence of an organism and, ideally, the resistance pattern of the organisms as well.”

“One way to overcome antibiotic resistance would be to get more specific with treatment,” said George Pankey, MD, director of infectious disease research at Ochsner Clinic Foundation in New Orleans and member of the Infectious Disease News editorial board. “As is the case today, when there are not always specific tests to determine what is infecting the patient, doctors – especially primary care physicians – are put in a tenuous position.”

Pankey said that improved diagnostics could also have far-reaching benefits in reducing the severity and frequency of nosocomial infections. “Better diagnostics could tell us specifically what organisms are present in our intensive care units and hospitals,” Pankey said. “If clinicians know specifically what organisms are causing these infections, they could better direct patients’ treatment regimens, making it as specific as possible.”

Not a new challenge

Although antibiotic resistance has been an increasingly important concern in recent years, it is not a new challenge. “Antibiotic resistance has been an issue as long as antibiotics have been in use,” Pankey said. “Even when penicillin was initially developed, researchers saw that some organisms were resistant to it. With each new antibiotic, there has always been a percentage of organisms that were resistant.”

This is also not the first time that experts have warned about a looming risk of further antibiotic resistance. As O’Brien said, the medical community has faced similar challenges related to antibiotic resistance in the past.

“The problem of antibiotic resistance is really only about 70 years old, so it is remarkably recent as far as medical problems go,” O’Brien said. “The perspective that most people have today is based on the experiences of the past 25 years or so. We have been remarkably lucky during the past 25 years because we have had a strong arsenal of antibiotics to treat a wide range of infectious diseases. But prior to this era, there were several times when experts were concerned that antibiotic resistance would lead to the inability to treat patients. Looking at the past, these concerns often heightened in the years prior to the introduction of new, stronger antibiotics.”

O’Brien said that today’s concerns differ from previous eras because, unlike in the past, there is no strong pipeline of new antibiotics in development.

Today, many experts believe that when it comes to the issue of antibiotic resistance, we may be on the brink of a worsening problem. Several major medical associations have warned that antibiotic resistance is the No. 1 problem the medical community is now facing.

Evolution

In many ways, antibiotic resistance has developed along basic Darwinian evolutionary principles. As more and more antibiotics are used, organisms that possess genes that make them resistant to antibiotics are more likely to thrive and, therefore, are more likely to pass on those genes. Over many years, this pattern has had a significant effect on the evolution of infection-causing organisms.

“Some of [the spread of antibiotic resistance] has to do with the inherent biology of organisms,” Powers said. “The initial antibiotics were compounds made by organisms to defend themselves against other organisms. Therefore, organisms have innate built-in mechanisms whereby they try to avoid the action of compounds generated by competitors for their environmental niche. For instance, penicillin is the by-product of a mold. The mold made penicillin to try to inhibit the growth of bacteria in its environment.”

This pattern has now persisted for several decades, resulting in increasing virulence of many infection-causing organisms. This has also played a role in the emergence of new and stronger infectious diseases that can affect humans.

“Institute of Medicine Committees have identified 13 factors that contribute to infectious disease emergence; several of these are related to antimicrobial resistance,” Hughes said. “The most important is microbial adaptation and change. It is noteworthy that in this 200th anniversary of Charles Darwin’s birth, the microbes are demonstrating their ability to rapidly evolve in response to selective pressures in their environment.”

Exacerbating the problem

There is general consensus that the inappropriate and overuse of antibiotics has been a defining factor contributing to the rising rates of antibiotic resistance.

“One major contributor to resistance is inappropriate use of these drugs in animals and in humans,” Powers said. “Many people – and animals – receive antimicrobials in situations where there is little to no benefit. For instance, the benefit of antimicrobials as growth promoters in animals is questionable and there is no demonstrable benefit of antibiotics in viral infections in humans or animals. In addition, in some self-resolving bacterial diseases like acute sinusitis, the benefit of treatment with antimicrobials is small to none. However, there is widespread use of antibiotics in these situations.”

Most experts who study antibiotic resistance say overuse of the medications is having a significant correlation with their loss of effectiveness. “Patients often ask their doctor for an antibiotic when they have a common cold,” Pankey said. “But 80% of patients who present with common colds have viruses and do not need an antibiotic.”

Rosemary Johann-Liang, MD, chief medical officer at the U.S. Department of Health Resources and Services Administration, said the frequency with which doctors prescribe antibiotics unnecessarily is having significantly harmful consequences for patients who truly need an antibiotic.

“The majority of patients currently being prescribed antibiotics are ill with upper respiratory illnesses – many viral – which will resolve without antibiotics; our host immune system usually does the work,” Johann-Liang said. “However, because of the inappropriate use of antibiotics, which has led to antibiotic resistance, the patients who will really suffer are those who are very ill with infections and who are already ill-equipped to fight infections due to their inadequate or failing immune systems. Doctors should remember that it is not antibiotics alone that cure patients from infections; it is antibiotics plus the host immune system.”

Johann-Liang said reducing excessive and unnecessary use of antibiotics is essential to fight antibiotic resistance. “Appropriate and judicious use of antibiotics will go a long way to combat antibiotic resistance,” she said. “But this area needs a lot of work. Health care professionals need to learn to use these medical interventions not empirically, but with appropriate diagnosis and only when we know the benefit outweighs the adverse reactions inherent to antibiotics. This will help preserve our current drugs.”

But the situation can be difficult, especially for primary care physicians and pediatricians. Patients and parents often demand an antibiotic. The priority may be to provide optimal care to the patient in front of them, with less concern about the broader issue of antibiotic resistance.

Likewise, critical care specialists and surgeons face a similar challenge. These physicians typically want to take whatever precautions are necessary to prevent a patient from developing an infection following surgery or during a hospital stay. To prevent such infections, patients are often given powerful doses of antibiotics that can fight multiple causes of infection. This is typically a necessary strategy. But there are specific indications for antibiotic use prior to certain procedures. Deviating from these guidelines can have deleterious consequences.

“We cannot really fault the critical care specialists and surgeons,” Yu said. “Infectious disease specialists are concerned about antibiotic resistance in the future but for these doctors, a worst-case scenario is a patient dying on their watch from an infection. So they prescribe a strong antibiotic. But this has resulted in doctors treating huge numbers of patients who do not even have an infection in an effort to take care of the smaller number of patients that do have an infection.”

Varies by location

The extent of antibiotic resistance often varies by geographic location and is often associated with the differences in governments’ regulations regarding antibiotic prescriptions. In the United States, a prescription is required for an antibiotic. But in many other countries, patients can get antibiotics over the counter from a pharmacy with no prescription. This often leads to further excessive and unnecessary use of antibiotics.

Other factors are involved in the geographic differences. Certain resistant organisms seem to be more prevalent in certain parts of the world. “The extent of the overall problem does vary among geographic areas,” Hughes said. “The reasons for this are a subject for future research. But some specific areas are ‘hot spots’ for certain types of problems. Recent examples include community-associated MRSA and multiply-resistant gram-negative bacillary infections in the United States, multiply-resistant Acinetobacter baumanii infections in military personnel in Iraq, extensively drug-resistant Mycobacterium tuberculosis infections in South Africa and multidrug-resistant Plasmodium falciparum infection along the Thai-Cambodian border. In Western Europe, the frequency of resistance in a number of bacterial pathogens is higher in southern than in northern countries. These differences likely reflect different patterns of antimicrobial usage in some cases and limited public health capacity to address the underlying disease in other cases.”

The types of antibiotics typically used also vary from country to country. “Resistance patterns vary dramatically from area to area,” McGowan said. “This is often in response to local patterns regarding how patients are being cared for. The resistant organisms we see emerging in different countries is often related to which drugs are being used to treat patients. The lack of availability of some agents in certain parts of the world further affects patterns of resistance.”

The pipeline

In recent years, many pharmaceutical companies have reduced investments in antibiotic research and development because the more profitable drugs are those intended to treat chronic diseases over many years.

A further concern is that if – or when – a new antibiotic is developed, there may be pressure to limit its use to treatment of only the most serious cases or when there is resistance to other antibiotics.

IDSA response

The Infectious Diseases Society of America has made fighting antibiotic resistance one of its top priorities. The organization has been sounding the alarm for the past few years about the risks associated with antibiotic resistance.

In 2004, the IDSA launched its “Bad Bugs, No Drugs” campaign. The ongoing campaign is designed to educate health care professionals and the general public about the dangers of antibiotic resistance and to discourage their excessive use. The campaign also encourages the development and use of improved infection control and immunization policies and practices, as well as safer alternatives to antibiotic use in plants and animals.

A major component of the IDSA’s campaign is encouraging policymakers to support the fight against antibiotic resistance. IDSA officials are petitioning members of Congress to increase public funding for the CDC, FDA and NIAID to improve research aimed at fighting antibiotic resistance. Policymakers have also been asked to support incentives that may help stimulate the development of new antibiotics and to fund research aimed at such outcomes.

The answer to fighting antibiotic resistance may be multifaceted. As Pankey said, experts should be exploring all areas of research to find solutions. “We need better diagnostics, better drugs, better infection control, better immunization and better ways to handle animals and feed,” he said. “Researchers should be working on various aspects simultaneously now, because the answer is not going to come from just one place.” – by Jay Lewis

For more information:

• DiazGranados C, Cardo D, McGowan J. Antimicrobial resistance: International control strategies, with a focus on limited-resource settings. Int J Antimicrob Agents. 2008;1:1-9.
• Singh N, Rogers P, Atwood C, et al. Short-course empiric antibiotic therapy for patients with pulmonary infiltrates in the intensive care unit: A proposed solution for indiscriminate antibiotic prescription. Am J Respir Crit Care Med. 2000;162:505-511.