FDA Adopts New Antibiotic Labeling Regulations
By Kelly M. Pyrek
The Food and Drug Administration (FDA) is taking decisive action in the campaign against antibiotic resistance by issuing new labeling regulations. The final rule, "Labeling Requirements for Systemic Antibacterial Drug Products Intended for Human Use," was published in the Feb. 6, 2003 Federal Register and will take effect in February 2004. This final rule endeavors to reduce the inappropriate prescription of antibiotics for common ailments such as ear infections and chronic coughs.
Antibiotics are often prescribed to patients whose cause of symptoms such as a cough or slight fever may be viral as opposed to bacterial. The danger of prescribing antibiotics to individuals with viral infections is that it can hasten the development of bacterial strains that are resistant to that antibiotic. These individuals who carry antibiotic-resistance strains of flora may pass these bacteria to others, making treatment of their illnesses even more complicated. In addition, many patients who suffer from mild viral infections would get better without a course of antibiotic treatment.
The new rule applies to all systemically absorbed human antibacterial drugs and requires statements in several places in the physician labeling advising that these drugs should be used only to treat infections believed to be caused by bacteria. The rule also requires a statement in the labeling encouraging physicians to counsel their patients about the proper use of these drugs and the importance of taking them exactly as directed. This is part of ongoing efforts at FDA to encourage the development of new antimicrobials while preserving the usefulness of already existing ones.
"Antibacterial resistance is a serious and growing public health problem in the United States and worldwide," said FDA Commissioner Mark McClellan, MD, PhD. "Without effective antibiotic drugs, common infections that were once easily treated can create a serious health threat to children and adults alike."
Many bacterial species, including the species that cause pneumonia and other respiratory tract infections, meningitis, and sexually transmitted diseases, are becoming increasingly resistant to the antibacterial drugs used to treat them. Several bacterial species have developed strains that are resistant to every approved antibiotic.
Adoption of the rule represents the achievement of one of the objectives of the Public Health Action Plan To Combat Antimicrobial Resistance, a joint initiative of the FDA, the Centers for Disease Control and Prevention (CDC) and the National Institutes of Health (NIH).
According to the CDC, half of the 100 million prescriptions a year written by office-based physicians in the United States are unnecessary because they are prescribed for the common cold and other viral infections, against which antibiotics are not active. Unnecessary use of antibiotics in hospitals is also reportedly common.
The FDA believes educating physicians and the general public about the resistance problem and discouraging the unnecessary use of antibiotics are important steps to decrease the prevalence of resistance as well as slow its future development and spread. The agency believes the new labeling requirements will contribute to this campaign.
The FDA says that a recent report of a reduction in antibiotic prescribing raises hopes that the trend in antibiotic overuse can be reversed. Studies were conducted in children seen in outpatient practice and have not been confirmed in either adults or inpatient environments. Nevertheless, researchers and authors of these studies believe efforts such as education campaigns or labeling regulations will help stem and eventually turn the tide of antibiotic overuse.
The final rule provides the FDA's definition of inappropriate use, which includes using antibiotics for viral infections, failure to prescribe an adequate length of treatment, failure of patients to complete the entire course of treatment, skipping doses and using a broad-spectrum antibiotic when a narrow-spectrum antibiotic would have sufficed.
The final rule contains specific instructions for the labeling of antibiotics, a new mandate to be followed by the approximately 101 large and small U.S. pharmaceutical companies. The FDA estimates that manufacturers will be required to modify labeling of 669 antibacterial drug products and that these manufacturers would incur costs of about $4,300 per product to revise product labels. The FDA estimates that an average of 100,000 package inserts are printed annually for each antibacterial drug product marketed in the U.S. and changes in printing would incur costs of about $37 per affected product.
The labeling must state in the "indications and usage" section that to reduce the development of drug-resistant bacteria and maintain the effectiveness of the antibiotic, the drug product should only be used to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. The labeling also must state that when culture and susceptibility information are available, they should be considered in selecting or modifying antimicrobial therapy. In the "general" subsection of the "precautions" section, the labeling must state that prescribing the antibacterial drug product in the absence of a proven or strongly suspected bacterial infection of a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
In the "information for patients" section, the labeling must state that patients should be counseled that antibacterial drugs should only be used to treat bacterial infections and that they do not treat viral infections such as the common cold. The labeling must state that when an antibiotic is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. The labeling also must advise physicians to counsel patients that skipping doses or not completing the full course of therapy may decrease the effectiveness of the immediate treatment and increase the likelihood that bacteria will develop resistance and will not be treatable by the drug or any other antibiotic in the future.
Clinicians Comment on the Final Rule
As is customary, citizens are invited to submit their comments on proposed rules. Although the rule and the labeling regulations received widespread approval, one comment challenged the source of resistance, saying that a more likely cause other than misuse of antibiotics is a "breakdown in basic infection control practices and hygiene" such as handwashing and immunization. Another comment maintained that all antimicrobials have built-in obsolescence, therefore there will be a natural progression of selection for resistance regardless of how appropriately physicians prescribe antibiotics.
The FDA received several comments stating that labeling would not influence physicians' prescribing practices, that they are already aware of the information contained in the proposed labeling, and that they may be offended by the warnings. Other comments contained suggestions that the FDA should assess whether prescribers understand the proposed labeling and will change their behavior, and suggested the FDA send periodic letters to clinicians, giving them updates on antibiotic resistance and prudent use of antibiotics because physicians may not read package inserts. The FDA responded to these comments by saying the agency believes that physician labeling can contribute to (addressing resistance) by reminding physicians their individual prescribing decisions have a collective impact on the resistance problem. "The agency believes that physicians frequently consult selected portions of the package insert and thus will encounter one or more of the statements on antibiotic resistance that appear in multiple, significant locations in the package insert."
Many of the comments about the final rule suggested alternative means to educate clinicians, including holding educational and scientific forums through the CDC and the American Medical Association. While the FDA agrees that labeling alone is not sufficient to reduce or prevent antibiotic resistance, it said, "It is one of many ongoing efforts that already encompasses advisory meetings with industry, open public meetings, and workshops with industry and academia to focus on the creation of new antimicrobials while preserving the usefulness of existing drug products."
One comment of particular interest to infection control practitioners asserted that since resistant infections are most often acquired in hospitals ands then spread to the community, the FDA should work with public health agencies and state boards of health to establish more effective healthcare facility infection control programs, rather than addressing the resistance problem through labeling. The FDA responded by saying it is working with the CDC and other agencies "to establish more effective infection control programs and to develop means for educating physicians and communicating current information on the problem. However, the agency believes that labeling is also needed as a part of a multi-faceted attack on the resistance problem. The FDA noted that some resistant organisms like penicillin-resistant Streptococcus pneumoniae are acquired in the community rather than in the hospital."
The broader scope of the problem was recognized by several comments from individuals who questioned whether or not resistance can be encouraged through the use of topical antibiotics and antiseptics, and wondered if statements concerning antibiotic resistance will eventually be included in the labels of antiviral, antifungal and antimycobacterial agents, topical antibacterials and topical antiseptics. The FDA says that these agents raise different scientific and regulatory issues than do systemic antibiotics, and the agency is currently considering how to address concerns about the development of resistance from the use of these other products, and will consider if additional rule-making is necessary.
It is no surprise that the final rule drew fire from some clinicians who charged the proposal is outside the scope of labeling and that its real purpose should be how to dispense drugs safely, not tell the physicians how to practice medicine. One comment declared, "Product labeling should not dictate medical practice, which requires individualized clinical assessment of the patient and the circumstance under which the patient is being diagnosed. " Another comment asserted, "The choice of antibiotic should be made by the physician after weighing the overall benefits and risks to the patient."
The FDA, not surprisingly, defended its position, saying it has long recognized its role is "neither to regulate physician conduct nor to train physicians." In 1972 Congress declared that the FDA is charged with the responsibility for judging the safety and effectiveness of drugs and the truthfulness of their labeling, and that the physician is then responsible for making the final judgment as to which drugs patients will or will not receive.
New costs incurred by the labeling regulations are being weighed against the benefits of the campaign. The FDA projects the annualized costs to comply with the final rule to be less than $600,000 and adds that if the revised labeling reduces direct and indirect costs attributable to resistant bacteria by 1 percent, the annual benefit will be $10 million. Central to the costs issue is the question of whether the FDA's economic analysis included the costs of follow-up physician visits or the costs of culture and sensitivity tests. The FDA did not include these costs as healthcare facilities already currently order susceptibility tests, especially when there is a high incidence of resistant bacterial infections locally. Some public comments on the final rule questioned the cost-effectiveness of susceptibility testing, while another comment stated that waiting to initiate drug therapy would lead to additional morbidity and mortality costs. The FDA said, "While the agency agrees that any delay in starting therapy can increase the direct and indirect costs of infection, the final rule does not suggest that healthcare providers postpone treatment once they strongly suspect an infection is caused by bacteria. The agency agrees that costs can increase when resistant bacteria are not initially identified as the cause of an infection. In one study on bloodstream infections, the length of hospital stay increased by 6.4 days and mortality increased from 11.9 percent to 29.9 percent with inadequate treatment."
While industry thinks in terms of the bottom line, clinicians are concerned about infections' toll on human life. In the final rule, the FDA admits, "The total number of annual infections caused by resistant bacteria is uncertain" and that diagnostic codes for infectious conditions in patient medical records can only provide an estimate of the minimum numbers of cases of drug-resistant infections in a given year. The National Hospital Discharge Survey estimates about 18,000 and 43,000 cases of infections by resistant organisms for 1995 and 1997, while the Healthcare Cost and Utilization Project estimates 84,000 diagnoses of resistant infections in community hospitals for 1997. CDC hospital surveillance data for five known strains of resistant bacteria for 1995 suggests approximately 279,000 cases. For its analysis, the FDA assumed 150,000 nosocomial infections per year are attributable to resistant bacteria, and if patients incur additional hospital charges of $2,500 per resistant infection, the total hospital cost attributable to antibacterial resistance is estimated at $375 million annually.
In the final rule, the FDA states that the threat of mortality appears to be greater from hospital-acquired infections than from community-acquired ones. According to the CDC, about 40 percent of all community-acquired infections from S. pneumoniae are penicillin-nonsusceptible, and can cause bacteremia, pneumonia, meningitis and otitis media. Until the mid-1990s, surveillance data for S. pneumoniae showed few cases of resistant bacteria; however, current surveillance shows the incidence of resistant bacteria has increased dramatically.
Two recent studies on the effects of methicillin-resistant Staphyloccoccus aureus (MRSA) reported significantly different lengths of stay for patients infected with resistant bacteria compared to control groups. One study found that patients with infections from resistant bacteria stayed an average of 9.5 days in an intensive care unit vs. control-group patients who stayed five days. Another study showed patients with resistant infections stayed 21 days vs. 12.5 days for the control group.
One public comment on the final rule asserted there is no scientific consensus on the need to use narrow-spectrum antibiotics targeted at organisms that have been identified through cultures, and the subject was discussed in January 2003 by the FDA's Anti-Infective Drugs Advisory Committee. The FDA says that using narrower spectrum, more targeted therapy can reduce resistance because they have less impact than the normal organisms that colonize the body and that this flora may even protect the body from more pathogenic bacteria. It also stated that normal flora exposed to an antimicrobial may become resistant to that drug and pass resistant genes on to more pathogenic bacteria. They concluded, therefore, that prescribing narrower spectrum drugs may limit the spread of resistance while still treating the organisms causing illness.
The FDA's response is that regardless of whether all antibiotics will eventually lead to resistant bacteria, "there are great benefits to delaying that progression as long as possible," citing CDC statistics that as much as 50 percent of antibiotic use is unnecessary, such as when they are prescribed for illnesses like the common cold.
Perioperative Antibiotic Prophylaxis
Many clinicians believe that the widespread use of perioperative prophylaxis makes surgical procedures a critical component of the overall campaign about smart antibiotic use. Smith writes, "Attempts to reduce costs and limit the emergence of resistance among pathogenic bacteria by altering antibiotic use must therefore encompass surgical prophylaxis. Several recent reports have linked the use of third-generation cephalosporins with beta-lactam resistance in gram-negative bacteria and with vancomycin resistance in Enterococcus. Fortunately, susceptibility can often be restored by replacing third-generation cephalosporins with drugs that are less likely to foster resistance; a penicillin/beta-lactamase inhibitor combination is often a suitable substitute." Smith adds, "An antibiotic resistance management program can affect the type of changes in antimicrobial use necessary to reverse an outbreak of resistant pathogens." Smith reports that when such a plan was implemented at his hospital, the prevalence of VRE, MRSA and other resistant gram-negative bacilli were all reduced.