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FDA Adopts New Antibiotic Labeling Regulations
By Kelly M. Pyrek
TheFood and Drug Administration (FDA) is taking decisive action in the campaignagainst antibiotic resistance by issuing new labeling regulations. The finalrule, "Labeling Requirements for Systemic Antibacterial Drug ProductsIntended for Human Use," was published in the Feb. 6, 2003 Federal Registerand will take effect in February 2004. This final rule endeavors to reduce theinappropriate prescription of antibiotics for common ailments such as earinfections and chronic coughs.
Antibiotics are often prescribed to patients whose cause of symptoms such asa cough or slight fever may be viral as opposed to bacterial. The danger ofprescribing antibiotics to individuals with viral infections is that it canhasten the development of bacterial strains that are resistant to thatantibiotic. These individuals who carry antibiotic-resistance strains of floramay pass these bacteria to others, making treatment of their illnesses even morecomplicated. In addition, many patients who suffer from mild viral infectionswould get better without a course of antibiotic treatment.
The new rule applies to all systemically absorbed human antibacterial drugsand requires statements in several places in the physician labeling advisingthat these drugs should be used only to treat infections believed to be causedby bacteria. The rule also requires a statement in the labeling encouragingphysicians to counsel their patients about the proper use of these drugs and theimportance of taking them exactly as directed. This is part of ongoing effortsat FDA to encourage the development of new antimicrobials while preserving theusefulness of already existing ones.
"Antibacterial resistance is a serious and growing public health problemin the United States and worldwide," said FDA Commissioner Mark McClellan,MD, PhD. "Without effective antibiotic drugs, common infections that wereonce easily treated can create a serious health threat to children and adultsalike."
Many bacterial species, including the species that cause pneumonia and otherrespiratory tract infections, meningitis, and sexually transmitted diseases, arebecoming increasingly resistant to the antibacterial drugs used to treat them.Several bacterial species have developed strains that are resistant to everyapproved antibiotic.
Adoption of the rule represents the achievement of one of the objectives ofthe Public Health Action Plan To Combat Antimicrobial Resistance, a jointinitiative of the FDA, the Centers for Disease Control and Prevention (CDC) andthe National Institutes of Health (NIH).
According to the CDC, half of the 100 million prescriptions a year written byoffice-based physicians in the United States are unnecessary because they areprescribed for the common cold and other viral infections, against whichantibiotics are not active. Unnecessary use of antibiotics in hospitals is alsoreportedly common.
The FDA believes educating physicians and the general public about theresistance problem and discouraging the unnecessary use of antibiotics areimportant steps to decrease the prevalence of resistance as well as slow itsfuture development and spread. The agency believes the new labeling requirementswill contribute to this campaign.
The FDA says that a recent report of a reduction in antibiotic prescribingraises hopes that the trend in antibiotic overuse can be reversed. Studies wereconducted in children seen in outpatient practice and have not been confirmed ineither adults or inpatient environments. Nevertheless, researchers and authorsof these studies believe efforts such as education campaigns or labelingregulations will help stem and eventually turn the tide of antibiotic overuse.
The final rule provides the FDA's definition of inappropriate use, whichincludes using antibiotics for viral infections, failure to prescribe anadequate length of treatment, failure of patients to complete the entire courseof treatment, skipping doses and using a broad-spectrum antibiotic when anarrow-spectrum antibiotic would have sufficed.
The final rule contains specific instructions for the labeling ofantibiotics, a new mandate to be followed by the approximately 101 large andsmall U.S. pharmaceutical companies. The FDA estimates that manufacturers willbe required to modify labeling of 669 antibacterial drug products and that thesemanufacturers would incur costs of about $4,300 per product to revise productlabels. The FDA estimates that an average of 100,000 package inserts are printedannually for each antibacterial drug product marketed in the U.S. and changes inprinting would incur costs of about $37 per affected product.
The labeling must state in the "indications and usage" section thatto reduce the development of drug-resistant bacteria and maintain theeffectiveness of the antibiotic, the drug product should only be used to treator prevent infections that are proven or strongly suspected to be caused bysusceptible bacteria. The labeling also must state that when culture andsusceptibility information are available, they should be considered in selectingor modifying antimicrobial therapy. In the "general" subsection of the"precautions" section, the labeling must state that prescribing theantibacterial drug product in the absence of a proven or strongly suspectedbacterial infection of a prophylactic indication is unlikely to provide benefitto the patient and increases the risk of the development of drug-resistantbacteria.
In the "information for patients" section, the labeling must statethat patients should be counseled that antibacterial drugs should only be usedto treat bacterial infections and that they do not treat viral infections suchas the common cold. The labeling must state that when an antibiotic isprescribed to treat a bacterial infection, patients should be told that althoughit is common to feel better early in the course of therapy, the medicationshould be taken exactly as directed. The labeling also must advise physicians tocounsel patients that skipping doses or not completing the full course oftherapy may decrease the effectiveness of the immediate treatment and increasethe likelihood that bacteria will develop resistance and will not be treatableby 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 proposedrules. Although the rule and the labeling regulations received widespreadapproval, one comment challenged the source of resistance, saying that a morelikely cause other than misuse of antibiotics is a "breakdown in basicinfection control practices and hygiene" such as handwashing andimmunization. Another comment maintained that all antimicrobials have built-inobsolescence, therefore there will be a natural progression of selection forresistance regardless of how appropriately physicians prescribe antibiotics.
The FDA received several comments stating that labeling would not influencephysicians' prescribing practices, that they are already aware of theinformation contained in the proposed labeling, and that they may be offended bythe warnings. Other comments contained suggestions that the FDA should assesswhether prescribers understand the proposed labeling and will change theirbehavior, and suggested the FDA send periodic letters to clinicians, giving themupdates on antibiotic resistance and prudent use of antibiotics becausephysicians may not read package inserts. The FDA responded to these comments bysaying the agency believes that physician labeling can contribute to (addressingresistance) by reminding physicians their individual prescribing decisions havea collective impact on the resistance problem. "The agency believes thatphysicians frequently consult selected portions of the package insert and thuswill encounter one or more of the statements on antibiotic resistance thatappear in multiple, significant locations in the package insert."
Many of the comments about the final rule suggested alternative means toeducate clinicians, including holding educational and scientific forums throughthe CDC and the American Medical Association. While the FDA agrees that labelingalone is not sufficient to reduce or prevent antibiotic resistance, it said,"It is one of many ongoing efforts that already encompasses advisorymeetings with industry, open public meetings, and workshops with industry andacademia to focus on the creation of new antimicrobials while preserving theusefulness of existing drug products."
One comment of particular interest to infection control practitionersasserted that since resistant infections are most often acquired in hospitalsands then spread to the community, the FDA should work with public healthagencies and state boards of health to establish more effective healthcarefacility infection control programs, rather than addressing the resistanceproblem through labeling. The FDA responded by saying it is working with the CDCand other agencies "to establish more effective infection control programsand to develop means for educating physicians and communicating currentinformation on the problem. However, the agency believes that labeling is alsoneeded as a part of a multi-faceted attack on the resistance problem. The FDAnoted that some resistant organisms like penicillin-resistant Streptococcuspneumoniae are acquired in the community rather than in the hospital."
The broader scope of the problem was recognized by several comments fromindividuals who questioned whether or not resistance can be encouraged throughthe use of topical antibiotics and antiseptics, and wondered if statementsconcerning antibiotic resistance will eventually be included in the labels ofantiviral, antifungal and antimycobacterial agents, topical antibacterials andtopical antiseptics. The FDA says that these agents raise different scientificand regulatory issues than do systemic antibiotics, and the agency is currentlyconsidering how to address concerns about the development of resistance from theuse of these other products, and will consider if additional rule-making isnecessary.
It is no surprise that the final rule drew fire from some clinicians whocharged the proposal is outside the scope of labeling and that its real purposeshould be how to dispense drugs safely, not tell the physicians how to practicemedicine. One comment declared, "Product labeling should not dictatemedical practice, which requires individualized clinical assessment of thepatient and the circumstance under which the patient is being diagnosed. "Another comment asserted, "The choice of antibiotic should be made by thephysician after weighing the overall benefits and risks to the patient."
The FDA, not surprisingly, defended its position, saying it has longrecognized its role is "neither to regulate physician conduct nor to trainphysicians." In 1972 Congress declared that the FDA is charged with theresponsibility for judging the safety and effectiveness of drugs and thetruthfulness of their labeling, and that the physician is then responsible formaking the final judgment as to which drugs patients will or will not receive.
New costs incurred by the labeling regulations are being weighed against thebenefits of the campaign. The FDA projects the annualized costs to comply withthe final rule to be less than $600,000 and adds that if the revised labelingreduces direct and indirect costs attributable to resistant bacteria by 1percent, the annual benefit will be $10 million. Central to the costs issue isthe question of whether the FDA's economic analysis included the costs offollow-up physician visits or the costs of culture and sensitivity tests. TheFDA did not include these costs as healthcare facilities already currently ordersusceptibility tests, especially when there is a high incidence of resistantbacterial infections locally. Some public comments on the final rule questionedthe cost-effectiveness of susceptibility testing, while another comment statedthat waiting to initiate drug therapy would lead to additional morbidity andmortality costs. The FDA said, "While the agency agrees that any delay instarting therapy can increase the direct and indirect costs of infection, thefinal rule does not suggest that healthcare providers postpone treatment oncethey strongly suspect an infection is caused by bacteria. The agency agrees thatcosts can increase when resistant bacteria are not initially identified as thecause of an infection. In one study on bloodstream infections, the length ofhospital stay increased by 6.4 days and mortality increased from 11.9 percent to29.9 percent with inadequate treatment."
While industry thinks in terms of the bottom line, clinicians are concernedabout infections' toll on human life. In the final rule, the FDA admits,"The total number of annual infections caused by resistant bacteria isuncertain" and that diagnostic codes for infectious conditions in patientmedical records can only provide an estimate of the minimum numbers of cases ofdrug-resistant infections in a given year. The National Hospital DischargeSurvey estimates about 18,000 and 43,000 cases of infections by resistantorganisms for 1995 and 1997, while the Healthcare Cost and Utilization Projectestimates 84,000 diagnoses of resistant infections in community hospitals for1997. CDC hospital surveillance data for five known strains of resistantbacteria for 1995 suggests approximately 279,000 cases. For its analysis, theFDA assumed 150,000 nosocomial infections per year are attributable to resistantbacteria, and if patients incur additional hospital charges of $2,500 perresistant infection, the total hospital cost attributable to antibacterialresistance is estimated at $375 million annually.
In the final rule, the FDA states that the threat of mortality appears to begreater from hospital-acquired infections than from community-acquired ones.According to the CDC, about 40 percent of all community-acquired infections fromS. pneumoniae are penicillin-nonsusceptible, and can cause bacteremia,pneumonia, meningitis and otitis media. Until the mid-1990s, surveillance datafor S. pneumoniae showed few cases of resistant bacteria; however, currentsurveillance shows the incidence of resistant bacteria has increaseddramatically.
Two recent studies on the effects of methicillin-resistant Staphyloccoccusaureus (MRSA) reported significantly different lengths of stay for patientsinfected with resistant bacteria compared to control groups. One study foundthat patients with infections from resistant bacteria stayed an average of 9.5days in an intensive care unit vs. control-group patients who stayed five days.Another study showed patients with resistant infections stayed 21 days vs. 12.5days for the control group.
One public comment on the final rule asserted there is no scientificconsensus on the need to use narrow-spectrum antibiotics targeted at organismsthat have been identified through cultures, and the subject was discussed inJanuary 2003 by the FDA's Anti-Infective Drugs Advisory Committee. The FDA saysthat using narrower spectrum, more targeted therapy can reduce resistancebecause they have less impact than the normal organisms that colonize the bodyand that this flora may even protect the body from more pathogenic bacteria. Italso stated that normal flora exposed to an antimicrobial may become resistantto that drug and pass resistant genes on to more pathogenic bacteria. Theyconcluded, therefore, that prescribing narrower spectrum drugs may limit thespread of resistance while still treating the organisms causing illness.
The FDA's response is that regardless of whether all antibiotics willeventually lead to resistant bacteria, "there are great benefits todelaying that progression as long as possible," citing CDC statistics thatas much as 50 percent of antibiotic use is unnecessary, such as when they areprescribed for illnesses like the common cold.
Perioperative Antibiotic Prophylaxis
Many clinicians believe that the widespread use of perioperative prophylaxismakes surgical procedures a critical component of the overall campaign aboutsmart antibiotic use. Smith writes, "Attempts to reduce costs and limit theemergence of resistance among pathogenic bacteria by altering antibiotic usemust therefore encompass surgical prophylaxis. Several recent reports havelinked the use of third-generation cephalosporins with beta-lactam resistance ingram-negative bacteria and with vancomycin resistance in Enterococcus.Fortunately, susceptibility can often be restored by replacing third-generationcephalosporins with drugs that are less likely to foster resistance; apenicillin/beta-lactamase inhibitor combination is often a suitablesubstitute." Smith adds, "An antibiotic resistance management programcan affect the type of changes in antimicrobial use necessary to reverse anoutbreak of resistant pathogens." Smith reports that when such a plan wasimplemented at his hospital, the prevalence of VRE, MRSA and other resistantgram-negative bacilli were all reduced.