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July 2002 CE.
This first article in a three-part series provides healthcare representatives with an understanding of the antibiotic selection process.
J. Peter Rissing, M.D., FACP, FIDSA, chief of Infectious Diseases Section, Sydenstricker Professor of Medicine, Medical College of Georgia, Augusta, GA; and John C. Rotschafer, Pharm.D., FCCP, Section of Clinical Pharmacy, Regions Hospital, and professor, College of Pharmacy, University of Minnesota, St. Paul, MN, served as consultants for this article for the Certified Medical Representatives Institute Inc.
• Describe the four levels of infectious disease prevention.
• Explain how antimicrobials are used to combat infection.
• List manual and automated systems for antibiotic susceptibility testing.
• Define empiric therapy and explain why it is used in most office and clinic settings.
• Describe five factors that influence the physician's choice of antibiotic when treating an infection empirically.
Physicians in the United States write about 150 million outpatient prescriptions for antibiotics each year, according to the Centers for Disease Control and Prevention, and almost half of all hospitalized patients receive antibiotics. Because antibiotics represent such a large percentage of drug expenditure, their usage is increasingly scrutinized for appropriate and effective patient outcomes.
Infectious disease prevention
As shown in the accompanying graphic (see page 35), infectious disease prevention and control can be regulated through four levels: individuals, institutions, communities and the global environment. Disease prevention focusing on the individual is mainly the responsibility of the clinician who provides individuals with treatment to prevent the development of an infection. The second level of disease prevention involves institutions, such as healthcare facilities, nursing homes, day-care centers and schools. The third level of disease prevention is at the community level, namely the local, state or national public health agencies. Finally, global prevention strategies address the impact of international travel, importation and immigration on infectious disease.
An evaluation of each specific pathogen, in terms of its reservoir, mode of transmission and effect on a host, needs to be performed in order to develop appropriate disease prevention and control programs. For example, the chlorination of public water supplies serves as a method of eliminating pathogenic reservoirs and their potential mode of transmission. Screening food, water or blood supplies that may serve as vehicles of pathogenic spread may also prevent the transmission of disease. Lastly, emphasis of disease prevention may be targeted toward the host through immunization or improving the nutritional status of an individual or a population.
In addition to these disease control activities, there are numerous prevention strategies that may be employed, including:
• Primary prevention, which refers to the protection of health by personal or community-wide efforts.
• Secondary prevention, which is defined as measures available to individuals and populations for early detection of disease and intervention.
• Tertiary prevention, which involves measures to reduce or eliminate long-term impairments and disabilities from individuals suffering from existing conditions.
Antimicrobial agents used to combat infection. There are several types of antimicrobial agents that are used to combat infection, including antibiotics, antifungal agents and antiviral agents. Antimicrobials may be administered to treat an existing infection or may be given prophylactically as a means to prevent infection. Primarily, the prophylactic use of antibiotics is to prevent infection associated with surgical or diagnostic procedures. Antibiotics are also used prophylactically to prevent endocarditis in patients with heart murmurs who are undergoing dental work. In addition, individuals traveling to high-risk areas may be administered prophylactic antibiotics to prevent the development of diseases such as malaria.
Antibiotics are chemical substances produced by various species of microorganisms (e.g., bacteria and fungi) that kill or suppress the growth of other microorganisms and may eventually destroy them. The term antibiotics as it is commonly used also refers to synthetic antibacterial agents (e.g., sulfonamides and fluoroquinolones) that have been artificially created and are not products of microbes.
Antibiotics are often classified by their mechanism of action, that is, how they destroy bacteria. Commonly used antibiotics include penicillin-binding protein inhibitors, muramyl pentapeptide inhibitors, DNA gyrase complex inhibitors, 30S and 50S ribosome inhibitors, and folic acid metabolism inhibitors.
Antibiotic susceptibility testing
Selecting the appropriate antibiotic is an important component of the prevention and treatment of infectious disease. When a patient has symptoms of an infectious disease, the physician often collects a sample of tissue or biologic fluid (e.g., urine, blood or sputum) that is likely to contain the microorganisms causing the infection (pathogens). The sample is sent to a microbiology laboratory for identification of the microorganisms. With automated laboratory systems, preliminary studies can often be done in four hours, 24 hours a day. Once the pathogen has been identified by the laboratory and antibiotic susceptibility results are known, the physician can select an antibiotic known to have efficacy against that organism. In order to start therapy quickly, the physician may prescribe an antibiotic before receiving the laboratory results. This is referred to as empiric therapy, which will be discussed in detail later in this article.
In addition to identifying the pathogen causing an infection, the microbiology laboratory tests its susceptibility to several antibiotics to determine how well each one may inhibit the growth of the pathogen. The physician receives the susceptibility test results, and based on the susceptibility of the bacterial strain to a particular antibiotic, the physician may switch from the antibiotic prescribed empirically to one that has better efficacy against the pathogen.
There are several manual methods of antibiotic susceptibility testing, including:
• Methods for determining minimum inhibitory concentrations:
– Agar dilution.
– Broth dilution.
– The E-test.
• A method for determining minimal bactericidal concentration.
• Disk diffusion.
However, automated technology enables clinical laboratories to increase productivity and provide more accurate data in a shorter period of time. Examples of automated systems include the MS-2, Vitek and Autobac systems. Manual backup testing may still be necessary to accurately detect some resistant organisms.
Healthcare representatives and pharmaceutical companies, particularly those with agents used in larger institutional settings, will have to address the issue of how to include a new antibiotic in these automated testing panels. Often, the agents to be tested or reported are restricted to those on the institution's formulary. Physicians will not be likely to prescribe a formulary or nonformulary antibiotic that has not undergone routine antimicrobial susceptibility testing. In cases where antibiotic susceptibility testing is performed by classes rather than individually, it is important for healthcare representatives to make sure their antibiotics are listed individually on the laboratory report that goes to physicians. Therefore, it is very important for healthcare representatives to be aware of the importance of the microbiologist and the staff of the microbiology laboratory in gaining acceptance for their products.
A company representative who intends to try to have a new antibiotic placed on formulary may need to provide the laboratory staff with disks or E-test strips until the drug is placed on Vitek panel. Usually there is a delay between formulary approval and the inclusion of a new drug in automated testing systems. In part, this delay may be due to many hospitals purchasing their automated testing panels in bulk quantities to reduce costs. They will want to use up their existing supply before adding a new agent.
Healthcare representatives should also note that most laboratories are reducing staff and implementing other means of controlling costs because of the economic challenges facing many hospitals. This further restricts the amount of reporting and other services performed by laboratory staff. While this may limit the amount of time and attention that the microbiology laboratory can give to your product, it also means that they will be receptive to any cost-saving measures your company may be able to offer.
Antibiotic therapy selected on a demonstrated knowledge of the pathogen involved and its antibiotic susceptibility is known as definitive therapy, and this method is preferred. However, nonautomated culture results may not be available for 24 to 48 hours for many of the common pathogens, such as streptococci, staphylococci and Enterobacteriaceae. In addition, pneumococci may take three to four days to grow in a culture, and other organisms (e.g., mycobacteria and chlamydia) will require a longer period.
Therefore, before the isolation and susceptibility testing of the microorganism, physicians usually begin empiric therapy rather than lose valuable treatment time while waiting for laboratory results, particularly when a life-threatening infection is involved. Empiric therapy is the administration of antibiotics based on clinical symptoms and the likelihood of an infectious pathogen. In most office and clinic settings, the physician does not take a culture and treats the infection empirically.
By treating likely infections empirically, the physician gets a head start on battling the suspected pathogen if it is bacterial. The Gram stain is a simple yet reliable stain that can provide preliminary important information on the type of bacterium or bacteria causing the infection. Once the laboratory results verify the specific organism of the infection, the therapy can be continued or changed based upon the pathogen identified and its susceptibilities.
Factors influencing empiric therapy. When treating an infection empirically, there are several important factors that influence a physician's choice of antibiotic, including the site of infection, patient characteristics and preferences, the presence of copathogens, the likelihood of resistance, and formulary restrictions.
The site of infection is important because it can influence how well and how quickly the antibiotic will reach the infecting organism and achieve tissue concentrations.
Patient characteristics that often influence the choice of therapy include:
• Pregnancy or breast-feeding.
• In children, the availability of chewable tablets or an oral suspension in a likeable flavor.
• Allergic reactions to certain agents.
• Renal or hepatic dysfunction, which may require agents to be administered at lower dosages so that they do not worsen the patient's condition.
• Patient age, since drugs are cleared from the body more slowly in the elderly.
• Medication already being taken for another condition, such as heart disease or hypertension.
• Immunocompromised patients or patients with HIV infection.
• Previous antibiotic therapy and antibiotic failures.
Patients may also have preferences for certain products based on recommendations or past experience.
When physicians consider treating an infection empirically, they may have to take into account whether this type of infection is likely to be caused by more than one type of pathogen. When copathogens are suspected, the physician may want to start treatment with a broad-spectrum agent capable of exerting a bacteriostatic or bactericidal effect on many types of organisms. The physician may also select a combination of two antibiotics with different spectrums of microbiologic activity to destroy a wider array of suspected pathogens or to produce synergy.
If a microorganism has been highly susceptible to a certain antibiotic, it makes sense for a physician to prescribe a similar antibiotic when that microorganism is suspected of causing an infection. However, the pattern of sensitivity and resistance first demonstrated by a microorganism can change significantly due to the mechanisms of drug resistance. Knowledge of local bacterial susceptibility patterns can help the physician decide whether therapy should be based on the possibility of resistant organisms. Local susceptibility patterns are usually published periodically by hospital laboratories. This report is called an antibiogram.
Many physicians are limited in their selection of antibiotics to only those agents that are listed on their healthcare facility's formulary. The pharmacy and therapeutics committee selects antibiotics for formulary inclusion on the basis of several factors, including efficacy, spectrum of activity, local resistance patterns, safety, cost and pharmacoeconomic data.
Although there are general and clinical practice guidelines regarding the types of antibiotics selected as initial treatment, a physician's treatment decision often depends on whether or not a pathogen has acquired resistance to a particular antibiotic. No matter how effective an antibiotic may be, the development of resistance eventually becomes a major obstacle to its continued success. Resistance may develop during clinical trials, or it may not appear until many years later. Resistance can also develop during treatment (i.e., type I beta-lactamase). In any case, once bacteria become resistant to a particular antibiotic, they are no longer susceptible to and might not be inhibited or killed by that class of drug.
* Infectious disease prevention and control can be regulated through four levels: individuals, institutions, communities and global environment.
* Antibiotics, antifungal agents and antiviral agents are used to combat infection.
* Antibiotics are chemical substances produced by various species of microorganisms (e.g., bacteria and fungi) that suppress the growth of other microorganisms and may eventually destroy them.
* Primarily, prophylactic use of antibiotics is to prevent infection associated with surgical or diagnostic procedures.
– Also used to prevent endocarditis in patients with heart murmurs undergoing dental work.
– May be used for those traveling to high-risk areas to prevent the development of diseases such as malaria.
* When a patient has symptoms of an infectious disease, the physician often collects a sample of tissue or biologic fluid and sends the sample to a microbiology laboratory for identification of microorganisms.
* Once the pathogen has been identified, the physician can select an antibiotic known to have efficacy against the organism.
* There are several manual methods of antibiotic susceptibility testing (e.g., MICs, MBC and disk diffusion).
* However, automated technology (e.g., MS-2, Vitek and Autobac) enables clinical laboratories to increase productivity.
* Physicians usually begin empiric therapy rather than lose valuable time while waiting for laboratory results.
* Factors that influence a physician's choice of antibiotic include: site of infection, patient characteristics and preferences, presence of copathogens, likelihood of resistance, and formulary restrictions.
* A physician's treatment decision often depends on whether or not a pathogen has acquired resistance to a particular antibiotic.
© 2002 The Certified Medical Representatives Institute Inc., Roanoke, VA 24018. All rights reserved. No part of this article may be reproduced by any method or in any form without written permission from the CMR Institute. Reprints of this article are available from the CMR Institute. Request Continuing Education article DR-1.