Antibiotics - What, How, Where, When, and Why Antibiotics 101 Paul Dorr NCSU College of Veterinary Medicine Population Health and Pathobiology North Carolina State University Introduction: Antibiotics and antimicrobials are very important in the treatment of bacterial infections in both humans and animals. Of equal importance is the judicious use of these substances. In today’s swine industry, producers must be very aware as to what exactly they are treating their animals with, and what they are treating their animals for. One cannot judiciously use antimicrobials without a basic understanding of what they are, how they work, where and when one uses them, and why they are used. Furthermore, the recognition of certain antimicrobials and other therapeutic agents that should never be found on any swine farm is essential knowledge that producers must have. So, what is an antibiotic, and what is the difference between an antibiotic and an antimicrobial? According to the FDA an antibiotic is defined as, “A chemical substance produced by a microorganism. It has the capacity, in dilute solutions, to inhibit the growth of or to kill other microorganisms.” (1) So, essentially antibiotics are produced by various types of bacteria and fungi. The following is an example of some common antibiotics and their bacterial/fungal origins. –Tetracycline - Streptomyces aureofaciens –Neomycin - Streptomyces fradiae –Lincomycin - Streptomyces lincolnensis –Ceftiofur - Cephalosporium acremonium –Gentamicin - Micromonaspora purpurea (2) An antimicrobial may be defined as a compound that inhibits the growth or kills microorganisms. This includes antibiotics in addition to various compounds that are not of microorganism origin.(1) This definition would include synthetic products such as sulfas, quinolones, and nitrofurans. This leaves us with the next question, how do these substances work? Antibiotics are usually grouped according to their method of action and their spectrum of activity. There are 5 general methods of action (MOA) that antibiotics exhibit. These include inhibition of ribosomal protein synthesis, inhibition of DNA replication, alteration of metabolism, disruption of cell membrane function, and disruption of cell wall synthesis. (2,3) Also, antibiotics may have either a broad or narrow spectrum of activity. Simply put, a broad spectrum antibiotic is an antibiotic that is effective against both gram positive and gram negative bacteria. A narrow spectrum antibiotic is an antibiotic that is effective only for a limited or specific type of bacteria.(1) The different classes of antibiotics, their spectrum of activity, and various general methods of action are summarized in Table 1. Antibiotic class Antibiotic name examples Spectrum Method of action Narrow to Penicillins Potassium Pen G, Ampicillin, Amoxicillin broad disruption of cell wall synthesis Cephalosporins Ceftiofur Broad disruption of cell wall synthesis Aminoglycosides Streptomycin, Neomycin, Gentamycin Narrow inhibition of ribosomal protein synthesis Spectinomycin Spectinomycin Broad inhibition of ribosomal protein synthesis Chloramphenicol Florfenicol Broad inhibition of ribosomal protein synthesis Tetracyline, Oxytetracycline, Tetracyclines Chlorteteracycline Broad inhibition of ribosomal protein synthesis Macrolides Erythromycin, Tylosin, Tilmicosin Narrow inhibition of ribosomal protein synthesis Lincosamides Lincomycin Narrow inhibition of ribosomal protein synthesis Polymyxin Polymyxin B Narrow disruption of cell membrane function Bacitracin Bacitracin Narrow disruption of cell wall synthesis Tiamulin Tiamulin Narrow alteration of metabolism Sulfas Sulfathiazole, Sulfamethazine, Sulfadiazine Broad alteration of metabolism Table 1. Summary of antibiotic class, name, spectrum of activity and method of action of antibiotics commonly used in swine production. (2,4,5) Where then, do we use these substances, or more succinctly, how are they administered? To answer this question, a few things must be considered. First, WHAT DOES THE LABEL SAY! This is by far the most important consideration when administering antibiotics. Various antibiotics may be administered a number of different ways and have different withdrawal times which are indicated on the label. The various routes of administration that may be listed on the labels of different products include oral (dosing pump, water, feed), intravenous, intramuscular, and subcutaneous. The second aspect that must be considered is the bioavailability of the antibiotic given the route of administration and antibiotic type. For example, potassium penicillin G has a bioavailability of approximately 5% when administered orally (i.e. 5% is absorbed into the blood and the rest is excreted in the feces). So this would not be a good choice of antibiotic when trying to treat a systemic infection like Strep . even though the bacteria may be susceptible. When do we use these substances? Obviously when the pigs are sick. As with the label information, there are some important points to consider. First, antibiotics are not virusidial, i.e. they will have no direct effect on killing viral agents like PRRS, SIV, and TGE. Second, they are not a silver bullet for general illness or disease of unknown etiology. You have to know what you are up against. Third, culture and sensitivity data must be utilized. You have to know what works. Fourth, what kind of infection is it, respiratory, enteric, or systemic? All of these factors play a part when considering when to use antibiotics and which ones to use. Now we must consider why the label must be followed. A lot of research has been done to determine the optimal blood concentration or bioavailability at the site of infection that these antibiotics must obtain in order to be effective against the bacteria they are labeled to protect against. The effects of underdosing and overdosing will both have a detrimental effect on the health on the pig. Underdosing may provide an opportunity for bacterial proliferation when blood concentrations of the antibiotic are low, as seen in Figure 1. Antibiotic Blood Levels Bacterial growth will 8 occur here Blood level of 6 antibiotic 4 Level 2 Minimum blood level of antibiotic Relative Blood Blood Relative 0 where bacteria are killed Hours 4 12 20 28 36 44 52 60 68 Figure 1. Relative antibiotic blood levels when patient is under dosed. Figure 2. Relative antibiotic blood levels with a correct dosing schedule. Antibiotic Blood Levels Blood level of antibiotic 10 8 6 Minimum blood 4 levels level of antibiotic 2 where bacteria Relativeblood are killed 0 Ho urs 4 12 20 28 36 44 52 60 68 Some possible ramifications of underdosing include, but are not limited to: having to treat the animal longer, persistence of infection (resulting in decreased ADG and FE), and selection and proliferation of resistant subpopulations of bacteria. Overdosing may result in toxicity which will affect various body systems depending on the agent. If the bacterial infection that is being treated is persisting beyond the scheduled treatment period, many things must be considered. First, the animal(s) may have a superinfection in which the bacteria overwhelm the antibiotic at the given dose and bodies own defenses cannot fight off the bacteria. Along these same lines the animal may be immunocompromised as is the case with PRRS infection. Other reasons include failure of the antibiotic to reach the site of infection, the pH of the tissues is to high or to low, the bacteria is resistant to the current therapy, an incorrect dose was used, the antibiotic is outdated, an incorrect route of administration was used, or the dosing schedule was altered. (3). Part of using antimicrobials judiciously includes knowing which ones not to use and being able to identify substances on the farm that are currently illegal for use in animals. Many of these substances have adverse human and animal health implications. Furthermore, a few products, which are listed below, are legal for use in some animals, but not in swine. Table 2 contains a list of products that should never be found on a swine farm. Substances That Should Never Be Found On A Swine Farm Chloramphenicol – aplastic anemia in humans Clenbuterol Diethylstilbesterol - (DES) carcinogenic Nitroimidazoles - (dimetridazole, ipromidazole) carcinogenic Nitrofurans - (nitrofurazone) carcinogenic, mutagenic Sulfonamides – There are some approved ones, check label Fluoroquinolones - (enrofloxacin - Baytril 100) Dipyrone!!! Glycopeptides - (Vancomycin) human Staph. aureus resistance concern Table 2. Substances that should never be found on a swine farm.(6) Judicious use of antimicrobials is of great importance in today’s production systems. Un-judicious use of these substances has both human and animal health implications and legal ramifications. The most important take home message is: Be Responsible! Treat the animals that need to be treated. Follow the directions on the label/prescription paying special attention to withdrawal time, dose, dosing schedule, spectrum of activity, and route of administration. Furthermore, always be aware of what is on your farm with regards to outdated product and products not approved for use in swine. Always consult your veterinarian with any questions regarding these issues. Following these simple guidelines concerning antimicrobial use will help to ensure a healthier hog out the door. Sources 1. Judicious Use of Antimicrobials for Pork Producers. Department of Health and Human Services, Public Health Service, Food and Drug Administration Center for Veterinary Medicine. Aug. 2001. 2. Plumb, DC. Veterinary Drug Handbook. Third Edition. Iowa State University Press. Ames, IA. 3. Berg, J. Pathogenic Bacteriology and Mycology in Veterinary Medicine. VM553 note set. University of Missouri – Columbia. Fall 2000. 4. Butaye, P, et. al. Influence of different medium components on the in vitro activity of the growth promoting antibiotic flavomycin against enterococci. Journal of Antimicrobial Chemotherapy (2000) 46, 713-716. 5. Compendium of Veterinary Products. 7 th Ed. Bayer. North American Compendiums, Ltd. 2003. 6. Drugs Prohibited From Extralabel Use In Food Animals. http://www.saanendoah.com/prohibiteddrugs.html . 2003 .