If the best defense is a good offense, we’re in trouble—at least when it comes to modern microbes. Growing resistance has sidelined our top-tier players such as methicillin and vancomycin increasingly often. Drug companies have redirected resources away from the anti-infective fight toward more profitable contests of heart disease, cancer and inflammation.1 What now, with infectious organisms outmaneuvering even our drugs of last resort? "Nightmare bacteria," including totally drug-resistant tuberculosis, carbapenem-resistant enterobacteriaceae (CRE) and vancomycin-resistant Staphylococcus aureus (VRSA), prompt proclamations like, "The worst has finally happened”2 and that this "worldwide human health risk” has us facing "an apocalypse."3 "Nightmare bacteria" did not develop overnight. Instead, many attest that the bulk of antibiotic resistance arises from unhealthful and, at times, inhumane cattle-, pig- and chicken-raising practices. The American Veterinary Medical Association sidesteps this accusation by asserting, "There is little to no evidence that restricting or eliminating the use of antimicrobials in food-producing animals would improve human health or reduce the risk of antimicrobial resistance to humans."4 If antibiotics weren’t to blame, why have so many countries across the globe, other than the United States, banned the use of growth-promoting antibiotics in animal feed? Why are researchers from the National Animal Disease Center in Ames, Iowa, calling for a "nationally coordinated, interdisciplinary, multi-agency (human and animal health) effort to encourage research on promising antibiotic alternatives,"5 insisting that options are "urgently needed"?6 In 2012, even the U.S. Food and Drug Administration announced a plan to eliminate drugs such as penicillin and tetracyclines for "production uses" such as promoting weight gain.7 Furthermore, a startling new study found that antibiotic-resistant genes can and have spread through manure and contaminated soil. The authors of this report insist, "Intensive animal husbandry is believed to be a major contributor to the increased environmental burden of antibiotic resistant genes (ARGs). ... abundance of ARGs correlated directly with antibiotic and metal concentrations." They found 149 unique and "diverse, abundant and potentially mobile" genes in manure and soil on a large-scale Chinese pig farm heavily reliant on antibiotics.8 Recycling that manure into fertilizer introduces ARGs and genetic traits in the soil used to grow plants that drains into irrigation ditches, drinking water and streams. Some Options Some have argued that industrialized meat production requires the continuous use of in-feed antibiotics to ensure economic viability.9 They may contend that eliminating routine antibiotic delivery could lead to starvation in developing countries. Critics point out the fallacy of these claims. One author found that if all animal producers eliminated routine antibiotics from animal feed, the average daily protein supply for meat eaters in developing countries would drop by no more than 0.1 gram. "Work-around" non-antibiotic growth promoters such as sepiolite, formerly considered innocuous,10 actually can produce resistance. Sepiolite and other minerals adsorb DNA and form nanoneedles that, through the force of friction, release genetic strands into bacteria who benefit from this information. In so doing, sepiolite serves as a vehicle for the direct exchange of genetic material between different strains and species of bacteria. Can anything more be done? How did animals and humans survive infections prior to penicillin? Botanicals. Treating infections with plants has far more history than do pills, feed supplements and injections.11 Watching how animals self-medicate (a process called "zoopharmacognosy") originally informed humans about the healing properties of plants.12 Coming up Botanics Botanical compounds are no lightweights; some even act against resistant bacterial strains, including methicillin-resistant Staphylococcus aureus (MRSA). Acanthospermum hispidum DC, a wild tropical herb, treats chronic MRSA infection in the skin.13 Pannarin, an isolate from Chilean lichens, produces antimicrobial effects comparable to antibiotics.14 Antibacterial ingredients from the Chinese herb Sophora flavenscens AITON (Leguminosae), demonstrated activity against MRSA isolates15 and synergistic effects when combined with antibiotics.16 Even silibinin from milk thistle confers synergistic effects with oxacillin or ampicillin against MRSA isolates.17 Other well-known herbs with anti-MRSA potential include licorice, oregano, aloe, neem, guava, pomegranate and more.18 For ethnoveterinary purposes, noni fruit (Morinda citrifolia) puree was shown to enhance immunity in neonatal calves suffering from salmonellosis.19 Catechins from dried green tea promote growth in pigs and fight infection without inducing antibiotic resistance.20 Mechanisms of action of antimicrobial plants are many. In part, aromatic herbs contain large amounts of ether oils that fight bacteria; typical herbs in this category include chamomile, sweet basil, lemon balm, yarrow and rosemary.21 Immunoactive polysaccharides from plants (and mushrooms) activate neutrophils and macrophages as well as stimulate the release of immune-enhancing cytokines.22 Raising awareness about herbal approaches to superbugs and developing consistent and effective herbs will entail a multi-step process. Veterinarians need to seek scientifically based information about plants—discussions about poorly defined properties pertaining to "plant energies" and "heat-dispelling properties" fall far short of what medicine needs to move botanical treatments forward. Researchers will need to screen species for active agents and then follow with clinical trials; proper plant importation, identification and authentication of species; good manufacturing guidelines and quality control; and regulatory oversight.23,24 While bacteria can develop resistance to herbs, they do so more slowly because, unlike drugs, plants have numerous compounds with which microorganisms must contend.25 In that they also stimulate immune function, herbs further strengthen the host against offending organisms.26 Animals used for food should at least be able to move about freely and forage to find plant-based medicines.27 According to an April 2013 release in Science, "[T]he study of animal [self] medication will have direct relevance for human food production and health. Disease problems in agricultural organisms can worsen when humans interfere with the ability of animals to medicate. An ultimate objective of [zoopharmacognosy and ethnomedicine] research is to integrate our results into local health care and livestock management systems so that locally-available plants can be properly used to the benefit of all."28 So, plants provide hope. The question is, is there still time? Dr. Robinson, Dipl. ABMA, FAAMA, oversees complementary veterinary education at Colorado State University. FOOTNOTES Wetzstein C. Antibiotic-resistant ‘superbugs’ alarm health care industry. The Washington Times. March 19, 2013 2 Stratton C. VRSA: the worst has finally happened. Medscape Infectious Disease. September 27, 2002. Accessed at http://www.medscape.org/viewarticle/442206 on 04-15-13. 3 Casey G. Antibiotics and the rise of superbugs. Kai Tiaki Nursing New Zealand. 2012;18(10):20-24. 4 American Veterinary Medical Association. Frequently asked questions about antimicrobial use and antimicrobial resistances. Accessed at https://www.avma.org/KB/Resources/FAQs/Documents/antimicrobial_use.pdf on 04-15-13. 5 Stanton TB. A call for antibiotic alternatives research. Trends in Microbiology. 2013;21(3):111-113. 6 Allen HK, Levine UY, Looft T, et al. Treatment, promotion, commotion: antibiotic alternatives in food-producing animals. Trends in Microbiology. 2013;21(3):114-119. 7 Downing J. FDA seeks veterinary oversight of ‘medically important’ antibiotics in livestock. VIN News Service. April 11, 2012. Accessed at http://www.vin.com/Members/CMS/Misc/VINNews/Default.aspx/3d22320 on 04-13-13. 8 Zhu Y-G, Johnson TA, Su J-Q, et al. Diverse and abundant antibiotic resistance genes in Chinese swine farms. Proceedings of the National Academy of Sciences of the United States of America. February 11, 2013. [Epub ahead of print]. 9 Collignon P, Wegener HC, Braam P, et al. The routine use of antibiotics to promote animal growth does little to benefit protein undernutrition in the developing world. Clinical Infectious Diseases. 2005;41:1007-1013. 10 Rodriguez-Beltran J, Rodriguez-Rojas A, Yubero E, et al. The animal food supplement Sepiolite promotes a direct horizontal transfer of antibiotic resistance plasmids between bacterial species. Antimicrob Agents Chemother. 2013; March 25 [Epub ahead of print]. 11 Carlsen A. On call in the wild: animals play doctor, too. Health News: NPR. April 22, 2013. Accessed at http://www.npr.org/blogs/health/2013/04/09/176694090/on-call-in-the-wild-animals-play-doctor-too. 12 Huffman MA. Animal self-medication and ethno-medicine: exploration and exploitation of the medicinal properties of plants. Proc Nutr Soc. 2003;62(2):371-381. 13 Arena ME, Cartagena E, Gobbato N, et al. In vivo and in vitro antibacterial activity of Acanthospermal B, a sesquiterpene lactone isolated from Acanthospermum hispidum. Phytotherapy Research. 2011;25:597-602. 14 Celenza G, Segatore B, Setacci D, et al. In vitro antimicrobial activity of pannarin alone and in combination with antibiotics against methicillin-resistant Staphylococcus aureus clinical isolates. Phytomedicine. 2012;19:596-602. 15 Chan BC-L, Yu H, Wong C-W, et al. Quick identification of kuraridin, a noncytotoxic anti-MRSA (methicillin-resistant Staphylococcus aureus) agent from Sophora flavescens using high-speed counter-current chromatography. Journal of Chromatography B. 2012;880:157-162. 16 Cha J-D, Moon S-E, Kim J-Y, et al. Antibacterial activity or sophoraflavanone G isolated from the roots of Sophora flavescens against methicillin-resistant Staphylococcus aureus. Phytotherapy Research. 2009;23:1326-1331. 17 Kang H-K, Kim H-Y, and Cha J-D. Synergistic effects between silibinin and antibiotics on methicillin-resistant Staphylococcus aureus isolated from clinical specimens. Biotechnology Journal. 2011;6(11):1397-1408. 18 Skariyachan S, Krishnan RS, Siddapa SB, et al. Computer aided screening and evaluation of herbal therapeutics against MRSA infections. Bioinformation. 2011;7(5):222-233. 19 Brooks VJ, De Wolfe RJ, Paulus TJ, et al. Ethnoveterinary application of Morinda citrifolia fruit puree on a commercial heifer rearing facility with endemic salmonellosis. Afr J Tradit Complement Altern Med. 2013;10(1):1-8. 20 Ohno A, Kataoka S, Ishii Y, et al. Evaluation of Camellia sinensis catechins as a swine antimicrobial feed additive that does not cause antibiotic resistance. Microbes Environ. 2013;28(1):81-86. 21 Davidovic V, Joksimovic todorovic M, Stojanovic B, et al. Plant usage in protecting the farm animal health. Biotechnology in Animal Husbandry. 2012; 28(1):87-98. 22 Davidovic V, Joksimovic todorovic M, Stojanovic B, et al. Plant usage in protecting the farm animal health. Biotechnology in Animal Husbandry. 2012; 28(1):87-98. 23 Smith-Hall C, Larsen HO, and Pouliot M. People, plants and health: a conceptual framework for assessing changes in medicinal plant consumption. Journal of Ethnobiology and Ethnomedicine. 2012; 8:43. 24 Yeung KS, Gubili J, and Cassileth B. Evidence-based botanical research: applications and challenges. Hematol Oncol Clin N Am. 2008;22:661-670. 25 Tong YQ, Jia SJ, and Han B. Chinese herb-resistant clinical isolates of Escherichia coli. J Alt Complement Med. 2012; 18:1-2. 26 Borsuk OS< Masnaya NV, Sherstoboev SY, et al. Effects of drugs of plant origin on the development of the immune response. Bulletin of Experimental Biology and Medicine. 2011;151(2):194-196. 27 De Roode JC et al. Self-medication in animals. Science. 2013;340: 150-151. 28 Huffman MA. Animal self-medication and ethno-medicine: exploration and exploitation of the medicinal properties of plants. Proceedings of the Nutrition Society. 2003;62:371-381.
