Fate and Transport of Antibiotic Residues and Antibiotic Resistance Genes following Land Application of Manure Waste Yu-Feng Lin Illinois State Water Survey

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Fate and Transport of Antibiotic Residues and Antibiotic Resistance Genes following Land Application of Manure Waste Yu-Feng Lin Illinois State Water Survey
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  TECHNICAL REPORTS 1086  Antibiotics are used in animal livestock production for therapeutic treatment of disease and at subtherapeutic levels for growth promotion and improvement of feed effi ciency. It is estimated that approximately 75% of antibiotics are not absorbed by animals and are excreted in waste. Antibiotic resistance selection occurs among gastrointestinal bacteria,  which are also excreted in manure and stored in waste holding systems. Land application of animal waste is a common disposal method used in the United States and is a means for environmental entry of both antibiotics and genetic resistance determinants. Concerns for bacterial resistance gene selection and dissemination of resistance genes have prompted interest about the concentrations and biological activity of drug residues and break-down metabolites, and their fate and transport. Fecal bacteria can survive for weeks to months in the environment, depending on species and temperature, however, genetic elements can persist regardless of cell viability. Phylogenetic analyses indicate antibiotic resistance genes have evolved, although some genes have been maintained in bacteria before the modern antibiotic era. Quantitative measurements of drug residues and levels of resistance genes are needed, in addition to understanding the environmental mechanisms of genetic selection, gene acquisition, and the spatiotemporal dynamics of these resistance genes and their bacterial hosts. Tis review article discusses an accumulation of findings that address aspects of the fate, transport, and persistence of antibiotics and antibiotic resistance genes in natural environments, with emphasis on mechanisms pertaining to soil environments following land application of animal waste effl uent. Fate and Transport of Antibiotic Residues and Antibiotic Resistance Genes following Land Application of Manure Waste  Joanne C. Chee-Sanford* USDA-ARS, University of Illinois Roderick I. Mackie and Satoshi Koike University of Illinois Ivan G. Krapac Illinois State Geological Survey  Yu-Feng Lin Illinois State Water Survey Anthony C. Yannarell and Scott Maxwell University of Illinois Rustam I. Aminov Rowett Research Institute  A   are routinely used in the livestock industry to treat and prevent disease. In addition, subtherapeutic concentrations of antimicrobials are commonly added to animal feed and/or drinking water sources as growth promoters, and have been a regular part of swine ( Sus scrofa  ) production since the early 1950s (Cromwell, 2001). When used in this manner, antibiotics can select for resistant bacteria in the gastrointestinal tract of production animals, providing a potential reservoir for dissemination of drug resistant bacteria into other animals, humans, and the environment (Andremont, 2003). Bacteria have been shown to readily exchange genetic information in nature, permitting the transfer of different resistance mechanisms already present in the environment from one bacterium to another (Salyers and Amábile-Cuevas, 1997; Amábile-Cuevas and Chicurel, 1992; Stewart, 1989). ransfer of resistance genes from fecal organisms to indigenous soil and water bacteria may occur (Nielsen et al., 2000; Daane et al., 1996; DiGiovanni et al., 1996; Lorenz and Wackernagel, 1994), and because native populations are generally better adapted for survival in aquatic or terrestrial ecosystems, persistence of resistance traits may be likely in natural environments once they are acquired. Antibiotic resistance has received considerable attention due to the problem of emergence and rapid expansion of antibiotic resistant pathogenic bacteria.Te potential for long-term, cumulative inputs of antibiotics and correspondingly, their potential effects on acquisition and mainte-nance of antibiotic resistance mechanisms in bacteria, collectively sug-gest a degree of impact on the occurrence, persistence, and mobility Abbreviations: CAFOs, concentrated animal feeding operations; MICs, minimum inhiabitory concentrations; OTC, oxytetracycline; PCR, polymerase chain reaction; RPPs, ribosomal protection proteins; SCP, sulfachlorpyridazine; UCS, Union of Concerned Scientists.J.C. Chee-Sanford, USDA-ARS, 1102 S. Goodwin Ave., Urbana, IL 61801, and Dep. of Crop Sciences, Univ. of Illinois, 1102 S. Goodwin Ave., Urbana, IL 61801; R.I. Mackie, S. Koike, and A.C. Yannarell, Dep. of Animal Sciences, and Division of Nutritional Sciences, Univ. of Illinois, 1207 W. Gregory, Urbana, IL 61801; R.I. Mackie, Institute for Genomic Biology, Univ. of Illinois, 1206 W. Gregory, Urbana, IL 61801; I.G. Krapac, Illinois State Geological Survey, 1910 Griffi th Dr., Champaign, IL 61820; Y.-F. Lin, Illinois State Water Survey, 2204 Griffi th, Champaign, IL 61820; S. Maxwell, Dep. of Natural Resources and Environmental Sciences, Univ. of Illinois, 1102 S. Goodwin Ave., Urbana, IL 61801; R.I. Aminov, Rowett Research Institute, Greenburn Rd., Bucksburn, Aberdeen AB21 9SB, Scotland, UK. Copyright © 2009 by the American Society of Agronomy, Crop Science Society of America, and Soil Science Society of America. All rights reserved. No part of this periodical may be reproduced or transmitted in any form or by any means, electronic or mechanical, including pho-tocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher.Published in J. Environ. Qual. 38:1086–1108 (2009).doi:10.2134/jeq2008.0128Received 14 Mar. 2008. *Corresponding author (cheesanf@illinois.edu).© ASA, CSSA, SSSA677 S. Segoe Rd., Madison, WI 53711 USA   REVIEWS AND ANALYSES  Chee-Sanford et al.: Fate & Transport of Antibiotic Residues & Antibiotic Resistance Genes 1087 of resistance genes in natural environments. A number of reviews, reports, and opinion papers have emerged to address the possible link between antibiotic use and the impact on antibiotic resistance development (e.g., Kümmerer, 2004; Shea, 2004; Isaacson and or-rence, 2002; Séveno et al., 2002; USGAO, 1999; Khachatourians, 1998; Gustafson and Bowen, 1997). Tese papers have highlighted various issues related to antibiotic use in agriculture, often focusing on the link to emerging antibiotic resistant bacteria, gene transfer mechanisms, and consequent risks to human and animal health.In the following review, we seek to provide a comprehensive overview of the dissemination and fate of antibiotic residues, and the environmental persistence, mobility, and transferability of antibiotic resistance determinants and their bacterial hosts fol-lowing the practice of land application of livestock waste (Fig. 1). Te significance of these issues pertains to continuing efforts in determining the true ecological impact of antibiotics and antibi-otic resistance genes on entry into natural environments. Antibiotic Use in Animal Agriculture In commercial livestock production, antibiotics are used: (i) therapeutically to treat existing disease conditions, (ii) prophy-lactically at subtherapeutic doses to mitigate infection by bacte-rial pathogens of livestock animals undergoing high stress situ-ations, and (iii) subtherapeutically to enhance growth. A survey of members of the Animal Health Institute reported that overall, the ionophores/arsenicals and tetracycline classes of antibiotics  were the most commonly used antimicrobials in animal produc-tion (able 1; AHI, 2001). Among the antibiotics commonly used in swine, poultry, and beef cattle ( Bos taurus  ), penicillins, macrolides, polypeptides, streptogramins, and tetracyclines are used not only for purposes of disease treatment and disease pre-vention, but for growth promotion too (able 2). Other classes, such as quinolones, lincosamides, and aminoglycosides are pri-marily used only in disease treatment or prevention.Te Animal Health Institute (AHI, 2001) and Union of Con-cerned Scientists (UCS) (Union of Concerned Scientists, 2001) recently reported two different estimates of antibiotic usage in agriculture. Te AHI reported a total of 20.5 million pounds of antibiotics sold for all animal use in 1999. Of the 20.5 mil-lion pounds, 17.7 million pounds were used for treatment and prevention of disease and only 2.8 million pounds were used for improving feed effi ciency and enhancing growth. In con-trast, the UCS reported 24.6 million pounds of antibiotics were used for nontherapeutic purposes alone in the swine, poultry, and cattle industries. According to the UCS report, livestock use accounts for the major share of total antimicrobials used in the United States, estimated at 50 million pounds annually, based on extrapolation from a 1989 Institute of Medicine report (Insti-tute of Medicine, 1989). Despite the discrepancy over usage, it is clear that the amount of antibiotics used in agriculture is large. Management of Animal Waste from Production Agriculture Historically, until the mid- to late 1970s, livestock opera-tions were usually part of larger integrated farming operations that produced crops. Manure management practices differ de-pending on number of head, the type of livestock and opera-tion, and production stage of the animals. Te direction to- ward large operations using total animal confinement facilities has led to major issues of waste storage and disposal in livestock (poultry, beef, and swine) production. Swine production, in particular, has seen a trend toward specialized large produc-tion facilities (e.g., farrow to weaning, farrow to feeder, nursery, finishing, farrow to finish). Over the last 25 yr swine produc-tion has largely shifted from such integrated farming systems to concentrated animal feeding operations (CAFOs) that may house thousands of animals. In 1984, there were approximately 690,000 U.S. producers producing 20 billion pounds of pork. By 2000, about 95,000 producers were producing 26 billion pounds of pork (USDA NASS, 2002). Due to geographic pat-terns of feed grain production and other market forces, swine CAFOs have become concentrated in certain geographic re-gions in the United States, primarily North Carolina and sev-eral Midwest states, with Iowa, Minnesota, and Illinois among the largest producers. United States Department of Agriculture surveys performed in 2000 found that 28.3% of swine facilities  were located within a half mile of another swine production site and 53.9% were within one mile of another site (USDA, 2001a, 2001b). While the following review derives much of the information from the large number of studies with swine  waste, antibiotics are administered in all the major animal pro-duction industries (able 1, able 2).Under the earlier integrated system of production, produc-ers typically owned large tracts of land necessary for agronomic activity. Waste and effl uent from a modest number of animals  was applied rotationally over different fields, effectively diluting nutrients and recycling waste for fertilizer use. Swine each typi-cally produce approximately 1.5 tonnes of fresh manure in the 5 to 6 mo it takes to grow them to a market weight of 114 kg (ca. 250 lbs) (Richert et al., 1995). Te National Agricultural Statis-tics Service (NASS) estimated that in 2002, 185 million head of swine were sold in the United States, generating approximately 2.8 × 10 8  tonnes of fresh manure annually. Chicken ( Gallus gal-lus  ) production in the United States in 2006 was estimated at nearly 9 billion head, generating approximately. 4.6 × 10 8  tonnes of manure. Beef cattle estimates in the United States in 2007  were 33.3 million head (Nebraska Beef Council, 2007), produc-ing approximately 3.6 × 10 6  tonnes of manure (USDA-NASS, 2002; USDA-NRCS, 1995). With the advent of CAFOs, large quantities of waste are concentrated in a single location and/or region, and producers may not own or access suffi cient tracts of land suitable for disposal of manure through land application.Methods of waste storage vary among operations, but par-ticular to the confined operations of the swine industry, these usually follow one of three primary types: (i) a slatted floor over a deep concrete pit, (ii) a slatted floor over a shallow pit with out-door areas for slurry storage, and (ii) a slatted floor over a shal-low pit with outdoor lagoon treatment. Additional land is often required to house secondary waste storage systems. In lagoon systems, manure solids are partially degraded and organic N is converted to inorganic forms and released from the lagoon pri-  1088 Journal of Environmental Quality • Volume 38 • May–June 2009 marily through ammonia volatilization and as N 2  or N 2 O gases (Harper et al., 2004; Rotz, 2004). Te loss of N and the seques-tering of much of the P in wastes in lagoon sludge can reduce the amount of land required for waste disposal to meet agronomic guidelines for best management practices (Beegle, 1997).Te most common method to dispose of swine and feedlot cattle waste effl uent in the United States following lagoon or pit storage is through land application, where application of liquid manure at agronomic rates can produce crop yields that equal those obtained with chemical fertilizers (Schmitt et al., 1995; Sarmah et al., 2006). o use and dispose of the manure effl u-ent, CAFO operators often contract with neighboring growers to apply effl uent to their land or apply it to land surrounding the facility. Because it is costly to transport liquid effl uent any great distance, there is an incentive to apply effl uent as close to the source as possible. In the United States the crop cycles coincide  with seasonal cycles, with the application of manure occurring between crop cycles. For many locations, manure is stored for 6 mo to 1 yr before being applied to crop fields as fertilizer. Ef-fluent differs from fresh manure in that it has a much greater Fig. 1. Conceptualized view showing the possible fates of antibiotic residues and mechanisms of antibiotic resistance gene acquisition and dissemination by bacteria, beginning with land application of animal waste as the source of entry of drugs, bacteria, and resistance genes into the soil environment. AB = antibiotic, ABR = antibiotic resistance.Table 1. Survey of the most commonly used antibiotics in animal production (AHI, 2001).Antibiotic classAmount metric tonnesIonophores/Arsenicals3520 Tetracyclines3239Other antibiotics-includes macrolides, lincosamides,polypeptides, streptogramins, cephalosporins1937Penicillins821Sulfonamides269Aminoglycosides117Fluoroquinolones16 Table 2. Antibiotics commonly used in swine, poultry, and beef cattle production industries (USGAO, 1999; USDA, 2007).Antibiotic class Industry Aminoglycosides Swine, poultry, beef cattleβ-Lactams Swine, poultry, beef cattleChloramphenicol Beef cattleIonophores Poultry, beef cattleLincosamides Swine, poultryMacrolides Swine, poultry, beef cattlePolypeptides Swine, poultryQuinolones (and Fluoroquiniolones) Poultry, beef cattleStreptogramins Swine, poultry, beef cattleSulfonamides Swine, poultry, beef cattle Tetracyclines Swine, poultry, beef cattleOthers:Glycolipids (Bambermycin) Swine, poultry, beef cattleCarbadoxSwineAminocoumarins (Novobiocin)PoultryAminocyclitols (Spectinomycin)Swine, poultry  Chee-Sanford et al.: Fate & Transport of Antibiotic Residues & Antibiotic Resistance Genes 1089  water volume. Fresh swine waste contains approximately 10% solids, while deep pit and lagoon effl uents are 4 to 8% solids and <0.5 to 1%, respectively (Fulhage and Post, 2005). O’Dell et al. (1995) found the solids content ranged from 4 to 10 g/L in 18 separate tank loads of swine effl uent that had been agitated for 24 h before application, suggesting effl uent application rates can be highly variable. Te practice of stockpiling fresh manure and applying directly to fields is also used in the beef cattle industry, however, little is known about the effects on the nutrient prop-erties (Dolliver and Gupta, 2008; Larney et al., 2006). Poultry  waste management differs somewhat from swine and cattle in that poultry litter is a dry mixture of excrement, bedding mate-rial, and feed, and the composition and disposal largely depends on the type of bird produced. Pit storage is often used in pro-duction of layer hens and for all types of poultry, direct land ap-plication of litter is the primary method of disposal, with a small percentage using composting (MacDonald, 2008).It is clear that the amounts of manure generated by com-mercial livestock is high, and while the types of antibiotics in use may differ between industries, similar issues are raised con-cerning environmental exposure to animal waste that may relate broadly across the entire animal production industry. Confine-ment livestock production, especially large animal facilities, is increasingly a source of surface- and groundwater contamina-tion, and elevated levels of antibiotic resistance in humans and animals have been linked to the practice of antimicrobial growth promotant use at poultry and swine farms (Gilchrist et al., 2007). Te widespread practice of land application prompted the Envi-ronmental Protection Agency (EPA) in the 1990s to require nu-trient management plans for CAFOs. Initially, nutrient manage-ment plans were N-based, requiring manure to be applied at a rate that would not exceed crop N requirements. Swine manure, however, has a high P content relative to N content; as excreted, swine manure contains a P 2 O 5 /N ratio of approximately 0.86:1 (Livestock and Poultry Environmental Stewardship, 2005). Ap-plying effl uent to meet the N requirements of a crop often leads to a buildup of P in the soil, in some instances to values in excess of 2000 mg/kg of total soil P (Lehmann et al., 2005).Te three primary methods used to apply effl uent include: (i) surface application, (ii) surface application followed by in-corporation, and (iii) direct soil injection. One primary reason to incorporate surface-applied effl uent is to limit the loss of N by at least 50% compared to surface application alone (Rotz, 2004). Other reasons include odor reduction and minimization of surface runoff. Te preferred method of application from a nutrient management standpoint is deep injection into the soil, which eliminates the N loss associated with other meth-ods, reduces odor, and virtually eliminates the possibility of surface runoff. Due to cost or soil conditions, direct injection or incorporation of waste may not always be feasible options.Because surface application has been associated with N loss, it is often considered “environmentally unfriendly,” yet it has merits as a method of managing pathogen loads. Hutchison et al. (2004) reported that the mean D value, or time needed to reduce the vari-able being measured by one order of magnitude, for four zoonotic pathogens, Salmonella   sp., Escherichia coli   0157, Listeria   sp., and Campylobacter   sp., was 1.42 d for unincorporated pig slurry and 2.48 d for slurry incorporated immediately after application. Tese pathogens also declined at similar rates regardless of sea-son (summer vs. winter). Dessication may be an important factor in population decline because more intense UV radiation in the summer would be expected to accelerate cell mortality (Hoerter et al., 2005; Booth et al., 2001). A significant rainfall event immedi-ately following surface application of effl uent would likely result in vertical movement of bacteria and mobile compounds into the soil profile as well as off-site movement due to surface runoff (Saini et al., 2003). Surface applications to frozen soil are usually avoided because of the likelihood of significant runoff. Entry of Antibiotics into the Environment  Antibiotics used in animal agriculture can enter the environ-ment via a number of routes, including the drug manufacturing process, disposal of unused drugs and containers, and through the use and application of waste material containing the drugs (Bu-chberger, 2007; Utah Department of Health, 2007; Daughton, 2004). Te excretion of waste products by grazing animals, atmo-spheric dispersal of feed and manure dust containing antibiotics, and the incidental release of products from spills or discharges are also potential pathways of antibiotic residue entry into the envi-ronment. Animal agriculture is only one potential source of entry of drug residues in the environment, and good estimates of the quantities contributed by various sources is not available.Many antibiotics are not completely absorbed in the gut, re-sulting in the excretion of the parent compound and its break-down metabolites (Boxall et al., 2004; Halling-Sørensen et al., 1998; Feinman and Matheson, 1978). Elmund et al. (1971) estimated that as much as 75% of the antibiotics administered to feedlot animals could be excreted into the environment. Fein-man and Matheson (1978) suggested that about 25% of the oral dose of tetracycline is excreted in feces and another 50 to 60% is excreted unchanged or as an active metabolite in urine. Oral administration of the macrolide tylosin resulted in a maximum of 67% of the antibiotic excreted, mainly in the feces.Te practice of land application of livestock manure pro-vides large area scale for introduction of antibiotics into the environment. Once released into the environment, antibiotics can be transported either in a dissolved phase or (ad)sorbed to colloids or soil particles into surface- and groundwater (Kra-pac et al., 2004; Yang and Carlson, 2003; Campagnolo et al., 2002; Kolpin et al., 2002). Manure and waste slurries poten-tially contain significant amounts of antibiotics and their pres-ence can persist in soil after land application (Gavalchin and Katz, 1994; Donohoe, 1984). Chemical Characteristics of Antibiotics and Behavior in Soil and Water Veterinary antibiotics comprise a group of organic com-pounds that have a wide variety of functional groups that affect their chemical properties. Te octanol-water partition coeffi -cient (K  ow  ) is used as a general measure of hydrophobicity, and most antibiotics have log K  ow   values <5 indicating that they are  1090 Journal of Environmental Quality • Volume 38 • May–June 2009 relatively nonhydrophobic (olls, 2001). Additionally, the wa-ter solubility for many antibiotics exceeds 1 g/L suggesting that they are relatively hydrophilic (able 3). olls (2001) and Box-all et al. (2004) compiled sorption coeffi cients (K  d ) for a variety of antibiotics, soils, and soil components measured over the course of many studies. Based on K  d  values, antibiotics exhibit a range of affi nities for the solid phase (K  d  0.2–6000 L/kg) with consequent effects on their mobility in the environment. Esti-mations of antibiotic organic carbon-normalized sorption coef-ficients (K  oc ) made by using a compound’s octanol-water parti-tion coeffi cient (K  ow  ) generally results in underestimates of the K  oc  value, suggesting that mechanisms other than hydrophobic partitioning occur. Cation exchange, surface complexation, and hydrogen bonding are included as likely mechanisms for antibiotic sorption to soils. Many of the acid dissociation con-stants (pK  a  ) for antibiotics are in the range of soil pH values, such that the protonation state of these compounds depends on the pH of the soil solution (olls, 2001).Studies have shown that under a broad range of environ-mental conditions, tetracyclines (tetracycline, chlortetracy-cline, and oxytetracycline) can adsorb strongly to clays (Al-laire et al., 2006; Sithole and Guy, 1987a, 1987b; Pinck et al., 1961a,1961b), soil (Krapac et al., 2004), and sediments (Rabolle and Spliid, 2000). Sorption of chlortetracycline also occurred rapidly in sandy loam soil (Allaire et al., 2006). Mac-rolides such as tylosin have a weaker tendency to sorb to soil materials (Rabolle and Spliid 2000), however a sorption kinetic study showed 95% of tylosin was sorbed within 3 h in both sandy loam and clay soils (Allaire et al., 2006). Sulfonamides exhibit weak sorption to soil, and likely are the most mobile of the antibiotics (olls, 2001). Pinck et al. (1962) determined that two macrolide antibiotics (carbomycin and erythromy-cin) sorbed significantly (231–263 mg/g) to montmorillonite and to a much lesser extent (0–39 mg/g) to vermiculite, illite, and kaolinite. In a literature review on the fate of antibiotics in the environment Huang et al. (2001) concluded that there  was little information on the sorption of aminoglycoside and β -lactam antibiotics. Because aminoglycosides can be proto-nated under acidic conditions, they could be sorbed to clay minerals under certain conditions, while β -lactams are highly polar compounds and would not be expected to sorb readily to soil components. Because of the strong sorption of the tet-racycline and macrolide antibiotics, their mobility in the envi-ronment may be facilitated by transport with manure and soil colloidal material (Kolz et al., 2005a). Interestingly, although most antibiotics do not require metal ion coordination to exert biological action, other compounds like bacitracin, streptoni-grin, bleomycin, and tetracycline have prerequisites for bind-ing of metals ions to function properly (Ming, 2003). Sorption of these drug compounds in clays, where intercalation of metal complexes occur, may provide suitable conditions for the drug to exert a biological effect. Table 3. Chemical properties and fate of selected veterinary antibiotics (modi󿬁ed from Beausse, 2004; Boxall et al., 2004; Tolls, 2001).AntibioticSolubility in waterLog K  ow Log K  oc K  d  pK  a  and chemical degradationMobility g/LL/kgLincomycin(hydrochloride salt)freelyND†NDNDpK  a  7.6In spiked soil 10 mg/kg undetectable after 11 wk and 80% lost after 7 wk Immobile especially in high organic matter/clay soil based on manufacturer column tests.Sulfathiazole0.6 0.052.304.9pK  a1  2, pK  a2  7.24Medium mobility based on K  d Sulfamethazine1.5 0.891.78–2.320.6–3.1pK  a1  2.65, pK  a2  7.65Biodegradable but persistent in water phaseHigh to medium based on K  d  Tylosin5 3.52.74–3.908.3–240pK  a  7.1Stable at pH 4 to 9, < pH 4 desmycosin is formed.Low to immobile based on K  d Virginiamycin0.054– 0.080 1.5–1.72.7–2.8NDT 1/2 : 87–173 d89% inactivated within 18 d and undetectable after 84 d.Activity decreases rapidly in water and increasing temperature. Degrades under alkaline pH. Immobile due to low water solubility, high lipophilicity and rapid inactivation in soil. Tetracycline1.7 –1.19ND >400–1620pK  a1 -3.30, pK  a2 -7.68, pK  a3 -9.69Immobile based on K  d Chlortetracycline0.6 –0.62ND282–2608T 1/2  in manure 1 wk at 37°C & > 20 d at 4° or 28°C85% of CTC added to soil was recovered.Immobile based on K  d Oxytetracycline1 –1.221.2–5.00.3–1030pK  a1  3.27, pK  a2  7.32, pK  a3  9.11Stable compared to CTCImmobile based on K  d Cipro󿬂oxacin30 0.44.78430pK  a1  5.9, pK  a2  8.89Immobile based on K  d Enro󿬂oxacin130 1.14.22–5.89260–6310pK  a1  6.27, pK  a2  8.3Immobile based on K  d Penicillin 4 1.87NDNDpK  a  2.79Unstable, rapidly degrades to penicilloic acid. T 1/2  < 7 dWeakly sorbed to soils† ND = not determined or not found in the literature reviewed.
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