There are few recent publications relating to the use of antibiotics on crops and those that do exist often cite review papers that refer to earlier sources. Literature that describes contemporary use of antibiotics on plants is usually confined to that of extension literature (https://extension.psu.edu/pear-disease-fire-blight), or reporting concerns over the development of antibiotic resistance in populations of plant pathogens (Sundin and Wang 2018; Farfán et al. 2014). Exceptions to this are two recent papers from China that provide some insights into antibiotics being recommended by extension services in the country (Zhang et al. 2017; Wan et al. 2019). These papers use information derived from plant clinics in China and suggest that antibiotics appear in between 2.5 and 4.5% of the recommendations.
The data generated through the Plantwise clinics is unique as it comes from ‘grassroots’ agricultural advisors, most of whom are employed by the ministries of agriculture. Unlike pesticide sales data, the information gives an insight into the knowledge of the agricultural advisors and what management options are routinely given to small scale farmers in low and middle-income countries (LMICs). The data-set is substantial, covering 32 countries and over 400,000 recommendations. Caution needs to be exercised when drawing conclusions about antibiotic use by farmers as the POMS database is of recommendations given to farmers and does not necessarily reflect the behaviour of the farmers. There has been no attempt in this study to assess what level of recommendations are enacted upon by the farmers, although previous studies in Plantwise suggest that rates of adoption of advice by farmers attending clinics, particularly of chemical control measures, are high (Silvestri et al. 2019). Despite this caveat, these data appear to indicate that the use of antibiotics in crop production is more extensive than most of the literature would suggest. Given the dearth of other sources of information, particularly from LMICs we believe that the Plantwise POMS database is an important resource in assessing the level of antibiotic use in countries where it is not monitored and regulations are either minimal or not enforced.
Extent of antibiotic use
Calculations of global antibiotic use in crops are based almost exclusively from data obtained from the USA against fire blight caused by Erwinia amylovora on apple and pear (Gusberti et al. 2015; McManus 2014; Vidaver 2002; McManus and Stockwell 2000). This literature suggests that the amount of antibiotics used for crops in the USA is relatively low, in comparison to the quantities used in livestock and aquaculture, with estimates ranging from 0.26% to 0.5% of total agricultural antibiotic consumption (McManus et al. 2002; McManus 2014). This has led authors to conclude that curtailing antibiotics use on crops would not lead to a major reduction in world use (FAO and WHO 2019a). However, the lack of surveillance programs, in many countries, combined with the lack of application records, frustrates any attempts to estimate the real amounts of antibiotics being applied. Where in-depth studies have been undertaken results may be surprising. In Costa Rica it has been suggested that the amounts of tetracycline and gentamicin used in on crops may be 200–700 times the quantities used in human medicine (Rodríguez Sánchez 2008).
Throughout this study the data is divided into the regions based on the WHO classification system and countries are not identified individually so as to protect national identity, whilst providing some insight into the use of antibiotics. Not only is there extreme variation between the regions, as seen from the results presented (Africa with no use at all and SEA with nearly 2.5% of all recommendations containing an antibiotic), but there is enormous variation in the amounts of antibiotics used by various countries within the regions; data not disclosed. The regional and national differences in antibiotic recommendations may be due to price, legislation, product availability, cropping regimes, agronomic advisors’ knowledge, or the nature of the pathogens that are problems. It can only be speculated as to which combination of these factors causes the differential in antibiotic use.
Sundin and Wang (2018) suggest that antibiotics are not more widely used because of the expense involved, but that does not appear to be the case as the bulk costs of tetracycline and streptomycin are available at $10 and $1 per kilo respectively, a similar price to copper oxychloride (Alibaba.com price correct as of 2019). However, it is interesting to note that within the data set there are no antibiotics recommended in the African countries.
Bacterial pathogens are present throughout the world and on all crops. Given the variety of crops and cropping systems used across the African continent it is considered unlikely that the types of pathogens encountered in Africa are sufficiently different from the remainder of the world. In many LMICs, including those in Africa, antibiotics are freely available through unregulated supply chains and over-the-counter sales. It is therefore unlikely that the discrepancy in antibiotic use in Africa as compared to other regions of the world is due to their unavailability. This would indicate that some other factor(s) are preventing (or limiting) antibiotic use in this region. In China, the use of antibiotics in crop production is higher than that recorded within our data (Zhang et al. 2017). Of the recommendations made by cooperative based extension workers 4.5% of them contained an antibiotic (Zhang et al. 2017). The use of antibiotics on crops in China is at least partially fuelled by government subsidies aimed at promoting their use (Zhang et al. 2017).
What crops are antibiotics being used on ?
Within the data, rice dominates the crops on which antibiotics are recommended and it is not possible to determine if that is due to the nature of the crop or the countries in which it is grown. The preponderance of antibiotic-containing recommendations on rice in SEA dominates the regional differences within the data. In SEA 7.4% of the recommendations for rice appeared to contain an antibiotic and, in some years, this was nearly 10%. When rice is removed from the calculations the proportion of recommendations containing an antibiotic in SEA was reduced to a much more modest 0.6%. The next greatest consumer of antibiotics are the Americas with 1.62% of all recommendations containing an antibiotic, despite no rice appearing in the POMS data. It would appear that for some reason antibiotic application on rice in SEA is prolific relative to other rice growing areas and other crops. However, research workers in one SEA country claim that the use of antibiotics on rice is relatively minor and is dwarfed by that used on ornamental crops for religious purposes. The residue of tetracycline was clear to see on a rose on a recent visit to the region by the lead author (Fig. 2).
Which antibiotics are being used?
The 18 tradenames of antibiotic products within the POMS dataset is only fraction of that available to treat crop diseases in many areas of the world (especially in the WP Region). Of the eleven antibiotics contained within the data, 6 of them (streptomycin, tetracycline, oxytetracycline, gentamicin, cefadroxil, amoxicillin) are considered to be critically important antimicrobials for human medicine as defined by the WHO (World Health Organisation 2019). The other antibiotics (oxolinic acid, kasugamycin, ningnanmycin, validamycin and aureofungin) are restricted to use in agricultural settings against bacterial, and in some cases, fungal diseases.
Regional differences
Our results confirm that of others, indicating that streptomycin is the most commonly used antibiotic on crop plants (McManus 2014; Zhang et al. 2017) with tetracycline and kasugamycin in second and third position. Interestingly, the antibiotic zhongshengmycin, does not appear in our data, despite it being the second most widely recommended antibiotic in Chinese plant clinics (over a quarter of antibiotic recommendations) (Zhang et al. 2017).
Kasugamycin was widely used in all regions, but the use of other antibiotics shows considerable regional variation with six of the 11 antibiotics only appearing in one region. Despite the large number of records from SEA, only 3 antibiotics form the bulk of the data (99%), namely kasugamycin, streptomycin and tetracycline. Almost all of the kasugamycin used in SEA was on rice (only 14% on non-rice crops) and yet kasugamycin was the antibiotic of choice in America (72% of all records containing an antibiotic), yet there are no records of rice being brought to clinics in the data from the Americas.
Other antibiotics show similar regional restrictions, for example oxolinic acid was used in the WP (35% of all antibiotic recommendations), but nowhere else, similarly in SEA 38% of recommendations contain tetracycline, yet this antibiotic only appears on three occasions outside of this region. Indeed, we speculate that records of “tetracycline” in areas outside of SEA are actually an abbreviation of “oxytetracycline”.
It is considered unlikely that the regional variation in antibiotics is due to their specificity against the bacterial diseases of the region. However, resistance to an antibiotic may be driving some of the differences, as farmers turn to alternatives when products become ineffective (Manulis et al. 1999; Goodman 1980). Alternatively, regional differences may be due to manufacturers initial selection, production facilities and marketing. The huge variation (orders of magnitude) in the use of antibiotics between similar countries that border each other (data not shown) is interesting in itself, but it also throws doubt on the legitimacy of extrapolating antibiotic use from one country to another (Van Boeckel et al. 2015).
What problems are the antibiotics being recommended against?
Antibiotics are generally used against bacterial pathogens in both medical and veterinary settings. Based on the written diagnosis about 60% of the diagnoses were against a named bacterium or a bacterial disease (64% when based on checkboxes). It is reasonable to assume that in most of these cases the application of antibiotics would have been beneficial to the health of the crop, but in 6% of the cases, where the diagnosis was “bacterial wilt”, a spray antibiotic treatment would not have had any effect.
The second largest category of organisms where antibiotics were recommended was against insects and/or mites 12% (18% when based on checkboxes). This is surprising as antibiotics have no activity against arthropods. The use of antibiotics against insects and mites is particularly prevalent in SEA, which accounted for over 90% of antibiotic recommendations against this group. In addition to antibacterial effects some antibiotics including, streptomycin, kasugamycin, aureofungin, ningnanmycin, oxolinic acid and validamycin have activity against other pathogen groups including fungi (Vallad et al. 2010; Lee et al. 2005), water moulds (Tso and Jeffrey 1956) and viruses (Han et al. 2014).
Antibiotics were recommended for managing fungal problems in all four regions, however the practice was most prevalent in the EM and SEA regions where 33% and 17% of records containing an antibiotic were against fungal targets respectively. It is not possible to determine to what extent agricultural advisors are aware of the antifungal activity of some of the antibiotics, but there is evidence from the data to suggest awareness for at least some pathogen/crop combinations. An example of this was the use of aureofungin for Ganoderma (fungal pathogen) control in coconut. This antibiotic has antifungal activity and is an established management practice for this disease (Kandan et al. 2010). In SEA all but two of the records featuring aureofungin were for Ganoderma management.
Kasugamycin is an agricultural antibiotic originally developed for use in rice with action against the fungal disease, rice blast (Mangnaporthe oryzae). In SEA, when kasugamycin was recommended against a fungal problem it was almost exclusively against rice blast, whereas this antibiotic was not recommended against fungal diseases of rice in any other region. Streptomycin and tetracycline were also recommended against rice blast in SEA despite them having no effect on this disease, perhaps pointing to a misunderstanding of the properties of these two antibiotics.
It is a common misconception in human medicine that antibiotics can kill viruses (Jordan 2014), but that does not appear to translate into recommendations that relate to crop production. Based on checkboxes, 4.4% of all records in the entire data set (not just those for which an antibiotic has been recommended) are solely for a viral disease, whereas of the records that feature an antibiotic in the recommendation only 0.54% are deemed to be caused by a virus. Interestingly the antibiotic ningnanmycin has, in experimental studies, demonstrated some antiviral activity (Han et al. 2014). However, in our data ningnanmycin was restricted to relatively few records in the SEA region and none of these were against viral problems. It is clear that in some cases antibiotics are being used effectively against non-bacterial targets however, their profligate use could lead to the conclusion that agricultural advisors are unaware of their limited spectrum of activity. However, it was observed that in many cases, especially in SEA, the recommendations were identical regardless of the diagnosis. We speculate that the agricultural advisors in SEA routinely combine an insecticide with a fungicide and an antibiotic in a single application so as to deal with the current issue and to prevent/control other problems not yet present or residing at a low level.
Stage of development severity and area treated with antibiotics
The focus of the Plantwise programme is to assist the advisors of smallholder farmers and this was indeed the case as the plot size to which the recommendations refer had a median size of 0.6 Ha. The mean area is not quoted as it is potentially misleading due to what appear to be misplaced decimal points on the plantwise forms. Antibiotics are applied to crops midway through their production as the vast majority of antibiotic applications were on crops that were in the “intermediate” stage of growth and were applied to the “leaves” of the plants. Less than 5% of the records related to treatment of seedlings. Interestingly there were five records recommending post-harvest application of antibiotics which obviously raises concerns over residues levels for consumers. When considering the severity of attack, 96% of the records indicated that the diagnosed problem was affecting a quarter or less of the crop stand indicating that antibiotics are used before the problem has become widely established.
Doses of antibiotic
The concentration of antibiotic applied and the actual dose received by the leaves depends on the amount of water used to dilute the concentrate, as run-off will soon be reached if the crop were young, or if the volume of spray were too high. However, this would not affect the total amount of antibiotic being sprayed into the environment. To estimate the amount of antibiotics being applied it is useful to pick a crop and region and examine in more detail how much product is applied. In the SEA region 7.4% of all recommendations on rice contained an antibiotic. Plantomycin (the most widely recommended antibiotic in the region) is a mixture of streptomycin and tetracycline. For the basis of this calculation it was assumed that the recommended rate was applied to 7.4% of the entire rice growing area of the region (estimated to be in excess of 75 million Ha (http://ricestat.irri.org:8080/wrsv3/entrypoint.htm). If this were the case then a single application would represent over 63 tonnes of streptomycin and 7 tonnes of tetracycline. This may well be an underestimate as the manufacturers recommended dose is frequently doubled by the agricultural advisors.
These data are just a small snapshot of chemical applications, and these amounts are relatively small compared to the livestock sector, but nevertheless significant especially when their environmental fate is considered.
What other control methods are used against bacterial plant pathogens?
Unlike the vast arsenal of chemicals active against fungi and water moulds (85 in the entire dataset) there are relatively few chemicals represented that are effective in reducing bacterial diseases. Some fungicides such as Mancozeb have limited action against bacterial diseases and there are specialist bactericidal compounds such as Bronopol and Bismerthiazol, but based on our data these are not widely used. Bismerthiazol is often blended with antibiotics, indeed there are 6 products commercially available in Vietnam which comprise Bismerthiazol blended with antibiotics (Noghiệp bộ nông và phát triển nông thôn [Ministry of Agricultural Development] 2016).
Our data would suggest that by far the most widely used chemical against bacterial diseases are copper salts. In the entire data set over 13% of records that have the “Bacterial” checkbox ticked have the word “copper” in the recommendation. This however, is a considerable underestimate of copper-based products as many are recommended by trade name only, or as “Bordeaux mixture”. The proportion of records that contain an antibiotic and the word “copper” is 21% (again an underestimate). It is common for copper salts to be preblended with antibiotics and in Vietnam alone there are over 9 products (not represented in the POMS dataset) that are antibacterial chemicals comprising a blend of antibiotics and copper salts (Noghiệp bộ nông và phát triển nông thôn [Ministry of Agricultural Development] 2016).
Copper salts are a very widely used active ingredient, popular with agricultural advisors as they are commonly available and active against fungal, water mould and bacterial diseases. These antimicrobial properties make it a popular choice amongst agricultural advisors, especially if they are unable to make a definitive diagnosis, as a copper containing product will have a beneficial effect against all these classes of pathogen.
Spread of antibiotic resistance to animal and human pathogens
There is great concern over the use of antibiotics in agriculture due to the potential for resistance to spread to medically important bacteria. Most of the concern has been based around the use of antibiotics in animal husbandry and the use within crop production has largely not been commented upon, possibly because the use is thought to be very low in comparison to the quantities used in livestock, or because the medical community were unaware of their use in this regard. The regulations pertaining to antibiotic use on plants differs widely between countries and regions. The European Union and Brazil do not approve any antibiotics as active ingredients in pesticides (Donley 2019), whereas some countries permit their use for certain crops or in emergency situations, others have no legislation on this topic at all. Moreover, many countries of SEA and WP, consider the use of antibiotics in crop production as an important means of controlling pathogens whilst at the same time protecting the environment.
It is only recently that international bodies such as FAO and WHO have started to raise concerns over the use of antibiotics in the management of crop diseases. In a recent joint meeting on pesticide management, a recommendation was made that antibiotics used for human and animal health should not be registered as pesticides (FAO and WHO 2019b). These concerns relate to antibiotic use creating selection pressure in a cropping environment that accelerates the spread of antibiotic resistance from soil bacteria to human pathogens. However, the full extent to which antibiotic use in these systems accelerates the emergence of antibiotic resistance in zoonotic pathogens present on crops is yet to be determined (FAO and WHO 2019c).
There is however good evidence to suggest that crops (especially those eaten raw) are a potential vehicle for resistant bacteria to enter the human gut (Boehme et al. 2004; Hassan et al. 2011; Raphael et al. 2011; Rodríguez et al. 2006; Ruimy et al. 2010; Schwaiger et al. 2011; Walia et al. 2013). Some authors even suggest that these resistant bacteria could be a source of genetic material for lateral gene transfer subsequent to ingestion, giving rise to antibiotic resistant pathogens in the gut (Bezanson et al. 2008).
One unique aspect of antibiotic use on crops is that they are routinely mixed with other agrochemicals. This use has led to concerns over interactions that might promote cross-resistance or co-selection for antibiotic resistance. One study demonstrated that bacteria develop antibiotic resistance up to 100,000 times faster when exposed to certain herbicides/antibiotic mixtures relative to exposure to antibiotics alone (Kurenbach et al. 2018). Preblended, or on-farm blends of antibiotics and copper salts similarly give cause for concern as soil bacterial communities from soil contaminated with copper have been reported to be significantly more tolerant to vancomycin and tetracycline than control soil bacterial communities (Pal et al. 2015). Additionally, bacteria harbouring genes conferring resistance to certain metal ions including copper are significantly more likely to also have genes for antibiotic resistance as compared to bacteria without metal resistance genes (Pal et al. 2015). Thus, despite the relatively low amounts of antibiotics used in crop production their use in combination with other plant production products represent a potentially important risk factor for selection and dissemination of resistant microorganisms and genes from plants to humans and animals.
This said, those who advocate the use of antibiotics to control plant diseases point out that there is no proven evidence of resistance having spread from plant pathogenic bacteria to human or animal pathogens despite over 50 years of continual use. Indeed one study reports that the proportion of antibiotic resistant bacteria was greater in an orchard that had not been sprayed with antibiotics as compared to one that had received regular antibiotic sprays (Yashiro and McManus 2012).