SUMMARY
Anthelmintic Resistance (RA) in ruminant nematodes is a serious sanitary-productive problem throughout the north-central area of Argentina. The use of anthelmintics has allowed a significant increase in ruminant productivity, but it is exerting severe selection pressure on the parasite genome. The prevalence is particularly high in nematodes of small ruminants where even cases of simultaneous resistance to two or more anthelmintics (imidazothiazoles, benzimidazoles, macroicyclic lactones and closantel) have been repeatedly reported. In bovine nematodes, a rapid increase in AR is also being observed, although documented cases of multiple resistance to broad-spectrum anthelmintics are not so numerous to date and imidazothiazoles are still active. It is obvious that in sheep, goats and cattle, the current control practices based exclusively on this input technology are no longer sustainable. Alternatives are required for the management of resistant populations and future control programs that maintain animal productivity, but at the same time exert less selection pressure on parasites. In this context, early diagnosis, refuge populations current control practices based solely on this input technology are no longer sustainable. Alternatives are required for the management of resistant populations and future control programs that maintain animal productivity, but at the same time exert less selection pressure on parasites. In this context, early diagnosis, refuge populations current control practices based solely on this input technology are no longer sustainable. Alternatives are required for the management of resistant populations and future control programs that maintain animal productivity, but at the same time exert less selection pressure on parasites. In this context, early diagnosis, refuge populations, the possibility of carrying out selective and not massive treatments, the exclusive use of anthelmintics under professional prescription and the eventual use of drug combinations are discussed in this review, attempting a holistic view of the problem.
Keywords: Small ruminants; cattle; Argentina; Anthelmintic resistance.
ABSTRACT
Anthelmintic resistance (AR) in nematodes of ruminants is a serious productive and health problem in the northern and central areas of Argentina. The use of anthelmintics has led not only to a significant increase in ruminant productivity but also a severe selection pressure on the parasite genome. Parasite resistance is particularly high in nematodes of small ruminants. Simultaneous resistance to two or more anthelmintics (imidazothiazoles, benzimidazoles, closantel and macrociclic lactones) has been repeatedly reported. In cattle nematodes exist also a rapid increase in AR, although documented cases of multiple resistance to broad-spectrum anthelmintics so far are not as numerous and imidazothiazoles still remain active. It is obvious that for sheep, goats and cattle, current management practices based solely on anthelmintics are no longer sustainable. Alternatives are required for the management of resistant populations and future monitoring programs to maintain animal productivity but also exert less selection pressure on parasites. Early diagnosis, populations in refuge, the possibility of selective and non-mass treatment, the exclusive use of anthelmintics under prescription and the eventual use of combinations of drugs are discussed in this review attempting a holistic view of the problem.
Keywords: Small ruminants; Cattle; Argentina; Anthelmintic resistance.
Introduction
Gastrointestinal nematodes constitute serious limitations for the health, productivity and well-being of all domestic herbivores and their control depends almost exclusively on the administration of anthelmintic drugs. In our country ,As in most of the world, for the past 30 years anthelmintics have been very efficient and safe production inputs. However, the development of nematodes resistant to these drugs is becoming a serious threat by making it difficult to reduce the costs inherent in parasitism control. Anthelmintic Resistance (AR) is basically defined as the decreased efficacy of an anthelmintic against parasite populations that are normally susceptible to it at a given dose (Sangster and Gill, 1999). This may be the consequence of a genetic modification or of an increase in the frequency of expression of a hereditary character, but in both cases the nematodes that survive the treatment will transmit these resistant alleles to their progeny.
In Argentina, the prevalence of AR is particularly high in small ruminant nematodes, but it is also seriously increasing in cattle and horses (Anziani, 2013). In this context, a redefinition of parasite control and the use of available drugs is required. The objectives of this review are: 1) to update the knowledge about the prevalence of this phenomenon in domestic herbivores in our country and 2) to review and discuss strategies for the management of AR or to delay its development, prioritizing control alternatives that can be sustainable without affecting animal health and productivity.
General considerations on anthelmintics in different ruminants
In Argentina there are three chemical groups registered by the National Agrifood Health and Quality Service (SENASA) as broad-spectrum nematodicides for cattle: benzimidazoles (the best known: albendazole, fenbendazole, oxibendazole, ricobendazole), imidazothiazoles (levamisole) and the macrocyclic lactones with the avermectins (ivermectin, abamectin, doramectin and eprinomectin) and the milbemycins (moxidectin). According to the Argentine Chamber of Veterinary Products (CAPROVE), this last group constitutes 84% of the doses of anthelmintics marketed annually in our country for this species (some 135 million doses) and within it the specific participation of ivermectin represents a similar percentage. In sheep, in addition to the three aforementioned groups,et al. , 2011). For both ruminant species, narrow-spectrum nematodicides ( Haemonchus spp.) are also available, such as the group of salicinalides (closantel as the best known, as well as nitroxinil and rafoxanide).
The use of anthelmintics in goats deserves special consideration since in most countries there are very few registered drugs that include the indication for use in this species. In Argentina, for example, the wide-spectrum anthelmintics registered in bovines exceed one hundred commercial formulations, while for goats they do not exceed half a dozen. Currently, only some benzimidazoles (mainly fenbendazole) and levamisole are commercially available and specifically indicated for goats by SENASA. Despite this, avermectins (and especially ivermectin) appear as the most used drugs in goat herds, as shown by some preliminary work carried out in the central area of our country (Anzianiet al. , 2009, Rossanigo, personal communication). This paradox increases the irregularity in the use of these inputs, since the use of unregistered products for an animal species should be exceptional and subject to strict professional supervision (SENASA Resolution No. 48/2013), which is not the case. in goat production characterized by a low level of veterinary assistance.
Another situation that requires attention and correction is the dosage of anthelmintics in goats, since in general they are used from the recommended doses for sheep and cattle. However, it is well demonstrated that in goats the absorption of anthelmintics is lower than in other ruminants and that they are also metabolized and eliminated more quickly (Lespineet al. , 2012). This lack of knowledge has led to underdosing in goats for years, which could have favored the development of anthelmintic resistance, especially in strains of nematodes with multiple resistance (Zajac and Gipson, 2000). The situation is not yet contemplated by the veterinary pharmaceutical industry which, at least in our country and in the few registered products, continues to advise the use of the same doses in sheep and goats (Anziani et al .., 2010). In general, except for lactating goats, the doses of ivermectins and benzimidazoles should be twice the ovine dose and, in the case of levamisoles (due to their lower safety margin), not exceed 1.5 times the same. Regardless of the ruminant species involved, the strict regulations and costs associated with drug development make it unlikely that new anthelmintics for food-producing animals will emerge in the near future in the same way that they have in the past (Kaplan, 2004). ; von Samson-Himmenelstjerna and Blackhall, 2005). For example, In cattle, the last chemical group introduced in Argentina were the macrocyclic lactones (with ivermectin as the best known) in 1981 and since then no drugs with new modes of action have been incorporated for this species. Assuming that other technologies have not succeeded in substituting chemical control, the rational use of currently available drugs is essential to maintain their efficacy and useful life.
Development of resistance: treatments, selection pressure and refuge populations
The selection pressure exerted by an anthelmintic drug strongly depends on the way it is used in the field. In addition to the massive and frequent use, another form of selection pressure is the application of anthelmintics when the chances of reinfection are low (minimum refuge). The nematode populations that are not reached by the anthelmintics when the treatments are carried out are called refuge (Van Wyk, 2001). The refuge is mainly the eggs and larval stages found in fecal matter and pastures and nematodes found in animals that are not treated. This refuge subpopulation represents a reservoir of susceptible parasites that can reproduce with resistant nematodes that survive treatment. Thus,
Refuge conservation is currently considered the most important factor in reducing selection pressure and resistance development (Van Wyk, 2001), demonstrated both in field studies (Martin et al., 1981; Waghorn et al . , 2008), as well as in simulated models (Dobson et al. , 2011; Leathwick, 2012). Although this information has only been obtained in sheep, there is a consensus in considering shelter as the key factor in delaying anthelmintic resistance in nematodes of other domestic herbivores such as horses (McArthur and Reinemeyer, 2014; Nielsen et al ., 2014). In cattle in our country, recent field evidence points to the importance of selection pressure exerted through frequent antiparasitic treatments under reduced refuge conditions on the development of resistance in cattle. Thus, in the north of the province of Santa Fe, five massive treatments every 35 days with long-acting ivermectin for the eradication of Riphicephalus microplus ( Boophilus ) at times when the populations of nematodes in the pastures were low (August-January 2013). resulted in the rapid loss of susceptibility of the genus Cooperia to the drug (Anziani et al. , 2014).
Although the size of the refuge is very important in the development of anthelmintic resistance, the final impact on it can be modified by numerous factors. Climatic conditions regulate the development and survival of the preparasitic or free-living stages and, therefore, determine the magnitude of the refuge available. This information is critical for the rational management of resistance, but unfortunately in Argentina and in the case of bovines, most of the solid studies on the dynamics and environmental modifications that can affect these stages are over a decade old or are circumscribed. to the provinces of Buenos Aires (Steffan and Fiel, 1986; Fiel et al., 2012), La Pampa (Suarez and Lorenzo, 2000, Suarez, 2001), San Luis (Rossanigo, 1999) and southern Córdoba (Download 2001). For the other species of herbivores, knowledge is even more fragmentary. In the opinion of the authors of this paper, it is imperative to resume these bioecology studies and obtain similar information in areas such as the NEA and NOA, if a change of scenery in parasite control is sought based more on knowledge than on new inputs.
Diagnosis of anthelmintic resistance
The methods for the detection of AR have been recently reviewed in ruminants of our country by a group of parasitologists from different universities and from INTA, for which reason, on this specific subject, it is suggested that said work be consulted (Carcostantógolo et al . , 2013). Briefly, it should be noted that the in vivo methods are currently considered the reference or gold standard.for the diagnosis of RA. These methods determine, by necropsy of the treated animals, the number of adult nematodes that survive the treatment (controlled efficacy test) or, failing that, the egg laying by the females of the surviving nematodes through a reduction test in egg count (TRCH). The TRCH compares the number of eggs per gram of feces (epg) before and after treatment, it does not require the sacrifice of the hosts and it is the most widespread worldwide since it can be used in different species of herbivores and is safe. to determine susceptibility or resistance to all types of anthelmintics under field conditions. In general it is assumed that reductions of less than 90 or 95% (depending on the herbivore, anthelmintic,et al ., 1992). In addition, in vitro
diagnostic alternatives are being evaluated through the effects of anthelmintics on the development or mobility of different stages of the nematodes but, up to now, their use has been limited to experimental work and greater standardization of their methods is necessary. the same for its massive use. There are also methods that use molecular markers, which generally present greater sensitivity than in vivo methods to detect resistant nematodes, especially when these phenomena are emerging (Hoglund et al. , 2009; Guzman et al.., 2011). However, currently these methods cannot quantify or indicate the magnitude of the phenomenon and therefore the correlation between the detection of resistance and the efficacy of a certain drug is difficult to establish. For example, and for a certain establishment, it does not seem to make sense to stop using an anthelmintic that shows reductions in egg laying close to 100% even though the molecular markers indicate the presence of resistance. (Kaplan and Vidyashankar, 2012).
Current status of resistance to anthelmintics in sheep nematodes
In the nematodes that parasitize this species, RA is widespread throughout the center-north of Argentina . A national study carried out a decade ago (Caracostantogolo et al. , 2005) indicated that more than 60% of the flocks had populations of nematodes with resistance to any of the available anthelmintics (avermectins, benzimidazole, levamisoles and closantel). The biggest problem is observed in the NEA and especially in the province of Corrientes, in which AR has increased dramatically since the first studies carried out by Romero et al.. (1998) until the aforementioned national study of 2005, in which all the establishments studied in this province (n=9) had nematodes resistant to ivermectin and benzimidazoles ( table 1 ) while 55% also had resistance to levamisole already closantel. The genera involved were Haemonchus, Teladorsagia and Trichostrongylus for ivermectin, benzimidazoles and levamisole, and Haemonchus for closantel (Caracostantogolo et al. , 2005; Romero et al. , 2007). The development of resistance continued to increase in this region and in the period 2010-2011; closantel showed efficacy in only 20% of populations ofHaemonchus studied (Romero et al. , 2013).
Table 1. Prevalence of AR in Argentine sheep in 2006. Egg count reduction test. (adapted from Caracostantógolo et al. , 2005; Cristel 2006)
*establishments with nematodes carrying multiple resistance
Currently, and of particular concern, is the increase and spread of isolates with resistance to various anthelmintics. Thus, for example, isolates of Haemonchus contortus (the most economically important nematode in small ruminants) with multiple resistance to two, three and four drugs with different modes of action have been reported in sheep, not only in the NEA (Romero et al . . , 2007) but also in provinces of the central area of Argentina such as Buenos Aires (Entrocasso et al., 2008; Steffan et al., 2011) and Santa Fe (Anziani and Muchiut, 2014). Currently, the only broad-spectrum anthelmintic with which RA has not been documented in our country is monepantel, a new drug introduced into the Argentine veterinary market in 2011 for use in sheep. However, there are also concerns about the future of this new anthelmintic as cases of resistance have recently been reported in New Zealand and Australia, after only four years of use of the drug in these countries (Scott et al., 2013 ; Love , 2014 a).
Current status of resistance to anthelmintics in nematodes of South American goats and camelids
In general, goats are the ruminants most susceptible to parasitism by gastrointestinal nematodes and also to the rapid development of RA phenomena, but in our country the knowledge about this phenomenon is more fragmentary than that reported in sheep and cattle. As in sheep, the Haemonchus genus appears as the most prevalent and economically important for goats, at least for central and northwestern Argentina (Anziani et al. , 2009; Aguirre and Cafrune, 2013). The first documented works on RA in goat nematodes were carried out in dairy goats from the provinces of Buenos Aires and Salta (Fiel et al ., 2000; Aguirre et al.., 2000). In the first of them, resistance of Haemonchus contortus and Trichostrongylus colubriformis to fenbendazole was reported . Subsequently, the resistance of both genera to ivermectin was reported, highlighting the earlier appearance in goats than in sheep in the same establishment, using a similar frequency of treatments in both species (Romero et al., 2001 ) . Between 2007 and 2009, evaluations in the center-north of Córdoba to determine the prevalence of anthelmintic resistance in 16 herds in the region indicated that more than 60% and 80% of the establishments showed ineffectiveness of fenbendazole and the ivermectin respectively to control Haemonchus (table 2 ). The multiple resistance of this genus towards both drugs was observed in more than 60% of the herds and total inefficacy (0% in TRCH) in approximately 20% of them (Anziani et al., 2009 ) . Information on multiple resistance of another common genus in goats, such as Trichostrongylus, was also observed with ivermectin, ricobendazole and levamisole in the province of Salta (Aguirre et al. , 2005). In this last province, an isolate of Trichostrongylus with resistance to moxidectin in dairy goats from the Lerma Valley was recently reported (Suarez et al. , 2013).
Table 2. Prevalence of AR in goats from the center-north of Córdoba. Egg count reduction test. (Adapted from Anziani et al. , 2009)
An interesting observation with this last drug is that, as observed in sheep, in goats it is common for moxidectin to be effective against Haemonchus with marked resistance to ivermectin (Anziani et al. , 2008). Although both drugs belong to the macrocyclic lactones and present a certain degree of cross-resistance, the mechanisms for the development of resistance are not identical (Prichard et al. , 2012) and compared to certain genera, moxidectin at the same dose may present a greater resistance. relative potency than ivermectin (Lanusse et al. , 2013). However, there is plenty of evidence that this increased efficacy may only be temporary (Kaplan 2004; Kaplanet al. , 2007). In South American camelids, there is a suspicion of resistance to ivermectin by the nematode Lamanema chavezi , a specific parasite of these ruminants (Aguirre and Cafrune 2013). Failures of ivermectin administered in 1 or 3.15% formulations to control nematodes of the Trichostrongylidae family parasitizing South American camelids have also been recently reported (Anziani, 2013). The genus involved was Haemonchus,probably acquired by grazing these animals on pastures previously used by a goat herd with a history of severe resistance to avermectins. The recognized pathogenicity of both nematodes, the widespread use of ivermectin and the absence of specific dosages for these ruminants call for additional studies to confirm these efficacy failures as well as their potential spread.
Current status of resistance to anthelmintics in bovine nematodes
The first findings of resistant bovine nematodes were reported almost simultaneously during the second semester of 2000 in the provinces of Santa Fe and Buenos Aires (Anziani et al ., 2001; Fiel et al ., 2001 a). On both occasions, the antiparasitics belonged to the avermectin family (ivermectin and doramectin) and the genus involved was Cooperia with the species C. pectinata and C. oncophora .in the first and second cases, respectively. Since then, new cases of resistance of this genus to avermectins have been observed in the provinces of Buenos Aires, Entre Ríos, Santa Fe, Córdoba, and La Pampa (Anziani and Fiel, 2004). Information obtained in the provinces of Córdoba (Mejía et al ., 2003) and Santa Fe (Anziani et al ., 2004) broadened the spectrum of Cooperia ‘s resistance to oral and injectable benzimidazoles. Unfortunately, other genera of more pathogenic nematodes such as Haemonchus , (Fiel et al. , 2004; Anziani et al. , 2004) and Ostertagia have also developed resistance.(Suarez and Cristel, 2007; Descarga, C. personal communication). Currently, multiple resistance does not seem to be as widespread as in small ruminants, although isolates of H. placei and H. contortus with multiple RA to avermectins and to benzimidazoles (Fiel et al. , 2004; Anziani et al. , 2004). The aforementioned 2005 national study (point 4) showed that of 69 bovine herds, 60% had failures to control nematodes using avermectins or benzimidazoles (Caracostantógolo et al .., 2005) and circumstantial evidence would indicate that currently this percentage may be even higher. A synthesis of the genera and species of nematodes parasitizing cattle that currently show RA and recovered by necropsy (controlled efficacy test) is presented in table 3 .
Table 3. Genera and species of AR nematodes observed in bovine necropsies in Argentina. Controlled efficacy test. (Adapted from Fiel et al. , 2009; Fiel and Stefan, 2012)
Until now, no cases of resistance of bovine gastrointestinal nematodes to levamisoles have been documented for our country. In the future, and especially due to its potency against Cooperia spp ., this drug should play an important role in chemical control in the central area of Argentina where this genus is prevalent during most of the year. However, due to its lower efficacy against Ostertagia spp., in those areas where this genus can potentially become more important, such as: Buenos Aires, La Pampa, southern Santa Fe and Córdoba, its use in rotation or with other drugs of greater activity would seem to be advisable.
Economic impact of resistance
In the production of ruminants in our country, with the exception of some herds or bovine wintering, live weight determinations are not systematically carried out to measure productive performance and in this context the costs of parasitism by nematodes and the consequences of using ineffective anthelmintics due to RA. Thus, producers continue to use antiparasitics that are ineffective, generating subclinical losses in most of them and favoring the dissemination of resistant genes. In general, clinical losses are observed when abomasal genera such as Haemonchus and Ostertagia are involved.with mortality and severe signs of gastrointestinal dysfunction as has been demonstrated in wintering establishments in the central area of Argentina (Anziani et al. , 2004; Fiel et al. , 2005). Likewise, in some intestinal genera of less relative pathogenicity such as Cooperia , AR allows the accumulation of large populations that end up also causing mortality and severe clinical symptoms (Download, 2013). However, the use of ineffective treatments for the control of resistant intestinal genera such as Cooperia spp ., results mostly in subclinical forms that can compromise consumption, growth and time to finish in bovines. In studies that involved more than 1,800 heifers in feedlots, Reinhardt et al. (2006) in the USA demonstrated that poor control of ivermectin or doramectin on Cooperia spp . (and to a lesser extent Trichostrongylusspp.) resulted in significant decreases in consumption, daily weight gain and final carcass weight. In Argentina, the available information on the productive impact of AR by nematodes in beef cattle has recently been described in grazing systems and in penning. Thus, for example, in cattle under situations of continuous reinfection such as those produced by direct grazing, resistance to ivermectin due to mixed infections of nematodes can decrease daily weight gain by up to 50% for a period of 90 days of grazing (Fiel et al. , 2011). In systems where reinfections do not occur, such as typical feedlots, the ineffectiveness of ivermectin to control Cooperiaspp . can result in 9.3% decreases in daily weight gain for 75 days after confinement of calves caused by nematodes surviving the entry treatment (Fazzio et al., 2011 ). The economic impact of anthelmintic resistance can be calculated, not only by live weight but also by a perhaps more relevant measure such as the value of the carcass in the refrigerator. Sutherland et al. (2010) reported that in sheep the reduction in carcass weight expressed as a percentage may be a more sensitive, reliable and easily internationally extrapolated indicator of the effects of RA.
Finally, there is an indirect economic impact as a result of using ineffective anthelmintics. Although it is recognized by veterinarians and professional advisers that the development of resistance is driven by the use of anthelmintics without prior diagnosis and separated from epidemiological information, this trend of use continues en masse. It even seems to exist a vicious circle in which the increase in the frequency of treatments or the concentrations and doses of some drugs (such as ivermectin) tries to be a practical response to the problem. As a corollary, the presence of residues of these drugs is acquiring extreme economic importance, as shown by the recently observed reduction in the export of thermo-processed meat from our country to the United States. as a result of the detection of ivermectin residues in shipments to that destination (Iriarte, I., “The reconversion of the export industry” La Voz del Interior, June 8, 2012). In this context, in May 2014, the health authorities of Brazil, the world’s largest beef exporter, in an attempt to reduce these problems, have prohibited the production, import, sale and use of all drugs considered as lactones. long-acting macrocyclics (Aba, 2014).
How to prevent, delay and manage resistance problems
The importance of early diagnosis
Currently, and given the prevalence of RA in our country, it is practically impossible to assume that treatment with any of the available drugs is effective in eliminating gastrointestinal nematodes. Because chemical control remains irreplaceable in terms of efficacy and practicality, each facility should first monitor the need for the treatment and then the efficacy of the treatment through routine stool testing (fpg). This information is basic to limit the negative impact on productivity, health and animal welfare and constitutes the first step for the rational use of anthelmintics (Fiel et al., 2001). Unfortunately, carrying out coproparasitological analysis is a practice that is rarely adopted in our country, so that most livestock establishments continue with empirical control practices without the support of parasitological diagnosis (Fiel and Steffan, 2012). In the last decade, conferences, workshops and other extension activities with producers and advisers from all over the country have intensified, promoted by official organizations (universities and INTA), among which the sustainable parasite control program (CPS) based on in the importance of laboratory support and integrated control practices (Fiel and Steffan, unpublished). So far, more than 1,700 veterinarians and 1. 400 producers as well as 48 veterinary diagnostic laboratories in Argentina. However, and like other livestock countries such as Australia (Love, 2014 b), the development and expansion of AR does not seem to have driven a significant increase in the number of establishments that routinely use epg tests for intake. decision-making (parasitological monitoring) and to evaluate the efficacy of anthelmintics (TRCH). Coproparasitological analyzes are far from being sophisticated or expensive and allow the control of subclinical parasitosis; while the TRCH can be implemented without modifying the usual management of the establishment and act as a screening test for efficacy after treatment. Suspicions of ineffectiveness can be identified and confirmed later with more demanding protocols if necessary, allowing the producer to quickly change drugs and avoid possible production losses. In fact, the information, based on such simple parasitological techniques, has been the basis of early diagnostic investigation of these resistance phenomena at the regional and global level, favoring the rational and sustainable use of anthelmintics.
selective treatments
The RA requires a profound reformulation of the current control programs as well as new recommendations if a balance between sustainability and productivity is to be maintained. The new strategies should allow (and favor) a certain level of parasites in refuge through less intensive and massive treatments (van Wyk, 2006; Stafford et al ., 2009; Greer et al., 2010). One of the most promising strategies is that of Selective Treatments (TS) which is based on the principle of selecting individuals within the animal group and leaving the rest without treatment. This very simple principle is in contrast to current mass treatments and the biggest advantage of these TS is that all animals likely to benefit from anthelmintics are included and those least likely to benefit are excluded. The rationale is that nematodes in herbivores follow the negative binomial distribution with the minority of the latter supporting the greatest number of parasites or suffering the greatest productive impact (Morgan et al., 2005; Kenyon et al .., 2009). From a theoretical perspective, TS could target only 20 or 30% of the animals that constitute the main risk group, decreasing the use of anthelmintics, minimizing the selection pressure on the parasite genome and preserving the useful life of the parasites. drugs.
An example of these TS in small ruminants is the control of Haemonchus contortus, the most pathogenic nematode for small ruminants and whose main characteristic is hematophagy. The system known as FAMACHA and based on the clinical evaluation of the conjunctival mucosa as an indicator of the levels of anemia caused by parasites, allows the identification of individuals who require treatment and has been reported in countries such as South Africa, the USA and Brazil (van Wyk and Bath, 2002; Kaplan et al ., 2004; Molento et al ., 2004). The method presents an interesting potential for use for small and medium-sized producers in north-central Argentina (Suarez et al. , 2014; Rossanigo et al ., 2014) where HaemonchusIt is the predominant genus in sheep and goats, but it has limitations with respect to other parasitic genera that do not cause blood loss, such as Trichostrongylus or Teladorsagia.
In cattle, a TS regimen based on animal performance (body condition, milk production or weight gain) could be a relatively reliable indicator of the need to treat only certain animals, decreasing the use of anthelmintics and allowing time, the presence of parasite populations in refuge without compromising animal productivity. Periodic measurements of weight gain seem to adapt well to these selective treatments and in grazing systems it can be an indicator to identify animals that may benefit from treatments (Greer et al ., 2010; Hoglund et al., 2009). In an experience carried out at the EEA INTA Rafaela with calves of dairy biotypes, comparing weight gain during seven months in suppressive treatments (sentinel animals) or under TS, the use of anthelmintics was reduced by 40% without a negative impact on animal productivity ( 2012-EEA INTA Rafaela, unpublished data) and more than 50% of the animals required a single treatment during this period. On the one hand, in this preliminary study, no associations were observed between the weight gain of each calf and the number of eggs eliminated in its feces, in line with what was reported by other authors (Hoglund et al., 2009; Greer et al .., 2010) emphasizing for bovines the difficulty of using this parameter in the individual prediction of the productive impact and in contrast to other works carried out in our country with dairy cows (Mejia et al .., 2011). On the other hand, TS based on periodic weight determinations imply a significant amount of time (and manpower) and alternatives are necessary for their simplification. For certain productive conditions, automatic weighing systems and electronic identification of bovines could offer greater practicality and in the near future comparisons and decisions could be made “up the sleeve” to determine which animals need treatment and which do not. Regardless of the practicality of implementation, these TS need to be validated and consistent information is required in different regions, categories, biotypes, productive and environmental conditions before they can be recommended in national bovine production.
The possibility of recovery of anthelmintic efficacy (reversal of resistance)
There is a consensus to consider that once AR is established, the abandonment of the application of a certain chemical group does not result in the recovery of susceptibility status to it (Leathwick, 2013). This condition augurs a compromised future due to the scarcity of available therapeutic resources, the low probability of new developments and the fact that the development of “clean” alternatives is advancing slowly in the process of complementing/replacing the current chemical control (Steffan et al . , 2012). In this context, work has recently begun in our country aimed at recovering the efficacy of active principles strongly compromised by anthelmintic resistance, especially Cooperiaresistant to avermectins in cattle and Haemonchus resistant to benzimidazoles in sheep. Although these experiences go through the second and first year respectively, the common hypothesis is that it would be possible to replace the resistant strain with a sensitive one through the application of epidemiological knowledge (the “seeding” of sensitive strains in low refuge conditions), with the expectation that the efficiency recovery process can be completed in about two years. Preliminary results, at least in bovines under field conditions, indicate progress in the process where an initial efficacy of ivermectin on the Cooperia genus of the order of 39% exceeded 75% in 7 months of experiment (Fiel and Steffan, not published).
Drug combinations: yes or no?
The combination of drugs with different modes of action is currently suggested as an alternative to delay the appearance of resistance phenomena or to control parasite populations with already declared existence (Bartram et al., 2012; Geary et al., 2013 ; Leathwick et al . ., 2009). The use of combinations of different molecules was developed primarily for the control of agricultural pests and these principles are now being assumed in the use of anthelmintics. In this context, there is a series of preconditions for its use, including a) the absence of cross-resistance between the components of the combination; b) that the resistant alleles are recessive and of low frequency; and c) that there is a refuge population with susceptible genotypes that allows resistant genotypes to be diluted (Bartram et al., 2012; Leathwitck et al ., 2009; Leathwick, et al., 2012). If these conditions or requirements are unknown, in practice it is very difficult to quantify and establish when the combinations maintain or lose their benefits in the presence of resistant parasites (Hosking 2013). For example, in a recent experiment carried out in Santa Fe sheep with Haemonchus spp . showing multiple resistance, the simultaneous administration of three anthelmintics with different modes of action (febendazole, levamisole and ivermectin) did not result in greater activity than that observed independently with these drugs (Anziani and Muchiut, 2013). Similar results were reported by Entrocasso et al. (2008) in the province of Buenos Aires with H. contortusresistant to ivermectin and albendazole. Likewise, in Uruguay the co-administration of levamisole+albendazole+ivermectin against H. contortus with multiple resistance did not result in better efficacy compared to treatment with only the last of these drugs (Suarez et al. , 2014). Some of the previously considered requirements probably did not exist in these nematode populations indicating that with high levels of resistance to individual components, the efficacy of these combinations could be (at least) questionable.
The joint administration of drugs can give rise to pharmacokinetic interactions (modifications of the drug at the level of the site where the receptors are located) or pharmacodynamics resulting in indifference, antagonism and synergism of addition or potentiation (Alvarez, 2011). The effects of pharmacokinetic interactions (potentially positive or negative) are not yet well known and prior clarification of these aspects has been suggested before anthelmintic combinations are introduced to the veterinary market (Lanusse et al., 2014 ) . Regarding pharmacodynamic interactions, additive effects or sum synergism between benzimidazoles and levamisole have been observed between these drugs (Anderson et al., 1991; Bartley et al. , 2004). Potentiation synergism has been reported after the use of combinations of fenbendazole and levamisole with reductions in TRCH of 62% compared to reductions of 1 and 23% respectively when these drugs were administered individually (Miller and Craig, 1996). However, most of the pharmacodynamic interactions between anthelmintics with different modes of action would be reduced to their additive effects (Lanusse et al. , 2013).
In summary, although the combination of anthelmintics with different modes of action is being promoted in many countries, the available information still shows inconsistencies regarding the potential beneficial effects and their use under field conditions. There is consensus to consider that the combinations could be important to delay the appearance of RA before it is detectable or with populations of nematodes with a low frequency of resistance genes. However, the utility seems to be reduced in the presence of high levels of resistance and emphasizes the need to meet a series of requirements or preconditions to justify its widespread use. The alternatives of the combinations appear to be unsustainable in sheep and goat production in north-central Argentina with already generalized levels of low efficacy of a large part of the available drugs. A different situation could arise in bovine nematodes, where drugs such as levamisole (and to a lesser extent, benzimidazoles) maintain high efficacy, so there would be potential for the use of combinations to delay the development of resistance (Lanusseet al. , 2014). In all cases, the combinations should not be seen as a simplification of the problem and a shortcut to previous diagnosis. Each establishment should know its resistance status and this information is critical for the choice of anthelmintics to use. This is the first step for a rational and sustainable parasite control, although unfortunately the adoption of this work methodology continues to be very low (see point 6.6).
anthelmintic prescription
The RA is promoting actions aimed at reducing the intensity and massiveness of the treatments (currently favored by the abusive use of low-cost generic drugs) for a more rational use of anthelmintics and previous veterinary prescription. In this context, the Danish legislature in 1999 prohibited the use of routine mass treatments and restricted the application of all veterinary anthelmintics for large animals to prior diagnosis and professional prescription (Nielsen et al ., 2006). Other European countries such as Finland, Sweden, the Netherlands and Italy have adopted similar legislation that prevents the sale of veterinary anthelmintics without the corresponding professional prescription and there are also partial restrictions in the United Kingdom and Germany (Nielsen et al., 2014 ) . Recently, in March 2013, the Federation of European Veterinarians called for the legislators of the European Economic Community to promote a measure similar to that applied in Denmark in the other member countries for the use of all anthelmintics in food-producing animals. ( www.fve.org/news/) .
Currently, in our country, producers can acquire anthelmintic drugs through veterinary employees, foragers, online, and even by direct purchase from pharmaceutical companies. There is no doubt that the application of anthelmintics is currently the most effective and practical method for parasite control, but it is imperative to reduce their frequency, maximizing their rational use and integrating processes that accompany a new input technology based more on the biological and epidemiological knowledge of the parasites than in the availability of new drugs. The selection of the anthelmintic to be used has become a complex decision since it can vary depending on the category of animals to be treated, the species of parasites involved, seasons of the year, presence or absence of refuge, toxicity and drug residues, as well as susceptibility or resistance to them in each geographic region. Veterinarians should be the only actors qualified to perform in a scenario such as the one described and the professional prescription of anthelmintics could be, also in our country, the first step for their rational and responsible use. Some endectocide formulations have waiting periods in meat or milk that exceed 90 days and it is reasonable to consider that this type of product should be under exclusive professional control. Although the process is relatively recent to assess the effects of these restrictions,et al., 2014). Similar studies are being carried out in the UK on producers and veterinarians involved with sheep, cattle, pigs and horses (http://www.moredun.org.uk/news/moredun-review-how-anthelmintics-are-prescribedand -distributed).
Obviously this action should be accompanied by a strong professional participation that goes beyond the simple recipe. The prescription by itself does not guarantee the best use of anthelmintics, if it is not accompanied by permanent professional training and even changes in the degree training of future veterinarians. The challenge is great and undoubtedly in the short term, interests that can cause conflicts will be affected, but in countries that do not yet have similar legislation, the time to introduce these changes should be now before the problem becomes unmanageable (Kaplan, 2013). ).
Conclusions and proposal for future actions
Currently, the nematode populations of all our domestic herbivores have developed resistance to anthelmintics and the spread and severity of this is increasing rapidly. Of special concern is the development of multi-drug resistant nematodes, mainly in small ruminants and also in cattle. It is obvious that the complete dependence on frequent treatments must be changed by more sustainable alternatives that integrate process technologies, reducing the use of anthelmintics without these practices affecting productivity or animal welfare. However, integrating processes and management activities that are less dependent on chemicals are more complicated and difficult to implement. Up-to-date and consistent information is required on the epidemiology of the local and regional parasitic species that act, their interactions with different domestic hosts, their biotypes and breeds, size of herds, flocks or herds, and different production systems. The refuge, or the nematode populations that are not exposed to treatment constitute a reservoir of unselected or susceptible genes that should always be considered when indicating a treatment. This concept: “the greater the refuge, the less development of resistance” requires a holistic vision and must be incorporated by professional advisors and their producers and even by veterinary students. Systematic monitoring of the status of nematode populations in different production systems is an important control tool. As in the control of weeds and resistant agricultural pests, in pastoral livestock and in light of the escalation that we are observing in the RA, monitoring “is not an option, but an obligation” if you want to prevent and avoid productive losses . The information available in our country emphasizes the need to perform epg determinations on a regular basis (monitoring) to assess the need for treatment and the efficacy of the anthelmintics used (TRCH). This methodology guarantees that the treatment is necessary and effective, but it is being poorly adopted and, generally,
Combinations of anthelmintic drugs with different modes of action (common in New Zealand and Australia) appear as a resource that deserves to be evaluated under our production conditions in some ruminant species and regions, but in others their usefulness may be doubtful and more information is needed. on possible additive or synergistic effects of this drug co-administration is necessary before its recommendation. In this complex context represented by RA, and at the authors’ discretion, anthelmintics should be obtained by producers and owners exclusively from the prescription and advice of an authorized and trained veterinarian. This should tend to the most appropriate and responsible use of a limited resource such as antiparasitic drugs.
THANKS
To the agreement INTA AUDEAS CONADEV 940143 and the Faculty of Veterinary Sciences (UNCPBA) for financing some of the works presented here.
BIBLIOGRAPHY
- Aba, L. 2014. Prohibit theuse of long acting avermectins in Brazil. Motivate. Issue N.° 139, July 2014, pp. 9 and 10. [ Links
- Aguirre, D.; Cafrune, MM; Viñabal, AE; Salatin , AO 2000. Mortality due to nematodiasis associated with the ineffectiveness of albendazole in dairy goats from Valle de Lerma (Salta). Rev. Asoc. Arg. Prod. Anim. 20 (suppl. 1): 341. [ Links]
- Aguirre, D.; Cafrune , MM 2013. Epidemiology and productive impact of nematodes in the NOA region. In: Parasitic Diseases of Clinical and Productive Importance in Ruminants. Epidemiological foundations for its prevention and control. Fiel C. and Nari A. Editorial Hemisferio Sur, SRL (Uruguay),115-129. [ Links]
- Aguirre, D.; Cafrune, MM; Salatin, AO; Viñabal AE 2005. Multiresistance to broad-spectrum nematodecides in goats from northwestern Argentina. Res. 17 Latin American Congress of Parasitology. Mar del Plata, Buenos Aires, Argentina. [ Links]
- Anderson , N.; Martin , P.J.; Jarret , R.G. 1991. The efficacy of mixtures of albendazole sulphoxide and levamisole against sheep nematodes resistant to benzimidazole y levamisole. Aust. Vet. J. 68: 127-132. [ Links]
- Anziani , O.S. 2013. Anthelmintic resistance in nematodes of herbivores hosts in Argentina. 2013. Proceedings 24th International Conference of the World Association for the Advancement of Veterinary Parasitology, Perth, Australia. [ Links]
- Anziani , O.S.; Guglielmone , A.A.; Zimmermann , G.; Vazquez , R.; Suarez , V.R. 2001. Avermectin resistance to Cooperiapectinata in cattle in Argentina. Vet. Rec. 149: 58-59. [ Links]
- Anziani, OS; Fiel , CA 2004. Current status of anthelmintic resistance (gastrointestinal nematodes) in cattle from Argentina. vet. Arg. 21: 86-101. [ Links]
- Anziani , O.S.; Suarez , V.; Guglielmone , A.A.; Wanker , O.; Grande , H., Coles G. 2004. Resistance to benzimidazole and avermectin anthelmintics in cattle nematodos in Argentina.Vet. Parasitol. 122: 303-306. [ Links]
- Anziani, OS; Caffe, G.; Aguilar, S.; Cervilla, N.; Litterio, N.; Boggio, J. 2008. Efficacy of moxidectin in the control of Haemonchus spp. isolates. resistant to ivermectin in goats. xviii Argentine Conference and xiii Latin American Conference on Pharmaco-Toxicology. Buenos Aires. [ Links]
- Anziani, OS; Caffe, G.; Cervilla, N.; Litterio, N.; Aguilar, S.; Cooper, L.; Boggio , J. 2009. Anthelmintic resistance in gastrointestinal nematodes of goats in the north of the province of Córdoba, Argentina. 32 Argentine Congress Animal Production Association, Malargue, Mendoza, Argentina. [ Links]
- Anziani, OS; Caffe, G.; Cooper, L.; Caparros, J.; Mohn, C.; Aguilar S. 2010. Internal parasites and milk goats. Part 1. Control Considerations for Gastrointestinal Nematodes Dairy Research Results. dairy project. Technical Sheet no. 14 www.inta.gov.ar/lechería[ Links]
