Review

An Overview of Anthelmintic Resistance in Domestic

Ruminants in Brazil
Lucia Oliveira Macedo 1 , Samuel Souza Silva 1,2 , Leucio Câmara Alves 3 , Gílcia Aparecida Carvalho 1
and Rafael Antonio Nascimento Ramos 1, *

1 Laboratory of Parasitology, Federal University of the Agreste of Pernambuco, Garanhuns 55292-270, Brazil;
[email protected] (S.S.S.); [email protected] (G.A.C.)
2 Postgraduate Program in Animal Bioscience, Federal Rural University of Pernambuco,
Recife 52171-900, Brazil
3 Department of Veterinary Medicine, Federal Rural University of Pernambuco, Recife 52171-900, Brazil;
[email protected]
* Correspondence: [email protected]

Abstract: Gastrointestinal nematodes (GIN) significantly, negatively impact livestock worldwide, and
their control depends on the use of chemotherapy drugs. However, this approach is unsustainable as
anthelmintic resistance (AR) is growing widespread. This article provides a comprehensive overview
of the historical and current data published on AR in domestic ruminants in Brazil. Alternative
measures of GIN control have been discussed to provide helpful information to prevent the develop-
ment of AR in the country. This review consisted of a search of technical and scientific publications
between January 1960 to January 2023, using online sources such as PubMed, Scielo and Google
Scholar. Eighty-three articles published over the last six decades reporting AR in sheep (n = 43), goats
(n = 20) and cattle (n = 20) were included. A total of 37.3%, 25.4% and 37.3% evaluated one, two and
three or more molecule classes, respectively. Among all studies, 82.1% used fecal egg count reduction
test as a method of AR diagnosis. In conclusion, AR is an urgent and emerging issue for ruminant
production in Brazil. It is necessary to evaluate on a large scale the distribution and management of
anthelmintic drugs and discuss strategies that delay this phenomenon’s development.

Citation: Macedo, L.O.; Silva, S.S.;

Keywords: ruminant livestock; macrocyclic lactones; benzimidazoles; nematodes; chemotherapy
Alves, L.C.; Carvalho, G.A.; Ramos,
drugs
R.A.N. An Overview of Anthelmintic
Resistance in Domestic Ruminants in
Brazil. Ruminants 2023, 3, 214–232.
https://doi.org/10.3390/
ruminants3030020 1. Introduction
Gastrointestinal nematodes (GIN) are important pathogens of grazing ruminants,
Academic Editor: Alessia L.
Gazzonis
responsible for economic losses in animal production worldwide [1–3]. The controlling
of these parasites has been a challenge for producers and there is an emerging need to
Received: 27 June 2023 seek effective alternatives that do not cause animal toxicity [4]. Among Brazilian ruminant
Revised: 9 August 2023 livestock, the most common GIN are those belong to the following genera: Haemonchus
Accepted: 23 August 2023 and Ostertagia (parasite of abomasum); Trichostrongylus (parasite of small intestine and
Published: 29 August 2023 abomasum); Cooperia (parasite of small intestine); and Oesophagostomum, also known as
the nodular worm, which parasitizes the large intestine [5–7]. Infections by these parasites
are characterized by lesions in the gastrointestinal mucosa, which impair the absorption
of nutrients, reducing body weight gain and milk production. In addition, some species
Copyright: © 2023 by the authors.
Licensee MDPI, Basel, Switzerland.
(e.g., Haemonchus contortus) are hematophagous [8]. Studies have already been conducted
This article is an open access article
in Brazil to assess the economic impact of GIN infection in ruminants [9,10]. For instance, a
distributed under the terms and
reduction of 0.6 kg/cow/day of milk in dairy cattle is estimated, with a potential annual
conditions of the Creative Commons loss of up to USD 1870.48/animal [11]. In sheep, losses may reach approximately USD
Attribution (CC BY) license (https:// 400/animal/year [12].
creativecommons.org/licenses/by/ GIN control has been largely achieved by using both broad (benzimidazoles, imida-
4.0/). zothiazoles, hydropyrimidines and macrocyclic lactones) and narrow-spectrum (salicy-

Ruminants 2023, 3, 214–232. https://doi.org/10.3390/ruminants3030020 https://www.mdpi.com/journal/ruminants

Ruminants 2023, 3 215

lanilides, nitrophenols and organophosphate) anthelmintics [13]. More recently, amino-

acetonitrile derivatives have emerged as a new chemical class of synthetic anthelmintics,
effective against GIN of sheep [14]. Nevertheless, the excessive dependence on these
substances has led to the development of anthelmintic resistance (AR) in all species of
domestic ruminants to all classes of anthelmintics [15]. In Europe [16–18], Africa [19–21],
Asia [22,23], Oceania [24–26] and the Americas [27–30], this phenomenon is associated with
multiple drugs, threatening the viability of ruminant livestock production, especially small
ruminants [18,31,32].
In Brazil, the first AR reports were on thiabendazole and ivermectin in sheep in the
country’s southern region [33,34]. Similarly, benzimidazoles resistance was also detected in
goats from the northeast region. In the same period, AR was also detected in goats treated
with albendazole, parbendazole and levamisole [35], which raises the discussion about
different dosages for small ruminants [36]. Soon after, the resistance of Haemonchus spp. to
oxfendazole and albendazole was detected in cattle from the southern region [37]. With the
recent increase in AR in Brazilian herds, the development of new compounds is pivotal, as
well as the integration of rational GIN control [38,39].
No articles have gathered data on AR in domestic ruminants in the country. Few
studies have been conducted singly, such as a study on AR in small ruminants [40] and
resistance to the class of benzimidazoles [41]. Therefore, this article provides a comprehen-
sive overview of the historical and current data published on AR in domestic ruminants in
Brazil. Additionally, alternative measures of GIN control have been discussed to provide
helpful information to prevent the development of AR in the country.

2. Methods
Review Procedures and Map Construction
This review consisted of a comprehensive search of technical and scientific reports
published from January 1960 to January 2023 using online sources such as PubMed, (US
National Library of Medicine National Institutes of Health/National Center for Biotechnol-
ogy Information Search database), Scielo (Scientific Electronic Library Online) and Google
Scholar. Keywords, including “ruminants”, “small ruminants”, “anthelmintic resistance”,
“sheep”, “goat”, “cattle” and “Brazil”, were combined for search articles. All articles written
in English or Portuguese were included in this review.
Articles were included whether they described AR exclusively through the fecal egg
count reduction test (FECRT) or associated with other tests such as the egg hatchability test,
larval development test, molecular tests and controlled efficacy tests. Studies that described
resistance using necropsy were also included. Finally, they were screened to assess their
originality, time of publication, aim, technique employed for diagnosis and reliability in
presenting results.
Two maps were constructed to represent graphical data of the distribution of AR and
the class of drugs used. Geographic coordinates were used through the Google Maps
platform of the municipalities where the studies were carried out; then, these coordinates
were incorporated into the QGIS program (version 3.22.10) together with the vector layer
(Shapfiles, version 2017) obtained in the database of the Brazilian Institute of Geography
and Statistics.

3. Results and Discussion

Eighty-three peer-reviewed articles reporting AR in domestic ruminants (sheep, goats
and cattle) were published over the last six decades. Of all these studies, 51.8% (43/83)
were reported in sheep, 24.1% (20/83) in goats and 24.1% (20/83) in cattle. Most of the
studies were carried out with molecules from different classes. Of all studies, 37.3% (31/83)
evaluated only one class, 25.4% (21/83) two drug classes and 37.3% (31/83) three or
more drug classes. Figure 1 illustrates the map with a graphical representation of the
distribution of the class of drugs used in the considered articles: macrocyclic lactones
(24.1%; 20/83), combination of benzimidazole + macrocyclic lactones (14.5%; 12/83) and
 Eighty-three peer-reviewed articles reporting AR in domestic ruminants (sheep,
goats and cattle) were published over the last six decades. Of all these studies, 51.8%
(43/83) were reported in sheep, 24.1% (20/83) in goats and 24.1% (20/83) in cattle. Most of
the studies were carried out with molecules from different classes. Of all studies, 37.3%
Ruminants 2023, 3 (31/83) evaluated only one class, 25.4% (21/83) two drug classes and 37.3% (31/83) three or 216
more drug classes. Figure 1 illustrates the map with a graphical representation of the
distribution of the class of drugs used in the considered articles: macrocyclic lactones
(24.1%; 20/83), combination of benzimidazole + macrocyclic lactones (14.5%; 12/83) and
benzimidazole + macrocyclic lactones + other combinations (37.3%; 31/83). Most of these
benzimidazole + macrocyclic lactones + other combinations (37.3%; 31/83). Most of these
studies (83.1%) used FECRT as a method of AR diagnosis. Currently, for the interpretation of
studies (83.1%) used FECRT as a method of AR diagnosis. Currently, for the interpretation
FECRT, the recommendations of the World Association for the Advancement of Veterinary
of FECRT, the recommendations of the World Association for the Advancement of
Parasitology (WAAVP) are based on classification criteria that outline how the observed
Veterinary Parasitology (WAAVP) are based on classification criteria that outline how the
data (values for the upper and lower 90% CI or results of separate hypothesis tests) are
observed data (values for the upper and lower 90% CI or results of separate hypothesis
compared to the expected effectiveness and the lower limit of effectiveness (which serve
tests) are compared to the expected effectiveness and the lower limit of effectiveness
as(which
the values
serve for thevalues
as the upperfor
and
thelower
upperlimits of thelimits
and lower gray of
zone), accepting
the gray zone), aaccepting
Type 1 error
a
rate of 5% [41].
Type 1 error rate of 5% [41].

Figure 1. Geographic distribution of anthelmintic resistance according of the class of drugs used in
Figure 1. Geographic distribution of anthelmintic resistance according of the class of drugs used in
ruminants from Brazil.
ruminants from Brazil.
From 1960 to 1999, 18 articles (21.7%) reported AR in domestic ruminants, with one
From 1960 to 1999, 18 articles (21.7%) reported AR in domestic ruminants, with one
in cattle (5.6%; 1/18), three in goats (16.7%; 3/18) and fourteen (77.8%; 15/18) in sheep.
in cattle (5.6%; 1/18), three in goats (16.7%; 3/18) and fourteen (77.8%; 15/18) in sheep.
From 2000 to 2023, the number of reports tripled, with 65 articles (78.3%) distributed
From 2000 to 2023, the number of reports tripled, with 65 articles (78.3%) distributed across
14 states and 127 municipalities. Most of the studies were concentrated in the southern
(39.8%; 33/83), northeastern (31.3%; 26/83), southeastern (22.9%; 19/83) and midwestern
(6.0%; 5/83) regions. Despite lower reliability, some references [33,38,42–73] that do not
include animal numbers or locations were considered in this review. Figure 2 illustrates
the map with the graphical representation of the distribution of AR in domestic ruminants
from Brazil.
 across 14 states and 127 municipalities. Most of the studies were concentrated in the
southern (39.8%; 33/83), northeastern (31.3%; 26/83), southeastern (22.9%; 19/83) and
midwestern (6.0%; 5/83) regions. Despite lower reliability, some references [33,38,42–73]
Ruminants 2023, 3 that do not include animal numbers or locations were considered in this review. Figure 2 217
illustrates the map with the graphical representation of the distribution of AR in domestic
ruminants from Brazil.

Figure 2. Geographic distribution of anthelmintic resistance according to published records in cattle,

Figure 2. Geographic distribution of anthelmintic resistance according to published records in cattle,
goats and sheep from Brazil.
goats and sheep from Brazil.
3.1. Anthelmintic Resistance in Small Ruminants
3.1. Anthelmintic Resistance in Small Ruminants
Sixty-three (75.9%) peer-reviewed articles have been published on small ruminant
Sixty-three (75.9%) peer-reviewed articles have been published on small ruminant AR,
AR, including 51.8% (43/83) in sheep and 24.1% (20/83) in goats. Anthelmintic resistance
including 51.8% (43/83) in sheep and 24.1% (20/83) in goats. Anthelmintic resistance was
was reported in 92 municipalities from four regions of the country: (i) south—states of
reported in 92 municipalities from four regions of the country: (i) south—states of Paraná,
Paraná, Rio Grande do Sul and Santa Catarina; (ii) southwest—states of Minas Gerais, Rio
Rio Grande do Sul and Santa Catarina; (ii) southwest—states of Minas Gerais, Rio de Janeiro
de Janeiro and São Paulo; (iii) midwest—state of Mato Grosso do Sul; and (iv) northeast—
and São Paulo; (iii) midwest—state of Mato Grosso do Sul; and (iv) northeast—states of
states of Ceará, Paraíba, Pernambuco and Rio Grande do Norte (Tables 1 and 2). The lack
Ceará, Paraíba, Pernambuco and Rio Grande do Norte (Tables 1 and 2). The lack of
of information in the north of the country does not mean the absence of AR. However, it
information in the north
is worth mentioning that of theregion
this country does
of the not mean
country the absence
concentrates of AR. However,
the smallest number ofit is
worth
small ruminants (2.3% of total Brazilian herd—IBGE, 2021), while the northeasternof
mentioning that this region of the country concentrates the smallest number small
and
ruminants (2.3% of total Brazilian herd—IBGE, 2021), while the northeastern and
southern regions possess the vast majority of goats and sheep (91.9%). Additionally, mostsouthern
regions possesshas
of the research thebeen
vastconducted
majority ofin goats and sheep (91.9%). Additionally, most of the
these regions.
research has been conducted in these regions.
Ruminants 2023, 3 218

Table 1. Distribution of anthelmintic resistance in sheep from Brazil.

Region/State Municipality Anthelmintics Number of Animals Diagnostic Method References

Southern
RS NI THI 308 FECRT [34]
NI NI LEV NI NI [41]
NI NI LEV NI NI [42]
NI NI LEV 6 Necropsy [43]
RS Uruguaina RAF 9 FECRT [44]
RS Bagé ALB, LEV NI FECRT [45]
RS Bagé IVE 89 FECRT [34]
RS NI ALB, LEV, IVE, CLO, ALB + LEV NI FECRT [46]
PR NI ALB, CLO, LEV, FEB, IVE, TET, DIS + TET 480 FECRT [47]
RS NI LEV, ALB, FEB, OXF, MEB 870 FECRT [48]
PR Cambé, Tamarana and Londrina IVE, ALB, MOX 850 FECRT [74]
PR NI OXF, IVE, CLO, CLO + OXF, LEV, MOX NI FECRT [49]
SC NI IVE, LEV, CLO, ALB 7529 FECRT [50]
Passos Maia, Vargeão, Ponte Serrada, Faxinal
SC IVE, ALB, MOX, CLO, LEV 450 FECRT [75]
dos Guedes, Xanxere and Xaxim
PR NI CLO + ALB, IVE 120 FECRT [51]
LEV, MON, ALB, IVE, NIT, DIS, TRI, CLO, IVE +
RS NI 500 FECRT [76]
LEV + ALB
SC NI CLO, LEV, ALB, ALB + LEV 135 FECRT [52]
PR NI MON 50 FECRT/CT [53]
RS NI MOX, FEB 78 FECRT [54]
RS NI ABA, ALB, CLO, LEV, MON, TRI 1540 FECRT [55]
São Pedro do Sul, São Gabriel
RS MON NI FECRT [56]
and São Martinho da Serra
São Gabriel, São Martinho da Serra,
Dilermando de
RS IVE, DOR, MON, LEV, ALB, CLO 366 FECRT [57]
Aguiar, Bagé, Capão do Cipó, São Francisco de
Assis and Santa Maria
Ruminants 2023, 3 219

Table 1. Cont.

Region/State Municipality Anthelmintics Number of Animals Diagnostic Method References

Southeastern
SP São Manuel OXF, IVE, LEV 540 FECRT [58]
SP Jaboticabal MOX 24 FECRT [77]
SP Pratânia ALB, LEV, MOX, IVE, TRI, CLO 42 FECRT [78]
Campos dos Goytacazes, Cardoso Moreira,
RJ Quissamã, São Francisco de Itabapoana, Santo ALB, CLO, DIS, FEB, IVE, MON, NIT 770 FECRT [79]
Antonio de Pádua and São João da Barra
Montes Claros, Bocaiúva, Janaúba, Pirapora,
MG ALB 252 FECRT [80]
Francisco Sá, Coração de Jesus and Januária
SP NI ALB, CLO, IVE, LEV, MON 1617 FECRT [81]
Jaboticabal, Viradouro, Pontal, Morro Agudo,
SP Sertãozinho, Ribeirão Preto, Taquaritinga and IVE, MOX 160 Necropsy [82]
São João da Boa Vista
SP Araçatuba ALB, LEV, IVE, MON, CLO, IVE + LEV + ALB 350 FECRT [59]
SP NI ALB, LEV, IVE, MON, THI 245 FECRT/LDT [83]
ES Alegre MON 20 FECRT/Necropsy [84]
MG NI ALB, IVE, LEV 381 FECRT [60]
Midwest
Angélica, Camapuã, Campo Grande, Corumbá,
Coxim, Ivinhema, Miranda, Porto Murtinho,
MS Ribas do Rio Pardo, São Gabriel do Oeste, ALB, CLO, IVE, LEV, MOX, TRI, ALB + IVE + LEV 120 FECRT [85]
Sidrolândia, Terenos, Camapuã, Campo Grande,
Miranda and Porto Murtinho
Northeastern
CE Sobral NET, IVE 20 FECRT [61]
CE Pentecoste CLO, OXF 38 FECRT [86]
Limoeiro do Norte, Palhano, Jaguaruana,
CE Itaiçaba, Aracati, Alto Santo, Morada Nova OXF, LEV, IVE 768 FECRT [87]
and Jaguaribe
Ruminants 2023, 3 220

Table 1. Cont.

Region/State Municipality Anthelmintics Number of Animals Diagnostic Method References

CE Limoeiro do Norte, Aracati e Jaguaribe OXF 144 FECRT [88]
RN NI ALB, IVE 54 FECRT [89]
PE Recife, Vitória de Santo Antão and Garanhuns ALB NI FECRT [90]
PB Gado Bravo IVE, LEV 234 FECRT [62]
Aparecida, Marizópolis, Patos, Souza, São José
PB da Lagoa Tapada, São josé de Piranhas and São ALB, IVE, CLO, LEV, MON 600 FECRT [63]
José do Rio do Peixe
EHT,
CE Caucaia ALB, IVE, LEV 74 [91]
FECRT/LDT/qPCR
ALB: albendazole; OXF: oxfendazole; FEB: febendazole; PYR: pyrantel; RAF: rafoxanide; THI: thiabendazole; TET: tetramisole; LEV: levamisole; DOR: doramectin; IVE: ivermectin;
MOX: moxidectin; CLO: closantel; TRI: trichloform; NIT: nitroxynil; DIS: disophenol; NET: netobimin; MEB: mebendazole; MON: monepantel; ABA: abamectin; (+): associations of
drugs; (NI): not informed; FECRT: fecal egg count reduction test; CT: controlled efficacy test; LDT: larval development test; EHT: egg hatch test; qPCR: quantitative real-time PCR.

Table 2. Distribution of anthelmintic resistance in goats from Brazil.

Region/State Municipality Anthelmintics Number of Animals Diagnostic Method References

Southern
RS Gravataí CLO, LEV 40 FECRT [92]
RS Porto Alegre IVE 12 FECRT [93]
ALB, ABA, CLO, NIT, LEV, MOX, IVE,
SC São Francisco do Sul 63 FECRT [94]
IVER + LEV + ALB
PR NI MOX 45 FECRT [95]
Southeastern
Jaboticabal, Viradouro, Pontal, Morro Agudo,
SP Sertãozinho, Ribeirão Preto, Taquaritinga and São IVE, MOX 160 Necropsy [82]
João da Boa Vista
Northeastern
CE Sobral OXF, FEB, ALB, THI 25 FECRT [35]
CE Pentecoste IVE, CLO 29 FECRT [87]
CE NI OXF, LEV 1020 FECRT [96]
Ruminants 2023, 3 221

Table 2. Cont.

Region/State Municipality Anthelmintics Number of Animals Diagnostic Method References

Limoeiro do Norte, Palhano, Jaguaruana, Itaiçaba,
CE OXF, LEV, IVE 336 FECRT [88]
Aracati, Alto Santo, Morada Nova and Jaguaribe
AL Mar Vermelho IVE, ALB 40 FECRT [64]
CE Sobral EPR 24 FECRT [65]
PB NI ALB, IVE 120 FECRT [97]
RN NI ALB, IVE 54 FECRT [89]
RN Mossoró ALB, IVE 1350 FECRT [98]
PB Monteiro ALB, IVE, LEV 264 FECRT [66]
Sertânia, Paudalho, Camocim de São Félix and
PE ALB, IVE NI FECRT [90]
Taquaritinga do Norte
PB Gado Bravo IVE 270 FECRT [62]
PB Sumé ALB 40 FECRT [99]
BA Santa Inês, Cravolândia and Ubaíra ALB, IVE, LEV, MOX, CLO 360 FECRT [100]
PE Petrolina ALB, IVE, LEV, MOX, CLO 420 FECRT [101]
ALB: albendazole; OXF: oxfendazole; FEB: febendazole; PYR: pyrantel; THI: thiabendazole; LEV: levamisole; NIT: nitroxynil; IVE: ivermectin; MOX: moxidectin; CLO: closantel;
TRI: trichloform; EPR: eprinomectin; (+): associations of drugs; (NI): not informed; FECRT: fecal egg count reduction test.
Ruminants 2023, 3 222

Overall, 24,449 animals were assessed primarily through FECRT (85.7%; 54/63). These
studies evaluated different classes of drugs but mainly molecules belonging to the class of
benzimidazole (i.e., albendazole, thiabendazole, oxfendazole, mebendazole and febenda-
zole), macrocyclic lactones (i.e., ivermectin, doramectin, abamectin and moxidectin) and
imidazothiazole (i.e., levamisole and tetramisole).
The AR is more serious than has been documented so far. The gradual growth from its
somewhat sporadic occurrence in the early 1960s to the current situation threatens the sus-
tainability of production systems. The primary tool adopted for controlling GIN parasites
is the use of anthelmintics, which generally positively impact the well-being and health
of domestic and production animals [3]. It is known that AR is an evolutionary process
that is unpredictable if anthelmintics are used intensively in a herd [102]. Nonetheless, it
is possible to reduce the rate of resistance development by modifying anthelmintic use
strategies [15]. Particularly in sheep, resistance of H. contortus is associated with economic
losses and mortality [3,103]. In addition, there is more research and wider availability of
drugs for this animal species (51.8%), reflecting more AR reports compared with goats and
cattle. For example, the nematodes of sheep treated intensively with monepantel may show
resistance to this drug in three months [104]. Similarly, lambs treated with levamisole every
42 days may present resistant nematode populations after the third treatment [7].
With the decreasing effectiveness of anthelmintics, the prophylaxis of GIN infections
in small ruminants has become more challenging. Hence, the rational and integrated use of
these compounds with sustainable measures of control is necessary to prevent AR [105].
Unfortunately, GIN of sheep developed resistance to a more recent molecule available
commercially, the amino-acetonitrile derivatives [14,106–108].

3.2. Anthelmintic Resistance in Cattle

Twenty articles were found reporting AR in cattle. These reports originated from
51 municipalities, distributed in the southern (Rio Grande do Sul and Santa Catarina),
southeastern (Minas Gerais and São Paulo), midwestern (Mato Grosso do Sul) and north-
eastern (Paraíba) regions of Brazil (Table 3). In total, 6729 individual animals were assessed
for AR. Similarly, to small ruminants, most studies used FECRT (70.0%; 14/20) as a method
for resistance detection. These studies evaluated different classes of drugs but mainly
evaluated drugs from the class of macrocyclic lactones (avermectins and milbemycins).
In cattle, using chemical compounds to control infections by GIN is commonly con-
ducted with broad-spectrum molecules (macrocyclic lactones, benzimidazoles, imidazoth-
iazoles and salicylanilides). Mainly, macrocyclic lactones are used worldwide in ruminant
livestock. They are available in different formulations, concentrations and associations,
with ivermectin being the predominant chemical compound [31]. Frequently, these drugs
are administered without any technical criteria for drug selection, and this empirical and
indiscriminate use has favored AR development. This incorrect use has additional impli-
cations for the effectiveness of anthelmintic treatments, as it causes the emergence and
spread of parasite resistance [56]. Unlike the development of resistance in small ruminants,
in cattle, this phenomenon occurred slower; however, in recent decades, there has been
a rapid increase in reports of AR in GIN infection of cattle worldwide [29,56,109–111]. It
is imperative to address the AR issue in cattle, with the view of a significant threat to
cattle productivity [102].
Ruminants 2023, 3 223

Table 3. Distribution of anthelmintic resistance in cattle from Brazil.

Region/State Municipality Anthelmintics Number of Animals Diagnostic Method References

Southern
RS NI ALB, OXF 16 FECRT [37]
SC NI IVE, LEV, ALB 2340 FECRT [112]
RS São Pedro do Sul IVE, DOR, ABA, MOX, ALB 149 FECRT [113]
RS Butiá IVE 144 Necropsy [67]
São Martinho da Serra, Dilermando de Aguiar, Cacequi,
IVE, DOR, EPR, MOX, LEV, ALB, FEB, CLO,
RS São Gabriel, Itaqui, São Borja, Santiago 1704 FECRT [114]
NIT, DIS, ALB + CLO, DOR + CLO
and São Vicente do Sul
RS São Gabriel, São Martinho da Serra and Dilermando de IVE, DOR, MON, LEV, ALB, CLO 384 FECRT [56]
RS São Gabriel IVE, DOR, ABA, EPR, MOX 70 FECRT [115]
Southeastern
SP NI IVE 187 FECRT [116]
SP Castilho MOX 20 FECRT [117]
MG NI IVE 24 Necropsy [68]
MG Teófilo Otoni IVE, ALB, ABA, DOR 84 FECRT [118]
Candeias, Formiga, Pimenta, Caldas, Prata, Jaboticabal
MG/SP IVE 144 Necropsy [67]
and São José do Rio Pardo
MG NI IVE, MOX 40 FECRT/Necropsy [69]
SP Jaú, Botucatu and Avaré IVE 99 FECRT [119]
Midwest
MS NI IVE, MOX NI FECRT [70]
Bandeirantes, Campo Grande, Porto Mortinho
MS IVE NI LMIT [120]
and Nova Alvorada do Sul
MS NI DOR, IVE 24 FECRT/Necropsy [71]
MS Ribas do Rio Pardo MOX, IVE, ABA, ABA + IVE 300 FECRT [121]
Northeastern
PB NI IVE, ALB, OXF, LEV, TET, CLO, DIS, PYR, MOR 200 FECRT [72]
Uiraúna, Aroeira, S. J. Rio do Peixe, Caturité, Barra de
Santana, Soledade, Lagoa, Patos, Bom Sucesso, Campina
PB Grande, Santa Cruz, Boa Vista, Gado Bravo, Barra de ALB, IVE, CLO, LEV 800 FECRT [29]
Santa Rosa, Brejo do Cruz, Joca Claudino, Catolé do
Rocha, Belém do Brejo do Cruz, Souza and Aparecida
ALB: albendazole; OXF: oxfendazole; FEB: febendazole; EPR: eprinomectin; PYR: pyrantel; LEV: levamisole; DOR: doramectin; IVE: ivermectin; MOX: moxidectin; CLO: closantel;
TRI: trichloform; NIT: nitroxynil; DIS: disophenol; MON: monepantel; MOR: Morantel; ABA: abamectin; (+): associations of drugs; (NI): not informed; FECRT: fecal egg count reduction
test; LMIT: larval migration inhibition test.
Ruminants 2023, 3 224

The most frequent helminths in Brazilian cattle herds are Cooperia spp. and Haemonchus
placei [122], which were identified in several reports of AR [67,71,116]. Resistance of the genus
Cooperia is also common in countries such as Argentina [73], United Kingdom [123], Mexico [124],
Sweden, Belgium, Germany [125], United States [126,127] and Australia [128,129]. Most of
these reports are related to resistance to ivermectin. Infection by Cooperia punctata can sig-
nificantly impact productivity by reducing weight gain and decreasing feed intake [127]. In
addition, it influences phosphorus kinetics, reducing food intake and altering phosphorus
absorption and retention [130].

4. Current Methods for Detection of AR

The primary method for detecting resistance is FECRT, which can be used with all
anthelmintic groups. Nematode eggs are counted at pre- and post-treatment times defined
according to the anthelmintic group used [131]. However, it is unsuitable for detecting
resistance levels below 25% [132]. Several factors must be considered when planning an
FECRT (i.e., study design, sample size considerations, choice of fecal egg count (FEC)
method, statistical data analysis and interpretation) [133]. Other in vitro tests have been
used less, such as the EHT, established to detect drug resistance in the benzimidazole
class [134]. In addition, it is possible to use tests evaluating larval development and
motility (LDT and LMIT) [15]. Particularly in cattle, most animals in a herd, even the young
ones, have lower FEC, making diagnosing AR difficult [20]. For example, the McMaster
technique is the most used method in studies of AR detection but it has a detection limit
of 50 EPG [135]. The use of methods with higher detection, such as FLOTAC (one EPG)
and Mini-FLOTAC (five EPG), might be encouraged in this kind of analysis [136,137]. The
consensus is that there is a need for improvements in the AR detection methods, such as
more reliable parasitological tests and an increase in the number of animals required for
simultaneous testing on several drugs [119].
With the limitations of current in vivo and in vitro resistance tests, molecular tools
can potentially improve drug resistance diagnosis [138]. The development of molecular
diagnostics for anthelmintic resistance has been one of the leading research topics involving
the molecular mechanisms of drug resistance [139]. Thus, developing molecular markers
for diagnosing resistance can help develop new anthelmintic drugs [140]. The molecular
mechanism of resistance is better understood for benzimidazoles; therefore, it offers a
potential opportunity to expand molecular diagnostic tests for drugs of this class [141]. For
example, in Brazil, some studies were conducted using the β-tubulin isotype gene, a marker
to monitor resistance [141–143]. In addition, molecular characterization is an essential tool
for the validation and phylogenetic analysis of nematodes, such as allele-specific poly-
merase chain reaction, endpoint polymerase chain reaction (PCR), semi-quantitative PCR,
quantitative PCR (qPCR), high-resolution melt curve analysis (HRMC) and “Nemabiome”
internal transcribed spacer 2 (ITS-2) amplicon sequencing [144,145].
A recent development in large-scale surveillance is the “Nemabiome” approach, which
applies deep amplicon sequencing of barcoded PCR products [146]. Although initially
developed for species identification and quantification, it has recently been adapted to
assess the presence of resistance by benzimidazoles by deep sequencing of β-tubulin
amplicons [147]. In general, molecular tests have greater sensitivity and specificity and can
provide powerful tools to overcome many of the disadvantages of classical methods of AR.
However, it requires further research to be used as a practical universal tool in the field.

5. How to Prevent AR Development?

It has already been proved that the excessive and incorrect use of anthelmintics
to control GIN infections has resulted in AR. However, concerns about the use of these
products are more comprehensive than studies of AR itself. Recently, with the improvement
in awareness about the consumption of organic products, there has been a rise in concern
with the potential residual effect of these products in meat and milk, derived products from
ruminants that are widely consumed worldwide [148]. Despite reducing the withdrawal
Ruminants 2023, 3 225

period, the risks associated with residues in milk intended for human consumption and
dairy products may be present and should be considered [149]. For example, a study
with moxidectin demonstrated that this molecule may be present in goat milk for up to
21 days [150]. Additionally, to the direct consequence of using anthelmintics, the excretion
of these by-products may also be considered an essential threat from an environmental
perspective [151]. The access of anthelmintic residues into the environment resulting from
the direct excretion of the original drugs and metabolites in pastures during grazing, as
well as through the dispersion of the manure and slurry containing anthelmintic residues,
represents a potential risk for the environment [152].
Hence, studies focusing on controlling GIN but with a rational use of these chemical
molecules might be encouraged. Investigating the antiparasitic activity of natural bio-
products can contribute to the development of alternative treatments and a reduction in
dependence on conventional chemotherapy [153]. The antiparasitic activity of plants de-
rives mainly from biologically active compounds known as secondary metabolites, which
could lead to the detection of new antiparasitic molecules [154]. For example, flavonoids
and condensed tannins may have anthelmintic effects, as demonstrated in a study inhibit-
ing in vitro sheathing of larvae (L3) of H. contortus [155]. In addition, using nanoparticles
can provide good results in the treatment of parasitic infections because they increase the
bioavailability and biodistribution of drugs. However, the safety of using nanoparticles
from a broader perspective needs to be better investigated [156,157].
So far, most of the studies have been conducted in lab conditions, as they have low
cost, repeatability and allow the use of different stages (i.e., eggs and larvae) [152]. Al-
though these plant alternatives can be cheap and accessible, they have limitations. These
molecules’ potential adverse toxicity effects in vivo are generally controversial or com-
pletely unknown [157,158]. In vivo studies consist of oral administration of the leaves
(fresh, hay and flour), aqueous or ethanolic extracts and oil of plants to ruminants infected
naturally or experimentally with GIN [151,159]. Therefore, the association of standardized
in vivo and in vitro methods is paramount for evaluating the effectiveness of plant prod-
ucts, especially for the determination of EC50 and EC90 (50% and 90% maximal effective
concentration, respectively), which allows comparing the activities of different plants [160].
In order to postpone the development of AR, it is necessary to integrate GIN control
measures. Therefore, some factors are essential to be considered: (i) good management has
a direct effect on the health of animals with feeders and drinkers that avoid waste and con-
tamination [161]; (ii) strategies such as grazing rotation, co-grazing with other appropriate
species and manure management are alternatives to reduce the use of anthelmintics [162];
(iii) the improvement of animal resistance through genetic selection to reduce the use of
chemoprophylaxis [163]; and (iv) to optimize the effectiveness of anthelmintics in pop-
ulations of multiresistant nematodes, drug combinations can be used [114]. It is worth
emphasizing the importance of carrying out anthelmintic efficacy tests for choosing the
chemical groups to be used. The need to develop new anthelmintics for the management of
AR is evident; however, it is a slow and expensive process [164]. Furthermore, it is crucial
to use existing anthelmintics in a way that minimizes the impact of AR [165].

6. Conclusion Remarks and Perspective for Future Research

The present review demonstrates that AR is an urgent and emerging issue for rumi-
nant production in Brazil, especially in the southern and northeastern regions, where most
of the data discussed herein were produced. It is necessary to evaluate on a large scale the
distribution and management of anthelmintic drugs currently available and discuss strate-
gies to prevent the development of this phenomenon. Technological advances in diagnostic
tools associated with individual management of animals with continuous monitoring are
fundamental issues to better guide the control of GIN infections. Several challenges remain,
and we hope to enter a new anthelmintic era, including innovative, integrated control
approaches and more sensitive and cost-effective diagnostic tools.
Ruminants 2023, 3 226

Author Contributions: Conceptualization, L.O.M. and R.A.N.R.; writing—original draft preparation,

L.O.M., R.A.N.R., S.S.S., L.C.A. and G.A.C.; writing—review and editing, L.O.M., R.A.N.R., S.S.S.,
L.C.A. and G.A.C.; figure editing, L.O.M. and S.S.S. All authors have read and agreed to the published
version of the manuscript.
Funding: This research received external funding from the Fundação de Amparo à Ciência e Tecnolo-
gia do Estado de Pernambuco (FACEPE) (Grant number: APQ-1481-5.05/22).
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Acknowledgments: This article is based on the post-doctoral stage of the first author, developed at
the Federal University of the Agreste of Pernambuco, and supported by a grant fellowship from the
Fundação de Amaparo a Ciência e Tecnologia do Estado de Pernambuco (FACEPE) and Conselho
Nacional de Desenvolvimento Centífico e Tecnológico (CNPq).
Conflicts of Interest: The authors declare no conflict of interest.

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