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51

Research / Researchers Find Multiple Effects on Soil from Manure from Cows Administered Ant

« Last post by LamiyaJannat on April 12, 2021, 12:20:14 PM »

Researchers Find Multiple Effects on Soil from Manure from Cows Administered Antibiotics

These effects include alteration of the soil microbiome and ecosystem functions, soil respiration, and elemental cycling
For the study, researchers analyzed ecosystems exposed to manure from cattle given no antibiotics and manure from cattle given a common antibiotic, as well as a control sample not exposed to manure.

Use of antibiotics is under heightened scrutiny due to the increased prevalence of antibiotic-resistant pathogens. While the primary focus is on more stringent use of antibiotics in medical settings, the use of antibiotics in the livestock sector is gaining increased attention.

A new study led by Colorado State University and the University of Idaho found multiple effects on soils from exposure to manure from cows administered antibiotics, including alteration of the soil microbiome and ecosystem functions, soil respiration, and elemental cycling.

The team also saw changes in how plants allocated carbon below ground and take up nitrogen from the soil. In addition, they observed a decrease in ecosystem carbon use efficiency. This means that when antibiotics are used, less carbon is stored in the soil and more is lost to the atmosphere as carbon dioxide.

The study, "Prolonged exposure to manure from livestock-administered antibiotics decreases ecosystem carbon-use efficiency and alters nitrogen cycling," was published Oct. 9 in Ecology Letters.
Carl Wepking, the lead author and a postdoctoral fellow in the Department of Biology at CSU, said the findings give him "pause" due to the widespread use of antibiotics. "There's no environment on earth that is free from the effects of antibiotics," he said.

In the US, 80 percent of antibiotics are used in livestock production. Globally, livestock antibiotic use is projected to increase by 67 percent by the year 2030.

For the study, researchers analyzed ecosystems exposed to manure from cattle given no antibiotics and manure from cattle given a common antibiotic, as well as a control sample not exposed to manure. All of the manure samples were collected from standard dairy operations maintained by researchers from the Virginia Tech Department of Dairy Science.

Previous research on this topic found researchers injecting antibiotics into manure, then adding it to the soil, or adding raw antibiotics to the soil, said Wepking. The design of this study offered a much more realistic and applicable design.

The research team also used a pulse-chase experiment, a technique to examine elemental cycling, focusing on the manure's effect on whole ecosystems. Scientists took samples over the course of seven days, and found that in the presence of antibiotics, carbon traveled into the above ground plant material, to the roots of the plants, into the soil and respired back out as carbon dioxide much faster than any of the others.

"There was much less of that new carbon retained in the system compared with other soils we sampled," explained Wepking, who also serves as executive director of the Global Soil Biodiversity Initiative, which is housed in the School of Global Environmental Sustainability at CSU.

It's often thought that manure is a helpful fertilizer, and that it adds nutrients and carbon to soil but this benefit might be offset if antibiotics are administered to livestock.

While more research is needed, Wepking said given the study's findings, people may want to consider the effects of antibiotics in the soil when using manure as fertilizer.

"Research is expanding more and more, to look at antibiotic exposure and resistance in agricultural landscapes," said Wepking. "It's already well-documented that overuse of antibiotics is a problem for humans, and that we are running out of effective antibiotics to treat bacterial infections. Based on this research, we have learned that antibiotic use also has environmental effects."

Source: Colorado State University
University Square, 1311 S College Ave, Fort Collins, CO 80524, USA

52

Anthelmintic / Resistance to Anthelmintics

« Last post by LamiyaJannat on April 07, 2021, 04:47:44 PM »

Resistance to Anthelmintics

The development of nematode and trematode resistance to various groups of anthelmintics is a major problem. Compared with development of antibiotic resistance in bacteria, resistance to anthelmintics in nematodes has been slower to develop under field conditions. However, resistance is becoming widespread, because relatively few chemically dissimilar groups of anthelmintics have been introduced over the past several decades. Most of the commonly used anthelmintics belong to one of three chemical classes, benzimidazoles, imidazothiazoles, and macrocyclic lactones, within which all individual compounds act in a similar fashion. Thus, resistance to one particular compound may be accompanied by resistance to other members of the group (ie, side-resistance).

In nematodes of small ruminants, and especially in Haemonchus contortus, resistance to all classes of broad-spectrum anthelmintics has reached serious levels in many parts of the world. Resistance also has been found in Trichostrongylus spp, Cooperia spp, and Teladorsagia spp in sheep and goats. Reports of multiple resistance to most major classes of anthelmintics are increasing. Recently, resistance to monepantel has occurred in the field (New Zealand) in at least two nematode species (Teladorsagia circumcincta and Trichostrongylus colubriformis) after being administered on 17 separate occasions to different stock classes and in <2 yr of the product first being used on the farm.

Resistance to benzimidazoles is widespread in cyathostome nematodes of horses. Parascaris equorum resistance to macrocyclic lactones (ivermectin and moxidectin) has been reported in many countries. Macrocyclic lactone resistance in cyathostomes is only occasionally suspected, however, and the problem is still not considered to be serious.

There are limited reports of resistance against levamisole, pyrantel, and benzimidazoles in Oesophogostomum dentatum in pigs.

Multidrug (benzimidazoles and macrocyclic lactones) resistance in cattle nematodes has been documented on farms in New Zealand, the Americas, and Europe, and this will probably become more widespread. In most cases of resistance against macrocyclic lactones, Cooperia spp were identified as the resistant worm species, but macrocyclic lactone resistance is also emerging in Ostertagia ostertagi. The full extent of anthelmintic resistance in cattle nematodes is unknown.

The development of significant levels of resistance seems to require successive generations of helminths exposed to the same class of anthelmintic. However, evidence suggests that genes for resistance are invariably present, at a low frequency, for any given anthelmintic. Selection for resistance simply requires the preferential killing of the susceptible parasites and survival of the parasites with the resistance genes. Side-resistance is frequently seen between members of the benzimidazole group because of their similar mechanisms of action; control of benzimidazole-resistant parasites by levamisole can be expected because of its different mode of action. Although there is no evidence for cross-resistance between levamisole and benzimidazoles, this does not mean that worms resistant to both kinds of drugs will not evolve if both types of anthelmintics are used frequently. Nematodes resistant to levamisole are cross-resistant to morantel because of the similarities of their mechanisms of action. When resistance to the recommended dose rate of an avermectin appears in some species of nematodes, a milbemycin, at its recommended dose rate, may still be effective. However, there is side-resistance among the avermectins and the milbemycins, which are within the same class of anthelmintics, and continued use of either subgroup will select for macrocyclic lactone resistance.

Recently, it was demonstrated in Haemonchus contortus and Onchocerca volvulus that macrocyclic lactone anthelmintics can affect β-tubulin, although no mechanistic explanation for this has been published. However, it suggests that macrocyclic lactone use may select for benzimidazole resistance, because benzimidazole resistance appears to be largely due to a single polymorphism being selected. However, benzimidazole resistance was widely reported before the commercial use of macrocyclic lactones. Ivermectin resistance has usually been reported in areas of the world where benzimidazole resistance is already widespread. In using anthelmintic combinations or rotations, consideration should be given to the genetic interactions in the parasite between benzimidazole and macrocyclic lactone anthelmintics in terms of selection for the alleles that confer benzimidazole resistance.
Every exposure of a target parasite to an anthelmintic exerts some selection pressure for development of resistance. Therefore, management practices designed to reduce exposure to parasites and to minimize the frequency of anthelmintic use should be recommended. The development of an anthelmintic resistance problem may theoretically be delayed by rotating chemicals with different modes of action annually between dosing seasons. Drug combinations may be another appropriate choice, provided the anthelmintics used in the combination are both effective and select for different resistance mechanisms.

In parasite control, economic benefit is best obtained by careful management practices. Planned (or targeted) treatment of a whole flock or herd should be based on the biology, ecology, and epidemiology of the parasite(s), with particular reference to climatic conditions. There is a trend among parasitologists to recommend replacing current practice for worm control involving repeated dosing of whole groups of animals with “targeted selective treatments” in which only individual animals showing clinical signs or reduced productivity are given drugs.

By
Jozef Vercruysse , DVM, Ghent University;
Edwin Claerebout , DVM, PhD, DEVPC, Department of Virology, Parasitology and Immunology, Faculty of Veterinary Medicine, Ghent University

53

Anthelmintic / Safety of Anthelmintics

« Last post by LamiyaJannat on April 07, 2021, 04:45:27 PM »

Safety of Anthelmintics

Most anthelmintics have wide safety margins, ie, the dosage that can be given to an animal before adverse effects are induced is much higher than the dosage recommended for use. The wide safety margin of benzimidazoles is because of their greater selective affinity for parasitic β-tubulin than for mammalian tissues. Nonetheless, this selective toxicity is not absolute; some toxic effects based on antimitotic activity (teratogenicity or embryotoxicity) can occur in some target species, and some benzimidazoles, depending on the dose rate, are contraindicated in early pregnancy.

The safety index (SI) is not as wide for levamisole (SI = 4–6), nor for most of the chemicals active against liver flukes (SI = 3–6). Mammalian toxicity with levamisole is seen more often than with benzimidazoles, although toxic signs are unusual unless the normal therapeutic dosage is exceeded. Levamisole toxicity in the host animal is largely an extension of its antiparasitic effect, ie, cholinergic-type signs of salivation, muscle tremors, ataxia, urination, defecation, and collapse. In fatal levamisole poisoning, the immediate cause of death is asphyxia due to respiratory failure. Atropine sulfate can alleviate such signs. Levamisole may cause some inflammation at the site of SC injection, but usually this is transient. Toxicity increases if other anticholinergic drugs (eg, organophosphates) are given at the same time.

Because of their low absorption from the gut, tetrahydropyrimidines have a high safety margin. Adverse effects (vomiting in dogs and cats) are rare. Toxicity increases when other cholinergic drugs (eg, levamisole, organophosphates) are used simultaneously.

The margin of safety for organophosphates is generally less than that of the benzimidazoles, and strict attention to dosage is necessary. Generally, their toxicity is additive; thus, concurrent use of other cholinesterase-inhibiting drugs should be avoided. Atropine and 2-PAM are used as antidotes to organophosphate toxicity (also see Organophosphates (Toxicity)). Organophosphates also can be hazardous to people. Being lipid soluble, they are readily absorbed through unbroken skin. Sprays, collars, and washes of organophosphates used for small animals can present significant hazards to young infants after ingestion, inhalation, or transcutaneous absorption.
Mammals are generally not adversely affected by macrocyclic lactones. The SI for the macrocyclic lactones is typically wide, but both abamectin and moxidectin are contraindicated in calves and foals <4 mo old, respectively, because of narrow safety margins in these classes of stock. Otherwise, single administration at ~10 times and multiple administration at 3 times the recommended therapeutic dose levels do not have any secondary effects on healthy host animals.

Mammalian safety appears to depend on P-glycoprotein activity in the blood-brain barrier. A P-glycoprotein deficiency in certain animals decreases the ability to pump avermectins, milbemycins, and other drugs across cell membranes. The net effect is an increase in systemic bioavailability, because animals deficient in P-glycoprotein are not able to actively pump the macrocyclic lactones out of the CNS or efficiently process these drugs. This decreases the ability to redistribute, metabolize, and excrete macrocyclic lactones, as well as antineoplastic drugs, opioids, acepromazine, digoxin, and ondansetron, resulting in toxicity with what would be considered normal doses in most animals. There have been cases of CNS depression in cattle breeds (Murray Grey) and in individual dogs of multiple breeds, but these were first recognized in purebred and crossbred Collies. Nervous signs (idiosyncratic reactions), including depression, muscle weakness, blindness, coma, and death, were seen when high doses were administered.

Because salicylanilides, substituted phenols, and aromatic amides are general uncouplers of oxidative phosphorylation, their SIs are lower than those of many other anthelmintics. Nonetheless, they are safe if used as directed. Adverse effects are most commonly seen in animals that are severely stressed, in poor condition nutritionally or metabolically, or have severe parasitic infections. Mild anorexia and unformed feces may be seen after treatment at recommended dosages. High dosages may cause blindness, hyperthermia, convulsions, and death—classic signs of uncoupled phosphorylation.

The amino-acetonitrile derivatives target a nematode-specific receptor that is absent in mammals and other organisms. Because of this specific mode of action, monepantel has a very favorable safety profile. Monepantel has been administered to lambs in doses up to 30 times higher than the recommended dose without any adverse effects. In addition, repeated oral administration of monepantel at three times the recommended dose every 5 days over an entire reproductive cycle was not associated with any treatment-related adverse effects on the reproductive performance of rams or ewes or on the viability of their offspring, and it was systemically very well tolerated.

Emodepside appears to be of low acute toxicity in a variety of laboratory animal species and by a variety of routes. Although overt signs of toxicity include depressed neurologic and respiratory function, they occur only at dose rates far in excess of the recommended therapeutic dose in cats. Repeated treatment at three times the therapeutic dose was tolerated in pregnant and lactating dams/queens, so adverse effects on reproductive function of the dams and/or kitten health are not anticipated when the product is administered at the recommended treatment dose. Safety in dogs was established only for puppies ≥12 wk old.
The combination of derquantel and abamectin did not result in any adverse clinical effects in ewes and lambs under field conditions, other than a commonly reported, mild, transient coughing.

By
Jozef Vercruysse , DVM, Ghent University;
Edwin Claerebout , DVM, PhD, DEVPC, Department of Virology, Parasitology and Immunology, Faculty of Veterinary Medicine, Ghent University

54

Anthelmintic / Withholding Periods After Anthelmintic Treatment

« Last post by LamiyaJannat on April 07, 2021, 04:43:03 PM »

Withholding Periods After Anthelmintic Treatment

Last full review/revision Sep 2014 | Content last modified Oct 2014 Most anthelmintics have withholding periods if milk or meat from treated animals is intended for human consumption; the specific requirements for each must be observed. Of the benzimidazoles, thiabendazole is absorbed and excreted most quickly; fenbendazole, oxfendazole, and albendazole are absorbed and excreted over a longer period, which necessitates withholding periods of 8–14 days before slaughtering for meat and 3–5 days before milking for human consumption. Other members of the group have withholding periods between these extremes, but withholding periods are longer for bolus formulations.

A similar relationship between the rate of metabolism and activity against immature parasites also exists with certain fasciolicides. Closantel, rafoxanide, and nitroxynil bind more strongly to blood proteins than does oxyclozanide, and therefore remain in the blood for longer periods. While this greater persistence is associated with greater activity against immature liver flukes, the withholding period for slaughter is also longer: 21–77 days for closantel, rafoxanide, and nitroxynil, compared with 3–14 days for oxyclozanide. The low plasma-protein binding of diamfenetide, coupled with the rapid excretion of its active metabolite, necessitates only a short withdrawal time. Similarly, withholding periods for milk vary widely. Closantel and nitroxynil cannot be used in lactating animals when milk is intended for human consumption, whereas oxyclozanide has a withdrawal time of only 60 hr.

Levamisole and morantel are rapidly excreted; thus, withholding periods for meat are short, and frequently there is no, or only a short, withholding period for milk. However, in some countries, levamisole cannot be used in lactating animals when milk is intended for human consumption.

Ivermectin and doramectin are excreted in milk and are not recommended when milk is intended for human consumption. Commensurate with the long period of activity of macrocyclic lactones, ivermectin, abamectin, doramectin, and moxidectin have significant withholding periods before slaughter (eg, 35 days), which vary with the formulations and local regulations. Residual concentrations of moxidectin in milk after topical administration are below threshold limits, resulting in no milk withholding period in many countries. The chemical structure of the macrocyclic lactone molecule has been manipulated to change the milk partitioning coefficients in lactating dairy animals. For example, only 0.1% of the total dose of eprinomectin is eliminated in the milk, resulting in no withholding period for milk worldwide.

Monepantel has a withdrawal period of 7–14 days for meat and is not approved for use in lactating animals producing milk for human consumption.

In combination with abamectin, derquantel has a withholding period of 14 days for meat and is not approved for use in lactating animals producing milk for human consumption.

By
Jozef Vercruysse , DVM, Ghent University;
Edwin Claerebout , DVM, PhD, DEVPC, Department of Virology, Parasitology and Immunology, Faculty of Veterinary Medicine, Ghent University

55

Anthelmintic / Pharmacokinetics of Anthelmintics

« Last post by LamiyaJannat on April 07, 2021, 04:40:08 PM »

Pharmacokinetics of Anthelmintics

After administration, anthelmintics are usually absorbed into the bloodstream and transported to different parts of the body, including the liver, where they may be metabolized and eventually excreted in the feces and urine. The disposition of anthelmintics throughout the body is considerably more complex than can be described by a set of pharmacokinetic parameters in the peripheral circulation. Improved drug performance requires knowledge of drug behavior in the multicompartmental system, including the complex interaction between formulation and route of administration, physicochemical properties of the compound, and physiology of the compartment into which the drug is distributed.
Although many helminth parasites reside in the lumen or close to the mucosa, others live at sites such as the liver and lungs; for action against these, absorption of drug from the GI tract, injection site, or skin is essential. Intestinal parasites come in contact not only with the unabsorbed drug passing through the GI tract but also with the absorbed fraction in the blood as they feed on the intestinal mucosa, and with any that is recycled into the gut. This is an important aspect of efficacy of many of the benzimidazoles.

The pharmacokinetics of an anthelmintic, its rate of metabolism and excretion, and its safety profile determine the length of the withdrawal time; this period can vary among species and can also be affected by route of administration and dose. The usual site of metabolism of anthelmintics is the liver, where oxidation and cleavage reactions commonly occur.

Benzimidazoles and Probenzimidazoles:

With a few exceptions, eg, albendazole, oxfendazole, and triclabendazole, only limited amounts of any of the benzimidazoles are absorbed from the GI tract of the host. The limited absorption is probably related to the poor water solubility of these drugs. The little absorption that occurs is generally rapid, 2–7 hr after dosing with flubendazole and 6–30 hr after dosing with albendazole, fenbendazole, and oxfendazole, depending on the species. Many of the benzimidazoles and their metabolites re-enter the GI tract by passive diffusion, but the biliary route is the most important pathway for secretion and recycling of benzimidazoles in the GI tract.

A number of benzimidazoles (eg, febantel, thiophanate, netobimin) exist in the form of prodrugs that must be metabolized in the body to the biologically active benzimidazole carbamate nucleus. Febantel is hydrolyzed to the active metabolite fenbendazole, and netobimin undergoes processes of reduction, cyclization, and oxidation to yield albendazole sulfoxide. Benzimidazole sulfoxides such as oxfendazole and albendazole sulfoxide bind poorly to parasite β-tubulin and probably act as prodrugs for fenbendazole and albendazole, respectively. The thiometabolites have high affinity for helminth tubulin.

Metabolism of the benzimidazoles is variable and may alter their activity; eg, albendazole is rapidly and reversibly oxidized to its sulfoxide form. The sulfoxide may be irreversibly oxidized to its sulfone, which is significantly less active than the sulfoxide. Similarly, fenbendazole and oxfendazole (fenbendazole sulfoxide) are interchangeable, but the oxidation product fenbendazole sulfone is less active and is not reduced back to the sulfoxide or thio metabolites.

In ruminants, the benzimidazoles are most effective if deposited into the rumen. Administration directly into the abomasum, via the esophageal groove, may shorten the duration for drug absorption and increase the rate of excretion in the feces, which may reduce efficacy. For example, immediate arrival of oxfendazole in the abomasum after dosing reduces its efficacy from 91% to 45% against thiabendazole-resistant strains of Haemonchus contortus. The rumen acts as a drug reservoir from which plasma concentrations can be sustained, slowing the passage of unabsorbed drug through the GI tract.

Imidazothiazoles:

The absorption and excretion of levamisole is rapid and not affected by the route of administration or ruminal bypass, because it is highly soluble. In cattle, blood concentrations of levamisole peak <1 hr after SC administration. These concentrations decline rapidly; 90% of the total dose is excreted in 24 hr, largely in the urine.

Tetrahydropyrimidines:

Pyrantel tartrate (or citrate) is well absorbed by pigs and dogs, less well by ruminants. The pamoate salt (synonym embonate) of pyrantel is poorly soluble in water; this offers the advantage of reduced absorption from the gut and allows the drug to reach and be effective against parasites in the large intestine, which makes it useful in horses and dogs.

Metabolism of pyrantel is rapid, and the metabolites are excreted rapidly in the urine (40% of the dose in dogs); some unchanged drug is excreted in the feces (principally in ruminants). Blood concentrations usually peak 4–6 hr after PO administration.

Morantel is the methyl ester analogue of pyrantel and, in ruminants, it tends to be safer and more effective than pyrantel. It is absorbed rapidly from the upper small intestine of sheep and metabolized rapidly in the liver; ~17% of the initial dose is excreted in the urine as metabolites within 96 hr after dosing.

Macrocyclic Lactones:

Macrocyclic lactones are hydrophobic, an important characteristic of this class of anthelmintics. Regardless of their route of administration, macrocyclic lactones are distributed throughout the body and some concentrate in adipose tissue. Liver tissue contains the highest residue for the longest, reflecting the route of elimination. Although the magnitude of lipophilicity differs among chemical types, the limited vascularization and slow turnover rate of body fat and the slow rate of release or exchange of drug from these lipid reserves can prolong the residence of drug in the peripheral plasma. Ivermectin is arguably the least lipophilic macrocyclic lactone, with the possible exception of eprinomectin. Moxidectin is ~100 times more lipophilic than ivermectin. Doramectin is less lipophilic than moxidectin but more than ivermectin or eprinomectin.

Ivermectin was the first commercially available macrocyclic lactone and has been the most extensively studied. When given IV, ivermectin has an elimination half-life of 32–178 hr, depending on species. Despite the higher dose rate of the injectable formulation in pigs (300 mcg/kg) compared with that of cattle (200 mcg/kg), the maximum concentration (Cmax) and area under the curve (AUC) in peripheral plasma in pigs are about one-third those in cattle. Although the elimination half-life after SC and IV administration of ivermectin is of similar duration, slow absorption from the injection site may broaden the concentration-time profile, with Cmax in peripheral plasma of cattle occurring as late as 96 hr. The Cmax and AUC in pigs and goats are considerably lower than those in cattle, horses, and sheep. Pigs, and possibly goats, may metabolize ivermectin faster than other species.

In ruminants, the macrocyclic lactones are, like benzimidazoles, most effective if deposited directly into the rumen. A 3- to 4-fold decrease in Cmax and AUC of ivermectin after intra-abomasal compared with intraruminal administration has been reported. Significantly, time to maximal concentration of ivermectin was reduced from 23 hr to 4 hr with the former route of delivery.

Concentrations of ivermectin are high in digesta sampled from the distal intestine, indicating that biliary secretion is an important pathway for clearance of macrocyclic lactones. This pathway also has been conclusively demonstrated for clearance of benzimidazole compounds. The extended high concentration in bile is influenced by prolonged exchange of drug from lipid reserves and the enterohepatic recycling of biliary compounds through the portal and biliary pools. The macrocyclic lactones are primarily excreted in the feces, the remainder (<10%) in the urine. The more lipophilic macrocyclic lactones are also excreted in milk.

Salicylanilides and Substituted Phenols:

Secretion via the liver and bile is especially important for drugs active against adult Fasciola spp. The fasciolicidal effects of salicylanilides (such as rafoxanide) in sheep depend on persistence of the drug in plasma, which influences their transport throughout the body and rate of elimination. Closantel, rafoxanide, and oxyclozanide have long terminal half-lives in sheep (14.5, 16.6, and 6.4 days, respectively), which are related to the high plasma-protein binding (>99%) of these three drugs. Residues in liver are detectable for weeks after administration. Associated with persistence, however, is the need for longer withholding periods. Oxyclozanide also is bound to plasma protein and then metabolized in the liver to the anthelmintically active glucuronide and excreted in high concentration in the bile duct, where it encounters the mature flukes.

Immature flukes in the liver parenchyma ingest mainly liver cells, which contain little anthelmintic; plasma-protein binding limits entry of the drug into the tissue cells. As the flukes grow and migrate through the liver, they cause extensive hemorrhaging and come into contact with anthelmintic bound to plasma protein. When they reach the bile ducts, they are in the main excretory channels for the active metabolites of the fasciolicides and are exposed to toxic concentrations. This may explain why mature flukes are more vulnerable to most fasciolicides than immature ones. The higher concentrations of fasciolicides and their metabolites in feces than in urine suggest that the bile ducts are their main excretory pathways.
It is important to understand the pharmacokinetics of prescribed anthelmintics. For example, nitroxynil has good efficacy against F hepatica in cattle and sheep and against H contortus, but because rumen bacteria metabolize and destroy the activity of nitroxynil, it must be injected.

Amino-acetonitrile Derivatives

After PO administration, monepantel is quickly absorbed into the bloodstream and metabolized to a major extent within 4 hr into monepantel sulfone. The sulfone expresses in vitro anthelmintic activity similar to that of the parent molecule and is responsible for the anthelmintic effect in animals, because 95 % of the administered dose is metabolized into the sulfone. The Cmax of monepantel sulfone was 4 fold-higher compared with that measured for the parent compound. After PO administration in sheep of the recommended dosage of 2.5 mg/kg, the elimination half-life of the sulfone metabolite in plasma was 48.7 hr, with a mean residence time of 79.3 hr. Approximately 27% of the administered dose is excreted through the feces in the form of the sulfone derivative. The remaining amount is further metabolized and partly excreted through urine (up to 30% of the administered dose). In addition to the sulfone, the parent monepantel contributes to the anthelmintic activity against abomasal nematodes, because the concentration of the parent monepantel is considerably higher in the abomasum than in plasma.

Cyclic Octadepsipeptides
Studies in rats have been done to assess the general distribution, metabolism, and excretion patterns of emodepside after PO and IV administration. Bioavailability after PO administration is ~50%. Emodepside is distributed throughout the whole organism, but highest concentrations are found in fat tissues, where it forms a deposit that is slowly released. Emodepside is excreted predominantly via the bile and then eliminated in the feces. Approximately half of the administered dose is excreted within the first 24 hr. The elimination half-life after both PO and IV administration is 39–51 hr. Approximately 45%–56% of the administered dose is excreted unchanged, the rest in the form of inactive metabolites. After topical administration in cats, emodepside is absorbed slowly into the bloodstream. Maximum plasma levels are reached 2–3 days after treatment. Absorption after PO administration in dogs is higher if administered to fed animals.

Spiroindoles

Pharmacokinetics demonstrate that after a single oral administration, maximum concentrations of derquantel were reached at 4.2 hr. The terminal half-life of derquantel was 9.3 hr, and the absolute bioavailability was 56.3%. Metabolism of derquantel is extensive and complex. Derquantel undergoes biotransformation to a large number of metabolites over a short time and, as a result, extensive variation in metabolites has been found in tissues and over time periods.

Praziquantel

Praziquantel is rapidly and almost completely absorbed from the GI tract. After absorption, praziquantel is distributed to all organs; it is believed to re-enter the intestinal lumen via the mucosa and bile in dogs. Praziquantel is rapidly hydroxylated into inactive forms in the liver and secreted in bile. It has a wide safety margin.

By
Jozef Vercruysse , DVM, Ghent University;
Edwin Claerebout , DVM, PhD, DEVPC, Department of Virology, Parasitology and Immunology, Faculty of Veterinary Medicine, Ghent University

56

Anthelmintic / Mechanisms of Action of Anthelmintics

« Last post by LamiyaJannat on April 07, 2021, 04:34:53 PM »

Mechanisms of Action of Anthelmintics

Anthelmintics must be selectively toxic to the parasite. This is usually achieved either by inhibiting metabolic processes that are vital to the parasite but not vital to or absent in the host, or by inherent pharmacokinetic properties of the compound that cause the parasite to be exposed to higher concentrations of the anthelmintic than are the host cells. While the precise mode of action of many anthelmintics is not fully understood, the sites of action and biochemical mechanisms of many of them are generally known. Parasitic helminths must maintain an appropriate feeding site, and nematodes and trematodes must actively ingest and move food through their digestive tracts to maintain an appropriate energy state; this and reproductive processes require proper neuromuscular coordination. Parasites must also maintain homeostasis despite host immune reactions. The pharmacologic basis of the treatment for helminths generally involves interference with the integrity of parasite cells, neuromuscular coordination, or protective mechanisms against host immunity, which lead to starvation, paralysis, and expulsion or digestion of the parasite.

Cellular Integrity:

Several classes of anthelmintics impair cell structure, integrity, or metabolism: 1) inhibitors of tubulin polymerization—benzimidazoles and probenzimidazoles (which are metabolized in vivo to active benzimidazoles and thus act in the same manner); 2) uncouplers of oxidative phosphorylation—salicylanilides and substituted phenols; and 3) inhibitors of enzymes in the glycolytic pathway—clorsulon.

The benzimidazoles inhibit tubulin polymerization; it is believed that the other observed effects, including inhibition of cellular transport and energy metabolism, are consequences of the depolymerization of microtubules. Inhibition of these secondary events appears to play an essential role in the lethal effect on worms. Benzimidazoles progressively deplete energy reserves and inhibit excretion of waste products and protective factors from parasite cells; therefore, an important factor in their efficacy is prolongation of contact time between drug and parasite. Cross-resistance can exist among all members of this group, because they act on the same receptor protein, β-tubulin, which is altered in resistant organisms such that none of the benzimidazoles can bind to the receptor with high affinity.

Uncoupling of oxidative phosphorylation processes has been demonstrated for the salicylanilides and substituted phenols, which are mainly fasciolicides. These compounds act as protonophores, allowing hydrogen ions to leak through the inner mitochondrial membrane. Although isolated nematode mitochondria are susceptible, many fasciolicides are ineffective against nematodes in vivo, apparently due to a lack of drug uptake. Exceptions are the hematophagous nematodes, eg, Haemonchus and Bunostomum.

Clorsulon is rapidly absorbed into the bloodstream. When Fasciola hepatica ingest it (in plasma and bound to RBCs), they are killed because glycolysis is inhibited and cellular energy production is disrupted.

Neuromuscular Coordination:

Interference with this process may occur by inhibiting the breakdown or by mimicking or enhancing the action of neurotransmitters. The result is paralysis of the parasite. Either spastic or flaccid paralysis of an intestinal helminth allows it to be expelled by the normal peristaltic action of the host. Specific categories include drugs that act via a presynaptic latrophilin receptor (emodepside), various nicotinic acetylcholine receptors (agonists: imidazothiazoles, tetrahydropyrimidines; allosteric modulator: monepantel; antagonist: spiroindoles), glutamate-gated chloride channels (avermectins, milbemycins), GABA-gated chloride channels (piperazine), or via inhibition of acetylcholinesterases (coumaphos, naphthalophos).
Organophosphates inhibit many enzymes, especially acetylcholinesterase, by phosphorylating esterification sites. This phosphorylation blocks cholinergic nerve transmission in the parasite, resulting in spastic paralysis. The susceptibility of cholinesterases by host and parasite varies, as does the susceptibility of these different species to organophosphates.
The imidazothiazoles are nicotinic anthelmintics that act as agonists at nicotinic acetylcholine receptors of nematodes. Their anthelmintic activity is mainly attributed to their ganglion-stimulant (cholinomimetic) activity, whereby they stimulate ganglion-like structures in somatic muscle cells of nematodes. This stimulation first results in sustained muscle contractions, followed by a neuromuscular depolarizing blockade resulting in paralysis. Hexamethonium, a ganglionic blocker, inhibits the action of levamisole.

Monepantel, the only commercially available amino-acetonitrile derivative, is a direct agonist of the mptl-1 channel, which is a homomeric channel belonging to the DEG-3 family of nicotinic acetylcholine receptors. Binding of monepantel to the receptor results in a constant, uncontrolled flux of ions and finally in a depolarization of muscle cells, leading to irreversible paralysis of the nematodes. These receptors are unique in that they are found only in nematodes.

Derquantel, a semisynthetic member of the spiroindole class of anthelmintics, is an antagonist of B-subtype nicotinic acetylcholine receptors located at the nematode neuromuscular junction; it inhibits 45-pS channels, leading to a flaccid paralysis of nematodes.

Piperazine acts to block neuromuscular transmission in the parasite by hyperpolarizing the nerve membrane, which leads to flaccid paralysis. It also blocks succinate production by the worm. The parasites, paralyzed and depleted of energy, are expelled by peristalsis.

The macrocyclic lactones act by binding to glutamate-gated chloride channel receptors in nematode and arthropod nerve cells. This causes the channel to open, allowing an influx of chloride ions. Different chloride channel subunits may show variable sensitivity to macrocyclic lactones and different sites of expression, which could account for the paralytic effects of macrocyclic lactones on different neuromuscular systems at different concentrations. The macrocyclic lactones paralyze the pharynx, the body wall, and the uterine muscles of nematodes. Paralysis (flaccid) of body wall muscle may be critical for rapid expulsion, even though paralysis of pharyngeal muscle is more sensitive. As the macrocyclic lactone concentration decreases, motility may be regained, but paralysis of the pharynx and resultant inhibition of feeding may last longer than body muscle paralysis and contribute to worm deaths. None of the macrocyclic lactones are active against cestodes or trematodes, presumably because these parasites do not have a receptor at a glutamate-gated chloride channel. Emodepside acts presynaptically at the neuromuscular junction, where it attaches to a latrophilin-like receptor. This receptor belongs to the group of so-called G-protein coupled receptors. Stimulation of the latrophilin-like receptor by emodepside activates a signal transduction cascade via Gq-protein and phospholipase C, causing an increase in intracellular calcium and diacylglycerol levels. At the end of the signal transduction cascade, vesicles containing inhibitory neuropeptide fuse with presynaptic membranes. After fusion of these membranes, inhibitory neuropeptides may be released into the synaptic cleft to then stimulate a postsynaptic receptor. Recent findings indicate that a second emodepside target is the calcium-activated potassium channel slo-1. Binding to the latrophilin receptor and the slo-1 ion channel leads to inhibition of pharyngeal pumping, paralysis, and death.

The mode of action of praziquantel is not certain, but it rapidly causes tegumental damage and paralytic muscular contraction of cestodes, followed by their death and expulsion.[/size]

By
Jozef Vercruysse , DVM, Ghent University;
Edwin Claerebout , DVM, PhD, DEVPC, Department of Virology, Parasitology and Immunology, Faculty of Veterinary Medicine, Ghent University

57

Anthelmintic / Overview of Anthelmintics

« Last post by LamiyaJannat on April 07, 2021, 04:31:33 PM »

Overview of Anthelmintics

Many highly effective and selective anthelmintics are available, but such compounds must be used correctly, judiciously, and with consideration of the parasite/host interaction to obtain a favorable clinical response, accomplish good control, and minimize selection for anthelmintic resistance. Any decrease or increase of the recommended dose rate must always be discouraged. Underdosing is likely to result in lowered efficacy and possibly increased pressure for development of resistance. Overdosing may result in toxicity without necessarily increasing product efficacy.

Most anthelmintics generally have a wide margin of safety, considerable activity against immature (larval) and mature stages of helminths, and a broad spectrum of activity. Nonetheless, the usefulness of any anthelmintic is limited by the intrinsic efficacy of the drug itself, its mechanism of action, its pharmacokinetic properties, characteristics of the host animal (eg, operation of the esophageal groove reflex), and characteristics of the parasite (eg, its location in the body, its degree of hypobiosis, susceptibility of the life stage, or susceptibility to the anthelmintic).

There are several classes of anthelmintics: benzimidazoles and probenzimidazoles, salicylanilides and substituted phenols, imidazothiazoles, tetrahydropyrimidines, organophosphates, macrocyclic lactones and, more recently introduced, the amino-acetonitrile derivatives, the cyclic octadepsipeptides, and the spiroindoles. Although it may be thought that chemotherapeutic control of helminth infections is currently satisfactory, selection for parasite resistance is an increasing concern.

By
Jozef Vercruysse , DVM, Ghent University;
Edwin Claerebout , DVM, PhD, DEVPC, Department of Virology, Parasitology and Immunology, Faculty of Veterinary Medicine, Ghent University

58

Vitamins & Minerals / Vitamins AND minerals for livestock – not vitamins OR minerals

« Last post by LamiyaJannat on April 07, 2021, 12:44:44 PM »

Vitamins AND minerals for livestock – not vitamins OR minerals

Quite often, nutrition experts are presented with the question, “What’s better? Vitamin or mineral injections?”
Answering this question is a little like answering “What’s better on my roast lamb? Mint or rosemary?” There is no one thing better than the other, but it is actually the combination of both that makes the best dish. The same is true for vitamins and minerals.

What is the difference between vitamins and minerals?

“Vitamins and minerals are completely different,” said Dr Jerry Liu, comparative nutritionist and product manager for Virbac. “In some shape or form, all vitamins and minerals are required by animals for life and production.”
“Ruminants have the ability to synthesise certain vitamins, but even then, others like vitamins A and and E must be obtained through feed or supplements. Minerals can’t be synthesised at all. So they need to be obtained entirely through feed or even an injection.”

The vitamins versus minerals question is becoming increasingly commonly asked by farmers in recent years, particularly since Multimin has grown in popularity. “I often get asked by farmers whether Multimin is similar to ADE”, stated Dr Liu. “Other than both being injectables, the products have absolutely nothing in common. Multimin is a multi-mineral injection, while ADE is an injectable multi-vitamin supplement. The nutrients in both products are needed by the animals, but they have completely different functions within the body.”

Dr Liu’s statements make a lot of sense when you look at the functions of different vitamins and minerals. For example, the trace mineral zinc (present in Multimin) is needed for the body to produce around 100 different enzymes, which are responsible for things like sperm production and maintaining the uterus for embryo implantation. Vitamin A (present in ADE injections) is needed to form components of the eye needed for vision. Simply put, the function of a mineral cannot be replaced by a vitamin, with the exception of cobalt by vitamin B12.

“Nutritional science is always evolving”, added Dr Liu. “I’ve seen it countless times in both human and animal nutrition. It is easy to get confused and even experts are always learning. Fantastic concepts and technologies are constantly being introduced, but they are not always the easiest to understand.”

Multimin is an effective trace mineral ‘top up’

One such innovation is Multimin, a highly bioavailable mineral injection which introduced the “top up” concept. Unlike oral supplements, which are excellent for day-to-day use, Multimin is used to top up the animal’s mineral levels 30 days before a critical event, like joining, weaning, and calving, when demands increase.
“Cattle are pretty good with some minerals like phosphorus. They know when they are deficient, so they will seek out this mineral. But most of the time, it is difficult for them to optimise their own mineral levels. Even I don’t know how much of something to eat just by the way I feel. It’s unreasonable to expect the same from livestock,” explained Dr Liu. He continued, “Plus, antagonism makes it very hard for them to absorb enough when demands are high.” Antagonism is a process when essential minerals are bound to other components in the feed (e.g. calcium and iron), which will result in the mineral being unavailable to the animal. Injecting a product like Multimin will prevent antagonism and ensure that each animal is getting the required dose when it is needed most.

MULTIMIN® INJECTION FOR CATTLE contains copper, zinc, selenium, and manganese in a chelated form. It provides a rapidly absorbed source of trace minerals that can be strategically used to help increase health, immunity, fertility, and productivity.

Source: https://au.virbac.com/health-care/cattle-nutrition/vitamins-and-minerals-cattle

59

Article / How Drugs are Given in Animals

« Last post by LamiyaJannat on April 05, 2021, 07:02:21 PM »

How Drugs are Given in Animals

A wide range of dosage formulations and delivery systems has been developed to provide for the care and welfare of animals. Using the correct dosage is very important in terms of effectiveness and safety. Drug treatment and delivery strategies can be complicated because of the variety of species and breeds treated, the wide range in body sizes, different animal rearing practices, seasonal variations, and the level of convenience, among other factors.

Drugs Given by Mouth
Oral dosage forms (given by mouth) include liquids (solutions, suspensions, and emulsions), semi-solids (pastes), and solids (tablets, capsules, powders, granules, premixes, and medicated blocks).

A solution is a mixture of 2 or more components that mix well and form a single phase that is consistent down to the molecular level (such as sugar water). Solutions are absorbed quickly and generally cause little irritation of the lining of the stomach and intestine. However, the taste of some drugs is more unpleasant when in solution. Oral solutions provide a convenient means of drug administration to newborn and young animals.

A suspension is a coarse dispersion of insoluble drug particles in a liquid (for example, flour mixed in water). Suspensions are useful for administering insoluble or poorly soluble drugs or in situations when the presence of a finely divided form of the material in the stomach and intestinal tract is required. The taste of most drugs is less noticeable in suspension than in solution because the drug is less soluble in suspension. Suspensions must typically be shaken vigorously just prior to administering.

An emulsion consists of 2 non-mixable liquids, one of which is dispersed throughout the other in the form of fine droplets (such as oil and vinegar salad dressing). Emulsions for oral administration are usually oil (the active ingredient) in water. They facilitate the administration of oily substances such as castor oil or liquid paraffin in a more palatable form.

A paste is a 2-component semi-solid in which a drug is dispersed as a powder in a liquid or fatty base. It is critical that pastes have a pleasant taste or are tasteless. Pastes are a popular dosage form for treating cats and horses, and can be easily and safely administered by owners.

A tablet consists of one or more active ingredients mixed with fillers. It may be a conventional tablet that is swallowed whole or a chewable tablet. Conventional and chewable tablets are the most common forms used to administer drugs to dogs and cats. Tablets can be more physically and chemically stable than liquid forms. The main disadvantages of tablets are the low absorption rate of poorly water-soluble drugs or simply poorly absorbed drugs, and the local irritation of the stomach or digestive tract lining that some drugs may cause.

A capsule is usually made from gelatin and filled with an active ingredient and fillers. Two common capsule types are available: hard gelatin capsules for solid-fill formulas, and soft gelatin capsules for liquid-fill or semi-solid-fill formulas. Capsules have no taste and are therefore good for drugs that are otherwise hard to give because of their bad flavor.

A powder is a formulation in which a drug powder is mixed with other powdered fillers to produce a final product. Most powders are added to food. Powders have better chemical stability than liquids and dissolve faster than tablets or capsules. Unpleasant tastes can be a factor with powders and are a particular concern when used in food because the animal may not eat all of it. In addition, sick animals often eat less and may not eat enough of the powdered drug for it to be effective.

A granule consists of powder particles that have been formed into larger pieces. Granulation is used when combining more than one form of medication. Granulation is especially effective for combining particles that are of different sizes because it helps prevent the separation or settling of the different particle sizes during storage or dose administration. Imagine granola clusters—if you just have granola mix, the smaller pieces fall to the bottom and are not eaten as often, but if you form it into clusters (large granules), you get every type of ingredient in each bite.

Drugs Given as Injections or Implants
A drug that is given parenterally—that is, by injection or as an implant—does not go through the gastrointestinal system. These drugs may be formulated in several different ways for use in animals, including solutions, suspensions, emulsions and as a dry powder that is mixed with a liquid to become a solution or a suspension immediately prior to injection. Dry powders are used for those drugs that are unstable in liquid form.
The majority of implants used in veterinary medicine are compressed tablets or dispersed matrix systems in which the drug is uniformly dispersed within a nondegradable polymer.

Drugs Applied to the Skin or Mucous Membranes
The dosage forms applied to the skin or mucous membranes that are available for treating animals include solids (dusting powders), semi-solids (creams, ointments, and pastes), and liquids (solutions, suspension concentrates, and emulsifiable concentrates). These are known as topical drugs. Of special interest are transdermal delivery systems that work by carrying medications across the skin barrier to the bloodstream. Examples of these are transdermal gels and patches that are used in pets. There are also dosage forms that are unique to veterinary medicine, such as spot-on or pour-on formulations developed for the control of parasites.

A dusting powder is a fine-textured insoluble powder containing ingredients such as talc, zinc oxide, or starch in addition to the drug. Some feel gritty, and some have a smooth texture. Some dusting powders absorb moisture, which discourages bacterial growth. Others are used for their lubricant properties. The use of dusting powders is good for skin folds and not good for use on wet surfaces, as caking and clumping is likely to result.

A cream is a semi-solid emulsion formulated for application to the skin or mucous membranes. Cream emulsions are most commonly oil-in-water but may be water-in-oil. The oil-in-water creams easily rub into the skin (commonly called vanishing creams), and are easily removed by licking and washing. Water-in-oil emulsions are skin-softening and cleansing. Water-in-oil creams are also less greasy and spread more readily than ointments.

An ointment is a greasy, semi-solid preparation that contains dissolved or dispersed drugs. A range of ointment bases is used. Ointments are often effective at soothing because they block the skin from irritation. Ointments are useful for chronic, dry skin conditions and are not good for oozing or weeping areas of the skin.

A paste for skin use is a stiff preparation containing a high proportion of finely powdered solids such as starch, zinc oxide, calcium carbonate, and talc in addition to the drug(s). Pastes are less greasy than ointments. Pastes do not seal wounds.
Solutions are liquid formulations. Topical solutions include eye drops, ear drops, and lotions.

A transdermal delivery gel consists of a gel that delivers the active drug through the skin to the bloodstream. Not all drugs are suitable for this type of transdermal application, however. Transdermal gels have been used to treat several diseases in dogs and cats, including undesirable behavior, cardiac disease, and hyperthyroidism. The dose is applied to the inner surface of the ear, making it easy to administer, especially in cats.

A transdermal delivery patch typically consists of a drug incorporated into a patch that is applied to the skin. The drug is absorbed across the skin over a long period of time. One type of pain reliever, which produces reactions like the body’s own natural pain relievers, is delivered by transdermal patch in dogs, cats, and horses.

A spot-on formulation is a solution of active ingredient(s), which also typically contains a co-solvent and a spreading agent to ensure that the product is distributed to the entire body.
Insecticidal collars are plasticized polymer resins that contain an active ingredient. Collars for the control of ticks and fleas on dogs and cats release the active ingredient as a vapor, a dust, or a liquid, depending on the chemical. The animal’s activity is an important factor in how well the insecticide moves from the collar to the animal.

By Philip T. Reeves, BVSc (Hons), PhD, FANZCVS, Veterinary Medicines and Nanotechnology, Australian Pesticides and Veterinary Medicines Authority;
Camille Roesch, PhD, Australian Pesticides and Veterinary Medicines Authority, Symonston, Australia;
Michelle Nic Raghnaill, PhD, National Academy of Science, Canberra, Australia

60

Antibiotics / Categorisation of antibiotics for use in animals for prudent and responsible use

« Last post by LamiyaJannat on April 05, 2021, 04:05:27 PM »

Categorisation of antibiotics for use in animals for prudent and responsible use

Prudent and responsible use of antibiotics in both animals and humans can lower the risk of bacteria becoming resistant. This is particularly important for antibiotics that are used to treat both people and animals and for antibiotics that are the last line of treatment for critical infections in people.
The Antimicrobial Advice Ad Hoc Expert Group (AMEG) has categorised antibiotics based on the potential consequences to public health of increased antimicrobial resistance when used in animals and the need for their use in veterinary medicine.The categorisation is intended as a tool to support decision-making by veterinarians on which antibiotic to use.
Veterinarians are encouraged to check the AMEG categorisation before prescribing any antibiotic for animals in their care.The AMEG categorisation does not replace treatment guidelines, which also need to take account of other factors such as supporting information in the Summary of Product Characteristics for available medicines, constraints around use in food-producing species, regional variations in diseases and antibiotic resistance, and national prescribing policies.

Category A: Avoid
• antibiotics in this category are not authorised as veterinary medicines in the EU
• should not be used in food-producing animals
• may be given to companion animals under exceptional circumstances

Category B: Restrict
• antibiotics in this category are critically important in human medicine and use in animals should be restricted to mitigate the risk to public health
• should be considered only when there are no antibiotics in Categories C or  D that could be clinically effective
• use should be based on antimicrobial susceptibility testing, wherever possible

Category C: Caution
• for antibiotics in this category there are alternatives in human medicine
• for some veterinary indications, there are no alternatives belonging to Category D
• should be considered only when there are no antibiotics in Category D that could be clinically effective

Category D: Prudence
• should be used as first line treatments, whenever possible
• as always, should be used prudently, only when medically needed

For antibiotics in all categories
• unnecessary use, overly long treatment periods, and under-dosing should be avoided
• group treatment should be restricted to situations where individual treatment is not feasible

Categorisation of antibiotic classes for veterinary use

Category- A: AVOID

Amdinopenicillins

   Mecillinam
   Pivmecillinam

Carbapenems

   Meropenem
   doripenem

Carboxypenicillin and ureidopenicillin, including combinations with beta lactamase inhibitors

   piperacillin-tazobactam

Drugs used solely to treat tuberculosis or other mycobacterial diseases

   Isoniazid
   Ethambutol
   Pyrazinamide
   Ethionamide

Glycopeptides

   Ancomyci

Glycylcyclines

   Igecycline

Phosphonic acid derivates

   Fosfomycin

Pseudomonic acids

   Mupirocin

Ketolides

   Telithromycin

Monobactams

   Aztreonam

Lipopeptides

   Daptomycin

Oxazolidinones

   Linezolid

Other cephalosporins and penems (ATC code J01DI), including combinations of 3rd-generation cephalosporins with beta lactamase inhibitors

   Ceftobiprole
   Ceftaroline
   ceftolozane-tazobactam
   faropenem

Rifamycins (except rifaximin)

   Rifampicin

Riminofenazines

   Clofazimine

Sulfones

   dapson

Streptogramin

   Pristinamycin
   virginiamycin

Substances newly authorised in human medicine following publication of the AMEG

   Categorisationto be determined

Category- B: RESTRICT

Cephalosporins, 3rd- and 4th-generation, with the exception of combinations with β-lactamase inhibitors

   Cefoperazone
   Cefovecin
   Cefquinome
   Ceftiofur

Polymyxins

   Colistin
   polymyxin B

Quinolones: fluoroquinolones and other quinolones

   Cinoxacin
   Danofloxacin
   Difloxacin
   Enrofloxacin
   Flumequine
   Ibafloxacin
   Marbofloxacin
   Norfloxacin
   Orbifloxacin
   oxolinic acid
   pradofloxacin


Category- C: CAUTION

Aminoglycosides (except spectinomycin)

   Amikacin
   apramycin
   dihydrostreptomycin
   framycetin
   gentamicin
   kanamycin
   neomycin
   paromomycin
   streptomycin
   tobramycin

Aminopenicillins, in combination with beta lactamase inhibitors
   amoxicillin + clavulanic
   acidampicillin + sulbactam

Amphenicols
   chloramphenicol
   florfenicol
   thiamphenicol

Cephalosporins, 1st- and 2nd-generation, and cephamycins
   Cefacetrile
   Cefadroxil
   Cefalexin
   Cefalonium
   Cefalotin
   Cefapirin
   Cefazolin

Lincosamides
   Clindamycin
   Lincomycin
   Pirlimycin

Macrolides
   Erythromycin
   Gamithromycin
   Oleandomycin
   Spiramycin
   Tildipirosin
   Tilmicosin
   Tulathromycin
   Tylosin
   Tylvalosin

Pleuromutilins
   Tiamulin
   Valnemulin

Rifamycins: rifaximin only
   Rifaximin


Category- D: PRUDENCE

Aminopenicillins, without beta-lactamase inhibitors
   Amoxicillin
   Ampicillin
   Metampicilli

Aminoglycosides: spectinomycin only
   Spectinomycin

Anti-staphylococcal penicillins (beta-lactamase-resistant penicillins)
   Cloxacillin
   Dicloxacillin
   Nafcillin
   Oxacillin

Cyclic polypeptides
   Bacitracin

Nitroimidazoles
   Metronidazole

Nitrofuran derivatives
   Furaltadone
   Furazolidone

Natural, narrow-spectrum penicillins (beta lactamase-sensitive penicillins)
   benzathine benzylpenicillin
   benzathine phenoxymethylpenicillin
   benzylpenicillin
   penethamate hydriodide
   pheneticillin
   phenoxymethylpenicillin
   procaine benzylpenicillin

Steroid antibacterials
   fusidic acid

Sulfonamides, dihydrofolate reductase inhibitors and combinations
   Formosulfathiazole
   Phthalylsulfathiazole
   Sulfacetamide
   Sulfachlorpyridazine
   Sulfaclozine
   Sulfadiazine
   Sulfadimethoxine
   Sulfadimidine
   Sulfadoxine
   Sulfafurazole
   Sulfaguanidine
   Sulfalene
   Sulfamerazine
   Sulfamethizole
   Sulfamethoxazole
   Sulfamethoxypyridazine
   Sulfamonomethoxine
   Sulfanilamide
   Sulfapyridine
   Sulfaquinoxaline
   Sulfathiazole
   Trimethoprim

Tetracyclines
   Chlortetracycline
   Doxycycline
   Oxytetracycline
   Tetracycline

Other factors to consider

The route of administration should be taken into account alongside the categorisation when prescribing antibiotics. The list below suggests routes of administration and types of formulation ranked from the lowest to the highest estimated impact on antibiotic resistance.

•Local individual treatment (e.g. udder injector, eye or ear drops)
•Parenteral individual treatment (intravenously, intramuscularly, subcutaneously)
•Oral individual treatment (i.e. tablets, oral bolus)
•Injectable group medication (metaphylaxis), only if appropriately justified
•Oral group medication via drinking water/milk replacer (metaphylaxis), only if appropriately justified
•Oral group medication via feed or premixes (metaphylaxis), only if appropriately justified

Source: EUROPEAN MEDICINES AGENCY