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Unique Pharmacokinetic and Pharmacodynamic Parameters of Antimicrobials in Goats

Pharmacokinetics, the process that involves drug absorption, distribution, metabolism and excretion (ADME) of antimicrobials, determines pharmacodynamic response, that is, what drugs do to the body. Therefore, of all the pharmacokinetic parameters, elimination half-life (T 1 / 2 β ), volume of distribution (Vd), maximum plasma concentration (Cmax) and maximum time reached (Tmax) are the most important parameters. Hence, the parameters are unique in determining pharmacokinetic and pharmacodynamic response of antimicrobials. However, it is elimination half-life and minimum inhibitory concentration (MIC) that determine the dosing interval of antimicrobials. The dose range of 2.5 mg/kg for gentamicin passing through 4 mg/kg (ciprofloxacin), 4.2 mg/kg (ampicillin L/A), 5 mg/kg (kanamycin, enrofloxacin, gatifloxacin and norfloxacin), 7 mg/kg (mequindox), 10 mg/kg (amikacin, enrofloxacin, lincomycin, pefloxacin, cefpirome, erythromycin and isoniazid), 20 mg/kg (oxytetracycline) and 30 mg/kg (metronidazole) have elimination half-life of 1.2 – 67.2 h, Cmax of 0.12 – 54.4 μ g/ml, Tmax of 0.2 – 24 h, bioavailability of 16 – 99.8% and plasma protein binding of 0 – >80% when administered intramuscularly, intravenously and orally. Human equivalent dose formula could be used to extrapolate human-goat therapeutic doses of antimicrobials. How-ever, some antimicrobials such as sulfadimidine, tulathromycin, oxytetracycline and azithromycin may have high residues in the milk, kidneys, liver, intestines, brain and skeletal muscles and may portend high risk of antimicrobial resistance, hypersensitivity reaction, epidermal necrolysis, Stevens-Johnson syndrome and other adverse drug reactions.


Introduction
Antimicrobials are either synthetic or natural products (antibiotics) that are used in killing (bactericidal) or controlling the growth (bacteriostatic) of pathogenic microbes. Sometimes, antimicrobial and antibiotic are interchangeably used. Goats belong to species (caprine) and serve as the source of meat and milk [1], and the money realized from sales meet financial obligations of small-and large-scale goat farmers [2]. There are up to 800 million goats in the world [3]. The economic species of goats spread across the globe are not limited to Teddy, Kilis, Ardi, Gram-negative bacilli [7,8] Amikacin i.v.   --Gram-negative [42] Key: -, non-available data.  Table 3.
Half-life, tissue residues and withdrawal period of some antimicrobials.

Biopharmaceutical classification of oral antimicrobials
This is a system of classifying antimicrobials based on aqueous solubility and intestinal permeability. The four major factors being considered in this classification system are dosage form, dissolution rate, solubility and permeability. Hence, antimicrobials are tested in vitro and classified into four classes: Class 1: High solubility À high permeability Class 2: Low solubility À high permeability Class 3: High solubility À low permeability Class 4: Low solubility À low permeability All the classes of dissolution can occur in a pH range of 1-2, 4-5 and 6-8 [46]. Nevertheless, administration of highly toxic antimicrobials such as aminoglycosides (e.g. gentamicin) should be monitored since it damages the kidney.

Pharmacokinetic equations of antimicrobials
Bioavailability, absorption half-life (T 1 / 2 α), mean absorption time (MAT), mean residence time (MRT), apparent volume of distribution (Vd), volume of distribution, steady state (Vdss), area under curve (AUC), area under the first moment curve (AUMC), peak time (Tmax), elimination half-life (T 1 / 2 β) and systemic clearance (Cl) are the pharmacokinetic parameters commonly determined in all species of animals and humans [7,9,[47][48][49]. The most important of all these parameters are elimination half-life, volume of distribution and plasma concentration of the antimicrobials.
The pharmacokinetic process of antimicrobials in goats obeys first-order kinetic (Figures 1 and 2) which could be mono-exponential or bi-exponential. The exponential equation commonly used for determination of pharmacokinetic parameters is CP = A e αt + B e Àβt . Other equations are: Clb ¼ Dose AUC (8) However, peak time (Tmax) and Cmax can be estimated from the pharmacokinetic graph [47].

Comparative pharmacokinetics of antimicrobials in domestic goats
Species variations in response to antimicrobials are very important. Various antimicrobials from different chemical classes, their routes of administration, doses, elimination half-life, bioavailability, maximal concentration, peak time, breed and spectra of activity are presented in Table 1. The therapeutic doses of fluoroquinolones in goats are 1.2 mg/kg subcut for levofloxacin, 5 mg/kg i.v. (orfloxacin, enrofloxacin, norfloxacin and gatifloxacin) and 20 mg/kg oral (pefloxacin). The elimination half-life (2.8 AE 0.02 h) of kanamycin (5 mg/kg) and half-life (1.94 AE 0.1 h) of amikacin (10 mg/kg) in Teddy and Indian native goat, respectively, show that the disposition kinetics of aminoglycosides in goats is dependent on the dose of drugs. Also, disposition kinetics of antimicrobials in goats could be species dependent. For example, Cmax (236.3 AE 0.00 μg/ml) of sulfadimidine in West African dwarf (Figure 1) is higher than that of Pakistan female goat (6.0 AE 3.0 μg/ml) and Shiba goat (2.14 AE 1.05 μg/ml), respectively [16]. Tmax of West African dwarf (1.1 AE 0.3 h) is lower than that of Shiba (2.0 AE 1.2 h) and Netherland dwarf (2.0 AE 0.5 h), respectively [18,19]. But Vd (3.9 AE 0.8 L/kg) in West African dwarf is higher than that of Nubian (0.32 AE 0.0 L/kg), Shiba (0.4 AE 0.2 L/kg) and cross-breed (0.3-0.5 L/kg), respectively [17,19,20], suggesting the difference in breed response to antimicrobials. However, half-life of kanamycin (5 mg/kg) was higher in buffaloes (4.35 AE 0.24 h), cow (6.0 AE 0.50 h) and sheep (3.4 AE 0.1 h) than that of goat (2.8 AE 0.2 h), respectively, indicating that goat is the species most sensitive to kanamycin among these species of herbivores. Also, difloxacin is effective at 5 mg/kg [8]. But normal milk reduces the activity of enrofloxacin against E. coli [50]. However, T1/2β (1.94 AE 0.1 h) of kanamycin for normal goat is lower than the T1/2β (3.17 AE 0.13 h) for febrile goat. Maintenance of therapeutic concentration (2 mg/ml) requires a priming dose of 14.73 mg/kg and maintenance dose of 13.95 mg/kg at an 8-h interval, respectively [8]. Plasma concentration of levofloxacin is higher in healthy goats (15.51 AE 1.41 μg/ml) than mastitis goats (12.48 AE 1.36 kg/ml). This plasma concentration does not affect levofloxacin elimination [9].

Pharmacokinetics of antimicrobials in wild goats
Although the information on pharmacokinetics of wild goats is rare, allometric scaling can be applied for extrapolation of some parameters including Vd and Cl except T1/2β [58]. Ceftazidime (10 mg/kg) administered to Creole goat showed high serum concentration, good penetration and high bioavailability of the drug [45]. But cephalexin (10 mg/kg) administered (subcut, i.m. and i.v.) to Lama glama showed high bioavailability of 72% (i.m.) and 89% (i.v.), respectively. The MIC90 values of cephalexin against coagulase-positive staphylococci and E. coli were 1.0 μg/ml and 8.0 μg/ml, respectively [59]. But MIC90 value (0.01-0.1 μg/ml) of ceftazidime against E. coli, Salmonella species, Pasteurella haemolytica and P. multocida [45] shows that ceftazidime is more active and efficacious than cephalexin, which can be administered 8 mg/kg i.m. or subcut every 12 or 24 h, respectively [59]. Other modes of administration such as ballistic implants and impregnated beads can be employed for some antimicrobials to avoid frequent administration as seen in cefovecin with very long half-life in dogs and cats, allowing a dosing interval of 14 days [60,61]. This strategy may reduce the chance of resistance by microorganisms against antimicrobials. For example, an amoxicillin formulation with half-life of 130 h can be administered every 6 days, and ceftiofur with half-life of 37 h can be administered every 2 days in goats [62]. Orbifloxacin

Pharmacodynamics of antimicrobials
Pharmacokinetics determine maximal therapeutic effect that depends on plasma drug concentration, drug receptors, health status and co-administration of antimicrobial with another drug that shares same or different binding receptors. Slowly eliminated and accumulated antimicrobials are least compared by poor dosing interval [64]. The maximal effect of antimicrobials is dependent on moleculereceptor interaction and drug-affinity response. Therefore, Kaff ¼ 1 ED 50 (21) However, antimicrobial treatments can be monitored as follows: However, when the body weight of goat is reduced by diarrhea or intoxicated by antimicrobials, there may be a need for fluid infusion to maximize balanced pharmacokinetic/pharmacodynamic process of antimicrobials. Clinical correlates of weight loss as a measure of dehydration (>5-12%) must be considered.
Only half of calculated deficit should be administered in 1-2 h. Half replacement in 4-6 h is safer and should be completed in 2 days [65]. Isotonic solutions such as 5% dextrose and 0.9% normal saline can be administered via all routes. But hypotonic and hypertonic solutions should be administered intravenously to avoid tissue reaction.
Weighted AUC approach accounts for a more powerful PK/PD link and reveals uniqueness outcome of therapeutic indices and problems of antibiotic resistance [66]. A combination of ampicillin/sulbactam (20 mg/kg) in ratio 2:1 was administered to goat with elimination half-life of ampicillin (0.71 AE 0.12 h), and sulbactam (1.02 AE 0.36 h) shows that the preparation could be administered at the same dosing rate in both sheep and goats [67]. Also, intramuscular dose (2 mg/kg) of cefquinome (Cobactan 2.5%) daily yielded effective MICs against a variety of susceptible pathogenic microbes of goat including Micrococcus luteus [68]. Serum concentration and AUC integrated with MIC values can predict clinical success. The efficacy of macrolides, penicillins and tetracyclines is determined by the length of time, the serum concentration exceeds the MIC of a pathogenic microbe. But fluoroquinolones, aminoglycosides and metronidazole have concentrationdependent bactericidal activity [69]. The ratio of Cmax/MIC indicates potential of antibacterial activity. Amikacin has the lowest MIC90, whereas kanamycin has the highest [55]. Co-administration of two or more drugs could also affect pharmacokinetics and pharmacodynamics of a drug. For example, West African dwarf goats are more sensitive to sulfadimidine co-administered with piroxicam (Figure 2) [15].

Intraspecies and interspecies scaling of antimicrobials in goats
Variation is an important factor in development of antimicrobials for all species of animals including wild and domestic goats. The problems encountered are how to scale up the pharmacokinetic data from animals to human and how to extrapolate in vitro data to in vivo data for efficacy and safety [70]. There is no enough data on 13 Unique Pharmacokinetic and Pharmacodynamic Parameters of Antimicrobials in Goats DOI: http://dx.doi.org /10.5772/intechopen.84551 toxicological effects of antimicrobials in goats. Hence, several extrapolations are necessary in order to arrive at safe therapeutic and toxic doses [71]. The effective therapeutic doses of some antimicrobials translated from goats to human are given in Table 2.
The formulas used for calculation of extrapolated doses are as follows [13,72,73]. whereas H = height, W = weight and K = constant. But goat's BSA = W O.67 Â 10 À3 and dosimetric adjustment factor (DAF) is body weight of goat over body weight of humans and can be scaled up to 0.25, 0.33 and 0.58. However, body weight exponent of 0.67 and 10 À3 safety factor should be applied to goat, and the exponent of 0.528 should be applied to human weight and height, respectively [72,74].

Antimicrobial tissue residues in goats
Tissue residues of some antimicrobials above recommended thresholds are of public health importance. The presence of sulfadimidine residues (>0.1 ppm) in the liver, kidney, skeletal muscle, spleen, lung, brain and heart after administration of the drug (100 mg/kg) shows that the withdrawal period is longer than 30 days. Hence, sulfadimidine is not easily excreted in West African dwarf goats [13]. This may be due to the presence of desamino-sulfonamide, a sulfadimidine metabolite [75] which is eliminated slowly, thereby increasing the withdrawal time [76]. Lack of adequate water to dilute crystals of sulfadimidine in the kidney can lead to crystalluria that can consequently cause nephrosis in the affected animals [44], and consumptions of meats with high residues of sulfadimidine can cause Steven-Johnson syndrome in sensitive humans who may be slow or fast acetylators [13,23]. Based on the tissue tolerance limit in cattle (5 ppm), the withdrawal period for tulathromycin is 19 days in cattle and 34 days in goat when administered subcutaneously [5]. The quantity of erythromycin residues (2.06 AE 0.36 μg) is above the recommended threshold and may portend risk to public health. The bioavailability of tylosin in goat is 72.6AE 2.3%, and its withdrawal period (48 h) [43] shows that the higher the bioavailability, the lower may be the withdrawal period in milk. Residues of antimicrobials in various tissues are presented in Table 3. A kid that feeds on milk with residues of antimicrobials may be vulnerable to resistance of microorganisms against the antimicrobials.

Antimicrobial resistance
Goats are exposed to antimicrobials via prevention, treatment of diseases and growth promotion. This has caused the emergence of resistant Salmonella, Campylobacter, Pasteurella, Actinobacillus, Enterococcus and Escherichia species. The resistance is transferred by genes. But good and improved management practices and increased use of vaccines and probiotics could minimize emergence and spread of resistance genes [77].Off-label use of antimicrobials in goats could also contribute to emergence of resistance. Meanwhile, lack of official-generated data on consequences of extra-label use of drugs in goats cannot rule out its potential risks to goats and other species of animals [78]. However, T-phage, transposon and integrin are used for resistance gene transfer. Unfortunately, the worldwide consumption of antimicrobial drugs is increasing, and the manufacturing industries are not keeping pace. The worst of it at the moment is the emergence of superbugs and super drugs. Therefore, there is a need for green antibiotics to minimize the chance of resistance [79].

Determination of creatinine and glomerular filtration rate as indices of renal function in goats
Kidneys are responsible for water-electrolyte balance in the body, usually affected by activity-rest rhythm under hormonal influence. The diurnal changes are useful in chronobiology and chronopharmacology [80]. Many xenobiotics including antimicrobials are toxic to the kidney, and renal impairment can be assessed using creatinine clearance which is physiologically, pharmacologically and toxicologically related to body weight, clearance, volume of urine creatinine, plasma creatinine, serum creatinine, urine volume, glomerular filtration rate, creatinine clearance, creatinine half-life and depuration [81]. The plasma creatinine of Boer-Cross (0.60 mg/dl), Nubian (0.55 mg/dl) and Spanish (0.57 mg/dl) goat have been reported [82], whereas creatinine value (1.03-1.24 mg/dl) has been reported for healthy captive, Persian wild goat [83]. Area under curve could be used to determine creatinine clearance and plasma clearance as demonstrated in the equations given below [81]. For example, paracetamol reduced glomerular filtration rate and induced less urinary excretion of isoniazid. Also, renal handling of isoniazid involved glomerular filtration, back diffusion and active tubular secretion [84]. Glomerular filtration rate which is a function of creatinine clearance can be affected by environmental and genetic factors as may be seen in native Pakistan goats administered ampicillin (20 mg/kg) with renal clearance of 0.08 ml/min/kg [85]. Hence, GFR is lower in Pakistan native than the foreign goats [86] unlike renal handling of marbofloxacin in Lohi sheep that involves both glomerular filtration and active tubular secretion [87] indicating that environment has physiological effects on various breeds of goats. This agrees with Bergmann's rule which states that light animals tend to live in hot regions of the world as opposed to fatty animals that tend to live in cold regions [88]. Since 8% of total body weight determines total blood volume, red cell volume and plasma volume could also be determined from hematocrit as indicated in the equation given below [89].

Conclusion
Pharmacokinetic, pharmacodynamic, intraspecies and extraspecies scaling are some parameters that can affect physiological functions of antimicrobials in goats. Lack of judicious and extralabel use of antimicrobials in goats could cause high tissue residues and development of resistance by susceptible microorganisms against the antimicrobials in both goats and humans. Tissue residues of sulfadimidine may cause Stevens-Johnson syndrome in the vulnerable individuals. Dehydrated goats may be more susceptible to antimicrobial toxicity. GFR can be used to assess the level of kidney damage caused by antimicrobials, and rehydration therapy is useful in dissolution of antimicrobial crystals formed in the kidney. In case of fervent need for extralabel use of antimicrobials, the relevant formulas reported herein could be used to translate goat dose to human dose and vice versa.