Interaction of any drug with nutritional components is an important clinical phenomenon having significant impact on therapeutic prognosis of diseased animals. Drug-Nutrient Interactions (DNIs) occur either directly between drug and nutrient or indirectly between drug and nutritional status or vice-versa. Antimicrobials being the largest segment of veterinary pharmaceuticals used clinically need special attention in this aspect. Abnormal nutritional status including protein-energy malnutrition and obesity has great impact on drug disposition. Foods may affect the disposition processes of antimicrobial drugs and their negative clinical impact can be minimized by correcting nutritional status, altering time interval between administration of drug and food, or by adjusting dosage regimen. Thus, proper knowledge of such interactions is indispensable to minimize harmful effects like therapeutic failure, emergence of antimicrobial resistance, nutritional adversities and drug-toxicities. .
Drug interactions with food and nutritional status of animal under treatment are of great concern to all animal health care professionals. The incidence of drug-nutrient interactions in human beings is well known and appears to be wide-spread. More than 400 medications out of the almost 900 drugs and fixed drug combinations used in USA may interact with food or its components, and almost that many may deplete specific nutrients, whereas more than 300 drugs demonstrate interaction with dietary supplements (Schopick, 2005). Foods, and the nutrients they contain, can interact with medications taken by a patient. Such Drug-nutrient interactions (DNIs) have been recognized since many decades which may or may not be detrimental from clinical point of view. Improper management of harmful DNIs may lead to therapeutic failure or may cause adverse effects to patients (Chan, 2002; Santos and Boullata, 2005 and Fettman et al., 2010). Information or literature for DNIs is much lesser available than that exist for topic ‘Drug-Drug Interactions’ (Boullata and Hudson, 2012). Further, information is scanty on the influence of antimicrobials on nutritional status in DNI issues (Wallace, 2004) and out of which, very little information pertaining to veterinary patients is available (Michel and Higgins, 2002). Only few literatures are available on antimicrobial DNIs that mostly exist in the form of pharmacokinetic studies in animal species.
Drug – Nutrient Interactions (DNIs) and Their Types
The term Drug – Nutrient Interaction (DNI) is synonymous with ‘Food – Drug Interaction’ and has been defined as “An alteration of kinetics or dynamics of a drug or nutritional element, or a compromise in nutritional status as a result of the addition of a drug” (Chan, 2013). Another widely accepted definition of DNI is given by Boullata and Barber (2004) as “Result of a physical, chemical, physiologic, or patho-physiologic relationship between a drug and nutrient status, a nutrient, multiple nutrients, or food in general”. Chan (2002) described four types of drug-food interaction based on their nature and mechanisms-
It refers to interactions between the drug and the nutrient or their formulation through biochemical or physical reactions like hydrolysis, oxidation, neutralization, precipitation and complex formation. These interactions usually occur in the delivery device.
They cause either an increase or decrease in the oral bioavailability of a drug by affecting absorption. The nutritional factors may modify the function of enzymes or transport mechanisms that are responsible for biotransformation.
They affect the systemic or physiologic disposition and occur once the drug or the nutritional element has been absorbed from the gastrointestinal tract and entered the systemic circulation. It generally involves changes in the cellular or tissue distribution, systemic transport, or penetration to specific organs or tissues.
It refers to the elimination or clearance of drugs or nutrients, which may involve the antagonism, impairment or modulation of renal and/or enterohepatic elimination.
Impact of Nutritional Status on Antimicrobial Drug Disposition
Poor nutritional status such as protein-energy malnutrition (PEM) and obesity influence antimicrobial drug disposition. In clinical cases, malnutrition leads to chronic protein deficiency and metabolism is consistently reduced. In chronic malnutrition, hepatic protein synthesis is reduced and protein carriers for drugs distribution become limited, resulting in greater concentrations of drug available in free form (Walter-Sack and Klotz, 1996). Thus, PEM can alter the synthesis of plasma proteins, drug distribution and pharmacokinetics. The activities of the mixed-function oxidases (MFOs), flavoprotein reductase and cytochrome b5 are decreased by dietary protein restriction. High-protein, low-carbohydrate foods enhance the hepatic metabolism and excretion of most of drugs. Sulfur-containing amino acids can promote hepatic drug metabolism by increasing glutathione synthesis and subsequent conjugation reactions. Starvation can reduce the activity of glutathione-S-transferase and the synthesis of glutathione for conjugation. Impact of malnutrition on sulfadiazine disposition in young rhesus monkeys was evaluated. Total absorption of sulfadiazine was not affected, but the peak (time to reach maximum absorption) was delayed in the group of monkeys with PEM. The volume of distribution (peripheral), elimination rate constant and clearance rate of the drug were reduced. It was suggested that the reduced volume of distribution of drug may be a key factor in reducing drug elimination (Nehru et al., 1988).
Oukessou and Toutain (1992) studied the effect of high digestible protein diet on disposition of gentamicin (4 mg/kg body weight) in Moroccan sheep. They fed sheep with diet high in digestible proteins (120 g/day) and with low in digestible proteins (25 g/day) in other group. The serum gentamicin concentrations were consistently higher in ewes that received a low protein diet. Gentamicin clearance as well as volume of distribution at steady state was lower in the ‘low digestible proteins’ group. It was concluded that the protein content of the diet modified the distribution of body water and renal function. In similar studies, increased dietary protein intake in dogs (from 9.4 to 27.3% on a dry matter basis) increases the elimination of gentamicin and thus, reduces the potential for nephrotoxicity, apparently by stimulating renal blood flow. Dogs fed the high-protein diet had higher creatinine clearance, lower serum creatinine concentration, lower fractional clearance of sodium, lower urinary excretion of N-acetyl-beta-D-glucosaminidase and lower trough serum gentamicin concentration, compared with dogs fed the medium and low protein diets (Behrend et al., 1994; Grauer et al., 1994).
Hypoproteinemia may have marked effects that can result in either toxicity due to increased free drug concentration or decreased efficacy due to increased elimination by glomerular filtration (e.g., cefpodoxime, an oral, third-generation cephalosporin antibiotic) because drugs not bound to protein are more subjected to glomerular filtration (Guengerich, 1995; Fettman et al., 2010). High carbohydrate intake in the form of parenteral glucose demonstrated reduced oxidative drug metabolism in monogastric animals. Since, carbohydrate is also required for Uridine Diphosphate (UDP)-glucuronyl transferase activity for glucuronidation of oxidized drug metabolites, so, short-term deprivation of carbohydrates can also decrease rates of conjugation (Fettman et al., 2010).
Obesity can influence the tissue distribution of a drug and its effect is more likely to occur on α1-acid glycoprotein than on albumin, thus, it affects the unbound fraction of basic antimicrobial drugs like aminoglycosides and macrolides (Benedeck et al., 1984). As dietary lipids are also essential for optimal induction of CYP-450 metabolic enzymes; foods deficient in essential fatty acids result in decreased rates of drug metabolism. Activities of liver CYP-450 isoenzymes (P-450 2, 2A1, 2B1, 2C11, 2E1 and 3A) showed double activity in experimental rats when they were fed a 20% corn-oil diet for four days as compared rats fed a fat-free diet (Yoo et al., 1992). In obese cats, required subcutaneous dose of gentamicin was found lower than that calculated for normal cats. The calculated subcutaneous dose in obese cats to produce an average steady-state concentration equal to 4 µg/ml is 2.5 mg/kg every 8 h compared to 3.0 mg/kg in normal-weight cats (Wright et al., 1991).
Impact of Food on Antimicrobial Drug Disposition
For antimicrobial drugs, attaining effective bacteriocidal or bacteriostatic concentrations at the site of infection is must to eliminate the infection as well as to prevent the inevitable problem of drug resistance. When an antimicrobial drug is administered with food, their dispositional interaction is well reflected by influences of food on drug plasma levels. Drugs, if given with food, either may influence the absorption and oral bioavailability of drugs in many ways like by decreasing, increasing, accelerating or delaying absorption, or may have no net effect on absorption (Welling, 1996). Such food-drug interactions depend on the physical and chemical nature of the food and the drug, meal size and type (dilute vs. concentrated), the type of drug formulation, the order in which the food and drug are provided and the time interval between their consumption (Toothaker and Welling, 1980; Roe, 1989).
Gastric emptying of drugs is an important factor for consideration of rate of absorption of drugs and is delayed when they are administered with a meal. Gastric emptying of drugs is about 15 minutes in normal fasted dogs but it extends up to three hours in dogs fed a full meal. Feeding also stimulates acid secretion in dogs, which markedly increases the absorption of drugs with low pKa i.e. weak acids. Similarly, conditions like achlorhydria or hypochlorhydria reduce absorption of drugs which are weak acid in nature like ketoconazole. Dogs and cats are carnivorous animals, they do not possess basal secretion of hydrochloric acid in the stomach, and thus the gastric pH varies in fasted and fed animals. Greater systemic availability of some drugs like doxycycline or ketoconazole takes place when administered with feeding. Ketoconazole also needs acidic pH in the stomach to be absorbed, thus it should to be given with food. In contrast, several antimicrobials like ampicillin, oxytetracycline and chlortetracycline should be administered to fasted animals, as feeding significantly decreases absorption (Fettman et al., 2010 and Jerzsele, 2012).
Overall rate of absorption of drugs depends upon critical factors like drug dissolution and liberation, extent of intestinal permeability, and gastric emptying time, whereas release of drug into solution in the GI tract is a rate-limiting step in the drug absorption process. Each of these factors can be influenced by type of food. Moreover, both intestinal and hepatic first-pass metabolism also play crucial role along with above described factors to affect systemic drug availability. For some drugs which are unstable in stomach acid, gastric residence time is a critical physiological variable. Gastro-intestinal pH is region-dependent and it varies in different segments of GI tract which affects ionizable drug solubility which is a function of pH. Furthermore, it can also affect intestinal permeability of ionizable drugs. Hydrophilic drugs possess good aqueous solubility and dissolve quickly but do not permeate lipid membranes very readily. The absorption of hydrophilic drugs is therefore rate limited by membrane permeability rather than dissolution (Williams et al., 1996; Martinez and Amidon, 2002 and Fleisher et al., 2004).
In ruminants, the presence of the reticulorumen has also significant clinical consequences. Large volume of the ruminal fluid (100-150 liters in cattle) dilutes the drugs and decreases their rate of absorption and thus delaying the effect of orally administered medicines (Baggot and Brown, 1998, Jerzsele, 2012). Ruminal microbial flora restricts the oral usage of many antibacterial agents in adult ruminants and plays an important role in the biotransformation or degradation of certain antimicrobial drugs like chloramphenicol. However, antibiotics can be given orally with more favorable results in calves as they do not possess a mature ruminal microflora (Jerzsele, 2012). The mechanisms by which rate or extent of absorption of a medication may be altered by the presence of food include action as a physical barrier to absorbing surfaces, alterations in gastrointestinal tract motility, GI secretions, and chemical reactions between food and drugs. On the contrary, food can also increase the absorption of some medications, showing a beneficial effect by enhancing the efficacy. However, the increased drug bioavailability can also results into toxicities due to elevated serum concentrations. Fat rich feed and high food temperature significantly increase gastric emptying time of drug and thus, drug reaches the small intestine late where it is presented to the absorptive surface of the proximal region, resulting into delayed absorption (Kirk, 1995; Segal and Kaminski, 1996; Welling, 1996 and Maka and Murphy, 2000). Scientific reports for effect of food on disposition of some important antimicrobials in animals are presented below.
In a study, either amoxicillin or ampicillin suspended in milk replacer, water, and a glucose-glycine-electrolyte solution (GGES) were orally given to calves (n = 64). Both amoxicillin and ampicillin were more bioavailable in calves when administered in GGES than when administered with water or milk. The bioavailability of ampicillin was significantly more altered by administration with milk as compared with water. Amoxicillin suspended in milk replacer had a delayed absorption, compared with that suspended in water, but the relative bioavailabilities from milk replacer and water were similar (Palmer et al., 1983). In another study in dogs (Watson et al., 1986), ingesta adversely affected the systemic availability of ampicillin, amoxicillin and cloxacillin from all preparations tested. Feeding dogs inhibited oral absorption of ampicillin, amoxicillin and cloxacillin tablets upto 38%, 25% and 74%, respectively. It was suggested that these drugs should be given to dogs that are fasting to minimize impairment of bioavailability by ingesta.
Kung et al. (1995) assessed effect of the duration between feeding and drug administration on absorption of oral ampicillin (20 mg/kg) in 8 dogs of various breeds in four groups. Group A dogs were fasted for 12 hours before and after ampicillin administration. In group B, the dogs received ampicillin immediately after, in group C one hour before and in group D two hours after the meal. It was observed that with both dry and canned food, ampicillin absorption was better in fasting dogs. It was recommended to give ampicillin for clinical use to fasted dogs and to wait at least one hour before feeding.
Cefadroxil and cephalexin are two first generation oral cephalosporins. Food may enhance absorption of cefadroxil but not cephalexin (Campbell and Rosin, 1998). Food may increase degradation of cephalexin due to delayed gastric emptying and acid lability (Wallace, 2004). Cefixime is a third-generation oral cephalosporin. Quick oral absorption for cefixime is a marked feature in dogs but its administration with food can decrease its oral bioavailability by one half (Lavy et al., 1995). The serum disposition kinetics of cefixime in calves following oral administration was evaluated by Ziv et al. (1995). Mean serum cefixime concentrations 12 hours post oral administration (5 mg/kg) were lower (1.05 μg/mL) for the milk-fed calves than those for the fasted calves (1.76 μg/mL).
Schumacher et al. (1991) studied effect of two different types of feeds viz. alfalfa hay and whole oats on gentamicin sulfate disposition to appraise gentamicin-induced nephrotoxicosis. All horses were given gentamicin IV (5 mg/kg of body weight) every 12 hours for 22 days. Mean peak concentrations of gentamicin were 23.16 and 14.07 µg/ml, respectively for horses fed oats and those fed alfalfa. Mean Urinary gamma-glutamyl-transferase to urinary creatinine (UGGT: UCr) for horses fed alfalfa and oats were 47.1 and 100.0, respectively. Thus, it was found that horses fed on whole oats showed more persistence of gentamicin in body with high concentration as compared to when fed on alfalfa hay and poses more risk of nephrotoxicosis upon long term use of gentamicin.
In a study conducted by Palmer et al. (1983), oxytetracycline was given orally to calves (n = 64) in milk replacer, water, or a glucose-glycine-electrolyte solution (GGES) and it was found that oxytetracycline was bound strongly (63% binding) to milk replacer and responsible for low serum concentrations. Polyvalent cations present in foods like milk and other dairy products (mainly Ca2+, Zn2+, Fe2+ and Mg2+ ) can easily chelates tetracyclines and thus, can decrease its oral absorption several fold, if co-administered with such food. However, such effects are minimal and not important for other members like doxycycline and minocycline (Riviere and Papich, 2009; Giguere, 2013). However, iron markedly decreases absorption of doxyxcyline (Shaw and Rubin, 1986).
Nielsen and Gyrd-Hansen (1996) determined the oral disposition kinetics of oxytetracycline, tetracycline (both 45 mg/kg) and chlortetracycline (40 mg/kg) in pigs; in both a fasted and a fed condition. In both conditions, the presence of food prolonged the absorption phase for all three tetracyclines. For tetracycline, there was a significantly higher bioavailability in fasted (18%) than in fed (5%) pigs; whereas for chlortetracycline, it was 11% in fasted vs. 6% in fed pigs. The influence of food on the kinetic profile and bioavailability of antimicrobial drug in birds was evaluated by Laczay et al. (2001). They studied doxycycline absorption pattern after a single oral dose of 10.0 mg/kg body weight in 7-week-old fasted and fed broiler chickens. Fast and substantial absorption was noticed after oral administration to fasted chickens, whereas the presence of food in the intestinal tract decreases and delays the absorption.
Macrolide drugs are being generally formulated in form of enteric-coated tablets that start to disintegrate when they reach the middle region of the small intestine to reduce negative food effects. Enteric-coated tablets of erythromycin can be given with feed but if it is crushed and introduced into stomach through a feeding tube, the result was decreased absorption or inactivation of the drug (Michel and Higgins, 2002).
Effect of feeding on the oral absorption of erythromycin in dogs was evaluated by Eriksson et al. (1990). Different salt preparations and formulations of erythromycin (acistrate or stearate salts as tablets or granules with different coatings) were given to dogs at dose rate of 20 mg/kg body weight. The dogs were given the antibiotic associated with fasting (12 hour before and 6 hour after dosing), and with feed. Therapeutic serum concentrations were not achieved when any preparation was given with food, and interestingly, the serum concentrations of the drug given without food were also not consistent, possibly because of damage to the enteric coating by chewing.
Effects of prior feeding on oral disposition of microencapsulated erythromycin base (25 mg/kg of body weight) in foals were determined by Lakritz et al. (2000). Foals were given one dose after overnight fasting, and the other was administered after foals had consumed hay. Plasma concentrations of erythromycin for foals were lower after feeding than concentrations when food was withheld. Thus, it was concluded that foals should be given microencapsulated erythromycin base before they are fed hay.
Chloramphenicol drug is known to be biodegraded by ruminal enzymes when given orally in ruminant animals. Biodegradation of this drug was studied by Samuriwo et al. (1990) by incubating it at different concentrations viz. 72, 48 and 24 µg/ml with ruminal fluid samples from dwarf goats fed two different diets. Animals which were fed with hay and concentrate showed faster biodegradation of the drug than in those goats which were fed grass pellets only.
Like tetracyclines, fluoroquinolones are also reported to form slightly soluble complex with metal ions of food and thus, have reduced bioavailability (Furedi et al., 2009). Casein and calcium present in milk are known to decrease the absorption of ciprofloxacin (Papai et al., 2010). However, in a disposition study of enrofloxacin in fasted and fed pigs at dose rate of 10 mg/kg orally, non-significant differences were observed for mean bioavailability of enrofloxacin in both the groups of pigs (Nielsen and Gyrd-Hansen, 1997).
Disposition kinetics of combination of sulfadiazine and trimethoprim were compared between two groups of male Holstein calves viz. milk-fed and grain-fiber-fed ruminating calves. Bioavailability of trimethoprim was found higher in milk-fed calves than in grain-fiber-fed ruminating calves whereas rate of sulfadiazine absorption was slightly faster in ruminating calves (Shoaf et al., 1987). Oral bioavailability of sulphadiazine (at dose rate of 40 mg/kg body weight) and trimethoprim (8 mg/kg body weight) given in combination, were measured in healthy fasted and fed pigs (Nielsen and Gyrd-Hansen, 1994). The oral bioavailabilities for sulphadiazine and trimethoprim in the fed pigs were 85 % and 92 %, and in the fasted pigs 89 % and 90 %, respectively. It was found that the presence of food did not affect the absorption of both drugs, but it prolongs the absorption phase.
In a series of study conducted on sulphachlorpyridazine and trimethoprim in equines (horses/ponies) by Van Duijkeren et al. (1995 and 1996), it was found that for both drugs, mean peak plasma concentrations (Cmax) and the bioavailabilities (F) were reduced significantly when the drugs were mixed with concentrate. The percentage of in vitro binding of sulphachlorpyridazine and trimethoprim to hay, grass silage and concentrate was high, ranging from 60% to 90%. They concluded that binding of both the drugs to food was a major cause of the limited bioavailability of these drugs in the horse.
Interaction of food with drug and impact of nutritional status on disposition parameters of an antimicrobial drug are clinically very important phenomenon which must be taken care while prescribing such drugs to diseased animals to combat various infections. Proper knowledge of interaction between food and antimicrobial drug can help to minimize harmful effects like therapeutic failure, emergence of antimicrobial resistance, nutritional adversities and drug-toxicities. Negative clinical impact of antimicrobial drug –nutrient interactions can be minimized by providing nutritional supplements, altering time interval between administration of drug and food or by adjusting dosage regimen. Thus, exploring interactions between food and antimicrobial drugs is of great importance for veterinary healthcare professionals.