Guidelines for Drug Use in Equine Neonates

There are several important differences between neonates and adults in the way drugs are absorbed, distributed, metabolized and eliminated from the body [1,2]. Consequently, dosage regimens used for drugs in adult horses may not be appropriate for use in neonatal foals. With regard to drug administration, it does appear that normal equine neonates are more mature than neonates of many other species and that maturation after birth occurs more rapidly. Considerable maturation occurs in foals within the first 3 or 4 days of life and many metabolic and excretory processes are relatively mature by 1 week. Thereafter, maturation continues for many months but, in most respects, foals of >1 month of age handle drugs in a manner similar to adults.

I. Differences between Equine Neonates and Adults Important in Drug Therapy

1. Comparatively larger ECF volume in foals means most drugs have a larger volume of distribution. Thus, for equivalent doses, plasma concentrations of some drugs will be lower than in adults. This does not necessarily mean that tissue levels are lower or that the dose needs to be increased, since other features of distribution and elimination also influence drug concentrations.
2. Lower plasma protein in neonates means that a greater proportion of drugs which are highly bound to plasma protein, e.g. penicillin G, sulfonamides, trimethoprim, and phenylbutazone, are present in the circulation in the unbound (active) form.
3. The hepatic metabolic pathways (oxidation, reduction, hydrolysis and conjugation) are not fully functional at birth and are impaired further in premature foals. Thus drugs which undergo complete or partial hepatic metabolism prior to excretion may experience delayed elimination, especially during the first 3 or 4 days of life.
   Examples include chloramphenicol, trimethoprim, sulfonamides, phenobarbital, phenytoin, and theophylline. Maturation of hepatic function to near adult capacity occurs rapidly in term foals during the first 7 to 14 days of life.
4. Renal excretion is the principal process of elimination for most polar drugs (e.g. penicillins and aminoglycosides) and the majority of drug metabolites. The renal excretory mechanisms of glomerular filtration, tubular secretion and tubular reabsorption are relatively more mature in foals than in neonates of many other species. While not fully mature at birth, renal excretory mechanisms in foals mature rapidly during the first week of life.
5. Premature foals may have retarded maturation of their drug metabolizing and excreting mechanisms.
6. Absorbable drugs administered orally are generally better in neonates than in adults. The resultant serum concentrations of drugs such as ampicillin, amoxicillin, trimethoprim and sulfonamides tend to be higher [3,4]. This effect is especially marked during the first 24-48 hours and can be used to advantage therapeutically. However, enhanced absorption also has the potential to enhance toxicity, particularly when clearance mechanisms are also immature.
7. Neonates have a poorly developed blood-brain barrier. This may be useful when treating meningitis but can pose problems when selecting doses for CNS depressants (e.g. barbiturates, xylazine).
8. Neonates have a lower content of body fat so there is less sequestration of lipid-soluble drugs. This can lead to higher plasma concentrations and more profound effects, e.g. with barbiturates.

II. Antibiotics [5-8]

1. Almost all systemic neonatal bacterial infections involve Gram negative (often enteric) organisms, with or without accompanying Gram positive organisms. (The opposite is usually the case in adults).
2. Septicemic foals deteriorate rapidly. Antibiotic treatment should be started as soon as cultures have been collected and later modified, if necessary, after culture and susceptibility results are available. Front line antibiotics should have excellent activity against Gram negative bacteria and specific combination therapy is rational to broaden the spectrum. The most useful antibiotics for initiating treatment of suspected or confirmed sepsis are the aminoglycosides, e.g. amikacin or gentamicin, in combination with penicillin G, ampicillin, ticarcillin or a cephalosporin antibiotic. Depending on the susceptibility of bacterial isolates, other antibiotics which may prove useful include trimethoprim/sulfonamide, 3rdgeneration cephalosporins, or ticarcillin/clavulanic acid.
3. Bactericidal drugs are preferred because neonates have suboptimal defense mechanisms and most infected foals have total or partial failure of passive transfer of colostral antibodies.
4. The disease process can interfere with drug absorption, therefore parenteral routes should be used in systemically ill foals -the IV route is preferred initially.
5. Avoid using antimicrobials which require extensive hepatic metabolism prior to excretion (e.g., chloramphenicol, erythromycin) especially in systemically ill foals with impaired liver function, and in premature foals.
6. Use drugs which are excreted unchanged in urine, e.g. penicillins, aminoglycosides [10,11], cephalosporins or those which undergo only limited hepatic metabolism, e.g. trimethoprim/sulfonamide [9].

1. Aminoglycosides, especially amikacin and gentamicin are very useful drugs because of their activity against Gram negative bacteria. They have been used for 14 days or more at standard doses in normally hydrated foals without apparent problems but they are potentially nephrotoxic. The following precautions should be taken:

1. In patients with renal disease, alternative antibiotics should be used if possible. If aminoglycosides are used the dosage interval should be adjusted (lengthened) according to measured peak and trough plasma concentrations.
2. Ensure patients are adequately hydrated (dehydration enhances toxicity).
3. Monitor urine for evidence of tubular damage proteinuria, casts, RBC, (1+ proteinuria normal in newborn foals for 2-3 days).

2. Current Dosing Regimens for Aminoglycosides [10-15]

1. A once daily dosing regimen for aminoglycosides is more effective and often less nephrotoxic than the older lower dose, multiple dosing protocols in man and other species. Efficacy of aminoglycosides such as gentamicin or amikacin is concentration dependent. The magnitude of initial serum concentrations and area-under-the serum concentration vs. time curve (AUC) are more important in bacterial killing and in determining a post-antibiotic effect than is the duration that concentrations remain above the MIC of microbes. In adult horses, such a dosing regimen (6.6 mg/kg q 24 h) with gentamicin has been shown to produce significantly higher peak serum concentrations and AUC as compared to standard dosing protocols (2.2 mg/kg q 8 hr). Similar peaks and pharmacokinetics consistent with increased efficacy were determined in a study involving 21 mg/kg of amikacin administered once daily to neonatal foals for 10 days.
2. Nephrotoxicity was not observed after a 10 day course of once daily administered gentamicin in adults and amikacin in neonatal foals. A retrospective study also showed that hospitalized neonatal foals had optimal pharmacokinetics of amikacin when administered at a dose of 2O-25 mg/kg once daily, based on therapeutic drug monitoring.
3. Therapeutic drug monitoring (TDM) ensures dosing intervals and quantities that are both safe and effective. TDM entails measuring serum concentrations of aminoglycosides from two serum samples, one obtained one hour after administration (after the distribution phase is complete) and a second obtained before the next dosing. In the case of once daily therapy, this second sample should be obtained 4-8 hours after dosing. Peak and trough concentrations can then be obtained. Target trough concentrations are minimum target concentrations to minimize the risk for nephrotoxicity, and are ≤1 μg/ml and ≤4 μg/ml for gentamicin and amikacin, respectively. Target peak concentrations should be a minimum of >10 μg/ml and 14 μg/ml for gentamicin and amikacin, respectively.
4. Patients on aminoglycoside therapy should be monitored for signs of nephrotoxicity, especially if hypovolemia or reduced renal perfusion is suspected. Serum concentrations of creatinine and blood urea nitrogen can be used, however, urine indices (urine specific gravity, urinalysis, fractional excretions) are more sensitive and will detect toxicity earlier.
5. When on IV fluids: Just as therapeutic drug monitoring is important for patients with lowered volumes of distribution (dehydration, hypovolemia) to ensure safety, it is similarly important for those patients with increased volumes and clearance, such as those on intravenous fluid therapy, to ensure adequate peaks.
6. Intraosseous therapy of aminoglycosides has been shown to closely approximate the pharmacokinetics of these drugs given intravenously, and is a viable alternative route for patients where venous access is limited [12].