Chapter 38.

Antimicrobial Drug Use in Zoological Animals

Before extrapolation of any drug dose, the veterinarian

should appreciate not only the mathematical assump
tions but also the limitations that are associated
with allometry. Careful consideration of the available
literature to understand the route of elimination and the
extent of metabolism of therapeutic agents will greatly
assist in determining allometric relationships of phar
macokinetic parameters. There is a continuing need to
consider and apply methods for reducing the size and
risk of extrapolation error, as this can affect both target
animal safety and therapeutic response. Data from at
least one large animal (non-human and a body
weight> 70 kg) should be included to reduce potential
error (Mahmood et al., 2006).

A Practical Example of Allometry

and Breakpoints

639

Table 38.1. Breakpoints for select antituberculous drugs

used in elephants.

Breakpoint Concentration (g/ml)

Agent
lsoniazid
Rifampin
Ethambutol
Pyrazinamide
Levofloxacin
Moxifloxacin
Ofloxacin
Streptomycin

7H10 agar
0.2
1.0
5.0
10
NR
1.0
0.5
2.0
2.0
10

7H11 agar
0.2
1.0
7.5
NR
NR
ND
0.5
2.0
2.0
10

NR=not recommended; ND=not determined. Where multiple values are

provided, the second is when resistance has occurred and the drugs are
used as "second-line therapies" (modified from M24-A2; CLSI, 2011).

An example of how the above information can be inter

preted and potentially misused is the case of
There are published reports on the "population''
Mycobacterium tuberculosis susceptibility testing and
the treatment of this bacterial disease in elephants pharmacokinetics of several antituberculous drugs in
(Loxodonta africana and Elephas maximus). Unlike cat African and/or Asian elephants that were used to
tle and other livestock, which are more apt to be infected develop the multidrug treatment protocols for elephants
with M. bovis and are euthanized if positive, in the published in the USDA elephant TB guidelines and were
United States, elephants are recognized for their rarity modeled after the disease in people (Peloquin et al.,
and value and are treated rather than culled. Mandatory 2006). The issues with these types of extrapolation have
testing and treatment of elephants with TB is overseen been previously discussed (Hunter and Isaza, 2008).
by the U.S. Department of Agriculture (USDA), and Using the human breakpoints for isoniazid established
guidelines for drug administration in pachyderms have by the CLSI and the plasma concentrations reported
been derived from those established for humans by Maslow et al. (2005) one could conclude that the
(USDA, 2008). Susceptibility testing for this pathogen is likelihood for efficacy is high with all reported con
described in detail, for human isolates, in the CLSI centrations> 0.2 g/mL for the doses and routes of
M24-A2 document. The results of in vitro susceptibility administration evaluated, but many concentrations
testing of these agents appear to correlate well with the were greater than 5 times, which seems excessive and
clinical effectiveness of these agents in human patients. could be contributing to the adverse events reported by
The interpretive criteria, or breakpoints, are provided some clinicians. Maslow et al. (2005) suggest that area
under the curve (AUC) may be the driving pharmaco
in Table 38. I.
In elephant, the pharmacodynamics and pharma dynamic parameter, which is not surprising given the
cokinetics of antituberculous drugs differ considerably slow growth of the target pathogen, but the target PK/
compared to people. In addition, the metabolic state of PD relationship is currently unknown in elephants, and
Mycobacterium tuberculosis significantly affects its is very likely to be different than that reported for
susceptibility to antimicrobials. Optimization of dosage humans. This idea is further supported when the fluoro
of antituberculous drugs is necessary to achieve maxi quinolones are evaluated. While in human medicine an
mum drug exposure at the site of infection in order to AUC/MIC ratio of;, 125 for fluoroquinolones has been
maximize reduction in M. tuberculosis viable organisms shown to eradicate a particular bacterial disease, this
and to minimize the emergence and selection of resist ratio cannot be directly extrapolated across species,
indication, or pathogen, nor has it been determined for
ance (de Steenwinkel et al., 2010).

640 Section IV. Antimicrobial Drug Use in Selected Animal Species

antituberculous drugs. The effective AUC:MIC ratio has

been reported to be different between species (Aliabadi
et al., 2003). Opinions also differ within the human
literature, where some report that a ratio> 25 is best,
while others state that the ratio must be greater than 350
(Barger et al., 2003). This is complicated by the fact that
for the fluoroquinolone ciprofloxacin, 100% of success
fully treated patients had an AUC:MIC ratio> 3.6
(Barger et al., 2003). It should be remembered that the in
vivo antimicrobial effect is the result of dynamic expo
sure of the pathogen to the antimicrobial and the host
immune system. The comments and issues raised here
also apply to rifampin (Peloquin et al., 2006) and etharn
butol (Maslow et al., 2005).
Unfortunately, numerous serious adverse effects have
occurred in the majority of elephants undergoing
treatment. In niany cases, these were severe enough that
treatment needed to be discontinued, at least temporarily.
Reported adverse effects include anorexia, depression,
diarrhea, kidney and liver insults, blepharospasm, and
death. The high incidence of severe adverse effects sug
gests that the doses of drugs required to achieve serum
levels comparable to those targeted in people, may, in
fact, be toxic to elephants (Wiedner and Schmitt, 2007).

Techniques of Administration
Administration of medications to zoo and wildlife
species can be made considerably easier by training the
animals to accept them. Such training has increasingly
become part of the general animal care routine at many
zoological institutions. A remarkable variety of species
have been taught to tolerate injections, swallow tablets,
and accept various other forms of drug administration.
Such training requires a significant time commitment
both for teaching the behaviors as well as for ongoing
practice to maintain them, using placebos when the
animal is healthy.

Oral Administration

Oral medication can be hidden in feed. Generally, this

requires that the patient be physically separated from its
social group for feeding. For some species, such as large
carnivores, this is routine. For others, separation from
conspecifics can cause stress. Typically, the medication
is hidden in something the animal particularly enjoys

such as a meatball for a carnivore or a watermelon for an

elephant. Non-human primates are often more willing
to take medication if it is mixed with sweet substances
such as jams or juices. Compounding pharmacies that
make flavored medications for children can be helpful in
developing mixtures that are appealing to captive
primates who require oral medication
It is unknown whether drug bioavailability is affected
by its concealment in food. Another issue is that
zoo animals often become very adept at identifying
"doctored'' food items, and will pick carefully around
drugs hidden in grain balls, meat balls, and similar, leav
ing the medication untouched. Thus, it is important for
the animals' caretakers to observe ingestion of the
medication.
Pachyderms can be trained to accept oral medications
using a bite block. Even using this device, however, ele
phants often learn to hide medications within their mas
sive mouths for hours, only to spit them out hours later
when they are unobserved (Isaza and Hunter, 2004).

Injectable Administration

Most injectable antimicrobials are given via the intra

muscular route in zoo and wildlife species. Although
under anesthesia, both the intravenous or subcutaneous
routes are possible for a single dose, anesthetizing a sick
animal repeatedly for the purpose of administering a
course of antimicrobials is generally not desirable. In
some situations, an intraosseous (IO) or intravenous
(IV) catheter can be placed. Reptiles, birds and severely
debilitated animals that will be housed in a hospital
environment are best suited for this. In determining
whether a particular patient is an appropriate candidate
for an indwelling catheter, the clinician should assess
the ease of maintaining patency and cleanliness of the
catheter, and the likelihood of the animal's removing it.
If these are concerns, a catheter is generally not suitable.
In several groups of animals, anatomical and/or living
situations make indwelling catheters inappropriate or
extremely difficult. These include very small animals,
such as songbirds, animals with extremely thick skins
such as hippos and aquatic animals that cannot be
dry-docked.
In some situations, intramuscular injections can be
given via hand injection into animals trained to present
body parts against the pen, chute, or cage bars (flank or
thigh muscles for large carnivores; neck for hoofstock;

Chapter 38. Antimicrobial Drug Use in Zoological Animals

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