Effect of erythromycin and gentamicin on abomasal emptying rate in suckling calves.

Effect of Erythromycin and Gentamicin on Abomasal Emptying Rate
in Suckl ing Calves
M. Nouri, M.R. Hajikolaee, P.D. Constable, and A. Omidi
Background: Commonly used dosage protocols for antimicrobial agents may alter the rate of gastric emptying.
Hypothesis: Parenteral administration of erythromycin increases and gentamicin decreases the rate of abomasal emptying.
Animals: Five male Holstein-Friesian calves (8–15 days of age).
Methods: Calves received each of the following 4 IM treatments in random order: control, 2mL of 0.9% NaCl;
erythromycin, 8.8mg/kg; low-dose gentamicin, 4.4mg/kg; high-dose gentamicin, 6.6mg/kg. Abomasal emptying rate was as-
sessed by acetaminophen and glucose absorption. Calves were fed 2L of cow’s milk containing acetaminophen (50mg/kg body
weight) 30 minutes after each treatment was administered, and jugular venous blood samples were obtained periodically after
suckling. The maximum observed plasma acetaminophen concentration (actual Cmax) and time of actual Cmax (actual Tmax)
were determined, and pharmacokinetic modeling was used to calculate model Cmax and model Tmax.
Results: Erythromycin increased abomasal emptying rate, as indicated by a shorter time to actual Tmax and model Tmax
(P o .05). Abomasal emptying rate after injection of low-dose gentamicin was similar to that of control. Administration of
high-dose gentamicin resulted in a longer time to actual Tmax (P 5 .021) but did not change model Tmax (P 5 .62).
Conclusions and Clinical Relevance: IM injection of erythromycin increased abomasal emptying rate in dairy calves, where-
as low-dose and high-dose gentamicin did not alter the rate of abomasal emptying as measured by acetaminophen kinetics and
glucose absorption. The clinical relevance of these findings remains to be determined.
Key words: Aminoglycoside; Glucose absorption curve; Macrolide; Prokinetic.
Impaired abomasal motility is suspected to play amajor role in the development of abomasal disorders
in cattle, such as left displaced abomasum in lactating
dairy cows and abomasal tympany in calves.1 A number
of factors such as hypocalcemia,2 endotoxemia,3 alka-
lemia,4 hyperglycemia,5 and increased abomasal luminal
osmolality and energy content6 have been shown to
decrease abomasal emptying rate in cattle, and it would
be clinically helpful to identify therapeutic agents that de-
crease abomasal emptying rate as an unwanted adverse
effect. It would also be clinically helpful to identify effec-
tive prokinetic agents that stimulate, coordinate, and
restore abomasal, pyloric, and small intestinal motility in
cattle suspected to have abomasal hypomotility. Currently
neostigmine, bethanechol, metoclopramide, and erythro-
mycin are being used as part of the treatment of cattle
suspected to have gastrointestinal hypomotility.7–10, a
Erythromycin and related macrolides have become the
treatment of choice for gastric paresis in humans.11–13
Erythromycin currently is the most effective gastric pro-
kinetic agent available, in that IV or PO administration
increases the rate of gastric emptying in humans by 30 to
60%, which is substantially greater than the effect of oth-
er gastric prokinetic agents such as metoclopramide and
domperidone.11,13 Erythromycin has a similar prokinetic
effect in domestic animals such as dogs and horses.14–16
Administration of erythromycin at the labeled anti-
microbial dosage (8.8–10mg/kg, IM) exerted a substan-
tial prokinetic effect in milk-fed calves17 and adult cattle.a
Specifically, erythromycin increased the abomasal emp-
tying rate by 37% in calves as assessed by change in
abomasal volume that was determined ultrasonographi-
cally,17 and by 44% in adult cattle immediately after
surgical correction of left displaced abomasum.a The
magnitude of the increase in abomasal emptying rate in
calves and adult cattle was similar to the effect of
erythromycin in humans.11,13
Gentamicin is an aminoglycoside antibiotic effective
against most Gram-negative and some Gram-positive
bacterial infections and has been used in the past as part
of the treatment of sick neonatal calves with septicemia
or calf diarrhea.18 Gentamicin therefore may be admin-
istered to critically ill calves that are suspected to have
abomasal hypomotility. However, in vitro gentamicin
concentrations of 20 to 400mg/mL (42–837mM) decrease
the peristaltic response of guinea pig ileum,19 and genta-
micin concentrations of 150 to 300mM decrease the in
vitro contractility of uterine smooth muscle from preg-
nant and nonpregnant cows.20,21 Because the smooth
muscle in the calf’s abomasum may be more sensitive to
the effects of gentamicin than uterine smooth muscle, we
were concerned that parenterally administered gen-
tamicin might decrease the abomasal emptying rate in
the calf. Accordingly, the aims of the study reported here
were to determine and compare the effect of administer-
ing the recommended parenteral dose of erythromycin
(positive control) and 2 different doses of gentamicin
(test substance) in healthy suckling dairy calves. We
expected the results of the study to confirm previous find-
ings17 that erythromycin is an effective prokinetic agent
in calves, and to determine the effect, if any, that parent-
eral administration of gentamicin has on abomasal
emptying rate.
From the Department of Clinical Sciences, School of Veterinary
Medicine, University of Shahid Chamran, P.O. Box: 61355-145,
Ahvaz, Iran (Nouri, Hajikolaee, Omidi); and the Department of
Veterinary Clinical Sciences, Purdue University, West Lafayette, IN,
(Constable).
Corresponding author: M. Nouri, Department of Clinical Sciences,
School of Veterinary Medicine, University of Shahid Chamran, P.O.
Box: 61355-145, Ahvaz, Iran; e-mail: mn_2207@yahoo.com.
Submitted March 8, 2007; Revised May 29, 2007; Accepted
August 10, 2007.
Copyright r 2008 by the American College of Veterinary Internal
Medicine
10.1111/j.1939-1676.2007.0027.x
J Vet Intern Med 2008;22:196–201

Material and Methods
Five male Holstein-Friesian colostrum-fed calves (body weight
range, 31–48 kg) were obtained from local farms. Calves at the time
of experiments were between 8 and 15 days of age. Calves were kept
unrestrained in individual stalls and fed fresh cow’s milk twice a day
(60mL/kg body weight) by a bottle with a teat.
Abomasal emptying was measured by acetaminophen absorption
and glucose absorption. Acetaminophen is a widely used oral anal-
gesic and antipyretic drug in humans, and its absorption provides an
accurate method of determining the emptying rate of liquid phase
meals in calves.22,23 When administered PO, acetaminophen is ab-
sorbed in the small intestine24 with the rate limiting step for
absorption being the rate of gastric emptying in animals with nor-
mal small intestinal function.25 Because the apparent rate of
absorption is much faster than the rate of elimination in suckling
calves,22 the time to maximal acetaminophen concentration after
oral ingestion is primarily dependent on the rate of abomasal emp-
tying. Glucose absorption provides a crude measure of abomasal
emptying rate in neonatal calves.6
An IV catheter was placed in the jugular vein and secured to the
neck. Each calf was given the following 4 IM treatments in random-
ized order: control, 2mL of 0.9%NaCl; erythromycin lactobionateb
(8.8mg/kg body weight); low-dose gentamicin sulfatec (4.4mg/kg);
and high-dose gentamicin sulfatec (6.6mg/kg). Calves were fed by
suckling 2L of whole cow’s milk containing acetaminophen (50mg/
kg body weight) 30 minutes after the treatment was administered.
This time difference was selected because prokinetic agents usually
are administered to humans 15 to 30 minutes before meals26 and
because maximal plasma concentrations of gentamicin occur at
45 minutes after IM administration in cattle.27 The dosage protocol
for erythromycin was based on the results of a previous study in
suckling calves.17 The dosage protocol for gentamicin was based on
pharmacokinetic studies in calves and adult cattle.18,27,28 At least 36
hours elapsed between each study in order to ensure an adequate
wash-out period; during this time calves were fed fresh cow’s milk.
Venous blood samples for determination of plasma acetamino-
phen and glucose concentrations were obtained at�30, 0, 15, 30, 45,
60, 90, 120, 150, 180, 210, 240, 300, 360, 420, and 480 minutes after
the start of suckling cow’s milk. The sampling times were selected
in an attempt to have at least 6 data points before and after the time
of maximal acetaminophen concentration in order to facilitate
nonlinear regression analysis. Samples were collected into 6mL
tubes containing heparin centrifuged at 3000 �g for 15 minutes and
3mL of plasma harvested and stored at�20 1C foro4 weeks before
analysis.
Plasma was thawed at room temperature and acetaminophen
concentrations were determined spectrophotometrically by a colori-
metric titration assay as described previously.22 The maximum
observed plasma concentration (actual Cmax) and time of maximum
observed plasma concentration (actual Tmax) were obtained from a
plot of plasma acetaminophen concentration–time data. The first
derivative of Siegel’s modified power exponential formula was used
to model the plasma acetaminophen concentration-time relation-
ship, as described previously.22 The equation was derived from the
fact that the acetaminophen concentration-time relationship repre-
sented as a cumulative dose curve is an inverse analog of the
scintigraphic curve: C(t) 5 mkbe�kt(1 – e�kt)b�1, where C(t) is the
acetaminophen concentration in plasma (mg/mL) at time t in min-
utes, and m, k, and b are constants; m is the total cumulative
recovery of acetaminophen when t is infinite, k is an estimate of the
rate constant for abomasal emptying, and b provides an estimate of
the duration of the lag phase before an exponential rate of emptying
is reached. Nonlinear regressiond was used to estimate values for m,
k, and b, as previously described.22 The time to calculated Cmax
(model Tmax) was obtained as follows: model Tmax 5 ln(b)/k, and
the calculated value for model Cmax determined by applying the
values for m, k, b, and t 5 model Tmax to the cumulative dosage
curve.
Plasma glucose concentration was determined by use of an auto-
matic analyzer.e The maximum observed plasma concentration
(actual Cmax) and time of maximum observed plasma concentration
(actual Tmax) were obtained from a plot of the plasma glucose con-
centration versus time data. Although a delay in actual Tmax
suggests a slower rate of abomasal emptying,6 actual Tmax is an
insensitive and nonspecific index of abomasal emptying rate. This is
because the plasma-glucose time relationship is dependent on the
glucose or lactose concentration in the ingested meal, the rate of
abomasal emptying, the small intestinal transit time and surface
area available for absorption, the rate of glucose entry into cells
(which is dependent on the rate and magnitude of insulin release
after glucose absorption), and the magnitude of glucose loss in the
urine if plasma glucose concentration exceeds the renal threshold of
140–160mg/dL.6
Statistical Analysis
Data were expressed in tabular form as least squares mean and
95% confidence interval for the least squares mean, and graphically
as least squares mean and SE. A value of P o .05 was considered
significant. The primary variables of interest were actual Tmax and
model Tmax for the acetaminophen absorption curve. Repeated-
measures analysis of variance (ANOVA)f was used to determine the
effect of treatment on actual Tmax and Cmax for acetaminophen and
glucose absorption, and model Tmax and Cmax for acetaminophen
absorption. Repeated-measures ANOVAf (with repeated measures
on treatment and time) was used to determine the main effects of
treatment and time and the interaction between treatment and time
on plasma glucose concentration. Posthoc contrasts were confined
to the following: erythromycin to control, high-dose gentamicin to
control, and low-dose gentamicin to control.
Results
All calves remained healthy during the study period.
The time taken to suckle 2L of cow’s milk ranged from
1.6 to 3.0 minutes.
Acetaminophen absorption indicated that erythromycin
increased the abomasal emptying rate when compared
with control (Table 1, Fig 1), as indicated by a shorter
time to actualTmax (Po .001) andmodelTmax (Po .001).
The abomasal emptying rate after injection of
low-dose gentamicin (4.4mg/kg) was similar to that
of control (actual Tmax, P 5 .21; model Tmax, P 5 .82)
(Table 1, Fig 1). Administration of high-dose gentamicin
decreased abomasal emptying rate when compared with
control, as indicated by a longer time to actual Tmax
(P 5 .021) when compared with control. However, high-
dose gentamicin did not change the time to model Tmax
(P 5 .62) when compared with control.
The glucose absorption curve was similar for all 4
treatments (Fig 2), with the main effect of treatment (P5
.57) and treatment-time interaction (P 5 .78) not being
significant. The lack of a substantial interaction effect in-
dicated that treatment did not alter the change in glucose
concentration over time. There was a substantial main
effect of time on the plasma glucose concentration
(P o .001). Actual Tmax and Cmax were similar for all
treatments (Table 1).
197Effects of Erythromycin and Gentamicin on Abomasal Emptying Rate in Calves

Discussion
The first major finding of the study reported here
in healthy calves was that IM injection of erythromycin
increased the rate of abomasal emptying as assessed by
acetaminophen absorption. The second major finding
was that IM injection of low-dose (4.4mg/kg) or high-
dose (6.6mg/kg) gentamicin did not alter the rate of
abomasal emptying as measured by acetaminophen
kinetics (model Tmax) and glucose absorption.
Gastric emptying rate has been measured by direct and
indirect methods. A commonly used method in rodents is
removal of the stomach after a fixed time and measure-
ment of the remaining content of the nutrient under
investigation,29 or to use nonabsorbable or poorly ab-
sorbable markers such as phenol red30 or polyethylene
glycol.31 The main problem with these direct methods is
the requirement for a large number of animals, because
they measure percent emptying at only 1 point in time. In
contrast, the acetaminophen absorption method allows
the effect of treatment on emptying rate to be compared
on different days using each animal as its own control,
thereby decreasing the number of animals required for
study. Acetaminophen is a widely available and inexpen-
sive drug that is poorly absorbed from the stomach but
rapidly absorbed from the small intestine25,32 and has
been widely used as a marker for gastric emptying in
horses33 and humans.34 The acetaminophen method has
been validated against the gold standard method (scinti-
graphy) in humans,25,32 horses,33 and suckling calves.22
Antimicrobial agents may have adverse or beneficial
properties separate from their antibiotic activity.35,36
Diarrhea is an adverse effect of penicillin administration
in humans and horses.37–39 Erythromycin and other
macrolides have prokinetic effects in humans and
animals.15,17,40 Erythromycin exerts its effect on acceler-
ating gastric emptying by acting as a motilin agonist via
binding to motilin receptors on smooth muscle and nerve
cells in the pyloric antrum and on smooth muscle cells
in the proximal small intestine,41–43 or by the release of
endogenous motilin through cholinergic or serotonergic
pathways.44 Motilin is a 22 amino acid peptide that
is periodically released from endocrine cells in the
duodeno-jejunal mucosa, thereby initiating the migrating
Table 1. Abomasal emptying rate indices of 5 calves suckling 2L of cow’s milk and administered 4 treatments.
Factor Control
Erythromycin
(8.8mg/kg)
Low-dose Gentamicin
(4.4mg/kg)
High-dose Gentamicin
(6.6mg/kg)
Acetaminophen absorption
Actual Cmax (mg/mL) 30.1 (24.8, 35.4) 33.8 (28.3, 39.1) 27.9 (22.6, 33.2) 33.3 (28.0, 38.6)
Actual Tmax (minute) 120 (95, 145) 60
� (35, 85) 138 (113, 163) 156� (131, 181)
Model Cmax (mg/mL) 25.9 (20.6, 31.2) 28.9 (23.6, 34.2) 23.7 (18.4, 29.0) 28.4 (23.1, 33.7)
Model Tmax (minutes) 129 (104, 154) 67
� (42, 92) 132 (107, 157) 136 (111, 161)
Glucose absorption
Actual Cmax (mg/mL) 136 (120, 152) 125 (109, 141) 123 (107, 139) 121 (105, 137)
Actual Tmax (minutes) 111 (70, 152) 48 (7, 89) 96 (55, 137) 120 (79, 161)
Abomasal emptying rate was assessed by acetaminophen absorption and glucose absorption.Cmax is the maximal plasma acetaminophen or
glucose concentration and Tmax is the time at which Cmax occurred. Model Cmax and Tmax were obtained by fitting a nonlinear equation to the
cumulative dose curve for acetaminophen (see ‘‘Materials and Methods’’ for details). Data are least squares means and 95% confidence
interval for the least squares mean (in parentheses).
�Po .05 compared with control.
Fig 1. Change in plasma acetaminophen concentration (least
squares mean � SE) in 5 calves, each of which received 1 of 4 treat-
ments in a crossover study 30 minutes before suckling 2L of milk
containing acetaminophen (50mg/kg body weight).
Fig 2. Change in plasma glucose concentration (least squares
mean � SE) in 5 calves, each of which received 1 of 4 treatments in
a crossover study 30 minutes before suckling 2L of milk.
198 Nouri et al

motor complex (MMC) of the mammalian gut during the
interdigestive period; the MMC is the so-called ‘‘house-
keeper’’ of the small intestine. There is considerable
interest in the group of nonpeptide motilin agonists,
called the motilides (motilin-like macrolides), that inter-
act with the motilin receptor and promote gastric
emptying.41 Abomasal hypomotility and decreased
rate of abomasal emptying are complications of some
abomasal disorders.45,46 Acceleration of abomasal emp-
tying may be of therapeutic value in the treatment of
animals with delayed abomasal emptying.
Our results clearly demonstrate that the antimicrobial
dose of erythromycin is an effective prokinetic agent in
healthy suckling calves; this finding was consistent with
erythromycin’s effect in humans, dogs and horses.11–15
The findings in this study using acetaminophen absorp-
tion to assess emptying rate were similar to those in a
previous study in calves that used changes in the ultra-
sonographic dimensions of the abomasum to assess the
effect of erythromycin (8.8mg/kg, IM) on the rate of
abomasal emptying.17 The results of the ultrasonographic
study indicated that a prokinetic effect was not evident
when a 10-fold lower dose of erythromycin (0.88mg/kg,
IM) was administered.17 Erythromycin is labeled in the
United States for the treatment of pneumonia and bovine
respiratory disease caused by susceptible bacteria. The
recommended dosage is 2.2 to 8.8mg/kg IM q24h, and
meat withdrawal time is 6 days after a 5-day treatment at
8.8mg/kg.17 Parenteral administration of erythromycin
to calves and adult cattle specifically as a prokinetic agent
therefore constitutes extra label drug use. Because the
calves in our study were clinically healthy and did not
have any apparent signs of abnormal abomasal motility,
we cannot directly comment on the prokinetic effect of
parenterally administered erythromycin in sick calves.
However, erythromycin is highly effective in facilitating
gastric motility and increasing gastric emptying rate in
humans and dogs with gastric paresis,47,48 and the treat-
ment of gastric hypomotility is considered the most
promising area of application.49 The results of a recent
study indicated that the prokinetic effect of erythromycin
is clinically relevant in adult cattle with abomasal hypo-
motility, in that erythromycin (10mg/kg IM) increased
the rate of abomasal emptying and milk production in the
immediate postoperative period of cattle undergoing sur-
gical correction of left displaced abomasum.a Whether a
similarly beneficial clinical effect is produced by erythro-
mycin in calves suspected to have abomasal hypomotility
(such as calves with abomasal tympany) remains to be
determined.
Gentamicin was administered in an unapproved and
extra label manner to the calves in the study reported
here. Because of the potential for causing violative resi-
dues in treated animals, the American Association of
Bovine Practitioners issued a revised position statement
in 2005 regarding the extralabel use of aminoglycosides
in cattle:g ‘‘The American Association of Bovine Practi-
tioners, being cognizant of food safety issues and
concerns, encourages its members to refrain from the
intramammary, IM, SC or IV extra label use of
the aminoglycoside class of antibiotics in bovines.’’ This
recommendation is consistent with a 1998 position state-
ment from the American Veterinary Medicine
Association and a 2005 consensus statement issued by
the American College of Veterinary Internal Medicine.50
Accordingly, the main purpose in administering gent-
amicin to the calves in the study reported here was to
determine whether the IM administration of gentamicin
altered the rate of gastric emptying. Demonstration of
such an effect would have clinical implications for the use
of gentamicin in sick horses and companion animals.
The recommended IM dosage for gentamicin in adult
cattle is 3.5 to 5mg/kg of body weight27,28 but because
calves have a larger extracellular fluid space than do
adult cattle, the recommended dosage should be in-
creased in calves in order to achieve appropriate tissue
concentrations.18 We therefore elected to administer
2 dosages (4.4 and 6.6mg/kg) of gentamicin. In contrast
to the reported contractile effect of erythromycin in uter-
ine smooth muscle,51,52 gentamicin inhibits spontaneous,
KCl-, and agonist-induced contraction of myometrium
isolated from nonpregnant cows in a dose-dependent
manner.20,21 However, the inhibitory in vitro effect of
gentamicin on the frequency and amplitude of uterine
smooth muscle contraction has been documented to
occur at gentamicin concentrations of 150 and 300mM,
respectively.21 The relevance of the observed in vitro
effects on cow uterine small muscle to abomasal motility
in a calf administered gentamicin at 6.6mg/kg IMmay be
questionable, because the highest plasma concentration
achieved in cows administered 5.0mg/kg IM was pre-
dicted to be 17.2mg/mL,27 equivalent to 36 mM, which is
much lower than the concentration required (150 mM)
to decrease the frequency of bovine uterine smooth
muscle contraction.21 However, because in vitro gent-
amicin concentrations of 20 mg/mL (42 mM) decreased
the peristaltic response of guinea pig ileum,19 it remains
possible that high-dose administration of gentamicin
(particularly when administered IV) might adversely
affect gastrointestinal motility. High luminal gentamicin
concentrations obtained after PO administration of gent-
amicin also could decrease gastrointestinal motility; for
example, administering gentamicin sulfate PO at a dose of
250mg (equivalent to 5mg/kg) in 2L of milk to a 50-kg
calf produces an abomasal luminal concentration of
125mg/mL (260mM).
In conclusion, the results of this study indicate that IM
injection of erythromycin increased abomasal emptying
rate in dairy calves, whereas IM injection of low-dose or
high-dose gentamicin did not alter the rate of abomasal
emptying as measured by acetaminophen kinetics and
glucose absorption. It remains to be determined whether
erythromycin-induced alterations in abomasal emptying
rate occur in sick cattle and whether this adverse effect of
erythromycin treatment is clinically important.
Footnotes
aWittek T, Tischer K, Gieseler T, et al. Effect of erythromycin and
flunixin-meglumin on abomasal emptying rate of dairy cows
199Effects of Erythromycin and Gentamicin on Abomasal Emptying Rate in Calves

immediately after surgical correction of left displaced abomasum.
Proceedings of the XXIVth World Buiatrics Congress 2006, #385
bErythromycin, Cytochemia, Tehran, Iran
cGentamicin 80, Alborz Daru, Tehran, Iran
d PROC NLIN, SAS Inc, Cary, NC
eHitachi 704 automatic analyzer, Hitachi, Tokyo, Japan
f PROC MIXED, SAS Inc Cary, NC
g http://www.avma.org/onlnews/javma/dec05/051201j.asp; accessed
May 2007
Acknowledgments
Work done at University of Shahid Chamran. This
work was supported, in part, by a grant from the
University of Shahid Chamran, Ahvaz, Iran.
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