Treatment of Antibiotics in Dogs and

Cats During Pregnancy

Abstract.-

Due to the substantial physiological changes that may influence the

pharmacokinetics of medications and the possible effects on the fetus, the use of
pharmacological agents in pregnant females poses a major therapeutic issue. The
goal of this study is to evaluate our current understanding on the use of antibacterial
medications during pregnancy and to provide guidance on how to choose an
antibacterial drug wisely for treatment for bitches and queens who are pregnant. The
ability of a substance to penetrate the fetal circulation and create toxic effects
determines the risk to the fetus. Due to the presence of transporters and
metabolizing enzymes, the placenta serves as a barrier that protects the fetus during
pregnancy, both enzymes and transporters' presence and activity may change.
Antimicrobials such as betalactams, macrolides, and lincosamides have been
demonstrated to be safe to use during pregnancy. In all species, pharmacotherapy
during pregnancy has the potential to harm the growing embryo; consequently, it
should be avoided whenever possible.

1.- Introduction

The use of pharmacological medicines in pregnant women is a difficult clinical

problem. On the one hand, the significant physiological changes brought on by
pregnancy may induce changes in medication pharmacokinetics (absorption,
distribution, biotransformation, and excretion), necessitating dose adjustments. On
the other hand, transplacental medication transfer from maternal to fetal blood and
tissues, with potentially harmful consequences on the fetus, is a serious worry. To
achieve a reasonable decision, both the mother and the fetus must be included in
the risk/benefit analysis, comparing the therapeutic advantages of the therapy for the
mother against the possible harm to the fetus.

There is currently insufficient information in veterinary medicine on pharmacological

therapies for pregnancy. This might be due to a number of causes. First, doing study
on pregnant females, especially in nonhuman species like our household animals,
raises legitimate ethical issues. Second, while many animal models have been used
to study various aspects of pregnancy, there are significant variations across
species, making extrapolation of results from one species to another problematic.
Third, changes during pregnancy are dynamic rather than static, resulting in
significant variations across individuals of the same species and even within the
same individual at various stages of pregnancy. Fourth, while some ex vivo/in vitro
methods for studying transplacental transfer, such as the dual recirculating placental
perfusion model and the use of transporters overexpressing cell lines, have shown to
be useful, they still have the limitations of studies conducted in isolated organs or cell
cultures. Fifth, the current conservative strategy in human and veterinary medicine is
to avoid medical interventions in pregnant females as much as possible; as a result,
clinical observed results are limited.

Because antibacterial therapy is the most likely pharmacotherapy to be administered

to a pregnant bitch or queen, the purpose of this paper is to briefly review our
knowledge on the use of drugs during pregnancy, and to provide information for the
judicious selection of an antimicrobial treatment for use during pregnancy.
2.- Pharmacokinetics in pregancy.

The concentration of a medication at the site of action determines its

pharmacological effects. Low (subtherapeutical) levels can result in therapeutic
failures, while excessive (supratherapeutical) levels can cause toxic consequences.
Concerns in the pharmacological therapy of medical problems in pregnant females
stem from changes in any of the physiological processes that occur after the
administration of a medication. Major pharmacokinetic characteristics, notably total
body clearance and volume of distribution, acquired from research done in healthy
non-pregnant persons, are used to establish therapeutic dosing regimens of
medicines, that is, dose and dosage interval. Because of the physiological changes
that occur during pregnancy, a drug's absorption, distribution, and rate of elimination
may need to be adjusted for safe and clinically effective usage.

During pregnancy, increased progesterone levels cause a decrease in

gastrointestinal motility and an increase in intestinal blood flow. These changes may
impact a drug's oral absorption and hence its bioavailability (increase, decrease, or
neither).

In order to keep the fetus alive, the mother undergoes extensive cardiovascular
adaptation. Blood volume and cardiac output rise, and blood flow to the various
organs is redistributed.

Polar medicines are typically found in extracellular fluids due to their poor lipid
solubility, which prevents them from passing through biological membranes and
entering the intracellular region. Total body water rises during pregnancy as a result
of intravascular and extravascular expansion, causing changes in the volume of
distribution of polar medicines. The profile of plasma proteins changes throughout
pregnancy. C-reactive protein, serum amyloid A, fibrinogen, and ceruloplasmin are
among the acute phase proteins that are considerably elevated, but the increase in
plasma volume causes dilutional hypoalbuminemia since the synthesis of this protein
is not altered. Drug protein binding may be affected by changes in plasma protein
concentrations, notably albumin, altering the free fraction of medicines. This fraction
is the pharmacologically active medication because it spreads extravascularly and
reaches the site of action. If the concentration of maternal albumin in the blood
drops, the free fraction of the medication may rise. This might have clinical
consequences for strongly bound medicines such AINEs, furosemide, and digoxin.
However, if the drug's protein binding is maximum even at the low albumin
concentrations observed during pregnancy, no pharmacokinetic changes are likely.

The clearance of lipid-soluble medicines, which are largely removed by metabolism,

might show opposite and unanticipated alterations as a result of pregnancy changes.
Pregnancy may improve medication biotransformation by two mechanisms:
increased drug availability to the site of metabolism, mainly the liver, and increased
enzymatic system activity, notably the hepatic cytochrome P-450 (CYP) family.
Increased hepatic blood flow may promote liver biotransformation of high hepatic
extraction medicines, whereas decreased binding to plasma proteins owing to
pregnancy-related hypoalbuminemia may increase liver metabolization of low
hepatic extraction pharmaceuticals. The action of the sexual hormones progesterone
and oestradiol may influence the activity of various drug metabolizing enzymes,
either increasing or decreasing it. The expression of genes encoding hepatic
CYP450 superfamily of microsomal enzymes may be reduced during pregnancy.

Increases in plasma volume and cardiac output, as well as blood flow redistribution
to the kidney, result in significant increases in glomerular filtration rate. As a result,
when water-soluble medicines are administered during pregnancy, plasma
concentrations of hydrophilic, polar pharmaceuticals may be lower and half-lives may
be shorter.

Antimicrobial drugs' pharmacokinetic behavior in pregnant females of various

species has been studied. Changes in extracellular fluid and glomerular filtration rate
can have a big impact on betalactam kinetics. Piperacillin and imipenem in pregnant
women, as well as penicillin in sheep, have been shown to have increased volume of
distribution and clearance, resulting in lower maternal serum concentrations. The
oral bioavailability of cefatrizine was reduced in pregnant women. The
pharmacokinetics of amoxicillin, ceftriaxone, and the aminoglycoside tobramycin in
pregnant women, on the other hand, showed no alterations linked to pregnancy. The
pharmacokinetic disposition of gentamicin did not alter in mares, but it was shown to
have higher clearance and a shorter half-life in pregnant women and ewes near the
end of pregnancy.

3.-Drug Transfer and Placental Functions

The number of cellular layers between maternal and fetal circulation, endocrine
activity, blood flow patterns, permeability to xenobiotics, and metabolizing activity of
the placenta all alter throughout pregnancy and between species, resulting in a wide
range of placental function. Changes in placental thickness and surface area, as well
as disparities in mother and fetal blood flows, might explain some of the differences
in placental function between species, as well as increases in placental transfer
throughout late pregnancy. The placenta metabolizes and transmits a wide range of
pharmacological substances in addition to endogenous chemicals. By paracellular or
transcellular processes, drugs can penetrate the placenta and reach the fetus. Only
transcellular diffusion and active transport have been recognized as significant
processes in medication placental transfer to this point. The physicochemical
characteristics of the medication, such as lipid solubility, pKa and degree of
ionization, and molecular weight, are all strongly connected to the kind of transit.
Small compounds that are lipid-soluble, non-ionized, and have minimal protein
binding can traverse the placenta quickly by diffusion, relying simply on the
concentration gradient between maternal and fetal circulation and blood flow. The
transmission of tiny, lipid-soluble medicines may be hampered by extensive plasma
protein binding. The lipoprotein structure of biological membranes prevents
water-soluble, highly ionized medicines from dissolving. As a result, additional
methods of accessing the fetal compartment, particularly carrier-related trafficking,
play an important role. Water-filled canals in the placenta may allow water-soluble
compounds to pass through. Pore diameters vary between species, with sheep
having a pore radius of 0.5 nm and rabbits having a pore radius of 15–30 nm. This
transplacental transit, however, is hampered by many tight connections between
cells. More significantly, many transporters for delivering nutrients and disposing of
waste materials are distributed differently across the maternal and fetal sides of the
placenta. These carriers may transmit xenobiotics through processes comparable to
those that enable them to perform their physiological functions. The substrate
affinities of transporters may be wide and overlapping. Some of these transporters,
notably the P-glycoprotein, restrict the transfer of xenobiotics from the maternal to
the fetal compartment by serving as an efflux pump that extrudes substrates that
have crossed the cellular membrane into the extracellular fluid. The breast cancer
resistant protein (BCRP) and the multidrug resistance associated proteins are two
more placental transporters that act as efflux pumps (MRPs). Placental transporters
may be useful in preventing xenobiotics from entering the fetus. Furthermore, a
chemical may be removed by several transporters, as is the case with glyburide, an
oral hypoglycemic medication that is removed from the fetal compartment by BCRP
and MRP3, both of which are found on the maternal side of the placenta. On the
other hand, because only OTC3 is present in the placenta, another oral
hypoglycemic drug, metformin, which is a substrate for OTC1 and OTC2 found in the
liver and renal tissues, is not eliminated. As a result, when diabetic women are
treated with oral hypoglycaemic pharmacotherapy during pregnancy, metformin, but
not glyburide, is found in fetal tissues. Other transporters on the maternal and fetal
sides of the placenta, on the other hand, might be implicated in the placental transfer
of xenobiotics into the fetus.

Because the placenta has a variety of functionally active drug metabolizing enzymes,
it may digest xenobiotics from early pregnancy. Some xenobiotics are oxidized in the
placenta thanks to phase I metabolizing enzymes including CYP1A1, CYP4B1, and
CYP19 (steroid aromatase, which is responsible for the placental conversion of
androgens into estrogens). Several phase II enzymes have been identified in the
placenta, including glutathione transferases, N-acetyltransferase, sulfotransferase,
and UDP-glucuronosyltransferase. The capacity of the placenta to metabolize
xenobiotics, on the other hand, is less effective than that of the liver and varies
depending on the stage of pregnancy.
The term "placental barrier" is misunderstood as an anatomical feature of the
placenta. The diverse activities of transport and biotransformation supplied by
carriers and metabolizing enzymes are the primary components of the barrier effect
that shields the fetus from the effects of the mother's pharmaceutical therapies. As
with many biological processes, this protection may be effective for some medicines
but ineffective for others, therefore it's best to assume that drugs are always
transmitted to the fetus while using pharmaceuticals during pregnancy.

4.- Antibiotic Treatment and the Risk of Teratogenicity in Canine

and Feline Pregnancy

There is little research that the authors are aware of that look at the use of
pharmacological drugs during canine and feline pregnancy. The majority of the
information in the first section of this study came from accounts on human or animal
models of placental morphologies and functions (rhesus monkeys, sheep, mice, and
rats), and analogous experiences in dogs and cats are rare. As previously stated,
data gained in human research cannot be translated to a pregnant dog or cat due to
the anatomical and functional variety of the placenta among various species. The
following information, on the other hand, may be useful in deciding on a sensible
antimicrobial therapy for dogs and cats during pregnancy.

Plasma volume expansion and increased blood volume, increased heart rate and
cardiac output, increased gastric emptying time and decreased gastric and intestinal
motility, and increased plasma renal flow and glomerular filtration rate are among the
physiological changes reported in the pregnant bitch. Total plasma protein levels
drop or remain constant during pregnancy; acute phase proteins, such as C-reactive
protein and fibrinogen, rise, however this cannot be used to diagnose pregnancy. In
the queen, similar alterations may occur. These changes may not necessitate
dosage adjustments; nevertheless, to our knowledge, no pharmacokinetic studies
comparing antimicrobial disposition in pregnant and nonpregnant dogs or cats have
been undertaken.

The medication itself (fetal concentrations and possible toxicity) and the stage of
pregnancy during the exposure are two main factors of the magnitude of the
potential effects of pharmacotherapy on the fetus. Due to drug exposure during the
first trimester of pregnancy, the fetus is more susceptible to teratogenic
consequences. Embryotoxicity in the bitch can occur anywhere between 6 and 20
days following the preovulatory LH spike. At this point, the medication concentrations
in the uterine fluid bathing the embryo are comparable to those in the maternal
circulation. Feline implantation takes place 12 to 13 days following ovulation. In both
the cat and the dog, placentation is endotheliochorial, which means that the maternal
and fetal circulations are divided by four tissue layers. There have been no
investigations on the presence or lack of placental metabolizing enzymes or
transporters in the canine or feline placenta, which are important factors of its barrier
function as mentioned above. As a result, estimating the capacity of a medication to
pass the canine or feline placenta, and hence the exact risk of damaging the baby, is
extremely challenging.

In several canine breeds, a deletion mutation in the MDR1 gene has been identified
as the source of a functional P-glycoprotein deficiency. If P-glycoprotein is present in
the placenta of dogs and its activity is comparable to that of humans and rodents,
this genetic characteristic might be a cause of variations in P-glycoprotein-substrate
drug transfer. Antibiotics that might harm the fetus, such as fluoroquinolones,
including veterinary enrofloxacin, have been shown to be P-glycoprotein and BCRP
substrates.

Once medicines penetrate the placenta and enter the canine or feline fetal circulation
via the umbilical vein, they can either reach the liver (40–80%) or bypass it via the
ductus venosus, which connects the umbilical vein to the caudal vena cava. This
shift permits nutrient-rich maternal blood from the umbilical vein to reach the rest of
the fetus. Some xenobiotics may be taken up by the fetal liver and detoxified, sparing
the fetus from excessive amounts of drug exposure. The enzymatic activity of the
animal fetal liver, on the other hand, is typically lower than that of adults.

Papich and Davis categorized the teratogenic risk of commonly used veterinary
medicines in treating dogs and cats. Antibiotics such as betalactams (penicillin G,
ampicillin, amoxicillin, amoxicillin-clavulanic acid, carbenicillin, ticarcillin, and
cephalosporins), macrolides, and lincosamides have been found to be safe for usage
during pregnancy (clindamycin, erythromycin, and lincomycin). Because of their
minimal risk of damaging the fetus and low transplacental transit (due to simple
diffusion), betalactams are the primary choice for treating infections during
pregnancy. Macrolides are typically prescribed for individuals who are allergic to
betalactams. When macrolide antibiotics are used to treat maternal illnesses, the
placenta appears to provide a good barrier that reduces fetal exposure, therefore
these medicines are deemed low risk in fetal exposures. Clarithromycin did not
increase the risk of significant abnormalities in pregnant women, according to a
prospective controlled multicenter trial.

During pregnancy, nitrofurantoin, streptomycin, gentamicin, amikacin, tetracyclines

(doxycycline, oxytetracycline), sulphonamides, trimethoprim, and metronidazole are
not recommended since they have been linked to congenital abnormalities or
embryotoxicity. However, since Papich's discovery, human clinical experience and
current research have shown the availability of medicines such as aminoglycosides
(gentamicin, amikacin, and kanamicin) and fluoroquinolones that, despite their
potential dangers, might be used with caution.
Aminoglycosides are polar medicines that are strongly ionized in maternal plasma;
nonetheless, they have been shown to cross the placenta. Human studies suggest
that there is little harm to the fetus, however streptomycin is contraindicated owing to
fetal ear damage. Gentamicin is now used in conjunction with ampicillin in human
obstetrics to prevent group B streptococci infections in newborns. At large dosages,
toxic effects on rat embryonic kidneys and in children's kidneys have been identified.

Fluoroquinolones are not recommended for pregnant women; they are reserved for
patients who are intolerant to betalactams or macrolides. Fluoroquinolones have a
limited ability to pass the placenta. This obstructive passage might be caused by
reduced passive diffusion and/or active transporter extrusion from the placenta.
Some placental transporters are substrates for fluoroquinolones. This fact may be
the source of interspecies variability in fetal fluoroquinolone exposure and represents
an unknown in canine pregnancy; to our knowledge, no studies on the presence and
activity of transporters in the canine placenta have been published, and breed
differences due to genotype differences may exist. Newer fluoroquinolones have a
greater chance of crossing the placenta

Concerns about using fluoroquinolones during pregnancy stem from some of its side
effects, including the development of arthropathies in young animals.
Fluoroquinolones cause cartilage lesions in pups who are especially vulnerable. With
the growing number of compounds and increased clinical usage, the toxicological
profile of fluoroquinolones has become more complicated, and side effects such as
convulsions, photophobia, and ocular toxicity linked to the lens (in dogs) and retina
(in cats) have been reported. These side effects are more common after long-term
use or high dosages, as well as preclinical safety tests. A multicenter prospective
controlled trial of pregnant women who were exposed to quinolones found no
differences in the rate of abnormalities in their children compared to children of
mothers who were not exposed (controls).

5.- conclusions

In all species, pharmacotherapy during pregnancy has the potential to damage the
growing baby; thus, it should be avoided whenever feasible. However, some clinical
problems, like bacterial infections, must be addressed since they pose a significant
risk to the mother's health and consequently to the fetus.

Antimicrobial agent disposition changes during pregnancy are a key source of

concern. Not only may the outcome of therapy be harmed, as effective antimicrobial
treatment is dependent on adequate plasma and tissue concentrations, but resistant
bacteria could also be selected if antimicrobial concentrations aren't high enough to
give complete antibacterial action.

When choosing an antibiotic medication for a pregnant bitch or queen, two criteria
must be met: it must be the best treatment for the mother and it must provide the
least risk to the unborn.

The optimal therapy for the mother entails selecting an appropriate medicine with the
most therapeutic efficacy and fewest side effects, as well as administering it at the
correct dosage. There is less chance of subtherapeutic dosage in small animal
medicine than in human medicine, where fixed adult doses are utilized, even in
pregnant women, because dosages are generally calculated in mg/kg body weight.
This is important in antimicrobial therapy since it helps to achieve therapeutic
success while also reducing bacterial resistance.

The capacity of a medication to reach the fetal circulation and create harmful effects
on the fetus determines the danger to the fetus. During the organogenesis phase,
which lasts from day 20 of pregnancy in dogs and cats, more caution is required.
The physicochemical properties of a drug (lipid solubility, molecular weight, degree of
ionization, and protein binding), maternal concentrations (dose and route of
administration, length of treatment), and functional capability of the placenta in a
particular gestational period can all be used to estimate the drug's ability to cross the
placenta. This is the most difficult problem to deduce since there is a dearth of data
on the kind of placental blood flow in dogs and cats, as well as the presence and
functioning of placental transporters and enzymatic systems. As a result, the
physician must depend on his or her understanding of the medicines'
pharmacological characteristics to determine the degree of placental transit and the
risk to the fetus, as well as evidence from other species. Betalactams are the
first-line treatment for infectious diseases in pregnant hens and queens, and their
broad activity spectrum implies that they are effective against a wide range of
pathogens. Macrolides are similarly thought to pose little harm during pregnancy, but
further research on fluoroquinolones in pregnant dogs and cats is needed.