Macrolide Antibiotics

The macrolide antibiotics include erythromycin and tylosin. More recent derivatives include clarithromycin and azithromycin. The macrolide antibiotics are protein synthesis inhibitors that bind to the 50-S ribosomal subunit and interfere with the translocation reaction necessary for RNA-dependent protein synthesis in bacteria. The macrolides may be bactericidal for some Gram-positive bacteria, but for other bacteria these drugs are bacteriostatic. Their action is considered time-dependent. Their pharmacokinetics favor a time-dependent action because many in this class have long half-lives that produce drug concentrations above the minimum inhibitory concentration (MIC) in plasma, cells, or tissue for an extended time after dosing.

The activity of these drugs is better for Gram-positive bacteria than Gram-negative bacteria. Gram-positive bacteria accumulate macrolides to a greater extent than Gram-negative bacteria (as much as 100× for erythromycin). Subsequently, activity is almost nonexistent against Gram-negative bacteria, especially those of the Enterobacteriaceae (e.g., Escherichia coli). Their activity also includes GIT pathogens such as Campylobacter jejuni and Clostridium spp.

The clinical use of macrolides involves the use of erythromycin, tylosin, and occasionally azithromycin, administered orally. In some instances, such as with tylosin-responsive diarrhea this chapter (see “Tylosin-Responsive Diarrhea” section), the pathogens that are the target of successful treatment are not known.

Macrolide pharmacokinetics have been studied in most animals. Oral absorption of erythromycin is inconsistent because it is not stable in the stomach. Oral absorption is less than 20%. Various attempts have been made to improve stability in the stomach, including salts of erythromycin, poorly soluble esters, and enteric coating. Azithromycin requires some buffering of oral formulation, but its oral absorption is much higher than for erythromycin.

The poor oral absorption of erythromycin is probably responsible for one of its most common adverse effects; that is, diarrhea. This has obvious importance when treating diseases of the GIT. Usually, gastrointestinal adverse effects in small animals are fewer following administration of tylosin or azithromycin, but this is based on anecdotal experiences and has not been investigated in a controlled study.

The most common adverse effect reported from administration of erythromycin is vomiting in dogs. This may be caused either by irritation of the stomach, or stimulation of stomach contraction. In one study, erythromycin oral administration produced the most frequent adverse effects in comparison with other drugs.⁴ Stimulation of gastric motility occurs via an increase in activation of motilin receptors, via release of endogenous motilin, or via cholinergic mechanisms in the upper GIT and gallbladder.^5,6 This effect has been utilized therapeutically (see “Other Uses for Antimicrobials” section).

Lincosamides

Clindamycin and lincomycin are the most common drugs from this class. They are not related to the macrolides by chemical structure, but there are many overlapping properties such as pharmacokinetics and antimicrobial activity. Clindamycin differs from lincomycin by only the addition of chlorine on the parent molecule. This addition produces a more active drug against bacteria and some protozoa. Because clindamycin is the most often used from this group in small animals, lincomycin is not discussed further.

Like macrolides, these drugs are inhibitors that bind to the 50-S ribosomal subunit and interfere with protein synthesis. They are traditionally considered bacteriostatic (time-dependent in action), but more recent evidence shows that there is some bactericidal activity as well.

Susceptible bacteria important for the GIT include streptococci, C. jejuni, Clostridium spp., and some mycobacteria. There is little activity against most Gram-negative organisms, particularly the enteric bacteria (Enterobacteriaceae). Clindamycin has good activity against most anaerobic bacteria, but resistance has been documented among bacteria of the Bacteroides fragilis group.

For clindamycin, tablets, capsules, and an oral liquid (clindamycin hydrochloride) are available for small animals (Antirobe and generic) and clindamycin palmitate liquid (Cleocin), an ester that must be hydrolyzed in the GIT. Oral absorption of clindamycin hydrochloride is high in small animals.

The adverse effects are noteworthy because they predominantly affect the GIT. Clindamycin usage has been associated with bacterial overgrowth (especially Clostridium difficile) in the colon. Serious and fatal diarrhea has been reported in humans, rabbits, ruminants, and horses from oral administration. In people, clindamycin-associated diarrhea is common and a serious disease known as pseudomembranous colitis can occur as a consequence of clindamycin administration. Fortunately, such serious adverse effects have not been reported in dogs and cats, although mild diarrhea certainly is possible.

The other adverse effect that may affect the GIT in cats is esophageal injury caused by the oral administration of the hydrochloride formulation.⁷ Hydrochloride formulations of other drugs (e.g., doxycycline hyclate) also have been reported to produce esophageal injury to cats (see “Tetracyclines” section).

Fluoroquinolone Antibiotics

These drugs include enrofloxacin, marbofloxacin, orbifloxacin, and difloxacin. This class also includes ciprofloxacin, which is an approved human drug that is frequently administered to dogs. (Enrofloxacin is partially metabolized to ciprofloxacin in most animals.) For treatment of GIT disease, the fluoroquinolones owe their usefulness to the high activity against Gram-negative bacilli, particularly the Enterobacteriaceae. These drugs also have the favorable property of weak activity against anaerobic bacteria. Without anaerobic activity, these drugs are less likely than other oral antimicrobials to disrupt the anaerobic intestinal bacterial population.

The fluoroquinolones have a unique mechanism of action. They inhibit the DNA gyrase enzyme (also called topoisomerase type II), which catalyzes the conversion of relaxed closed circular DNA to the superhelical form. There are A and B subunits of this enzyme and quinolones usually inactivate the A subunit. As a result of this activity, the fluoroquinolones are highly bactericidal.

The fluoroquinolones are highly absorbed after oral administration. A summary of their individual pharmacokinetics is available in a recent book chapter.⁸ The exception to this generalization is the human drug ciprofloxacin. In cats the oral absorption of ciprofloxacin is low, and in dogs it is highly variable, ranging from approximately 30% to 80%. An advantage of fluoroquinolones is that they are excreted both by hepatic and renal mechanisms. Renal or hepatic insufficiency is not a contraindication to their use nor requires a dose adjustment.

The fluoroquinolones have a good safety record and can be used in a wide range of patients. The most notable adverse effects are arthropathy in young dogs (ages 4 to 28 weeks are the most susceptible) with high doses, and blindness in cats if the dose of enrofloxacin exceeds 5 mg/kg per day. Other adverse effects such as neurologic problems (seizures, tremors) are rare at the doses used for GIT diseases.

The formulation most often used is the tablet, which is available for every drug listed previously. Enrofloxacin is also available in an injectable formulation, which may be necessary in animals that cannot tolerate oral medications. When oral treatments are used, drug interactions are possible. The fluoroquinolones can be inactivated by di- and trivalent cations, producing poor oral absorption. This may be important for treatment of some GIT diseases because drugs known to contain these cations include antacids (magnesium, aluminum, and calcium), sucralfate (aluminum), and nutritional supplements (supplements containing magnesium or iron).

Tetracyclines

The tetracyclines include tetracycline, oxytetracycline, doxycycline, and minocycline. For small animals, the use is almost exclusively that of doxycycline. Tetracyclines are protein synthesis inhibitors. They bind to the 30-S ribosomal subunit and block the aminoacyl-transfer RNA from binding to the messenger RNA (mRNA) ribosome complex.

The tetracyclines are broad-spectrum drugs that are active against Gram-negative and Gram-positive bacteria, as well as Chlamydia, rickettsia, spirochetes, mycoplasma, L-form bacteria, and some protozoa (e.g., Plasmodium, Entamoeba). The family Rickettsiaceae includes Rickettsia and Ehrlichia and tetracyclines, particularly doxycycline, are considered the drug of first choice for these infections.

The oral route is the most common method of administration and doxycycline hyclate tablets, and occasionally doxycycline monohydrate, are the formulations most often administered to small animals. Oral absorption is sometimes erratic and unpredictable, but high enough for oral treatment in most animals. Calcium and other divalent cations will chelate tetracyclines and inhibit oral absorption (note that in “Fluoroquinolone Antibiotics” section, drugs were listed to treat GIT diseases contain these cations), although this is less of a problem for doxycycline than for other tetracyclines.

Most tetracyclines are metabolized minimally and rely on glomerular filtration for elimination. However, doxycycline and minocycline are metabolized more than the other tetracyclines and the renal excretion may not be as high as for other tetracyclines. Doxycycline and minocycline differ from the other tetracyclines because they are excreted into the intestinal lumen, which may be important for treatment of some intestinal diseases.

Tetracyclines can produce changes in the gastrointestinal microflora. This has been a problem in some animals (horses especially), but less so for small animals. Nevertheless, diarrhea can occur from oral administration. The other important adverse effect related to the GIT is esophageal injury. Doxycycline entrapped in the esophagus from a broken tablet or incompletely dissolved capsule can cause injury to the esophagus and stricture. In cats, a capsules or broken tablets can lodge in the esophagus unless administered with water. Therefore, one should be cautious about giving oral doxycycline medications to cats. This problem has been primarily associated with doxycycline hyclate (the form most common in the United States), rather than doxycycline monohydrate.

Ampicillin and Amoxicillin

Ampicillin and amoxicillin are aminopenicillins, derived semisynthetically from the parent drug penicillin. They have advantages over penicillin that include better oral absorption (although amoxicillin is better absorbed than ampicillin in small animals), and slightly better activity against Gram-negative bacilli. They are also active against many of the anaerobic bacteria and some enterococci.

The aminopenicillins are available in a variety of formulations, including tablets, capsules, liquid oral suspensions, and injectable forms. Their absorption is variable. In dogs the systemic availability for ampicillin is 30% to 40%, and for amoxicillin it is approximately 60% to 80%. A relatively high amount remains in the intestinal lumen and this forms the basis for the oral use of these drugs for treating GIT diseases. These drugs may also produce diarrhea in animals by disrupting the oral flora.

Chloramphenicol

Chloramphenicol is highly active against many pathogens that cause GIT disease. Chloramphenicol is a protein synthesis inhibitor that acts by binding to the 50-S subunit of the ribosome. This is the same site of action as macrolide antibiotics, therefore antagonism is possible. Binding to this subunit is reversible and results in inhibition of protein synthesis.

Chloramphenicol has been considered bacteriostatic, but some evidence suggests a more bactericidal action. Chloramphenicol has a wide spectrum of activity that includes both Gram-positive and Gram-negative bacteria, as well as some atypical organisms. The bacterial spectrum includes organisms that are important for GIT disease, including Salmonella, anaerobes (including Bacteroides), and enterococci.

Adverse effects must be considered whenever prescribing chloramphenicol. Dose-related anemia and pancytopenia may be associated with chronic treatment. This effect has been well-documented in cats and can occur after 14 days of therapy with standard dosages.⁹ Because of the potential injury to bone marrow cells, use in neonatal animals or pregnant animals should be avoided. The more serious effect of idiosyncratic aplastic anemia has been described in humans only. The incidence is rare but the consequences are severe. This can potentially occur by direct exposure from handling the medication; therefore, pet owners should properly be advised when receiving a prescription for their pets. Chloramphenicol also can be involved in drug–drug interactions. It decreases the clearance of other drugs that are metabolized by the same metabolic enzymes (e.g., barbiturates).

Florfenicol (Nufluor) is a chloramphenicol derivative used as an injectable formulation in pigs and cattle. It has been examined only experimentally in small animals. The requirement for frequent administration and poor absorption make it an impractical choice for treating dogs. The lack of a palatable oral formulation and inexperience with clinical use is a disadvantage for the use in cats.