Antimicrobial Drugs

I. INTRODUCTION



A. Selection of an antimicrobial drug. Antimicrobial therapy is based upon the selective toxicity of the drug for invading organisms rather than mammalian cells. It is important to select an agent to which the organism is sensitive and to maintain the effective tissue concentrations (above the minimal inhibitory concentration or MIC) until the infection is eliminated. A practical approach is to select an antimicrobial agent where the measured MIC is less than the concentration known as the breakpoint concentration. Sensitivity tests using either sensitivity disks or sensititer micro-well plates can be used to estimate the MIC of specific bacteria and then tables are consulted to see if the MIC is below the breakpoint. If the MIC is below the breakpoint, it is predicted that the microbe will be Susceptible (S) to therapy; if it is equal to the breakpoint, it is predicted that the microbe will be Intermediate (I)—where high therapeutic doses may work; if the MIC is above the breakpoint, it is predicted that the microbe will be Resistant (R). The breakpoint concentrations have been determined by groups like the Clinical and Laboratory Standards Institute (CLSI) following review of clinical and laboratory data. The pharmacokinetic data on data labels of more recently introduced antimicrobials contain breakpoint information. It is pointed out that the sensitivity tests and breakpoints are useful indicators for the clinical outcome, but in the whole animal, additional factors like drug binding, drug distribution, and an active immune system affect the outcome so that clinical experience is still essential.
Extra-label use of specific antimicrobial drugs in food animals is prohibited for reasons of safety or limitation of resistance spread. These drugs include the fluoroquinolones, chloramphenicol, nitroimidazoles, furazolidone, nitrofurazone and other nitrofurans, and sulfonamide drugs in lactating dairy cattle (except approved use of sufadimethoxine, glycopeptides, and vancomycin).

There are six selection questions that are helpful to use routinely to aid selection:

1. Is an antimicrobial agent required—is there an infection that will respond to your treatment? Avoid: “Just in case.”

2. Where is the infection (which organ/tissue)—what are the access problems to be overcome?

3. Which pathogen(s) are usually found at the location of the infection?

4. Which antimicrobial agent has the necessary pharmacokinetic properties to get to the location and also will get there at a concentration above the MIC so that the MIC is below the breakpoint?

5. What dose and route is necessary to achieve the desired effect?

6. How long should the treatment be for?

There are 4 additional factors to help the selection:

1. A bactericidal compound is preferable to a bacteriostatic compound.

2. Toxicity and cost limit the selection of an antimicrobial drug.

3. In food-producing animals, residues in milk and meat requiring the need for withdrawal times before slaughter (preslaughter withdrawal times) are very important and limit the use of specific antimicrobial drugs. Animals must not be slaughtered for meat or their milk used within the preslaughter period (see appendix for the withdrawal period for each drug).

4. It should be appreciated that the plasma concentration governs the dose intervals on a treatment regimen but it is the tissue residence times that govern the preslaughter withdrawal times in production animals.

B. Resistance to antimicrobials
1. Mechanisms by which bacteria manifest resistance:
a. Organisms may produce enzymes, constitutive or inducible, which inactivate the drug.

b. The permeability to or uptake of the drug by organisms may be decreased or transport out of the cell may be increased.

c. Alteration of the drug receptor or binding site may result in reduced drug affinity at target loci.

d. The organism may develop alternate metabolic or synthetic pathways to bypass or repair the effects of the antimicrobial.

2. Mechanisms by which bacteria develop resistance
a. Mutation. Within a large population of bacteria, chromosomal mutations may occur, which confer resistance either slowly, in a step-wise fashion with each succeeding generation of the mutant more resistant or rapidly, in a single step in which the bacterium is resistant after the initial mutation. Mutation is a random event. Antimicrobials do not induce mutations but may exert a selecting out of resistant strains by suppression of susceptible bacteria.

b. Conjugation. Certain Gram(–) bacteria undergo conjugation, a type of reproduction in which genetic material is transferred from cell to cell via a pilus that is encoded by a resistance transfer factor (RTF) on a plasmid. Resistance factors (R-factors) from plasmid DNA and/or chromosomal DNA may encode for resistance to multiple drugs and may be rapidly transferred to the bacterial population.
This is termed infectious drug resistance or transferable drug resistance and has been observed clinically in enteric infections with Salmonella spp., Shigella spp., and Escherichia coli.

c. Transduction. The process of transference of drug resistant genes by bacteriophage is termed transduction. It may be important in the development of resistant strains of Staphylococcus aureus.

d. Transformation. Bacteria may incorporate DNA encoding for drug resistance from their environment after its secretion or release by resistant organisms. Acquisition of resistance by this mechanism is relatively infrequent.

II. SULFONAMIDES



A. Chemistry. The sulfonamides are derivatives of p-aminobenzene sulfonic acid (Figure 15-1) and are structurally similar to p-aminobenzoic acid (PABA), an intermediate in bacterial synthesis of folic acid. They behave as weak organic acids which are poorly water soluble unless prepared as sodium salts. Concentrated solutions of the sodium salts of most sulfonamides are very alkaline and may be corrosive. The solubility of a sulfonamide is not influenced by the presence of other sulfonamides in the solution. This is termed the law of independent solubility and is the primary reason for the use of sulfonamide mixtures in order to increase the combined total sulfonamide concentration to prevent renal precipitation and thus reduce toxicity.

B. Mechanism of action. Sulfonamides competitively inhibit dihydropteroate synthase, the enzyme which catalyzes the incorporation of PABA into dihydrofolic acid (Figure 15-2). Folic acid is required for purine and DNA synthesis and thus bacterial growth is inhibited. Mammalian cells and bacteria that use preformed folic acid are not affected. Sulfonamides are broad spectrum (including protozoa) and bacteriostatic.

C. Therapeutic uses. Sulfonamides were widely used in the prevention and treatment of local and systemic infections in all species but now resistance is common. Examples of sulfonamides used in veterinary medicine include the following:
1. Sulfamethazine is used in cattle, sheep, and swine. It is slowly excreted and therapeutic levels are maintained in plasma for 24 hours with a single dose.

2. Sulfadimethoxine is a long-acting sulfonamide. It is more soluble and less toxic than sulfamethazine. The plasma t½ is 10–15 hours.

3. Sulfachlorpyridazine is a rapidly absorbed and rapidly excreted sulfonamide used orally in calves under 1 month of age and in swine for the treatment of respiratory and enteric infections, especially colibacillosis. Peak levels occur in 1–2 hours in nonruminants and in preruminant calves. The plasma t½ is 1.2 hours.

4. Sulfamethoxazole is used to treat urinary tract infections in small animals. It is rapidly excreted and very soluble. Thus high concentrations may be attained in urine with minimal danger of renal crystalluria.

5. Sulfacetamide is the only sulfonamide that can be prepared as the sodium salt at neutral pH and thus can be used in ophthalmic preparations.

6. Sulfasalazine is an “enteric” sulfonamide employed in the therapy of colitis and inflammatory bowel disease in dogs and cats. It consists of a molecule of sulfapyridine linked to a molecule of 5-aminosalicylic acid (5-ASA) by a diazo bond. This prevents absorption in the small intestine and allows drug transit to the large bowel where it is cleaved by gut bacteria to sulfapyridine and 5-ASA. These have antibacterial and anti-inflammatory actions, respectively.

7. Other sulfonamides used in veterinary medicine are sulfathiazole and sulfaquinoxaline.

FIGURE 15-1. General structure of the sulfonamides. The p-amino group at position 4 must be free for antimicrobial activity to occur. Substitution with a heterocyclic ring (e.g., thiazole, pyrimidine, pyridine) at the R position on position 1 distinguishes the various sulfonamides. Replacement of the hydrogen with sodium at position 1 greatly increases the water solubility of the sulfonamide. (Adapted from Figure 11-1, NVMS Pharmacology, by Ahrens, F. A. 1996.)


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FIGURE 15-2. Mechanism of action of sulfonamides. Sulfonamides block dihydrofolic acid synthesis by competing with p-aminobenzoic acid (PABA) for binding sites on dihydropteroate synthetase. Dihydrofolic acid is necessary for the synthesis of tetrahydrofolic acid, and ultimately, purines and DNA. Trimethoprim and ormetoprim inhibit dihydrofolic acid (DHFA) reductase, which is necessary for tetrahydrofolic acid synthesis. Therefore, potentiated sulfonamides (i.e., those combined with trimethoprim or ormetoprim) block the second step of protein synthesis.


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8. Potentiated sulfonamides are fixed combinations of a sulfonamide with trimethoprim or ormetoprim. This results in a synergistic action via sequential blockade of folate synthesis (Figure 15-2).
a. Trimethoprim and ormetoprim inhibit dihydrofolate reductase in bacteria (but not mammalian cells) and thus block the formation of tetrahydrofolic acid essential for purine and DNA synthesis.

b. Potentiated sulfonamides have a broader spectrum of action and a reduced rate of development of bacterial resistance.

c. Preparations include sulfadiazine plus trimethoprim, sulfamethoxazole plus trimethoprim, and sulfadimethoxine plus ormetoprim. They are used in the treatment of susceptible infections in all species.

d. Trimethoprim and ormetoprim are organic bases in contrast to the organic acid nature of the sulfonamides. They accumulate by ion-trapping in acidic environments and will concentrate differently in the tissues to the sulfonamides. Trimethoprim plasma t½ is 2–3 hours in most species.

D. Pharmacokinetics
1. Sulfonamides are well absorbed orally and widely distributed to tissues. Transcellular fluid concentrations are 80% of plasma concentration. Binding to plasma albumin varies with each sulfonamide but is generally 50–75%.

2. Metabolism by acetylation at N4 and glucuronide conjugation occurs in most species. Acetylation does not occur in the dog. Oxidation of the benzene and heterocyclic rings to quinone derivatives also occurs, especially in dogs. The type and extent of metabolism varies with the sulfonamide and the animal species.

3. Renal excretion of unchanged drug and metabolites is via glomerular filtration, active secretion, and passive tubular reabsorption. Reabsorption is pH–pKa dependent.

E. Administration. Sulfonamides and potentiated sulfonamides can be administered orally or by injection, depending on species. Frequency of dosing varies with the individual sulfonamides.

F. Bacterial resistance. Bacteria develop resistance by mechanisms, which include increased PABA production, decreased binding of sulfonamide to dihydropteroate synthase, and bacterial metabolism of sulfonamide. Bacteria which are resistant to one sulfonamide are resistant to all. Resistance to the potentiated sulfonamide does occur but is less common than to the sulfonamide. The spectrum of action of the potentiated sulfonamides is broader and the combination is considered bactericidal rather than bacteriostatic.

G. Adverse effects
1. Renal crystalluria due to precipitation of sulfonamides in neutral or acidic urine may occur with large or prolonged doses or inadequate water intake, especially with the older, less soluble sulfonamides such as sulfathiazole. Therapeutic regimens generally do not extend beyond 5 days and renal crystalluria is rare.

2. Keratoconjunctivitis sicca (KCS) may be observed in dogs treated with sulfonamides, such as sulfadiazine, which contain the pyrimidine nucleus. The mechanism of the toxic effect on lacrimal acinar cells is unknown.

3. Hypoprothrombinemia, thrombocytopenia, and anemia occur rarely and are probably immune-mediated reactions. Sulfonamides should not be used in animals with preexisting bleeding disorders.

III. FLUOROQUINOLONES



A. Chemistry. The fluoroquinolones consist of a quinoline ring to which is attached a carboxyl group, fluorine atom, and piperazine ring. They are weak acids and are lipophilic. Water-soluble salts are used in parenteral preparations.

FIGURE 15-3. Mechanisms of action of antibacterial drugs. The five general mechanisms are (1) inhibit synthesis of cell wall, (2) damage outer membrane, (3) modify nucleic acid/DNA synthesis, (4) modify protein synthesis, and (5) modify energy metabolism in the cytoplasm (at folate cycle). (Modified from Figure 46.2, Human Pharmacology, 2nd ed., by Brody, T. M., Larner, J., Minneman, K. P., and Neu, H. C. 1994.)


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B. Mechanism of action. The fluoroquinolones inhibit bacterial DNA gyrase, an enzyme which controls DNA supercoiling as the replicating strands separate. Inhibition of gyrase results in degradation of chromosomal DNA at the replicating fork. Fluoroquinolones are broad spectrum and bactericidal. Anaerobes tend to be resistant (Figure 15-3).

C. Therapeutic uses
1. Enrofloxacin is used in the treatment of dermal, respiratory, and urinary tract infections (including prostatitis) in dogs, cats, and birds and in respiratory infections in cattle.

2. Danofloxacin is used for the treatment of bovine respiratory infections including Mannheimia species.

3. Difloxacin is used for treatment of dermal, respiratory, and urinary tract infections in dogs.

4. Orbifloxacin and Marbofloxacin are used for the treatment of dermal, respiratory, and urinary tract infections of dogs and cats. Orbifloxacin is used for susceptible Gram(–) infections in horses.

5. Extralabel use of fluoroquinolones in food animals is prohibited.

D. Pharmacokinetics. Oral absorption of the fluoroquinolones is rapid with peak plasma concentrations at 1 hour in dogs. Distribution is wide and includes the CNS, bone, and prostate. Some hepatic metabolism occurs and both parent drug (15–50%) and metabolites are excreted in urine and bile. Renal tubular active secretion results in high urinary concentrations. The plasma t½ for enrofloxacin is 3–5 hours in dogs and 6 hours in cats and horses. The elimination t½ for difloxacin and marbofloxacin is 9–12 hours in dog and cats and for orbifloxacin is 6 hours in dogs and cats and 9 hours in horses.

FIGURE 15-4. General structure of penicillins. Substituents at R distinguish the various penicillins. (1) Thiazolidone ring. (2) β-Lactam ring. (3) Site of action of β-lactamases (penicillinases). (4) Site of amidase cleavage to yield 6-aminopenicillanic acid (6-APA) nucleus for semisynthetic penicillins. (5) site of salt formation (e.g., sodium, procaine). (Adapted from Figure 11-3, NVMS Pharmacology, by Ahrens, F. A. 1996).


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E. Administration. Fluoroquinolines are administered orally or parenterally once or twice a day in all species. Enrofloxacin is administered SC once a day for treatment of respiratory infections in cattle.

F. Resistance. Development of bacterial resistance is relatively rare. Long periods of subtherapeutic levels may allow the growth of mutants in which fluoroquinolones are not bound to DNA gyrase.

G. Adverse effects. Toxicity associated with fluoroquinolones is erosion of articular cartilage in young dogs and foals, particularly, if they are used at high doses for longer than 14 days in rapid growth phase. Enrofloxacin has also been reported to produce seizures in dogs on phenobarbital for epilepsy; other quinolones evoke headaches in humans. Retinal degeneration has been reported due to acute and diffuse retinal damage in cats.

IV. PENICILLINS



A. Chemistry. The structure of penicillins includes a β-lactam ring and a thiazolidone ring (Figure 15-4). Cleavage of the β-lactam ring destroys antibiotic activity. Amidase cleavage of the amide bond side chain yields the 6-amino-penicillanic acid (6-APA) nucleus used in producing semisynthetic penicillins. The carboxyl group attached to the thiazolidone ring is the site of salt formation (sodium, potassium, procaine, etc.) which stabilizes the penicillins and affects solubility and absorption rates.

B. Mechanism of action. Penicillins bind to and inhibit the transpeptidase involved in the cross-linking of the bacterial cell wall, the third and final step in cell-wall synthesis (Figure 15-3). The weakened cell wall ruptures, resulting in lysis and cell death. Penicillins also inhibit other peptidases (penicillin-binding proteins) involved in cell wall synthesis and block the inhibition of autolysins. Rapidly growing bacteria are most susceptible to the bactericidal effect of penicillin. The penicillins are primarily effective against Gram(+) aerobes and anaerobes. The broad-spectrum, semisynthetic penicillins are also effective against some Gram(–) pathogens.

C. Therapeutic uses
1. Natural penicillins
a. Penicillin G (benzylpenicillin) is used in all species for the treatment of infections caused by Gram(+), nonpenicillinase producing pathogens. It is the most potent penicillin for these organisms.

b. Penicillin V now used infrequently for long-term oral therapy of Gram(+) bacterial infections in dogs, cats, and horses.

2. Penicillinase-resistant penicillins include methicillin, oxacillin, and cloxacillin. Their use is suited for severe staphylococcal infections caused by β-lactamase-producing organisms (some bovine mastitis) but they are less effective against Streptococcus than the natural penicillins.

3. Broad-spectrum penicillins
a. Aminopenicillins. Ampicillin and amoxicillin are active against many Gram(–) aerobes (E. coli, Proteus, Haemophilus spp.) as well as Gram(+) pathogens. They are used in all species for the treatment of susceptible infections. They are acidstable but are not penicillinase stable. GI absorption of amoxicillin is better than ampicillin.

b. Carbenicillin and ticarcillin are carboxypenicillins that have antipseudomonal actions when used alone or in combination with or gentamicin or tobramycin. They are useful for ear and skin infections in dogs caused by Pseudomonas spp.

c. Piperacillin is an ureidopenicillin that has an extended Gram(–) spectrum including Pseudomonas, Enterobacter, and Klebsiella spp. Cost limits its use to the treatment of severe Gram(–) bacterial infections in dogs and cats.

4. Potentiated penicillins. Clavulanic acid has minimal antibacterial action but it inhibits many of the β-lactamases produced by penicillin-resistant organisms. It is combined with amoxicillin or ticarcillin in commercial preparations. Sulbactam has an action similar to clavulanic acid and is combined with ampicillin. The potentiated penicillins are used in small animals for extended spectrum antimicrobial action. Tazobactam is another β-lactamase inhibitor.

D. Pharmacokinetics. Many penicillins are broken down by gastric HCl and are thus poorly absorbed orally. These include penicillin G, methicillin, and ticarcillin. Acid stable penicillins are well absorbed orally. These include penicillin V, ampicillin, amoxicillin, oxacillin, cloxacillin, and the indanyl salt of carbenicillin. The distributions of penicillins are confined mostly to the extracellular spaces occur, but clinically effective concentrations in most tissues except for the CNS, bones, prostate, and eye. More than 90% of an administered dose is excreted unchanged in the urine by glomerular filtration and active tubular secretion. The remainder is metabolized by the liver to penicilloic acid derivatives, which may act as antigenic determinants in penicillin hypersensitivity.

E. Administration. Penicillins are generally administered IM. The acid-stable penicillins are administered orally 2–3 times a day. Procaine penicillin G is slowly absorbed from IM sites and may provide therapeutic levels for 24 hours with a single dose. Benzathine penicillin G is even more slowly absorbed over 48–72 hours but blood levels attained are relatively low. Sodium or potassium salts of penicillin G may be administered IV or IM every 4–6 hours.

F. Resistance. Inactivation of penicillins by bacteria-producing penicillinases (β-lactamases) is the most common mechanisms of resistance. Failure of the drug to bind to penicillin-binding proteins (PBPs) may also occur.

G. Adverse effects. Allergic reactions to penicillin may occur in animals, especially cattle. Signs include skin eruptions, angioedema, and anaphylaxis. Procaine salts of penicillin should not be used in birds, snakes, turtles, guinea pigs, or chinchillas because these species are sensitive to procaine. Procaine penicillin G should not be used in race horses 30 days before racing. Release of procaine due to high levels of plasma esterases in horses may produce CNS effects. Hyperkalemia and cardiac arrhythmias may result from IV administration of potassium penicillin in all species.

V. CEPHALOSPORINS



A. Chemistry. Cephalosporins are β-lactam antibiotics, which have a 7-aminocephalosporanic acid nucleus analogous to the 6-APA nucleus of penicillins. They are weak acids and are administered as the sodium salt, monohydrate, or free base.


C. Therapeutic uses. Cephalosporins may be used in penicillin-intolerant patients, but this should be done with caution since cross-reactivity can occur.
1. First generation cephalosporins include cephalexin (oral), cefadroxil (oral), cephapirin (parenteral), and cephalothin (parenteral). They are effective against Gram(+) aerobes. Cephalosporins are frequently employed for antibiotic prophylaxis because of their ability to penetrate tissues. They are a first alternate to penicillins in the treatment of many infections caused by Gram(+) pathogens.

2. Second-generation cephalosporins include cefaclor (oral) and cefoxitin (parenteral). Their antibacterial spectrum is broader than that of first-generation cephalosporins and includes some Gram(–) pathogens. They are not widely used in veterinary medicine.

3. Third-generation cephalosporins include ceftiofur, cefoperazone, cefotaxime, cefixime, and cefpodoxime (Simplicef®). They have an extended spectrum of action against Gram(–) organisms, are resistant to β-lactamases cephalosporinases), and penetrate the blood–brain barrier. Ceftiofur is used in the treatment of respiratory disease in cattle, horses, sheep, and swine following IM injection and for intramammary treatment of mastitis in cattle. It is also used for treating urinary tract infections and soft tissue infections in dogs and cats. Cefoperazone is used in dogs to treat soft tissue infections and Gram(–) bacteremia. Cefotaxime is used in dogs, cats, and foals to treat Gram(–) sepsis, soft tissue infections meningitis, and CNS infections. Cefpodoxime proxetil is the prodrug marketed for use in the treatment of skin infections in dogs and cats. Cefixime is used in the treatment of urinary tract infections and respiratory infections in dogs and cats and for bacterial endocarditis in dogs.

4. Fourth-Generation cephalosporins include cefepime and cefquinone and have more activity against bacteria, particularly Pseudomonas, showing resistance to other cephalosporins. Some manufacturers have implied incorrectly that their third-generation cephalosporins are fourth generation.

D. Pharmacokinetics. Most cephalosporins are unstable in gastric acid and must be given parenterally. Cephalexin and cefadroxil, cefachlor, and cefixime are acid stable and are well absorbed orally. Cephalosporins are distributed in the extracellular fluid and penetrate body tissues except the CSF. Metabolism is minimal except for a few cephalosporins such as cephalothin, which is deacetylated by the liver. The plasma t½ for most cephalosporins is 1–2 hours. The t½ for cefixime in dogs is 7 hours. The elimination t½ for ceftiofur in cattle is 8–12 hours following IM administration. Ceftiofur tissue concentration fall in food animals below tolerance levels in liver and kidney after 4 days. Renal excretion is by glomerular filtration and active tubular secretion like penicillins.

E. Administration. The acid-stable cephalosporins (cephalexin, cefadroxil, cefachlor, and cefixime) are administered orally every 8–12 hours in dogs and cats. Parental cephalosporins are administered IM, IV, or SC every 8–12 hours in all species. An exception is ceftiofur, which is administered once a day in cattle, horses, sheep, dogs, and cats.

F. Resistance. Bacterial β-lactamase production may confer resistance, although cephalosporins tend to retain efficacy in contrast to the penicillins.

G. Adverse effects. Side effects are rare and cephaolsporins are considered to be among the safest antimicrobials in use. Prolonged treatment or high doses may produce hemopoietic effects with anemia and bone marrow depression. Hypersensitivity and allergic reactions may occur.

VI. CARBAPENEMS



A. Chemistry. Carbapenems are β-lactams with a structure similar to penicillin but the –S-in the thiazolidine is replaced by a methyl group.


C. Therapeutic uses. The carbapenems are used to treat very serious infections like peritonitis associated with ruptured GI tract or intestinal spillage during surgery. They are effective against Gram(+) and Gram(–) aerobic and anaerobic bacteria including Pseudomonas and Enterobacteriaciae.

D. Pharmacokinetics. Oral administration is not possible because of acid hydrolysis and poor absorption. Imipenem is given IV over a period of 15–30 minutes and elimination in humans is governed by a t½ of 2 hours where 75% is eliminated by renal filtration and metabolism in the renal tubules. No information on t½ is available for animals. Imipenem undergoes extensive metabolism by the kidney dehydropeptidase (DHP-1) in the brush border of the proximal tubule. The metabolite is nephrotoxic and exhibits antimicrobial action in the urine. Imepenem is used with a DHP-1 inhibitor, cilastatin, to decrease toxicity and increase elimination t½. Meropenem is a more recent derivative that is more DHP-1 stable that does not need cilastatin to inhibit kidney metabolism.

E. Adverse effects. Side effects may include anorexia, vomiting, and diarrhea; CNS toxicity including seizures and tremors; and hypersensitivity reactions including pruritis, fever, and rarely, anaphylaxis.

VII. MONOBACTAMS



A. Chemistry. Monobactams have a β-lactam ring but the adjacent thiazolidine ring has been replaced.


C. Therapeutic uses. Aztreonem is used in humans to replace aminoglycosides, which are more toxic when used with macrolides and lincosamides. It may be used as a reserve antibiotic in veterinary medicine to treat severe Gram(–) infections.

D. Pharmacokinetics. When given parenterally, aztreonem has a similar distribution to penicillin G. Penetration of CSF is good. It is excreted by the kidneys with an elimination t½ of 1.2 hours in humans. No other information is available for animals.

E. Adverse effects. Hypersensitivity reactions may occur but cross-allergy with penicillins or cephalosporins has not been observed.

VIII. AMINOGLYCOSIDES



A. Chemistry. Aminoglycosides consist of two or three amino sugars joined to a hexose (aminocyclitol) by glycosidic bonds. Numerous amino groups contribute to their very polar and basic character. Sulfate salts are water soluble.

B. Mechanism of action. The aminoglycosides bind to the 30S ribosomal fragment and inhibit the rate of protein synthesis and the fidelity of mRNA translation which results in the synthesis of abnormal proteins (Figure 15-3). Their uptake by bacteria includes an energy-dependent step (EDP1), which is oxygen linked and is inhibited by an anaerobic or acidic environment and by Ca2+ or Mg2+. They are bactericidal against Gram(–) aerobes and are synergistic with β-lactams against many Gram(+) pathogens.

C. Therapeutic uses. The aminoglycosides are used in the treatment of Gram(–) infections in all species.
1. Streptomycin and dihydrostreptomycin are the oldest members of this class of antibiotics. Their use has declined with the advent of broader spectrum aminoglycosides such as gentamicin and amikacin.

2. Neomycin is used orally for the treatment of enteric infections and topically for treating skin, ear, and eye infections.

3. Gentamicin and amikacin are expanded spectrum aminoglycosides with activity against Pseudomonas, Proteus, Staphylococcus, and Corynebacterium spp., as well as Gram(–) aerobes. They are used in all species for the treatment of susceptible infections of the skin, respiratory tract, ear, eye, urinary tract, and septicemia. Tobramycin is similar to gentamicin but has more potent antipseudomonal activity and reduced nephrotoxicity.

4. Kanamycin has an antimicrobial spectrum similar to gentamicin except it is not effective against Pseudomonas spp. It is currently used in veterinary medicine only as an oral preparation combined with bismuth subcarbonate and aluminum magnesium silicate for the treatment of bacterial enteritis in dogs and for symptomatic relief of the associated diarrhea.

D. Pharmacokinetics. Aminoglycosides are not absorbed from the GI tract because of their high polar nature. They are distributed to the extracellular fluid and to transcellular fluids such as pleural and peritoneal fluids. Distribution is limited with penetration of the CNS or ocular tissue being minimal. Aminoglycosides tend to accumulate in the renal cortex and otic endolymph, which predisposes these tissues to their toxicity. They are excreted unchanged in the urine by glomerular filtration. The plasma t½ is 1–3 hours for most species. The prolonged residues values in kidney severely limits the use of aminoglycosides in production animals to label use only.

E. Administration. Aminoglycosides are administered IM or SC for systemic infections. Because the bactericidal effects of aminoglycosides are concentration-dependent for systemic infections, some clinicians advocate a high dose once daily (pulse therapy, rather than twice daily) to allow full clearance to reduce renal and cochlear toxicity. For enteric infections, an oral dose twice a day may be used.

F. Resistance. Inactivation of aminoglycosides by bacterial enzymes is the most common form of resistance. The numerous amino and hydroxyl side groups are sites of attack by acetylases, phosphorylases, and adenylases. Resistance may be plasmidmediated and develop quickly. Amikacin is more resistant to enzymatic degradation than other members of this class.

G. Adverse effects
1. The aminoglycosides are relatively more toxic than other classes of antimicrobials. Toxicity is reversible if the treatment is stopped early. Dosage regimens must be adjusted in animals with decreased renal function and they should not be used with other ototoxic or nephrotoxic drugs such as furosemide or amphotericin B.

2. Ototoxicity is due to progressive damage to cochlear sensory cells and/or vestibular cells of the inner ear resulting in deafness and ataxia, respectively.

3. Nephrotoxicity is due to the damage of the membranes of proximal tubular cells resulting in a loss of brush border enzymes, impaired absorption, proteinuria, and decreased glomerular filtration rate.

4. Neuromuscular blockade is a relatively rare adverse effect of aminoglycosides. It is caused by prejunctional blockade of acetylcholine (ACh) release and decreased postsynaptic sensitivity to ACh. Muscle paralysis and apnea are treated with calcium gluconate.

IX. TETRACYCLINES



A. Chemistry. The tetracyclines are polycyclic compounds that are amphoteric and that fluoresce when exposed to ultraviolet light. Most are prepared as the hydrochloride salt. They form insoluble chelates with cations such as Ca2+, Mg2+, Fe3+, and Al3+. They accumulate in growing teeth and bones.

B. Mechanism of action. Tetracyclines reversibly inhibit bacterial protein synthesis by binding to the 30S ribosome and preventing attachment of aminoacyl tRNA to the mRNA-ribosome complex (Figure 15-3). They block the addition of amino acids to the growing peptide chain. They are bacteriostatic and broad spectrum. Their antimicrobial spectrum includes Gram(+) and Gram(–) aerobes and anaerobes, Rickettsiae, Spirochetes, Chlamydiae, Mycoplasma, and some protozoans such as Anaplasma spp. and Haemobartonella spp.

C. Therapeutic uses
1. Large animals. Tetracycline, chlortetracycline, and oxytetracycline are used in the treatment of local and systemic bacterial, chlamydial, rickettsial, and protozoal infections in cattle, sheep, horses, and swine and as feed additive/growth promoters in cattle and swine.

2. Small animals. Doxycycline, minocycline, and tetracycline are used in the treatment of respiratory and urinary tract infections in dogs and cats and as specific therapy for Borrelia (Lyme disease), Brucella, Haemobartonella, and Ehrlichia spp. infections. They are also effective in the treatment of psittacosis in birds.

D. Pharmacokinetics. Oral absorption of tetracyclines ranges from 60–90% of the administered dose except for chlortetracycline, which is only 35% absorbed. Divalent or trivalent cations impair absorption and thus milk, antacids, or iron salts should be avoided 3 hours before and after oral administration. Distribution is wide and includes all tissues except those of the CNS. Doxycycline and minocycline are more lipid soluble than tetracycline, chlortetracycline, or oxytetracycline and penetrate the CNS, eye, and prostate at therapeutic concentrations. Metabolism is minimal in domestic animals, except for minocycline, which is extensively metabolized by the liver. Renal excretion by glomerular filtration is the major route of elimination for most tetracyclines, but small amounts are excreted into feces via bile and/or diffusion from the blood into the intestine. Doxycycline is unique in that intestinal excretion is the major route of elimination (75%). The plasma t½ ranges from 6–12 hours for most tetracyclines. A recent derivative of the glycylcyclines, tigecycline, has been developed that has an effect against methicillin-resistant S. aureus (MRSA).

E. Administration. Tetracyclines are administered orally or IV every 8–12 hours. IM injections produce pain, irritation, and sterile abscesses unless special buffered solutions are used. Oral therapeutic doses should be avoided in adult ruminants and used with caution in horses because of the danger of disrupting ruminal or colonic microflora, respectively.

F. Resistance is now common because of widespread use. Resistance may be plasmidmediated and is usually due to decreased drug uptake or active transport of the tetracycline out of the bacterial cell.

G. Preslaughter withdrawal of oxytetracycline in food animals
1. The Food Animal Residue Avoidance Databank (FARAD) recommends, in cattle, an extralabel withdrawal of 28 days for intrauterine treatment. It also recommends testing milk after intrauterine treatment, as there is inter-cow variability in the residue elimination profiles in milk.

2. FARAD recommends an extralabel preslaughter withdrawal of 28 days in sheep and goats after IM or SC oxytetracycline administration. A milk withdrawal of 96 hours is recommended for sheep and goats.

3. For swine, FARAD recommends an extralabel preslaughter period of 14 days following administration of tetracycline product in feed or water to swine.

H. Adverse effects
1. The tetracyclines (except doxycycline and minocycline) are potentially nephrotoxic and should be avoided if renal function is impaired.

2. Permanent staining of unerupted teeth may occur in young animals due to the formation of a tetracycline-calcium phosphate complex in enamel and dentine.

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May 28, 2017 | Posted by in GENERAL | Comments Off on Antimicrobial Drugs
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