Antimicrobials in practice part 2: specific antibiotic drugs (Proceedings)

The Gram-positives

Beta-lactam antibiotics

This class of antibiotics includes the penicillins, the cephalosporins, and the carbapenems. They have excellent activity against most gram-positive bacteria, and very few associated side effects.  They are considered bactericidal and time-dependent.  Post-antibiotic effects have been associated with some drugs in this class.  The mechanism of action involves penetration of the outer cell wall and binding to penicillin binding proteins (PBP).  This interferes with cell wall synthesis and opens channels through the cell wall to create pores that allow fluid into the cell, causing cell swelling and death. In general, the beta-lactam antibiotics have low plasma protein binding, distribute well to the extracellular fluid in most tissues, and are excreted renally.  With a few exceptions, they have a very short half-life and require frequent dosing.  Beta-lactams do not distribute well to protected sites, such as the CNS, the eye or the prostate. 

Penicillin G is still effective against Streptococcus species, and some anaerobes, although enteric bacteria are usually resistant.  Penicillin G is inactivated by beta-lactamases, therefore it is not useful for most staphylococci.  Oral absorption is limited due to instability in gastric acid, therefore the drug must be administered parenterally. The aminopenicillins, including ampicillin and amoxicillin, have the advantage of good oral absorption and an increased spectrum against gram-negative bacteria.  The aminopenicillins are susceptible to beta-lactamase unless combined with a beta-lactamase inhibitor (i.e. Clavamox). Ticarcillin, piperacillin, carbenicillin and azlocillin are known to have activity against Pseudomonas and other gram-negative bacteria. They are better able to penetrate the outer cell wall of these bacteria compared to other penicillins.  They are synergistic when administered with aminoglycosides, and have good activity against anaerobes.  Piperacillin may also have activity against enterococci. They are still susceptible to beta-lactamases, unless combined with an inhibitor (ticarcillin plus clavulanic acid).  These drugs are not absorbed orally. The anti-staphylococcal penicillins are inherently resistant to beta-lactamase and include methicillin, nafcillin, oxacillin, cloxacillin and dicloxacillin.  They have no activity against gram-negative or anaerobic organisms. Methicillin resistant staphylococci are those that methicillin cannot bind to the PBP.  Bacteria reported to be MRSA should also be considered to be resistant to all other beta-lactam antibiotics. Adverse effects: Adverse reactions to penicillins are rare, but can include Type I hypersensitivity reactions, vomiting and diarrhea.  At high concentrations, penicillins (and other beta-lactam antibiotics) can inhibit GABA and cause excitement and seizures.

The cephalosporins are often described as either 1st, 2nd, 3rd, or 4th generation.  The 1st generation drugs are active against gram-positive bacteria, including beta-lactamase positive staphylococci.  This group includes cefazolin, cefadroxil and cephalxin.  Of these, cefazolin has the most activity against gram-negative bacteria.  The 2nd generation drugs have greater activity against gram-negative bacteria, in general, although the activity against gram-positive bacteria is similar.  Drugs included in this group are cefoxitin, cefotetan, and cefaclor.  The 3rd generation cephalosporins have the most activity against gram-negative bacteria, but their activity against gram-positives is less than the 1st and 2nd generations (with the exception of ceftiofur).  Ceftazidime and cefoperazone are the only drugs in this group effective against Pseudomonas sp. The drugs of this group most commonly used orally in veterinary medicine include cefixime and cefpodoxime proxetil.  Cefpodoxime proxetil has recently been registered for use in dogs for the treatment of skin and soft tissue infections.  The newest cephalosporins are the 4th generation drugs, the first of which is cefixime.  It has activity against gram-positive cocci, gram-negative enteric bacilli, and Pseudomonas sp, as well as beta-lactamase producing E.coli. Cefquinome is a 4th generation cephalosporin currently available in Europe and the UK for veterinary use.  Adverse effects: Type I, II and III hypersensitivity reactions have been reported, and there is some cross-reactivity with penicillins.  Vomiting may occur after high oral doses due to irritation of the gastric mucosa.  A positive Coomb's test without associated hemolytic anemia has been seen in patients receiving cephalosporins.  False-positive glucose test on urinalysis may be seen with patients receiving cephalosporins if a copper-reduction test is used. Anemia and thrombocytopenia may occur with high doses of ceftiofur and cefpodoxime.  Bleeding disorders characterized by a prolonged PT, have been reported in humans and dogs receiving cephalosporins containing N-methylthiotetrazole (NMTT) side chains.  These drugs appear to interfere with Vitamin K dependent clotting factors and/or inhibit platelet function.  NMTT containing cephalosporins are rarely used in a clinical setting in veterinary medicine.  They include cefoperazone, cefotetan and cefomandole.

The macrolides

The macrolide antibiotics are considered bacteriostatic, and work through inhibition of protein synthesis at the level of the 50s ribosomal subunit.  Erythromycin is the prototypical macrolide, however, it has many disadvantages, including adverse GI effects, poor bioavailability, and a short half-life. Clarithromycin exhibits a broader spectrum of action, better tolerability and higher intracellular accumulation than erythromycin.  It has been used clinically in dogs (15-25 mg/kg/day in divided doses) and cats (10 mg/kg PO q24h), often combined with rifampin.  Azithromycin has a similar gram-positive spectrum as erythromycin, but it has some activity against anaerobes and other intracellular bacteria, better oral absorption, and persistence in the tissues and cells.  It comes in a convenient oral suspension.  Recommended dosing regimens for dogs are 3-10 mg/kg PO q24h for up to 5 days, and for cats 3-5 mg/kg PO q24-48h for up to 5 days.  Adverse effects: Erythromycin is a common cause of vomiting and diarrhea in small animals. This is thought to be related to the drug's effects on motilin receptors in the GI tract.  Erythromycin has also been shown to inhibit hepatic metabolizing enzymes, and may decrease the metabolism of some drugs. Tilmicosin is cardiotoxic and IV injections in dogs have caused sudden death.

The Gram-negatives

Aminoglycosides

Aminoglycosides are considered the drug of choice for severe gram-negative infections.  They also have activity against staphylococci. Their primary mechanism of action includes binding to the 30S ribosomal subunit causing the formation of nonfunctional proteins. Aminoglycosides have high water solubility, low protein binding and poor oral absorption. They distribute well to the extracellular fluid, but do not penetrate intracellularly or into the CNS, eye or prostate.  Aminoglycosides have a long post-antibiotic effect, allowing for once daily dosing which is important in preventing toxicity.  These drugs are excreted via glomerular filtration; they are also reabsorbed/sequestered in the proximal tubular epithelium. Adverse effects: The most important adverse effect cause by aminoglycoside antibiotics is a dose-dependent nephrotoxicity.  The basis for the nephrotoxicity is an active reuptake by the renal proximal tubular cells through pinocytosis into lysosomes.  The drug then accumulates within these cells and disrupts normal cellular phospholipid metabolism and mitochondrial function.  This results in acute tubular necrosis, with hyaline degeneration, nuclear pyknosis and karyolysis, cellular desquamation, and intraluminal protein and cast formation.  Ultrastructurally, there is an increase in the number of lysosomes, loss of tubular brush border and myelin figure formation, which may occur without clinical signs of nephrotoxicity, even after one dose.  Neomycin is the most nephrotoxic of the aminoglycosides, followed by gentamicin, tobramycin, kanamycin, amikacin and streptomycin.  The risk of nephrotoxicity is increased with dehydration, fever, coadministration of other nephrotoxic drugs, and pre-existing renal disease.  Furosemide should not be administered concurrently with aminoglycoside antibiotics, as this has been associated with an increase in nephrotoxicity, possible due to the dehydrating effects of the furosemide.  The nephrotoxicity associated with aminoglycosides is often reversible, although treatment can be prolonged due to the slow elimination of the drug from the proximal tubular cells.  Aminoglycosides are also known to cause an irreversible ototoxicity, due to accumulation in the perilymph and the organ of Corti.  Cats are particularly sensitive to this effect, particularly with amikacin.  Vestibular toxicity has also been described, with signs including head tilt, ataxia, impaired righting reflexes, and cochlear toxicity (nerve deafness at certain frequency ranges).  Aminoglycosides are also known as neuromuscular blockers, by competitively interfering with the transport of calcium at the motor endplate.  These drugs should not be administered concurrently with certain anesthetics, skeletal muscle relaxants, or in disease processes that affect the NM junction, such as botulism.  Aminoglycosides can produce impaired renal formation in the kidneys of fetal rats when administered during the first trimester of pregnancy, although this has not been investigated in other species.

Fluoroquinolones

The fluoroquinolones (FQ) are commonly used for the treatment of gram-negative infections caused by Enterobacteraceae and staphylococci. They are sometimes active against Pseudomonas sp., but higher doses are often needed.  Activity is poor against streptococci, and they are not active against enterococci.  Brucella, Legionella, Chlamydia, Leptospira and sometimes Mycobacteria are also sensitive. They work via inhibition of DNA gyrase (topoisomerase II), which is required for bacterial DNA replication, transcription, repair, and recombination.  Four FQs are labeled for use in small animals (enrofloxacin, marbofloxacin, orbifloxacin and difloxacin).  Resistance is mediated through chromosomal mutations in DNA gyrase (gyrA) which confers cross-resistance to other FQs. FQs distribute well to the tissues and penetrate well intracellularly.  Enrofloxacin reaches the highest concentration in the cells, due to high lipid solubility.  Enrofloxacin is metabolized in vivo to ciprofloxacin, which has higher antibacterial activity than other FQs.  Elimination is via the kidney, and these drugs are often highly effective for treating resistant UTIs. Ciprofloxacin is effective against Pseudomonas.  The oral absorption is poor in cats (22-33%) and does not reach therapeutic concentrations against gram-positive organisms. Newer generation FQs developed for use in humans have a broader spectrum of activity due to increased activity against topoisomerase IV, but may have adverse cardiac effects. Adverse effects: FQs can rarely cause vomiting, diarrhea and abdominal pain. High doses or rapid IV administration can cause excitement, confusion and seizures, through inhibition of GABA binding in the CNS.  These drugs should not be used in epileptic patients.  FQs can cause damage to the cartilage in joints of young, growing animals, particularly in foals and puppies.  Cats and calves appear more resistant.  The mechanism of cartilage injury is thought to be secondary to chelation of magnesium, which is necessary for cell-matrix interactions in the chondrocytes. In cats, enrofloxacin doses greater than 5 mg/kg have resulted in retinal degeneration and blindness.  Very high doses of orbifloxacin (45 and 75 mg/kg) induced mild ocular lesions, marbofloxacin was safe at doses up to 20x the label dose, and ciprofloxacin was safe up to 100 mg/kg. FQs may inhibit the metabolism of some drugs, for instance, theophylline.

The broad spectrum antibiotics

Trimethoprim/sulfonamide combinations

Trimethoprim/sulfonamide combinations (TMS) have activity against gram-positive and gram-negative bacteria with good tissue distribution and a reasonable half-life, allowing for once or twice daily dosing. They have a synergistic effect when administered simultaneously and the combination is bactericidal.  Each antibiotic works on a different step in the folic acid synthesis pathway.  The sulfonamides compete with the binding sites for bacterial PABA, and trimethoprim inhibits the dihydrofolate reductase enzyme.  Bacteria must make their own folic acid via this pathway, whereas mammalian cells rely on exogenous sources of folic acid.  TMS is an excellent choice for pyodermas, UTIs and soft tissue infections caused by susceptible bacteria.  They may even be effective in some cases of MRSA.  Resistance to these combinations is increasing, however, and side effects are not uncommon in small animals.

Adverse effects

The most common adverse effect associated with TMS combinations is keratoconjunctivitis sicca (KCS) in dogs.  This is thought to be due to a toxic effect of the sulfonamide component of the lacrimal gland tissue.  It most commonly occurs following prolonged administration, but can occur quickly, and may not be reversible following discontinuation of the drug.  Bone marrow suppression secondary to folate antagonism has also been reported, but is extremely rare and folate supplementation during treatment is not routinely necessary.  Bone marrow suppression can occur with the synergistic use of pyrimethamine and sulfonamides and can be corrected by the addition of folinic acid (5 mg/day) or by the addition of yeast (100 mg/kg BW daily) to the animal's diet.  Sulfamethoxazole and sulfadiazine have been associated with reversible, short-term hypothyroidism, which usually disappears within 3 weeks after discontinuation of the drugs.  Urinary crystal formation can occur following administration of TMS, mainly due to the sulfonamide component.  Sulfadiazine is particularly dangerous because it is the least soluble, and it can precipitate in the renal tubules in the acidic pH of the urine.  The formulations used today are less likely to cause this problem than older preparations, however the practitioner should be careful to ensure that the patient stays well hydrated while on sulfa drugs as renal failure has been documented in dehydrated human patients. Sulfonamide induced drug allergies have also been reported and Doberman Pinschers appear to be particularly susceptible.  Signs include polyarthropathy, lymphadenopathy, fever, polymyositis, glomerulonephropathy, and focal retinitis.  These changes are typically reversible. Cutaneous reactions similar to Stevens-Johnson syndrome and toxic epidermal necrolysis in people, have been reported in dogs, and may be related to the hypersensitivity reactions.  Hepatitis has been reported in dogs, and may be a result of the hypersensitivity reactions, or it may result from increased formation of toxic metabolites, since dogs lack the ability to acetylate drugs. Drug-drug interactions have been reported between trimethoprim-sulfonamide combinations and dapsone, cyclosporine, rifampin, methenamine and detomidine.

Tetracyclines

Tetracyclines are considered broad spectrum and have activity against gram-positive and gram-negative bacteria, Chlamydia, rickettsia, spirochetes mycoplasma, L-form (cell wall deficient) bacteria and some protozoa. Of this group, doxycycline is the most active. The mechanism of action involves binding to the 30S ribosomal subunit and blocking protein synthesis.  This binding is reversible, making tetracyclines bacteriostatic. Resistance is widespread among staphyclococci, streptococci, Pseudomonas sp, and Enterobacteraceae.  Enterococci are not susceptible to tetracyclines. Resistance is plasmid-mediated, and relates to a failure of the active transport system necessary to penetrate the bacterial cell. Oral absorption of the tetracyclines can be erratic, since these drugs are excellent chelators, and cations in the stomach can bind the drugs and prevent oral absorption.  These drugs should be given on an empty stomach. The one exception is doxycycline, which is less affected by feeding status. Tetracyclines distribute well to most tissues, with the exception of the CNS and the eye, and are mainly eliminated by the kidneys.  Doxycycline is again an exception, in that a significant amount of excretion is through the intestine. Tetracyclines accumulate within cells, making them ideal for intracellular infections. They are considered the first choice antibiotic for infections caused by Ehrlichia, Rickettsia, and Mycoplasma haemofelis (formerly Hemobartonella felis) in dogs and cats, and Chlamydophila psittaci (formerly Chlamydia psittaci) in birds.

Adverse effects

High doses or prolonged administration may result in renal tubular necrosis, particularly with drug formulations containing propylene glycol, or older, outdated products. Idiosyncratic toxic hepatitis has been reported in humans, particularly in pregnant women.  Tetracyclines may produce dental discoloration and inhibit the growth of long bones in young animals and in the offspring of pregnant animals treated with tetracyclines.  Doxycycline is less likely to cause tooth discoloration.  Hypersensitivity and fevers have been reported with treatment, particularly in cats.  Photosensitivity may occur, particularly with doxycycline and demeclocycline.  Oral doxycycline given as a broken tablet or capsule to cats can cause direct mucosal damage with resultant esophageal ulcers and stricture. Rapid IV administration of tetracyclines, particularly those in propylene glycol vehicles, can cause hypotension and collapse.

Chloramphenicol and derivatives

Chloramphenicol and its derivatives, thiamphenicol and florfenicol, reversibly bind to the 50S ribosome subunit, resulting in protein synthesis inhibition. They are bacteriostatic.  Competitive antagonism may occur when co-administered with macrolide antibiotics, since they share the same site of action. These antimicrobials are broad spectrum, with activity against gram-positive and gram-negative bacteria, as well as anaerobes, Rickettsia, Chlamydia, and Mycoplasma spp.  Activity against Enterobacteraceae is unpredictable, and activity against Pseudomonas is poor. Resistance, particularly among gram-negative bacteria, occurs via acetylation and inactivation of chloramphenicol by bacterial enzymes.  Cross-resistance between chloramphenicol and florfenicol does not always occur, and florfenicol appears to be more resistance to these bacterial enzymes. Chloramphenicol is well absorbed following oral administration.  The exception is chloramphenicol palmitate in cats, which is an insoluble ester of chloramphenicol that must be hydrolyzed by the gut prior to absorption. Chloramphenicol undergoes extensive metabolism by the liver.  This metabolism is deficient in very young animals, resulting in a prolonged half-life. It distributes well to most tissues of the body, and drug concentrations may persist longer in the tissues than in the plasma or serum. Adverse effects: Chloramphenicol causes a dose-dependent hematologic toxicity in dogs and cats.  This is due to inhibition of mitochondrial protein synthesis in the bone marrow.  Cats are more susceptible than dogs, due to the lack of the metabolizing enzyme, glucuronyl transferase.  Doses of 60 mg/kg/day have caused reversible bone marrow suppression and CNS depression in cats.  Rare neutropenia and aplastic anemia have been reported in dogs.  Care should be taken when prescribing this drug for owners to administer as an idiosyncratic, irreversible aplastic anemia has been reported in some people.  Immunosuppression and decreased antibody synthesis have been documented with chloramphenicol use.  Chloramphenicol is an inhibitor of hepatic microsomal enzymes, and may therefore decrease the clearance of other drugs.

References available from the author.