New Advances in Antibiotic Treatment for Animals
Mark G. Papich, DVM, MS, Diplomate ACVCP
Professor, College of Veterinary Medicine, North Carolina State University
Raleigh, North Carolina, USA
The first-generation cephalosporins represented by the oral drugs cephalexin and cefadroxil, and the injectable drug cefazolin have a spectrum of activity that includes staphylococci, streptococci, and many of the enteric gram-negative bacilli. However, resistance among gram-negative bacteria develops easily, primarily from synthesis of ß-lactamase enzymes that can hydrolyze these drugs. Extended-spectrum cephalosporins include those from the 2nd, 3rd, and 4th generation have been used in resistant infections caused by Escherichia coli, Klebsiella pneumoniae, Enterobacter species, Proteus species (especially indole-positive), and Pseudomonas aeruginosa.
Of the 2nd-generation cephalosporins, the ones used most often in veterinary medicine are cefoxitin and cefotetan. Their use has been valuable for treating organisms resistant to the 1st generation cephalosporins or in cases in which there are anaerobic bacteria present. Anaerobic bacteria such as those of the Bacteroides fragilis group can become resistant by synthesizing a cephalosporinase enzyme. Cefoxitin and cefotetan, which are in the cephamycin group, are resistant to this enzyme and may be active against these bacteria. Therefore, these drugs may be valuable for some cases such as septic peritonitis that may have a mixed population of anaerobic bacteria and gram-negative bacilli.
The 3rd -generation cephalosporins are the most active of the cephalosporins against gram negative bacteria, especially enteric bacteria resistant to other cephalosporins. Almost all drugs in this group (exceptions discussed below) should be administered IV or IM. For convenience, some have been administered to animals SC. But one should be warned that the IM or SC administration of these drugs could be painful. One of the most frequently administered drugs in this group is cefotaxime (Claforan) because of its potency and activity against most enteric gram-negative bacteria and some streptococci. Compared to other cephalosporins, ceftazidime is the most active against Pseudomonas, against which all of the other cephalosporins, except cefoperazone, have little or no activity. Since the drugs mentioned are all injectable, there has been a need for an oral extended-spectrum cephalosporin. Of the ones available, cefixime (Suprax) has been used in dogs because it is one of the few third-generation cephalosporins that can be administered orally. The doses have ranged from 5 to 10 mg/kg twice daily orally. Another oral 3rd generation cephalosporin is cefpodoxime proxetil (Vantin). The use of this drug has not been reported in veterinary medicine, but the dose used in dogs and cats, (extrapolated from the human dose) is 5 mg/kg orally every 12 hours. The most recent development in this class is the 4th generation cephalosporins. The first 4th generation cephalosporin is cefepime (Maxipime). It is unique from other cephalosporins because of its broad spectrum of activity that includes gram-positive cocci, enteric gram-negative bacilli, and Pseudomonas. It has the advantage of activity against some extended-spectrum ß-lactamase (ESBL) producing strains of Klebsiella and E. coli that have become resistant to many other ß-lactam drugs and fluoroquinolones. Except for one investigation in dogs, adult horses, and foals, the use of cefepime has been limited in veterinary medicine.
The carbapenems are beta-lactam antibiotics that include imipenem-cilastatin sodium (Primaxin) and meropenem (Merrem). Imipenem is administered with cilastatin to decrease renal tubular metabolism. Cilastatin does not affect the antibacterial activity. Imipenem has become a valuable antibiotic because it has a broad spectrum that includes almost all bacteria that may be resistant to other drugs (Edwards & Betts, 2000). Imipenem is not active against methicillin-resistant staphylococci or resistant strains of Enterococcus faecium. The high activity of imipenem is attributed to its stability against most of the ß-lactamases (including ESBL) and it's ability to penetrate porin channels that usually exclude other drugs (Livermore 2001). The carbapenems are more rapidly bactericidal than the cephalosporins and less likely to induce release of endotoxin in an animal from gram-negative sepsis. Resistance to carbapenems has been extremely rare in veterinary medicine.
The disadvantages of carbapenems include induction of resistance, inconvenient administration, and high cost. A common dose for small animals is 10 mg/kg q8h or 5 mg/kg q6h. One of the adverse effects caused from imipenem therapy is seizures. Meropenem, one of the newest of the carbapenem class of drugs has antibacterial activity approximately equal to, or greater than imipenem. Its advantage over imipenem is that it is more soluble and can be administered in less fluid volume and more rapidly. Meropenem can be administered subcutaneously with almost complete absorption. There also is a lower incidence of adverse effects to the central nervous system, such as seizures (Edwards & Betts, 2000). Based on experiments in our laboratory, the recommended dose is 12 mg/kg every 8 hours SC, or 24 mg/kg IV, every 24 hours. For sensitive organisms in the urinary tract, 12 mg/kg, SC, every 12 hours can be used. In our experience, these doses have been well tolerated except for slight hair loss over some of the SC dosing sites.
The fluoroquinolones include enrofloxacin, marbofloxacin, difloxacin, and orbifloxacin, which are currently approved for small animals. In the U.S. all of these drugs are approved for dogs; orbifloxacin, marbofloxacin, and enrofloxacin are approved for cats. Enrofloxacin 100 mg/mL injection is approved for cattle. A new topical formulation of enrofloxacin and silver sulfadiazine (Baytril Otic) was recently registered for treating otitis in dogs. There are several other fluoroquinolones approved for use in human medicine (ciprofloxacin, lomefloxacin, enoxacin, ofloxacin), but their used has been limited in veterinary medicine, except for ciprofloxacin.
The mechanism of action and important pharmacological properties have been reviewed elsewhere (Papich & Riviere, 2001). These drugs have as their advantages: (1) spectrum of activity that includes most gram-negative bacteria and many gram-positive bacteria, including staphylococci, (2) oral administration, and (3) good safety profile. Important deficiencies in the spectrum of activity include gram-positive cocci, especially enterococci (Enterococcus faecalis and Enterococcus faecium), and anaerobic bacteria. The newest generations of fluoroquinolones (referred to by some authors as the 3rd-generation fluoroquinolones) include trovafloxacin, grepafloxacin, gatifloxacin, sparfloxacin, and moxifloxacin. Two of these, trovafloxacin and grepafloxacin, have already been discontinued for use in people because of adverse effects (abnormal cardiac rhythms and hepatic injury). The new generation of fluoroquinolones, with substitutions at the C-8 position, (C-8 methoxy for example) have as their advantage a broader spectrum that includes anaerobic bacteria and gram-positive cocci. The difference in spectrum of activity is largely caused by increased activity against the DNA-gyrase of gram-positive bacteria, rather than activity against Topoisomerase IV, which is the target in gram-positive bacteria for the older quinolones (Pestova et al, 2000; Hooper, 2000), but other factors also may play a role (Hooper, 2000). Premafloxacin, a veterinary 3rd generation quinolone is not yet available, but has been examined for its potential in veterinary medicine (Watts et al, 1997). Moxifloxacin has been used on a limited basis for treatment of infections in dogs and cats caused by bacteria that have been refractory to other drugs.
Of the currently available fluoroquinolones, all have a similar spectrum of activity, but they may vary in potency. Against some gram-negative bacilli, especially Pseudomonas aeruginosa, the human drug ciprofloxacin is more active than veterinary quinolones. Enrofloxacin in small animals is metabolized to ciprofloxacin, which may account for 10-20% of the total quinolone maximum plasma concentrations (CMAX) stop here and as much as much as 35% of the total AUC (Cester et al 1996).
Among the possible adverse effects are central nervous system effects, such as seizures. In young animals, especially dogs and foals, arthropathy of the developing cartilage is possible, leading to joint injury and lameness. Recently, blindness in cats caused by fluoroquinolones has attracted attention. The labeled dose for enrofloxacin (Baytril) use in cats in the U.S. was recently changed by the drug manufacturer (Bayer Corporation). Because of dose-related ocular toxicosis, the previous dose of 5 to 20 mg/kg/day, was changed to not exceed 5 mg/kg/day. In studies performed by the manufacturer, there were no adverse effects observed in cats treated with 5 mg/kg/day of enrofloxacin. However, the administration of enrofloxacin at 20 mg/kg or greater caused salivation, vomiting, and depression. At doses of 20 mg/kg or greater, there were mild to severe fundic lesions on ophthalmologic examination including changes in the fundus and retinal degeneration. Ocular problems have not been reported in other species.
Besides enrofloxacin, the other fluoroquinolones registered for use in cats are orbifloxacin(Orbax) and marbofloxacin (Zeniquin). In a published study, (Kay-Mugford et al, 2001) orbifloxacin produced ocular lesions only at the high doses 18 and 30 x the manufacturer's recommendations. When marbofloxacin was administered to there were no ocular lesions in cats (manufacturer's data), even at 55.5 mg/kg (10 x the lowest label dose) for 14.
NEW MACROLIDES AND DERIVATIVES
Erythromycin is an effective drug that has been available for many years. However, it has disadvantages, which include a narrow antibacterial spectrum, adverse gastrointestinal effects (nausea and vomiting), poor oral absorption, short half-life, and need for frequent dosing intervals. There are now new derivatives of this macrolide drug that are designed to improve therapy and produce fewer adverse reactions. Azithromycin (Zithromax) is the first drug in the class of azalides. (Lode et al, 1996) Azalides are derived from erythromycin and these drugs share a similar mechanism of action. (Erythromycin is a 14 member ring, and azithromycin has a 15 member ring structure.) The important difference between azithromycin and erythromycin is better oral absorption, it is better tolerated, has a much longer half-life (especially in tissues), and has a broader spectrum of activity. The primary pharmacokinetic difference between azithromycin and erythromycin is the long half-life and high concentration in tissues. The tissue concentrations of azithromycin can be as much as 100 x serum concentrations and the concentrations in leukocytes may be 200x the concentrations in serum.
Azithromycin is active against gram-positive aerobic bacteria (staphylococci and streptococci) and anaerobes. The activity of azithromycin against staphylococci is not superior to erythromycin, but it has activity against intracellular organisms such as Chlamydia, and Toxoplasma. (Clinical efficacy against these pathogens has not been confirmed, however.) It is also active against mycobacteria and Mycoplasma. There are no published clinical reports on the use of azithromycin in dogs, cats, horses, and birds but the use is increasing. Because of the long half-life and persistence of drug in tissues, the regimen employed in people is to administer a dose once daily for 3 to 5 days, at which time effective drug concentrations are expected in tissues for up to 10 days. In dogs, doses of 5-10 mg/kg once daily, orally for 1 to 5 days has been suggested. In cats, doses of 5 mg/kg once daily, or every other day, orally for 1 to 5 days have been used. It is available in a 250 mg capsule, tablets, and an oral suspension.
1. Cester CC, Schneider M, Toutain P-L: Comparative kinetics of two orally administered fluoroquinolones in dog: Enrofloxacin versus marbofloxacin. Revue Méd Vét 147: 703-716, 1996.
2. Edwards JR, Betts MJ: Carbapenems: the pinnacle of the Beta-lactam antibiotics or room for improvement? J Antimicrob Chemother 2000; 45: 1-4.
3. Hooper DC. Mechanisms of action and resistance of older and newer fluoroquinolones. Clin Infect Dis 31(Suppl 2): S24-S28, 2000.
4. Kay-Mugford PA, Ramsey DT, Dubielzig RR, et al. Ocular effects of orally administered orbifloxacin in cats. American College of Veterinary Ophthalmologists 32nd Annual Meeting. (abstract) October 9-13, 2001.
5. Livermore DM. Of Pseudomonas, porins, pumps, and carbapenems. J Antimicrob Chemother 47: 247-250, 2001.
6. Lode H, Borner K, Koeppe P, and Schaberg T: Azithromycin: review of key chemical, pharmacokinetic, and microbiological features. J Antimicrob Chemother 37 (Suppl C): 1-8, 1996.
7. Papich MG, & Riviere JE. Fluoroquinolone antimicrobial drugs, Chapter 45. In H.R. Adams (ed) Veterinary Pharmacology and Therapeutics, 8th Edition. Ames Iowa, Iowa State University Press. 2001; Page 898-917.
8. Pestova E, Millichap JJ, Noskin GA, Peterson LR. Intracellular targets of moxifloxacin: a comparison with other fluoroquinolones. J Antimicrob Chemother 45: 583-590, 2000.
9. Watts JL, Salmon SA, Sanchez MS, Yancey RJ. In vitro activity of Premafloxacin, a new extended-spectrum fluoroquinolone, against pathogens of veterinary importance. Antimicrob Agents Chemother 41: 1190-1192, 1997.
Mark G. Papich, DVM, MS, Diplomate ACVCP