Destruction of Bacterial Cell Walls

Antibiotics that inhibit synthesis or promote destruction of bacterial cell walls include the β-lactam ring antibiotics (e.g., penicillins, cephalosporins, carbapenems, and monobactams), vancomycin, bacitracin, polymyxin, and the antifungal drugs nystatin, amphotericin B, and the imidazoles. β-Lactams function by binding to penicillin-binding proteins (PBPs) in the cell wall, thereby impairing cell wall synthesis. This in turn reduces its strength and rigidity, ultimately causing increased permeability and cell lysis. β-Lactam antibiotics tend to be bactericidal.

Aminopenicillins (i.e., amoxicillin, ampicillin) are effective against many Gram-positive aerobes and some Gram-positive and Gram-negative anaerobes. The carboxypenicillins (e.g., ticarcillin) have better Gram-negative and anaerobe spectrums than the aminopenicillins, whereas the ureidopenicillins (e.g., piperacillin, mezlocillin) have the best Gram-negative spectrums of all the penicillins. Resistance to penicillins is mediated by bacterial penicillinases (a type of β-lactamase), decreased permeability of the cell wall to penicillins as a result of altered porin size, and altered PBP structure that resists binding with penicillin (e.g., methicillin-resistant staphylococci). Penicillinase inhibitors may be combined with penicillins (e.g., amoxicillin or ticarcillin plus clavulanic acid, ampicillin plus sulbactam, piperacillin plus tazobactam) to enhance their activity. Penicillins are “time-dependent,” meaning it is important to administer the drugs frequently enough so that MBCs are maintained for 80% of the treatment interval to optimize their efficacy.

Cephalosporins (Table 9-1) are generally more effective than penicillins against Gram-negative rods (e.g., Enterobacteriaceae), but they may be inactivated by cephalosporinases (a type of β-lactamase). Most are poorly effective against anaerobes (cefoxitin is an exception). First-generation cephalosporins are effective against most Gram-positive and some Gram-negative organisms. Second-generation cephalosporins have greater activity against Gram-negative bacteria and anaerobes but have no additional efficacy against Gram-positive organisms. Third-generation cephalosporins are highly effective against more than 90% of Gram-negative bacteria, but they often are less active against Gram-positive organisms than first-generation cephalosporins. Some third-generation cephalosporins have specific Gram-negative spectra, and it is important to note that just because one third-generation cephalosporin is effective for a particular infection does not mean that another third-generation cephalosporin will be effective. Ceftiofur is a third-generation cephalosporin with prolonged antibacterial activity because its major metabolite is active; however, it does not have a broad spectrum of activity against serious Gram-negative infections. Cefepime (Maxipime) is a fourth-generation cephalosporin that is unique among the cephalosporins because of its broad spectrum of activity, which includes Gram-positive cocci, enteric Gram-negative bacilli, and Pseudomonas aeruginosa. Cefovecin is an injectable, repositol cephalosporin developed to treat Gram-positive bacteria; it maintains therapeutic blood concentrations (depending on the bacteria being treated) for 7 to 14 days after being injected subcutaneously. Resistance to cephalosporins is mediated by the same mechanisms that cause resistance to penicillins.

Imipenem (Table 9-2) and aztreonam are β-lactam antibiotics that are highly resistant to β-lactamases. They are as effective against Gram-negative organisms as aminoglycosides but are not nephrotoxic. Imipenem (a carbapenem) has the broadest antibacterial spectrum of any systemic antimicrobial and is effective against most clinically relevant bacterial species, including Gram-negative and Gram-positive anaerobes and aerobes. It is not active against methicillin-resistant staphylococci or resistant strains of Enterococcus faecium. Because of their importance in human medicine as “drugs of last resort,” use of carbapenems should be restricted to severely ill patients who fail to respond to other antibiotics (see “Drugs of Last Resort” on p. 88). Aztreonam, a synthetic monobactam, is unaffected by bacterial β-lactamase. It is highly effective against many Gram-negative aerobes but has little activity against anaerobes. It has no activity against Gram-positive bacteria and must be used in combination with other drugs to achieve broad-spectrum activity.

Inhibition of Protein Synthesis

Chloramphenicol, tetracycline, erythromycin, and clindamycin bind to bacterial ribosomes, causing reversible inhibition of protein synthesis. Chloramphenicol has broad-spectrum activity against streptococci, staphylococci, Salmonella spp., Brucella spp., Pasteurella spp., Ehrlichia spp., Rickettsia spp., and anaerobes, but it has poor activity against Pseudomonas spp. It is highly lipophilic and readily enters most tissues (e.g., CNS, prostate, eye). The drug may cause idiosyncratic fatal anemia in humans; but, dogs and cats usually experience only a mild, transient anemia, if that. Although considered a bacteriostatic drug, chloramphenicol can be bactericidal if present in adequate concentrations.

The tetracyclines (e.g., tetracycline, oxytetracycline, doxycycline, minocycline) are effective against many Gram-positive and Gram-negative bacteria, including Chlamydia spp., rickettsiae, spirochetes, Mycoplasma spp., bacterial L-forms, and some protozoa. They usually are ineffective against staphylococci, enterococci, Pseudomonas spp., and Enterobacteriaceae. Tetracyclines are distributed well to most tissues, although not to the CNS, and they achieve good intracellular concentrations. Calcium-containing products chelate tetracyclines and interfere with oral absorption. Binding of the drugs to calcium can be a problem in young or pregnant animals, and tooth discoloration and inhibited bone growth can occur. Doxycycline is used more commonly than tetracycline or oxytetracycline because it has fewer side effects, penetrates cells better, has less resistance developed to it, is excreted across the intestinal wall (instead of the kidney or liver), and is easier to administer. Minocycline is primarily used to treat Brucella infections.

Erythromycin is readily absorbed from the upper gastrointestinal system and diffuses well throughout most tissues; however, it has a narrow spectrum of activity and may be associated with nausea and vomiting because of its prokinetic activity. New derivatives include clarithromycin (Biaxin), azithromycin (Zithromax), and dirithromycin (Dynabac). Azithromycin (see Table 9-2) is active against aerobic bacteria (e.g., staphylococci, streptococci, Helicobacter spp.) and anaerobes. It also has good activity against Mycoplasma spp., intracellular organisms (e.g., Bartonella spp., Toxoplasma spp.), and atypical mycobacteria. Oral absorption of azithromycin is high, and it is well tolerated. The drug achieves extremely high tissue concentrations and needs to be given only once daily.

Clindamycin, a semisynthetic derivative of lincomycin, has a limited spectrum of activity compared with erythromycin. It is active against Gram-positive pathogens, including staphylococci, streptococci, clostridia, several Actinomyces spp., and some Nocardia spp. It is very effective against many anaerobic bacteria. Clindamycin often is used to treat infections resistant to penicillins and erythromycin or patients that cannot tolerate those drugs. It is effective against Toxoplasma gondii, Neospora, and staphylococcal osteomyelitis but ineffective against Gram-negative bacteria.

The aminoglycosides (e.g., amikacin, gentamicin, kanamycin, neomycin, netilmicin, tobramycin) disrupt protein synthesis. They bind irreversibly to bacterial ribosomes and are bactericidal. They are effective against Gram-negative and Gram-positive bacteria, including Enterobacteriaceae and pseudomonads, and often have a synergistic effect with β-lactam antibiotics. Their activity is reduced in necrotic tissue because of free nucleic acid material. Anaerobes are resistant to aminoglycosides because they lack the receptor necessary for transport into the bacterial cell. Aminoglycosides are polar and therefore lipid insoluble, meaning they have limited distribution in extracellular and cerebrospinal fluids. However, distribution into pleural fluid, bone, joints, and peritoneal cavity is good. Aminoglycosides are not well absorbed orally. They are “concentration dependent” rather than “time dependent,” meaning that they can be given at higher doses at longer intervals (e.g., once daily), which maintains effectiveness but reduces renal toxicity. Dehydration, electrolyte loss, preexisting renal disease, and concurrent use of other nephrotoxic drugs increase nephrotoxicity of aminoglycosides. Simultaneous use of nonsteroidal anti-inflammatory drugs and aminoglycosides reliably causes acute renal failure. Ototoxicosis and neuromuscular blockade are other possible adverse effects. Simultaneous use of a β-lactam and an aminoglycoside is often synergistic, plus it helps prevent bacteria from becoming resistant to these drugs.

Inhibition of DNA Synthesis

Fluoroquinolones (e.g., enrofloxacin, difloxacin, ciprofloxacin, ofloxacin, marbofloxacin) (see Table 9-2) and potentiated sulfas (e.g., trimethoprim-sulfa) inhibit DNA synthesis. Fluoroquinolones inactivate DNA gyrase, preventing uncoiling of the DNA molecule during DNA replication and transcription to messenger ribonucleic acid (mRNA). They are rapidly bactericidal and historically have been effective for soft tissue infections, pneumonia, osteomyelitis, and urinary tract infections caused by Gram-negative organisms and staphylococci. They also are effective against Rickettsia rickettsii and possibly L-form bacteria, but they are variably effective against Gram-positive cocci, especially enterococci (except staphylococci) and anaerobic bacteria. An additional reported advantage is activity against Pseudomonas aeruginosa, but reports suggest that higher than normal doses are required to achieve this effect. The dose of enrofloxacin varies depending on the target tissue (see Table 9-2). Possible side effects of quinolones include vomiting, CNS effects in animals of all ages, and cartilage and tendon lesions in developing animals. Like the aminoglycosides, the quinolones are concentration dependent, meaning that once-daily administration is typically preferred.

Oral ciprofloxacin is less expensive than enrofloxacin, but it is also less bioavailable in dogs (approximately 30% to 40%) than in people (approximately 70% to 80%). Therefore, it is commonly underdosed when administered to dogs. Marbofloxacin has a broad spectrum of activity against the major pathogens encountered in surgical infections. It is safe in dogs, and a single IV injection of 2 to 4 mg/kg maintains plasma concentrations above the MIC for Enterobacteriaceae and staphylococci for 12 to 24 hours.

In recent years, many isolates of pseudomonads, Escherichia coli, Enterococcus, and Staphylococcus spp. have become resistant to quinolones. In one human hospital, 80% of methicillin-resistant Staphylococcus aureus (MRSA) developed resistance to ciprofloxacin within 1 year of its introduction. In the United States and Europe, the prevalence of MRSA was less than 3% in the early 1980s but rose as high as 40% in the 1990s. Infections caused by MRSA have become a significant global health issue with serious consequences for all areas of human hospitals, especially operative rooms and intensive care units. Veterinary workers appear to be at an increased risk for colonization by MRSA, which might increase the rate of nosocomial infection in hospitalized patients although the risk to both staff and patients for clinical disease appears low (McLean and Ness, 2008; Walther et al, 2009). Methicillin-resistant Staphylococcus pseudintermedius (MRSP) has similar antibiotic resistance patterns and currently is of greater concern to most veterinarians than MRSA. MRSP rarely causes disease in people, and it infrequently causes extra-dermatologic infections in dogs or cats. The risk of MRSP transmitting the mecA gene (which causes methicillin resistance) to other bacteria is unclear, and this possibility has caused consternation among veterinarians. Indiscriminate use of antibiotics will continue to encourage the development of resistant strains in both human and veterinary hospitals.

Trimethoprim-sulfonamide combinations are effective for the treatment of osteomyelitis, prostatitis, pneumonia, tracheobronchitis, pyoderma, and urinary tract infections. These combination drugs are bactericidal and function by inhibiting sequential steps in folate synthesis. Also, combination therapy is less likely to allow development of resistant strains. Trimethoprim-sulfonamide combinations have a broad spectrum of activity, including most streptococci, many staphylococci, and Nocardia spp, but they are usually ineffective against pseudomonads. In vitro and in vivo susceptibilities do not always correlate. Sulfas tend to have poor efficacy in the presence of pus or necrotic tissue, but they penetrate most body tissues well. Possible side effects include keratoconjunctivitis sicca, thrombocytopenia, anemia, bone marrow suppression, vomiting, hypersensitivity (i.e., vasculitis or arthritis), and hepatic disease. Some breeds, such as Doberman Pinschers and Rottweilers, and some families of dogs seem more likely to suffer side effects.

Metronidazole is very effective against most anaerobic bacteria. It penetrates most body tissues well. Dose-dependent CNS toxicity is common if excessive doses are administered.