Empiric antibiotic therapy (Proceedings)

Empiric antibiotic therapy is the appropriate use of antibiotics without knowing the agent or before its susceptibility is known. It is usually started when depriving antibiotics until culture and sensitivity results are available may increase the risk of death or permanent damage, increase morbidity or prolong treatment time. It may also be employed in the initial management of selected uncomplicated infections in immunocompetent patients. When the agent is not known, antibiotics should be chosen based on the most likely bacteria in that particular site. The bacteria responsible for the majority of the infections in dogs and cats come from a small list with less than 10 genera, but their relative prevalence at a different organs varies. Once the bacteria are identified, antibiotic selection is simplified because the susceptibility pattern of many organisms is predictable. Staphylococcus intermedius is usually susceptible to beta-lactamase resistant antibiotics and first or third generation cephalosporins, whereas most anaerobic organisms can be treated wit penicillins, metronidazole, clyndamicin or the second generation cephalosporins. Sensitivity of gram negative bacteria is less predictable, but most enteric gram negative bacteria will be susceptible to fluorquinolones, aminoglycosides or second or third generation cephalosporins. Pseudomonas aeuroginosa may be resistant to the cephalosporines. Fluorquinolones are given at high doses in the treatment of Pseudomonas infections. Ideally, the antibiotic with the smallest spectrum should be used.

Antibiotics should be selected not only based on the efficacy against the organism, but also at its ability to achieve therapeutic concentrations at the site of the infection. For most tissues, plasma concentration will adequately predict tissue concentration, and antibiotic diffusion is limited only by blood supply. Poor blood supply may become a problem in abscesses and granulation tissue. In addition, diffusion may be limited into an abscess due to low surface to area ratio. Lipid membranes also may prevent diffusion in some tissues (central nervous system, eye, prostate, bronchial epithelium). Lipid-soluble drugs will achieve greater concentration across those barriers.

Antibiotic concentration should be maintained above the minimum inhibitory concentration (MIC) for at least a portion of the time to be effective. Antibiotics with "time-dependent" killing (beta-lactams and most bacteriostatic drugs) work best with continual exposure to drug concentrations above the MIC. Increasing frequency of administration (decreasing time between doses) will increase efficacy, whereas increasing the dose will not. Time-dependent antibiotics should be given at the recommended intervals. Reducing the frequency of administration for convenience, even if the dose is increased, may lead to therapeutic failure. For antibiotics with "concentration-dependent" killing (e.g.; aminoglycosides), the higher the concentration, the greater the effect. Thus, increasing dose enhances efficacy.

Common antibacterial drugs

Beta-lactam antibiotics (penicillins and cephalosporins)

Spectrum: Early penicillins target especially gram-positive and anaerobes, whereas newer agents (antipseudomonas penicillins and third generation cephalosporins) show a better gram negative spectrum, but less gram positive coverage. Efficacy against anaerobes depends on the particular drug. Cefoxitin (30 mg/kg SQ q8h for dogs) and cefotetan (30 mg/kg SQ q12h for dogs) are second generation cephalosporins with good spectrum including anaerobes. Most beta-lactam have poor CNS penetration (exception ceftriaxone)

With beta-lactams, increase in frequency of administration will increase efficacy. Intervals should be shorter for gram-negative infections because they are less susceptible and have higher MIC than gram-positives. Since almost all beta-lactams are excreted by the kidneys, some patients with renal failure may require a dose adjustment. Beta-lactams have synergistic effect with aminoglycosides.

Aminoglycosides

Spectrum: Excellent gram-negative coverage with limited gram-positive, and no effect against anaerobes. Aminoglycosides possess post-antibiotic effect; even at concentrations below minimum bactericidal levels, surviving bacteria suffer a period of impaired replication allowing for less frequent dosing. To increase efficacy, dose (and never frequency) should be increased. They have poor bronchial and CNS penetration (even with inflammation), as well as poor activity in abscess or in presence of necrotic tissue.

Dose-dependent nephrotoxicity and ototoxicity are the principal toxic effect. The effect is less pronounced with amikacin than gentamicin. Nephrotoxicity is associated with the vale concentration. Thus, increasing dose and decreasing frequency (once daily administration), minimize nephrotoxicity. Aminoglycosides should only be used in well hydrated patients and concurrent use of furosemide (compete with the same transport system in the kidney) or NSAIDs should be avoided. Appropriate once a day doses: Amikacin 10 – 15 mg/kg for cats and 15 – 30 mg/kg for dogs; gentamicin 5 – 8 mg/kg for cats and 10 – 14 mg/kg for dogs

Fluoroquinolones

Spectrum: Broad spectrum with limited action against anaerobes and Streptococcus spp. They are effective against most intracellular organisms (exception Ehrlichia spp). Fluorquinolones may induce a mitogen encoding bacteriophage in Streptococcus canis. Lower doses are effective against susceptible Eschirichia coli or Pasteurella spp. Gram-positive cocci require slightly larger doses, whereas the highest dose is recommended for treatment of Pseudomonas infections. Dosage should be increases to increase efficacy. Sucralfate, AlOH, and calcium salts decrease oral absorption. Main toxic effect is cartilage damage in growing animals and retinal degeneration in cats (particularly with enrofloxacin). Acute blindness is more likely to occur with IV use, in old, dehydrated cats or in cats with renal disease.

Bacteriostatic drugs

Macrolydes (erythromycin and azithromycin) and lincosamides (lincomycin and clindamycin) have a good gram positive and anaerobic spectrum and are effective against intracellular organisms. Macrolides appear to be bactericidal against susceptible gram-positive bacteria. They all have poor CNS penetration. Macrolides down-regulate proinflammatory cytokines and have unconventional effects on microorganisms, including inhibiting Pseudomonas twitching motility and thus biofilm formation.

Tetracyclines have reasonably good spectrum. They are effective against intracellular organisms and spirochetes. Absorption is decreased by Sucralfate, AlOH, calcium salts, and dairy products. Tooth enamel discoloration (less with doxycycline) may occur in young animals.

Metronidazole spectrum is restricted to anaerobes. Good CNS penetration.

Sulfonamides provide good broad spectrum coverage with good CNS, bronchial and prostate concentration. They should be avoided in Dobermans due to a high risk for multisystemic hypersensitivity.

As a general rule for bacteriostatic drugs, increase in frequency of administration increases efficacy.

Empirical Choice

Empirical choice should consider the most likely organisms in a particular site, as well as the antibiotic concentration that can be achieved at the site. Most common bacteria will vary geographically and with origin (hospital versus community). Good first choices by system are described below.

• Urinary tract infections:

o Bacteria

• E. coli, Proteus, Pseudomonas, Enterobacter, Pasteurella (more in cats), Staphylococcus, Streptococcus, and Enterococcus.

o First choice

• Amoxicillin + clavulanate

• cephalosporin

o Options:

• Sulfonamides

• Fluorquinolones

• Tetracyclines

o In uncomplicated, never before treated, lower urinary tract infections in immunocompetent animals, amoxicillin + clavulanate is very effective against the most common pathogens (sulphonamides work better against E. coli)

• Prostatitis:

o Bacteria: E. coli, Staphylococcus, Klebsiella, Proteus, and Mycoplasma canis (?)

o First choice

• Sulfonamides

• Enrofloxacin

o Options

• Doxycycline

• Erythromycin (gram-positives only)

• Pneumonia:

o Bacteria: usually mixed with E. coli in complicated cases

o First-choice

• Amoxicillin + clavulanate

• Fluorquinolones

o Options

• Cephalosporins (do not effectively cross the blood-bronchus barrier; work for pneumonia)

• Aminoglycosides (do not effectively cross the blood-bronchus barrier)

• Sulphonamides

• Clindamycin (Streptococcus)

• Tracheobronchitis:

o Organisms

• Trachea: Bordetella, Mycoplasma.

• Bronchi: organisms associated with tracheitis and with pneumonia

o First-choice

• Amoxicillin + clavulanate

• Doxycycline

• Fluorquinolones

o Options

• Sulphonamides

• Clindamycin (Streptococcus)

• CNS infections

o First-choice

• Sulphonamides

• Enrofloxacin

o Options

• Metronidazole (anaerobes)

• Doxycycline (rickettsial infections)

• Ceftriaxone

• Skin infections

o Bacteria: Staphylococcus intermedius

o First-choice

• Cephalexin

• Cefadroxil

o Options

• Sulfonamides

• Clindamycin

• Sepsis:

o Organisms

• Dogs: Staphylococcus, E. coli, Streptococcus, Salmonella, Proteus.

• Cats: E. coli, Klebsiella, Salmonella, anaerobes.

o First-choice

• Amoxicillin+clavulanate + fluorquinolone

• Cephalosporin + fluorquinolone

o Options

• Second or third generation cephalosporines

• Aminoglycosides (gram-negative)

• Clindamycin (anaerobes)

• Discospondilitis

o Organisms: Staphylococcus, Streptococcus, (Brucella canis)

o First-choice

• Cephalosporins

o Options

• Enrofloxacin

References available upon request