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Requirements for Successful Antimicrobial Therapy

By Dawn Merton Boothe, DVM, PhD, Professor, Department of Anatomy, Physiology, and Pharmacology, College of Veterinary Medicine, Auburn University

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Clinical Diagnosis:

Successful chemotherapy usually requires a specific diagnosis, even though a reasonable preliminary diagnosis is often all that is possible, at least initially. The presence of bacteria requiring systemic therapy should be confirmed as much as possible; fever, inflammation, and leukocytosis are supportive of but not diagnostic for bacterial infection.

Microbiologic Diagnosis:

Treatment should be aimed at a specific pathogen whenever feasible. Care must be taken when predicting the infecting pathogen based on historic data, because often such data did not discriminate between commensal and pathogen. The use of cytology should not be overlooked. Examination of a direct smear stained with Wright’s or Gram’s stain may help to establish the types of pathogens involved (gram-positive or gram-negative rods or cocci) and direct initial antibacterial therapy. However, even if the pathogen is correctly identified, the ability to predict the susceptibility pattern of the infecting pathogen has markedly decreased in recent years. If the animal has not been previously exposed to antimicrobials, it is safer to assume that standard expected susceptibility patterns for first-tier drugs (eg, amoxicillin with or without clavulanic acid for E coli or cephalexin for Staphylococcus pseudintermedius) may be relevant. However, if exposure to antimicrobials has previously occurred, eg, because of recurrence of the current infection, treatment of a different infection, or even exposure to antimicrobials through another household member, culture and susceptibility testing might be prudent. Under field conditions, culture and susceptibility testing may be difficult to accomplish. Use of an antibiogram, either generated locally for the practice or based on national data, might help identify current susceptibility patterns. Antibiograms reflect current population susceptibility patterns. Package insert data or recent literature may also help select a drug based on population MIC statistics; such data can also be useful for design of dosing regimens. Even in the event of culture submission, empirical antimicrobial therapy may need to be initiated before susceptibility data are received. If susceptibility data indicate the isolate is resistant, therapy should not change if the animal has responded to the chosen drug. Reculture might be important after therapy has been completed. If the animal has not responded, the data collected before treatment may no longer accurately predict the infecting population because the drug may have changed susceptibility patterns.

Culture and Susceptibility Testing:

Isolation and characterization of the causative pathogen, susceptibility testing, and determination of the MIC provide a sound foundation from which to select the antimicrobial drug and the dosage regimen. However, culture and susceptibility data are only as good as how the sample was collected, handled, and tested. Samples must be collected without contamination. Free catch urines, swabs from endotracheal tubes, culture of drain tubes, and swabs from the surface of a contaminated wound are all examples of unacceptable culture samples. Swabs are less than ideal; not only is the temptation to collect a contaminated sample greater, but the swab itself can be inhibitory to growth. Whenever possible, a tissue or fluid sample is preferred, with handling of the sample left to the laboratory. Equally important is proper refrigeration. For example, with a reproduction rate as short as 20 min, E coli in an unrefrigerated urine sample can rapidly grow from 101 to >105 CFUs, thus transitioning from no infection to infection while overgrowing the true pathogens. The laboratory must also be selected carefully; it should follow guidelines promulgated by the Clinical Laboratory Standards Institute (CLSI), use veterinary rather than human materials, and be directed by a veterinary clinical microbiologist.

Of the culture and susceptibility procedures routinely used by laboratories, tube (or micro) dilution procedures are preferred to agar gel procedures, because they can provide a minimum inhibitory concentration (MIC) of the drug toward an isolate of the infecting organism that has been cultured from the animal. The MIC can be used to not only select the drug but also to design the dosing regimen. Some key points regarding susceptibility testing may facilitate interpretation. The S (susceptible), I (intermediate), or R (resistant) indicator accompanying each MIC is determined by comparing the MIC of the isolate to MIC "breakpoints" determined by CLSI. An isolate with an MIC below the breakpoint established for each drug is considered "S," versus an isolate with an MIC at or above the breakpoint, which is considered "R." Although the actual concentrations tested for all drugs are generally the same, the range tested varies for each drug, as do the breakpoints. For example, for enrofloxacin, tested concentrations generally range from 0.5 to 2 mcg/mL; for amikacin, from 4 to 32 mcg/mL; and for ticarcillin, from 16 to 128 mcg/mL. The current susceptible and resistant CLSI breakpoints (mcg/mL), respectively, established for each drug are <0.5 and >4 for enrofloxacin, and <4 and >64 for amikacin. These breakpoints are followed by any laboratory in the USA that follows CLSI protocols or guidelines. That the concentrations differ for each drug, reflects, in part, the different drug concentrations achieved in plasma (and thus tissues) for each drug when administered at recommended dosing regimens. Because the concentrations tested and achieved in the animal vary for each drug, an MIC of 0.25 mcg/mL for enrofloxacin should not be interpreted as being better than an MIC of 2 mcg/mL for amikacin. The drug to which the isolate is most susceptible to, based on susceptibility data, is the drug with the MIC most below the Cmax achieved in the animal at the recommended dose. However, this may not necessarily be the best drug to treat the infection, based on other host, microbial, and drug factors. Finally, just because an isolate has been indicated as "S" on a culture report does not mean the isolate has not developed some level of resistance. Rather, particularly for commonly used drugs, MIC for a specific isolate may be approaching the CLSI breakpoint. As such, it is still considered "S," despite it having developed some level of resistance. Therefore, doses for antimicrobials ideally should err on the side of higher doses (concentration- or time-dependent drugs) or shorter intervals (time-dependent drugs); the more at risk the animal is for therapy to fail, with development of a recurrent, resistant infection, the more important the design of the dosing regimen.

In addition, data from even appropriately collected samples tested under ideal conditions remain subject to limitations. Testing cannot take into account the impact of distribution to the site of infection, host factors such as inflammation, or microbial factors, including the size of the inoculum. These and other factors may indicate a need to modify the dosing regimen to assure adequate concentrations at the site of infection. Lipid-soluble drugs may become increasingly important as infection becomes more complex. Most antimicrobials are lipid soluble, with the β-lactams (penicillins, cephalosporins) being common exceptions.