Confirm need: identify target; keys to appropriate antimicrobial use - DVM
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Confirm need: identify target; keys to appropriate antimicrobial use


Pitfalls of susceptibility testing also reflect the drugs selected for testing. Not all companies are interested in establishing interpretive criteria and as such, not all drugs are available for testing. Because automated systems cannot accommodate, and laboratories (nor owners) cannot afford, testing all potential drugs used to treat an infection, one drug often is tested as a model for other drugs in the class (i.e., cephalothin for the first-generation cephalosporins; enrofloxacin for the fluorinated quinolones). For some classes of drugs, cross-reactivity can be similar within the class [for example, an organism that is R to one fluorinated quinolone (including ciprofloxacin) is likely to be R to all]. However, the same is not true for others. Amikacin is often more effective than gentamicin (hence both are often on a report). Cephalothin serves as a model for all first-generation cephalosporins, but it underestimates efficacy of cefazolin toward Gram-negative organisms. The spectrum of third- and fourth-generation cephalosporins is too variable to allow one to predict the susceptibility of others and as such, multiple drugs are likely to be included. Culture and susceptibility techniques may not accurately reflect resistance that has developed in the infecting organism to drug to which the organism is generally susceptible. These cephalosporins also offer another example of concern: they are susceptible to extended spectrum beta-lactamase that will be produced in vivo but not in vitro and despite an "S" designation, therapeutic failure may occur. Ceftazidime is often used as a test for the presence of extended spectrum beta-lactamase; imipenem and clavulanic acid generally are not susceptible to these enzymes. Laboratories currently are generating methods intended to detect this level of resistance.

Interpreting culture and sensitivity (pharmacodynamic) information is most helpful when considered in the context of the animal. The first step should focus on comparing what is needed — the MIC of the isolate for the drug of interest — to what is achieved. Even if samples are properly collected and cultured, culture and sensitivity information is inherently deficient because in vitro methods cannot mimic in vivo conditions. For example, the isolate is exposed to the constant conditions, including drug concentrations throughout the in vitro incubation period; in vitro methods cannot take into account host factors that detract from efficacy. Among the most problematic concerns is interpretation of MIC. The breakpoint MIC (MICBP) is based, in part, on peak plasma drug concentrations (Cmax) which, ideally, is determined in the species of interest and tested against pathogens infecting the targeted animals.

Many drugs used by veterinarians are approved for use in humans. Although interpretive MIC data has been determined by CLASI for some drugs in animals, many have not and interpretation may be inappropriate. Ciprofloxacin is an excellent example. Its oral bioavailability in dogs is 30 percent to 40 percent of that in humans, and despite its increased potency compared to enrofloxacin toward Gram-negative organisms, its potential efficacy (MICBP) is equivalent to or less for many organisms. Susceptibility data also does not take into account active metabolites, again exemplified by enrofloxacin, which is metabolized to ciprofloxacin: both Cmax and area under the curve (AUC) of bioactivity of enrofloxacin may increase up to 50 percent or more by ciprofloxacin; as such, culture and sensitivity information might underestimate efficacy.

MICBP generally are based on the highest labeled dose, but higher doses might be safely administered for many antibiotics. If recommended doses change, the manufacturer should provide CLASI with updated pharmacokinetic information so that interpretive criteria may change accordingly, and automated systems should incorporate those changes in their methods. Again, enrofloxacin offers an example. Originally approved at 2.5 mg/kg, 1 microgram/ml (< 1= S; > 2 =R) was the MICBP; the current dose is up to 20 mg/kg and new interpretive criteria identify > 4 micrograms/ml = R.


Source: DVM360 MAGAZINE,
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