Antimicrobials and UTIs: part 3-building the dosing regimen (Proceedings)
Dosing regimens for antimicrobials should be related to MIC. However, simply achieving the MIC in the patient is not likely to be sufficient for a variety of reasons. This reflects, in part the fact that susceptibility cards used by microbiology laboratories only test in a very limited range. Thus an isolate that is designated as "S" may very well have already implemented the first step toward resistance, resulting in a higher MIC that is still considered "S". Thus, culture procedures largely test for resistance, not susceptibility, failing to provide information about how susceptible an isolate is to the drug of interest.
Pitfalls of susceptibility testing
Although culture and susceptibility data (C&S) can be a powerful tool to guide selection, it nonetheless is an in vitro test applied to in vivo conditions; over-reliance on the information can contribute to to therapeutic failure. C&S data is no more accurate than the sample collection; close adherence to recommended procedures including but not limited to site selection, site preparation and sample handling are critical to proper interpretation. For UTI, there is no question that cystocentesis is the preferred technique, even if an animal is catheterized. Just as absence of growth does not indicate absence of infection, isolation of an organism is not necessarily evidence of infection. Clearly, culture of an organism from a tissue that is normally sterile indicates infection. For the urine, 1000 CFU/ml might be a reasonable threshold. Shipment of urine specimens may complicate colony counts; accordingly, a urine paddle system should be considered. The C&S procedures themselves are fraught with potential errors. For practices that provide in- house susceptibility testing, care must be taken to follow guidelines established and published by (or comparable to) the Clinical and Laboratory Standards Institute (CLASI) or comparable federal agency. Materials, including interpretive standards, should be validated by the appropriate agency. Minor changes in pH, temperature, humidity, etc can profoundly affect results. Personnel should be trained specifically in culture techniques and hospitals that provide this service (as do diagnostic labs) should maintain well designed and adequately collected quality control data to validate their procedures (CLASI indicates control organisms). 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 can not accommodate and laboratories (nor clients) can not afford to test all potential drugs used to treat an infection, one drug often tested as a model for other drugs in the class. For some classes of drugs, cross-reactivity can be similar within the class (for example, an organism that is R to one fluorinated quinonolone (including ciprofloxacin) is likely to be R to all). However, the same is not true for others. Amikicacin is often more effective than gentamicin for (hence both are often on a report). Cephalothin serves as a model for all 1st generation cephalosporins but it underestimates efficacy of cefazolin toward Gram negative organisms. The spectrum of 3rd and 4th 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 susceptbility 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 (ESBL) that will be produced in vivo but not in vitro and despite an "S" designation, therapeutic failure may occur.Bactericidal versus bacteriostatic drugs
The term "bactericidal" is so often abused that the distinction from bacteriostatic should be underemphasized. Although it is appropriate for clinicians to reach for a drug that is "cidal" rather than "static", it is not appropriate to assume that the ability of that drug to kill rather than simply inhibit an organisms will enhance therapeutic efficacy. This may be true, but only if concentrations of the drug achieved at the site of infection are sufficient to kill the microbe. The term "bactericidal" is an in vitro definition and is based on killing rates (eg, 99.9% reduction in bacterial inoculum within a 24 hr period of exposure) as well as the proximity of the minimum bactericidal concentration (MBC) of a drug to the MIC. The MBC is determined based on kill curves, or following tube dilution procedures: tubes with no observable growth are inoculated on agar gel. For "bacteriostatic" drugs, growth on the agar plate will occur for several tube dilutions above the MIC, indicating that organisms were not killed. However, bacteriostatic drugs are capable of killing (eg, some organisms are exquisitely sensitive to the effects of selected drugs; some "static" drugs are acculumulated to concentrations that are likely to be cidal [eg, macrolides and lincosamides in phagocytes; urine concentration). However, killing concentrations are generally more likely to be achieved for a cidal drugs compared to a static concentration.