What type of susceptibility test should be considered for difficult UTIs?
Two main types of antimicrobial susceptibility tests are currently in common use: 1) the disc diffusion susceptibility test,
and 2) the antibiotic dilution susceptibility test. The agar disc diffusion test (Kirby-Bauer test) of antimicrobic susceptibility
was primarily designed for treatment of infections based on knowledge of serum concentrations of the antimicrobial drug. Therefore,
the concentration of antimicrobics (except nitrofurantoin) in the paper discs is comparable to expected serum concentrations
of drugs when given at commonly used dosages. However, many drugs attain concentrations in urine that are 10 to 100 times
greater than that observed in serum. Therefore, disc-diffusion tests underestimate the potential efficacy of many antimicrobial
drugs in patients with lower urinary tract infections. Examples of some drugs that are excreted in high concentration in urine
include ampicillin, cephalexin, chloramphenicol, enrofloxacin, oxytetracycline, penicillin G and trimethoprim). Agar diffusion
antimicrobial susceptibility tests may be useful for patients with renal infections and acute bacterial prostatitis since
renal and prostate tissue concentrations of antibiotics are more likely to correspond to serum concentrations of antibiotics.
The second type of commonly used susceptibility test is the antibiotic dilution susceptibility test. It is designed to determine
the minimum concentration of the antimicrobial drug that will inhibit the growth of uropathogens (MIC). The MIC is then compared
to antimicrobial concentrations expected to be present in urine following administration of therapeutic dosages of the drug.
In general, the antimicrobial agent is likely to be effective in vivo if it can achieve a concentration of four times the
MIC (Table 2, p. 6S). Note that the MIC is several dilutions lower than the minimum bactericidal concentration (MBC) of drugs.
Caveat: The MIC of an antimicrobial drug varies with each type of infecting pathogen. In addition, the MIC for the same type of pathogen
may vary with different episodes of relapsing infections. A reliable way to assess the in vivo effectiveness of an antimicrobic
in a timely fashion is to re-culture the urine during and after therapy.
Serum and urine concentrations
Why should serum and urine concentrations of antimicrobics be considered to treat difficult UTIs?
Serum or urine concentrations of antimicrobial agents do not necessarily reflect tissue concentrations. In context of this
limitation, we make the following recommendations: 1) select agents that have high urine concentrations (at least four times
the MIC) for treatment of lower urinary tract infections, and 2) select antimicrobial agents that attain high concentrations
in serum and (if possible) urine for treatment of acute bacterial infections of the prostate gland or bacterial infections
of the kidneys.
Caveat: Special precautions must be taken when selecting antimicrobial agents for treatment of patients with renal failure. If the
standard dosage regimen is given to patients with reduced renal function, increased serum concentrations of drugs dependent
on the kidneys for elimination from the body could predispose the patient to adverse drug reactions. Likewise, renal failure
could reduce the effectiveness of drugs normally excreted in high concentrations in urine.
Dosages and maintenance schedules
What drug dosage and maintenance schedule should be selected?
To help eradicate bacterial pathogens from the site(s) of infection, the concentration of the drug must be maintained at varying
concentrations above the MIC for at least a portion of the dosing interval. However, peak drug concentrations and the time
drug concentrations remain above the MIC during the dosing interval varies with different antimicrobial agents and different
sites of infection. In addition, recall that the MIC varies with different bacterial pathogens, and may vary with different
episodes of relapsing infections caused by the same pathogen. Thus, the optimum dosage of an antimicrobial drug to treat bacterial
UTI varies with the susceptibility of each pathogen, the sites of infection, and the integrity of host defense and repair
mechanisms. These principles justify the value of flexible label dosing of various antimicrobial drugs such as enrofloxacin.
In general, dosage and intervals between maintenance dosages should conform to the recommendations of the manufacturer. Strive
for maintenance of high concentrations of antimicrobial agents in urine to treat infections of the lower urinary tract, and
high serum concentrations for treatment of infections of the renal parenchyma.
Frequency of administration of a drug is based on whether its antimicrobial activity is best correlated with, 1) the drug's
peak serum concentration (concentration dependent), or 2) the time during the dosing interval that serum concentration of
the drug is higher than the MIC (time dependent). For example, to maximize the value of drugs whose antimicrobial efficacy
is time dependent (such as beta lactams), they should be given more frequently and not just at higher doses. The antimicrobial
activity of fluoroquinolones is concentration dependent. The ability of companion animal owners to comply with recommendations
must also be considered when selecting drug dosage intervals.