Antimicrobials and UTI: A clinical pharmacologist's perspective (Proceedings)

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Antimicrobials and UTI: A clinical pharmacologist's perspective (Proceedings)

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Apr 01, 2009

The goal of antimicrobial therapy for UTI is to resolve clinical signs of infection, eliminate bacteruria, and also avoid resistance. Increasingly, the latter is difficult to do. In order of importance, the three most important steps (in the author's opinion) to take when treating.

Confirming the need for infection

Antimicrobial therapy should be used only when reasonable evidence of infection exists. Generally, a quantitative culture yielding less than 105 CFU/ml may not need treatment, and if the risk of resistance is likely, avoiding treatment might be more prudent. Mitigating circumstances might mandate treatment (eg, immunesuppression, pyelonephritis, etc) that can lead to worsening of infection etc). In humans, the presence of bacturia is not necessarily an indication of the need for therapy. In order to avoid resistance, treatment generally is not indicated in asymptomatic bacturia except under certain conditions in which the patient is at risk, such as pregnancy, or invasive surgical procedures.Enterococcus infection in particular may be amenable to no treatment (see adjuvant therapies). Bacterial UTI occurs much less frequently in cats than in dogs, and clinical signs indicative of cystitis in cats should not be interpreted as a need for antimicrobial therapy. Cats might be cultured to detect occult infection and to rule out the presence of bacteria. Clearly, if the decision is made to treat a UTI, then therapy must be aggressive, designed to kill invading pathogens as well as emerging mutants as rapidly as possible.

Identifying the bug and matching it to the drug



The role of empirical selection in treatment of UTI should be questioned, particularly in complicated cases. That broad-spectrum, and even narrower spectrum drugs (eg, FQ) impact microflora and contribute to resistance is clear. Increasingly, scientific data supports the inappropriateness of this approach for all but the simplest of infections. An uncomplicated infection is one in which no underlying structural, neurologic, or functional abnormality can be identified. Previous antimicrobial therapy within the last 3 to 12 weeks is a clear indication for a properly collected culture (see below). E. coli is the organism targeted with empirical therapy. However, in the author's retrospective and prospective studies in dogs and cats, E .coli was the causative organism in only 50% of UTI cases. More importantly, of the E coli, and up to 50% of isolates were resistant to first choice drugs (amoxicillin-clavulanic acid, TMPS, FQs, and cephelixin; 20% resistant to cefpodoxime). In women with risk factors for infection with resistant bacteria, or in the setting of a high prevalence of TMP/SMX resistance, a FQ or nitrofurantoin is recommended for empirical treatment. In humans, the goal of treatment is eradication of infection using shorter courses of therapy (ie, 3 days) with with once-a-day dosing of a selected drug or a single dose of a particularly efficacious antibiotic. Nitrofurantoin does not share cross-resistance with more commonly prescribed antimicrobials and its use is justified from a public health perspective as a FQ-sparing agent. The need to avoid FQs is exemplified by the fact that single-dose ciprofloxacin prophylaxis increased the prevalence of ciprofloxacin-resistant faecal E. coli from 3 to 12%. After treatment with ciprofloxacin for prostatitis, 50% resulted in post-treatement faecal colonization with quinolone-resistant E. coli genetically distinct from the prostatic infection. Indeed, in humans, although FQs are effective as short-course therapy for acute cystitis, widespread empirical use is discouraged because of potential promotion of resistance. An exception is made for acute (non-obstructive) pyelonephritis, but only if culture results direct continuing therapy. The more complicated the infection or the patient, the more important is basing therapy on susceptibility data. In human patients, diagnosis of UTI in asymptomatic patients is based on at least two clean-catch midstream urine collections. The point is not to sample clean catch urines in dogs or cats, but to point out that the presence of bacturia in the absence of clinical signs is not an indication for therapy. The same organism must be present in significant (see earlier) amounts in both cultures for treatment to be recommended. A single culture is sufficient in the presence of symptoms. Urinary cultures should be the basis of antimicrobial selection in complicated infections (e.g., re-infection or relapse; history of antimicrobial use within the past 4 to 6 weeks) or if the infection represents a risk to the patient's health. Infection after recent urinary catheterization also should lead to culture collection. Quantitative urine culture should be used to discriminate harmless bacterial contaminations (e.g., from the urethra) from pathogenic organisms. In a properly collected urine sample, bacterial counts of more than 105 are indicative of infection; counts between 103 and 105 organisms are considered suspect and should lead to a second culture. Samples collected by catheterization or midstream catch techniques are more likely to yield falsely positive cultures than are samples collected by cystocentesis, particularly in females. Thus, cystocentesis is preferred. Note that if therapy is begun as culture results are pending, and the results indicate the wrong drug was selected, the microbial population that is present at the time that the results are received may not (probably does not) reflect the population that was cultured and reculture may be necessary before a new drug is begun.

Design a dosing regimen such that sufficient drug will get to the site that all CFU in the inoculum are killed.



Ideally, a drug that is renally excreted should be selected for treatment of UTIs. Urinary concentrations of such drugs often surpass serum concentrations (up to 300-fold), and as such susceptibility data should be based on urinary rather than plasma drug concentrations. Indeed, drugs that might not be useful for treatment of non-UTIs (because of failure to achieve MIC in blood or tissues) often can be used to treat UTIs (e.g., carbenicillin, nitrofurantoin). In addition, renal elimination may result in bactericidal concentrations of drugs for which only bacteriostatic concentrations can be safely achieved in serum. Many antimicrobials are characterized by a short elimination half-life. This becomes problematic when designing effective, yet convenient dosing intervals for time dependent drugs (see sister Proceedings). For renally eliminated drugs, however, plasma elimination half-life may not accurately reflect contact time of drug in the target tissue (i.e., urine). Presumably, drug eliminated in the urine will be in contact longer with the infected tissue (i.e., lower UTI) longer than other tissues, and therefore the basis for a recommendation to use drugs at a shorter interval when treating UTIs compared with other infections may not be as relevant for UTIs. Contact between drug and microbe in the urinary tract can be facilitated by administration of a drug immediately after micturition or before an anticipated micturition-free period (e.g., at night).However, several caveats must be recognized, when basing antimicrobial selection on renal elimination and anticipation of high urine drug concentrations: 1. If the UTI is associated with infection in the blood (or in the presence of bacteremia), kidney, or prostate, then antimicrobial selection should be based on anticipated plasma (or tissue) drug concentrations and serum breakpoint MIC. Urine concentrations, albeit higher than plasma concentrations, will be helpful, but do not translate to higher concentrations in any tissue other than the urine itself. 2. Exceptions to higher concentrations will occur in the presence of decreased renal function as kidneys fail to concentrate.3. Some renally-excreted drugs present a greater risk of nephrotoxicity. This risk is even greater in the patient with renal disease.