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A reminder about treating urinary tract infections
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Recent data have indicated the importance or lack of importance for screening and treating patients for asymptomatic bacteriuria. These recommendations to avoid cultures in nonpregnant, asymptomatic individuals are based on risks for collateral damage due to antimicrobial overuse, including resistance and adverse events when bacteria are detected.
Equally as important to consider is the appropriate treatment of urinary tract infections when they do occur. Increasing antimicrobial resistance has forced practitioners to look outside the primary agents for treating this infection and to use newer drugs or older agents with limited data to support this practice. Not all antimicrobial agents, however, have adequate urine penetration to treat infections at this site. In recent months, we have begun to see a rise in the number of patients with refractory infections due to treatment with drugs without reliable urinary concentrations. This brief review will discuss the major classes of antimicrobials regarding their urinary penetration and will highlight those agents that should not be relied upon to treat UTIs.
It is important to note that the following discussion is limited to treating bacteria in the urine and not the use of these antibiotics for infections of the urinary tract where tissue penetration may be the more pertinent factor in drug selection.
Bacterial infections
It is estimated that close to 11% of women in the United States develop a symptomatic bacterial UTI each year. This translates to national antibiotic expenditures of more than $650 million dollars annually for community-acquired infections and between $400 and $450 million dollars for health care–associated diseases. In the current setting where all health care expenditures are scrutinized, it is important to avoid inappropriate antibiotic use due not only to resistance but also lack of activity at the site of infection.
The quinolones (such as ciprofloxacin) and sulfonamides are the mainstays of treating UTIs and have been for many years. In addition, two agents with activity limited to the urine, nitrofurantoin and methenamine, are also available. These drugs can be relied upon for clinical response in the absence of antimicrobial resistance; however, what about other commonly employed systemic antibacterials?
Beta-lactam antibiotics
All of the penicillins have high urinary drug concentrations and therefore can be reliably used to treat UTIs due to susceptible organisms. The same is true for all cephalosporin agents. With the exception of only a few agents, cephalosporins are eliminated primarily unchanged via the kidney. Even for those agents that are metabolized or eliminated via the biliary route, sufficient parent drug or active metabolites can be found in the urine at adequate concentrations to treat clinically relevant pathogens. The remaining beta-lactam antimicrobial agents, the carbapenems, the monolactams such as aztreonam (Azactam, Elan) and the beta-lactam/beta-lactamase inhibitor combinations also all provide sufficient urinary penetration for treating disease.
Tetracyclines
The traditional tetracyclines — tretracycline, doxycycline and minocycline — demonstrate various degrees of lipid solubility that produces high biliary concentrations of these drugs. Historically, this has led to clinical concerns about using these drugs for treatment of UTIs. These agents all have different routes of elimination. Minocycline is primarily excreted by the kidney, and therefore, high urinary concentrations are reached. Although minocycline undergoes hepatic metabolism, the approximately 10% penetration in the urine has been shown to effectively treat disease at this site. Doxycycline is eliminated mostly in the feces and cannot be used to treat infections isolated to the urine.
The new glycylcycline antibiotic, tigecycline (Tygacil, Wyeth), is extensively hepatically eliminated with less than 20% of parent drug being recovered in the urine. No clinical data are available, however, regarding use of the drug to treat UTIs.
Macrolides
Erythromycin has variable urinary tract penetration based on the formulation being administered. Following IV administration, approximately 15% of the dose is recovered unchanged in the urine compared with less than 5% of the oral formulations. Urinary distribution of azithromycin approximates that of erythromycin at approximately 12% of serum drug concentrations. Clarithromycin is dependent on renal elimination for both parent drug and the active metabolite, and available urine concentrations should be adequate if urinary coverage is desired.
Quinolones
The quinolones are among the most commonly used agents to treat UTIs, due to their ease of administration and broad spectrum of activity. Recent increases in resistance, however, have made these less desirable agents in the nosocomial setting in some instances during recent years. With the exception of moxifloxacin, all of the agents in this class that are currently commercially available can be used to treat UTIs. Treatment of infections in the urine is a common misuse of moxifloxacin, and clinicians should be careful about use of this agent for these infections as the small amount recovered in the urine is insufficient to treat infections.
Agents with activity against resistant gram-positive infections
The three agents currently used exclusively for treating gram-positive infections, vancomycin, linezolid and daptomycin all have reasonable concentrations detected in the urine. Vancomycin is excreted unchanged in the urine and has been the agent most often used for patients with UTIs due to resistant gram-positive infections. Daptomycin is also primarily eliminated in the urine, and although limited data are available regarding use of this agent in treating UTIs, this should not be a concern. Finally, although linezolid undergoes hepatic metabolism, urinary excretion accounts for up to 85% of drug elimination, and this agent has been used with clinical success in treating patients with resistant gram-positive infections in the urine. Although an important consideration whenever initiating an antimicrobial for UTIs, it is particularly important to consider the possibility of chronic colonization before initiating one of these therapies for use in patients with resistant, gram-positive organisms.
Other antiinfective agents
Aminoglycosides are among the antibacterials with some of the best urinary penetration available. When treating pathogens in the urine with these agents, their ability concentration in the urine translates to the ability to use lower doses than required for systemic infections with the same pathogens. Although they require parenteral administration and can be associated with significant clinical toxicity, they remain ideal agents for treating infections in the urine, particularly when resistant pathogens are present.
Although the use of chloramphenicol had been largely abandoned for many years, its use is returning in light of multidrug-resistant pathogens and for treating patients with severe beta-lactam allergy. Despite extensive hepatic metabolism, between 5% and 10% of the parent drug can be recovered in the urine, and this is sufficient to treat disease in patients without renal impairment.
Another agent that has regained popularity for treating resistant infections is colistin. This drug has high urinary concentrations (exceeding 15 mc/mL) and unlike early polymyxins (polymyxin B) does not have a 12- to 24-hour delay following systemic administration before urinary concentrations can be detected.
Fungal infections
Despite the increase in the number of available antifungal agents during the past 10 years, few of these agents have expanded our treatment options for fungal infections in the urine. Fluconazole (Diflucan, Pfizer) and flucytosine (Ancobon, Valeant) are the only two available agents with reliable urinary drug concentrations, although the tissue penetration of the other agents is sometimes sufficient, depending on the extent of disease.
For more information:
- Foxman B. Epidemiology of urinary tract infections: incidence, morbidity and economic costs. Am J Med. 2002;113:5S-13S.
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