Discussion

This study provides current information regarding the etiologic agents that cause community-acquired UTI in women in the outpatient setting and their antimicrobial susceptibility patterns in relation to age and geographic region on a national basis. By using this large national database and by restricting the analyses to female outpatients within these 2 age groups, we have defined the population that is most amenable to empirical therapy as recommended in the recently published IDSA guidelines. The safety and efficacy of such empirical therapy depends upon periodic assessment of antimicrobial resistance profiles.

The frequency distribution of etiologic organisms within each age group is quite consistent with the findings of previous, smaller studies of acute cystitis in women that were conducted in individual centers [8, 9]. E. coli and S. saprophyticus were more prevalent in younger women, whereas other gram-negative rods and enterococci were more prevalent in older women. Therefore, the agents that cause acute cystitis remain highly predictable, although they vary by age, even as the susceptibility patterns of these organisms change.

These data illustrate several important points regarding the drugs that are most frequently considered for empirical therapy for community-acquired UTI in women. First, rates of resistance to ampicillin range from 30% to 40% among E. coli and non-E. coli isolates nationwide. This resistance does not vary greatly by age group, either nationally or within each of the geographic regions that we studied. Although there is significant geographic variability in resistance to ampicillin, it is unacceptably high (⩽25%) throughout the United States. Therefore, as has been recommended by the IDSA and others [8], ampicillin should be avoided in first-line therapy for patients with community-acquired UTIs.

Resistance to TMP-SMZ, the drug that was recommended for use as first-line therapy in the IDSA treatment guidelines, is ∼15% nationally in women in both age groups. However, rates of resistance of E. coli to this drug vary significantly according to geographic region, ranging from a high of 22% in the western United States to a low of 10% in the Northeast. Within regions, there is not much variation in rates of resistance to TMP-SMZ according to age group. Therefore, TMP-SMZ remains a reasonable first-line choice for empirical therapy in the northern and eastern states, although it may no longer be appropriate in western and southwestern states. Of note, a similar geographic distribution in TMP-SMZ resistance was recently reported by Talan et al. [10] among E. coli strains that cause acute pyelonephritis in a nationwide study.

How much variation there may be from locale to locale within each region cannot be readily ascertained from the database. The cause of this geographic variation in resistance to TMP-SMZ is also not apparent. One possibility could be regional differences in the use of TMP-SMZ as prophylaxis for patients with HIV infection or AIDS or for other uses. An alternative possibility could be introduction of TMP-SMZ-resistant strains into the western and southwestern United States from sources in Mexico or Asia, where markedly increased rates of resistance to TMP-SMZ are seen.

Alternative drugs that have been recommended by the IDSA for empirical treatment of patients with acute cystitis include fluoroquinolones and nitrofurantoin [1]. In general, resistance to the fluoroquinolones was minimal among women aged 15–50 years and did not vary by geographic region. Susceptibility to this class of drug was somewhat reduced among older women, mainly because of the resistance and higher prevalence of enterococci among women in this age group. Overall, the activity of fluoroquinolones was better than that of TMP-SMZ against all isolates combined in each age group; therefore, fluoroquinolones would be reasonable choices for empirical therapy in cases in which TMP-SMZ could not be used.

Nitrofurantoin also demonstrated activity against the majority of isolates that cause UTIs that were recovered from women aged 15–50 years. Older women were less likely to be infected with a strain susceptible to nitrofurantoin, mainly owing to the decreased activity of this drug against Proteus species and Klebsiella species, both of which are relatively more prevalent among women in this age group than they are among younger women. In general, the rates of susceptibility of isolates that were recovered from younger women to nitrofurantoin were better than the rates of susceptibility to TMP-SMZ; however, the isolates recovered from older women had equivalent rates of susceptibility to the 2 drugs.

In contrast to TMP-SMZ, however, susceptibility to nitrofurantoin did not differ by geographic region; therefore, this drug would be a reasonable alternative choice for therapy in areas where rates of resistance to TMP-SMZ are high. However, studies to date have demonstrated that 3-day regimens of nitrofurantoin have lower cure rates than do regimens of TMP-SMZ or fluoroquinolones [1, 11], so a 7-day regimen is currently recommended [1]. Further studies of the efficacy of 3-day regimens of this drug would be of interest.

The extremely large database and the ability to define urinary isolates with regard to patient age, sex, region, and community versus nosocomial acquisition are major strengths of this study. The recently published IDSA guidelines make these data particularly relevant, because the guidelines provide practitioners with an estimate of susceptibility rates within well-defined geographic regions and patient groups. Local resistance patterns are clearly best when they are available, but they are increasingly not available because of the empirical treatment (without culture) of UTI in women.

The data do have certain limitations that are inherent to laboratory-based surveys. For example, because cultures are not performed for all empirically treated patients, unrecognized biases may cause physicians to obtain specimens for culture from some patients but not from others, thus influencing the susceptibility data that they obtain. In addition, although we have reported in vitro susceptibility data from those patients who are most likely to represent the population amenable to empirical therapy for cystitis (namely, adult women seen in the outpatient setting), we do not have specific data regarding the presence and nature of symptoms and signs or of complicating factors such as diabetes, recent hospitalization, catheterization, and urological or gynecologic surgery.

An unknown proportion of the women in the study undoubtedly had asymptomatic bacteriuria, complicated UTI, or pyelonephritis that was evaluated in the outpatient setting. However, the fact that the distribution of uropathogens and their rates of susceptibility are consistent with those from previous studies of women known to have acute uncomplicated cystitis suggests that the number of such cases is likely small. For example, the overall national rates of susceptibility for all isolates that were recovered from women who were 15–50 years of age in this study are very similar to the rates of susceptibility that we recently reported following a population-based study in Seattle in which we were able to specifically identify women with symptomatic acute uncomplicated cystitis and to exclude those with complicated UTI or pyelonephritis [2]. Likewise, the distribution of uropathogens is similar to that found in clinical trials of treatment of patients with acute uncomplicated cystitis [12]. Therefore, it is likely that the great majority of isolates included in our analyses were indeed recovered from patients who experienced episodes of acute uncomplicated cystitis.

Finally, it is important to note that the clinical significance of in vitro resistance in patients with uncomplicated cystitis has been little studied. McCarty et al. [13] found a 50% rate of bacterial eradication and a 60% rate of clinical cure among 10 women who were infected with a TMP-SMZ-resistant uropathogen and who had been randomized to receive treatment with TMP-SMZ. However, more studies are needed before definitive conclusions can be made regarding the implications of in vitro resistance in patients with cystitis. Certainly, factors such as clinical presentation, level of infection (upper vs. lower urinary tract), and cost need to be weighed in addition to prevalence of resistance when therapeutic agents are chosen.

In conclusion, the in vitro susceptibility of community-acquired uropathogens varies according to age and geographic region, even among adult women who were seen in the outpatient setting. This information needs to be considered when empirical therapy for acute cystitis is chosen. As the magnitude and variation of antimicrobial resistance in the community grow, so does the need for continuous large-scale surveillance systems such as TSN, which has yielded a database that can link epidemiological and clinical factors with laboratory results. In addition, studies of the clinical outcomes associated with in vitro resistance are needed. The more detailed the clinical and epidemiological data, the more precise the analyses that result can be. Clearly, continued surveillance is essential to maintaining the safety and cost-effectiveness of empirical therapy as a management strategy for acute cystitis.