Interaction between Antibiotic Resistance, Resistance Genes, and Treatment Response for Urinary Tract Infections in Primary Care

DISCUSSION

In our study of a predominantly female cohort, with a high proportion of elderly, we observed high levels of resistance to ciprofloxacin and co-trimoxazole, which were still being prescribed. For amoxicillin-clavulanate, which was most commonly prescribed, those with resistant isolates were less likely to report early symptom resolution. Moreover, genotypic markers of plasmid-mediated resistance were identified in a substantial number of isolates.

When compared with proportions of E. coli isolates from the study in 2009 (5), similar proportions were susceptible to amoxicillin-clavulanate (89% versus 91% in 2009) and ciprofloxacin (71% versus 76%), but the proportion susceptible to co-trimoxazole was slightly higher (71% versus 62%; P = 0.049). However, the 2009 study relied on retrospective chart reviews of urine cultures. Since physicians may selectively test more complicated patients or those who fail treatment (18), that study may have overestimated antibiotic resistance levels compared to those in our current study, which prospectively obtained urine cultures from all UTI patients and arguably provides a more accurate assessment of current antibiotic susceptibility profiles.

Globally, antibiotic susceptibility of uropathogens varies widely (19). We observed less resistance of E. coli to amoxicillin-clavulanate compared to that of some other community settings (7, 20). Ciprofloxacin and co-trimoxazole resistance was comparable to that of data from primary care in Hong Kong (21) and less prevalent than in India, Iran, and Turkey (20). Resistance in uncomplicated UTIs may be correlated with antibiotic consumption (22). Antibiotics cannot be obtained without prescription by licensed physicians in Singapore. However, one study suggests large variations in primary care prescriptions of antibiotics for upper respiratory tract infection (from 0% to 70% of episodes) (23). The moderate levels of resistance observed in Singapore should hence motivate additional legislative (24) and physician education interventions to improve antibiotic stewardship (25).

Among Enterobacteriaceae, factors independently associated with resistance to amoxicillin-clavulanate were Indian ethnicity and DM. Potential explanations may lie in travel-related exposures to the high prevalence of antibiotic-resistant bacteria in South Asia for the former (26) and greater exposure of DM patients to health care interventions for the latter (27). Associations between ciprofloxacin and co-trimoxazole resistance with past UTI diagnosis is consistent with extant literature (28, 29), and the association between ciprofloxacin resistance and hospitalization may be related to the substantially higher resistance prevalence in hospital settings (30).

Regardless of the specific patterns of resistance, we believe that the findings with wider relevance were our follow-up data on how matching empirical antibiotic to uropathogen susceptibility affects early symptom resolution, but also how this relationship was imperfect. The small proportion (27%) reporting early resolution despite not receiving empirical antibiotics was consistent with the clinical course of untreated uncomplicated cystitis, where 25% to 42% may experience resolution (4). In those given antibiotics, the “90/60” rule has been proposed, where infections due to susceptible and resistant isolates would correspondingly respond 90% and 60% of the time (31). In our study, 67% of treated patients with susceptible isolates and 45% of treated patients with nonsusceptible isolates reported early resolution. Our short follow-up duration may account for the lower proportions reporting symptom resolution (67/45 instead of 90/60), though interestingly, the ratio between groups appeared to be consistent with the 90/60 rule.

However, while we demonstrated the overall impact of appropriate empirical antibiotic therapy on early symptom resolution, our findings also caution us about the validity of extrapolating efficacy purely based on in vitro susceptibility testing alone. In patients prescribed amoxicillin-clavulanate, symptoms appeared less likely to resolve when genotypic resistance markers were present than when they were absent. For those prescribed ciprofloxacin, early symptom resolution rates were lowest (about 50%), and outcomes did not differ significantly between patients with susceptible and nonsusceptible isolates. There were no striking differences in patients prescribed ciprofloxacin compared to those prescribed other antibiotics to account for these intriguing results. However, underdosing may have contributed to the poorer than expected response. Patients prescribed a dose of 250 mg twice a day appeared to have poorer outcomes than those given 500 mg twice a day, although this observation was likely underpowered (P = 0.095). These doses were chosen by primary care doctors and might not have represented any renal dose adjustment or adherence to professional guidelines.

The effectiveness of ciprofloxacin is a function of peak concentration divided by MIC (32). Particularly in the elderly, where there is decreased renal excretion, the drug may not reach sufficient concentrations in the urine with a 250-mg twice daily prescription. A 500-mg once a day dosing regimen has been shown to deliver higher drug concentrations in the urine, and this regimen at minimum should be prescribed to optimize outcomes (32).

Overall, with regard to empirical therapy, the vast majority of isolates remained susceptible to fosfomycin and nitrofurantoin. Both of these are recommended antibiotics for uncomplicated UTIs in international guidelines (over amoxicillin-clavulanate, which is thought to have lower efficacy, more adverse effects, and broader spectrum of cover) (19) and are viable alternatives that should be considered for Singapore. Given the levels of resistance observed (>20%), ciprofloxacin and co-trimoxazole are less preferred in our setting without ordering urine cultures to guide treatment. In turn, the need for urine cultures could be guided by the risk factors highlighted in this study. Furthermore, appropriate dosing of ciprofloxacin, as discussed above, is vital to ensuring a favorable response to therapy.

Only a low proportion of isolates (<10%) in our primary care setting carried the bla_CTX-M, ampC, and qnr resistance genes, which are highly prevalent among hospital Enterobacteriaceae isolates in Singapore (33, 34). However, of these, 75% were not associated with hospitalization in the past 6 months, and acquisition may thus be occurring within the community. The rising prevalence of resistance, including strains carrying key resistance genes with possible clinical significance, compounded by the imperfect correlation between susceptibility testing results with actual clinical effectiveness, is likely an emerging and important issue which will increasingly complicate management of UTI in primary care settings around the world.

In the face of rapidly changing resistance profiles, strategies are urgently needed for rationalizing how best to determine guidelines for UTI treatment outside of the hospital, where there is typically no routine surveillance or follow up with patients. We argue that a robust approach may need to go beyond surveillance of antimicrobial susceptibility testing results and include routine monitoring of a sample of patients for symptom resolution and possibly the use of genotypic markers of resistance.

The strengths of our study include using a prospective (rather than a potentially biased retrospective) approach to determine the distribution of uropathogens presenting in the primary care setting and their antibiotic susceptibility profiles, with the cohort design demonstrating how antibiotic choices potentially interact with susceptibility profiles and genotypic markers of resistance to affect a clinically relevant endpoint. However, our study has some limitations. Our cohort was predominantly elderly and reflective of the catchment of polyclinics, which provide subsidized primary care services, though this may also reflect the ageing of the population in Singapore (35). We did not split and analyze patients according to different types of UTI (from uncomplicated cystitis to acute pyelonephritis). However, our intent in this paper was to provide generalizable results for UTI in primary care. Some culture results obtained may have been false positives, which would have affected the accuracy of our study, although this number is likely to be small, since the criteria for recruitment were initial presentation with symptoms of UTI. Our symptom resolution endpoint may have been too brief to document complications and risk of recurrent UTI known to occur with inappropriate treatment (8), and we had only a small number of patients untreated with antibiotics for comparison. Some subgroup analyses were also limited by the sample size. Our study only focused on patients with culture-positive UTIs, although a recent study showed that a high proportion of symptomatic women with negative urine cultures did actually have UTI, most commonly due to E. coli (36). Further studies are needed to evaluate whether treatment outcomes in culture-negative patients are similar to culture-positive patients.

In conclusion, our study profiled antibiotic susceptibilities for uropathogens in our primary care setting and identified risk factors for resistance, which may guide the decision to obtain initial urine culture to guide therapy. While patients given active empirical antibiotics were most likely to report early symptom resolution, the correlation with in vitro susceptibility was imperfect. Strategies are needed to monitor clinical effectiveness of treatment options for UTI in primary care in the face of rapidly changing resistance patterns.