Escherichiae coli urinary tract infections (UTIs) are among the most common reasons for antibiotic use in ambulatory settings, resulting in >8.3 million ambulatory visits.Reference Schappert and Rechtsteiner1 With increasing rates of antimicrobial resistance, healthcare systems have established antimicrobial stewardship programs to encourage the appropriate use of antibiotics.Reference Etienne, Lefebvre, Frebourg, Hamel, Pestel-Caron and Caron2, Reference Davey, Marwick and Scott3 Although antimicrobial stewardship programs can limit the misuse of antibiotics, they require close monitoring to identify antibiotic resistance trends as prescribing patterns change.Reference Zhanel, Hisanaga and Laing4
At Denver Health, previous antimicrobial stewardship guidelines recommended trimethoprim-sulfamethoxazole (TMP-SMX) and levofloxacin to treat uncomplicated cystitis in nonpregnant, female adult patients.Reference Burman, Breese and Murray5, Reference Johnson, Sabel and Burman6 With each guideline change, use of each antibiotic and resistance of E. coli to both antibiotics increased. In 2008, Denver Health changed its recommended treatment for uncomplicated UTI to nitrofurantoin and aligned its UTI stewardship program with Infectious Disease Society of America (IDSA) guidelines.Reference Gupta, Hooton and Naber7
In this study, we provide a descriptive analysis of the changes in nitrofurantoin and levofloxacin prescribing and changes in E. coli resistance with stewardship guideline changes. We additionally performed a retrospective case-control analysis to identify risk factors that may correlate with nitrofurantoin resistance.
Methods
Denver Health is a community safety-net hospital with a 525-bed main hospital, emergency department (ED), and 9 federally qualified community health clinics. We chose the study period of January 2008–December 2014 to include the time between the change in stewardship guidelines at Denver Health and the start of the study, and to be consistent with a previous analysis.Reference Johnson, Sabel and Burman6 Using ambulatory data, we identified the number of nitrofurantoin and levofloxacin prescriptions per 1,000 outpatient prescriptions.
In our case-control analysis, episodes of uncomplicated cystitis due to E. coli were identified by their International Classification of Disease, Ninth Revision (ICD-9) code. Inclusion criteria included episodes of uncomplicated cystitis due to E. coli with an associated urine culture of >100,000 colony-forming units in ambulatory, nonpregnant female patients aged 18–89 years. We excluded UTIs treated in inpatient settings. We utilized manual chart review of the 12 months prior to the UTI development to identify risk factors and comorbid conditions associated with nitrofurantoin resistance, to ensure that patients had documentation of symptoms (eg, urinary frequency, hesitancy, urge, dysuria, pelvic pain) consistent with UTI, to exclude asymptomatic bacteriuria, and to exclude cases of ascending infection. If patients had multiple UTIs during the study period, we included only the first episode in our analysis.
Cases were defined as those patients with a nitrofurantoin-resistant E. coli isolate resistant to nitrofurantoin, and controls were defined as those with a nitrofurantoin-susceptible E. coli isolate. We randomly matched 2 controls to each case to adequately power the study and to avoid overmatching, which would limit our analysis of potentially significant risk factors for nitrofurantoin resistance.
To determine the significance of risk factors associated with nitrofurantoin resistance in E. coli UTIs, we performed an unadjusted logistic regression for each categorical variable. For continuous variables, we performed a t test. A statistical analysis was completed using SAS version 9.4 software (SAS Institute, Cary, NC). P < .05 was predetermined to be statistically significant.
This study was approved by the Colorado Multiple Institutional Review Board, and a waiver of consent was granted.
Results
In total, 2,104 E.coli UTIs were identified in nonpregnant, female, adult patients in ambulatory settings during the study period. Of all bacteria isolates, 39 E. coli isolates (1.9%) were resistant to nitrofurantoin. Among E. coli susceptibilities from all culture sources in the study period, nitrofurantoin resistance remained stable at 2% (P = .16). Resistance to levofloxacin increased from 13% to 15% (P < .0001), and resistance to TMP-SMX remained relatively stable from 26% to 28% (P = .37) (Fig. 1). The prescription rate for nitrofurantoin remained relatively stable from 3.53 to 4.01 per 1,000 outpatient visits (P = .20). During the study period, prescriptions of levofloxacin decreased from 4.76 to 3.2 per 1,000 outpatient visits (P = .001), and prescriptions of TMP-SMX decreased from 6.54 to 3.52 per 1,000 outpatient visits (P < .0001),
Rate of nitrofurantoin, levofloxacin, and trimethoprim-sulfamethoxazole prescriptions per 1,000 outpatient visits and rate of E. coli isolate resistance for January 2008–December 2015.
Within the case-control analysis, 38 cases of nitrofurantoin-resistant E. coli UTI met inclusion criteria (1 case was excluded due to pregnancy), and we matched 77 controls of nitrofurantoin-susceptible E.coli UTI. The most significant risk factor for nitrofurantoin resistance was the presence of concomitant levofloxacin resistance (odds ratio [OR], 2.72; 95% confidence interval [CI], 1.04–7.17; P = .04). We observed a nonsignificant trend toward nitrofurantoin-resistant E. coli in patients with diabetes mellitus (OR, 2.07; 95% CI, 0.914.71; P = .08), nitrofurantoin use in the preceding 12 months (OR, 2.15; 95% CI, 0.9–5.16; P = .09), and surgery in the previous 12 months (OR, 3.25; 95% CI, 0.96–11.04; P = .06). No significant risk for nitrofurantoin resistance was associated with the presence of chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), congestive heart failure (CHF), coronary heart disease, immunosuppressive medications, cirrhosis, or malignancy, nor amongst continuous variables including previous number of UTIs, duration of previous hospitalization, or duration of previous antibiotic exposure in the preceding 12 months to the study UTI.
Discussion
At Denver Health over a 7-year period, there appears to be benefit in treating uncomplicated cystitis using narrower-spectrum agents, limiting the development of antibiotic resistance locally. After changing UTI stewardship guidelines, there was increased, though not statistically significant, nitrofurantoin use, but there was no increase in E. coli resistance to nitrofurantoin. This finding is encouraging and contrasts with previous experiences at Denver Health with TMP-SMX and levofloxacin.
Within this single-center case-control analysis, the risk factor most associated with E. coli resistance to nitrofurantoin was concomitant resistance to levofloxacin. We observed nonsignificant trends toward nitrofurantoin resistance in the presence of diabetes, with the use of nitrofurantoin in the previous 12 months, and with surgery in the previous 12 months. There were no significant associations with other suspected risk factors for nitrofurantoin resistance.
Even when E. coli isolates acquire nitrofurantoin resistance, there appears to be less risk of developing resistance to other antimicrobial classes compared to levofloxacin-resistant isolates. One hypothesis for this occurrence is the mechanism of resistance to levofloxacin via efflux pumps; E. coli spp have been known to overexpress the acrAB efflux pump in times of stress.Reference Webber and Piddock8, Reference Sulavik, Houseweart and Cramer9 Another proposed mechanism for nitrofurantoin-resistant isolates having less resistance with other antimicrobials is due to decreased nitrofurantoin delivery to the large intestine; there is less “collateral damage” with endogenous flora exposure to nitrofurantoin.Reference Paterson10 Additionally, nitrofurantoin’s multimodal mechanism of action is thought to be protective in limiting resistance.
In terms of study limitations, the quality of the data was reliant upon the documentation available in the electronic health record and ICD-9 coding. During the study period, clinical documentation was hand written and scanned into an electronic health record, making legibility of documentation challenging. Additionally, direct causation of the risk factors identified for nitrofurantoin resistance could not be inferred from these results based upon the retrospective nature of this study. Lastly, the small sample size from a single institution for a single diagnosis limits the generalizability of the findings.
Further study should assess how frontline providers access antimicrobial stewardship guidelines and how often they adhere to guidelines. Additional research should assess risk factors for nitrofurantoin resistance among a larger cohort of patients to increase the generalizability of the results and limit the risk of type II error.
This study demonstrates that in changing antimicrobial stewardship guidelines to recommend nitrofurantoin for the treatment of uncomplicated UTIs, there is less risk of developing antimicrobial resistance locally. These findings support the use of narrower-spectrum agents in antimicrobial stewardship programs.
Author ORCIDs
Patrick Ryan, 0000-0002-9702-5823
Acknowledgments
We are grateful to Dr Raymond Estacio, MD, for his valuable feedback and critiques in the preparation of this manuscript.
Financial support
No financial support was provided relevant to this article.
Conflicts of interest
All authors report no conflicts of interest relevant to this article.
