0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Brief Report |

Increasing Prevalence of Antimicrobial Resistance Among Uropathogens Causing Acute Uncomplicated Cystitis in Women FREE

Kalpana Gupta, MD, MPH; Delia Scholes, PhD; Walter E. Stamm, MD
[+] Author Affiliations

Author Affiliations: Department of Medicine/Division of Allergy and Infectious Diseases, University of Washington School of Medicine (Drs Gupta and Stamm), and the Center for Health Studies, Group Health Cooperative of Puget Sound (Dr Scholes), Seattle.


JAMA. 1999;281(8):736-738. doi:10.1001/jama.281.8.736.
Text Size: A A A
Published online

Context Guidelines for the management of acute uncomplicated cystitis in women that recommend empirical therapy in properly selected patients rely on the predictability of the agents causing cystitis and knowledge of their antimicrobial susceptibility patterns.

Objective To assess the prevalence of and trends in antimicrobial resistance among uropathogens causing well-defined episodes of acute uncomplicated cystitis in a large population of women.

Design Cross-sectional survey of antimicrobial susceptibilities of urine isolates collected during a 5-year period (January, May, and September 1992-1996).

Setting Health maintenance organization.

Patients Women aged 18 to 50 years with an outpatient diagnosis of acute cystitis.

Main Outcome Measures Proportion of uropathogens demonstrating in vitro resistance to selected antimicrobials; trends in resistance over the 5-year study period.

Results Escherichia coli and Staphylococcus saprophyticus were the most common uropathogens, accounting for 90% of the 4342 urine isolates studied. The prevalence of resistance among E coli and all isolates combined was more than 20% for ampicillin, cephalothin, and sulfamethoxazole in each year studied. The prevalence of resistance to trimethoprim and trimethoprim-sulfamethoxazole rose from more than 9% in 1992 to more than 18% in 1996 among E coli, and from 8% to 16% among all isolates combined. There was a statistically significant increasing linear trend in the prevalence of resistance from 1992 to 1996 amongE coli and all isolates combined to ampicillin (P<.002), and to cephalothin, trimethoprim, and trimethoprim-sulfamethoxazole (P<.001). In contrast, the prevalence of resistance to nitrofurantoin, gentamicin, and ciprofloxacin hydrochloride was 0% to 2% among E coli and less than 10% among all isolates combined, and did not change significantly during the 5-year period.

Conclusions While the prevalence of resistance to trimethoprim-sulfamethoxazole, ampicillin, and cephalothin increased significantly among uropathogens causing acute cystitis, resistance to nitrofurantoin and ciprofloxacin remained infrequent. These in vitro susceptibility patterns should be considered along with other factors, such as efficacy, cost, and cost-effectiveness in selecting empirical therapy for acute uncomplicated cystitis in women.

The management of acute uncomplicated cystitis, one of the most common community-acquired infections in women, has dramatically changed in the managed care era.1 In many clinical settings, urine cultures are no longer performed and women with symptoms of acute cystitis are treated empirically.14 The rationale for this strategy is based on the narrow spectrum of etiologic agents causing acute cystitis and knowledge of their antimicrobial resistance patterns. To date, however, most studies reporting antimicrobial resistance have been based on surveys of laboratory isolates, generally without correlation with clinical or epidemiological factors such as the presence and nature of symptoms, age, sex, and whether the infection was complicated. Data from such laboratory-based studies do not provide the information needed to select empirical therapy for women with uncomplicated urinary tract infections (UTIs). To address this issue, we determined the prevalence of and trends in antimicrobial resistance among uropathogens isolated from a large and well-defined population of female health maintenance organization (HMO) enrollees who presented with acute uncomplicated cystitis.

Computerized outpatient visit forms from women aged 18 to 50 years seen at the outpatient linics or emergency departments of the Group Health Cooperative of Puget Sound (GHC), Seattle, Wash, that were coded with an International Classification of Diseases, Ninth Revision (ICD-9) diagnosis of acute cystitis were crossmatched by patient identification number with a computer database of urine isolates and antimicrobial susceptibility test results. To be included, a urine culture had to be positive for at least 103 colony-forming units per milliliter (CFUs/mL) of a single uropathogen within 2 days before or after an outpatient visit that resulted in an ICD-9 diagnosis of acute cystitis. To obtain the final desired sample size, as well as seasonal representation, isolates from January, May, and September of each year from 1992 through 1996 were included. Isolates from women with a previous episode of acute cystitis in the same month, hospitalization in the 30 days preceding or subsequent to the visit date, or diabetes were excluded.

We randomly selected 150 medical charts for review to validate the accuracy of the visit diagnosis and laboratory data. Because a clinical practice guideline for empirical therapy of acute uncomplicated cystitis, using trimethoprim-sulfamethoxazole as the primary drug, was instituted at GHC in 1995 and 1996, we selected 100 charts from these years to assess whether cultures obtained then included more women for whom empirical therapy had failed.

Cultures and antimicrobial susceptibility tests were performed on clean-catch midstream urine specimens collected at the outpatient clinics, transported to a central laboratory at GHC, and quantitatively cultured using a standard calibrated loop technique.5 Susceptibility testing was done using the Kirby-Bauer disk diffusion method.6 Resistant and intermediate isolates were grouped together for analysis in this study.

Because not all organisms are tested for susceptibility to each antimicrobial agent, we calculated the proportion of resistant organisms based on the number of organisms actually tested for each antimicrobial agent each year. Significance tests for trends in resistance over time were performed using the χ2 test for linear trend in binomial proportions.7

A total of 4342 urine isolates from 4082 patients who made clinic visits for acute cystitis were included in the study. Review of 142 charts (8 of the 150 randomly selected charts were not available) confirmed that more than 95% of the visits were for uncomplicated cystitis; clinical evidence of pyelonephritis or recurrent cystitis was found in 4.9% of reviewed charts. Only 2 of 100 charts from 1995 and 1996 revealed a recent guideline treatment failure, confirming that more than 95% of cultures obtained in the study represented episodes of acute uncomplicated cystitis. The etiologic uropathogen identified in the laboratory database was confirmed in 100% of the chart reviews.

The causative uropathogens included Escherichia coli (86%), Staphylococcus saprophyticus (4%), Proteus species (3%), Klebsiella species (3%), Enterobacter species (1.4%), Citrobacter species (0.8%), and Enterococcus species (0.5%). Other less-frequent isolates in aggregate caused 1.3% of infections. There were no significant changes in the distribution of uropathogens seen during the 5-year study.

More than 20% of E coli isolates were resistant to ampicillin, cephalothin, and sulfamethoxazole in each year studied (Table 1). On the other hand, only 0% to 2% of E coli isolates and less than 10% of all isolates combined were resistant to ciprofloxacin hydrochloride, gentamicin, or nitrofurantoin in any study year. Resistance of E coli to trimethoprim and trimethoprim-sulfamethoxazole was essentially parallel throughout the study years and rose from 9% in 1992 to 18% in 1996. The resistance patterns of all isolates combined were similar to those of E coli alone, except for ampicillin and nitrofurantoin, for which there was a higher prevalence of resistance when combining all isolates. The increasing linear trend in the prevalence of resistance among both E coli and all isolates from 1992 through 1996 was statistically significant for ampicillin, cephalothin, trimethoprim, and trimethoprim-sulfamethoxazole (Table 1). The overall prevalence of antimicrobial resistance among the individual non–E coli species is shown in Table 2.

Table Graphic Jump LocationTable 1. Percentages of Urinary Isolates From Women With Acute Uncomplicated Cystitis Resistant to Selected Antimicrobial Agents*
Table Graphic Jump LocationTable 2. Percentage of Non–Escherichia coli Isolates From Women With Acute Uncomplicated Cystitis Resistant to Selected Antimicrobial Agents, 1992-1996*

We used the automated databases available at GHC to define a large population of women with acute uncomplicated cystitis and link each patient visit with the microbiological data of interest. The accuracy of this approach was confirmed by medical record review, which demonstrated greater than 95% concordance between the computer-generated and manual review, and by the consistency of both etiologic agents and susceptibility profiles from year to year.

Although several factors influence the choice of an antimicrobial agent for empirical therapy of acute cystitis, the in vitro susceptibilities of common uropathogens clearly are an important consideration. The high prevalence of resistance to the 2 β-lactams we studied, ampicillin and cephalothin, has long been appreciated813 and precludes their use in empirical treatment. Of considerably greater concern is the increasing prevalence of resistance to trimethoprim and trimethoprim-sulfamethoxazole that we observed. Similar trends have also been reported among urinary isolates from women attending outpatient clinics whose more detailed clinical status was unknown.8,9 These data suggest that trimethoprim and trimethoprim-sulfamethoxazole, which are now commonly used as first-line regimens in the treatment of acute cystitis,3,14 may not be acceptable choices for empirical therapy for much longer. Although the effect of in vitro resistance to trimethoprim-sulfamethoxazole on clinical outcome needs further study, in our view, neither trimethoprim nor trimethoprim-sulfamethoxazole should be used empirically when the prevalence of resistance among cystitis isolates exceeds 15% to 20%.

The 2 oral agents with the best in vitro susceptibility profiles in our study (and, thus, candidates for empirical therapy if trimethoprim-sulfamethoxazole cannot be used) were nitrofurantoin and ciprofloxacin. Nitrofurantoin remains highly active against E coli and most non–E coli isolates and is a reasonable option for empirical therapy. However, cure rates with 3-day regimens of nitrofurantoin have been lower than those seen with trimethoprim-sulfamethoxazole or fluoroquinolones,15 so 7 days of therapy may be required to achieve higher cure rates. Ciprofloxacin, which we tested as a representative of the fluoroquinolone class of antimicrobials, remains highly active against both E coli and non–E coli isolates in vitro. Although other studies have reported increasing fluoroquinolone resistance among E coli,12,13 we did not identify any such isolates in this patient group. For this reason, as well as the high clinical cure rate and cost-effectiveness of short-course fluoroquinolone regimens in treating acute cystitis,3,15 these drugs will likely be used more frequently as trimethoprim-sulfamethoxazole resistance becomes increasingly prevalent. Of obvious concern is the likelihood that increased use of fluoroquinolones for the treatment of acute cystitis in women will promote the emergence of resistance to these drugs.

In conclusion, these data demonstrate a significant increase in the prevalence of resistance to several commonly used antimicrobial agents among a large group of isolates from women with well-defined episodes of acute uncomplicated cystitis. When selecting empirical therapy for such patients, in vitro susceptibility patterns of common uropathogens such as those reported here must be considered along with other factors, such as expected efficacy, adverse effects, cost, cost-effectiveness, and selection of resistant strains. The continued evolution of antimicrobial resistance among community-acquired isolates is worrisome and mandates both further surveillance and new approaches to slow the emergence of resistance.

Hooton TM, Stamm WE. Diagnosis and treatment of acute uncomplicated urinary tract infection.  Infect Dis Clin North Am.1997;11:551-581.
Patton JP, Nash DB, Abrutyn E. Urinary tract infection.  Med Clin North Am.1991;75:495-512.
Stamm WE, Hooton TM. Management of urinary tract infections in adults.  N Engl J Med.1993;329:1328-1334.
Bacheller CD, Bernstein JM. Urinary tract infections.  Med Clin North Am.1997;81:719-730.
Koneman EW, Allen SD, Janda WM.  et al.  Color Atlas and Textbook of Diagnostic Microbiology4th ed. Philadelphia, Pa: JB Lippincott Co; 1992:77-83.
Bauer AW, Kirby WMM, Sherris JC, Turck M. Antibiotic susceptibility testing by a standardized single disk method.  Am J Clin Pathol.1966;45:493-496.
Rosner B. Fundamentals of Biostatistics4th ed. Belmont, Calif: Wadsworth Publishing Co; 1995:397-398.
Gruneberg RN. Changes in urinary pathogens and their antibiotic sensitivities, 1971-1992.  J Antimicrob Chemother.1994;33(suppl):S1-S8.
Maartens G, Oliver SP. Antibiotic resistance in community-acquired urinary tract infections.  S Afr Med J.1994;84:600-602.
Weber G, Riesenberg K, Schlaeffer F, Peled N, Borer A, Yagupsky P. Changing trends in frequency and antimicrobial resistance of urinary pathogens in outpatient clinics and a hospital in southern Israel, 1991-1995.  Eur J Clin Microbiol Infect Dis.1997;16:834-838.
Jinnah F, Islam MS, Rumi MA, Morshed MG, Huq F. Drug sensitivity pattern of E. coli causing urinary tract infection in diabetic and non-diabetic patients.  J Int Med Res.1996;24:296-301.
Thomson KS, Sanders WE, Sanders CC. USA resistance patterns among UTI pathogens.  J Antimicrob Chemother.1994;33(suppl):S9-S15.
Winstanley TG, Limb DI, Eggington R, Hancock F. A 10 year survey of the antimicrobial susceptibility of urinary tract isolates in the UK: the Microbe Base Project.  J Antimicrob Chemother.1997;40:591-594.
Kunin CM. Urinary tract infections in females.  Clin Infect Dis.1994;18:1-12.
Hooton TM, Winter C, Tiu F, Stamm WE. Randomized comparative trial and cost analysis of 3-day antimicrobial regimens for treatment of acute cystitis in women.  JAMA.1995;273:41-45.

Figures

Tables

Table Graphic Jump LocationTable 1. Percentages of Urinary Isolates From Women With Acute Uncomplicated Cystitis Resistant to Selected Antimicrobial Agents*
Table Graphic Jump LocationTable 2. Percentage of Non–Escherichia coli Isolates From Women With Acute Uncomplicated Cystitis Resistant to Selected Antimicrobial Agents, 1992-1996*

References

Hooton TM, Stamm WE. Diagnosis and treatment of acute uncomplicated urinary tract infection.  Infect Dis Clin North Am.1997;11:551-581.
Patton JP, Nash DB, Abrutyn E. Urinary tract infection.  Med Clin North Am.1991;75:495-512.
Stamm WE, Hooton TM. Management of urinary tract infections in adults.  N Engl J Med.1993;329:1328-1334.
Bacheller CD, Bernstein JM. Urinary tract infections.  Med Clin North Am.1997;81:719-730.
Koneman EW, Allen SD, Janda WM.  et al.  Color Atlas and Textbook of Diagnostic Microbiology4th ed. Philadelphia, Pa: JB Lippincott Co; 1992:77-83.
Bauer AW, Kirby WMM, Sherris JC, Turck M. Antibiotic susceptibility testing by a standardized single disk method.  Am J Clin Pathol.1966;45:493-496.
Rosner B. Fundamentals of Biostatistics4th ed. Belmont, Calif: Wadsworth Publishing Co; 1995:397-398.
Gruneberg RN. Changes in urinary pathogens and their antibiotic sensitivities, 1971-1992.  J Antimicrob Chemother.1994;33(suppl):S1-S8.
Maartens G, Oliver SP. Antibiotic resistance in community-acquired urinary tract infections.  S Afr Med J.1994;84:600-602.
Weber G, Riesenberg K, Schlaeffer F, Peled N, Borer A, Yagupsky P. Changing trends in frequency and antimicrobial resistance of urinary pathogens in outpatient clinics and a hospital in southern Israel, 1991-1995.  Eur J Clin Microbiol Infect Dis.1997;16:834-838.
Jinnah F, Islam MS, Rumi MA, Morshed MG, Huq F. Drug sensitivity pattern of E. coli causing urinary tract infection in diabetic and non-diabetic patients.  J Int Med Res.1996;24:296-301.
Thomson KS, Sanders WE, Sanders CC. USA resistance patterns among UTI pathogens.  J Antimicrob Chemother.1994;33(suppl):S9-S15.
Winstanley TG, Limb DI, Eggington R, Hancock F. A 10 year survey of the antimicrobial susceptibility of urinary tract isolates in the UK: the Microbe Base Project.  J Antimicrob Chemother.1997;40:591-594.
Kunin CM. Urinary tract infections in females.  Clin Infect Dis.1994;18:1-12.
Hooton TM, Winter C, Tiu F, Stamm WE. Randomized comparative trial and cost analysis of 3-day antimicrobial regimens for treatment of acute cystitis in women.  JAMA.1995;273:41-45.

Letters

CME
Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles