Abstract
Ciprofloxacin-resistant Escherichia coli isolates (n = 1,858) from outpatient midstream urine specimens at 40 North American clinical laboratories in 2004 to 2005 were frequently resistant to ampicillin (79.8% of isolates) and trimethoprim-sulfamethoxazole (66.5%); concurrent resistance to cefdinir (9.0%) or nitrofurantoin (4.0%) was less common. Only 10.8% of isolates were resistant to ciprofloxacin alone. Fluoroquinolone-resistant isolates of E. coli from urine were frequently multidrug resistant.
The most recently published in vitro surveillance data from centers across the United States and Canada indicate that approximately 10 to 25% of urinary tract isolates of Escherichia coli from female outpatients are resistant to trimethoprim-sulfamethoxazole (SXT) (3, 7, 10, 11, 12, 21, 22, 25, 26). Culture selection and sample selection biases inherent in published urinary isolate surveillance studies and hospital antibiograms have been summarized previously (8). Resistance to SXT may complicate the management of urinary tract infections (20), and physician concern regarding resistance to SXT (24) has resulted in fluoroquinolones and nitrofurantoin being more frequently prescribed as empirical therapy for cystitis (7, 9, 15).
Currently, the majority of urinary isolates of E. coli and most other uropathogens causing uncomplicated cystitis and pyelonephritis in the United States and Canada remain susceptible to fluoroquinolones (5, 10, 11, 12, 21, 22, 25, 26); however, the prevalence of fluoroquinolone-resistant isolates of E. coli has been reported to be increasing over time in some centers in the United States and Canada (3, 7, 11, 12, 13, 18, 23, 25), and resistance rates have been shown to vary markedly by center, with some hospital laboratories reporting >25% of their E. coli isolates as fluoroquinolone resistant (3, 23). Given that a transition in the therapy for outpatient urinary tract infections may be occurring, or appears imminent (7, 8, 9, 15), and that fluoroquinolone-resistant isolates of E. coli are not uncommon in some centers, we determined the in vitro susceptibilities of prospectively collected fluoroquinolone-resistant midstream urine isolates of E. coli from outpatients to other agents used for the treatment of acute cystitis because these isolates may be encountered by clinicians and no prospective study specifically studying fluoroquinolone-resistant isolates has been published.
From January 2004 to June 2005, fluoroquinolone-resistant E. coli isolates from midstream urine specimens from outpatients were collected from 30 medical centers in the United States (n = 1,483) and from 10 Canadian medical centers (n = 375) (25). Each isolate was deemed to be a significant urinary tract isolate by each participating laboratory's urine culture algorithm. Isolates and limited demographic information (patient gender and age) were submitted to the Health Sciences Centre in Winnipeg, Canada, where the isolates were confirmed to be E. coli by conventional methodology (17) and where Clinical and Laboratory Standards Institute-specified broth microdilution testing was performed with ampicillin, cefdinir, ciprofloxacin, ertapenem, nitrofurantoin, and SXT (2, 16). Of the 1,858 isolates tested, 1,440 (77.5%) were from females, 30 (1.6%) were from patients <15 years of age, 470 (25.3%) were from patients 15 to 50 years of age, and 1,358 (73.1%) were from patients >50 years of age. Statistical analyses were performed by χ2 testing with Epi Info Statcalc, version 6.0 (Centers for Disease Control and Prevention); P values of <0.05 were reported as statistically significant.
The MICs at which 50% of isolates were inhibited (MIC50s), MIC90s, MIC ranges, and overall rates of resistance for the 1,858 ciprofloxacin-resistant E. coli isolates are provided in Table 1. Of the orally available agents tested, ampicillin (79.8%) and SXT (66.5%) demonstrated the highest rates of resistance; resistance to nitrofurantoin (4.0%) and cefdinir (9.0%) was less frequent. All isolates were susceptible to ertapenem, a parenteral carbapenem.
TABLE 1.
Rates of resistance to ampicillin, cefdinir, ertapenem, nitrofurantoin, and SXT in a 2004 to 2005 collection of 1,858 outpatient midstream urine isolates of E. coli resistant to ciprofloxacin
| Isolate class (no. of isolates) | Agent | MIC (μg/ml)
|
% of isolates:
|
||||
|---|---|---|---|---|---|---|---|
| 50% | 90% | Range | Susceptible | Intermediate | Resistant | ||
| All isolates (1,858) | Ampicillin | 256 | ≥2,048 | ≤0.5-≥2,048 | 19.1 | 1.1 | 79.8 |
| Cefdinir | 0.5 | 2 | ≤0.06->32 | 88.7 | 2.3 | 9.0 | |
| Ertapenem | ≤0.015 | 0.03 | ≤0.015-1 | 100 | |||
| Nitrofurantoin | 8 | 64 | ≤2-1,024 | 90.0 | 6.0 | 4.0 | |
| SXT | 256 | ≥1,024 | ≤0.25-≥1,024 | 33.5 | 66.5 | ||
| Isolates with ciprofloxacin MICs | Ampicillin | 256 | ≥2,048 | ≤0.5-≥2,048 | 26.0 | 1.0 | 73.0 |
| of 4-16 μg/ml (411) | Cefdinir | 0.25 | 1 | ≤0.06->32 | 96.1 | 0.7 | 3.2 |
| Ertapenem | ≤0.015 | ≤0.015 | ≤0.015-0.12 | 100 | 0 | 0 | |
| Nitrofurantoin | 8 | 32 | ≤2-1,024 | 91.7 | 3.9 | 4.4 | |
| SXT | 256 | ≥1,024 | ≤0.25-≥1,024 | 31.6 | 68.4 | ||
| Isolates with ciprofloxacin MICs | Ampicillin | 256 | ≥2,048 | ≤0.5-≥2,048 | 18.9 | 0.9 | 80.2 |
| of 32-64 μg/ml (1,126) | Cefdinir | 0.5 | 2 | ≤0.06->32 | 91.0 | 7.0 | 2.0 |
| Ertapenem | ≤0.015 | 0.03 | ≤0.015-1 | 100 | 0 | 0 | |
| Nitrofurantoin | 16 | 64 | ≤2->1,024 | 92.2 | 5.1 | 2.7 | |
| SXT | 256 | ≥1,024 | ≤0.25-≥1,024 | 33.4 | 66.6 | ||
| Isolates with ciprofloxacin MICs | Ampicillin | 512 | ≥2,048 | 2-≥2,048 | 10.0 | 2.5 | 87.5 |
| of ≥128 μg/ml (321) | Cefdinir | 1 | >32 | 0.12->32 | 71.0 | 5.9 | 23.1 |
| Ertapenem | ≤0.015 | 0.12 | ≤0.015-1 | 100 | 0 | 0 | |
| Nitrofurantoin | 16 | 64 | ≤2->1,024 | 79.1 | 12.8 | 8.1 | |
| SXT | 256 | ≥1,024 | ≤0.25-≥1,024 | 34.6 | 65.4 | ||
Approximately 78% of isolates (n = 1,447) had ciprofloxacin MICs of ≥32 μg/ml, with 17% of isolates (n = 321) having ciprofloxacin MICs of ≥128 μg/ml. When isolates were placed into three groups based upon ciprofloxacin MICs (4 to 16, 32 to 64, and ≥128 μg/ml), increasing rates of resistance to ampicillin (from 73.0 to 80.2 to 87.5%) (P < 0.01), cefdinir (from 3.2 to 2.0 to 23.1%) (P < 0.01), and nitrofurantoin (from 4.4 to 2.7 to 8.1%) (P < 0.01) were observed; the rates of resistance to SXT were similar (68.4, 66.6, and 65.4%, respectively) (P > 0.05) regardless of ciprofloxacin MIC (Table 1). Although no isolates resistant to ertapenem were identified, the ertapenem MIC90 increased from ≤0.015 μg/ml to 0.12 μg/ml for isolates with ciprofloxacin MICs of 4 to 16 and 32 to 64 μg/ml compared to isolates with ciprofloxacin MICs of ≥128 μg/ml.
When isolates were grouped by patient age into three groups (<15, 15 to 50, and >50 years), the percentages of isolates with ciprofloxacin MICs of 4 to 16, 32 to 64, and ≥128 μg/ml were similar (P > 0.05) for each age group (<15 years, 2.2, 1.7, and 0.6%; 15 to 50 years, 25.1, 25.8, and 24.0%; >50 years, 72.7, 72.6, and 75.4%) (data not shown). When isolates were grouped by patient gender, the ratios of males to females were similar (P > 0.05) for those isolates with ciprofloxacin MICs of 4 to 16 μg/ml (males, 19.8%; females, 80.2%) and 32 to 64 μg/ml (males, 21.8%; females, 78.2%), but in comparison with those ratios ciprofloxacin MICs of ≥128 μg/ml were more commonly associatedwith males and less commonly with females (males, 29.8%; females, 70.2%) (P < 0.01) (data not shown).
Table 2 depicts the numbers of ciprofloxacin-resistant isolates that were susceptible to all other agents tested (10.8% of isolates) or concurrently resistant to one (27.3%), two (54.1%), three (7.4%), or four (0.4%) other oral antimicrobial agents and the relative contributions of each agent to multidrug-resistant phenotypes. Approximately 90% of isolates resistant to ciprofloxacin were also resistant to at least one or two additional agents, most commonly ampicillin and SXT. Resistance to cefdinir and nitrofurantoin was most common in ciprofloxacin-resistant isolates already resistant to ampicillin and SXT. The ciprofloxacin MIC50s, MIC90s, and MIC ranges for each of the five groups in Table 2 (resistance to ciprofloxacin and zero, one, two, three, and four additional agents) were 32, 64, and 4 to ≥128 μg/ml; 32, 128, and 4 to ≥128 μg/ml; 32, 128, and 4 to ≥128 μg/ml; 64, ≥128, and 4 to ≥128 μg/ml; and 128, 128, and 16 to 128 μg/ml, respectively (data not shown).
TABLE 2.
Resistance to one or more additional oral antimicrobial agents in a 2004 to 2005 collection of 1,858 outpatient midstream urine isolates of E. coli resistant to ciprofloxacin
| No. of additional agents to which resistance showna | Total % (no.) of isolates | % (no.) of isolates resistant to:
|
|||
|---|---|---|---|---|---|
| Ampicillin | Cefdinir | Nitrofurantoin | SXT | ||
| 0 | 10.8 (200) | ||||
| 1 | 27.3 (507) | 66.7 (338) | 0 | 2.7 (14) | 30.6 (155) |
| 2 | 54.1 (1,005) | 99.5 (1,000) | 5.6 (56) | 1.1 (11) | 93.8 (943) |
| 3 | 7.4 (138) | 100 (138) | 73.9 (102) | 29.0 (40) | 97.1 (134) |
| 4 | 0.4 (8) | 100 (8) | 100 (8) | 100 (8) | 100 (8) |
61.9% (1,151/1,858) of isolates were resistant to ciprofloxacin and two or more additional oral antimicrobial agents.
Previously published retrospective studies have demonstrated that a ciprofloxacin-resistant phenotype without concurrent resistance to other classes of antimicrobials, including ampicillin, SXT, and nitrofurantoin, was uncommon among outpatient isolates of E. coli (4, 10, 11, 12, 21, 22, 26), that by pulsed-field gel electrophoresis analysis fluoroquinolone-resistant E. coli isolates were genomically diverse (4), and that associations between fluoroquinolone resistance and other resistance determinants such as extended-spectrum β-lactamases (14, 19) may be emerging. The majority of ciprofloxacin-resistant isolates in the present study (73.1%) were isolated from patients aged >50 years. This observation was not unexpected given that fluoroquinolones are more commonly prescribed to older patients (>50 years of age) than younger patients (15, 21). The present study and previously published reports both suggest that fluoroquinolone resistance typically arises in isolates of E. coli already harboring ampicillin and/or SXT resistance determinants. The clonal expansion of multidrug-resistant isolates may be furthered by exposure to any single agent for which resistance exists. Currently, it is unknown if the selection of fluoroquinolone-resistant mutants of E. coli is more frequent for multidrug-resistant isolates than for pansusceptible isolates.
In conclusion, in vitro resistance to fluoroquinolones appears to be increasing in some hospitals and regions and is associated with multidrug-resistant phenotypes. Close attention is required to monitor fluoroquinolone susceptibility patterns and the association of multidrug resistance with fluoroquinolone resistance in isolates of E. coli and other bacteria causing urinary tract infections and other infections. The broad-spectrum activity and convenience of use of fluoroquinolones are well recognized; however, increased prescription of fluoroquinolones as first-line therapy for common infections such as cystitis will facilitate the emergence of resistance to this class of compounds and promote the emergence of multidrug-resistant strains and, therefore, should be discouraged as it will undermine the efficacy of fluoroquinolones to treat more-serious infections (1, 6, 7, 8, 15). Fluoroquinolone-sparing agents should be given higher priority than fluoroquinolones in the treatment of cystitis (8). Continued surveillance of urinary tract isolates of E. coli and other pathogens is important, and appropriate clinical use of fluoroquinolones is imperative as they become more widely prescribed (9). SXT remains first-line empirical therapy for female outpatients with acute uncomplicated bacterial cystitis (8, 24).
Acknowledgments
We thank the investigators and laboratory site staff at each medical center that participated in the North American Urinary Tract Infection Collaborative Alliance-Quinolone Resistance study. The medical centers (investigators) in the United States were as follows: Stanford Hospital and Clinics, Stanford, CA (E. J. Baron); Geisinger Medical Center, Danville, PA (P. Bourbeau); University of California, San Francisco, CA (G. Brooks); UCLA Medical Center, Los Angeles, CA (D. Bruckner and J. Hindler); Johns Hopkins Hospital, Baltimore, MD (K. Carroll); Creighton University Medical Center/St. Joseph's Hospital, Omaha, NB (S. Cavalieri); University of Tennessee Medical Center/Dynacare Tennessee, Knoxville, TN (M. Cole); ARUP Laboratories Inc., Salt Lake City, UT (A. Croft); Columbia Presbyterian Medical Center, New York, NY (P. Della-Latta); Summa Health System, Akron, OH (J. Di Persio); University of Rochester Medical Center/Strong Memorial Hospital, Rochester, NY (D. Hardy); Memorial Hospital of Rhode Island, Pawtucket, RI (J. Heelan); Iowa Methodist Medical Center, Des Moines, IA (A. Herring); Medical College of Wisconsin/Froedtert Memorial Lutheran Hospital, Milwaukee, WI (S. Kehl); University of North Carolina Hospitals, Chapel Hill, NC (M. Miller); University of Kentucky Hospital, Lexington, KY (S. Overman); Shands Hospital/University of Florida, Gainesville, FL (K. Rand); Mount Sinai Medical Center, New York, NY (I. Rankin); Audie Murphy VA Hospital, San Antonio, TX (M. Rinaldi); Laboratory Sciences of Arizona, Tempe, AZ (M. Saubolle); University of Illinois Medical Center at Chicago, Chicago, IL (P. Schreckenberger); Dartmouth-Hitchcock Medical Center, Lebanon, NH (J. Schwartzman); University of Texas Medical Branch, Galveston, TX (M. Smith); New Hanover Regional Medical Center, Wilmington, NC (G. Steinkraus); Barnes-Jewish Hospital, St. Louis, MO (J. Vetter); University of Alabama at Birmingham, Birmingham, AL (K. Waites); Emory University School of Medicine/Grady Memorial Hospital, Atlanta, GA (Y. Wang); Fletcher Allen Health Care, Burlington, VT (W. Washington Jr.); Denver Health Medical Center, Denver, CO (M. Wilson); and St. Luke's Hospital, Jacksonville, FL (J. Yao). The medical centers (investigators) in Canada were as follows: Royal University Hospital, Saskatoon, SK (J. Blondeau); Queen Elizabeth II Health Sciences Centre, Halifax, NS (R. Davidson); Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC (J. Dubois); Health Sciences Centre/St. Boniface General Hospital, Winnipeg, MB (D. Hoban); Victoria General Hospital, Victoria, BC (P. Kibsey); South East Health Care Corp., Moncton, NB (M. Kuhn); Hôpital Maisonneuve-Rosemont, Montreal, QC (M. Laverdière); Mount Sinai Hospital, Toronto, ON (D. Low); University of Alberta Hospitals, Edmonton, AB (R. Rennie); and Ottawa General Hospital, Ottawa, ON (K. Ramotar).
The study was financially supported in part by Procter & Gamble (Cincinnati, OH).
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