Emergence of Ciprofloxacin Resistance in Escherichia coli Isolates after Widespread Use of Fluoroquinolones

Emergence of Ciprofloxacin Resistance in Escherichia coli Isolates after Widespread Use of Fluoroquinolones Javier Ena, Marı´a del Mar Lo´pez-Perezagua, Carmen Martı´nez-Peinado, Marı´a de los Angeles Cia-Barrio, and Isabel Ruı´z-Lo´pez

The evolution (from 1990 to 1996) of fluoroquinolone consumption and resistance and the current patterns of fluoroquinolone usage were examined in a 250-bed community hospital in Spain. Fluoroquinolone consumption increased from 1392 g in 1990 to 3203 g in 1996 (p , 0.05). A significant increase in ciprofloxacin resistance was observed in Escherichia coli isolated from urine samples (from 3 to 20%, p , 0.00001), but not in those E. coli isolated from blood or other sample cultures. In 69 randomly selected clinical charts, fluo-

roquinolone was used as prophylaxis, empirical therapy, and specific directed therapy in 20%, 65%, and 15%, respectively. Evaluation of quinolone indication was: first choice agents (29%), alternative agents (49%), experimental agents (4.3%) and, agents with no role (1.4%). Our study shows that the increase in the use of fluoroquinolones is associated with the emergence of ciprofloxacin-resistant E. coli from urinary tract sources. Based on their indications, current quinolone usage can be greatly reduced. © 1998 Elsevier Science Inc.

INTRODUCTION

in patients with permanent urinary catheters (Blaise et al. 1994; Karp et al. 1987; Van der Wall et al. 1992). Although it has been stated that fluoroquinolones will retain wide therapeutic use and will remain effective in the setting of their current usage pattern (Fish et al. 1992), recent reports from Europe and USA show a progressive decrease in fluoroquinolone activity against clinical isolates (Garcı´a-Rodriguez et al. 1995; Kresken et al. 1994; Thomson et al. 1994). The first resistant strains were seen in Staphylococcus and Pseudomonas, microorganisms that are inherently less susceptible. However, resistance has been recently broadened to Escherichia coli and other Enterobacteriaceae. To determine the effect of fluoroquinolone usage over the susceptibility of E. coli to ciprofloxacin, we studied the evolution of fluoroquinolone use and ciprofloxacin resistance in E. coli isolates and the current patterns of fluoroquinolone usage.

Since their introduction in the late 1980s, there has been a tremendous explosion in the usage of fluoroquinolones as antimicrobial agents. Currently, ciprofloxacin has achieved astonishing popularity among physicians, making this drug the second most common antimicrobial prescribed in Spain and the fourth in USA (Anonimus 1990; Grupo de Trabajo 1995). Indication for use of fluoroquinolones has been expanded from therapy for well-documented or suspected infections caused by Gram-negative bacteria, to prophylaxis during neutropenia, liver cirrhosis, or From the Internal Medicine Division, Microbiology Division and Pharmacy Division, Hospital Marina Baixa, Villajoyosa, Alicante, Spain. Address reprint requests to Dr. Javier Ena, Servicio de Medicina Interna, Hospital Marina Baixa, Villajoyosa 03570, Alicante, Spain. Received 11 July 1997; accepted 21 October 1997.

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MATERIALS AND METHODS Hospital The Hospital Marina Baixa, Alicante, Spain, is a 250bed community institution that provides care for 110,000 inhabitants belonging to the National Health System in the eastern region of Spain (Servei Valencia` de Salut). The hospital has an average yearly admittance of 8000 patients. In our institution, two fluoroquinolones, norfloxacin and ciprofloxacin, were being used. Ciprofloxacin was included in the category of restricted antimicrobials since its introduction for therapy at our institution in 1990 (physicians prescribing ciprofloxacin were requested to complete a special order form for restricted antimicrobials). Use of quinolones is not restricted in primary care centers in the area.

Study Design Two different studies were performed. The first was a review of the fluoroquinolone rates of usage and the evolution of ciprofloxacin resistance in E. coli isolates from January 1990 to December 1996 (Trend Study). The second was a prospective study from June 1995 to December 1995 conducted to assess the characteristics of patients receiving fluoroquinolone and the indications for its usage (Usage Study).

Trend Study The amount of consumption (g) of fluoroquinolones was provided by the hospital’s Pharmacy Service. Data about the evolution of ciprofloxacin resistance among E. coli isolates were provided by the Microbiology Service. Replicative cultures were eliminated for resistance rate calculations. E. coli was identified and susceptibility tests were performed using standard techniques (Microscan, American Microscan, West Sacramento, CA). Susceptibility tests were interpreted as described by the National Committee for Clinical Laboratory Standards (NCCLS 1990). The MIC was recorded as the lowest concentration giving complete inhibition of growth. Isolates with ciprofloxacin MIC values $4 mg/mL were considered as resistant. Molecular typing of ciprofloxacin-resistant isolates was not carried out.

Usage Study From June to December 1995, we reviewed at random 50% from a total of 138 orders for fluoroquinolone usage (norfloxacin and ciprofloxacin) in hospitalized patients. Fluoroquinolone usage was classified as prophylaxis in the setting of patients with neutropenia, with liver cirrhosis, or with in-

dwelling catheters in the absence of signs or symptoms of infection. Empirical therapy was defined as administration of fluoroquinolone before or without information regarding culture results. After a bacterial pathogen was identified and antimicrobial susceptibilities were known, the use of fluoroquinolones was considered specific therapy. Fluoroquinolone usage was additionally categorized as first choice agent, alternative agent, experimental agent, or agent with little or no role (Hooper and Wolfson 1991).

Statistical Analysis The association between year and fluoroquinolone consumption (g) was examined by simple linear regression analysis (Spearman correlation coefficient). The evolution of ciprofloxacin resistance by clinical sample and year was tested using a x2 analysis for trends. Statistical analysis was performed with EpiInfo as the statistical package (Centers for Disease Control, Atlanta, GA). All reported p values are twotailed. P values less than 0.05 were considered as statistically significant.

RESULTS Trend Study Between 1990 and 1996, fluoroquinolone consumption increased at our institution from 1392 to 3203 g (p , 0.05) (Table 1). In the same period, resistance to ciprofloxacin in E. coli isolates from urine samples increased from 3 to 20% (p , 0.00001). Figures of urine samples sent for culture increased over time as more primary care centers were incorporated to the hospital area. Ciprofloxacin-resistant E. coli did not show any spatial or temporal distribution during the studied period. The proportion of ciprofloxacin resistance did not change over time in E. coli isolates from blood culture or from another clinical sample’s culture.

Usage Study Among 69 patients receiving fluoroquinolones, 49% of patients were aged 65 years or older and were hospitalized in internal medicine wards (49%), urology areas (28%), and other wards (26%). The indication for quinolone use in the 69 reviewed charts was classified as empirical in 65%, as specifically directed therapy in 15%, and as prophylaxis in 20%. Briefly, grams devoted to empirical therapy, specifically directed therapy, and prophylaxis were 150, 83, and 63, respectively. The assessment of indication (Table 2) showed that fluoroquinolone was used as first choice

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TABLE 1 Evolution of Fluoroquinolone Consumption and Resistance in E. coli Isolates from Clinical Samples Year 1990 a

Fluoroquinolone consumption (g) Sample culture Urine No. of isolates No. (%) of resistant isolatesb Blood No. of isolates No. (%) of resistant isolates Other sample No. of isolates No. (%) of resistant isolates a b

1991

1392

2280

1992 2475

1993 3325

1994 3273

1995 2852

1996 3203

295 9 (3)

317 56 (18)

381 47 (12)

455 52 (11)

459 99 (21)

554 113 (20)

791 159 (20)

27 0 (0)

24 2 (8)

35 3 (9)

34 4 (12)

22 1 (5)

28 1 (5)

30 4 (13)

70 10 (14)

96 1 (1)

71 6 (8)

61 7 (11)

78 7 (9)

119 17 (14)

141 12 (8)

Spearman correlation coefficient: 0.81; 95% confidence interval: 0.16–0.97, p , 0.05. x2 for trends: 44.1, p , 0.00001.

TABLE 2 Evaluation of Fluoroquinolone Usage Indication Noncomplicated UTI Complicated UTI Bacterial gastroenteritis Chronic bronchitis exacerbation Community-acquired pneumonia Tuberculosis MAI infection Osteomyelytis Skin and soft tissue infections Gram-negative bacteremia Pseudomonas bacteremia Staphylococcal bacteremia Prophylaxis in SBP Prophylaxis urology Lack of criteria of infection Total

First Choice Agent Alternative Agent Experimental Agent Agent with No Role No. (%) No. (%) No. (%) No. (%) 24 (35) 12 (17) 8 (11) 3 (4) 2 (3) 1 (1) 1 (1) 2 (3) 1 (1)

3 (4) 1 (1) 1 (1) 1 (1) 7 (10)

23 (33)

34 (50)

9 (13)

2 (3) 3 (4)

UTI, urinary tract infection; MAI, Mycobacterium avium-intracellulare; SBP, spontaneous bacterial peritonitis.

agent in 29% of patients. A high proportion, 49% of indications, was classified as alternative agents, where another more active, less toxic, or less expensive antimicrobial was indicated. In 4.3% patients, fluoroquinolones were used as experimental agents for therapy or prophylaxis of infections in the absence of enough data in the literature for such indication. Finally, in 1.4% of patients, fluoroquinolones were used as agents with no role.

DISCUSSION Our study shows the association of increasing fluoroquinolone usage with emergence of ciprofloxacinresistant E. coli in urinary isolates, from a baseline proportion of 3 to 20%. After evaluating the current

patterns of usage, we found that fluoroquinolones are mostly used in empirical therapies and against infections in which these antimicrobials are not considered first choice agents. Initially, the incidence of fluoroquinoloneresistant strains was reported to be extremely low (Dornbusch et al. 1990; Kresken et al. 1988). However, in the last 5 years, there has been several reports of emergence of resistance in patients with profound neutropenia or cirrhosis treated with fluoroquinolones as standard preventive strategy (Carratala´ et al. 1995; Duyperon et al. 1994; Kern et al. 1994). Nevertheless, the emergence of fluoroquinolone-resistant infections acquired in the community has been a recent fact. Such changes have a dramatic impact on the utility of these potent an-

106 timicrobials because there is virtual cross-resistance among all currently available quinolone members. The results of consumption found in our study illustrated that most of fluoroquinolone prescriptions in hospitalized patients were devoted for empirical therapies of noncomplicated urinary tract infections and for prophylaxis in urological manipulations. Results on the consumption and indications for fluoroquinolone use in the primary care centers of the area were not available in the studied period. However, it is anticipated that fluoroquinolone usage is greater in ambulatory settings, as has been demonstrated by other authors (Pen˜a et al. 1995), where initial empirical therapies are often started and cultures are not so often requested. The use of fluoroquinolones for empirical therapy of noncomplicated urinary tract infection is explained in our country by the fact that a great proportion of E. coli shows resistance to ampicillin and trimethoprimsulfamethoxazole (Alo´s et al. 1988). Therefore, fluoroquinolones are used in Spain as first line antimicrobials for community-acquired urinary tract infections. In a previous study (Ena et al. 1995), we found that prior treatment with fluoroquinolones, urinary tract abnormalities, patient age (65 years or older), and urinary catheterization were the independent risk factors for acquisition of urinary tract infections caused by ciprofloxacin-resistant E. coli. Urinary catheters and previous use of antimicrobials are well-known risk factors for colonization and infec-

J. Ena et al. tions caused by antibiotic-resistant microorganisms (Bjork et al. 1984; Gaynes et al. 1985). In our particular area, for patients with suspected ciprofloxacinresistant infections, alternative antimicrobials such as third generation cephalosporins and aztreonam might constitute good empirical options because they still maintain full activity against E. coli isolates. In regions with greater consumption of fluoroquinolones, there has been a significant increase not only in ciprofloxacin-resistant E. coli isolated from urine samples, but also from bloodstream infections (Pen˜a et al. 1995). Therefore, to maintain fully the effectiveness of fluoroquinolones, it will be necessary not only to limit the number of fluoroquinolones available in the formulary of hospitals, but also to implement restrictive and educational measures in both hospital and ambulatory settings. At the hospital level, these measures will likely have impact on the susceptibilities of bacteria causing nosocomial acquired infections, whereas in ambulatory settings, the impact will be observed in bacteria causing community-acquired infections. In summary, emergence of ciprofloxacin-resistant infections can be expected in areas with widespread use of fluoroquinolones. Restricting the use of fluoroquinolones in hospitals and ambulatory settings to those indications in which they are first choice antimicrobials can reduce dramatically their consumption.

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Ciprofloxacin-Resistant E. coli and Fluoroquinolone Usage

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