Microbial Ecology in Health and Disease. 2005; 17: 69 /74
ORIGINAL ARTICLE
Fluoroquinolone-resistant Escherichia coli isolated from healthy broilers with previous exposure to fluoroquinolones: Is there a link?
REZVAN MONIRI1 & KAMRAN DASTEHGOLI2 1
Department of Microbiology and Immunology, Kashan University of Medical Sciences and Health Services, 2Kashan Veterinary Network, Kashan, Iran
Abstract The occurrence of resistance to quinolones and fluoroquinolones in Escherichia coli isolated from healthy chickens and its relation to previous use of fluoroquinolones in Kashan, Iran, was evaluated. A total of 181 E. coli isolates was collected. Ninety-five (52.5%) of the chickens had a history of previous use of both flumequine and enrofloxacin; 86 (47.5%) chickens had not been exposed to antimicrobial agents previously. The proportion of strains resistant to nalidixic acid and ciprofloxacin was 100% and 41.9%, respectively. The differences between ciprofloxacin resistance rates in strains from chickens with previous expose to fluoroquinolones compared with isolates from chickens without a history of drug use was significant (49.5% vs 33.7%, p / 0.0461). It seems that use of fluoroquinolones constitutes a major selective pressure for resistance. The results of this survey indicate very high levels of resistance to fluoroquinolones in E. coli from poultry production in Iran, and suggest that this reservoir of resistance may affect the therapeutic potential of fluoroquinolones in human and veterinary medicine.
Key words: Fluoroquinolones, Escherichia coli, healthy broilers, antimicrobial resistance
Introduction Escherichia coli is a major pathogen of worldwide importance in commercially produced poultry, contributing significantly to enormous economic loss in chickens (1). E. coli is one of the most frequently encountered bacterial species of animal and human commensal intestinal flora (2). This organism is used as an indicator species to monitor faecal contamination of drinking water and foods (1,3), and as an indicator of recent surveillance programmes to monitor the occurrence of antimicrobial resistance in the enteric microflora of both humans and farm animals (3). In addition, E. coli is the primary cause of urinary tract infections in humans (2) and is the most frequent nosocomial and community-acquired pathogen in all regions (4). Resistance to fluoroquinolones develops more rapidly in E. coli than in other members of the Enterobacteriaceae (5). Bacterial resistance to antimicrobials was first discovered in the 1940s, following the introduction of penicillin. However, more types of bacteria have
demonstrated resistance, at an increasingly swift rate, to newer and more powerful antimicrobials (6,7). In fact, some common strains of pathogenic bacteria show antimicrobial resistance in as many as 50/90% of isolates (7). Medical care costs associated with treating infections in humans due to antimicrobial-resistant microorganisms are estimated to be over $4 billion annually in the USA (7). Antimicrobial agents have been used on farms for almost half a century to treat and prevent diseases in animals (8). They are also used extensively in subtherapeutic doses to promote growth and increase body weight by improving feed utilization. In many countries, more antimicrobial agents are used on a tonnage basis in animals than in humans (9). It is estimated that 50% of all antimicrobials produced in the USA are administered to animals, mostly for subtherapeutic usage. The Union of Concerned Scientists recently estimated that, each year, 24.6 million lb (11.2 million kg) of antimicrobials are given to animals for non-therapeutic purposes and 2 million lb (900 000 kg) are given
Correspondence: Rezvan Moniri DVM, PhD, Department of Microbiology and Immunology, Kashan University of Medical Sciences and Health Services, PO Box 87155.111, Kashan 87154, Iran. Fax: /98 (361) 55 588 83. E-mail:
[email protected]
(Received 14 July 2004; accepted 7 April 2005) ISSN 0891-060X print/ISSN 1651-2235 online # 2005 Taylor & Francis DOI: 10.1080/08910600510038009
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for therapy; in contrast, 3 million lb (1.3 million kg) are given to humans (8,10). According to a survey from The Netherlands, enrofloxacin accounts for 14% of all veterinary antimicrobial use in poultry and the prevalence of fluoroquinolone resistance in faecal E. coli from poultry is 50% (11). Selective pressure caused by using these large quantities of antimicrobials occurs in hospitals, the community and farm and aquaculture settings as a factor (in addition to mutation and transformation phenomena) that leads to emergence of antimicrobial resistance (12), and enhances persistence of resistance in the environment (8). There is concern that resistant bacteria from food animals may transfer to humans either by direct contact or by consumption of contaminated foods (13). Thus, emergence and dissemination of resistant bacteria is an inevitable side effect of uncritical use of antimicrobials (14). When antimicrobials are constantly added to feeds at a subtherapeutic or therapeutic level, microorganisms develop resistance. Furthermore, the use of antimicrobials speeds up the spread of genes that encode resistance to them (15). After the introduction of a new antimicrobial not only the resistance rate of pathogenic bacteria, but also of commensal bacteria increases. Commensal bacteria constitute a reservoir of resistance genes for (potential) pathogenic bacteria. Their level of resistance is considered to be a good indicator of selection pressure by antimicrobial use and of resistance problems to be expected in pathogens (8,14). Resistant commensal bacteria of food animals, including zoonotic bacteria, might contaminate meat and its products and thereby enter the intestinal tracts of human beings (8,14,16). Animal wastes including manures may contain high levels of bacteria with antimicrobial resistance, and are dispersed into the soil and water where we grow our crops and can eventually leach into our groundwater, lakes and rivers, and cause further contamination of our drinking water, fish and environment (15). Resistant organisms may be present in or on animals as a result of previous drug use and can contaminate the carcass during slaughter or processing. When these resistant bacteria cause illness in a person, the medical therapy may be compromised due to difficulties in treatment (10). Fluoroquinolones belong to an important class of antimicrobials against infections caused by gramnegative bacteria with excellent activities against E. coli (1,2) and were approved for treatment of colibacillosis in poultry in 1995 (17,18). Although their use in poultry may be inappropriate, as a result of cross-resistance, resistance to one fluoroquinolone compound can compromise the effectiveness of
other fluoroquinolones in the treatment of important human enteric infections (1). The use of antimicrobials in food animals has been a human health concern for many years. As early as in 1969, the emergence of resistant bacteria in domestic animals led the Swann Committee (19) to recommend that antimicrobials that were of value for treatment of humans should not be approved for growth promotion in food animals. These guidelines have since been implemented in most European countries. However, the guidelines did not take into account antimicrobials that were of little or no significance in human medicine at the time when they were approved for growth promotion in food animals. Because of the emergence of multiply resistant bacteria causing infections in humans, some of these classes of antimicrobials have become important last resort drugs in the treatment of such infections (20). The aim of the present study is to describe the current susceptibility to fluoroquinolones of E. coli isolated from broilers in Iran and to determine the possible relationship between previous use of quinolones/fluoroquinolones in broilers and emergence of resistance to ciprofloxacin. Materials and methods The study included 181 E. coli strains isolated from 190 healthy broilers (only one isolate per bird was included and the number of collected samples was proportional to the number of broilers in the farm, i.e. one sample per 1000 broilers in the flock), of which 95 (52.5%) originated from broilers that previously had been exposed to both the quinolone (flumequine), and the fluoroquinolone (enrofloxacin) for treatment, and 86 (47.5%) originated from broilers that had no history of antimicrobial use (controls). The strains were collected from seven commercial poultry farms in Kashan, province of Isfahan, Iran, in 2001. In this study we determined the susceptibility of isolates to the following antimicrobials: amikacin (30 mg), ampicillin (10 mg), chloramphenicol (30 mg), ciprofloxacin (5 mg), doxycycline (30 mg), erythromycin (15 mg), gentamicin (10 mg), nalidixic acid (30 mg), nitrofurantoin (300 mg), tobramycin (10 mg) and trimethoprimsulfamethoxazole (SXT, 25 mg). Amikacin, nalidixic acid and tobramycin have not been licensed for use in food production animals at all, while prescription and use of chloramphenicol, ciprofloxacin and nitrofurantoin have been banned in Iran. Flumequine (quinolone) and enrofloxacin and difloxacin (fluoroquinolones) have been approved for use in veterinary practice in Iran. Identification of E. coli was based on Gram staining, indole, methyl red, VP, citrate (IMViC),
Fluoroquinolone-resistant E. coli isolated from healthy broilers oxidase and b-glucuronidase test results. The antimicrobial susceptibility testing was performed with all isolates by the disk diffusion method in MullerHinton agar with disks provided by Difco and BioMerieux according to standards developed by the National Committee for Clinical Laboratory Standards (NCCLS) guidelines (21). Nine controls were excluded from the study due to incomplete and doubtful history. The statistical procedures were: Fischer’s exact test and chi-square with Yates corrected. We considered differences significant at p B/0.05. The ethical committee of the Kashan University of Medical Sciences approved the study. Results The resistance rates for each antimicrobial agent included are given in Table I. The proportion of E. coli resistant to ciprofloxacin is shown in Table II. From the total of 76 ciprofloxacin-resistant E. coli , 47 isolates (49.5%) originated from farms that had been using both flumequine and enrofloxacin previously, versus 29 isolates (33.7%) from farms without any history of antimicrobial use. Of the antimicrobials included, the highest rates of resistance were found for nalidixic acid (181 strains resistant, 100%), followed by amikacin, doxycycline and SXT (128 strains resistant, 70.7%). The lowest rates of resistance were found for tobramicin (11 strains resistant, 6.1%) and gentamicin (13 strains resistant, 7.2%), while 76 strains (41.9%) were resistant to ciprofloxacin. E. coli strains isolated from broilers that previously had received both flumequine and enrofloxacin as treatment were significantly more resistant to ciprofloxacin than those isolated from broilers that had not been exposed to any antimicrobials (p / 0.0461).
Table I. The proportion of E. coli from healthy broilers in Iran resistant to various antimicrobial agents. Antibacterials (mg per disk) Ampicillin (10) Gentamicin (10) Tobramycin (10) Amikacin (30) Doxycycline (30) Erythromycin (15) Chloramphenicol (30) Nitrofurantoin (300) Trimethoprim-sulfamethoxazole (25) Ciprofloxacin (5) Nalidixic acid (30)
No. of resistant strains (%) 127 13 11 128 128 121 116 125 128 76 181
(66.8) (7.2) (6.1) (70.7) (70.7) (66.9) (64) (69.1) (70.7) (41.9) (100)
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Table II. Susceptibility to ciprofloxacin among E. coli from healthy broilers in Iran in relation to previous use of quinolones. Parameter
Resistant to ciprofloxacin Susceptible to ciprofloxacin Total
No drug Use of flumequine/ enrofloxacin n (%) used n (%)
Total n (%)
47 (49.5)
29 (33.7)
76 (41.9)
48 (50.5)
57 (66.3)
105 (58.1)
95 (52.5)
86 (47.5)
181 (100)
Discussion For many decades, the first line of defence against bacterial resistance has been the development of new antimicrobials. However, new classes of antimicrobials that can be used against resistant organisms are not likely to be available in the near future, and any new antimicrobials that are developed will have a short life if users do not adhere to prudent guidelines (22,23). There is an urgent need to implement strategies for prudent use of anitmicrobials in food animal production to prevent further increases in the occurrence of antimicrobial resistance in food-borne bacteria such as Campylobacter spp. and E. coli (24). The emergence of antimicrobial-resistant strains is a major therapeutic problem. The influence of excessive and/or inappropriate anitmicrobial use, particularly of broad-spectrum agents prescribed empirically, has been demonstrated. Reducing the number of prescriptions of a particular antimicrobial can lead to a decrease in resistant rates. Conversely, Ena et al. (25) observed an increase in the rate of ciprofloxacin resistance among E. coli strains from 3% to 20% concomitantly with a trebling in the rate of consumption of fluoroquinolones during the same period. Transmission of resistant isolates between people and/or by consumption of food from animals that had received anitmicrobials, and greater mobility of individuals all over the world, have also contributed to the spread of antimicrobial resistance (26). Our study indicates the existence of an association between resistance to ciprofloxacin and previous use of enrofloxacin and flumequine. A possible explanation for a large proportion of E. coli isolated with reduced susceptibility to fluoroquinolones could be the frequent exposure of broilers to these antimicrobials, due to their abundant use in commercial poultry farms and colonization by the resistant E. coli (2). In the present study all of the E. coli isolated from broilers (100%) were resistant to nalidixic acid (quinolone) and 49.5% were resistant to ciprofloxacin (fluoroquinolone). This could reflect the overuse of the fluoroquinolones for the prevention and/or
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treatment of infections, or the use of less active quinolones such as flumequine and also a fluroquinolone. The use of short-term treatment with fluoroquinolones, could also have been a contributory factor for selection of mutant isolates (5). Mutations at the target site appear to be the major mechanism for development of fluoroquinolone resistance in E. coli (2). It has been recommended that the use of quinolones should be reduced or at least rationalized, to save this potent class of antimicrobials and avoid the development of resistance among the Enterobacteriaceae (5). The high recovery rate of fluoroquinolone-resistant E. coli from broilers in Iran was troubling, but not surprising, given the routine application of the quinolone (flumequine) and the fluoroquinolones (enrofloxacin), at subtherapeutic doses for prophylactic and therapeutic purposes by farmers, without prescription and for treatment by veterinary prescription in absence of documented laboratory findings. In addition, the owners do not pay attention to excretion of drug during withdrawal time, and the important existence of antimicrobial residuals in meat and eggs that may lead to increased resistance patterns in microflora of humans, directly or indirectly, by zoonotic resistant bacteria (27). The World Health Organization (WHO) has recently sounded the alarm about the re-emergence of deadly diseases caused by antimicrobial-resistant bacteria (10). Thus support for antimicrobial surveillance programmes at local and national levels is suggested (5). Overuse and misuse of newer broadspectrum antibacterial agents has accelerated the problem (7,12). Misuse of antimicrobials in viral infections can contribute to the emergence of antimicrobial resistance in bacteria as well (28). Agricultural use of antimicrobials should be limited to short-term use under the care of licensed veterinarians unless the drug sponsor can show that the antimicrobial in question is not used in human medicine, is not medically related to such drugs, and does not select for multi-drug resistance in bacteria (29). Perhaps the most striking finding from this study was the widespread resistance to quinolones and fluoroquinolones. All E. coli isolates were resistant to nalidixic acid and /41% were resistant to ciprofloxacin. Without an advisable use of antimicrobials, we may be faced with a public health crisis and return to the pre-antimicrobial era (12). Somewhat similar findings have been reported in a recent study of clinical E. coli isolates from China, wherein /50% of all isolates were resistant to ciprofloxacin (30). Similar findings were also reported for E. coli isolates recovered from chickens
and swine in Spain, where 90% of chicken isolates and 50% of swine isolates were resistant to ciprofloxacin (31). But Kijima to Tanaka et al., in their study of 1018 E. coli isolated from food-producing animals in Japan, reported that 10% of broilers isolates were resistant to fluoroquinolones. They mentioned that antimicrobial resistance rates in E. coli have declined in recent years, with the exception of resistance to fluoroquinolones among broiler isolates, which has increased in their country (32). Ngeleka et al., in their study of 104 E. coli isolates collected from internal tissues and the cloacae of broilers with colibacillosis or from the cloacae of healthy birds in Canada, reported that /10% of isolates were resistant to most of the antimicrobials included. However, less resistance to enrofloxacin and norfloxacin was observed (33). Chu et al., in a study from Hong Kong reported an 85.9% prevalence of quinolone resistance in Campylobacter jejuni from 85 human and 13 chicken carcasses, and mentioned that replacement of the threonine-86 residue in the gyrase subunit A was the major resistance mechanism (34). Ciprofloxacinresistant Campylobacter was isolated from 10% of 180 broilers products in 1999 in the USA. Ciprofloxacin resistance has emerged among Campylobacter since 1990 and has increased in prevalence since 1997 (35). Fluoroquinolone resistance was detected in 12 of 370 (3.24%) Australian human Campylobacter isolates; 10 of these were travel-associated, and for 2 isolates travel status was unknown. No resistance was found in isolates known to be locally acquired. In Australia, fluoroquinolones have not been licensed for use in food-producing animals, a policy that may have relevance for countries with fluoroquinolone-resistant Campylobacter (36). The results of a study including 922 samples of the major meat species (pork, beef and poultry) to evaluate the resistance rate against antimicrobials of food isolates of the five major food-borne pathogens such as thermophilic Campylobacter , Salmonella , Yersinia enterocolitica , pathogenic E. coli and Listeria monocytogenes showed that resistance rates in enteric bacteria seem to be much higher than in pathogens found in a variety of environments (37). Campylobacter is today the most common cause of human bacterial enteritis in Sweden, as well as in most other industrialized countries. Only 7% of the human domestic strains and 2% of the chicken strains were resistant to the quinolones tested. As a comparison, /94% of strains isolated from travellers to Asia and southern Europe showed resistance to one or more antimicrobials (38). The molecular investigations into the underlying quinolone resistance mechanisms revealed that all quinolone-resistant isolates possessed the typical
Fluoroquinolone-resistant E. coli isolated from healthy broilers mutations in the topoisomerase genes, gyrA and parC , reported by other studies (39,40). Although quinolone resistance results mostly from chromosomal mutations, it may also be mediated by a plasmid-encoded qnr gene in members of the family Enterobacteriaceae (41). Other mechanisms of fluoroquinolone resistance exist besides mutations in the genes encoding DNA gyrase and topoisomerase IV. These include decreased production of porin proteins and up-regulation of multi-drug resistance efflux pumps (42). Systems to monitor antimicrobial resistance in pathogenic and commensal bacteria should cover relevant bacteria from the entire farm-to-fork chain and monitor resistance towards antimicrobial drugs used in both animals and humans, including growth promoters. Antimicrobial agents should not be used for growth promotion if they are used in human therapeutics or are known to select for crossresistance to antimicrobial drugs used in human medicine (43). Finally, until there is a better understanding of the precise forms of antimicrobial use and overuse most responsible for fluoroquinolone resistance in E. coli , it is recommended that the appropriateness and necessity of all quinolone use, including the use of fluorinated and non-fluorinated quinolones in humans and animals, be carefully reconsidered (2).
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Acknowledgements
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We gratefully acknowledge Kashan University of Medical Sciences and Health Services, (Kashan, Iran) for their financial support of this work. We thank Dr Mohsen Shafiee for his assistance with the preparation of the specimens, and Mr Gholam Abbas Mossavi for his assistance with the statistical analysis of data.
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