1 Antimicrobial Research Laboratory, National Public Health Institute, Turku; 2 Department of Medicine, Turku University Central Hospital, Turku; 3 Laboratory of Enteric Pathogens, National Public Health Institute, Helsinki, Finland
Received 16 July 2003; returned 15 August 2003; revised 25 September 2003; accepted 27 September 2003
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Abstract |
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Methods: During 19952000 we collected 376 C. jejuni strains, of which 354 were of foreign origin from multiple countries and 22 were of domestic origin. The MICs of 12 antimicrobial agents against the isolates were determined.
Results: Of the 376 strains, 174 (46%) were resistant to ciprofloxacin. Among other antimicrobials, resistance was most common to tetracycline (46%) and ampicillin (17%). Of the ciprofloxacin-resistant strains, 68% and 25%, respectively, were resistant to tetracycline and ampicillin, and 3% were resistant to erythromycin, gentamicin or clindamycin. One (0.6%) ciprofloxacin-resistant isolate was resistant to co-amoxiclav and none was resistant to imipenem. Resistance to three or more antimicrobial groups was detected in 22% of the isolates. Multidrug resistance was significantly associated with ciprofloxacin resistance (33% versus 12%; P < 0.01). Eight (2%) strains were resistant to macrolides, of which 75% were also resistant to ciprofloxacin, but none was resistant to co-amoxiclav or imipenem.
Conclusions: Macrolides still appear to be the first-choice alternative for suspected C. jejuni enteritis, if antimicrobial treatment is needed. The in vitro susceptibilities suggest that clinical trials to treat enteritis caused by multidrug-resistant C. jejuni with co-amoxiclav, and life-threatening infections with a carbapenem, may be valuable.
Keywords: drug resistance, fluoroquinolones, macrolides, diarrhoea
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Introduction |
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Materials and methods |
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A total of 376 clinical human faecal C. jejuni strains were isolated from Finnish patients (one isolate per patient). The strains were isolated in the laboratory of a large private hospital in Helsinki, Finland, over two distinct time periods between 1995 and 2000. Subjects were treated as outpatients and no data on antimicrobial usage prior to faecal sampling were available. Two hundred and sixteen consecutive strains were isolated between January 1995 and November 1997, and 160 between October 1998 and January 2000. The strains were identified by standard microbiological methods. The strains isolated from patients travelling abroad within 2 weeks preceding their symptoms were classified as foreign isolates, all other strains were classified as domestic isolates. The countries of origin for the foreign isolates have been described previously.1
The MICs of antibiotics for the isolates were determined by the agar plate dilution method. MuellerHinton II agar (BBL, Becton Dickinson and Company, Cockeysville, MD, USA) supplemented with 5% sheep blood was used as the culture medium. The plates were incubated at 35°C for 48 h in a microaerobic atmosphere (CampyPak; BBL). The antimicrobials evaluated were nalidixic acid, ciprofloxacin, erythromycin, azithromycin, clindamycin, ampicillin, co-amoxiclav, cefotaxime, imipenem, tetracycline, gentamicin and chloramphenicol. C. jejuni RH 3583 (a local control strain, originally isolated in Edinburgh, UK as C. jejuni 143483) was used as a control in susceptibility testing and also as a growth control strain.3 The MIC breakpoints used for resistance to ciprofloxacin, cefotaxime, imipenem, tetracycline, gentamicin and chloramphenicol were those recommended by the NCCLS for non-Enterobacteriaceae.4 For nalidixic acid, ampicillin and co-amoxiclav, which lack breakpoints for non-Enterobacteriaceae, we used those recommended by the NCCLS for Enterobacteriaceae.4 The resistance breakpoints for erythromycin, azithromycin and clindamycin were chosen on the basis of earlier publications and histogram analysis (Figure 1). They were 16 mg/L for erythromycin,5
4 mg/L for azithromycin2 and
8 mg/L for clindamycin.6 For the isolates exhibiting MICs
16 mg/L of erythromycin, we also determined MICs of clarithromycin and telithromycin. Multidrug resistance was defined as resistance to three or more antimicrobial groups. The antimicrobial groups were as follows: (i) quinolones (ciprofloxacin and nalidixic acid); (ii) macrolides (erythromycin and azithromycin) and clindamycin; (iii) tetracycline; (iv) ß-lactams; (v) gentamicin; and (vi) chloramphenicol.
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The susceptibility data were analysed using the WHONET5 computer program (available from www.who.int/emc/WHONET/WHONET.html).
Statistical analysis was made using the 2-test and the Fishers exact test. The statistical data were analysed using the SAS (v. 8.2) program.
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Results |
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Of all 376 isolates, 174 (46%) were resistant to ciprofloxacin (Table 1). Among the other antimicrobial groups studied, resistance was most common to tetracycline (46%) and ampicillin (17%). Only 2% of the isolates were resistant to erythromycin, azithromycin or clindamycin. Similarly, 2% were resistant to cefotaxime, but the proportion of intermediately cefotaxime-resistant isolates was 40%. Resistance to chloramphenicol was 3% and to gentamicin 2%. There was no resistance to imipenem, and only one (0.3%) isolate was resistant to co-amoxiclav (Table 1). The histograms illustrating the MICs are presented in Figure 1.
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Multidrug resistance was detected in 81 (22%) isolates. While 57 (33%) of the 174 ciprofloxacin-resistant isolates had three or more additional resistance properties, 24 (12%) of the 202 quinolone-susceptible isolates were resistant to three or more antimicrobial agents (P < 0.01). Cefotaxime was excluded from the multidrug-resistance profile analysis because of the high number of intermediately cefotaxime-resistant isolates.
All of the eight erythromycin-resistant C. jejuni isolates were multidrug resistant, six (75%) of them being resistant to ciprofloxacin. None was resistant to co-amoxiclav or imipenem. The five isolates for which the erythromycin MICs were between 16 and 32 mg/L had MICs of clarithromycin between 8 and 32 mg/L and of telithromycin between 4 and 32 mg/L. The three isolates for which the erythromycin MICs were >256 mg/L had MICs of clarithromycin 128 mg/L and of telithromycin between 16 and >128 mg/L.
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Discussion |
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In this study, C. jejuni resistance to ciprofloxacin was found to be significantly associated with resistance to three or more antimicrobial groups. Multidrug resistance is problematic, but a number of drugs are still effective against these fluoroquinolone-resistant and multidrug-resistant C. jejuni strains. Macrolides are currently the first-choice antimicrobials for the empirical treatment of suspected C. jejuni enteritis in many countries.2,7,8 Fortunately, macrolide resistance has so far remained relatively uncommon, with only 2% of all our isolates and 3% of the ciprofloxacin-resistant isolates classified as macrolide resistant. Thus, also in Finland, macrolides still appear to be the best alternative in suspected C. jejuni enteritis, if antimicrobial therapy is needed.
Higher macrolide resistance rates have been reported from some other countries. According to a recent survey, the rate of erythromycin resistance among C. jejuni was 17% in both Spain and Taiwan.7,8 In another study, the azithromycin resistance rate in Thailand was only 6%, but it was alarming that all azithromycin-resistant isolates were also fluoroquinolone resistant.9 A similar finding has been made by another group.2 In the present work, as many as 75% of the erythromycin-resistant isolates were ciprofloxacin resistant, and all erythromycin-resistant isolates were multidrug resistant. Based on in vitro results, no apparent benefits are afforded by the use of newer macrolides or ketolides in the treatment of erythromycin-resistant C. jejuni infections, since all isolates with elevated erythromycin MICs exhibited elevated MICs of clarithromycin and telithromycin. Among our entire C. jejuni collection, however, only one isolate was resistant to co-amoxiclav, and none was resistant to imipenem. These in vitro susceptibilities suggest that co-amoxiclav might be a candidate for clinical trials in enteritis caused by multidrug-resistant C. jejuni, and if the situation is life-threatening, a carbapenem may be the drug of choice. Nevertheless, it must be kept in mind that very few data exist on the clinical efficacy of co-amoxiclav or carbapenems,10 or of the other ß-lactams,11 for the treatment of C. jejuni infections.
In Finland, ciprofloxacin-resistant strains that had not existed in 1980 composed 9% of the strains isolated in 1990 and tested by Rautelin et al.5 In that study, no efforts were made to determine the origin of all ciprofloxacin-resistant C. jejuni isolates identified. Yet, the authors regarded it as plausible that the majority, if not all, of their resistant strains were derived from abroad. This assumption is consistent with our finding that ciprofloxacin resistance is still significantly more common among the foreign isolates than among those domestic in Finland, with only 9% of the domestic isolates resistant to ciprofloxacin. Despite the low rate of ciprofloxacin resistance among our domestic C. jejuni isolates, fluoroquinolones are of limited usefulness in the treatment of campylobacteriosis in Finland, since at least 80% of the clinical strains in our country are acquired abroad.5 This may be the reason for the discrepancy between the numbers of the foreign and domestic isolates included in the present study: when consecutive C. jejuni isolates are collected in one hospital, domestic isolates inevitably remain in the minority in Finland.
In conclusion, multidrug resistance was found to be significantly associated with resistance to ciprofloxacin. Macrolides still appear to be the first-choice alternative for suspected C. jejuni enteritis. The in vitro susceptibilities found suggest that co-amoxiclav might be a candidate for clinical trials in enteritis caused by multidrug-resistant C. jejuni, and if the situation is life-threatening, a carbapenem may be the drug of choice. The widespread emergence of multidrug resistance among C. jejuni is of great concern.
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Acknowledgements |
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Footnotes |
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References |
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