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Antimicrobial Agents and Chemotherapy, November 1999, p. 2607-2611, Vol. 43, No. 11
Department of Microbiology, Centre
Hospitalier Universitaire Saint-Antoine, Assistance
Publique-Hôpitaux de Paris, Université Paris VI, Paris 12, France,1 and Department of Microbiology,
University of Louvain, Brussels, Belgium2
Received 7 December 1998/Returned for modification 24 March
1999/Accepted 18 August 1999
Glycopeptides (vancomycin and teicoplanin) and metronidazole are
the drugs of choice for the treatment of Clostridium
difficile infections, but trends in susceptibility patterns have
not been assessed in the past few years. The objective was to study the MICs of glycopeptides and metronidazole for unrelated C. difficile strains isolated in 1991 (n = 100) and
in 1997 (n = 98) by the agar macrodilution, the
E-test, and the disk diffusion methods. Strain susceptibilities to
erythromycin, clindamycin, tetracycline, rifampin, and chloramphenicol
were also determined by the ATB ANA gallery (bioMérieux, La
Balme-les-Grottes, France). The MICs at which 50% of isolates are
inhibited (MIC50s) and MIC90s of glycopeptides
and metronidazole remained stable between 1991 and 1997. All the
strains were inhibited by concentrations that did not exceed 2 µg/ml
for vancomycin and 1 µg/ml for teicoplanin. Comparison of MICs
determined by the agar dilution method recommended by the National
Committee for Clinical Laboratory Standards and the E test showed
correlations (±2 dilutions) of 86.6, 95.9, and 99% for metronidazole,
vancomycin, and teicoplanin, respectively. The E test always
underestimated the MICs. Strains with decreased susceptibility to
metronidazole (MICs, Clostridium difficile is
an anaerobic, gram-positive rod. Toxigenic strains are responsible for
20 to 25% of cases of antibiotic-associated diarrhea and for virtually
all cases of pseudomembranous colitis (4, 17, 20, 30).
C. difficile is the most common agent of nosocomial diarrhea
in adults from industrialized countries (22). Since 1980, outbreaks of C. difficile diarrhea have increasingly been
reported among hospitalized patients (2, 9, 11, 15, 28).
Currently, the drugs most commonly used to treat diseases caused by
C. difficile are metronidazole and vancomycin, both of which
should be given orally for a full 10-day course. Clinical trials
indicated that these two antibiotics are equivalent for the treatment
of mild disease (29, 31, 32). Other glycopeptides such as
teicoplanin have been shown to have efficacies equivalent to that of
vancomycin (12).
In vitro determination of C. difficile susceptibility to
these antibiotics is not routinely performed in France. The reasons are
that the method is time-consuming and that the use of susceptibility breakpoints based on the levels of therapeutic drugs in serum are not
relevant for itraluminal infections, in which higher drug concentrations can be achieved. Thus, resistance patterns of C. difficile still remain imprecise. Studies from the mid-1980s have shown that this bacterium is highly susceptible to metronidazole (MICs,
0.06 to 2 µg/ml), vancomycin (MICs, 0.125 to 4 µg/ml), and
teicoplanin (MICs, 0.03 to 2 µg/ml); but antimicrobial susceptibility trends have not been assessed in the past few years (5, 16, 18,
25). One very recent report from Spain described a dramatic increase in the number of strains with decreased susceptibility to
metronidazole in 1998 and the emergence of strains with decreased susceptibility to vancomycin (27). The aims of the present
study were (i) to compare the MICs of metronidazole and glycopeptides for strains isolated in 1991 and 1997 by the agar macrodilution method
and the E test; (ii) to determine trends in patterns of susceptibility
to other drugs such as erythromycin, clindamycin, tetracycline,
rifampin, and chloramphenicol; and (iii) to establish correlations
between the resistance patterns of C. difficile strains and serogroups.
Patients and strains.
One hundred ninety-eight C. difficile strains isolated in 1991 (n = 100) and
1997 (n = 98) from hospitalized adults suspected of
having C. difficile diarrhea or colitis were studied.
Strains were epidemiologically unrelated and nonrepetitive. They were isolated on TCCA medium (brain heart agar supplemented with 5% defibrinated horse blood, 0.1% taurocholate, 250 µg of cycloserine per ml, 10 µg of cefoxitin per ml). The plates were incubated for
48 h in an anaerobic atmosphere. Suspicious colonies (on the basis
of morphology, Gram smear results, and odor) were identified by using
RapID 32A galleries (bioMérieux, La Balme-les-Grottes, France).
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Copyright © 1999, American Society for Microbiology. All rights reserved.
Antimicrobial Susceptibilities and Serogroups of
Clinical Strains of Clostridium difficile Isolated in France
in 1991 and 1997
ABSTRACT
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
8 µg/ml) were isolated from six patients
(n = 4 in 1991 and n = 2 in 1997).
These strains were also detected by the disk diffusion method (zone
inhibition diameter, 
21 mm); they belonged to nontoxigenic serogroup
D (n = 5) and toxigenic serogroup H
(n = 1). Decreased susceptibility to erythromycin
(MICs, 1 µg/ml), clindamycin (MICs, 2 µg/ml), tetracycline
(MICs, 8 µg/ml), rifampin (MICs, 4 µg/ml), and chloramphenicol
(MICs, 16 µg/ml) was observed in 64.2, 80.3, 23.7, 22.7, and 14.6%
of strains, respectively. Strains isolated in 1997 were more
susceptible than those isolated in 1991, and this trend was correlated
to a major change in serogroup distribution. Periodic studies are
needed in order to detect changes in serogroups and the emergence of
strains with decreased susceptibility to therapeutic drugs.
INTRODUCTION
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
MIC determination by agar dilution method. MICs were determined by the agar dilution method described by the National Committee for Clinical Laboratory Standards (23) with a Steers replicator. Serial twofold dilutions of teicoplanin (Merrell Dow, Neuilly-sur-Seine, France), vancomycin (Lilly, Saint-Cloud, France), and metronidazole (Specia, Rhône-Poulenc Rorer, Paris, France) were incorporated into Wilkins-Chalgren agar (Oxoid, Dardilly, France), with antibiotic concentrations ranging from 0.016 to 32 µg/ml. Inocula were prepared from brain heart infusion broth (Diagnostics Pasteur, Marnes-la-Coquette, France) in which the organisms were grown at 37°C for 24 h. Cultures were adjusted to an optical density on the McFarland scale of 0.5, and 10 µl (105 CFU/spot) was applied with a Steers replicator to prereduced Wilkins-Chalgren agar. Assays were performed at least in duplicate for each strain. The plates were observed after 48 h of incubation in anaerobic jars (HP11; Oxoid, Dardilly, France) at 37°C. The MIC was defined as the lowest concentration of each antibiotic that inhibited visible growth.
MIC determination with E-test strips. A C. difficile suspension (no. 1 McFarland standard) was swabbed in three directions on prereduced Wilkins-Chalgren agar and was then dried for 15 min on the bench. Strips of vancomycin, teicoplanin, and metronidazole (BMD, Marne-la-Vallée, France) were applied onto the agar surface, and the plates were incubated in an anaerobic atmosphere for 24 h. MICs were read at the point at which the zone of complete inhibition intersects the MIC scale.
Disk diffusion method. Colonies of C. difficile were suspended in sterile saline buffer (no. 1 McFarland standard) and were swabbed on prereduced Wilkins-Chalgren agar. Standard disks of vancomycin (30 µg), teicoplanin (30 µg), and metronidazole (4 µg [Sanofi Diagnostics Pasteur, Marnes la Coquette, France] and 16 µg [Rosco, Taastrup, Denmark]) were used. The plates were incubated for 24 h in anaerobic jars.
ATB ANA susceptibility test. The ATB ANA strips (bioMérieux, Marcy l'Etoile, France) permit determination of the susceptibility of anaerobic bacteria to antibiotics in a semisolid medium under conditions similar to those used for the agar dilution method. A suspension of no. 3 McFarland standard was prepared by homogenizing without shaking C. difficile colonies in 0.85% saline buffer, and 200 µl was transferred into an ampoule of ATB-S medium; 135 µl was then distributed into each cupule of the strip containing dehydrated antimicrobial agents. The strips were incubated for 24 h at 37°C in an anaerobic atmosphere. The turbidimetries of the cupules were observed by visual reading, and interpretation was performed according to the manufacturer's recommendations. The breakpoints to be used for interpretation of the results were as follows: 1 to 4 µg/ml for erythromycin, 2 µg/ml for clindamycin, 8 µg/ml for tetracycline, 4 to 16 µg/ml for rifampin, and 16 µg/ml for chloramphenicol.
Serotyping. Serotyping of the C. difficile strains was performed by the method of Delmée et al. (14). Eleven antisera specific for serogroups A1, A5, A8, A9, A10, C, D, F, G, H, and K were used in an enzyme-linked immunosorbent assay format, as described previously (14).
Toxigenicity. The presence of C. difficile toxin B was determined by demonstrating a specific cytopathic effect on MRC-5 cells, as described previously (1).
Statistical methods. The significance of differences in susceptibility patterns or serogroup distribution was analyzed by the chi-square test or Fisher's exact two-tailed test with EpiInfo 6.0 software (Centers for Disease Control and Prevention, Atlanta, Ga.). A P value of <0.05 was considered statistically significant.
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RESULTS |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Distribution of serogroups. Among the 198 strains, only 21.7% were nontypeable with the 11 antisera that we used. Serogroups A, C, D, G, H, and K accounted for 9, 22, 8, 4, 19, and 14% of strains, respectively. The distribution of serogroups showed wide variations between 1991 and 1997 (Fig. 1). Indeed, strains from serogroup C were largely predominant in 1991 compared to their proportion in 1997 (36 versus 6%; P < 0.01).
|
) and 1997 (
). NT, not typeable.
Susceptibility to glycopeptides and metronidazole.
All the
strains were inhibited by concentrations that did not exceed 2 µg/ml
for vancomycin and 1 µg/ml for teicoplanin, with MICs distributed
over a narrow range (Table 1). There was
no significant change in the MICs at which 50% of strains are
inhibited (MIC50s) and the MIC90s of the
glycopeptides between 1991 and 1997.
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21 and 30 mm with Diagnostic Pasteur tablets
and Rosco tablets, respectively). The zone inhibition diameters for
these strains were clearly different from those for susceptible strains
(Fig. 2). Only one susceptible strain had
a zone inhibition diameter of 21 mm (Pasteur tablets), but the MIC for
this strain was 4 µg/ml.
|
|
1.5 µg/ml, as determined by the E test, and the strains were distinguishable from the fully susceptible strains (MICs, 0.5
µg/ml).
|
Correlation between serogroups and antimicrobial
susceptibility.
Decreased susceptibilities to erythromycin (MICs,
1 µg/ml), clindamycin (MICs, 2 µg/ml), tetracycline (MICs, 8
µg/ml), rifampin (MICs, 4 µg/ml), and chloramphenicol (MICs, 16
µg/ml) were observed for 64.2, 80.3, 23.7, 22.7, and 14.6% of the
strains respectively. Strains isolated in 1997 showed a pattern of
greater susceptibility than those isolated in 1991 (Table
4).
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16 µg/ml belonged
almost exclusively to serogroup C. Strains of serogroup G exhibited the
pattern of the greatest susceptibility. Decreased susceptibility to
tetracycline (MICs, 8 µg/ml) was common in serogroups C and K
(Table 5). Fifty percent of serogroup C
strains were characterized by a multiple-drug resistance pattern, with
resistance to erythromycin, rifampin, tetracycline, and
chloramphenicol, and this pattern was observed only among strains of
this serogroup.
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DISCUSSION |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Among the 198 strains studied, strains of serogroups C, H, K, and A were predominant. These data are consistent with those from a previous report (1). Nevertheless, the percentage of serogroup C strains was higher in 1991 than in 1997. This observation cannot be explained by outbreaks of C. difficile-associated diarrhea since patients have been hospitalized in different wards and different hospitals and strains were selected to be epidemiologically unrelated. We can hypothesize that the high rate of C. difficile from serogroup C observed in 1991 is biased by the high proportion of strains isolated from human immunodeficiency virus-positive patients treated with clindamycin for cerebral toxoplasmosis. This antimicrobial agent has previously been shown to select for strains of serogroup C which are usually resistant to clindamycin (3, 13). In 1997, since the introduction of protease inhibitors, the incidence of opportunistic infections such as cerebral toxoplasmosis among human immunodeficiency virus-positive patients declined, as has the level of use of clindamycin (26).
Our results show that there was no significant change in the MIC50s and MIC90s of glycopeptides between 1991 and 1997. All the strains were inhibited by concentrations that did not exceed 2 µg/ml for vancomycin and 1 µg/ml for teicoplanin, with the MICs distributed over a narrow range. In fact, in agreement with previous findings (5, 6, 18, 25), the MICs of teicoplanin ranged from 0.12 to 1 µg/ml, generally being two or four times lower than those of vancomycin, which ranged from 0.12 to 2 µg/ml. We did not confirm the recent data from a Spanish survey that found that 10% of clinical strains of C. difficile had decreased susceptibility to vancomycin (27).
Six C. difficile strains (3%) exhibited decreased
susceptibility to metronidazole, with the MICs for the strains ranging
from 8 to 32 µg/ml. The frequency of occurrence of these strains
remained stable from 1991 (4%) to 1997 (2%). These results are
concordant with the rate of 3% usually reported. Nevertheless, two
recent studies suggested the increasing emergence of strains with
decreased susceptibility to metronidazole; these strains represented
20% of equine isolates of C. difficile (19) and
14% of clinical strains isolated in Spain in 1998 (versus 6% in 1993)
(27). The clinical impact of these strains needs to be
further evaluated. Indeed, the MICs for these strains might be above
the concentrations of 3.3 µg/g (wet weight of feces) usually found in
feces of patients who ingested 500 mg of metronidazole twice a day
(8). In the present study, the clinical impact of such
strains seems to be limited since five of six strains belonged to
serogroup D, which is never toxigenic and which is thus never
implicated in diarrhea or colitis. Nevertheless, these findings
highlight the need for periodic surveys of the antimicrobial
susceptibilities of C. difficile strains. The disk diffusion
method seems to be a reliable method for detection of strains with
decreased susceptibility to metronidazole since all the strains
exhibited zone inhibition diameters of 21 and 30 mm with Pasteur
tablets and Rosco tablets, respectively.
We found a good correlation (±2 dilutions) between the E test and the agar dilution method, although the E test always underestimated the MICs. The E test was performed according to the recommendations of Bolmström (7), who showed that results obtained with a suspension of a no. 1 McFarland standard and a reading after 24 h of incubation best matched those obtained by the standard agar dilution procedure. The good correlation between the E test and the agar dilution method for anaerobic bacteria has previously been demonstrated by Citron et al. (10), Bolmström (7), and Wüst and Hardegger (33) for various combinations of antimicrobial agents and bacteria. This is the first large-scale report of a correlation for C. difficile with glycopeptides and metronidazole.
Decreased susceptibility to erythromycin, clindamycin, tetracycline, rifampin, and chloramphenicol was observed in 64.2, 80.3, 23.7, 22.7, and 14.6% of the strains, respectively. These findings suggest a pattern of greater resistance compared to those found in others studies (13, 21, 24) except for that for chloramphenicol. Indeed, antimicrobial susceptibility depends on the different methodologies and breakpoints used and may fluctuate from one medical center to another as well as from one geographic region to another.
We tried to correlate susceptibility to erythromycin, clindamycin, tetracycline, rifampin, and chloramphenicol to serogroups from an epidemiological point of view. In vitro resistance to chloramphenicol was almost exclusively observed among strains of serogroup C. Resistance to tetracycline was common in strains of serogroups C and K. Serogroup C was characterized by a typical multiple-drug resistance pattern and was the only serogroup resistant to both chloramphenicol and tetracycline or rifampin. All these data are consistent with those reported by Delmée and Avesani (13), who studied 308 strains of C. difficile from different origins in 1988. The high prevalence of serogroup C in 1991 can account for the antimicrobial resistance patterns that we observed.
In conclusion, the MIC50s and MIC90s of glycopeptides and metronidazole remained stable between 1991 and 1997, and these antimicrobial agents still remain the drugs of choice for the treatment of C. difficile infections. Results obtained by the agar dilution method and the E test showed a good correlation, although the E test always underestimated the MICs. Three percent of strains, most of which belonged to nontoxigenic serogroup D, exhibited decreased susceptibility to metronidazole, but the clinical impact of such strains seems to be limited. These strains were easily detected by the disk diffusion method. Strains isolated in 1997 were more susceptible to erythromycin, clindamycin, tetracycline, rifampin, and chloramphenicol than those isolated in 1991 because of a major change in serogroup distribution. Periodic studies are needed in order to detect changes in serogroups and the emergence of strains resistant to therapeutic drugs.
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ACKNOWLEDGMENTS |
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This work was supported by grants from INSERM (grant PARMIFR 9609) and from the UPRES Research Group on Clostridium difficile.
We thank M. Gomis and D. LeCunff for technical assistance.
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FOOTNOTES |
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* Corresponding author. Mailing address: Service de Bactériologie-Virologie, Hôpital Saint-Antoine, 184, rue du Faubourg Saint-Antoine, 75 571 Paris Cedex 12, France. Phone: 33 (1) 49 28 29 10. Fax: 33 (1) 49 28 24 72. E-mail: frederic.barbut{at}sat.ap-hop-paris.fr.
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Abstract
Introduction
Materials and Methods
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Discussion
References
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Antimicrobial Agents and Chemotherapy, November 1999, p. 2607-2611, Vol. 43, No. 11
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Copyright © 1999, American Society for Microbiology. All rights reserved.
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