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Journal of Clinical Microbiology, November 1999, p. 3452-3457, Vol. 37, No. 11
Centre National de Référence des
Toxémies à Staphylocoques,
Received 7 May 1999/Returned for modification 6 July 1999/Accepted 29 July 1999
Oxacillin (methicillin) resistance in methicillin-resistant
Staphylococcus aureus (MRSA) is associated with an
increased incidence of resistance to other antibiotics, which has
increased since it was first reported in 1969. In 1992 a new
phenotype of MRSA arose in France; this was characterized by a
heterogeneous expression of resistance to oxacillin and susceptibility
to various antibiotics, including gentamicin but also tetracycline,
minocycline, lincomycin, pristinamycin, co-trimoxazole, rifampin, and
fusidic acid. In French hospitals a longitudinal nationwide
surveillance of antibiotic resistance in S. aureus has
allowed for the detection of changes in antibiotic susceptibility
profiles. Seven French clinical laboratories (six from the mainland and
one from the West Indies) reported the results of susceptibility
testing of 57,347 S. aureus strains isolated in their
institutes between 1992 and 1998. Over a 7-year period the incidence of
isolation of gentamicin-susceptible MRSA (GS-MRSA) strains has steadily
increased to represent, in 1998, 46.8 to 94.4% of the MRSA strains,
irrespective of the overall incidence of MRSA. Two predominant types
recognized by pulsed-field gel electrophoresis (PFGE) accounted for the
majority of the GS-MRSA in different mainland hospitals, both differing
from the predominant type observed in the French West Indies. Some
GS-MRSA and gentamicin-resistant MRSA (GR-MRSA) strains had closely
related PFGE profiles, and hybridization studies confirmed the lack in
GS-MRSA of the aac6'-aph2" gene, which confers resistance
to all aminoglycosides, with conservation of the ant4'
gene, which confers resistance to kanamycin, tobramycin, and amikacin.
Thus, it is likely that certain GS-MRSA strains could have emerged from
GR-MRSA strains by excision or deletion of the aac6'-aph2" gene.
In many countries oxacillin
(methicillin)-resistant Staphylococcus aureus (MRSA) has
become a significant nosocomial pathogen. MRSA was first reported in
the United Kingdom in 1961, soon after the introduction of methicillin,
and by the mid-1970s had become endemic in many countries
(26). Some strains of MRSA have been designated epidemic
strains; these are associated with a higher prevalence and have been
shown to have spread within hospitals, between hospitals, and between
countries (1, 10, 16, 17, 21). The first MRSA isolates
expressed so-called heterogeneous phenotypic resistance to oxacillin,
meaning that the oxacillin MICs for only subpopulations of isolates are
high. Progressively, the heterogeneous oxacillin-resistant phenotype
was replaced by the homogeneous oxacillin-resistant phenotype, which is
characterized by the expression of oxacillin resistance by all
populations. Initially, early isolates were also resistant to various
other drugs, including penicillin, tetracycline, and, usually,
streptomycin (some strains were also resistant to erythromycin,
lincomycin, neomycin, kanamycin, and novobiocin). In 1969, the first
clinical gentamicin-resistant MRSA (GR-MRSA) strain was isolated
(11), and by the 1980s GR-MRSA had become epidemic in
Australia, the United States, and Europe (5). Such GR-MRSA
strains were usually resistant to a broad number of other antibiotics,
including trimethoprim and, more recently, ciprofloxacin and mupirocin.
In addition to increasing multi-antibiotic drug resistance, the overall
incidence of MRSA isolation has gradually increased in many countries
to present levels of around 30% in Spain, France, and Italy
(26) and up to 54% in Japan (14). The emergence
of new epidemic MRSA strains more susceptible to antibiotics has been
recently reported by two French hospitals (2, 12). These
strains were characterized mainly by the unexpected reappearance of
heterogeneous resistance to oxacillin, susceptibility to gentamicin,
and variable resistance to macrolides, lincosamides, and streptogramin
type B antibiotics; they remained resistant to tobramycin, which was
associated with the presence of the aminoglycoside
nucleotidyltransferase ANT(4') (2, 12). A marked decrease in
the use of gentamicin was suspected to be a factor contributing to the
emergence of gentamicin-susceptible MRSA (GS-MRSA) from predominantly
GR-MRSA populations (2, 12).
The aim of the present study was to investigate whether the previously
reported evolution of antibiotic resistance of MRSA in two hospitals in
the Paris area could be relevant at the nationwide level, by collecting
antibiotic susceptibility data from seven French clinical laboratories
between 1992 and 1998. Subsets of isolates were retrieved and studied
in more detail in an attempt to better understand the molecular basis
of increasing gentamicin susceptibility.
Source of bacterial strains and analysis of antibiotic
susceptibility.
Clinical laboratories from seven hospitals
dispersed throughout French territory (hospitals A, B, and C in Paris;
hospital D in Lille [northern France]; hospital E in Lyon [central
France]; hospital F in Bordeaux [southwestern France]; and hospital
G in Fort-de-France, French West Indies) reported data for
susceptibility to oxacillin and gentamicin of 57,347 S. aureus isolated between 1992 and 1998, after omission of
consecutive isolates from the same patients. In addition, hospitals E
and G were selected as representative hospitals for exhaustive
antibiotic susceptibility analysis of their respective strains. All
reported antibiotic susceptibility data were derived from the routine
clinical laboratory databases of the participating hospitals and were
determined according to the guidelines set by the Committee for
Antimicrobial Testing of the French Society for Microbiology
(6). Hospitals A to C and E to G used the agar diffusion
technique as the antibiotic resistance detection method, whereas
hospital D used the ATB expression system (bioMérieux, Marcy
l'Etoile, France). Strains were considered resistant to oxacillin if
the MIC was >2 µg/ml or if there was a diameter of inhibition of
<20 mm around a 5-µg oxacillin disk (6). The disk
diffusion assay with oxacillin disks was performed either on
Mueller-Hinton agar plates incubated for 24 h at 30°C or on
Mueller-Hinton agar plates supplemented with 2% NaCl and incubated for
24 h at 37°C. Susceptibility testing with the ATB expression
system was performed according to the instructions of the manufacturer
(bioMérieux). Population analysis, in order to determine
oxacillin resistance classes of referred isolates, was performed as
described by Tomasz et al. (25). Briefly, stationary-phase culture (109 to 1010 CFU/ml) were plated at
seven dilutions (10 PFGE.
SmaI macrorestriction patterns were obtained by
using a contour-clamped homogeneous electric field system with a CHEF
DR-II (Bio-Rad, Richmond, Calif.) apparatus as previously described (9, 13). Comparisons of resolved macrorestriction patterns were based on the recommendations of Tenover et al. (23).
Strains differing in up to three fragments only were deemed clonally
related and were described as subtypes of a given clonal type. In the case of no differences between banding patterns, strains were considered identical. When they differed by four or more fragments, strains were considered separate types. Letters were used to denote major genotypes, and each variant subtype was indicated by a numerical suffix.
Hybridization studies.
SmaI macrorestriction profiles
were vacuum transferred onto nylon membranes (19). Probe
labeling and hybridization were carried out by using the nonradioactive
digoxigenin DNA labeling and detection kit (Boehringer Mannheim). The
GenBank data for the methicillin resistance gene (mecA)
(accession no. X52593); the 4'-4"-aminoglycoside nucleotidyltransferase
gene (ant4'), responsible for tobramycin resistance
(M19465); and the bifunctional 2"-aminoglycoside
phosphotransferase-6'-aminoglycoside acetyltransferase gene
(aac6'-aph2"), responsible for amikacin, tobramycin, and gentamicin cross-resistance (M18086) were used to design PCR primers
allowing the synthesis of gene-specific DNA probes. S. aureus ATCC 6583P was used as a negative control strain for the mecA, ant4', and aac6'-aph2" genes.
S. aureus CIP6525, BM3002, and FK422 were used as positive
control strains for the mecA, ant4', and
aac6'-aph2" genes, respectively.
In 1992, the frequency of GS-MRSA within the total population of
MRSA was below 7.4% in all of the study hospitals (data were not
available for hospital F) (Fig. 1). From
1992 to 1998, this rate progressively increased to reach between 46.8%
(hospital D) and 94.4% (hospital G) (Fig. 1). Since the overall
incidence of isolation of MRSA remained stable (hospitals A and E),
increased slightly (hospitals F and G), or decreased slightly
(hospitals B, C, and D) (Fig. 1), this strongly suggested that GS-MRSA
strains were supplanting the GR-MRSA population. In the cases of
hospitals F and G, the slight increase in the overall incidence of MRSA suggests that the GS-MRSA population arose partly in addition to the
endogenous GR-MRSA population.
For practical reasons, hospitals E and G were selected as a model for
studying the evolution of the antimicrobial resistance associated with
oxacillin resistance, and the susceptibility data from these hospitals
were further analyzed for all MRSA isolates collected in 1996 after
omission of consecutive isolates from the same patients. All GS-MRSA
strains from hospital E expressed heterogeneous resistance to oxacillin
in that, after incubation at 30°C, they showed a clear zone of
inhibition around the oxacillin disk and the presence of colonies near
the disk, in contrast to all GR-MRSA strains, which showed homogeneous
resistance with confluent growth right up to the oxacillin disk (Table
1). Population analysis showed class 1 phenotypic expression for selected GS-MRSA strains in that only a very
low proportion (10
0095-1137/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Emergence and Spread in French Hospitals of
Methicillin-Resistant Staphylococcus aureus with Increasing
Susceptibility to Gentamicin and Other Antibiotics
ABSTRACT
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
INTRODUCTION
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
1 to 107) on a series of
agar plates containing serial twofold dilutions of oxacillin at
concentrations ranging from 0 to 1,000 µg/ml. The plates were
incubated at 37°C for 48 h before the colonies were counted. The
number of bacteria capable of forming colonies was plotted against the
concentration of oxacillin, producing population analysis profiles.
Statistical analysis was performed with Epi-Info software (version 5;
Centers for Disease Control and Prevention, Atlanta, Ga.). One hundred
eighty-three MRSA isolates (145 GS-MRSA and 38 GR-MRSA) originating
from the seven participating hospitals were randomly selected for
molecular typing by pulsed-field gel electrophoresis (PFGE). All
strains were kept frozen at 
80°C until used.
RESULTS
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
View larger version (59K):
[in a new window]
FIG. 1.
Percentage of S. aureus strains resistant to
oxacillin ( 
), and percentages of GS-MRSA (
) and GR-MRSA (
)
among MRSA. Mean numbers of S. aureus strains isolated per
year: hospital A, 548; hospital B, 1,839; hospital C, 1,321; hospital
D, 952; hospital E, 1,188, hospital F, 2,425; hospital G, 612. Data for
1992 and 1993 are not available for hospital F. Data were obtained from
a total of 57,347 S. aureus isolates.
7 to 108) of bacteria
could form colonies in the presence of oxacillin at up to 25 µg/ml or
more (data not shown) (25). GS-MRSA strains were
significantly more frequently susceptible to kanamycin, tobramycin, lincomycin, pristinamycin, tetracycline, minocycline, co-trimoxazole, rifampin, and fusidic acid, and were more frequently resistant to
chloramphenicol, than GR-MRSA strains (Table 1). No significant differences between GR- and GS-MRSA in resistance to erythromycin, ofloxacin, and fosfomycin were observed. For hospital G, the analysis of antibiotic susceptibility patterns, while not including exactly the
same antibiotics, showed susceptibility profiles similar to those for
the isolates from hospital E, except for fusidic acid (Table 1).
TABLE 1.
Antibiotic resistance of MRSA strains (one isolate per
patient) isolated in 1996 in hospital E (mainland) and in hospital G
(French West Indies)
Molecular typing analysis using PFGE was performed for 184 randomly selected isolates from the seven participating hospitals. For each isolate, macrorestriction profiles generated by SmaI cleavage comprised 15 to 17 fragments varying in size from <80 to 700 kb (Fig. 2). PFGE profiles of GS-MRSA strains were mostly clustered into three major PFGE types: types A and B, comprising 42% (48 of 114 isolates) and 41% (47 of 114 isolates), respectively, of GS-MRSA strains from the six mainland hospitals, and type C, representing the dominant GS-MRSA type (64% of GS-MRSA strains) in the French West Indies hospital (Table 2). Type A and B strains were seldom detected among isolates derived from the French West Indies, and conversely, type C strains were not detected among isolates derived from mainland hospitals.
|
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GR-MRSA isolates available from hospitals E and G comprised several
types (including type A) and subtypes (Table 2). In several cases, the
PFGE profiles of GS- and GR-MRSA strains of the same type differed by
two bands only (Table 2 and Fig. 2). Moreover, some other GS-MRSA
strains that were resistant to kanamycin and tobramycin had PFGE types
strictly identical to those of MRSA strains that were susceptible to
all aminoglycosides (Fig. 2). Southern blot hybridizations with the
mecA-specific and ant4'-specific probes were
positive for the 19 representative isolates of PFGE types A and B, on
the same 
185- to 215-kb SmaI fragment, except for one
isolate which was susceptible to all aminoglycosides and showed
negative hybridization with the ant4'-specific probe (Table 3). Hybridization with the
aac6'-aph2" gene probe occurred on an SmaI
fragment of 490 kb or above 700 kb for the GR-MRSA isolates only
(Table 3), thus confirming the lack of the bifunctional enzyme in
GS-MRSA strains.
|
Spontaneous GS-MRSA derivatives (with no changes in any other
antibiotic resistance) were obtained after long-term storage (2 years)
at room temperature from two GR-MRSA strains (A960651 and A960649). In
contrast, no change from the original GR-MRSA phenotype was observed in
strains maintained for the same time period at 80°C. The PFGE types
of the parent GR-MRSA strains and revertant GS-MRSA strains were
indistinguishable (Fig. 2, lanes 5 to 8). Hybridization studies
confirmed the loss of the aac6'-aph2" gene in the GS-MRSA derivatives.
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DISCUSSION |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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S. aureus, and in particular MRSA, has long been one of the more serious and problematic nosocomial pathogens, repeatedly responding to the challenge of new antistaphylococcal antibiotics by acquiring new resistance (3). A more prudent use of antibiotics, in addition to the implementation of better infection control and hygiene measures for reducing nosocomial infections, has been encouraged in many countries and may play a role in reducing the incidence of multiply resistant organisms. Although these implemented measures may have been responsible for the major decline in the incidence of MRSA in Denmark from 15 to 0.2% between 1971 and 1984 (18), they have been relatively unsuccessful in other, larger countries, where the prevalence of MRSA seems to be still increasing (22, 26). It is clear that in most French hospitals, not only hospitals nationwide within the mainland but also a geographically distinct hospital situated in the French West Indies, distinct MRSA clones that are more susceptible to multiple antibiotics, particularly gentamicin, are increasing in incidence, often replacing the endogenous classical MRSA clones, while the overall prevalence of oxacillin resistance among S. aureus isolates remains stable or varies slightly (Fig. 1). This observation confirms the recent reports from two French hospitals (one of which is included in the present study) (2, 12) of the emergence of new epidemic MRSA strains that are more susceptible to antibiotics.
We showed that the same two GS-MRSA PFGE types, types A and B, were predominant in each of the mainland hospitals (A to F) included in the study and that another distinct PFGE type, type C, predominated in hospital G located in the French West Indies. This is probably due to the frequent exchange of patients between hospitals A to F, while exchange between these mainland hospitals and hospital G in the French West Indies is uncommon, explaining the quasiabsence of common mainland MRSA types. Using the definition of a distinct PFGE type as one comprising strains showing no more than a three-fragment variation, a limited number (i.e., 5 to 11) of MRSA types are usually recognized within a given area, always with the predominance of one type. For instance, among 189 MRSA isolates from a Spanish hospital between 1989 and 1993, 83.1% were classified into one among the 11 total PFGE types, whereas 0.5 to 5.3% were classified into the 10 other types (7). Again, 77% of 85 Brazilian MRSA strains from six different hospitals in five cities, isolated between 1992 and 1994, shared minor variants of a common PFGE type (24). Similarly, in Germany the so-called North German epidemic type has been identified and comprises 80% of all isolates in that region (28). The capacity of a dominant clone for geographic spread, at the expense of an already established clone (7, 20), has already been described, but these emergent dominant clones were not susceptible to gentamicin.
At the molecular level we showed that the switch from MRSA with multiple antibiotic resistance to more susceptible MRSA is correlated with the loss of the aac6'-aph2" gene, which confers resistance to all aminoglycosides although it reduces amikacin susceptibility only slightly, with conservation of the ant4' gene, which confers resistance to kanamycin, tobramycin, and amikacin (27). Since the aac6'-aph2" gene is frequently carried by transposon Tn4001 (4, 8), it is likely that certain GS-MRSA strains could have emerged from GR-MRSA strains by transposon excision or deletion, a phenomenon that we have reproduced in vitro by long-term storage of GR-MRSA strains at room temperature. The fact that both GR- and GS-MRSA strains have closely related PFGE types, which suggests a recent common ancestor for certain GS- and GR-MRSA isolates, supports this hypothesis. It is possible that this phenomenon has resulted from a long-term change in the aminoglycoside selective pressure over a period of 5 years or more (15), as also suggested in the two previous French studies (2, 12). A marked decrease in the use of gentamicin in the Henri Mondor Hospital (located near Paris) between 1983 and 1987 was reported, whereas that of amikacin increased by a factor of two (2); in this hospital GS-MRSA isolates represented 4.9 and 27.5% of the MRSA isolates in 1993 and 1995 respectively. However, data documenting changes in the level of use of aminoglycosides have not been reported for all hospitals. In any case, changes in aminoglycoside use cannot alone explain the increase in susceptibility to other antibiotics (e.g., kanamycin, tobramycin, lincomycin, rifampin, minocycline, and fusidic acid) (Table 1) and the return to heterogeneous resistance to oxacillin observed with the GS-MRSA population. This suggests that some other selective pressure(s) could be involved in the emergence and spread of these strains. The genetic event(s) responsible for this pleiotropic effect on antibiotic resistance is unknown, but the strong association of the loss of the bifunctional enzyme with the return to heterogeneous resistance to oxacillin in strains that likely derive from a recent common ancestor (Fig. 2) suggests that excision of Tn4001 also affected an accessory factor essential for homogeneous-heterogeneous resistance to methicillin. Further studies investigating both the genetic mechanism of and the selective advantage provided by this emerging phenotype should help elucidate the genetic events that are operative.
At a practical clinical level, the continuing emergence of GS-MRSA and the decline in the incidence of GR-MRSA could provide an opportunity for the controlled reintroduction of aminoglycosides for use as anti-MRSA therapies, alleviating the reliance on glycopeptide antibiotics.
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FOOTNOTES |
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* Corresponding author. Mailing address: Faculté de Médecine, Laboratoire de Bactériologie, Rue Guillaume Paradin, 69372 Lyon Cedex 08, France. Phone: 33 (0) 478 77 86 57. Fax: 33 (0) 478 77 86 58. E-mail: jetienne{at}univ-lyon1.fr.
Present address: MRL Pharmaceutical Services, 3554XD, Utrecht, The Netherlands.
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Journal of Clinical Microbiology, November 1999, p. 3452-3457, Vol. 37, No. 11
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Copyright © 1999, American Society for Microbiology. All rights reserved.
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[Abstract] [Full Text] -
Amorim, M. L., Faria, N. A., Oliveira, D. C., Vasconcelos, C., Cabeda, J. C., Mendes, A. C., Calado, E., Castro, A. P., Ramos, M. H., Amorim, J. M., de Lencastre, H.
(2007). Changes in the Clonal Nature and Antibiotic Resistance Profiles of Methicillin-Resistant Staphylococcus aureus Isolates Associated with Spread of the EMRSA-15 Clone in a Tertiary Care Portuguese Hospital. J. Clin. Microbiol.
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Hallin, M., Denis, O., Deplano, A., De Mendonca, R., De Ryck, R., Rottiers, S., Struelens, M. J.
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59: 465-472
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Ferry, T., Bes, M., Dauwalder, O., Meugnier, H., Lina, G., Forey, F., Vandenesch, F., Etienne, J.
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Layer, F., Ghebremedhin, B., Konig, W., Konig, B.
(2006). Heterogeneity of Methicillin-Susceptible Staphylococcus aureus Strains at a German University Hospital Implicates the Circulating-Strain Pool as a Potential Source of Emerging Methicillin-Resistant S. aureus Clones.. J. Clin. Microbiol.
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Vindel, A., Trincado, P., Gomez, E., Cabrera, R., Boquete, T., Sola, C., Valdezate, S., Saez-Nieto, J. A.
(2006). Prevalence and Evolution of Methicillin-Resistant Staphylococcus aureus in Spanish Hospitals between 1996 and 2002. J. Clin. Microbiol.
44: 266-270
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van der Mee-Marquet, N., Domelier, A.-S., Girard, N., Quentin, R., the Bloodstream Infection Study Group of the Relai,
(2004). Epidemiology and Typing of Staphylococcus aureus Strains Isolated from Bloodstream Infections. J. Clin. Microbiol.
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Wannet, W. J. B., Spalburg, E., Heck, M. E. O. C., Pluister, G. N., Willems, R. J. L., de Neeling, A. J.
(2004). Widespread Dissemination in The Netherlands of the Epidemic Berlin Methicillin-Resistant Staphylococcus aureus Clone with Low-Level Resistance to Oxacillin. J. Clin. Microbiol.
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Oteo, J., Baquero, F., Vindel, A., Campos, J., on behalf of the Spanish members of The European A,
(2004). Antibiotic resistance in 3113 blood isolates of Staphylococcus aureus in 40 Spanish hospitals participating in the European Antimicrobial Resistance Surveillance System (2000-2002). J Antimicrob Chemother
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Donnio, P.-Y., Preney, L., Gautier-Lerestif, A.-L., Avril, J.-L., Lafforgue, N.
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Strommenger, B., Kettlitz, C., Werner, G., Witte, W.
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Thouverez, M., Muller, A., Hocquet, D., Talon, D., Bertrand, X.
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Kikuchi, K., Takahashi, N., Piao, C., Totsuka, K., Nishida, H., Uchiyama, T.
(2003). Molecular Epidemiology of Methicillin-Resistant Staphylococcus aureus Strains Causing Neonatal Toxic Shock Syndrome-Like Exanthematous Disease in Neonatal and Perinatal Wards. J. Clin. Microbiol.
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Watson, J., Givney, R., Beard-Pegler, M., Rose, B., Merlino, J., Vickery, A., Gottlieb, T., Bradbury, R., Harbour, C.
(2003). Comparative Analysis of Multidrug-Resistant, Non-Multidrug-Resistant, and Archaic Methicillin-Resistant Staphylococcus aureus Isolates from Central Sydney, Australia. J. Clin. Microbiol.
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Heym, B., Le Moal, M., Armand-Lefevre, L., Nicolas-Chanoine, M.-H.
(2002). Multilocus sequence typing (MLST) shows that the 'Iberian' clone of methicillin-resistant Staphylococcusaureus has spread to France and acquired reduced susceptibility to teicoplanin. J Antimicrob Chemother
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Asseray, N., Caillon, J., Roux, N., Jacqueline, C., Bismuth, R., Kergueris, M. F., Potel, G., Bugnon, D.
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Donnio, P.-Y., Louvet, L., Preney, L., Nicolas, D., Avril, J.-L., Desbordes, L.
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Polyzou, A., Slavakis, A., Pournaras, S., Maniatis, A. N., Sofianou, D., Tsakris, A.
(2001). Predominance of a methicillin-resistant Staphylococcus aureus clone susceptible to erythromycin and several other non-{beta}-lactam antibiotics in a Greek hospital. J Antimicrob Chemother
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Blanc, D. S., Francioli, P., Le Coustumier, A., Gazagne, L., Lecaillon, E., Gueudet, P., Vandenesch, F., Etienne, J.
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Laurent, F., Lelievre, H., Cornu, M., Vandenesch, F., Carret, G., Etienne, J., Flandrois, J.-P.
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Pournaras, S., Slavakis, A., Polyzou, A., Sofianou, D., Maniatis, A. N., Tsakris, A.
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Carricajo, A., Fonsale, N., Vautrin, A. C., Aubert, G.
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