In vitro activity of ß-lactams against gentamicin-susceptible and gentamicin-resistant Staphylococcus aureus

A. Carricajo1, N. Fonsale, A. C. Vautrin and G. Aubert

Department of Bacteriology, CHU Bellevue Hospital, 42055 Saint-Etienne Cedex 02, France

Sir,

In recent years, we have observed a phenomenon described by many French hospitals, namely the emergence of a new epidemic of oxacillin (methicillin)-resistant Staphylococcus aureus (MRSA) characterized by heterogeneous methicillin resistance and gentamicin susceptibility.1,2 These strains remained resistant to tobramycin and were characterized by the presence of aminoglycoside nucleotidyltransferase (ANT 4'). Surprisingly, at the same time, MRSA isolates susceptible to all aminoglycosides (AS-MRSA) were also recovered. In our hospital in 1999, the frequency within the MRSA population of gentamicin-resistant MRSA (GR-MRSA), gentamicin-susceptible MRSA/tobramycin-resistant MRSA (GS-MRSA) and AS-MRSA was 9.4, 82.4 and 7.6%, respectively, whereas the corresponding frequencies in 1995 were 52.7, 46.4 and 0.2%, respectively. The aim of this study was to determine ß-lactam activity against clinical isolates of gentamicin-susceptible and gentamicin-resistant MRSA.

A total of 103 S. aureus strains isolated from patients at the Bellevue Teaching Hospital (Saint-Etienne, France) between 1996 and 1998 were studied: 30 methicillin-susceptible strains (MSSA) (mecA-negative) and 73 methicillin-resistant ones (MRSA) (mecA-positive). Of these 73 MRSA strains, 34 were kanamycin- and tobramycin-resistant but gentamicin-susceptible (GS-MRSA), 26 were resistant to all aminoglycosides tested (kanamycin, tobramycin and gentamicin) (GR-MRSA) and 13 were susceptible to all aminoglycosides tested (AS-MRSA). Five reference strains were used (Escherichia coli ATCC 25992, Pseudomonas aeruginosa ATCC 27853 and S. aureus ATCC 25923, ATCC 43866 and CIP 6525). The presence of the mecA gene was assessed using multiplex polymerase chain reaction (PCR) amplification.3 The antibiotics tested were as follows: cefepime and oxacillin (Bristol-Myers Squibb), cefotaxime, cefpirome and teicoplanin (Hoechst Marion Roussel), cephalothin, tobramycin and vancomycin (Lilly), gentamicin (Schering-Plough), imipenem (Merck Sharp Dohme) and meropenem (Zeneca-Pharma). MICs were determined by a two-fold serial agar dilution method using Mueller–Hinton medium (Becton Dickinson, Le Pont-de-Claix, France), both alone and supplemented with 2 or 4% NaCl for cefepime, cefotaxime, cefpirome, cephalothin, oxacillin, imipenem and meropenem, in order to detect heteroresistance.4 The final inoculum concentration was approximately 104 cfu per spot. The MIC was defined as the lowest concentration of an antibiotic allowing growth of fewer than three colonies on Mueller–Hinton agar after 48 h of incubation at 35°C.

MICs of the seven ß-lactams tested are given in the Table. Study of MICs performed with 0, 2 and 4% NaCl supplementation showed that GS-MRSA and AS-MRSA strains exhibited heterogeneous resistance to methicillin (except for one GS-MRSA strain), while GR-MRSA strains exhibited homogeneous resistance (except for eight strains, for which heterogeneous resistance was detected). The MICs obtained with 2 and 4% NaCl supplementation were similar for all ß-lactams tested.


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Table. In vitro activities (MIC, in mg/L) of various ß-lactams against clinical Staphylococcus aureus isolates
 
For MSSA strains, cephalothin was the most active of the cephalosporins tested, but its activity was lower than that of imipenem.

Imipenem was the most active ß-lactam against MRSA, in particular against GS-MRSA and AS-MRSA (MIC50 for GS-MRSA and AS-MRSA was 0.5 mg/L compared with 32 mg/L for GR-MRSA). Similarly, we confirmed that cefpirome was the most active cephalosporin against GS-MRSA and, like Pierard et al.,5 we reported that certain MRSA strains had MICs within the susceptibility range.

MIC90s of vancomycin and teicoplanin were higher among GR-MRSA strains (2 mg/L) than among GS-MRSA, AS-MRSA and MSSA strains (1 mg/L).5

This study shows the emergence of a new MRSA phenotype susceptible to all the aminoglycosides. The mechanism of the switch from GR-MRSA to GS-MRSA and AS-MRSA is unknown, but changes in use of aminoglycosides, as suggested by others, cannot in themselves account for this phenomenon.1 These AS-MRSA strains show heterogeneous phenotypic resistance to oxacillin, as seen with the GS-MRSA strains. We also confirmed the activity of cefpirome against certain MRSAs, particularly GS-MRSA and AS-MRSA, although this is probably not clinically relevant. However, this finding could be of use when cefpirome is used in combination with vancomycin. The synergy between vancomycin and cefpirome has been thoroughly investigated using in vitro tests.6 This combination could be useful for the empirical treatment of suspected mixed infection involving MRSA and Enterobacteriaceae, but animal experiments are required to determine the potential clinical value of these combinations.

Notes

J Antimicrob Chemother 2000; 46: 856–858

* Corresponding author. Tel: +33-4-77-12-77-35; Fax: +33-4-77-12-05-45; E-mail: anne.carricajo{at}univ-st-etienne.fr Back

References

1 . Lemaître, N., Sougakoff, W., Masmouni, A., Fievet, M. H., Bismuth, R. & Jarlier, V. (1998). Characterization of gentamicinsusceptible strains of methicillin-resistant Staphylococcus aureus involved in nosocomial spread. Journal of Clinical Microbiology 36, 81–5.[Abstract/Free Full Text]

2 . Lelièvre, H., Lina, G., Jones, M. E., Olive, C., Forey, F., Roussel-Delvallez, M. et al. (1999). Emergence and spread in French hospitals of methicillin-resistant Staphylococcus aureus with increasing susceptibility to gentamicin and other antibiotics. Journal of Clinical Microbiology 37, 3452–7.[Abstract/Free Full Text]

3 . Zambardi, G., Reverdy, M. E., Bland, S., Bes, M., Freney, J. & Fleurette, J. (1994). Laboratory diagnosis of oxacillin resistance in Staphylococcus aureus by a multiplex-PCR assay. Diagnostic Microbiology and Infectious Disease 19, 25–31.[ISI][Medline]

4 . Baker, C. N., Huang, M. B. & Tenover, F. C. (1994). Optimizing testing of methicillin-resistant Staphylococcus species. Diagnostic Microbiology and Infectious Disease 19, 167–70.[ISI][Medline]

5 . Pierard, D., Emmerechts, K., Lauwers, S. & Belgian Multicenter Study Group. (1998). Comparative in-vitro activity of cefpirome against isolates from intensive care and haematology/oncology units. Journal of Antimicrobial Chemotherapy 41, 443–50.[Abstract]

6 . Bergeret, M. & Raymond, J. (1999). In vitro bactericidal activity of cefpirome and cefamandole in combination with glycopeptides against methicillin-resistant Staphylococcus aureus. Journal of Antimicrobial Chemotherapy 43, 291–4.[Abstract/Free Full Text]





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