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. 2004 Sep;42(9):4412–4413. doi: 10.1128/JCM.42.9.4412-4413.2004

Cefoxitin Does Not Induce Production of Penicillin Binding Protein 2a in Methicillin-Susceptible Staphylococcus aureus Strains

Ana Lúcia da Costa Darini 1,*, Izabel Cristina Vanzato Palazzo 1
PMCID: PMC516335  PMID: 15365061

Beta-lactam resistance in methicillin-resistant staphylococci (MRS) is caused by the expression of penicillin-binding protein 2a (PBP2a), encoded by the mecA gene, which has low binding affinities to practically all beta-lactam antibiotics so far introduced into clinical use (7). Detection of this resistance is complicated because different methicillin resistance levels are expressed in the staphylococcus population.

Recently the cefoxitin disk has been proposed as an alternative method of detecting MRS (3, 10). Cefoxitin is a cephamycin-type antibiotic, and it has been described as an inducer of methicillin resistance by production of the PBP2a (9). The paper published by Annie Felten et al. (3) has been used as a reference suggesting the use of the cefoxitin disk as being helpful in oxacillin resistance detection. According to these authors, “surprisingly, cefoxitin induced the PBP2a production in vitro in MSSA isolates for which cefoxitin MICs were high.” The methicillin-susceptible Staphylococcus aureus (MSSA) strain referred to by these authors is S. aureus N315, which was isolated in Japan in 1982, and at that time it was identified as methicillin susceptible and cefoxitin resistant. This strain became resistant to methicillin after induction by cefoxitin (9). In 1992, it was known that this strain would not be classified as MSSA because it is a pre-methicillin-resistant S. aureus (MRSA) strain (5). So, when many researchers and clinical bacteriologists are looking for alternative methods for detection of low-level methicillin resistance, it is very important to explain that cefoxitin does not induce PBP2a production in vitro in MSSA isolates unless this isolate is pre-MRSA, with a functional mecI gene (6).

It has recently been revealed that the ability of PBP2a to affect cell wall synthesis in the presence of methicillin requires cooperation from the transglycosylase domain of native PBP2 (1). Also, PBP2 overproduction has been described as effective in raising methicillin resistance when combined with other concomitant phenotypic changes, such as increased cell wall synthesis in staphylococcus strains that do not contain the mecA gene (11). According to Urakami et al. (8), the susceptibility to cephamycin-type antibiotics is increased in MRSA defective in PBP2. Apparently, PBP2 has been involved in the mechanism of resistance to cephamycins (i.e., cefoxitin).

Based on published data, it may be postulated that low-level methicillin resistance in staphylococcus strains could be easily detected if the isolate was also resistant to cefoxitin due to the participation of native PBP2 (1, 2, 3, 4, 8). We did not exclude the possibility of the mechanism's association with participation of several native PBPs that permit the expression of methicillin resistance.

The mechanism of resistance to β-lactam in staphylococci is very complex, involving the participation of acquired and native genes. The function of each gene that participates in this mechanism of resistance is not completely understood, and this represents a challenge for researchers.

REFERENCES

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J Clin Microbiol. 2004 Sep;42(9):4412–4413.

Author's Reply

Annie Felten 1,*

A. L. da Costa Darini's comments are right. The performance of the cefoxitin disk diffusion test over S. aureus is extensively confirmed (1). Cefoxitin tests have been proposed and are actually recommended by a number of national committees for clinical laboratory standards, NCCLS among others.

At the beginning of my introduction I mentioned that infections caused by very-low-level MRSA were first reported in Japan, where MRSA was more prevalent than elsewhere. I acknowledge that instead of the sentence “Surprisingly, cefoxitin induced the PBP2a production in vitro in MSSA isolates for which cefoxitin MICs were high,” I could have written, “Cefoxitin induced the PBP2a production in vitro in undetectable low-level-MRSA, or in phenotypically MSSA.” The meaning was supposed to be obvious according to the course of my introduction and the microbiological background of the readers. I did not mean that cefoxitin would reveal a PBP2a protein, unless the isolate harbors the mecA gene.

I argue against A. L. da Costa Darini's assertion that cefoxitin would not induce the production of PBP2a in pre-MRSA without a functional mecI gene. Actually, PBP2a induction by cefoxitin is not restricted to the pre-MRSA or low-level or class 1 MRSA which harbors a mecI gene, since none of the 26 class 1 MRSA clinical isolates we presented harbored the mecI gene. Methicillin resistance was revealed by cefoxitin even in penicillinase nonproducer class 1 MRSAs (2).

The mechanisms of the interplay between PBP2a, other PBPs, interpeptide structure of the bacterial cell wall, and methicillin remain to be fully explored (3).

REFERENCES

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