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PubMed1996

Suppression of methicillin resistance in a mecA-containing pre-methicillin-resistant Staphylococcus aureus strain is caused by the mecI-mediated repression of PBP 2' production.

The mechanism of methicillin susceptibility was studied in Staphylococcus aureus N315P, a pre-methicillin-resistant S. aureus strain that is susceptible to methicillin, despite the presence of mecA in the chromosome. In the presence of mec regulator genes mecI and mecR1, transcription of the mecA gene was not inducible by the addition of methicillin to the culture medium. Inactivation of the mecI gene function by replacing it with tetL made N315P express heterogeneous-type methicillin resistance. The subclone, in which the mecI gene was replaced, subclone P delta I, produced 12 times greater amounts of mecA gene transcripts and 8.5 times more PBP 2' protein than N315P. These data indicate that the mecI gene-encoded repression of mecA gene transcription is responsible for the apparent methicillin susceptibility phenotype of pre-methicillin-resistant S. aureus N315P.

Bacterial Proteins↗

PubMed1994

[Multi-center evaluation to discriminate between the strains of methicillin-resistant Staphylococcus aureus (MRSA) and those susceptible (MSSA) by Showa oxacillin and methicillin disk susceptibility tests].

The Showa disk susceptibility test using two penicillinase-resistant penicillins, oxacillin and methicillin, was evaluated to discriminate between the strains of Staphylococcus aureus resistant to methicillin (MRSA) and those susceptible (MSSA) in the multi-center trials. The study included 651 clinical isolates of S. aureus, comprising of 329 MRSA and 322 MSSA isolates. The inhibitory zone diameters by Showa disks to oxacillin and methicillin highly correlated with minimum inhibitory concentrations (MICs) determined by standard agar dilutions with 0.961 and 0.930 correlation coefficients, respectively. Of 651 duplicate MIC determinations, 79.9% (oxacillin) and 80.3% (methicillin) were within +/- 1 log2 dilutions with each other. When Showa oxacillin and methicillin disks were incubated at 35 degrees C, sensitivity and specificity of oxacillin to detect MRSA were 95.4% and 98.1%, and those of methicillin were 94.8% and 95.2%. When tested on agar plates supplemented with 5% NaCl, sensitivity and specificity markedly improved to > 97%. Also, when incubated at 30 degrees C, sensitivity and specificity became to nearly 100%. Of 329 MRSA isolates, the interpretive criteria combined with incubation at 30 degrees C and testing onto 5% NaCl supplemented agar plates could correctly identify 324 (98.5%) and 329 (100%) isolates, respectively. In conclusion, when the Showa oxacillin and methicillin disk susceptibility tests were employed exactly according to the manufacturer's instruction, the test performances to detect MRSA were enough reliable to screen MRSA isolates in clinical microbiology laboratories.

Methicillin↗

PubMed1988

Amplification of a section of chromosomal DNA in methicillin-resistant Staphylococcus aureus following growth in high concentrations of methicillin.

Growth of two independently isolated strains of methicillin-resistant Staphylococcus aureus (MRSA) in increasing concentrations of methicillin (step-selection) resulted in increased resistance in these strains. When chromosomal DNA from the step-selected variants was probed using DNA sequences previously demonstrated to be associated with methicillin resistance in MRSA strains, amplification of the homologous chromosomal sequence was identified. Growth of these step-selected strains in the absence of methicillin resulted in loss of the amplified sequence, while the original sequence remained. There are differences between the two strains in the stability of maintenance of amplified sections. Prolonged storage of the variants on a high concentration of methicillin resulted in loss of amplified sections without concomitant loss of methicillin resistance. Thus amplification may be only one of at least two molecular mechanisms available to S. aureus to increase methicillin resistance in response to step-selection. Probing of cells of the highly resistant sub-population of a heterogeneously resistant MRSA strain showed that duplication of this mec-associated DNA is not involved in the mechanism of heteroresistance.

Chromosome Mapping↗

PubMed1998

Discrimination between methicillin-resistant and methicillin-susceptible Staphylococcus aureus using pyrolysis mass spectrometry and artificial neural networks.

Curie-point pyrolysis mass spectra were obtained from 15 methicillin-resistant and 22 methicillin-susceptible Staphylococcus aureus strains. Cluster analysis showed that the major source of variation between the pyrolysis mass spectra resulted from the phage group of the bacteria, not their resistance or susceptibility to methicillin. By contrast, artificial neural networks could be trained to recognize those aspects of the pyrolysis mass spectra that differentiated methicillin-resistant from methicillin-sensitive strains. The trained neural network could then use pyrolysis mass spectral data to assess whether an unknown strain was resistant to methicillin. These results give the first demonstration that the combination of pyrolysis mass spectrometry with neural networks can provide a very rapid and accurate antibiotic susceptibility testing technique.

Cluster Analysis↗

PubMed1996

In vitro activity of fifteen antimicrobial agents against methicillin-resistant and methicillin-susceptible Staphylococcus intermedius.

In this study the susceptibility of 91 methicillin-resistant and -susceptible Staphylococcus intermedius strains (MRSI and MSSI, respectively) against 15 antimicrobial agents was determined. The activity of the antimicrobial agents was studied at pH 7.2 and pH 8.5. Methicillin was more active at pH 7.2 (28 strains methicillin-resistant) than at pH 8.5 (55 strains methicillin-resistant). Gentamicin showed excellent activity, with only 3 strains resistant at pH 8.5. However, gentamicin would have to be administered parenterally. Oxytetracycline cannot be recommended for treatment of canine staphylococcal dermatitis, due to the high percentage (over 25%) of strains that were found to be resistant. Clindamycin showed little activity in inhibiting growth of the strains studied, the percent resistance at pH 7.2 was 93.4%. Rifampin behaved differently at the two pH values. However, a close relationship was noted between methicillin-resistant and rifampin-resistant strains, particularly at the lower pH. Of the fluoroquinolones, ciprofloxacin or enrofloxacin would be a good useful alternative for the treatment of methicillin-resistant strains of S. intermedius. Lastly, very high resistance to sulphamethoxypyridazine was found, as was the case with trimethoprim and a combination of trimethoprim/sulphamethoxypyridazine, against not only MRSI but also MSSI strains.

Acute Disease↗

PubMed1992

Survey of the methicillin resistance-associated genes mecA, mecR1-mecI, and femA-femB in clinical isolates of methicillin-resistant Staphylococcus aureus.

The restriction site polymorphism of the chromosomal femAB region and the first appearance of the regulatory element mecR1-mecI associated with the methicillin resistance determinant (mec) were analyzed in 192 initially methicillin resistant (Mcr) Staphylococcus aureus clinical isolates collected between 1965 and 1990 in the Zurich area. Forty-three of the strains lost the resistance spontaneously. All isolates that were still Mcr hybridized with mecA, the gene for the low-affinity penicillin-binding protein PBP 2'. Mcr strains isolated before 1977 lacked sequences that hybridized with mecR1-mecI, a regulatory element controlling the expression of mecA; exceptions to this were one strain isolated in 1966 and one strain isolated in 1972. The size of the EcoRV fragment carrying femA, a chromosomally encoded factor involved in pentaglycine side chain formation of the peptidoglycan and essential for the expression of methicillin resistance, was conserved in all strains but one, which was susceptible to methicillin even though it carried a functional mecA gene. The methicillin susceptibility of this particular strain was presumably due to a spontaneous femA-like mutation. The 192 strains belonged to seven different EcoRV restriction fragment patterns recognizable with a 10.5-kb probe covering the femAB region. Some 93% of the 149 Mcr strains belonged to pattern A, and the remaining Mcr strains shared patterns A' and B. The 42 isolates which spontaneously lost their resistance upon storage and revival represented all seven different patterns. This strong conservation of femA suggests an important role for femA in cell wall metabolism and methicillin resistance.

Genes, Bacterial↗

PubMed2005

Comparison of genotypes of methicillin-resistant and methicillin-sensitive Staphylococcus aureus in Finland.

The frequency of horizontal transfer of the staphylococcal cassette chromosome mec to methicillin-susceptible Staphylococcus aureus is unknown. In order to gain more information regarding this frequency in Finland, the genotypes of 299 clinical methicillin-sensitive Staphylococcus aureus isolates were compared to representatives of 24 epidemic methicillin-resistant Staphylococcus aureus genotypes. Sixty-eight percent of the methicillin-sensitive isolates had a genotype similar to eight of the epidemic methicillin-resistant strains. The remaining isolates (32%) showed 22 different genotypes. The results indicate that, in Finland, several methicillin-sensitive Staphylococcus aureus genotypes may have acquired the staphylococcal cassette chromosome mec.

Finland↗

PubMed2002

Comparative proteomics of Staphylococcus aureus and the response of methicillin-resistant and methicillin-sensitive strains to Triton X-100.

Proteomics is a powerful tool for analysing differences in gene expression between bacterial strains with alternate phenotypes. Staphylococcus aureus strains are grouped on the basis of their sensitivity to methicillin. Two-dimensional gel electrophoresis was combined with MS to compare the protein profiles of S. aureus strains COL (methicillin-resistant) and 8325 (methicillin-sensitive). Reference mapping via this approach identified 377 proteins that corresponded to 266 distinct ORFs. Amongst these identified proteins were 14 potential virulence factors. The production of 41 'hypothetical' proteins was confirmed, and eight of these appeared to be unique to S. aureus. Strain COL displayed 12 protein spots, which included alkaline-shock protein 23 (Asp23) and cold-shock proteins CspABC, which either were not present in strain 8325 or were present at a significantly lower intensity in this strain. Comparative maps were used to characterize the S. aureus response to treatment with Triton X-100 (TX-100), a detergent that has been shown to reduce methicillin resistance independently of an interaction with the mecA-encoded penicillin-binding protein 2a. In response to growth of the bacteria in the presence of TX-100, 44 protein spots showed altered levels of abundance, and 11 of these spots were found only in COL. The products of genes regulated by sigma(B) (the alternative sigma factor), including Asp23 and three proteins of unknown function, and SarA (a regulator of virulence genes) were shown to be present at significantly altered levels. SarA production was induced in TX-100-treated cultures. A protein of the sigma(B) operon, RsbV, was only detected in COL and its production was down-regulated in COL when the strain was treated with TX-100, whereas RsbW was present at reduced levels in both strains. Upon growth of both strains in the presence of TX-100, no effects on the production of the essential methicillin-resistance factor FemA were detected, whereas phosphoglucosamine mutase (GlmM) production was reduced in COL alone. This study suggests that proteins of the sigma(B) and sarA regulons, as well as other factors, are involved in methicillin resistance in S. aureus.

Bacterial Proteins↗

PubMed1980

Activity of cephalosporins against methicillin-susceptible and methicillin-resistant, coagulase-negative staphylococci: minimal effect of beta-lactamase.

Eight cephalosporins were tested for their activity against methicillin-susceptible and methicillin-resistant, coagulase-negative staphylococci and for their resistance to beta-lactamase from methicillin-resistant, coagulase-negative staphylococci. Susceptibility testing by the agar plate method was evaluated for the effect of inoculum size and duration of incubation. Methicillin-susceptible, coagulase-negative staphylococci were highly susceptible to the cephalosporins, with cephapirin and cepahlothin showing the greatest activity, followed by cefazolin and cefamandole. Methicillin-resistant, coagulase-negative staphylococci displayed nearly total cross-resistance to the cephalosporins. Resistance increased with increasing inoculum size. Beta-Lactamases produced by methicillin-resistant, coagulase-negative staphylococci had a minimal hydrolytic effect on cepahlothin, cephapirin, cefazolin, and cefamandole and no measurable effect on cefoxitin. There was no correlation between the anti-staphylococcal activity and resistance to beta-lactamases.

Cephalosporins↗

PubMed1987

Esterase electrophoretic polymorphism of methicillin-sensitive and methicillin-resistant strains of Staphylococcus aureus.

Methicillin-sensitive and methicillin-resistant strains of Staphylococcus aureus from diverse geographic origins were analysed by polyacrylamide-agarose gel electrophoresis for esterase polymorphism. Three kinds of esterase bands, designated A, B and C, were defined by their ranges of activity toward five synthetic substrates and their resistance to di-isopropyl fluorophosphate. There were five allozymes of esterase A, four of esterase B and four of esterase C. Eighteen distinct combinations of allozymes (zymotypes) were distinguished amongst 105 strains analysed. Two major zymotypes were represented by 35 and 19 strains respectively, whereas other zymotypes were represented by one or, at most, seven strains. The coefficient of genetic diversity was lower for methicillin-resistant strains than for methicillin-sensitive strains. Most of the methicillin-resistant strains are represented by the two major zymotypes which differed from each other by the electrophoretic behaviour of the three esterases. These results indicate that, on the basis of esterase electrophoretic polymorphism, methicillin resistance is expressed in genetically different strains.

Esterases↗

PubMed1996

Nosocomial Staphylococcus aureus bacteremia among nasal carriers of methicillin-resistant and methicillin-susceptible strains.

OBJECTIVES: To determine the relevance of nasal carriage of Staphylococcus aureus, either methicillin-sensitive (MSSA) or methicillin-resistant (MRSA), as a risk factor for the development of nosocomial S aureus bacteremia during an MRSA outbreak. PATIENTS AND METHODS: In this prospective cohort study, 488 patients admitted to an intensive care unit (ICU) during a 1-year period were screened with nasal swabs within 48 hours of admission and weekly thereafter in order to identify nasal S aureus carriage. Nasal staphylococcal carriers were observed until development of S aureus bacteremia, ICU discharge, or death. RESULTS: One hundred forty-seven (30.1%) of 488 patients were nasal S aureus carriers; 84 patients (17.2%) harbored methicillin-sensitive S aureus; and 63 patients (12.9%) methicillin-resistant S aureus. Nosocomial S aureus bacteremia was diagnosed in 38 (7.7%) of 488 patients. Rates of bacteremia were 24 (38%) of the MRSA carriers, eight (9.5%) of the MSSA carriers, and six (1.7%) of noncarriers. After adjusting for other predictors of bacteremia by means of a Cox proportional hazard regression model, the relative risk for S aureus bacteremia was 3.9 (95% confidence interval, 1.6-9.8; P = 0.002) for MRSA carriers compared with MSSA carriers. CONCLUSIONS: Among ICU patients, nasal carriers of S aureus are at higher risk for S aureus bacteremia than are noncarriers; in the setting of an MRSA outbreak, colonization by methicillin-resistant strains represents a greater risk than does colonization by MSSA and strongly predicts the occurrence of MRSA bacteremia.

Adult↗

PubMed1990

Presence of an additional penicillin-binding protein in methicillin-resistant Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, and Staphylococcus simulans with a low affinity for methicillin, cephalothin, and cefamandole.

The presence of an additional penicillin-binding protein (PBP) was demonstrated in methicillin-resistant strains of Staphylococcus epidermidis, S. haemolyticus, S. hominis, and S. simulans. In these four species, the apparent molecular mass of this protein was analogous to that of PBP 2' of methicillin-resistant S. aureus SR 1550-9. It exhibited a low affinity for methicillin, cephalothin, and cefamandole; and its synthesis was methicillin inducible. Peptide mapping of this PBP from the four species yielded identical results that were analogous to those obtained with S. aureus SR 1550-9. These results suggest that this protein is similar to, if not the same as, PBP 2' of S. aureus and that it is involved in methicillin resistance in the four species studied.

Bacterial Proteins↗

PubMed1998

Effects of subinhibitory concentrations of antibiotics on alpha-toxin (hla) gene expression of methicillin-sensitive and methicillin-resistant Staphylococcus aureus isolates.

Concentrations of antibiotics below the MIC are able to modulate the expression of virulence-associated genes. In this study, the influence of subinhibitory doses of 31 antibiotics on the expression of the gene encoding the staphylococcal alpha-toxin (hla), a major virulence factor of Staphylococcus aureus, was investigated with a novel gene fusion protocol. The most striking observation was a strong induction of hla expression by subinhibitory concentrations of beta-lactams and an almost complete inhibition of alpha-toxin expression by clindamycin. Whereas glycopeptide antibiotics had no effect, the macrolide erythromycin and several aminoglycosides reduced and fluoroquinolones slightly stimulated hla expression. Furthermore, Northern blot analysis of hla mRNA and Western blot (immunoblot) analysis of culture supernatants of both methicillin-sensitive and methicillin-resistant S. aureus strains revealed that methicillin-induced alpha-toxin expression is a common phenomenon of alpha-toxin-producing strains. Some methicillin-resistant S. aureus isolates produced up to 30-fold more alpha-toxin in the presence of 10 microg of methicillin per ml than in its absence. The results indicate that the novel gene fusion technique is a useful tool for studying the modulation of virulence gene expression by antibiotics. Moreover, the results suggest that the effects of certain antibiotics on virulence properties may be relevant for the management of S. aureus infections.

Anti-Bacterial Agents↗

PubMed2004

Investigation of colonization with methicillin-resistant and methicillin-susceptible Staphylococcus aureus in an outpatient population in Turkey.

Methicillin-resistant Staphylococcus aureus (MRSA), known as a nosocomial pathogen, has been isolated from community-acquired infections since the 1980s. It has been reported that there are carriers of MRSA in the community although the rate of carriers is low and the most important risk factor of community-acquired carriage is hospitalization or referral to healthcare facilities. We attempted to investigate methicillin-resistant and methicillin-susceptible S. aureus colonization, respectively, in nasal and axillary swabs obtained from 500 patients without a history of hospitalization who were admitted to outpatient clinics and from 102 healthcare workers chosen as a control group. Of the patients, 9.4% had nasal S. aureus colonization without methicillin-resistant strains. Of the health care workers, 8.8% had S. aureus colonization without methicillin-resistant strains and only one worker had MRSA. The nasal carriage ratio of S. aureus in children was found to be 19.1% (22 of 115), and that in adults was 6.5% (25 of 385). The difference between the two age groups was determined as statistically significant (P = 0.006).

Adult↗

PubMedDate not supplied

In vitro activity of fosfomycin against methicillin-susceptible and methicillin-resistant Staphylococcus aureus.

The in vitro antibacterial activity of fosfomycin was compared to that of oxacillin, cefazolin, ceftriaxone and vancomycin against isolates of Staphylococcus aureus from patients treated at the University of Vienna General Hospital. Of 211 strains, 104 were methicillin-susceptible and 107 were methicillin-resistant. Fosfomycin inhibited over 90% of the strains at concentrations of less than or equal to 64 mg/l, independent of methicillin susceptibility or resistance. The minimal bactericidal concentrations (MBC) were one dilution above the minimal inhibitory concentrations (MIC). Vancomycin showed activity similar to fosfomycin while other beta-lactam antibiotics such as oxacillin, cefazolin and ceftriaxone were inactive against methicillin-resistant S. aureus. Fosfomycin at a high dosage seems to be a potential drug for the treatment of infections due to methicillin-resistant S. aureus.

Anti-Bacterial Agents↗

PubMed1998

Bacteremia due to methicillin-resistant staphylococci occurs more frequently in neutropenic patients who received antimicrobial prophylaxis and is associated with higher mortality in comparison to methicillin-sensitive bacteriemia.

Bacteriemia due to coagulase-negative staphylococci (CNS) resistant to methicillin and sensitive only to glycopeptides in 220 cancer patients was prospectively analyzed for risk factors and outcome. A group of 33 cases of bacteriemia with CNS-sensitive only to glycopeptides was compared with a group of 187 cases with CNS sensitive to methicillin. All cases appeared in two affiliated major cancer institutes in Bratislava with the same antibiotic policy. Univariate analysis showed differences in recorded risk factors: acute leukemia (48 vs. 33%, P < 0.05), neutropenia (57 vs. 32%, P < 0.045), previous prophylaxis with quinolones (30 vs. 11%, P < 0.01) and penicillin-V (15 vs. 3%, P < 0.02) and previous colonisation with CNS (27 vs. 3%, P < 0.01) were more frequently associated with bacteriemia resistant to methicillin and sensitive only to glycopeptides. Attributable mortality was also higher in this subgroup in comparison to bacteriemias with CNS sensitive to methicillin (12 vs. 3%, P < 0.05) however, overall mortality was similar. Bacteriemias due to CNS caused by sensitivity only to glycopeptides occurred more frequently in neutropenic patients (1), with acute leukemia (2), receiving quinolone and penicillin prophylaxis (3), and previously colonized (4), patients and had worse prognosis in comparison to those with methicillin-sensitive staphylococcal bacteriemias.

Antibiotic Prophylaxis↗

PubMed1996

Tracking the evolutionary origin of the methicillin resistance gene: cloning and sequencing of a homologue of mecA from a methicillin susceptible strain of Staphylococcus sciuri.

The gene mecA, a central genetic determinant of methicillin resistance in Staphylococcus aureus and coagulase-negative staphylococci of human origin, has an unknown extra species origin in these human pathogens. After screening isolates representing over 15 different species within the genus Staphylococcus we could identify only one--S. sciuri--in which each of over 150 independent isolates showed positive hybridization with a mecA-specific DNA probe isolated from a methicillin-resistant strain of S. aureus, (MRSA). Yet, the majority of these isolates showed no resistance to penicillin or methicillin. The mecA gene homologue was cloned and sequenced from a S. sciuri strain and the sequence of mecA was compared to that of the mecA of prototype strains of methicillin resistant S. aureus and S. epidermidis. Similarly to mecA of MRSA, the mecA homologue of S. sciuri was composed of a putative transglycosylase and a transpeptidase domain the latter showing all the conserved motifs typical of the active sites of the penicillin binding domain of transpeptidases. Overall similarity between the deduced amino acid sequences of mecA of MRSA and the mecA homologue of S. sciuri was 88%. On the other hand, comparison of the transpeptidase domain of the S. sciuri mecA to the corresponding domain alone of the MRSA mecA showed a similarity of 96% and an identity of 91%, while comparison of the putative transglycosylase domains of the two bacteria showed only a 80% similarity and 68% identity of amino acid sequences. Our data suggests that mecA of methicillin-resistant strains of staphylococci pathogenic to Man originated within the genus of Staphylococcus from an evolutionary relative of the mecA homologue that we have identified in S. sciuri and which may perform a normal physiological function in this bacterium unrelated to beta-lactam resistance.

Animals↗

PubMed2002

Prospective comparison of risk factors and demographic and clinical characteristics of community-acquired, methicillin-resistant versus methicillin-susceptible Staphylococcus aureus infection in children.

CONTEXT: Community-acquired, methicillin-resistant (CA-MRSA) infections in children are increasing in frequency for unknown reasons. OBJECTIVES: To compare the presence of risk factors for methicillin resistance between patients with CA-MRSA and community-acquired methicillin-susceptible (CA-MSSA) infection and to compare the presence of risk factors among household contacts of the patients from both groups. To compare the demographic and clinical characteristics between children with CA-MRSA and CA-MSSA infection. DESIGN: Prospective observational study conducted between February 2, 2000 and November 14, 2000, excluding the month of May and the period between September 2 and October 15. SETTING AND PATIENTS: Texas Children's Hospital, Houston, TX; inpatients and outpatients with community-acquired infection. MAIN OUTCOME MEASURES: Proportion of MRSA among all community-acquired infections. The presence of risk factors associated with methicillin resistance among patients, and their household contacts, with CA-MRSA and CA-MSSA. RESULTS: The monthly rates of methicillin resistance of varied between 35 and 51%. CA-MSSA isolates were associated with deep-seated infections significantly more often (30%) than CA-MRSA isolates (11%; P= 0.01). CA-MRSA isolates were generally susceptible to clindamycin and trimethoprim-sulfamethoxazole and resistant to erythromycin. There were no significant differences in the exposure to risk factors between children with CA-MRSA and CA-MSSA infection. No significant risk factors for CA-MRSA were identified among household contacts. CONCLUSIONS: MRSA is an established, community-acquired pathogen in our area. This necessitates a change in empiric therapy of infections suspected to be caused by.

Adolescent↗