Comparative Study of the Susceptibilities of Major Epidemic Clones of Methicillin-Resistant Staphylococcus aureus to Oxacillin and to the New Broad-Spectrum Cephalosporin Ceftobiprole

ABSTRACT Multidrug-resistant strains of Staphylococcus aureus continue to increase in frequency worldwide, both in hospitals and in the community, raising serious problems for the chemotherapy of staphylococcal disease. Ceftobiprole (BPR; BAL9141), the active constituent of the prodrug ceftobiprole medocaril (BAL5788), is a new cephalosporin which was already shown to have powerful activity against a number of bacterial pathogens, including S. aureus. In an effort to test possible limits to the antibacterial spectrum and efficacy of BPR, we examined the susceptibilities of the relatively few pandemic methicillin-resistant S. aureus (MRSA) clones that are responsible for the great majority of cases of staphylococcal disease worldwide. We also included in the tests the highly oxacillin-resistant subpopulations that are present with low frequencies in the cultures of these clones. Such subpopulations may represent a natural reservoir from which MRSA strains with decreased susceptibility to BPR may emerge in the future. We also tested the efficacy of BPR against MRSA strains with reduced susceptibility to vancomycin and against MRSA strains carrying the enterococcal vancomycin resistance gene complex. BPR was shown to be uniformly effective against all these resistant MRSA strains, and the mechanism of superb antimicrobial activity correlated with the strikingly increased affinity of the cephalosporin against penicillin-binding protein 2A, the protein product of the antibiotic resistance determinant mecA.

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Antibiotic Resistance and Virulence Gene Characteristics of Methicillin-Resistant Staphylococcus aureus (MRSA) Isolated from Healthy Edible Marine Fish

International Journal of Microbiology ◽

10.1155/2020/9803903 ◽

2020 ◽

Vol 2020 ◽

pp. 1-9

Author(s):

Justine Fri ◽

Henry A. Njom ◽

Collins N. Ateba ◽

Roland N. Ndip

Keyword(s):

Staphylococcus Aureus ◽

Antibiotic Resistance ◽

Marine Fish ◽

Control Strategies ◽

Virulence Gene ◽

Multidrug Resistant ◽

Methicillin Resistant ◽

Vancomycin Mics ◽

Resistant Strains ◽

Mrsa Strains

Thirty-three (33) isolates of methicillin-resistant Staphylococcus aureus (MRSA) from healthy edible marine fish harvested from two aquaculture settings and the Kariega estuary, South Africa, were characterised in this study. The phenotypic antimicrobial susceptibility profiles to 13 antibiotics were determined, and their antibiotic resistance determinants were assessed. A multiplex PCR was used to determine the epidemiological groups based on the type of SCCmec carriage followed by the detection of staphylococcal enterotoxin-encoding genes sea-sed and the Panton Valentine leucocidin gene (pvl). A high antibiotic resistance percentage (67–81%) was observed for Erythromycin, Ampicillin, Rifampicin, and Clindamycin, while maximum susceptibility to Chloramphenicol (100%), Imipenem (100%), and Ciprofloxacin (94%) was recorded. Nineteen (58%) of the MRSA strains had Vancomycin MICs of ≤2 μg/mL, 4 (12%) with MICs ranging from 4–8 μg/mL, and 10 (30%) with values ≥16 μg/mL. Overall, 27 (82%) isolates were multidrug-resistant (MDR) with Erythromycin-Ampicillin-Rifampicin-Clindamycin (E-AMP-RIP-CD) found to be the dominant antibiotic-resistance phenotype observed in 4 isolates. Resistance genes such as tetM, tetA, ermB, blaZ, and femA were detected in two or more resistant strains. A total of 19 (58%) MRSA strains possessed SCCmec types I, II, or III elements, characteristic of healthcare-associated MRSA (HA-MRSA), while 10 (30%) isolates displayed SCCmec type IVc, characteristic of community-associated MRSA (CA-MRSA). Six (18%) of the multidrug-resistant strains of MRSA were enterotoxigenic, harbouring the see, sea, or sec genes. A prevalence of 18% (6/33) was also recorded for the luk-PVL gene. The findings of this study showed that marine fish contained MDR-MRSA strains that harbour SCCmec types, characteristic of either HA-MRSA or CA-MRSA, but with a low prevalence of enterotoxin and pvl genes. Thus, there is a need for continuous monitoring and implementation of better control strategies within the food chain to minimise contamination of fish with MDR-MRSA and the ultimate spread of the bug.

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The Continuing Threat of Methicillin-Resistant Staphylococcus aureus

Antibiotics ◽

10.3390/antibiotics8020052 ◽

2019 ◽

Vol 8 (2) ◽

pp. 52 ◽

Cited By ~ 41

Author(s):

Márió Gajdács

Keyword(s):

Staphylococcus Aureus ◽

Multidrug Resistant ◽

Resistant Bacteria ◽

Penicillin Binding Protein ◽

Methicillin Resistant ◽

Drug Candidates ◽

Modern Age ◽

Additional Resistance ◽

Infectious Disease Specialists ◽

Mrsa Strains

Staphylococcus aureus has been an exceptionally successful pathogen, which is still relevant in modern age-medicine due to its adaptability and tenacity. This bacterium may be a causative agent in a plethora of infections, owing to its abundance (in the environment and in the normal flora) and the variety of virulence factors that it possesses. Methicillin-resistant S. aureus (MRSA) strains—first described in 1961—are characterized by an altered penicillin-binding protein (PBP2a/c) and resistance to all penicillins, cephalosporins, and carbapenems, which makes the β-lactam armamentarium clinically ineffective. The acquisition of additional resistance determinants further complicates their eradication; therefore, MRSA can be considered as the first representative of multidrug-resistant bacteria. Based on 230 references, the aim of this review is to recap the history, the emergence, and clinical features of various MRSA infections (hospital-, community-, and livestock-associated), and to summarize the current advances regarding MRSA screening, typing, and therapeutic options (including lipoglycopeptides, oxazolidinones, anti-MRSA cephalosporins, novel pleuromutilin-, tetracycline- and quinolone-derivatives, daptomycin, fusidic acid, in addition to drug candidates in the development phase), both for an audience of clinical microbiologists and infectious disease specialists.

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Staphylococcus aureus PBP4 Is Essential for β-Lactam Resistance in Community-Acquired Methicillin-Resistant Strains

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00049-08 ◽

2008 ◽

Vol 52 (11) ◽

pp. 3955-3966 ◽

Cited By ~ 105

Author(s):

Guido Memmi ◽

Sergio R. Filipe ◽

Mariana G. Pinho ◽

Zhibiao Fu ◽

Ambrose Cheung

Keyword(s):

Staphylococcus Aureus ◽

Methicillin Resistance ◽

Healthy Individuals ◽

Penicillin Binding Protein ◽

Methicillin Resistant ◽

Fold Reduction ◽

Resistant Strains ◽

Mrsa Strains ◽

Hospital Acquired ◽

Major Target

ABSTRACT Recent cases of infections caused by community-acquired methicillin-resistant Staphylococcus aureus (MRSA) (CA-MRSA) strains in healthy individuals have raised concerns worldwide. CA-MRSA strains differ from hospital-acquired MRSAs by virtue of their genomic background and increased virulence in animal models. Here, we show that in two common CA-MRSA isolates, USA300 and MW2 (USA400), a loss of penicillin binding protein 4 (PBP4) is sufficient to cause a 16-fold reduction in oxacillin and nafcillin resistance, thus demonstrating that mecA, encoding PBP2A, is not the sole determinant of methicillin resistance in CA-MRSA. The loss of PBP4 was also found to severely affect the transcription of PBP2 in cells after challenge with oxacillin, thus leading to a significant decrease in peptidoglycan cross-linking. Autolysis, which is commonly associated with the killing mechanism of penicillin and β-lactams, does not play a role in the reduced resistance phenotype associated with the loss of PBP4. We also showed that cefoxitin, a semisynthetic β-lactam that binds irreversibly to PBP4, is synergistic with oxacillin in killing CA-MRSA strains, including clinical CA-MRSA isolates. Thus, PBP4 represents a major target for drug rediscovery against CA-MRSA, and a combination of cefoxitin and synthetic penicillins may be an effective therapy for CA-MRSA infections.

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Intravenous Antibiotics Used in the Treatment of Methicillin-Resistant Staphylococcus Aureus

AACN Advanced Critical Care ◽

10.4037/nci.0000000000000095 ◽

2015 ◽

Vol 26 (3) ◽

pp. 233-243

Author(s):

Kristine Anne Scordo

Keyword(s):

Staphylococcus Aureus ◽

Methicillin Resistant Staphylococcus Aureus ◽

Multidrug Resistant ◽

Medical Procedures ◽

Term Care ◽

Methicillin Resistant ◽

Intravenous Antibiotics ◽

Resistant Strains ◽

Hospital Acquired

Methicillin-resistant Staphylococcus aureus (MRSA) continues to cause significant morbidity and mortality. Despite advances in medical care, the prevalence of both community-acquired and hospital-acquired MRSA has progressively increased. Community-acquired MRSA typically occurs in patients without recent illness or hospitalization, presents as acute skin and soft tissue infections, and is usually not multidrug resistant. Hospital-acquired MRSA, however, presents in patients recently hospitalized or treated in long-term care settings and in those who have had medical procedures and is usually associated with multidrug-resistant strains. Both types of infections, if not properly treated, have the potential to become invasive. This article discusses current intravenous antibiotics that are available for the empiric treatment of MRSA infections along with a newer phenomenon known as the “seesaw effect.”

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Comparison of Methicillin-Resistant Staphylococcus aureus Isolates from Cellulitis and from Osteomyelitis in a Taiwan Hospital, 2016–2018

Journal of Clinical Medicine ◽

10.3390/jcm8060816 ◽

2019 ◽

Vol 8 (6) ◽

pp. 816 ◽

Cited By ~ 1

Author(s):

Kuo-Ti Peng ◽

Tsung-Yu Huang ◽

Yao-Chang Chiang ◽

Yu-Yi Hsu ◽

Fang-Yi Chuang ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Antibiotic Resistance ◽

Methicillin Resistant Staphylococcus Aureus ◽

Joint Infection ◽

Sccmec Type ◽

Multidrug Resistant ◽

Chang Gung Memorial Hospital ◽

Methicillin Resistant ◽

Mrsa Strains ◽

Resistance Rates

Methicillin-resistant Staphylococcus aureus (MRSA) causes superficial infections such as cellulitis or invasive infections such as osteomyelitis; however, differences in MRSA isolates from cellulitis (CL-MRSA) and from osteomyelitis (OM-MRSA) at the same local area remain largely unknown. A total of 221 MRSA isolates including 106 CL-MRSA strains and 115 OM-MRSA strains were collected at Chang-Gung Memorial Hospital in Taiwan between 2016 and 2018, and their genotypic and phenotypic characteristics were compared. We found that OM-MRSA isolates significantly exhibited higher rates of resistance to multiple antibiotics than CL-MRSA isolates. Genotypically, OM-MRSA isolates had higher proportions of the SCCmec type III, the sequence type ST239, and the spa type t037 than CL-MRSA isolates. Besides the multidrug-resistant lineage ST239-t037-SCCmecIII more prevalent in OM-MRSA, higher antibiotic resistance rates were also observed in several other prevalent lineages in OM-MRSA as compared to the same lineages in CL-MRSA. Furthermore, when prosthetic joint infection (PJI) associated and non-PJI-associated MRSA strains in osteomyelitis were compared, no significant differences were observed in antibiotic resistance rates between the two groups, albeit more diverse genotypes were found in non-PJI-associated MRSA. Our findings therefore suggest that deep infections may allow MRSA to evade antibiotic attack and facilitate the convergent evolution and selection of multidrug-resistant lineages.

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Missense Mutations in PBP2A Affecting Ceftaroline Susceptibility Detected in Epidemic Hospital-Acquired Methicillin-Resistant Staphylococcus aureus Clonotypes ST228 and ST247 in Western Switzerland Archived since 1998

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.04068-14 ◽

2015 ◽

Vol 59 (4) ◽

pp. 1922-1930 ◽

Cited By ~ 52

Author(s):

William L. Kelley ◽

Ambre Jousselin ◽

Christine Barras ◽

Emmanuelle Lelong ◽

Adriana Renzoni

Keyword(s):

Staphylococcus Aureus ◽

University Hospital ◽

Surveillance Program ◽

Missense Mutations ◽

Unknown Parameters ◽

Methicillin Resistant ◽

Content Type ◽

Resistant Strains ◽

Mrsa Strains

ABSTRACTThe development and maintenance of an arsenal of antibiotics is a major health care challenge. Ceftaroline is a new cephalosporin with activity against methicillin-resistantStaphylococcus aureus(MRSA); however, no reports concerning MRSA ceftaroline susceptibility have been reported in Switzerland. We tested thein vitroactivity of ceftaroline against an archived set of 60 MRSA strains from the University Hospital of Geneva collected from 1994 to 2003. Our results surprisingly revealed ceftaroline-resistant strains (MIC, >1 μg/ml in 40/60 strains; EUCAST breakpoints, susceptible [S], ≤1 μg/ml; resistant [R], >1 μg/ml) were present from 1998 to 2003. The detected resistant strains predominantly belonged to sequence type 228 (ST228) (South German clonotype) but also to ST247 (Iberian clonotype). A sequence analysis of these strains revealed missense mutations in the penicillin-binding protein 2A (PBP2A) allosteric domain (N146K or E239K and N146K-E150K-G246E). The majority of our ST228 PBP2A mutations (N146K or E150K) were distinct from ST228 PBP2A allosteric domain mutations (primarily E239K) recently described for MRSA strains collected in Thailand and Spain during the 2010 Assessing Worldwide Antimicrobial Resistance Evaluation (AWARE) global surveillance program. We also found that similar allosteric domain PBP2A mutations (N146K) correlated with ceftaroline resistance in an independent external ST228 MRSA set obtained from the nearby University Hospital of Lausanne, Lausanne, Switzerland, collected from 2003 to 2008. Thus, ceftaroline resistance was observed in our archived strains (including two examples of an MIC of 4 µg/ml for the Iberian ST247 clonotype with the triple mutation N146K/E150K/G246E), at least as far back as 1998, considerably predating the commercial introduction of ceftaroline. Our results reinforce the notion that unknown parameters can potentially exert selective pressure on PBP2A that can subsequently modulate ceftaroline resistance.

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Phenotypic and Molecular Typing of Nosocomial Methicillin-Resistant Staphylococcus aureus Strains Susceptible to Gentamicin Isolated in France from 1995 to 1997

Journal of Clinical Microbiology ◽

10.1128/jcm.38.1.185-190.2000 ◽

2000 ◽

Vol 38 (1) ◽

pp. 185-190

Author(s):

Jacques-Olivier Galdbart ◽

Anne Morvan ◽

Nevine El Solh

Keyword(s):

Staphylococcus Aureus ◽

Molecular Typing ◽

Insertion Sequence ◽

Methicillin Resistant Staphylococcus Aureus ◽

Phage Typing ◽

Methicillin Resistant ◽

Before And After ◽

Resistant Strains ◽

Mrsa Strains

ABSTRACT Methicillin-resistant strains susceptible to gentamicin (Gm s MRSA) have emerged since 1993 in several French hospitals. To study whether particular clones have spread in various French cities and whether some clones are related to gentamicin-resistant (Gm r ) MRSA strains, various methods (antibiotyping, phage typing, determination of Sma I macrorestriction patterns before and after hybridization with IS 256 transposase and aacA-aphD probes) were used to compare 62 Gm s MRSA strains isolated from 1995 to 1997 in nine cities and 15 Gm r MRSA strains. Eighteen major Sma I genotypes were identified, of which 11 included only Gm s MRSA strains and 5 included only Gm r MRSA strains. Each of the Gm r MRSA strains contained 6 to 13 Sma I fragments hybridizing with the insertion sequence IS 256 , of which a single band also hybridized with the aacA-aphD gene. No such hybridizing sequences were detected in 60 of the 62 Gm s MRSA strains. Thus, the divergence between Gm r and Gm s MRSA strains is revealed, not only by their distributions in distinct Sma I genotypes but also by the differences in hybridization patterns. Two of the 62 Gm s MRSA strains had the uncommon feature of carrying several Sma I bands hybridizing with IS 256 , suggesting that they are possibly related to the Gm r MRSA strains grouped in the same Sma I genotype. Five of the 11 Sma I genotypes including only Gm s MRSA strains contained strains from diverse cities, isolated during different years and with different antibiograms, suggesting that some clones have spread beyond their cities of origin and persisted.

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Livestock-Associated Methicillin-Resistant Staphylococcus aureus (MRSA) in Purulent Subcutaneous Lesions of Farm Rabbits

Foods ◽

10.3390/foods9040439 ◽

2020 ◽

Vol 9 (4) ◽

pp. 439 ◽

Cited By ~ 1

Author(s):

Vanessa Silva ◽

Telma de Sousa ◽

Paula Gómez ◽

Carolina Sabença ◽

Madalena Vieira-Pinto ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Antimicrobial Agents ◽

Methicillin Resistant Staphylococcus Aureus ◽

Multidrug Resistant ◽

Diffusion Method ◽

Spa Typing ◽

Disk Diffusion Method ◽

Methicillin Resistant ◽

Resistance To Penicillin ◽

Mrsa Strains

Methicillin-resistant Staphylococcus aureus (MRSA) are one of the main pathogens associated with purulent infections. MRSA clonal complex 97 (CC97) has been identified in a wide diversity of livestock animals. Therefore, we aimed to investigate the antibiotic resistance profiles of MRSA strains isolated from purulent lesions of food-producing rabbits. Samples from purulent lesions of 66 rabbits were collected in a slaughterhouse in Portugal. Samples were seeded onto ORSAB plates with 2 mg/L of oxacillin for MRSA isolation. Susceptibility to antibiotics was tested by the disk diffusion method against 14 antimicrobial agents. The presence of resistance genes, virulence factors and the immune evasion cluster (IEC) system was studied by polymerase chain reaction. All isolates were characterized by multilocus sequence typing (MLST), agr and spa typing. From the 66 samples analyzed, 16 (24.2%) MRSA were detected. All strains were classified as multidrug-resistant as they were resistant to at least three classes of antibiotics. All isolates showed resistance to penicillin, erythromycin and clindamycin. Seven isolates were resistant to gentamicin and harbored the aac(6′)-Ie-aph (2″)-Ia gene. Resistance to tetracycline was detected in 10 isolates harboring the tet(K) gene. The IEC genes were detected in three isolates. MRSA strains belonged to CC97, CC1, CC5, CC15 or CC22. The isolates were assigned to six different spa types. In this study we found a moderate prevalence of multidrug-resistant MRSA strains in food-producing rabbits. This may represent concern for food safety and public health, since cross-contamination may occur, leading to the spread of MRSA and, eventually, the possibility of ingestion of contaminated meat.

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β-Lactam Resistance in Methicillin-Resistant Staphylococcus aureus USA300 Is Increased by Inactivation of the ClpXP Protease

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02802-14 ◽

2014 ◽

Vol 58 (8) ◽

pp. 4593-4603 ◽

Cited By ~ 34

Author(s):

Kristoffer T. Bæk ◽

Angelika Gründling ◽

René G. Mogensen ◽

Louise Thøgersen ◽

Andreas Petersen ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Cell Envelope ◽

Penicillin Binding Protein ◽

Gene Encoding ◽

Resistance Level ◽

Methicillin Resistant ◽

Content Type ◽

Usa300 Strain ◽

Mrsa Strains ◽

Peptidoglycan Hydrolysis

ABSTRACTMethicillin-resistantStaphylococcus aureus(MRSA) has acquired themecAgene encoding a peptidoglycan transpeptidase, penicillin binding protein 2a (PBP2a), which has decreased affinity for β-lactams. Quickly spreading and highly virulent community-acquired (CA) MRSA strains recently emerged as a frequent cause of infection in individuals without exposure to the health care system. In this study, we found that the inactivation of the components of the ClpXP protease substantially increased the β-lactam resistance level of a CA-MRSA USA300 strain, suggesting that the proteolytic activity of ClpXP controls one or more pathways modulating β-lactam resistance. These pathways do not involve the control ofmecAexpression, as the cellular levels of PBP2a were unaltered in theclpmutants. An analysis of the cell envelope properties of theclpXandclpPmutants revealed a number of distinct phenotypes that may contribute to the enhanced β-lactam tolerance. Both mutants displayed significantly thicker cell walls, increased peptidoglycan cross-linking, and altered composition of monomeric muropeptide species compared to those of the wild types. Moreover, changes in Sle1-mediated peptidoglycan hydrolysis and altered processing of the major autolysin Atl were observed in theclpmutants. In conclusion, the results presented here point to an important role for the ClpXP protease in controlling cell wall metabolism and add novel insights into the molecular factors that determine strain-dependent β-lactam resistance.

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Characterization of methicillin-resistant Staphylococcus aureus strains in sewage treatment plants in Tehran, Iran

Journal of Water and Health ◽

10.2166/wh.2021.247 ◽

2021 ◽

Author(s):

Fateh Rahimi ◽

Mohammad Katouli ◽

Mohammad R. Pourshafie

Keyword(s):

Staphylococcus Aureus ◽

Sccmec Type ◽

Sewage Treatment ◽

Multidrug Resistant ◽

Methicillin Resistant ◽

Sewage Treatment Plants ◽

Type Iii ◽

Predominant Type ◽

Key Factor ◽

Mrsa Strains

Abstract Multidrug-resistant Staphylococcus aureus strains have been commonly found in hospitals and communities causing wide ranges of infections among humans and animals. Typing of these strains is a key factor to reveal their clonal dissemination in different regions. We investigated the prevalence and dissemination of different clonal groups of S. aureus with resistance phenotype to multiple antibiotics in two sewage treatment plants (STPs) in Tehran, Iran over four sampling occasions. A total of 576 S. aureus were isolated from the inlet, sludge and outlet. Of these, 80 were identified as methicillin-resistant S. aureus (MRSA) and were further characterized using a combination of Phene Plate (PhP) typing, staphylococcal cassette chromosome mec (SCCmec), ccr types, prophage and antibiotic-resistant profiling. In all, eight common type (CT) and 13 single PhP type were identified in both STPs, with one major CT accounting for 38.8% of the MRSA strains. These strains belonged to three prophage patterns and five prophage types with SCCmec type III being the predominant type. Resistance to 11 out of the 17 antibiotics tested was significantly (P < 0.0059) higher among the MRSA isolates than methicillin-sensitive S. aureus (MSSA) strains. The persistence of the strains in samples collected from the outlet of both STPs was 31.9% for MRSA and 23.1% for MSSA. These data indicated that while the sewage treatment process, in general, is still useful for removing most MRSA populations, some strains with SCCmec type III may have a better ability to survive the STP process.

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