Open access peer-reviewed chapter

Mechanistic Insights of Drug Resistance in Staphylococcus aureus with Special Reference to Newer Antibiotics

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Atamjit Singh, Kirandeep Kaur, Pallvi Mohana, Avneet Kaur, Komalpreet Kaur, Shilpa Heer, Saroj Arora, Neena Bedi and Preet Mohinder Singh Bedi

Submitted: 02 March 2021 Reviewed: 22 August 2021 Published: 15 September 2021

DOI: 10.5772/intechopen.100045

From the Edited Volume

Insights Into Drug Resistance in Staphylococcus aureus

Edited by Amjad Aqib

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Staphylococcus aureus is the most ubiquitous microorganism in both environment as well as animals and exists as commensal and pathogenic bacterium. In past few years it has been emerged as a superbug causing serious burden on healthcare system. This bacterium has been found to be the most resistant one toward most of the antibiotics due to its rapid structural and genetic modifications. This chapter will shed light on various types of molecular mechanisms responsible for resistance of Staphylococcus aureus showcasing how it has been emerged as a superbug. Moreover, the recent approaches which include exploring of different drug targets keeping in view the structural and functional behavior of the Staphylococcus aureus has also been discussed.


  • Antimicrobial resistance
  • Staphylococcus aureus
  • Superbug
  • Resistance Mechanism
  • Drug resistance
  • Bacterial resistance

1. Introduction

Staphylococcus aureus is a Gram-positive, catalase and coagulase positive strain of bacteria belongs to Micrococcaceae family. Staphylococcus spp. to which these bacteria belong is commonly found in nature and human flora. Staphylococcus aureus is generally isolated from community as well as hospital gained infections and have capability to cause superficial to life threatening infections [1, 2, 3]. However, the worst scenario in field of microbiology was observed in late 90’s when resistance among several microbes including Staphylococcus aureus was reported for various antibiotics. Staphylococcus aureus was the most prominent threat among all other pathogens due to the rapid emergence of resistance in it. The inappropriate use of antimicrobials in clinical therapy and agriculture, extensive antimicrobial consumption and transfer of antimicrobial resistant genes due to increased anthropogenic activity are potential risk factors for development of antimicrobial resistance and considered as primary reasons responsible for the rapidly growing resistance in Staphylococcus aureus [4, 5, 6]. Moreover, the intrinsic virulence of Staphylococcus aureus, its nature to adapt to the corresponding environment are some other factors which makes it the foremost challenge for microbiology scientists. Even though, many potential therapeutics have been synthesized/approved by USFDA for the treatment of Staphylococcus infections but unfortunately besides this the mortality rate of Staphylococcus bacteraemia is 20-40% [7, 8, 9]. Furthermore, the clinical sample (blood samples) of patients with nosocomial infections/staphylococcus infections were investigated which confirmed the resistant strains of Staphylococcus aureus against various antibiotics that include first- and second-generation fluroquinolones, β-Lactam antibiotics, trimethoprim sulphamethoxazole and vancomycin etc. [7, 10, 11]. Surprisingly, the number of antibiotics emerging for treatment of this bacteria is directly proportionate to the rapidly evolving resistance mechanisms within Staphylococcus aureus to combat the therapeutic efficacy of these antibiotics. In year of 2002-2003 Staphylococcus aureus was found resistant to the highly efficient antibiotic vancomycin which left the physicians with no competent antibiotic for its treatment. Subsequently it urged the need to explore more drug targets and novel approaches for new antibiotics to treat staphylococcus infections. Conclusively, the rapid structural and genetic modifications of Staphylococcus aureus counterbalance the effect of even magnificent antibiotics. Therefore, various molecular mechanisms of Staphylococcus aureus have been deeply explored in the recent past to overcome the life-threatening implications of this resistant bacteria [12, 13]. This chapter enlightens the historical evolution of resistance in Staphylococcus aureus, molecular mechanism of resistance for various antibiotics and the modified approaches for its treatment.


2. Quorum sensing in Staphylococcus aureus

Quorum sensing is a well-known phenomenon used mainly by prokaryotes for communication among themselves [14]. Particularly in bacteria quorum sensing is monitored by a set of signaling molecules called autoinducers as density dependent variables. They are released by bacteria around their surrounding environment which up on reaching at particular concentration develop a well-coordinated response. Density of autoinducers is monitored by bacteria for tracking changes in cell number and to alter the gene expression pattern. This is also a factor that is responsible for resistance of bacteria against antibiotics [15, 16]. Quorum sensing in Staphylococcus aureus has been coordinated through modified oligopeptide known as autoinducing peptide (AID). In the pathophysiology of Staphylococcus aureus regarding quorum sensing, biphasic mechanism exist. At lower cell density, Staphylococcus aureus generally express protein factors i.e. Coagulase and fibronectin binding proteins A and B etc. which promote their attachment as well as colonization while at higher cellular density Staphylococcus aureus repress these traits and initiate secretion of toxins and proteases that needed for dissemination. The switching of this gene expression is controlled by Agr quorum sensing system that consist of autoinducing peptide (AID) encoded by agrD and two other sensor kinase-response regulators called AgrC and AgrA (Figure 1) [17, 18, 19].

Figure 1.

Mechanistic insight of quorum sensing in Staphylococcus aureus.


3. Various resistance mechanisms of different classes of antibiotics in Staphylococcus aureus

3.1 Resistance to β-lactam antibiotics

In early 1940’s introduction of penicillin improved the outcome cases due to Staphylococcus infections but soon penicillin resistance Staphylococcus were recognized in early 1942 [20] which among late 1960’s reaches to 80% in both community and hospital-acquired staphylococcal isolates with well-established pattern of resistance [21]. Furthermore, blaZ gene is responsible for resistance in Staphylococcus aureus, that encodes for β-lactamase an enzyme which is synthesized when Staphylococcus aureus is exposed to β-lactam antibiotics by hydrolyzing the β-lactam ring, rendering the β-lactam inactive. blaZ is regulated by the two adjacent genes blaR1 and blaI. The gene blaR1 is anti-repressor and blaI is repressor [22]. For the synthesis of β-lactamase, the signaling pathway involves the sequential cleavage of these regulatory proteins such as blaR1 and blaI where on exposure to β-lactams, blaR1 which is a transmembrane sensor transducer cleaves itself [23, 24], cleaved protein acts as protease that directly or indirectly cleaves the repressor blaI and thus allowing the blaZ to synthesize enzyme [23]. Furthermore, Methicillin, the first semisynthetic penicillin which was resistance to penicillinase, introduced in 1961 and soon followed by the reporting of methicillin-resistance isolates [25]. The spread of Methicillin-resistant Staphylococcus aureus (MRSA) has been critical and the infections resulting from MRSA is worse than the infections outcome of methicillin ensitive strains [26]. MRSA isolates like the penicillin resistance strains too carried resistance genes for other antimicrobial agents [27]. For the resistance to methicillin, requires chromosomally localized mecA gene [28, 29], which is a part of large unique mobile genetic element, SCC mec found in all MRSA strains may contain additional genes for antimicrobial resistance [30, 31] is responsible for the synthesis of PBP2a/PBP2′ a 78-kDa protein which binds to penicillin (penicillin-binding protein 2a) [32, 33, 34]. Transpeptidation which is necessary for the cross-linkage of peptidoglycan chains is catalyzed by these membranes bound enzymes-PBPs, thought to have appeared and works similar as serine proteases. PBP2a blocks the binding of all β-lactams but allows transpeptidation and because of its low affinity it allows staphylococci to survive even in the high concentration exposure of β-lactam antibiotics. Isolates Resistance to methicillin shows resistance to all β-lactam agents, including cephalosporins [34, 35, 36]. In some MRSA strains its resistance mechanism by mecA via the mecI and mecR1 genes is regulated in the manner similar to the regulation of blaZ by the genes blaR1 and blaI when exposed to penicillin [37]. Fem genes (factor essential for resistance to methicillin resistance, also play a role in cross-linking the peptidoglycan strands and contribute in methicillin resistance [38]. Ceftaroline the fifth-generation cephalosporin according to the U.S. Food and Drug Administration (FDA) in 2010 has been considered superior among other comparator drugs for the treatment of complicated skin and soft tissue infections as well as pneumonia [39]. β -lactam antibiotics bind to other PBPs, named PBP1, −2, −3, and − 4 but in the presence of PBP2a they are unable to bind effectively to their PBP targets. Ceftaroline on other hand is active against MRSA strains because of its high binding affinity for PBP2a as comparison to other β -lactam [40]. Binding of PBPs by ceftaroline block these enzymes to catalyze the transpeptidase function that is important for the synthesis of staphylococcal cell wall [41]. Ceftaroline is generally considered safe and successfully used to treat wide infections alone and in combination with other active drugs often with daptomycin [42]. Several studied over MRSA clinal strains showed these were susceptible to ceftaroline in wide range such as >98.4% in North America [43], >83.3% in Latin America [44], >83% in Europe [45], 78.8% in Asia/South Pacific countries [46] the variation in resistance among MRSA may be due to the variation in geographical distribution of strains around the world [47, 48]. MRSA strains carry mobile genetic element known as SCCmec, which carries mecA gene [40]. Ceftaroline resistance is usually due to the nonsense mutations in mecA, resulting in amino acid sequence change in PBP2a hence a target protein mutation [49]. Glu447Lys mutation in mecA in presence of ceftaroline on SF8300 USA300 MRSA strain yields low level resistance isolates whereas COL common laboratory strain showed high ceftaroline resistance due to mutations in pbp2, pbp4 and gdpP not due to mecA [50]. There are strains developing resistance with no change in mecA [51].

3.2 Resistance to vancomycin

Vancomycin, a lipopeptide antibiotic approved by Food and Drug Administration of the United States in 1958 found in recent years that the MRSA isolates are resist to it [52]. Vancomycin works by binding to bacterial cell envelopes and inhibiting their cell wall synthesis instead of targeting protein like other antibiotics [53]. It binds to C-terminal D-Ala–D-Ala residue of the pentapeptide to inhibit the cross-bridge formation between pentapeptide and pentaglycine preventing cell wall synthesis [54]. MRSA strains shows different ranges of resistance against vancomycin according to their MIC and are named accordingly such as MRSA showing complete resistance to vancomycin is termed vancomycin-resistant Staphylococcus aureus (VRSA), showing medium resistance is termed as vancomycin intermediate-resistant Staphylococcus aureus (VISA) and least resistance as VSSA [55].

Failure in vancomycin treatment of MRSA results due to formation of intermediate-resistant isolates namely hetero resistant vancomycin-intermediate Staphylococcus aureus (hVISA) and vancomycin intermediate Staphylococcus aureus (VISA) [56] which includes features such as cell wall thickening, reduced autolytic activit and reduced growth rates [57]. Several studies found that the mutation in genes VraS(S329L), MsrR(E146K), GraR(N197S), RpoB(H481Y), Fdh2(A297V) and Sle1(67aa) were also responsible for vancomycin resistance in VISA strain Mu50 [58]. Other genes involving in high- and low-level resistance to vancomycin includes vanA, vanB, vanD, vanF, vanI, vanM, encodes for D-Ala:D-Lac ligases whereas vanC, vanE, vanG, vanL, and vanNgenes encoding D-Ala:D-Ser ligases (Figure 2) [59, 60].

Figure 2.

Molecular mechanism of Staphylococcus aureus resistance toward penicillin and vancomycin.

3.3 Resistance to lipopeptide based antibiotic daptomycin

The only approved and available lipopeptide in the US in the year 2003 with in vitro bactericidal activity and an alternative to vancomycin for various MRSA infections, is daptomycin [61]. However, during the treatment, the emergence of non-susceptible MRSA strains for daptomycin has been reported [62, 63]. Even before the approval of drug, Silverman et al. observed daptomycin non-susceptible mutants and identified number of changes such as increase in membrane fluidity, increase in net positive charge over the surface, decrease in susceptibility to daptomycin-induced depolarization and low in surface binding of daptomycin in the cytoplasmic membrane of non-susceptible strains [64, 65]. Though the basis for reduction in susceptibility to daptomycin in MRSA strains has not been fully clarified [66]. The transfer and addition of positively charged lysine molecules to phosphatidyl glycerol in the cell membrane associated with the activity of enzyme lysyl-phosphatidyl glycerol synthetase is encoded by mprF gene [67], Mutation in mprF gene causes an increase of lysyl-phosphatidyl glycerol in the outer layer of the cell membrane, leading to an increased positive charge resulting in reduced susceptibility to daptomycin [68]. mprF mutations are the most common type of mutation in MRSA strains with reduced susceptibility to daptomycin (Figure 3) [69]. Several more genes are also identified which are associated with the reduced susceptibility to daptomycin such as dsp1 or asp23. The inactivation of these genes leads to reduced daptomycin susceptibility and the overexpression of single or both of the genes leads increase in susceptibility [70] whereas expression of dltA gene contributes to the staphylococcal net positive surface charge [71]. Kanesaka et al. using transmission electron microscopy, found that the some of the strains which were exposed to daptomycin which shows resistance developed an increase in the thickness of their cell wall and their thickness decreases on revert to daptomycin susceptible [72].

Figure 3.

Molecular mechanism of Staphylococcus aureus resistance toward daptomycin via mprF.

3.4 Resistance to aminoglycosides

Aminoglycosides works by mistranslation and changing the conformation of tRNA during bacterial protein synthesis by binding to A-site present on 16S rRNA of the 30S ribosome. Some even acts by inhibiting initiation /or elongation phase thereby blocking bacterial protein synthesis [73]. Most common mechanism of resistance to aminoglycosides especially in Staphylococcus aureus includes Aminoglycoside modifying enzymes which works by acetylating, phosphorylating, or adenylating amino or hydroxyl groups therefore inactivating aminoglycosides. Hundreds of aminoglycosides modifying enzymes are known encoded by genes which are commonly found on plasmids and transposons [74]. On clinical practising with some aminoglycosides such as gentamicin, tobramycin, and amikacin these three among Aminoglycoside modifying enzymes such as ANT(4=) nucleotide transferase, bidomain AAC(6=)le-APH(2=)la acetyltransferase and phosphotransferase, and APH(3=)IIIa phosphotransferase which are common in MRSA isolates with varied appearance, shows resistance [75]. Plazomicin, a synthetic aminoglycoside showed in vitro activity against 55 MRSA isolates that expressed one or more aminoglycoside-modifying enzymes [76] and has no protection against other resistance mechanism such as 16 s rRNA methyltransferases that modifies the aminoglycoside target site but these enzymes are not reported in S. aureus (Figure 4) [77].

Figure 4.

Molecular mechanism of Staphylococcus aureus resistance toward aminoglycosides.

3.5 Resistance to oxazolidinones

Oxazolidinones, the synthetic antibiotics blocks the formation of functional 70S initiation complex thereby preventing bacterial protein synthesis. Linezolid and tedizolid types of drugs from Oxazolidinones works interrupting transitional RNA positioning by binding to the bacterial 23S rRNA at the ribosomal peptide-transferase center. Even with the similarity in both of the structure tedizolid still shows increased and better interactions at the binding site with increased potency [78]. All these resistance mechanisms make alteration to oxazolidinone binding site, most common are the point mutations occurring in the genes encoding for 23S rRNA mostly in the central loop of domain V [79]. S. aureus has four to seven copies of 23S rRNA gene collection of which determines the effect and degree of linezolid resistance [80, 81]. This kind of mutation, G2576T, in all five copies of its 23S rRNA gene has been found in the first clinical isolates of linezolid-resistant MRSA [82] are most common. Mutations in the genes which are encoding for L3 and L4 similar to mutation in 23S rRNA, induces a change in the linezolid binding site shows linezolid resistance. Studies showed structural rearrangement of the linezolid binding site due to deletion of one amino acid in L3 causing change in the position of several of the 23S rRNA bases as targeted by point mutations. Gene cfr (chloramphenicol-florfenicol resistance) linked with various mobile genetic elements also shows resistance to linezolid and other antibiotics by change in the drug binding site at the ribosomal peptide-transferase center by encoding a rRNA methyltransferase that causes change in position A2503 [83, 84, 85]. Several bacterial species port the cfr gene, a reservoir for drug resistance. MRSA isolates with cfr genes are more likely have additional antibiotic resistance genes as compared to non-cfr gene isolates. Another gene, optrA found commonly symbiosis with cfr gene in MRSA isolates also shows resistance to oxazolidinones [84]. Acts as an ATP-binding cassette transporter, which mediate the influx and efflux of drugs. Another optrA structurally similar gene poxtA first identified in MRSA isolates, shows in vitro resistance to oxazolones [86, 87, 88, 89].

3.6 Resistance to quinolones with a focus on novel antibiotic delafloxacin

The fluoroquinolones (FQ) were first introduced into clinical practice in the year 1962 along with the development of Nalidixic acid. Fluoroquinolones (FQ) are class of fully synthetic antibiotics which are active against a broad range of gram positive and gram-negative bacteria and have a pivotal role in multidrug resistance therapy in Mycobacterial infection (Tuberculosis and non-tuberculosis). To treat acute bacterial skin and skin structure infections (ABSSSIs) with both enteral and intravenous preparations FDA approved non zwitter ionic FQ delafloxacin in 2017 [90]. Due slower MICs against S. aureus than other FQs delafloxacin has a higher barrier to resistance, it can serve as ant staphylococcal drug as monotherapy. Delafloxacin is found to be effective against multiple like Streptococcus pneumoniae, anaerobic bacteria Legionella, Chlamydia pneumoniae, Neisseria gonorrhoeae, Mycoplasma spp., in addition to Staphylococcus aureus. Its activity against the enterococci is variable [91]. Delafloxacin shows a property of “dual-targeting” in which it can form complexes with DNA and topoisomerase IV or DNA gyrase. Double strand break can be produced by the inhibiting the one or both the enzymes which results in the death of bacterial cell as they lack enzymes that can repair double strand break in DNA. Delafloxacin shows more potency against Gram positive bacteria as it shows anionic behavior at neutral pH due to the substitution of the R7 position (3-hydroxy-1-azetidinyl) [90, 92]. An anionic behavior of delafloxacin makes diffusion and accumulation of drug within the bacteria more readily as it is retained in bacterial cell for longer duration at neutral intracellular pH [93]. These characteristics makes antibiotics more effective in acidic environments [94]. Depending upon the ambient pH it shows activity against biofilm related infections and intracellular infections [91]. Estimated concentration of Delafloxacin selecting resistant mutant is 8 to 32 times lesser than for other Fluoroquinolones. This difference is due to the drugs dual targeting mechanism of action. Point mutations are method by which resistance is shown by bacteria, resistance occurs due to point mutations in target enzyme or by the action of efflux pump. Point mutation in ParC subunit of topoisomerase IV results in resistance in case of Staphylococcus aureus. Delfatoxin resistance occurs due to various mutations in the target regions of topoisomerase IV [92, 93, 94, 95]. Resistance to the FQs, including delafloxacin, often involves point mutations in the target enzymes or the action of efflux pumps in bacterial cells. In S. aureus, resistance is usually mediated by point mutations in the ParC subunit of topoisomerase IV. Delafloxacin often retains potency against S. aureus resistant to other FQ drugs due to target gene mutations or modifications. This relative resistance seems related to the structure of delafloxacin (perhaps due to C-7 and C-8 substitutions); delafloxacin resistance occurs only with several mutations in the target regions of topoisomerase IV. NorA, NorB, NorC, MdeA, QacA, and QacB includes a resistant phenotype of Common S. aureus efflux pumps active against Fluoroquinolones. The antiseptic chlorhexidine gluconate is also removed from cells by the plasmid-encoded efflux pumps QacA and QacB, sometimes called antiseptic resistance genes and their acquisition in a S. aureus population is co-selected by use of chlorhexidine or FQs. Delafloxacin is not as active substrate for typical Staphylococcus aureus efflux pumps compared to other drugs in the class [96, 97, 98, 99].

3.7 Resistance to new class of antibiotics: pleuromutilins

In 1951 a compound Pleuromutilin a class of antibacterial which is isolated from a fungus called Pleurotomariids. Pleuromutilin and its natural molecule found to be effective against Gram-positive bacteria. For veterinary use Tiamulin used in livestock for the treatment of gastrointestinal and respiratory disease. Valnemulin is a second veterinary systemic Pleuromutilin antimicrobial approves and widely use in Asia and Europe. For systemic human use lefamulin was synthesized in 2006, lefamulin is novel pleuromutilin drug effective against most MRSA strains [100]. In phase 2 lefamulin was non inferior to intravenous Vancomycin. Pleuromutilin interferes with the process of protein synthesis by inhibiting the 50s subunit of the ribosome binding at site called peptidyl transfer centre [101, 102]. They specifically target the inhibition of initiation of translation. The extensive use of tiamulin and valenemulin for decades in livestock leads to MRSA strains and their mechanism of resistance to pleuromutilin are well studied. One of the resistance mechanisms involves alteration of target site on the ribosome which may require three or more mutations to develop resistant phenotype [103, 104, 105]. Resistant clones may be formed when Staphylococcus aureus acquire new genes by horizontal gene transfer including transferable cfr gene methylation a specific site on 23S rRNA. This methylation by cfr gene product results in resistance to several class of antibiotics including pleuromutilin, linezolid, streptogramin, phenicol, and lincosamides. In S. aureus is the family of at least four vga genes with variants, including vga(A)v, vga(A), vga(C), and vga(E), as well as lsa(E), all result in ribosomal protection results in cause of pleuromutilin resistance in S. aureus. Plasmid or transposons can carry strains vga(A) may become transmissible among strains. In ST398 livestock-associated MRSA strains found vga(c) strain also be carried on plasmid. The spread of mobile genetic elements among animal and human S. aureus strains raises concern for the emergence of widespread pleuromutilin resistance among human strains if drugs in this class are widely used [106, 107].

3.8 Resistance to mupirocin

Mupirocin was used as a decolonizing agent. It is widely used in CA-MRSA epidemic United States in 1990. But it was discovered in in 1970. Resistance to mupirocin by MRSA developed [10, 108]. Mupirocin resistance is developed due to ileS-2 gene [109]. The mupA and mupB genes responsible for resistance to mupirocin these genes encode novel isoleucyl-tRNA synthetases and can be carried out by plasmids [110]. The threes aspect of REDUCE-MRSA study was cluster-randomized trial that evaluate screening, isolation, and decolonization with chlorhexidine and mupirocin in intensive care unit patients [111]. Mupirocin is best suitable option for MRSA nasal decolonization but shows some side effects. Development of novel decolonization agent should be our propriety. We can also develop agents that can act synergistically with mupirocin as recently described [112, 113].

3.9 Resistance to lipoglycopeptides

Dalbavancin, oritavancin, and telavancin, the semisynthetic derivatives of glycopeptides are the three lipoglycopeptides available in the US. Glycopeptides usually inhibits bacterial cell wall synthesis by binding to D-alanyl-D-alanine (D-Ala-D-Ala) terminal of growing peptidoglycan chains [114]. Due to their distinctiveness in structural modifications of each drugs heptapeptide core, lipoglycopeptides are more powerful than vancomycin which contains lipid side chain that helps in holding the drug to cell membrane providing stability and an increase in concentration of local drug. In case of oritavancin and telavancin their interaction with the cell wall promotes another mechanism of action as concentration-dependent depolarization of cell membrane leading to increase in permeability. Because of the structure of oritavancin it allows several other mechanisms of action which includes binding to the secondary site in peptidoglycan chains, pentaglycyl bridging segment of lipid II, transpeptidation inhibition and RNA synthesis inhibition [115, 116]. A survey study conducted from 2010 to 2014 in US and Europe showed 99.9% isolates of S. aureus susceptible to oritavancin and 98% isolates susceptible to dalbavancin in global survey during 2002 to 2012 [117] with rare Lipoglycopeptide resistance among S. aureus. Recently for dalbavancin, Resistance in some clinical isolates has been reported. On structural analysis showed an increase in the thickening of cell wall and abnormal cell wall construction in dalbavancin non-susceptible isolates [118, 119].


4. Evolution of Staphylococcus aureus as superbug

Alexander Flaming accidently discovered penicillin as fungal contaminant also having bactericidal effect against Staphylococcus aureus which in turn led to bulk production of this antibiotic [120]. Consequently, death rate due to bacterial pneumonia and meningitis fell down during World War II. Penicillin was discovered to act by breaking peptidoglycan assembly within bacterial cell wall followed by cell death due to osmotic fragility [121]. In early 1940’s death rate of Staphylococcal infections was approximately 80%. However, resistance Staphylococcus aureus strains were observed after overuse of penicillin which got predominant in 1945 [122, 123, 124]. The major cause of this resistance was the eventual formation of plasmid encoded-lactamase which found to have ability of hydrolysing active moiety i.e. lactam ring of penicillin [124, 125]. The ability of plasmid encoded-lactamase to readily transfer which rises the penicillin against bacterial resistance rate up to 90-95%. Moreover, in 1950 a resistant clone of Staphylococcus aureus called phage 80/81 was responsible for the outbreak pandemic of skin infections, sepsis of skin and pneumonia. Initially it was concerned inside the premises of hospital but eventually it outspread within the public outside [126]. Australia, America and Canada were the majorly effected countries during this epidemic which lasted for almost 10 years until a methicillin came into market [127]. It was purposely designed in 1959 for the lactamase resistance strains of staphylococci and their treatment but surprisingly it worked efficiently for only one year because later on the methicillin resistance strain of Staphylococcus aureus was first observed in 1961 in United Kingdom [128]. The major cause of acquired resistance was mecA gene at specific site of chromosome. mecA gene was reported to encode an alternative penicillin binding protein gene called PBR2a and PBR2 which possessed very little binding affinity against penicillin, methicillin, nafcillin and cephem derivatives [129]. However, this resistance was found to be different from penicillin acquired resistance as it included broad spectrum antibiotics i.e. almost entire class of lactams except ceftaroline and ceftobiprole [130]. Adding on, a genetic element was found to be the prime carrier of mecA gene and was responsible for the broad-spectrum resistance as well as outbreak of its infections in 1980 [131]. Few countries that had major impact were Ireland, United States and United Kingdom. Despite the fact that it was first observed in 1961 it was highly appeared in 1980 and responsible for pandemic. MRSA was major risk for people having low immunity therefore death rate was approximately 15 times and bacteraemia was observed to be 24-fold than earlier [132]. MRSA outspread in Europe in early 1970’s was confirmed to be caused by one of the MRSA clones called 83 phages; an archaic clone which eventually became demolished and replaced by another five lineage clones of MRSA by 1980’s. The foremost MRSA infection case was observed in Sydney in 1965 followed by sporadic nosocomial MRSA infections in Melbourne, Sydney and other cities of Australia [133, 134]. Western Australia was rather reported to be free from these infections until late 1980’s when gentamicin susceptible Non-Multidrug Resistant (MDR) MRSA was observed first which later on outspread very fast [135, 136]. However, the quickest outbreak of MRSA was observed in Boston, United States of America in 1968 [137]. Number of cases increased drastically from 2.4–29% from 1968 to 1975 which rose to 56.1% till 2003 [138, 139]. Moreover, high rate of MRSA infections was observed in other parts across the world also [140, 141, 142, 143, 144, 145, 146, 147]. In japan MRSA infections invaded in academic hospitals in 1980 which later become community spread in 1990 [148]. Number of MRSA infected patients were comparatively lower than observed in America however mild increase was observed in frequency of MRSA patients from 3.8% - 9.6% in 1990-1994. But when only the outpatients were considered the MRSA infection rate was observed to be drastically rose from 4.5-35% in 1994 [149, 150]. The first clinical isolate of MRSA known to carry PVL gene in CA-MRSA era was observed in 2003. Furthermore, according to the data given by National Infectious disease register in 10-fold increase in MRSA infectious cases i.e. 120-1458 has been found in 2004. Meanwhile the countries like Norway, Sweden, Denmark and Netherland were found to be free from these infections due to strict surveillance. In the period of six years (2000-2006), Eastern Australia and Queensland were reported to have an increase of 75-315 patients per million. MRSA strains prevalent in these countries were majorly non-MDR strains which have susceptibility to ciprofloxacin and resistant at least to one of the β-lactams. It was a period of high emergence of non-MDR strains of MRSA. In 2011, surveillance studies were carried out in Asian countries to find out the patients with MRSA infections [151, 152, 153, 154]. Data revealed HA-MRSA prevalence was highest in Sri Lanka (86.5%) followed by Vietnam (74.1%), South Korea (65%), Thailand (57%) and Hong Kong (56.8%). However, the rate of infections in Indians and Philippines was quite low i.e. 22.6 and 38.1% approximately. Infected patients and staff were the major reason for the outbreak of MRSA across the countries and continents. With time and resistance MRSA had been found to be emerged, declined and modified accordingly. When initially observed, the MRSA strains were confined only to the hospitals and health care centres which later on becomes a pandemic via community spread. Moreover, livestock was also found to be affected by MRSA infections. According to last research report vancomycin was an antibiotic susceptible to MRSA however later on some investigations demonstrated Vancomycin Intermediate resistance Staphylococcus aureus (VISA) and Vancomycin Resistant Staphylococcus aureus (VRSA) in some clinical strains. If this trend gets continued to be followed further then MRSA will undoubtedly become completely resistant strain which is a serious topic of concern in field of infectious diseases [155, 156, 157, 158].


5. Conclusion

The rapid evolution of resistance in Staphylococcus aureus toward almost every antibiotic makes it a most challenging threat for human health as well as for the microbiology scientists. This bacteraemia has been reported to possess resistance mechanisms on the exposure of antibiotics only. Staphylococcus aureus quickly develop the defense/survival mechanism for even the new antibiotics which probably due to their fast structural and genetical alterations. Keeping this in view, several novel compounds are in pipeline to combat the resistant strains of Staphylococcus aureus. Moreover, identification of additional drug targets, better stewardship and combination therapies are also in process for the treatment of resistant strains of Staphylococcus aureus.



Authors are grateful to the University Grants Commission for providing NFOBC to Atamjit Singh. The authors are also thankful to Guru Nanak Dev University, Amritsar for providing various facilities to carry out the work.


Conflict of interest

The authors declare no conflict of interest.


  1. 1. Ali, E. A., Alshuaibi, O. N., & Ali, K. S. (2021). Evaluation of some antibiotic resistance in staphylococcus aureus isolated by medical laboratories aden, yemen. Electronic Journal of University of Aden for Basic and Applied Sciences, 2(1), 49-53
  2. 2. Rağbetli, C., Parlak, M., Bayram, Y., Guducuoglu, H., & Ceylan, N. (2016). Evaluation of antimicrobial resistance in Staphylococcus aureus isolates by years. Interdisciplinary perspectives on infectious diseases, 2016
  3. 3. Ioannou, C. J., Hanlon, G. W., & Denyer, S. P. (2007). Action of disinfectant quaternary ammonium compounds against Staphylococcus aureus. Antimicrobial agents and chemotherapy, 51(1), 296.C. J. Ioannou
  4. 4. Cohen, M. L. (1992). Epidemiology of drug resistance: implications for a post—antimicrobial era. Science, 257(5073), 1050-1055
  5. 5. Tomasz, A. (1994). Multiple-Antibiotic-Resistant Pathogenic Bacteria--A Report on the Rockefeller University Workshop. New England journal of medicine, 330(17), 1247-1251
  6. 6. Swartz, M. N. (1997). Use of antimicrobial agents and drug resistance
  7. 7. Lowy, F. D. (1998). Staphylococcus aureus infections. New England journal of medicine, 339(8), 520-532
  8. 8. Mandell, G. L., Bennett, J. E., & Dolin, R. (2000). Staphylococcus aureus (including Staphylococcal toxic shock). Bennett’s-Principles and Practice of Infectious Diseases
  9. 9. Mylotte, J. M., McDermott, C., & Spooner, J. A. (1987). Prospective study of 114 consecutive episodes of Staphylococcus aureus bacteremia. Reviews of infectious diseases, 9(5), 891-907
  10. 10. Diekema, D. J., Pfaller, M. A., Schmitz, F. J., Smayevsky, J., Bell, J., Jones, R. N., ... & SENTRY Participants Group. (2001). Survey of infections due to Staphylococcus species: frequency of occurrence and antimicrobial susceptibility of isolates collected in the United States, Canada, Latin America, Europe, and the Western Pacific region for the SENTRY Antimicrobial Surveillance Program, 1997-1999. Clinical Infectious Diseases, 32(Supplement_2), S114-S132
  11. 11. Hiramatsu, K., Hanaki, H., Ino, T., Yabuta, K., Oguri, T., & Tenover, F. C. (1997). Methicillin-resistant Staphylococcus aureus clinical strain with reduced vancomycin susceptibility. The Journal of antimicrobial chemotherapy, 40(1), 135-136
  12. 12. Centers for Disease Control and Prevention (CDC. (2002). Staphylococcus aureus resistant to vancomycin--United States, 2002. MMWR. Morbidity and mortality weekly report, 51(26), 565-567
  13. 13. Skinner, D., & Keefer, C. S. (1941). Significance of bacteremia caused by Staphylococcus aureus: a study of one hundred and twenty-two cases and a review of the literature concerned with experimental infection in animals. Archives of internal medicine, 68(5), 851-875
  14. 14. Rajput, A., Kaur, K. and Kumar, M., 2016. SigMol: repertoire of quorum sensing signaling molecules in prokaryotes. Nucleic acids research, 44(D1), D634-D639
  15. 15. Waters, C.M. and Bassler, B.L., 2005. Quorum sensing: cell-to-cell communication in bacteria. Annu. Rev. Cell Dev. Biol., 21, 319-346
  16. 16. Papenfort, K. and Bassler, B.L., 2016. Quorum sensing signal–response systems in Gram-negative bacteria. Nature Reviews Microbiology, 14(9), 576-588
  17. 17. Huang, J., Shi, Y., Zeng, G., Gu, Y., Chen, G., Shi, L., Hu, Y., Tang, B. and Zhou, J., 2016. Acyl-homoserine lactone-based quorum sensing and quorum quenching hold promise to determine the performance of biological wastewater treatments: an overview. Chemosphere, 157, 137-151
  18. 18. Queck, S.Y., Jameson-Lee, M., Villaruz, A.E., Bach, T.H.L., Khan, B.A., Sturdevant, D.E., Ricklefs, S.M., Li, M. and Otto, M., 2008. RNAIII-independent target gene control by the agr quorum-sensing system: insight into the evolution of virulence regulation in Staphylococcus aureus. Molecular cell, 32(1), 150-158
  19. 19. Queck, S.Y., Jameson-Lee, M., Villaruz, A.E., Bach, T.H.L., Khan, B.A., Sturdevant, D.E., Ricklefs, S.M., Li, M. and Otto, M., 2008. RNAIII-independent target gene control by the agr quorum-sensing system: insight into the evolution of virulence regulation in Staphylococcus aureus. Molecular cell, 32(1), 150-158
  20. 20. Rammelkamp, C. H., & Maxon, T. (1942). Resistance of Staphylococcus aureus to the Action of Penicillin. Proceedings of the Society for Experimental Biology and Medicine, 51(3), 386-389
  21. 21. Chambers, H. F. (2001). The changing epidemiology of Staphylococcus aureus?. Emerging infectious diseases, 7(2), 178
  22. 22. Kernodle, D. S. (2000). Gram-positive pathogens. Fischetti, VA, 609-620
  23. 23. Gregory, P. D., Lewis, R. A., Curnock, S. P., & Dyke, K. G. H. (1997). Studies of the repressor (BlaI) of β-lactamase synthesis in Staphylococcus aureus. Molecular microbiology, 24(5), 1025-1037
  24. 24. Zhang, H. Z., Hackbarth, C. J., Chansky, K. M., & Chambers, H. F. (2001). A proteolytic transmembrane signaling pathway and resistance to β-lactams in staphylococci. Science, 291(5510), 1962-1965
  25. 25. Jevons, M. P. (1961). Letter Br. Med J, 1, 124-125
  26. 26. Cosgrove, S. E., Sakoulas, G., Perencevich, E. N., Schwaber, M. J., Karchmer, A. W., & Carmeli, Y. (2003). Comparison of mortality associated with methicillin-resistant and methicillin-susceptible Staphylococcus aureus bacteremia: a meta-analysis. Clinical infectious diseases, 36(1), 53-59
  27. 27. Lyon, B. R., Iuorio, J. L., May, J. W., & Skurray, R. A. (1984). Molecular epidemiology of multiresistant Staphylococcus aureus in Australian hospitals. Journal of medical microbiology, 17(1), 79-89
  28. 28. Kernodle, D. S. (2000). Gram-positive pathogens. Fischetti, VA, 609-620
  29. 29. Chambers, H. F. (1997). Methicillin resistance in staphylococci: molecular and biochemical basis and clinical implications. Clinical microbiology reviews, 10(4), 781-791
  30. 30. Katayama, Y., Ito, T., & Hiramatsu, K. (2000). A new class of genetic element, staphylococcus cassette chromosome mec, encodes methicillin resistance in Staphylococcus aureus. Antimicrobial agents and chemotherapy, 44(6), 1549-1555
  31. 31. Ito, T., Katayama, Y., & Hiramatsu, K. (1999). Cloning and nucleotide sequence determination of the entire mec DNA of pre-methicillin-resistant Staphylococcus aureus N315. Antimicrobial agents and chemotherapy, 43(6), 1449-1458
  32. 32. Hartman, B. J., & Tomasz, A. (1984). Low-affinity penicillin-binding protein associated with beta-lactam resistance in Staphylococcus aureus. Journal of bacteriology, 158(2), 513-516
  33. 33. Utsui, Y. U. K. I. O., & Yokota, T. A. K. E. S. H. I. (1985). Role of an altered penicillin-binding protein in methicillin-and cephem-resistant Staphylococcus aureus. Antimicrobial agents and chemotherapy, 28(3), 397-403
  34. 34. Song, M. D., Wachi, M., Doi, M., Ishino, F., & Matsuhashi, M. (1987). Evolution of an inducible penicillin-target protein in methicillin-resistant Staphylococcus aureus by gene fusion. FEBS letters, 221(1), 167-171
  35. 35. Ghuysen, J. M. (1994). Molecular structures of penicillin-binding proteins and β-lactamases. Trends in microbiology, 2(10), 372-380
  36. 36. Lim, D., & Strynadka, N. C. (2002). Structural basis for the β lactam resistance of PBP2a from methicillin-resistant Staphylococcus aureus. Nature structural biology, 9(11), 870-876
  37. 37. Archer, G. L., & Bosilevac, J. M. (2001). Signaling antibiotic resistance in staphylococci. Science, 291(5510), 1915-1916
  38. 38. Berger-Bächi, B. (1994). Expression of resistance to methicillin. Trends in microbiology, 2(10), 389-393
  39. 39. Saravolatz, L. D., Stein, G. E., & Johnson, L. B. (2011). Ceftaroline: a novel cephalosporin with activity against methicillin-resistant Staphylococcus aureus. Clinical infectious diseases, 52(9), 1156-1163
  40. 40. Chung, M., Antignac, A., Kim, C., & Tomasz, A. (2008). Comparative study of the susceptibilities of major epidemic clones of methicillin-resistant Staphylococcus aureus to oxacillin and to the new broad-spectrum cephalosporin ceftobiprole. Antimicrobial agents and chemotherapy, 52(8), 2709-2717
  41. 41. Biek, D., Critchley, I. A., Riccobene, T. A., & Thye, D. A. (2010). Ceftaroline fosamil: a novel broad-spectrum cephalosporin with expanded anti-Gram-positive activity. Journal of antimicrobial chemotherapy, 65(suppl_4), iv9-iv16
  42. 42. Sakoulas, G., Moise, P. A., Casapao, A. M., Nonejuie, P., Olson, J., Okumura, C. Y., Rybak, M.J., Kullar, R., Dhand, A., Rose, W.E., & Nizet, V. (2014). Antimicrobial salvage therapy for persistent staphylococcal bacteremia using daptomycin plus ceftaroline. Clinical therapeutics, 36(10), 1317-1333
  43. 43. Sader, H. S., Farrell, D. J., Flamm, R. K., & Jones, R. N. (2015). Activity of ceftaroline and comparator agents tested against Staphylococcus aureus from patients with bloodstream infections in US medical centres (2009-13). Journal of Antimicrobial Chemotherapy, 70(7), 2053-2056
  44. 44. Biedenbach, D. J., Hoban, D. J., Reiszner, E., Lahiri, S. D., Alm, R. A., Sahm, D. F., Bouchillon, S.K., & Ambler, J. E. (2015). In vitro activity of ceftaroline against Staphylococcus aureus isolates collected in 2012 from Latin American countries as part of the AWARE surveillance program. Antimicrobial agents and chemotherapy, 59(12), 7873-7877
  45. 45. Farrell, D. J., Flamm, R. K., Sader, H. S., & Jones, R. N. (2013). Spectrum and potency of ceftaroline tested against leading pathogens causing skin and soft-tissue infections in Europe (2010). International journal of antimicrobial agents, 41(4), 337-342
  46. 46. Biedenbach, D. J., Alm, R. A., Lahiri, S. D., Reiszner, E., Hoban, D. J., Sahm, D. F., Bouchillon, S.K., & Ambler, J. E. (2016). In vitro activity of ceftaroline against Staphylococcus aureus isolated in 2012 from Asia-Pacific countries as part of the AWARE surveillance program. Antimicrobial agents and chemotherapy, 60(1), 343-347
  47. 47. Abbott, I. J., Jenney, A. W. J., Jeremiah, C. J., Mirčeta, M., Kandiah, J. P., Holt, D. C., Tong, S.Y.C., & Spelman, D. W. (2015). Reduced in vitro activity of ceftaroline by Etest among clonal complex 239 methicillin-resistant Staphylococcus aureus clinical strains from Australia. Antimicrobial agents and chemotherapy, 59(12), 7837-7841
  48. 48. Mubarak, N., Sandaradura, I., Isaia, L., O'Sullivan, M., Zhou, F., Marriott, D., Iredell, J.R., Harkness, J., & Andresen, D. (2015). Non-susceptibility to ceftaroline in healthcare-associated multiresistant MRSA in Eastern Australia. Journal of Antimicrobial Chemotherapy, 70(8), 2413-2414
  49. 49. Lahiri, S. D., McLaughlin, R. E., Whiteaker, J. D., Ambler, J. E., & Alm, R. A. (2015). Molecular characterization of MRSA isolates bracketing the current EUCAST ceftaroline-susceptible breakpoint for Staphylococcus aureus: the role of PBP2a in the activity of ceftaroline. Journal of Antimicrobial Chemotherapy, 70(9), 2488-2498
  50. 50. Chan, L. C., Basuino, L., Diep, B., Hamilton, S., Chatterjee, S. S., & Chambers, H. F. (2015). Ceftobiprole-and ceftaroline-resistant methicillin-resistant Staphylococcus aureus. Antimicrobial agents and chemotherapy, 59(5), 2960-2963
  51. 51. Lahiri, S. D., & Alm, R. A. (2016). Potential of Staphylococcus aureus isolates carrying different PBP2a alleles to develop resistance to ceftaroline. Journal of Antimicrobial Chemotherapy, 71(1), 34-40
  52. 52. Sarkar, P., & Haldar, J. (2019). Glycopeptide Antibiotics: Mechanism of Action and Recent Developments. Antibiotic Drug Resistance, 73-95
  53. 53. Lin, L. C., Chang, S. C., Ge, M. C., Liu, T. P., & Lu, J. J. (2018). Novel single-nucleotide variations associated with vancomycin resistance in vancomycin-intermediate Staphylococcus aureus. Infection and drug resistance, 11, 113
  54. 54. Tan, X. E., Neoh, H. M., Looi, M. L., Chin, S. F., Cui, L., Hiramatsu, K., Hussin, S., & Jamal, R. (2017). Activated ADI pathway: the initiator of intermediate vancomycin resistance in Staphylococcus aureus. Canadian journal of microbiology, 63(3), 260-264
  55. 55. Werner, G., Strommenger, B., & Witte, W. (2008). Acquired vancomycin resistance in clinically relevant pathogens
  56. 56. Gomes, D. M., Ward, K. E., & LaPlante, K. L. (2015). Clinical Implications of Vancomycin Heteroresistant and Intermediately Susceptible Staphylococcus aureus. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy, 35(4), 424-432
  57. 57. Chen, H., Xiong, Z., Liu, K., Li, S., Wang, R., Wang, X., ... & Wang, H. (2016). Transcriptional profiling of the two-component regulatory system VraSR in Staphylococcus aureus with low-level vancomycin resistance. International journal of antimicrobial agents, 47(5), 362-367
  58. 58. Katayama, Y., Sekine, M., Hishinuma, T., Aiba, Y., & Hiramatsu, K. (2016). Complete reconstitution of the vancomycin-intermediate Staphylococcus aureus phenotype of strain Mu50 in vancomycin-susceptible S. aureus. Antimicrobial agents and chemotherapy, 60(6), 3730-3742
  59. 59. Yoo, J. I., Kim, J. W., Kang, G. S., Kim, H. S., Yoo, J. S., & Lee, Y. S. (2013). Prevalence of amino acid changes in the yvqF, vraSR, graSR, and tcaRAB genes from vancomycin intermediate resistant Staphylococcus aureus. Journal of microbiology, 51(2), 160-165
  60. 60. Hollenbeck, B. L., & Rice, L. B. (2012). Intrinsic and acquired resistance mechanisms in enterococcus. Virulence, 3(5), 421-569
  61. 61. Humphries, R. M., Pollett, S., & Sakoulas, G. (2013). A current perspective on daptomycin for the clinical microbiologist. Clinical microbiology reviews, 26(4), 759-780
  62. 62. Murthy, M. H., Olson, M. E., Wickert, R. W., Fey, P. D., & Jalali, Z. (2008). Daptomycin non-susceptible meticillin-resistant Staphylococcus aureus USA 300 isolate. Journal of medical microbiology, 57(8), 1036-1038
  63. 63. Mammina, C., Bonura, C., di Carlo, P., Calà, C., Aleo, A., Monastero, R., & Palma, D. M. (2010). Daptomycin non-susceptible, vancomycin intermediate methicillin-resistant Staphylococcus aureus ST398 from a chronic leg ulcer, Italy. Scandinavian journal of infectious diseases, 42(11-12), 955-957
  64. 64. Silverman, J. A., Oliver, N., Andrew, T., & Li, T. (2001). Resistance studies with daptomycin. Antimicrobial Agents and Chemotherapy, 45(6), 1799-1802
  65. 65. Jones, T., Yeaman, M. R., Sakoulas, G., Yang, S. J., Proctor, R. A., Sahl, H.G., Schrenzel, J., Xiong, Y.Q. , & Bayer, A. S. (2008). Failures in clinical treatment of Staphylococcus aureus infection with daptomycin are associated with alterations in surface charge, membrane phospholipid asymmetry, and drug binding. Antimicrobial agents and chemotherapy, 52(1), 269-278
  66. 66. Bellido, J. L. M. (2017). Mechanisms of resistance to daptomycin in Staphylococcus aureus. Rev. Esp. Quimioter, 30, 391-396
  67. 67. Mishra, N. N., Yang, S. J., Sawa, A., Rubio, A., Nast, C. C., Yeaman, M. R., & Bayer, A. S. (2009). Analysis of cell membrane characteristics of in vitro-selected daptomycin-resistant strains of methicillin-resistant Staphylococcus aureus. Antimicrobial agents and chemotherapy, 53(6), 2312-2318
  68. 68. Ernst, C. M., Slavetinsky, C. J., Kuhn, S., Hauser, J. N., Nega, M., Mishra, N. N., Gekeler, C., Bayer, A.S., & Peschel, A. (2018). Gain-of-function mutations in the phospholipid flippase MprF confer specific daptomycin resistance. MBio, 9(6)
  69. 69. Roch, M., Gagetti, P., Davis, J., Ceriana, P., Errecalde, L., Corso, A., & Rosato, A. E. (2017). Daptomycin resistance in clinical MRSA strains is associated with a high biological fitness cost. Frontiers in microbiology, 8, 2303
  70. 70. Barros, E. M., Martin, M. J., Selleck, E. M., Lebreton, F., Sampaio, J. L. M., & Gilmore, M. S. (2019). Daptomycin resistance and tolerance due to loss of function in Staphylococcus aureus dsp1 and asp23. Antimicrobial agents and chemotherapy, 63(1)
  71. 71. Sabat, A. J., Tinelli, M., Grundmann, H., Akkerboom, V., Monaco, M., Del Grosso, M., Errico, G., Pantosti, A., & Friedrich, A. W. (2018). Daptomycin resistant Staphylococcus aureus clinical strain with novel non-synonymous mutations in the mprF and vraS genes: a new insight into daptomycin resistance. Frontiers in microbiology, 9, 2705
  72. 72. Kanesaka, I., Fujisaki, S., Aiba, Y., Watanabe, S., Mikawa, T., Katsuse, A. K., Takahashi, H., Cui, L., & Kobayashi, I. (2019). Characterization of compensatory mutations associated with restoration of daptomycin-susceptibility in daptomycin non-susceptible methicillin-resistant Staphylococcus aureus and the role mprF mutations. Journal of Infection and Chemotherapy, 25(1), 1-5
  73. 73. Vakulenko, S. B., & Mobashery, S. (2003). Versatility of aminoglycosides and prospects for their future. Clinical microbiology reviews, 16(3), 430-450
  74. 74. Ramirez, M. S., & Tolmasky, M. E. (2010). Aminoglycoside modifying enzymes. Drug resistance updates, 13(6), 151-171
  75. 75. Krause, K. M., Serio, A. W., Kane, T. R., & Connolly, L. E. (2016). Aminoglycosides: an overview. Cold Spring Harbor perspectives in medicine, 6(6), a027029
  76. 76. Díaz, M. C. L., Ríos, E., Rodríguez-Avial, I., Simaluiza, R. J., Picazo, J. J., & Culebras, E. (2017). In-vitro activity of several antimicrobial agents against methicillin-resistant Staphylococcus aureus (MRSA) isolates expressing aminoglycoside-modifying enzymes: potency of plazomicin alone and in combination with other agents. International journal of antimicrobial agents, 50(2), 191-196
  77. 77. Shaeer, K. M., Zmarlicka, M. T., Chahine, E. B., Piccicacco, N., & Cho, J. C. (2019). Plazomicin: A Next-Generation Aminoglycoside. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy, 39(1), 77-93
  78. 78. Rybak, J. M., & Roberts, K. (2015). Tedizolid phosphate: a next-generation oxazolidinone. Infectious diseases and therapy, 4(1), 1-14
  79. 79. Munita, J. M., Bayer, A. S., & Arias, C. A. (2015). Evolving resistance among Gram-positive pathogens. Clinical Infectious Diseases, 61(suppl_2), S48-S57
  80. 80. Pillai, S. K., Sakoulas, G., Wennersten, C., Eliopoulos, G. M., Moellering Jr, R. C., Ferraro, M. J., & Gold, H. S. (2002). Linezolid resistance in Staphylococcus aureus: characterization and stability of resistant phenotype. The Journal of infectious diseases, 186(11), 1603-1607
  81. 81. Livermore, D. M. (2003). Linezolid in vitro: mechanism and antibacterial spectrum. Journal of Antimicrobial Chemotherapy, 51(suppl_2), ii9-ii16
  82. 82. Belousoff, M. J., Eyal, Z., Radjainia, M., Ahmed, T., Bamert, R. S., Matzov, D., Bashan, A., Zimmerman, E., Mishra, S., Cameron, D., & Yonath, A. (2017). Structural basis for linezolid binding site rearrangement in the Staphylococcus aureus ribosome. MBio, 8(3)
  83. 83. Gu, B., Kelesidis, T., Tsiodras, S., Hindler, J., & Humphries, R. M. (2013). The emerging problem of linezolid-resistant Staphylococcus. Journal of Antimicrobial Chemotherapy, 68(1), 4-11
  84. 84. Li, S. M., Zhou, Y. F., Li, L., Fang, L. X., Duan, J. H., Liu, F. R., Liang, H.Q., Wu, Y.T., Gu, W.Q., Liao, X.P., & Liu, Y. H. (2018). Characterization of the multi-drug resistance gene cfr in methicillin-resistant Staphylococcus aureus (MRSA) strains isolated from animals and humans in China. Frontiers in microbiology, 9, 2925
  85. 85. Wang, Y., Lv, Y., Cai, J., Schwarz, S., Cui, L., Hu, Z., Zhang, R., Li, J., Zhao, Q., He, T., & Shen, J. (2015). A novel gene, optrA, that confers transferable resistance to oxazolidinones and phenicols and its presence in Enterococcus faecalis and Enterococcus faecium of human and animal origin. Journal of Antimicrobial Chemotherapy, 70(8), 2182-2190
  86. 86. Foster, T. J. (2017). Antibiotic resistance in Staphylococcus aureus. Current status and future prospects. FEMS microbiology reviews, 41(3), 430-449
  87. 87. Wang, Y., Li, X., Wang, Y., Schwarz, S., Shen, J., & Xia, X. (2018). Intracellular accumulation of linezolid and florfenicol in OptrA-producing Enterococcus faecalis and Staphylococcus aureus. Molecules, 23(12), 3195
  88. 88. Sharkey, L. K., Edwards, T. A., & O’Neill, A. J. (2016). ABC-F proteins mediate antibiotic resistance through ribosomal protection. MBio, 7(2)
  89. 89. Antonelli, A., D’Andrea, M. M., Brenciani, A., Galeotti, C. L., Morroni, G., Pollini, S., Varaldo, P.E., & Rossolini, G. M. (2018). Characterization of poxtA, a novel phenicol–oxazolidinone–tetracycline resistance gene from an MRSA of clinical origin. Journal of Antimicrobial Chemotherapy, 73(7), 1763-1769
  90. 90. Saravolatz, L. D., & Stein, G. E. (2019). Delafloxacin: A New Anti–methicillin-resistant Staphylococcus aureus Fluoroquinolone. Clinical Infectious Diseases, 68(6), 1058-1062
  91. 91. Lemaire, S., Tulkens, P. M., & Van Bambeke, F. (2011). Contrasting effects of acidic pH on the extracellular and intracellular activities of the anti-gram-positive fluoroquinolones moxifloxacin and delafloxacin against Staphylococcus aureus. Antimicrobial agents and chemotherapy, 55(2), 649-658
  92. 92. Van Bambeke, F. (2015). Delafloxacin, a non-zwitterionic fluoroquinolone in phase III of clinical development: evaluation of its pharmacology, pharmacokinetics, pharmacodynamics and clinical efficacy. Future microbiology, 10(7), 1111-1123
  93. 93. Bauer, J., Siala, W., Tulkens, P. M., & Van Bambeke, F. (2013). A combined pharmacodynamic quantitative and qualitative model reveals the potent activity of daptomycin and delafloxacin against Staphylococcus aureus biofilms. Antimicrobial agents and chemotherapy, 57(6), 2726-2737
  94. 94. Siala, W., Mingeot-Leclercq, M. P., Tulkens, P. M., Hallin, M., Denis, O., & Van Bambeke, F. (2014). Comparison of the antibiotic activities of daptomycin, vancomycin, and the investigational fluoroquinolone delafloxacin against biofilms from Staphylococcus aureus clinical isolates. Antimicrobial agents and chemotherapy, 58(11), 6385-6397
  95. 95. Wassenaar, T., Ussery, D., Nielsen, L., & Ingmer, H. (2015). Review and phylogenetic analysis of qac genes that reduce susceptibility to quaternary ammonium compounds in Staphylococcus species. European Journal of Microbiology and Immunology, 5(1), 44-61
  96. 96. Costa, S. S., Falcão, C., Viveiros, M., Machado, D., Martins, M., Melo-Cristino, J., Amaral, L., & Couto, I. (2011). Exploring the contribution of efflux on the resistance to fluoroquinolones in clinical isolates of Staphylococcus aureus. BMC microbiology, 11(1), 1-12
  97. 97. Muñoz-Bellido, J. L., Manzanares, M. A., Andrés, J. M., Zufiaurre, M. G., Ortiz, G., Hernández, M. S., & García-Rodríguez, J. A. (1999). Efflux pump-mediated quinolone resistance in Staphylococcus aureus strains wild type for gyrA, gyrB, grlA, and norA. Antimicrobial agents and chemotherapy, 43(2), 354-356
  98. 98. Remy, J. M., Tow-Keogh, C. A., McConnell, T. S., Dalton, J. M., & DeVito, J. A. (2012). Activity of delafloxacin against methicillin-resistant Staphylococcus aureus: resistance selection and characterization. Journal of antimicrobial chemotherapy, 67(12), 2814-2820
  99. 99. Greer, E. L., Banko, M. R., & Brunet, A. (2009). AMP-activated protein kinase and FoxO transcription factors in dietary restriction–induced longevity. Annals of the New York Academy of Sciences, 1170, 688
  100. 100. Prince, W. T., Ivezic-Schoenfeld, Z., Lell, C., Tack, K. J., Novak, R., Obermayr, F., & Talbot, G. H. (2013). Phase II clinical study of BC-3781, a pleuromutilin antibiotic, in treatment of patients with acute bacterial skin and skin structure infections. Antimicrobial agents and chemotherapy, 57(5), 2087-2094
  101. 101. Paukner, S., & Riedl, R. (2017). Pleuromutilins: potent drugs for resistant bugs—mode of action and resistance. Cold Spring Harbor perspectives in medicine, 7(1), a027110
  102. 102. Schwarz, S., Shen, J., Kadlec, K., Wang, Y., Michael, G. B., Feßler, A. T., & Vester, B. (2016). Lincosamides, streptogramins, phenicols, and pleuromutilins: mode of action and mechanisms of resistance. Cold Spring Harbor perspectives in medicine, 6(11), a027037
  103. 103. Gentry, D. R., Rittenhouse, S. F., McCloskey, L., & Holmes, D. J. (2007). Stepwise exposure of Staphylococcus aureus to pleuromutilins is associated with stepwise acquisition of mutations in rplC and minimally affects susceptibility to retapamulin. Antimicrobial agents and chemotherapy, 51(6), 2048-2052
  104. 104. Kehrenberg, C., Schwarz, S., Jacobsen, L., Hansen, L. H., & Vester, B. (2005). A new mechanism for chloramphenicol, florfenicol and clindamycin resistance: methylation of 23S ribosomal RNA at A2503. Molecular microbiology, 57(4), 1064-1073
  105. 105. Van Duijkeren, E., Greko, C., Pringle, M., Baptiste, K. E., Catry, B., Jukes, H., Moreno, M.A., Pomba, M.C.M.F., Pyörälä, S., Rantala, M., & Törneke, K. (2014). Pleuromutilins: use in food-producing animals in the European Union, development of resistance and impact on human and animal health. Journal of Antimicrobial Chemotherapy, 69(8), 2022-2031
  106. 106. Mendes, R. E., Paukner, S., Doyle, T. B., Gelone, S. P., Flamm, R. K., & Sader, H. S. (2019). Low prevalence of gram-positive isolates showing elevated lefamulin MIC results during the SENTRY surveillance program for 2015-2016 and characterization of resistance mechanisms. Antimicrobial agents and chemotherapy, 63(4)
  107. 107. Kadlec, K., & Schwarz, S. (2009). Novel ABC transporter gene, vga (C), located on a multiresistance plasmid from a porcine methicillin-resistant Staphylococcus aureus ST398 strain. Antimicrobial agents and chemotherapy, 53(8), 3589-3591
  108. 108. Miller, M. A., Dascal, A., Portnoy, J., & Mendelson, J. (1996). Development of mupirocin resistance among methicillin-resistant Staphylococcus aureus after widespread use of nasal mupirocin ointment. Infection Control & Hospital Epidemiology, 17(12), 811-813
  109. 109. Vasquez, J. E., Walker, E. S., Franzus, B. W., Overbay, B. K., Reagan, D. R., & Sarubbi, F. A. (2000). The epidemiology of mupirocin resistance among methicillin-resistant Staphylococcus aureus at a Veterans' Affairs hospital. Infection Control & Hospital Epidemiology, 21(7), 459-464
  110. 110. de Castro Nunes, E. L., dos Santos, K. R. N., Mondino, P. J. J., de Freire Bastos, M. D. C., & Giambiagi-deMarval, M. (1999). Detection of ileS-2 gene encoding mupirocin resistance in methicillin-resistant Staphylococcus aureus by multiplex PCR. Diagnostic microbiology and infectious disease, 34(2), 77-81
  111. 111. Patel, J. B., Gorwitz, R. J., & Jernigan, J. A. (2009). Mupirocin resistance. Clinical infectious diseases, 49(6), 935-941
  112. 112. Hayden, M. K., Lolans, K., Haffenreffer, K., Avery, T. R., Kleinman, K., Li, H., Kaganov, R.E., Lankiewicz, J., Moody, J., Septimus, E., & Huang, S. S. (2016). Chlorhexidine and mupirocin susceptibility of methicillin-resistant Staphylococcus aureus isolates in the REDUCE-MRSA trial. Journal of clinical microbiology, 54(11), 2735-2742
  113. 113. Lounsbury, N., Eidem, T., Colquhoun, J., Mateo, G., Abou-Gharbia, M., Dunman, P. M., & Childers, W. E. (2018). Novel inhibitors of Staphylococcus aureus RnpA that synergize with mupirocin. Bioorganic & medicinal chemistry letters, 28(6), 1127-1131
  114. 114. Zhanel, G. G., Calic, D., & Schweizer, F. (2010). Dalbavancin, oritavancin and telavancin: a comparative review. Drugs, 70, 859-886
  115. 115. Zeng, D., Debabov, D., Hartsell, T. L., Cano, R. J., Adams, S., Schuyler, J. A., McMillan, R., & Pace, J. L. (2016). Approved glycopeptide antibacterial drugs: mechanism of action and resistance. Cold Spring Harbor perspectives in medicine, 6(12), a026989
  116. 116. McCurdy, S. P., Jones, R. N., Mendes, R. E., Puttagunta, S., & Dunne, M. W. (2015). In vitro activity of dalbavancin against drug-resistant Staphylococcus aureus isolates from a global surveillance program. Antimicrobial agents and chemotherapy, 59(8), 5007-5009
  117. 117. Duncan, L. R., Sader, H. S., Smart, J. I., Flamm, R. K., & Mendes, R. E. (2017). Telavancin activity in vitro tested against a worldwide collection of Gram-positive clinical isolates (2014). Journal of global antimicrobial resistance, 10, 271-276
  118. 118. Kussmann, M., Karer, M., Obermueller, M., Schmidt, K., Barousch, W., Moser, D., Nehr, M., Ramharter, M., Poeppl, W., Makristathis, A., & Lagler, H. (2018). Emergence of a dalbavancin induced glycopeptide/lipoglycopeptide non-susceptible Staphylococcus aureus during treatment of a cardiac device-related endocarditis. Emerging microbes & infections, 7(1), 1-10
  119. 119. Werth, B. J., Jain, R., Hahn, A., Cummings, L., Weaver, T., Waalkes, A., Sengupta, D., Salipante, S.J., Rakita, R.M., & Butler-Wu, S. M. (2018). Emergence of dalbavancin non-susceptible, vancomycin-intermediate Staphylococcus aureus (VISA) after treatment of MRSA central line-associated bloodstream infection with a dalbavancin-and vancomycin-containing regimen. Clinical Microbiology and Infection, 24(4), 429.e1-429.e5
  120. 120. Fleming, A. (2001). On the antibacterial action of cultures of a penicillium, with special reference to their use in the isolation of B. influenzae. Bulletin of the World Health Organization, 79, 780-790
  121. 121. Lederberg, J. (1957). Mechanism of action of penicillin. Journal of bacteriology, 73(1), 144
  122. 122. Lowy, F. D. (2003). Antimicrobial resistance: the example of Staphylococcus aureus. The Journal of clinical investigation, 111(9), 1265-1273
  123. 123. Kirby, W. M. (1944). Extraction of a highly potent penicillin inactivator from penicillin resistant staphylococci. Science, 99(2579), 452-453
  124. 124. Rammelkamp, C. H., & Maxon, T. (1942). Resistance of Staphylococcus aureus to the Action of Penicillin. Proceedings of the Society for Experimental Biology and Medicine, 51(3), 386-389
  125. 125. Bondi Jr, A., & Dietz, C. C. (1945). Penicillin resistant staphylococci. Proceedings of the Society for Experimental Biology and Medicine, 60(1), 55-58
  126. 126. Smith, I. M., & Vickers, A. B. (1960). Natural History of 338 Treated and Untreated Patients with Staphylococcal septicaemia (1936-1955.). Lancet, 1318-22
  127. 127. Jessen, O., Rosendal, K., Bülow, P., Faber, V., & Eriksen, K. R. (1969). Changing staphylococci and staphylococcal infections: a ten-year study of bacteria and cases of bacteremia. New England Journal of Medicine, 281(12), 627-635
  128. 128. Jevons, M. P. (1961). “Celbenin”-resistant staphylococci. British medical journal, 1(5219), 124
  129. 129. Katayama, Y., Ito, T., & Hiramatsu, K. (2000). A new class of genetic element, staphylococcus cassette chromosome mec, encodes methicillin resistance in Staphylococcus aureus. Antimicrobial agents and chemotherapy, 44(6), 1549-1555
  130. 130. Hiramatsu, K., Asada, K., Suzuki, E., Okonogi, K., & Yokota, T. (1992). Molecular cloning and nucleotide sequence determination of the regulator region of mecA gene in methicillin-resistant Staphylococcus aureus (MRSA). FEBS letters, 298(2-3), 133-136
  131. 131. Hartman, B. J., & Tomasz, A. (1984). Low-affinity penicillin-binding protein associated with beta-lactam resistance in Staphylococcus aureus. Journal of bacteriology, 158(2), 513-516
  132. 132. Reynolds, P. E., & Brown, D. F. (1985). Penicillin-binding proteins of β-lactam-resistant strains of Staphylococcus aureus: effect of growth conditions. FEBS letters, 192(1), 28-32
  133. 133. Rountree, P. M., & Beard, M. A. (1968). Hospital strains of Staphylococcus aureus, with particular reference to methicillin-resistant strains. Medical Journal of Australia, 2(26), 1163-8
  134. 134. Mäkelä, M. J., Puhakka, T., Ruuskanen, O., Leinonen, M., Saikku, P., Kimpimäki, M., Blomqvist, S., Hyypiä, T., & Arstila, P. (1998). Viruses and bacteria in the etiology of the common cold. Journal of clinical microbiology, 36(2), 539-542
  135. 135. Torvaldsen, S., Roberts, C., & Riley, T. V. (1999). The continuing evolution of methicillin-resistant Staphylococcus aureus in Western Australia. Infection control and hospital epidemiology, 20(2), 133-135
  136. 136. Barret, F. F. (1968). Methicillin resistant Staphylococcus aureus at Boston City Hospital. N Engl J Med, 279, 441-448
  137. 137. Panlilio, A. L., Culver, D. H., Gaynes, R. P., Banerjee, S., Henderson, T. S., Tolson, J. S., Martone, W.J., & National Nosocomial Infections Surveillance System. (1992). Methicillin-resistant Staphylococcus aureus in US hospitals, 1975-1991. Infection Control & Hospital Epidemiology, 13(10), 582-586
  138. 138. Meyer, E., Schwab, F., Gastmeier, P., Jonas, D., Rueden, H., & Daschner, F. D. (2006). Methicillin-resistant Staphylococcus aureus in German intensive care units during 2000-2003: data from Project SARI (Surveillance of Antimicrobial Use and Antimicrobial Resistance in Intensive Care Units). Infection Control & Hospital Epidemiology, 27(2), 146-154
  139. 139. Alcoceba, E., Mena, A., Perez, M. C., de Gopegui, E. R., Padilla, E., Gil, J., Ramirez, A., Gallegos, C., Serra, A., Perez, J.L., & Oliver, A. (2007). Molecular epidemiology of methicillin-resistant Staphylococcus aureus in Majorcan hospitals: high prevalence of the epidemic clone EMRSA-15. Clinical microbiology and infection, 13(6), 599-605
  140. 140. Conceicao, T., Aires-de-Sousa, M., Füzi, M., Toth, A., Paszti, J., Ungvári, E., ... & De Lencastre, H. (2007). Replacement of methicillin-resistant Staphylococcus aureus clones in Hungary over time: a 10-year surveillance study. Clinical Microbiology and Infection, 13(10), 971-979
  141. 141. Durmaz, B., Durmaz, R., & Şahin, K. (1997). Methicillin-resistance among Turkish isolates of Staphylococcus aureus strains from nosocomial and community infections and their resistance patterns using various antimicrobial agents. Journal of Hospital Infection, 37(4), 325-329
  142. 142. Peng, Q., Hou, B., Zhou, S., Huang, Y., Hua, D., Yao, F., & shu Qian, Y. (2010). Staphylococcal cassette chromosome mec (SCCmec) analysis and antimicrobial susceptibility profiles of methicillin-resistant Staphylococcus aureus (MRSA) isolates in a teaching hospital, Shantou, China. African Journal of Microbiology Research, 4(9), 844-848
  143. 143. Fluit, A. C., Wielders, C. L. C., Verhoef, J., & Schmitz, F. J. (2001). Epidemiology and susceptibility of 3,051 Staphylococcus aureus isolates from 25 university hospitals participating in the European SENTRY study. Journal of clinical microbiology, 39(10), 3727-3732
  144. 144. Lin, Y. C., Lauderdale, T. L., Lin, H. M., Chen, P. C., Cheng, M. F., Hsieh, K. S., & Liu, Y. C. (2007). An outbreak of methicillin-resistant Staphylococcus aureus infection in patients of a pediatric intensive care unit and high carriage rate among health care workers. Journal of Microbiology, Immunology, and Infection, 40(4), 325-334
  145. 145. Manzur, A., Dominguez, A. M., Pujol, M., González, M. P. M., Limon, E., Hornero, A., Martín, R., Gudiol, F., & Ariza, J. (2008). Community-acquired methicillin-resistant Staphylococcus aureus infections: an emerging threat in Spain. Clinical Microbiology and Infection, 14(4), 377-380
  146. 146. Oteo, J., Baquero, F., Vindel, A., & Campos, J. (2004). Antibiotic resistance in 3113 blood isolates of Staphylococcus aureus in 40 Spanish hospitals participating in the European Antimicrobial Resistance Surveillance System (2000-2002). Journal of Antimicrobial Chemotherapy, 53(6), 1033-1038
  147. 147. Tiemersma, E. W., Bronzwaer, S. L., Lyytikäinen, O., Degener, J. E., Schrijnemakers, P., Bruinsma, N., Monen, J., Witte, W., Grundmann, H., & European Antimicrobial Resistance Surveillance System Participants. (2004). Methicillin-resistant Staphylococcus aureus in Europe, 1999-2002. Emerging infectious diseases, 10(9), 1627
  148. 148. Kayaba, H., Kodama, K., Tamura, H., & Fuhwara, Y. (1997). The spread of methicillin-resistant Staphylococcus aureus in a rural community: will it become a common microorganism colonizing among the general population?. Surgery today, 27(3), 217-219
  149. 149. Piao, C., Karasawa, T., Totsuka, K., Uchiyama, T., & Kikuchi, K. (2005). Prospective surveillance of community-onset and healthcare-associated methicillin-resistant Staphylococcus aureus isolated from a university-affiliated hospital in Japan. Microbiology and immunology, 49(11), 959-970
  150. 150. Udo, E. E., Pearman, J. W., & Grubb, W. B. (1993). Genetic analysis of community isolates of methicillin-resistant Staphylococcus aureus in Western Australia. Journal of Hospital Infection, 25(2), 97-108
  151. 151. Ito, T., Iijima, M., Fukushima, T., Nonoyama, M., Ishii, M., Baranovich, T., Otsuka, T., Takano, T., & Yamamoto, T. (2008). Pediatric pneumonia death caused by community-acquired methicillin-resistant Staphylococcus aureus, Japan. Emerging infectious diseases, 14(8), 1312
  152. 152. Takizawa, Y., Taneike, I., Nakagawa, S., Oishi, T., Nitahara, Y., Iwakura, N., Ozaki, K., Takano, M., Nakayama, T., & Yamamoto, T. (2005). A Panton-Valentine leucocidin (PVL)-positive community-acquired methicillin-resistant Staphylococcus aureus (MRSA) strain, another such strain carrying a multiple-drug resistance plasmid, and other more-typical PVL-negative MRSA strains found in Japan. Journal of clinical microbiology, 43(7), 3356-3363
  153. 153. Kerttula, A. M., Lyytikäinen, O., Kardén-Lilja, M., Ibrahem, S., Salmenlinna, S., Virolainen, A., & Vuopio-Varkila, J. (2007). Nationwide trends in molecular epidemiology of methicillin-resistant Staphylococcus aureus, Finland, 1997-2004. BMC Infectious Diseases, 7(1), 1-9
  154. 154. Andersen, B. M., Rasch, M., & Syversen, G. (2007). Is an increase of MRSA in Oslo, Norway, associated with changed infection control policy?. Journal of Infection, 55(6), 531-538
  155. 155. Skov, R., Gudlaugsson, O., Hardardottir, H., Harthug, S., Jakobsen, T., Jørn Kolmos, H., Olsson-Liljequist, B., Peltonen, R., Tveten, Y., Vuopio-Varkila, J., & Åhrén, C. (2008). Proposal for common Nordic epidemiological terms and definitions for methicillin-resistant Staphylococcus aureus (MRSA). Scandinavian journal of infectious diseases, 40(6-7), 495-502
  156. 156. Stenhem, M., Örtqvist, Å., Ringberg, H., Larsson, L., Olsson-Liljequist, B., Hæggman, S., & Ekdahl, K. (2006). Epidemiology of methicillin-resistant Staphylococcus aureus (MRSA) in Sweden 2000-2003, increasing incidence and regional differences. BMC Infectious Diseases, 6(1), 1-7
  157. 157. Nimmo, G. R., Fong, J., Paterson, D. L., & McLaws, M. L. (2008). Changing epidemiology of meticillin-resistant S. aureus in Queensland, Australia, 2000-2006: use of passive surveillance of susceptibility phenotypes. Journal of Hospital Infection, 70(4), 305-313
  158. 158. Song, J. H., Hsueh, P. R., Chung, D. R., Ko, K. S., Kang, C. I., Peck, K. R., Yeom, J.S., Kim, S.W., Chang, H.H., Kim, Y.S., & Carlos, C. C. (2011). Spread of methicillin-resistant Staphylococcus aureus between the community and the hospitals in Asian countries: an ANSORP study. Journal of antimicrobial chemotherapy, 66(5), 1061-1069

Written By

Atamjit Singh, Kirandeep Kaur, Pallvi Mohana, Avneet Kaur, Komalpreet Kaur, Shilpa Heer, Saroj Arora, Neena Bedi and Preet Mohinder Singh Bedi

Submitted: 02 March 2021 Reviewed: 22 August 2021 Published: 15 September 2021