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The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric. Find more information on the Altmetric Attention Score and how the score is calculated. The quantitative multiplexing capacity of isobaric tandem mass tags TMT has increased the throughput of affinity purification mass spectrometry AP-MS to characterize protein interaction networks of immunoprecipitated bait proteins.

However, variable bait levels between replicates can convolute interactor identification. Using a simple linear model of protein recovery in immunoprecipitates to simulate reporter ion ratio distributions, we found that correlation-derived t- statistics protect against bait variance while robustly controlling type I errors false positives. Deliberately varying bait levels over a large range fails to improve selectivity but does increase the robustness between runs.

The American Chemical Society holds a copyright ownership interest in any copyrightable Supporting Information. Files available from the ACS website may be downloaded for personal use only. Users are not otherwise permitted to reproduce, republish, redistribute, or sell any Supporting Information from the ACS website, either in whole or in part, in either machine-readable form or any other form without permission from the American Chemical Society.

For permission to reproduce, republish and redistribute this material, requesters must process their own requests via the RightsLink permission system. Proteome Res. More by Liangyong Mei. More by Maureen R. More by Guy M. More by Minh Tran. More by Athena Villa-Sharma. It solves the linkage between the amino acids threonine and glycine within the LPXTG sequence and introduces a covalent linkage between the threonine and the peptidoglycan , There is a considerable redundancy in functions: CWA proteins can bind to one or several human host factors, such as fibrinogen, fibronectin, thrombospondin, collagen, or vitronectin, and one human factor can be bound by several attachment factors.

So far, not all binding partners of all CWA proteins have been elucidated. Heterologous expression of fbe in Lactococcus lactis and analysis of an fbe -deficient mutant demonstrated a role for Fbe in the interaction of S. In vivo studies suggested Fbe to be a virulence factor, because an fbe deletion mutant was attenuated in an intravascular catheter-associated rat infection model Other surface proteins containing SD repeats identified in S.

Antibodies against SdrG and SdrH were found in 16 convalescent-phase patient sera, implying that these proteins are produced during infection SdrF binds to type I collagen via its B repeats Because binding to collagen is mediated by the SdrF B repeats but not by the putative ligand-binding N-terminal domain A, it was assumed that SdrF might be a multiligand adhesin and that further ligands have yet to be identified.

Furthermore, it was shown that SdrF contributed to the initiation of ventricular assist device driveline-related infections with S. Anti-SdrF antibodies were able to reduce the S. Antibodies against SesC were able to reduce the S.

Moreover, anti-SesC antibodies were able to decrease the number of S. The expression of sesC was elevated in cells grown in a biofilm in comparison with planktonically grown S. Together, these findings suggested SesC to be a promising target for the prophylaxis and treatment of biofilm-associated S. Indeed, it was shown recently that active vaccination against recombinant SesC inhibited S.

Another well-characterized CWA protein from S. Recently, it was reported that the Aap N-terminal domain A mediates adherence to human corneocytes, supporting a role for Aap in skin colonization In addition to proteins, teichoic acids are also involved in the adherence of S. Preincubation of either fibronectin-coated surfaces or bacteria with teichoic acid enhanced the attachment of S. After succeeding in primary attachment to biotic or abiotic surfaces, bacteria multiply and accumulate in multilayered cell aggregates, in a process that necessitates intercellular adhesion.

Intercellular adhesion may be mediated by different specific macromolecules, such as polysaccharide adhesins and certain proteins that induce cell aggregation. However, this finding was later identified as an artifact IcaA confers the proposed N -acetylglucosaminyltransferase activity.

However, IcaA alone shows only low transferase activity. Coexpression of the catalytic enzyme-encoding icaA gene together with icaD leads to a significantly increased activity and to the production of N -acetylglucosamine oligomers with a maximal length of 20 residues. IcaB is the cell surface-located enzyme that catalyzes the partial deacetylation of N -acetylglucosaminyl residues A study analyzing the pathogenic features of strains isolated from polymer-associated septicemic disease compared with saprophytic skin and mucosal isolates revealed that biofilm production and the presence of the ica operon essentially correlated with the disease isolates However, despite the presence of the ica gene cluster, the biofilms produced by the S.

Biofilm accumulation in S. Thus, Bap and the Bap-homologous protein Bhp may confer accumulative growth see above A biofilm-defective mutant was shown to lack a kDa surface protein, the accumulation-associated protein Aap. Aap is essential for biofilm accumulation on polymeric surfaces in certain S. Biochemical and functional properties clearly differentiate Aap from other factors known to mediate biofilm production.

Aap contains a domain A within its N-terminal portion, which is followed by a repeat domain B. The latter is characterized by a variable number of repeats with amino acids each, which mediate cell-to-cell adhesion and biofilm accumulation. Interestingly, the repeat domain B becomes active as an intercellular adhesin only upon removal of the Aap domain A via proteolysis, mediated by either endogenous staphylococcal or host proteases Upon transmission electron microscopic evaluation, Aap turned out to have a fibrillar structure, which might explain its function Antibodies against S.

The giant S. Upon biofilm maturation, individual bacteria or clusters of bacteria may dissociate and disperse via the bloodstream. Following this step, further locations in the body may be colonized by circulating bacteria, leading to metastasis of infection. The disintegration of biofilms may be mediated by different mechanisms, such as a variety of extracellular enzymatic activities or the so-called phenol-soluble modulins PSMs.

Biofilm detachment may be mediated by different enzymes conferring breakdown of the complex matrix that allows cells to stick together. The Gram-negative pathogenic bacterial species A. Interestingly, A. Moreover, dispersin B can disintegrate S. However, no such enzyme seems to be present in S. Hence, the presence of a nuclease reduces the production of S.

Thus, the secretion and activity of staphylococcal nucleases may also contribute to biofilm detachment. Indeed, it was recently demonstrated that the secreted thermonuclease Nuc has an inhibitory effect on S. Additionally, a second thermonuclease, Nuc2, also limits the biofilm formation of S. In contrast to S. Therefore, because of protein and polysaccharide factors involved in S. In these cases, treatment with DNase I and protease dissolved the biofilms, although sometimes only partially , — The protease-dependent dispersal of S.

Although a role for S. The gene encoding the kDa extracellular serine protease GluSE, also known as SspA or Esp, has been cloned and sequenced , — Surface-attached S. However, it was recently reported that Esp produced by commensal S. Moreover, there is a correlation between the colonization of the anterior nares of healthy individuals by S. Another study indicated that S.

Additionally, Esp seems to interfere with host-pathogen interactions, as it cleaves fibrinogen, fibronectin, and vitronectin Furthermore, Esp was shown to degrade Atl-associated bacteriolytic activities, thereby preventing the release of eDNA as a main component of the biofilm matrix and mediator of initial adherence , — Additional or alternative S. Possible proteases involved include the following: an extracellular metalloprotease with elastase activity, SepA, whose gene has been cloned and sequenced , ; an extracellular serine protease, EpiP, that is involved in epidermin processing ; and an extracellular cell wall-associated cysteine protease with elastase activity Ecp , see below.

However, although all factors mentioned above play a proven or potential role in biofilm detachment or dispersal in vitro , in vivo proof demonstrating the involvement of the respective factors in such functions in animal models has been lacking. Another strategy that leads to biofilm disintegration depends on the synthesis and release of small peptides called phenol-soluble modulins PSMs.

PSMs are short, amphipathic peptides which are secreted in an agr -controlled manner see below They were first described as proinflammatory agents in S. A preliminary indication that PSMs are involved in preventing biofilm formation came from the investigation of a significant number of S.

Because of their amphipathic nature, PSMs probably act as surfactants, thereby leading to biofilm dispersal As already widely accepted for S. It was recently demonstrated that AtlE not only binds to host factors but also mediates S. However, in contrast to S. SCVs have been described for several Gram-negative and Gram-positive species. While most work has been done on S. Irrespective of the species, the SCV phenotype is characterized by drastic changes in cellular metabolism, reflected by a reduced growth rate and substantial quantitative and qualitative modifications of the transcriptome, metabolome, and proteome , — These changes determine the auxotrophism expressed by almost all SCV isolates , — Metabolic changes also influence the colonial morphotype of SCVs, which are characterized by tiny colonies, reduced or lost pigmentation, and hemolysis compared to their wild-type counterpart Their intracellular location provides a survival niche in the host environment, shielding SCVs from host defenses and, additionally, from antimicrobial agents , , — The resulting habitation in an intracellular environment necessitates an adaptation to the anaerobic milieu Moreover, virulence and pathogenic behaviors are modified; for instance, S.

A serious consequence of S. Cell wall components, such as peptidoglycan and teichoic acid purified from S. A recent study investigated the contributions of different mechanisms involved in biofilm accumulation, i. Additionally, biofilm-positive S. This advantage, however, is found only with wild-type C.

Moreover, immunocompromised nematodes are equally sensitive to S. This may limit the influx of phagocytic neutrophils, thereby helping the bacteria to survive in the host. Extracellular enzymatic activities not only may be involved in biofilm detachment see above but also may determine the establishment of an infection and aid in the survival of bacteria in the host by enabling bacteria to invade host tissues and to evade host defense systems, respectively.

In this regard, CoNS have developed multiple mechanisms, including the production of a variety of extracellular proteins and enzymes, such as lipases, proteases, esterases, and phospholipases, as well as the production of hemolysins and other toxins. In particular, proteases may play an important role in i proteolytic inactivation of host defense mechanisms, such as antibodies, platelet microbicidal proteins, and AMPs; and ii the destruction of tissue proteins, thus causing increased invasiveness.

The extracellular serine protease Esp can degrade a wide spectrum of proteins, including complement protein C5 and fibrinogen, thereby providing S. The kDa extracellular metalloprotease SepA has a high capacity to inactivate AMPs by proteolytic cleavage , and also significantly promotes S. Moreover, Ecp, an extracellular cell wall-associated cysteine protease with elastase activity from S.

Most S. Furthermore, in human neutrophils, PSMs induce cellular degranulation, prime cells for an enhanced respiratory burst, and inhibit spontaneous apoptosis PSMs are also chemoattractants for both neutrophils and monocytes Because of these pronounced proinflammatory properties, PSMs may contribute to sepsis caused by S. In contrast to its parental strain, an agr mutant did not produce any of the PSM peptides Therefore, an agr QS mechanism was proposed that facilitates growth and survival in infected patients by adapting production of the proinflammatory PSMs to the stage of infection Some PSMs also exhibit moderately cytolytic activity see below.

Thus, either no or rather lowly aggressive virulence factors have been described for CoNS. Moreover, CoNS are still not generally accepted as producers of toxin superantigens. While some S. Nevertheless, S. Thus, S. These data indicate that the strategy of S.

Thus, so far, reasonable data are lacking to confirm the secretion of detectable amounts of classical PTSAgs in a significant proportion of CoNS isolates recovered from human specimens, or their involvement in clinical cases of TSS or food poisoning , However, an S. In general, cross-reactivities of immunological assays and possible misidentifications in the premolecular era may hinder an accurate assessment of respective study results.

For detailed information on the staphylococcal PTSAg family itself, please see the review recently published in this journal Clinical CoNS isolates possessing exfoliative toxins have not been reported so far. In particular, commensal staphylococci are known to produce antibiotic-like peptides that also fulfill the criteria for bacteriocins, namely, the so-called lantibiotics Lantibiotics belong to the class of cationic antimicrobial peptides CAMPs and are active against Gram-positive bacteria.

Their production may play a considerable role in bacterial interference on skin and mucous membranes, thereby creating an ecological niche for S. Type A lantibiotics induce pores in the cytoplasmic membrane. Lantibiotics produced by S. Later, epilancin K7, epidermicin NI01, and epicidin were identified. Further lantibiotics produced by CoNS were detected in S.

Knowledge concerning the regulation of S. Another global regulator controlling S. Furthermore, various other regulators were recently identified. QS systems are bacterial cell-cell communication systems in which small pheromone peptides or autoinducing peptides AIPs are used to communicate. At low cell densities, the concentration of AIPs is low. With increasing cell densities, the concentration of AIPs becomes elevated.

The QS system is induced by the activation of a transcriptional regulator when a certain AIP threshold concentration is reached, which typically occurs in the late exponential growth phase. The transcriptional regulator then regulates the expression of the target genes, which may be up- or downregulated.

The components of the agr QS system and their features and functions have been described previously in great detail , The similarity among the agr systems of S. Nevertheless, the sequences of S. The process of staphylococcal biofilm production is influenced by agr in a versatile manner. Generally, the agr QS system downregulates biofilm production: S.

Furthermore, agr transcription is considerably repressed during biofilm accumulative growth of S. This implicates that a nonfunctional agr system increases the chance of causing an S. The stronger biofilm-forming capacity of the agr mutant of S. Increased biofilm formation could also be explained by a decreased detachment rate, as thicker biofilms of the agr mutant may result from a lack of upregulation of different genes involved in biofilm detachment, such as proteases, nucleases, and PSMs, by agr , , The regulatory mechanisms controlling the colonization factors seem to differ in S.

Observed, partially conflicting findings may result from different experimental settings The function of the staphylococcal agr system in the growth phase-dependent regulation of protein synthesis and biofilm formation may be summarized as follows. In an early stage of infection, cell density is low and surface and surface-associated proteins with adhesive functions are expressed, allowing attachment to biotic and abiotic surfaces.

AI-2 is synthesized growth dependently, predominantly in the exponential growth phase. Mutation of S. Furthermore, the luxS mutant had a more pronounced capability to colonize and to initiate disease in a CVC-associated rat model of infection The luxS QS system has a pronounced effect on biofilm production and virulence in S.

Therefore, at least in the case of S. The Sar family of transcriptional regulators includes at least 12 paralogs in S. A global regulator, sarA , controls exoprotein synthesis by modulating the expression of agr. SarA of S. SarA is a positive regulator of S. Recently, additional mechanisms of sarA -dependent biofilm regulation have been identified. Inactivation of sarA in S. Other Sar paralogs recently identified in S.

SarZ is highly homologous to SarZ from S. Furthermore, sarZ influences the expression of other pathogenicity factors, such as proteases and lipases, and plays a role in biofilm-associated infections SarX has also been identified as a positive regulator of biofilm production of S. Many bacterial species express various alternative sigma factors when adapting gene expression to changing environmental conditions.

Like S. However, the presence of ethanol in the growth medium of the rsbU mutant completely restored biofilm formation, whereas salt stress did not. Thus, different regulatory mechanisms seem to be involved in S. Further results indicated that icaR , which codes for a negative regulator of icaADBC transcription, might be responsible for this differential regulation Recent analysis indicated that the decreased expression of the icaADBC operon in a sigB mutant is mediated via upregulation of IcaR The isolation and cultivation of CoNS are relatively easy and straightforward, as is also the identification of frequently encountered CoNS species.

From a diagnostic and clinical point of view, it is an essential requirement to make a clear and valid distinction between CoNS species and CoPS species, with the latter being overwhelmingly S. Species-level identification of CoNS associated with infection, especially in the case of a pure culture, has become customary Among CoNS, the accurate recognition of S.

The standard approach for detection and identification includes culturing on a nonselective blood agar plate as well as in enrichment broth, followed by biochemical and other related procedures, including the use of commercial systems for identification purposes. Today, biochemical identification approaches are increasingly being replaced by the application of matrix-assisted laser desorption ionization—time of flight mass spectrometry MALDI-TOF MS.

The most challenging problem in CoNS diagnostics is the assessment of their clinical relevance. Thus, the major diagnostic task is to assess whether a given CoNS isolate represents i a contamination of the specimen during sampling and processing, ii physiological colonization of the skin or mucous membranes, or iii clinically significant infection. This challenging situation becomes even more complicated in the case of polymicrobial infections by CoNS, particularly for the choice of antibiotics for therapy if the isolates exhibit different susceptibility patterns.

Finally, this cardinal diagnostic and clinical dilemma can be solved only with close cooperation between clinicians and microbiology laboratory specialists. In the following section, only the main aspects of the detection and identification of CoNS are given; for further details, please refer to respective textbooks and manuals , — The recovery rate can be increased by the simultaneous use of an enrichment broth e.

Usually, growth of most CoNS species occurs within 18 to 24 h. Isolates displaying the SCV phenotype, in contrast, often need about 48 to 72 h to display visible colonies. Since clinical findings alone have limited sensitivity and specificity in the diagnosis of CRBSIs, various semiquantitative or quantitative laboratory techniques have been developed.

The traditional approach, i. To detect bacteria not only from the external surface but also from the intraluminal surface, the catheter can be flushed with broth. Alternatively, by counting the absolute number of CFU per volume, examination of paired quantitative blood cultures drawn simultaneously from the catheter and a peripheral vein overcomes the necessity of catheter removal. This approach has been enhanced by the analysis of differential time to positivity , Detachment of biofilms from an implant surface by sonication may improve the diagnosis of the respective FBRI.

For explanted hip and knee prostheses, the culture of samples obtained by sonication of prostheses was more sensitive than conventional periprosthetic tissue culture, particularly for patients who had received antibiotics within 2 weeks prior to surgery Also, for other implants, such as removed electrophysiological cardiac devices and spinal and breast implants, an advantage of sonication prior to culturing has been shown , — The application of the extensive and labor-intensive scheme originally published by Kloos and Schleifer in , and subsequently supplemented several times , has been replaced in clinical microbiology laboratories by commercial identification systems based on biochemical procedures, including the use of semi automated systems.

In addition, nucleic acid-based molecular methods have become standard, in particular for the verification of ambiguous identification results. However, it still makes sense to test the basic criteria for the identification of CoNS: Gram-positive, catalase-positive, mostly oxidase-negative for exceptions, see Fig. This holds true in particular for plausibility control purposes or in the case of ambiguous results, if doubts arise as to whether a given isolate belongs to the genus Staphylococcus or the CoNS group, respectively.

As with all staphylococci, CoNS are Gram-positive, nonmotile, non-spore-forming cocci. They are usually arranged in pairs or tetrads but also occur singly, in irregular grape-like clusters, or in short chains of about three or four cells.

Direct microscopic examination may be helpful for analyzing normally sterile fluids e. Typically, most CoNS species display nonpigmented, smooth, entire, glistening, and opaque colonies. Strong slime producers may display a mucoid colony appearance. After 2 to 3 days of incubation, colony diameter reaches 3 to 6 mm. More or less gray-yellow, yellow, or yellow-orange pigmented colonies are a characteristic of the following CoNS species: S.

Other CoNS species may show a kind of yellowish pigmentation. Some CoNS species e. Sections of Columbia blood agar plates showing grayish, hemolytic colonies of S. The colonies are mostly less or nonhemolytic and less or nonpigmented Fig. Note that they often give the appearance of a mixed culture because colonies displaying the normal phenotype and those exhibiting the SCV phenotype coexist. Upon subculture, SCVs may remain stable or revert to the wild type Columbia blood agar plate showing an isogenic S.

The traditionally used approach in the clinical laboratory for the differentiation of S. To overcome these limitations and the long incubation time of the tube coagulase test, rapid latex and hemagglutination assays allowing presumptive identification of S. In particular, coagulase-negative but clumping factor-positive species, such as, in particular, S.

Lowered specificity may be the result of false-positive reactions occurring with some CoNS strains, due to their possessing, for example, the type 8 capsular polysaccharide as known for S. Testing of S. In the case of CoNS isolates recovered from urinary tract specimens, testing for resistance to novobiocin is routinely and almost exclusively used as a simple approach to distinguish the intrinsically resistant organism S.

Other novobiocin-resistant CoNS Table 2 are rather seldom found in human-derived specimens. Subsequent to the era of classical tests for fermentation, oxidation, degradation, and hydrolysis of various substrates, i. The Sherlock microbial identification system MIDI, Newark, DE combines cellular fatty acid analysis with computerized high-resolution gas chromatography.

These systems are fairly successful at differentiating common CoNS, such as S. For some of these systems, reliability depends on the performance of additional tests as recommended by the manufacturers. However, these assays may have also failed to distinguish commonly encountered CoNS species, in particular if isolates were recovered from livestock and food or if uncommon strains were isolated 89 , , This also holds true in the case of the differentiation of phenotypic variants The testing of volatile organic compounds VOCs in clinical samples appears to be a promising future tool for the noninvasive detection and monitoring of infectious diseases; it is based on VOC biomarker profiles representing metabolites of both the infecting pathogen and pathogen-induced host responses Note that a semiquantitative analytical cutoff value for CoNS has been set in this assay to avoid false-positive results due to CoNS contamination during blood sampling procedures.

One could speculate that these CoNS-adjusted multiplex PCR assays might underreport CoNS, particularly for patient groups where CoNS-positive findings frequently indicate true bloodstream infections, such as neutropenic hematological patients and preterm newborns For the identification of cultured CoNS, several nucleic acid-based approaches have been developed and evaluated based on amplification, hybridization, and sequencing procedures. Overwhelmingly, in the case of CoNS, conserved regions with embedded species-specific sequences of universally occurring genes are amplified, followed by sequencing and analysis of the part s , allowing differentiation at the species or subspecies level.

Note that the validity of results depends strongly on the quality of the database used for sequence analysis Sequencing of partial rpoB gene sequences was shown to be superior to partial 16S rRNA gene sequencing for the differentiation of Staphylococcus subspecies Several commercial tests are available, mainly for the molecular verification of cultured S. Additionally, some of these are able to identify some of the most clinically relevant CoNS e.

Microarray-based diagnostics may combine the advantages of high-throughput screening with the possibility of the identification of different genes useful for species determination and, in parallel, the identification of a multitude of virulence, drug resistance, and subtype-determining signatures. These assays have been tested successfully on clinical isolates , A qualitative nucleic acid hybridization assay S.

Spectroscopic methods, such as Fourier transform infrared FT-IR and Raman spectroscopy, offer an alternative approach for the rapid identification of staphylococci This nondestructive technology also allows discrimination between phenotypes, as shown for the SCV phenotype Comparable to the introduction of PCR, but with many fewer infrastructure requirements and much less necessity of specific skills, MALDI-TOF MS has become a revolutionary new diagnostic tool, leading to a fundamental shift in routine microbiological diagnostics This rapid, high-throughput diagnostic approach is based on peptidic spectra obtained by molecular weight determination for individual, specific fragments.

The capability of this method for valid identification has been demonstrated in the last few years for many microorganisms, including staphylococcal species. To reach this high specificity, the quality of the database and the standardization of variable parameters, such as culture conditions, are crucial.

Another method for high-throughput identification and further molecular characterization is an approach coupling PCR technology, based on universal and target gene-specific primer sets, to electrospray ionization-mass spectrometry ESI-MS The main question to be answered in the reporting of CoNS recovered from a clinical specimen is whether their detection reflects a true infection or only contamination or colonization.

Since in our experience a large proportion of the patient population with presumed false-positive CoNS findings is treated with antimicrobial agents, additional costs of treating patients and, in particular, unnecessary antibiotic selection pressures occur Factors helpful in the prediction of true infections include the isolation of a strain in pure culture from the infected site and the repeated isolation of the same strain over the course of an infection 1 , , , To reduce the misclassification of nosocomial BSIs due to CoNS, the following algorithm was defined: at least two blood cultures positive for CoNS within 5 days or one positive blood culture plus clinical evidence of infection This was corroborated by a 3-year retrospective cohort study based on data prospectively collected through hospital-wide surveillance; this revealed that a single positive blood culture, if associated with signs of sepsis, should also be considered clinically relevant For further details and strategies e.

This deteriorating situation is further aggravated by the phenomenon of multiresistance. In previous decades, a continuous loss of susceptibility toward most of the available antibiotics was recorded for CoNS. Strong and sometimes dramatic increases in the percentage of resistant isolates were noted particularly for penicillin, oxacillin, ciprofloxacin, clindamycin, erythromycin, and gentamicin , — A selection of recent studies concerning the percentage of resistant CoNS is given in Table 5.

For newer compounds without or with just recently established interpretative criteria, examples of CoNS studies analyzing their MIC values are listed in Table 6. Note that given the reduced susceptibility breakpoints for CoNS with the exception of S. Percentages of clinical CoNS isolates categorized as antibiotic resistant toward various antibiotic agents. In vitro activities of clinical CoNS isolates toward newer antibiotic agents.

This is of the utmost importance for human and veterinary medicine, because these genetic elements are mobile by nature. Thus, they may transfer into the medically most significant staphylococcal species, S. Highly penicillin-resistant S. This phenotype is caused by penicillinases, first described by Kirby in Today, as a result of huge selection pressures, CoNS isolated from clinical specimens are significantly more resistant to single-antibiotic and biocidic compounds, often appearing as multiresistant isolates, and penicillin-susceptible S.

Highly simplified schema not true to scale of the composition of the SCC family integrated into the S. Some examples of various SCC types, including those organized in composite islands, are given. Basic structures comprise the mec gene complex red , the ccr gene complex yellow , and the joining regions gray. Once detailed characterization of PBP2a structure and function became available at the end of the s , , proteins with very similar characteristics were described for CoNS As a few homologs of the mecA gene became known, this warranted a proposed nomenclature revision Table 7.

Results of bioinformatic analysis of the mecA gene polymorphisms revealed 32 unique alleles that clustered into four distinct branches Two further branches correspond to allotypes of the mecA gene, which have been described for subspecies of S. Both members of the S. Note that although the mecA1 gene is ubiquitously present among S. The same holds true for the branch that includes mecA alleles from S.

For intrinsically resistant S. However, it is postulated that the original chromosomal locus contained by S. Regarding the other known mec types, Macrococcus caseolyticus strains isolated from chicken meat were found to harbor a mec homolog, now categorized as mecB Table 7 The mecC gene represents the fourth of the hitherto known phylogenetic branches of the mec genes, comprising isolates that have been detected in the past few years in MRSA SCC mec type XI strains isolated from diverse human, livestock, and wildlife sources , — ; one mecC CoNS isolate probably S.

However, the isolate was phenotypically oxacillin susceptible due to a truncation of PBP2a by frameshift mutation Another mecC allotype, mecC2 , was recently reported for methicillin-resistant S. The mec genes are harbored by an SCC mec mobile genetic element inserted into the chromosome Fig.

The mec gene complex comprises the mecA gene itself and, when present, its regulatory genes, mecI a repressor and mecR1 a sensor inducer , as well as an insertion sequence, IS mec , — As discovered in the past few years, the intra-SCC mec diversity is enormous and very complex. This holds true not only for the J regions J1 to -3 , which contain diverse virulence, resistance, and other genes, as well as pseudogenes, and which vary in length, but also for the mec and ccr gene complexes essential for the function of the SCC mec.

To date, 11 types and several subtypes have been reported for the SCC mec element. Besides the SCC mec elements, characterized by the possession of both mec and ccr gene complexes, other, diverse elements occur that lack one or both of these complexes They are part of many different composite islands and can be differentiated into the following three groups: i arginine catabolic mobile elements ACMEs ; ii SCC-like elements, chromosome cassettes, or SCC mec insertion site genomic sequences; and iii SCC mec remnants ACMEs are highly prevalent among CoNS strains and are characterized by genetic diversity, with intact or truncated forms , , — SCC elements, including their pseudo-elements, often carry additional antibiotic resistance genes, mostly as part of integrated transposons and plasmid copies e.

In addition, other genes or loci, such as those involved in virulence, colonization, transmission, and cell wall synthesis, have been detected in these elements , , , In comparing S. In recent studies, the prevalence of clinical S.

In contrast, in healthy persons in northern Sweden, a near absence of oxacillin resistance was reported, and isolates of common hospital-associated clones of multidrug-resistant S. As occurs with MRSA, oxacillin-resistant CoNS isolates are, in general, more often multiresistant than oxacillin-susceptible isolates , In a Japanese study, mecA -positive S.

Ceftobiprole was approved for use in Switzerland and Canada, but sales were—possibly temporarily—discontinued in response to regulatory recommendations not to approve this substance in the United States and the European Union. Ceftaroline is approved by the U. A ceftobiprole MIC range of 0.

MIC ranges of 0. Also for S. In a large U. In a Canadian multicenter study, ceftaroline demonstrated a 2-fold greater potency against MR S. The exact mechanism of glycopeptide resistance among CoNS is still unclear. Heterogeneous susceptibility profiles, including reduced susceptibility for teicoplanin, may suggest some general predisposition to an intrinsic resistance to this antibiotic class Three phenomena leading to therapy failure after administration of glycopeptides have been discovered or postulated, mostly for S.

Their complex resistance mechanisms include cell wall alterations, resulting in reorganization and thickening, in addition to reduced autolytic activity , — Also, cell wall thickening has been reported for glycopeptide-resistant CoNS S. Some glycopeptide-resistant CoNS may possess an excess of glycopeptide-binding sites by virtue of the overproduction of cell wall peptidoglycan material Thus, one can consider that the basic mechanisms leading to a reduced susceptibility to glycopeptides may be similar in CoNS and S.

Up to the present, van gene-possessing S. Of potential importance, 6 of these 15 CoNS isolates S. These highly mobile wild songbirds may act as a vector to spread vancomycin resistance genes over a wide area A recent observation of 3 isolates carrying vanA and vanB1 genes, which were detected by PCR within a collection of 30 S.

This issue is a matter of debate, since other studies noted no changes or even reductions in vancomycin MIC values , So far, the creep phenomenon has not been reported for CoNS. A Swedish study analyzing bloodstream isolates of S.

Following the introduction of vancomycin into clinical practice in , clinical CoNS isolates with reduced susceptibility to vancomycin did not come to widespread attention for more than 2 decades, until the s , During this time, resistant S. Both species have been found to be the commonest CoNS species exhibiting reduced susceptibility to glycopeptides However, despite extensive, unabated vancomycin use, the vast majority of CoNS isolates tested have been shown to still be susceptible to vancomycin 64 , 75 , , — , , , , — Including clinical isolates of S.

Early studies certified comparable activities of vancomycin and teicoplanin teichomycin against CoNS, some with lower MIC values With time, it became evident that teicoplanin-resistant CoNS isolates were more common than those exhibiting resistance to vancomycin. In addition to some earlier reports on evaluated teicoplanin MICs , the first teicoplanin-resistant CoNS were reported in among a selection of methicillin-resistant S.

The first clinically silent case associated with a teicoplanin-resistant S. In the same year, a letter describing a real clinical case due to an S. Comparable results were attained in other studies if tests were conducted according to CLSI criteria , Notably, in testing the same isolates according to EUCAST interpretative criteria, higher resistance percentages were found for teicoplanin e. However, study populations with a higher prevalence of teicoplanin-resistant isolates have been reported, such as in a recent Polish study In a collection of clinical MR S.

This French study found that the prevalence of teicoplanin resistance increased in S. In a United Kingdom study, Only one isolate in this study exhibited resistance to both vancomycin and teicoplanin. For daptomycin, a bactericidal, cell membrane-targeting cyclic lipopeptide, diverse but not fully elucidated mechanisms leading to resistance have been assumed and have been studied mostly in S.

Through the accumulation of single nucleotide polymorphisms in several gene loci, especially the multipeptide resistance factor gene mprF and the yycFG components of the yycFGHI operon, cell membrane phenotypic changes occur in addition to other perturbations of the cell membrane , Also, modifications of the cell wall, including increased cell wall teichoic acid production, enhanced expression of the dlt operon, which is involved in d -alanylation of cell wall teichoic acids, and progressive cell wall thickening, may contribute to daptomycin resistance , — Daptomycin demonstrated high activity against more than 20 CoNS species, as shown in a study of more than 22, isolates from 42 countries as part of the SENTRY program to In that study, daptomycin inhibited Species having the highest MIC values for both glycopeptides in that study, such as S.

Bloodstream isolates of S. For lipoglycopeptides, potent in vitro activity against S. For PJI-associated S. However, CoNS that had reduced susceptibility to vancomycin and resistance to teicoplanin presented a ca. After many decades, the oxazolidinone linezolid represented the first and so far only of a novel antibiotic class available on the market with activity against Gram-positive microorganisms, including staphylococci.

So far, three mechanisms have been discovered that result in oxazolidinone resistance in staphylococci: i successive accumulation of single point mutations in the linezolid 23S rRNA domain V -binding site in at least two copies of the rRNA gene operons; ii rarely, mutations in the rplC and rplD genes, encoding the 50S ribosomal proteins L3 and L4, respectively, of the peptide translocation center of the ribosome; and iii acquisition of the plasmid-borne ribosomal methyltransferase gene, cfr , leading to posttranscriptional methylation of adenosine at position of 23S rRNA in the large ribosomal subunit , — Point mutations in the 23S rRNA gene e.

In contrast to the first two mechanisms, cfr -mediated resistance is of serious concern, due to its possible high horizontal transfer capability, its origin from animal-associated staphylococcal species, and its association with a PhLOPS A phenotype, exhibiting resistance to several antibiotic classes, including phenicols, lincosamides, oxazolidinones, pleuromutilins, and streptogramin A A multicity outbreak of a cfr -containing linezolid-resistant S. An isolate has been described in Spain with cooccurrence of all three mechanisms leading to linezolid resistance To date, more than seven different cfr -carrying plasmids and several types of chromosomal cfr segments have been identified in CoNS e.

Moreover, the phenomenon of linezolid dependence may additionally contribute to the escalating emergence of linezolid-resistant isolates In time-kill experiments, linezolid displayed a predominantly bacteriostatic activity against staphylococci Since its introduction in approximately , linezolid has proven to be at least as effective as glycopeptides for the treatment of patients with Gram-positive infections; however, the majority of data are derived from MRSA patients with SSTIs, supplemented by a few studies on pneumonia , Despite more than a decade of clinical use, linezolid resistance is still a rare phenomenon, but concerns are growing.

Within a surveillance study enrolling Canadian hospital-associated patients in , S. Also, results of the U. The incidences of linezolid resistance among CoNS isolates from the U. Other recent studies confirmed a still low prevalence of linezolid resistance among CoNS isolates , , Besides the species mentioned below see next paragraph , linezolid-resistant isolates among CoNS were also reported for S. Besides S. On Chinese pig, chicken, and duck farms, cfr -carrying isolates were found among S.

The justified concern surrounding linezolid resistance, whether cfr mediated or not, is underlined by reports of outbreaks and nosocomial spread of linezolid-resistant S. An impressive example is the regular recovery of linezolid-resistant strains of S. Resistance to tetracyclines is based primarily on the acquisition of mobile tet and otr genes, leading to ribosomal protection through dissociation of tetracyclines from their ribosomal binding sites and to drug efflux through active transportation of the agents out of the bacterial cell , Along with the significant decrease of tetracycline administration for outpatients in Europe , this phenomenon seems to be a continuation of an earlier trend, as The minocycline derivative tigecycline is the prototype compound of a new class of glycylcyclines with bacteriostatic broad-spectrum activity overcoming resistance development of classical cyclines due to not being substrates for tetracycline efflux pumps For staphylococci, the mechanism s of tigecycline resistance remains to be elucidated.

In studying S. Comparing the results from two German multicenter trials conducted prior to and after the introduction of tigecycline, no differences were found in the tigecycline susceptibility of S. However, three S. In contrast to the case for S. Although these three agents belong to different classes of antibiotics, they have one thing in common: a rapid development of resistance if administered as monotherapy.

Thus, they are used principally in combination therapy. However, combined medication with these agents is based on clinical experience rather than proven evidence and thus is a matter for debate Spontaneous mutations in the fusA gene leading to an altered ribosomal translocase i. A FusB mechanism in staphylococci includes an acquired chromosomal or plasmid-mediated fusB gene, encoding an inducible EF-G-protecting protein , Among S.

Interestingly, mutants of a further class, termed FusE, and some mutants of the FusA class display some phenotype characteristics of staphylococcal small-colony variants In Europe, large differences in fusidic acid resistance were found among 3, CoNS isolates, ranging from In both studies, the percentage of fusidic acid-resistant isolates was by far higher in the CoNS group than in the S. Resistance to fosfomycin phosphonomycin can be mediated by either chromosomal or plasmid-borne mechanisms.

In contrast to the case for Gram-negative microorganisms, little is known about the chromosomally mediated resistance, which is based on defects in the l -alpha-glycerophosphate glpT or hexose phosphate uhpT transport system that takes up fosfomycin In plasmid-mediated resistance, fosA encodes a glutathione S -transferase that inactivates fosfomycin by forming a covalent bond between fosfomycin and a sulfhydryl group in glutathione In staphylococci, a homolog, fosB , has been described Summarizing data from three studies evaluating fosfomycin susceptibility, Rifampin resistance in staphylococci is most frequently based on point mutations in the highly conserved regions of the rpoB gene, which encodes the beta subunit of the bacterial RNA polymerase, resulting in amino acid substitutions at or near the binding site for the drug , Data from Germany revealed 6.

In the case of CoNS, little is known about the real prevalence of resistance toward mupirocin, a topically administered antibiotic. In a German study performed in , rates of low- and high-level resistance were shown to be 9. What is especially worrying is that this resistance is mediated by plasmids carrying the ileS2 gene, also designated mupA , which could be transferred to S.

Moreover, these plasmids are recognized as being associated with resistance to other agents, such as clindamycin, erythromycin, levofloxacin, and tetracycline. Relatively little is known regarding the resistance of CoNS to antiseptics. In a recent study in a French neonatal ICU, Note that quaternary ammonium compound QAC resistance determinants are transferable and are located on plasmids and transposons together with antibiotic resistance genes encoding resistance to aminoglycosides, penicillin, and trimethoprim As with S.

For empirical calculated antibiotic therapy of CoNS—at least for S. Nevertheless, valid methicillin resistance determination is a necessity for CoNS, since in several circumstances, such as endocarditis and other invasive processes, the use of the most efficient therapeutic option, i. Of particular importance is the determination of methicillin susceptibility for S. Conversely, misidentification of MR-CoNS isolates as methicillin susceptible may lead to fatal treatment failure.

Furthermore, valid determination of glycopeptide susceptibility of CoNS isolates may have increasing future significance. It is noteworthy that traditional phenotype-based methods have reduced sensitivity and specificity for recognition of methicillin resistance in CoNS. This is caused by heteroresistance of respective isolates, a phenomenon also recognized in MRSA. Heteroresistance describes the fact that only a minority of cells of a given methicillin-resistant isolate express the genetically encoded capability of methicillin resistance under in vitro conditions, thus suggesting a false-susceptible result.

However, with the enhanced discriminatory power of applying cefoxitin as a test substance for detecting MR staphylococci, most of the diagnostic problems caused by heteroresistance have disappeared. The CLSI interpretative criteria are basically the same.

For CoNS other than S. MICs for glycopeptide testing are method dependent. The disc diffusion method is considered unreliable because it is not able to distinguish between isolates exhibiting the wild-type phenotype and those characterized by non- vanA -mediated resistance. Serious GISA infections are not treatable with high doses of glycopeptides. For the detection of heterogeneous resistance to glycopeptides, a modified population analysis profile-area under the curve PAP-AUC method is needed Since this method is laborious, complicated, and not suited for routine use, a number of screening assays have been developed for S.

This approach has also been applied for S. Rapid PCR-based approaches have been introduced only for the detection of MRSA directly from surveillance swabs for screening purposes. Commercial assays specifically developed for the detection of methicillin resistance in CoNS are not available. However, several in-house PCR approaches for the species differentiation and simultaneous methicillin resistance determination of cultivated CoNS isolates, together with detection of biofilm formation genes, have been reported , Key points that have to be considered for the treatment and management of CoNS infections include the species S.

Therapeutic options for the treatment of CoNS are limited because the vast majority of clinically recovered isolates are methicillin resistant. Thus, most infections by CoNS of the S. Alternatively, cotrimoxazole, if isolates are susceptible, or newer antibiotic agents, such as daptomycin, linezolid, or cephalosporins with MRSA activity, may be administered, in particular if methicillin resistance is probable or was detected.

When used simultaneously, antibiotics with cell wall activity combined with rifampin were shown to act synergistically. However, respective recommendations are based on limited, partly uncorroborated studies and some case reports for the treatment of severe infections, mostly by S. For CoNS, even fewer data are available. Thus, a careful risk-benefit assessment is mandatory if combination therapy is applied.

Sufficient controlled clinical study data on the efficacy of antimicrobial agents for S. Empirical treatment of S. Note that in cases of S. A recent analysis revealed that medical treatment alone was an independent risk factor for mortality For uncomplicated UTIs due to S. In contrast to the usual 3-day regimen for the treatment of uncomplicated UTIs, infections by this CoNS species may respond better to 7 days of therapy; however, the relevant data are sparse This longer treatment regimen may also be applied if other antimicrobial agents, such as fluoroquinolones, are administered For detailed treatment information, the annually updated edition of The Sanford Guide to Antimicrobial Therapy , respective national guidelines, and current manufacturer specifications should be consulted.

They frequently require removal of the device, often accompanied by the need for additional medical interventions and costs. CoNS-generated biofilms show significant resistance to antibiotics, caused by impaired penetration of the antibiotics and changes in bacterial metabolism and behavior.

With the exception of rifampin, approximately to 1,fold increases in minimal bactericidal levels have been demonstrated against most antibiotics For this reason, several key questions have to be addressed for the rational and successful management of FBRIs. They include the relevance of a presumed FBRI to clinical signs and how it can be confirmed, the presence of predisposing factors e.

In the case of CRBSIs, the absence of continuing bacteremia should be confirmed by blood culture diagnostics after catheter withdrawal. Alternatively, a short antibiotic treatment 5 to 7 days subsequent to removal of the catheter might be appropriate for uncomplicated CoNS-caused CRBSIs. If the catheter is retained, antibiotics should be administered for 10 to 14 days, along with antibiotic lock therapy , Alternative agents include daptomycin, linezolid, and quinupristin-dalfopristin For PJIs caused by staphylococci, intravenous antimicrobial therapy for 2 to 6 weeks should be administered subsequent to debridement and retention of the prosthesis This is followed by a longer oral course 3 to 6 months dependent on the nature of the PJI For methicillin-resistant staphylococci, vancomycin should be given; an alternative treatment, daptomycin or linezolid, or a combination therapy with rifampin is recommended irrespective of whether the isolate is methicillin resistant or not Modified recommendations exist for patients with PJI following a one-stage exchange or for other circumstances CoNS resemble very heterogeneous and versatile Gram-positive bacteria.

Their main ecological niches are skin and mucous membranes of humans and animals, and they are therefore always in a very close, and mainly symbiotic, relationship with their natural hosts. This also holds for the CoNS species preferentially found on humans. Except for S. However, groups of especially susceptible patients are increasing, either due to still undeveloped or impaired host response functions or due to inserted or implanted foreign bodies.

Consequently, CoNS have become a major nosocomial pathogen. Despite the normally subacute and low inflammatory course of these infections, they present a substantial clinical burden because of broad and severe treatment difficulties. In the case of foreign body infections, the removal of the infected device is most often ultimately required.

Many questions regarding the phylogeny, ecology, and pathogenesis of CoNS are still not answered. Just recently available new methodological tools will enable further research approaches. This may lead to new measures for effective therapy and for the prevention of CoNS infections.

Karsten Becker, M. He is the author of several medical textbooks and encyclopedias and more than scientific publications. Since the s, his interests have included the epidemiology, pathogenesis, diagnosis, prevention, and therapy of staphylococcal and micrococcal infections.

He has described novel species of the genera Staphylococcus and Kytococcus. In particular, he has done extensive research on the intracellular lifestyle of the staphylococcal small-colony variant SCV phenotype. A further focus is on the detection, identification, and characterization of MRSA strains. He is an academic editor and a member of the editorial boards of medical and bioscience journals.

Christine Heilmann, Ph. She undertook her Ph. After completing her Ph. She has worked in the area of staphylococcal research for more than 20 years, and her research focuses on the molecular basis of staphylococcal biofilm formation and host-pathogen interactions. Georg Peters, M. Since the beginning of his career, he has carried out research on the infectious biology of staphylococci and staphylococcal diseases.

Journal List Clin Microbiol Rev v. Clin Microbiol Rev. Author information Copyright and License information Disclaimer. Corresponding author. Address correspondence to Karsten Becker, ed. All Rights Reserved. This article has been cited by other articles in PMC. Abstract SUMMARY The definition of the heterogeneous group of coagulase-negative staphylococci CoNS is still based on diagnostic procedures that fulfill the clinical need to differentiate between Staphylococcus aureus and those staphylococci classified historically as being less or nonpathogenic.

TABLE 1 Historic and valid designations within the Staphylococcus genus reflecting the early dualism concept of pathogenic versus nonpathogenic staphylococci. Open in a separate window. Passet Welch, in , as a colonizer of the human epidermis found also in aseptic wounds FIG 1. Contemporary clinical concepts.

FIG 2. Taxonomy, Classification, and Phylogeny Current status of staphylococcal species and subspecies.

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