Multidrug resistance of Staphylococcus epidermidis: An emerging threat to global health

INTRODUCTION

The discovery of bacteria in the late 19th century has sparked the interest of mankind to search for preventive measures and therapeutic treatment for diseases caused by this group of microorganisms. This led to the discovery of antibiotics about half a century later, a turning point in human history that has brought about the revolution in medicine in controlling infectious diseases, thus saving millions of lives. Unfortunately, the effectiveness of these drugs has deteriorated due to the development of resistance in some bacteria strains against antibiotics. Such resistance is defined as the ability of the bacteria to survive in antibiotic concentrations that inhibit or kill others of the same species (Balaban et al., 2019).

In 2019, more than 1.2 million people died due to antibiotic-resistance bacterial infections, a number that is higher than the death by AIDS or malaria (Gregory, 2022) and the number is estimated to increase to 10 million by the year 2050 (Maillard et al., 2020; Strathdee et al., 2020). Hence, by the year 2050, death due to infections by antibiotic-resistant bacteria is expected to top the list, which exceeds the projected death due to cancer at 8.2 million (Dadgostar, 2019). In the US alone, reports from the Centers for Disease Control and Prevention’s (CDC’s) antibiotic resistance threats stated that more than 2.8 million antibiotic-resistant infections occur annually with more than 35,000 death (CDC, 2020).

Majority of Staphylococcus species is part of the normal microbiota of humans and play a major role in the spread of antibiotic resistance. The most prominent species of this group is Staphylococcus aureus, which causes a variety of human infections, such as bacteremia (Guo et al., 2020), endocarditis, osteomyelitis, and respiratory tract infection (Algammal et al., 2020). However, majority of commensal staphylococci species can be differentiated from S. aureus by their inability to produce the enzyme coagulase and are grouped together as the coagulase-negative staphylococci (CoNS). CoNS are known as nonpathogenic staphylococci that can be regularly found colonizing the skin and mucous membranes of humans and animals (Heilmann et al., 2019; Teixeira et al., 2019). The genus Staphylococcus has been expanded continuously, and to date, there are 41 main species and more than 20 subspecies of CoNS (Becker et al., 2020; França et al., 2021). Among the CoNS, Staphylococcus epidermidis, Staphylococcus haemolyticus, and Staphylococcus lugdunensis stand out as clinically significant species of growing importance (Chabi and Momtaz, 2019; Eladli et al., 2018).

The lifelong commensal relationship of a normal microbiota with its host can also be beneficial, with the normal microbiota contributing to the health and well-being of the host by preventing the colonization of more pathogenic species (Brown and Horswill, 2020; Eladli et al., 2018; Sharma et al., 2018). Commensal microbiota are known to contribute to host health and may play important roles in protecting the host against infections (O’Sullivan et al., 2018). Staphylococcus epidermidis plays a significant role in maintaining local homeostasis by balancing the skin’s microflora composition of the host (Brown and Horswill, 2020; Eladli et al., 2018; Sharma et al., 2018). In addition, by producing antimicrobial peptides, S. epidermidis can inhibit the growth of some pathogenic bacterial strains, hence indirectly helping in protecting the host.

The concept of contextual pathogenicity of certain skin microbes was first mooted by Dr. Philip B. Price in 1983. This concept helps to describe the nature of the relationship of a commensal with its host as either mutualistic or as an opportunistic pathogen (Guo et al., 2019; Sharma et al., 2018). The ability of S. epidermidis to cause infection was first reported in the infection of aseptic wound in 1981 (Becker et al., 2020). Since then, S. epidermidis has emerged as one of the most important causative agents of nosocomial (Lopes et al., 2021) and medical device-related infections (Gómez-Sanz et al., 2019; Xu et al., 2020). The treatment of these infections is rendered difficult due to the ability of S. epidermidis to acquire resistance to multiple antibiotics. A great majority of S. epidermidis strains in hospital settings was found to be methicillin-resistant, or methicillin-resistant S. epidermidis (MRSE) (Peixoto et al., 2020; Teixeira et al., 2019). The situation is further complicated with the observation that many MRSE are also resistant to multiple antibiotics (Eladli et al., 2018; Namvar et al., 2017; Wang et al., 2016). As such, the proliferation of multidrug-resistant (MDR) phenotype within the MRSE strains highlights the clinical significance of MRSE and their ability to acquire antibiotic resistance (Lopes et al., 2021).

Comparative genomic analyses have indicated the potential role of S. epidermidis as an important reservoir for resistance genes that can be transferred between the different species of staphylococci from different hosts and environments(Xu et al., 2018a). Such ability can be a potential threat if the resistance genes are transferred to a more pathogenic strain like S. aureus, thus suggesting the likely contribution to the further expansion of antibiotic resistance and subsequently resisting drug therapy (Haaber et al., 2017). However, despite these developments, S. epidermidis has remained inadequately represented in scientific literature, as compared to its more famous sibling S. aureus.

Staphylococcus epidermidis: duality nature as a commensal and a pathogen

Staphylococcus epidermidis is the most commonly isolated commensal species from the human epithelia (Brown and Horswill, 2020; Claudel et al., 2019). There is evidence that this bacterium’s interaction with the human begins as early as in the in utero stage of pregnancy, as they can be detected in the amniotic fluid (Sabaté Brescó et al., 2017). From there on, S. epidermidis begins to colonize the newborn shortly after birth (Dong et al., 2018), and subsequently assumes its role as the predominant commensal on the human skin. Generally, this bacterium can be found not only on the human skin but also on the mucous membranes, thus indicative of a ubiquitous trait (Brown and Horswill, 2020; Dong et al., 2018; Espadinha et al., 2019).

In 1891, US pathologist, W. H. Welch first discovered S. epidermidis colonizing aseptic wounds (Becker et al., 2020). As this bacterium was initially inferred to be harmless, the occurrence of S. epidermidis in a variety of infections continued to be frequently regarded as contaminants (Weinstein et al., 1997). However, with the heightened medical significance of CoNS in the last two decades (Michalik et al., 2020), the opportunistic pathogen nature of S. epidermidis is now an accepted reality.

The concept of contextual pathogenicity of skin microbes shown in Figure 1 summarizes the duality nature of the relationship between the host and microflora, which can be either mutualistic or pathogenic. This duality nature depends on host factors such as homeostatic or normal conditions, barrier breaches, and immunosuppression (Chen et al., 2018). Under normal conditions, S. epidermidis is a commensal of the skin (Claudel et al., 2019), but in case of breached skin, the barrier can completely transform the behavior of bacterium into pathogenic (Brown and Horswill, 2020). However, in CoNS, like S. epidermidis, the lines between pathogenic and nonpathogenic are often blurred as the status of the host immune system can influence the disease onset and outcome (Heilmann et al., 2019). Hence, distinguishing invasive from commensal strains can be challenging for this bacterium since virulence factors can be present in both (Murugesan et al., 2018).

However, the host factors are interrelated with the current situation in the medical field, such as the rising number of immunosuppressive patients and the continuous increase in invasive treatments and indwelling medical devices (Becker et al., 2020). As the host factors combine with current medical progress, S. epidermidis is no longer just an opportunistic pathogen but has emerged as a clinically significant pathogen. The current therapeutic and prophylactic use of antibiotics against this clinically significant pathogen invokes high selective antibiotic pressure, which will later facilitate the emergence and dissemination of MDR isolates (Heilmann et al., 2019). The host factors of the S. epidermidis pathogenicity are also dependent on the advancement of activities outside the medical field, such as animal therapeutics and the usage of antibiotics in sewage agriculture and other industries, which will also aid in the transmission of resistance within the community (Xu et al., 2018b).

Clinical significance of S. epidermidis

Staphylococcus epidermidis has been documented to cause a considerable range of diverse infections in humans, as shown in Table 1. Staphylococcus epidermidis was also implicated as an important pathogen in medical device-related infections, especially in hospital settings, due to the ability of this bacterium to form a biofilm structure that can attach to both biotic and abiotic surfaces. Hence, as the use of indwelling medical device increases, opportunistic infections by this bacterium via the medical device route has become a major clinical concern (Espadinha et al., 2019; Xu et al., 2020; Zalewska et al., 2021a).

Figure 1. Contextual pathogenicity of microbes on human skin (adapted from Chen et al., 2018). [Click here to view]

Table 1. The variety of S. epidermidis infections documented in humans. [Click here to view]

The majority of infections caused by S. epidermidis is nosocomial in nature, especially bloodstream infections (Otto, 2017; Zhou et al., 2020) and neonatal septicemia (Dong et al., 2018; Sheikh et al., 2019). Despite its growing clinical significance, the identification of S. epidermidis is frequently dismissed and infections suspected to be due to this species is often grouped as CoNS instead. For example, in a surveillance study on bloodstream infections conducted in China, CoNS was reported as the most prevalent isolates at 30.6%, followed by E. coli at 20.4%, while S. aureus was recorded in 1.3% of the isolates (Bai et al., 2019). In another surveillance study of nosocomial bloodstream infections in Brazil, the most common organisms isolated were CoNS at 21.3%, followed by Klebsiella species at 15.7% and S. aureus at 10.6% (Pereira et al., 2013). In both studies, the species of CoNS contributing to the infections were not identified.

Infections caused by S. epidermidis are mainly related to immunocompromised patients and individuals with indwelling medical devices (Grace et al., 2019; Teixeira et al., 2019). Such infections, if not managed properly, may lead to undesirable clinical outcomes such as longer intensive care unit stays, prolonged hospitalization, additional treatment cost, and increase in mortality rates (Heilmann et al., 2019). In Canada, an elderly patient died due to S. epidermidis bacteremia (Kou et al., 2015). In a study on prosthetic valve endocarditis, S. epidermidis not only accounted for about 13% of the infections but also 24% of the mortality rate (Chabi and Momtaz, 2019). For S. epidermidis medical device-related infections, the infections are mostly chronic as the host immune response is often insufficient to clear the infection (Nguyen et al., 2017). In neonates, the immunocompromised and premature newborns are the most vulnerable to CoNS sepsis, with S. epidermidis being the most prevalent species isolated (Cheung and Otto, 2010).

The role of MGEs in MDR S. epidermidis

One of the most important features of MGEs is that they can not only harbor antibiotic resistance genes together with many other genes conferring increased virulence and environmental persistence, but also be easily distributed between bacteria via horizontal gene transfer (Evans et al., 2020). Hence, MGE is not just a connecting bridge between the mutualistic and pathogenic nature of S. epidermidis whereby an acquisition of the virulent genes may turn this commensal into a pathogen, but it also serves a more important role as a directing passage of this bacterium into multidrug resistance.

SCCmec is one of the most important MGE in Staphylococcus (Monecke et al., 2016), which carries the mecA gene that characterizes the methicillin-resistant strains (Lopes et al., 2021).

Figure 2 shows a representative SCCmec element which comprises two main components, the mecA gene and the cassette chromosome recombinase ccr complex; and the interstitial regions in between are called the joining or the J regions. The ccr genes function in the integration and excision of SCCmec into and from the bacterial chromosome, while the J regions can carry additional genetic determinants, such as transposons, which may contain additional resistance genes (Rolo et al., 2017). Based on the various combinations of the ccr and mec gene complexes, 11 categories of SCCmec types are recognized in S. aureus, which is believed to be the origin of these genetic elements (França et al., 2021; Xu et al., 2020).

The mecA gene encodes a PBP2a protein with a low affinity to beta-lactam antibiotics including penicillins, cephalosporins, carbapenems, and monobactams (Xu et al., 2020). Hence, the mecA gene is the principal element in this cassette since it provides the staphylococci with the resistance ability to the extensive beta-lactam antibiotics (Rolo et al., 2017). The SCCmec may also carry additional antibiotic resistance genes through the insertion of other MGEs into the cassette such as Tn554 transposon, plasmid pT181, and pUB110 (Sansevere and Robinson, 2017). Hence, this provides an almost effortless path for MRSE strains to acquire additional multidrug resistance ability by the acquisition of these MGEs.

Figure 2. The main components of SCCmec. [Click here to view]

The methicillin resistance characteristic associated with the mecA gene is a critical factor that allows for the establishment of this bacterium as a nosocomial pathogen (Guo et al., 2019). It is estimated that as much as 75%–90% of all the S. epidermidis strains in hospital settings were MRSE strains, a proportion that is higher as compared to MRSA (Tang et al., 2020). These MRSE strains isolated from the hospital settings are also known as hospital-associated (HA) MRSE. Besides that, MRSE is also reported from other backgrounds such as community-associated (CA) and livestock-associated (LA) MRSE. However, as most CoNS are still viewed as minimally pathogenic in veterinary medicine (Morris et al., 2017), the study on LA-MRSE is scarce.

However, the significance and emergence of the CA-MRSE are increasing. A study in the UK reported that 61.9% of the community harbored MRSE isolates (Gómez-Sanz et al., 2019), while another study in Thailand recorded that all of the community S. epidermidis isolates were MRSE (Seng et al., 2017). Not only that, but the CA-MRSE may also cause moderate skin infection to severe necrotizing pneumonia, especially in persons with predisposing risk factors (Ekinci et al., 2018). For example, a case of CA-MRSE pyelonephritis in an immunocompetent child was reported in Japan in 2014 (Kanai et al., 2014).

Unfortunately, even though CA-MRSE strains, in general, do not cause serious infections, they may pose as an epidemiological concern in the health sector as these MRSE strains may persist as a genetic reservoir for the transmission of antibiotic resistance genes. The carrier of the CA-MRSE strains will also remain as a possible source of infections in the future where it may compromise the well-being of other patients in the same facility by transfer of the resistance. Although the significance of the CA-MRSE strains is clear, unfortunately, only a few studies have been conducted on this subject, and the majority of studies were focused generally on HA-MRSE instead (Gómez-Sanz et al., 2019; Seng et al., 2017; Xu et al., 2018b).

On the contrary, the incidence of HA-MRSE in nosocomial settings is evident. The percentage of HA-MRSE from nosocomial infections in most European and American countries was estimated to be around 75%–90% (Namvar et al., 2014). For example, a study in Portugal on S. epidermidis recorded that 79.1% of the isolates from patients in a tertiary care hospital were MRSE (Lopes et al., 2021). Studies on HA S. epidermidis in two South American countries, Columbia and Brazil, showed that 78.2% and 100% of the HA were MRSE, respectively (Castro-Orozco et al., 2019; Peixoto et al., 2020). Meanwhile, in a study in China in 2019, it was reported that 76.5% of the HA isolates were MRSE (Castro-Orozco et al., 2019; Xu et al., 2020). Another study in South Africa reported that all of the hospital-acquired isolates were MRSE (Ehlers et al., 2018). This exceptionally high recovery of MRSE in hospital settings certainly raises serious concerns.

However, the real threat is when some of the MRSE strains were found to be MDR as well. The high recovery of MRSE is further aggravated by the inclination of MRSE strains to develop an MDR phenotype, a phenomenon that is increasingly observed and reported in studies from various countries (Ehlers et al., 2018; Lopes et al., 2021; Peixoto et al., 2020). For example, a study in Brazil reported that 94.7% of the MRSE were also MDR (Peixoto et al., 2020). Another study in Portugal also recorded a high prevalence of MDR at 91.9% among their MRSE isolates (Lopes et al., 2021). Studies on S. epidermidis in South Africa and India reported that all the MDR strains isolated were also carriers of the mecA gene (Ehlers et al., 2018; Jena et al., 2017), which signifies MRSE (Lopes et al., 2021).

A bacterial strain is classified as MDR when it demonstrates resistance to three or more classes of antibiotics (Schmidt et al., 2018). The increase in the incidence of multidrug resistance in S. epidermis is evident from reports of MDR strains from all around the world (Imran et al., 2017), from either hospital or community settings, as shown in Table 2.

The data shown suggests that majority of the MDR S. epidermidis strain are HA or nosocomial in nature. Nevertheless, the proliferation of MDR S. epidermidis in the community should not be taken lightly as it may also cause diseases under permissible conditions (Ekinci et al., 2018). However, when the worldwide spread of these MDR S. epidermidis strains are coupled with the reduced pipeline of antibiotics, the treatment of the infections will be obstructed. Therefore, the infections caused by MDR strains are prone to associate with prolonged hospitalization and increased mortality (Kot et al., 2020).

Antibiotic-resistant genes (ARG) and their association with MGEs

Events like mutations or horizontal transfer of ARGs can change the nature of bacteria from being normal into resistant (Sánchez-Baena et al., 2021). However, as ARGs are often found on MGEs, like transposons and plasmids, it is more frequent for bacteria to acquire ARGs from the event of horizontal gene transfer (Checcucci et al., 2020; Sánchez-Baena et al., 2021) and become resistant rather than other events like mutations. In fact, one MDR strain is capable of carrying multiple ARGs conferring the resistance against a single antibiotic class such as bla, mec, and amp genes for penicillin resistance; aad, arm, and aph genes for resistance to aminoglycosides; and mph, msr, and mac genes for resistance to macrolides (Sánchez-Baena et al., 2021).

ARGs have been widely discovered within both pathogenic and commensal S. epidermidis whereby ARGs like tetK, tetM, ermA, ermB, msrB, and mecA are examples of resistance genes that are routinely discovered in this bacterium (Chabi and Momtaz, 2019). The association between ARGs and MGEs has been reported in S. epidermidis whereby the tetK and ermC were usually located on small multicopy plasmids, while the tetM and ermA genes were usually found on transposons (Chabi and Momtaz, 2019). However, the most prominent example will be the mecA gene located in SCCmec, which is harbored by many strains of S. aureus, S. epidermidis, and other CoNS species, and has a major role in the development of multidrug resistance (Rolo et al., 2017).

The association of the ARGs with a variety of MGEs not only explains the high mobility nature of ARGs in the development of MDR S. epidermidis, but also uncovers the potential of these ARGs to be spread widely to other species. The ability of MGEs to move horizontally to facilitate the spread of the ARGs was suggested to transverse taxonomic boundaries (Ebmeyer et al., 2021). For example, the tetM gene possesses the ability to confer an extensive host range of bacteria for tetracycline resistance (Zalewska et al., 2021b). As the tetM gene is also one of the ARGs found in S. epidermidis, it means that this gene can be transferred to other bacteria regardless of the taxonomies through S. epidermidis. Therefore, this initiates the investigation on the potential trait of S. epidermidis as a gene reservoir, which may intensify the threat of multidrug resistance.

Table 2. Reports on MDR S. epidermidis from various countries. [Click here to view]

Table 3. ARG of the SCCmec elements and its corresponding antibiotic resistance. [Click here to view]

CONCLUSION

With the increase in antibiotic resistance and the emergence of MDR strains together with its potential role as a genetic reservoir of resistance genes, S. epidermidis can no longer be underestimated, as this original human skin commensal can become an emerging threat to global health. If left unchecked, the advent of multidrug resistance in S. epidermidis may rival that of a notorious threat like MRSA. This highlights the need to study the virulence signature of S. epidermidis, and with continuous surveillance as an emerging pathogen, the extent and evolution of the MDR strains of this bacterium can be monitored. As S. epidermidis is an ever-present commensal on human epithelia, good hygienic exercise in individuals and proper infection prevention and control practices in clinical sectors, especially in the use of medical devices, are crucial to mitigate the spread of this bacterium. In general, various coordinated actions and global approaches from various sectors are required to control this threat, thus optimizing the management of infections by S. epidermidis.

CONFLICT OF INTEREST

The authors declare no conflict of interest.

FUNDING

Authors thank the Ministry of Higher Education Malaysia for funding through the Fundamental Research Grant Scheme (FRGS/1/2018/STG05/UITM/03/3) and the Faculty of Applied Sciences, Universiti Teknologi MARA (UiTM) Shah Alam, Malaysia.

AUTHOR CONTRIBUTIONS

All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agreed to submit to the current journal; gave final approval of the version to be published; and agree to be accountable for all aspects of the work. All the authors are eligible to be an author as per the international committee of medical journal editors (ICMJE) requirements/guidelines.

ETHICAL APPROVALS

This study does not involve experiments on animals or human subjects.

DATA AVAILABILITY

All data generated and analyzed are included within this research article.

PUBLISHER’S NOTE

This journal remains neutral with regard to jurisdictional claims in published institutional affiliation.

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