The wound microbiome associated with deep sternal wound infection: a scoping review

Introduction

Deep sternal wound infection (DSWI) is a rare but potentially life-threatening complication following cardiovascular (CV) surgery (1). DSWI occurs in 1.3–8.0% of patients after CV surgery and increases mortality up to 37% (2-5). Treatment of DSWI may involve additional medical interventions, such as antibiotic therapy, wound care, and, in severe cases, surgical procedures to remove infected tissue (6). These interventions can be time-consuming, physically demanding, and emotionally draining, and they have complications of their own. To reduce the incidence of DSWIs and their associated negative effects, researchers have studied the wound microorganisms responsible for causing DSWI and its poor outcomes.

The cause of DSWI is microorganisms gaining access to the surgical area either during CV surgery or shortly thereafter. These microorganisms invade the tissue and cause excessive inflammation and tissue damage (7,8). Understanding what these microorganisms are and their activity in the surgical site—the wound microbiome—is essential to understanding the pathophysiological processes associated with DSWI. However, identifying the microorganisms responsible for DSWI is not always straightforward. Clinical diagnosis of infection does not always align with culture results, as some patients show signs of infection despite negative cultures (9). This discrepancy suggests that reliance on culture-based methods alone may be insufficient for understanding the true microbial landscape of DSWI.

The wound microbiome plays an important role in wound healing by interacting with the host immune system (10). It can be characterized by four key dimensions: microbial load, microbial diversity, presence/abundance of common wound microorganisms, and biofilm formation (10-13). In non-cardiac surgery wounds (e.g., diabetic foot ulcers, chronic wounds), these dimensions are critical in developing wound infection and poor wound healing (10,14,15). A balanced microbiome, which is a diverse and stable community of microorganisms, may protect the wound against pathogens, while an imbalance can lead to infections and delayed healing (16).

Commensal microorganisms, such as Staphylococcus epidermidis (S. epidermidis), compete for space and nutrients, inhibiting pathogen growth (17). They also produce antimicrobial substances (i.e., antimicrobial peptides, bacteriocins) that kill pathogens and help control infections (17-19). Even pathogenic microorganisms, such as Staphylococcus aureus (SA), can also promote wound healing by inducing interleukin-1 (IL-1), which stimulates keratinocytes (20), crucial for wound closure and re-epithelialization (21). Thus, the wound microbiome is not necessarily detrimental, and understanding its role in DSWI is essential for improving prevention and treatment strategies.

The aims of this scoping review are: (I) summarize the definition of DSWI, the location and method of specimen acquisition, and the techniques of microbial identification; (II) synthesize the current body of literature regarding microbial load, microbial diversity, presence/abundance of common wound microorganisms, and biofilm formation in DSWI. We present this article in accordance with the PRISMA-ScR reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1648/rc).

Methods

Design and search strategy

A scoping review was employed to explore the wound microbiome associated with DSWI because a scoping review is useful to synthesize current knowledge and find gaps in the literature (22). Unlike a narrative review, which typically provides a selective overview of existing studies, a scoping review systematically maps the available literature without limiting the analysis to a specific hypothesis. The search strategy for this scoping review was designed and revised in collaboration with a library science expert. The microbiological studies on DSWI were searched to explore the literature about the wound microbiome associated with DSWI. The search was conducted in two electronic databases, PubMed and EMBASE, on January 11, 2023. For the database searches, terms related to the wound microbiome were combined with terms related to DSWI. Filters were also applied, including humans, the English language, adults, and journals. No limit on the date was placed on the database search.

Study selection

Consistent with the filters used for the search, inclusion criteria for studies were: (I) wound microbiome related to DSWI; (II) reported in English; (III) conducted on adults (18 years old or older); and (IV) reported in journals. Non-English studies were not included because they cannot be understood due to language barriers. Full details of the search strategy are provided in Appendix 1, along with the number of articles retrieved. Exclusion criteria were then applied to the retrieved articles by the author. Excluded studies were: (I) secondary source articles and case reports; (II) transplant populations; (III) nosocomial infections, including other surgical site infections, central venous catheter-related infections, urinary tract infections, respiratory tract infections, pneumonia, and other types of infections; and (IV) not full-text. Secondary source articles were excluded because these do not report original research data or findings, and case reports were excluded due to their low evidence level (23). Studies in transplant populations were excluded because immunosuppressed patients have deficient host defenses against infections compared to immunocompetent patients (24). Studies including all types of nosocomial infections were excluded to specifically characterize the wound microbiome in DSWI. After the exclusion criteria were applied, 71 studies were reviewed (Figure 1). The list of included studies for this scoping review is provided in Appendix 2.

Figure 1 Flow diagram for literature search and selection. DSWI, deep sternal wound infection.

Data extraction and summary

To conduct the scoping review, systematic data extraction was performed using a standardized form to record the study purpose, population details, study type, methods and variables, and findings. Following the extraction, key findings were synthesized to identify main themes in the literature. Additionally, definition of DSWI, the location and method of specimen acquisition, and the techniques of microbial identification were analyzed because high-quality microbiome research depends on rigorous methodologies, including precise specimen collection and standardized techniques. The collection site (e.g., incision site, wound exudate, mediastinum) and method (e.g., swab, tissue biopsy, aspiration) are critical factors that can significantly impact the detected microbial composition. Thus, accurate and well-documented collection methods are essential for determining data accuracy and comparability across studies. Similarly, the choice of microbial identification technique can influence the ability to characterize the wound microbiome.

Results

Studies on DSWI were described regarding the definition of DSWI, the location and method of specimen acquisition, the techniques of microbial identification, and their findings. Table 1 summarizes the literature review.

Definition of DSWI

Of 71 studies, 14 did not present their operational definition of DSWI. Thirty-seven studies used the diagnostic criteria provided by the Centers for Disease Control and Prevention (CDC) (25) for identifying DSWI. Nine studies applied the classification provided by El Oakley and Wright (26). Two studies used the classification provided by Pairolero and Arnold (27). These three identification and classification criteria for DSWI are provided in Tables 2-4. The remaining studies defined DSWI using their criteria, rather than relying on existing literature or established resources.

Location and method of specimen acquisition

Of 71 studies, 43 did not describe where they obtained wound specimens. Eighteen studies presented the acquisition location in a nonspecific way, such as sternal wounds, deep tissue, bone, and surgical material. Only 10 studies specified the specimen acquisition as being mediastinum. Of 71 studies, 53 did not report how they collected wound specimens. Eighteen studies described specimen acquisition methods. Among these, five used swabs, four used aspiration, three used drainage, two used debridement, and one used biopsy. Additionally, two studies used a combination of aspiration and surgical material, one used a swab and aspiration, one used aspiration and drainage, and one used a swab and biopsy.

Techniques of microbial identification

Among 71 studies, 65 used culture techniques only, and one study used a molecular analysis technique only. Four studies used both culture and molecular analysis techniques, and one study used culture and imaging techniques.

Dimensions of wound microbiome and findings

Culture studies

Seventy studies (65 culture techniques only, four culture combined with molecular analysis, and one culture combined with an imaging technique) that used culture techniques to examine the wound microbiome of DSWI focused on two dimensions: microbial diversity and presence/abundance of common wound microorganisms. Other dimensions of wound microbiome, such as microbial load and biofilm formation, were not examined in these culture studies.

Microbial diversity

Of 70 studies, 16 examined the polymicrobial status in deep sternal wounds. These studies defined polymicrobial status as the presence of more than one type of microorganism in the wounds. Some of these reported the actual number of different species within a specimen, with two or three microorganisms identified as polymicrobial infections.

These 16 studies reported that 1–52% of their wound samples showed microbial diversity. Enterobacteriaceae was the most common microorganism associated with microbial diversity in Ali et al. (28) and Charbonneau et al. (29). However, Lemaignen et al. (30) and Tocco et al. (31) found that coagulase-negative Staphylococci (CoNS) were the most frequently isolated microorganisms from deep sternal wounds with polymicrobial infections.

Presence/abundance of common wound microorganisms

All culture studies on DSWI examined the presence/abundance of common wound microorganisms in deep sternal wounds. SA was the most predominant microorganism, followed by CoNS and S. epidermidis. However, two studies reported that Gram-negative bacteria were the most prevalent microorganisms. Common Gram-negative bacteria isolated from deep sternal wounds include Enterobacteriaceae, Enterococcus faecalis, Escherichia coli (E. coli), Klebsiella pneumoniae, Serratia marcescens, Pseudomonas aeruginosa, and Morganella.

Molecular analysis studies

Five studies (one molecular analysis only and four molecular analyses combined with culture) examined the wound microbiome of DSWI using molecular analysis techniques. One used polymerase chain reaction (PCR) only, one used agarose gel electrophoresis with culture, two used pulsed-field gel electrophoresis (PFGE) with culture, one used PCR, PFGE, and culture, and one used PCR, fluorescence in situ hybridization (FISH), and culture. These studies examined two dimensions: the presence/abundance of common wound microorganisms or biofilm formation.

Presence/abundance of common wound microorganisms

PCR

Spindler et al. (32) used PCR to identify the presence of potential pathogens (i.e., SA, S. epidermidis, and Enterococcus faecalis) in deep sternal wounds. PCR detected S. epidermidis in two wounds, SA in one wound, and Enterococcus faecalis in one out of twelve wounds.

Two studies used multiplex PCR to examine the presence of antibiotic-resistant genes in the potential pathogens: Staphylococci and Enterobacteriaceae, respectively. Martineau et al. (33) examined the presence of genes resistant to gentamicin [aac(6’)-aph (2’’)], penicillin (blaZ), oxacillin (mecA), and erythromycin (ermA, ermB, ermC, msrA) in 149 deep sternal wounds infected with Staphylococci. Among these wounds, the blaZ was the most common gene in both SA and S. epidermidis strains. Abboud et al. (34) examined the presence of genes resistant to carbapenem and polymyxin (bla_KPC, bla_GES, bla_OXA-48-like, bla_NDM, bla_IMP, and bla_VIM) in 33 deep sternal wounds infected with carbapenem-resistant Enterobacteriaceae (CRE) strains. bla_KPC was the only antibiotic-resistance gene detected in the CRE wounds and was present in all CRE wounds.

PFGE

Unemo et al. (35) compared the DNA patterns of 24 Cutibacterium acnes strains isolated from 54 deep sternal wounds. They found that 42% of the total DNA patterns of Cutibacterium acnes strains showed genetic similarity. Abboud et al. (34) clustered 20 Klebsiella pneumoniae strains into two groups based on the similarity and differences in their DNA patterns. Of the 20 Klebsiella pneumoniae strains, 19 strains were clustered into one group and 1 strain was clustered into the other group.

Agarose gel electrophoresis

Yew et al. (36) compared 21 Mycobacterium fortuitum strains isolated from 21 deep sternal wounds. Agarose gel electrophoresis clustered nine of the 21 strains into one group and seven of the 21 strains into another group. The patterns of the remaining strains were too weak to distinguish.

Biofilm formation

FISH

Spindler et al. (32) examined biofilm formation in 12 DSWI patients using FISH combined with microscopy. They found that one patient had biofilms of S. epidermidis and the other had microcolonies of Enterococcus faecalis on the surface of deep sternal wounds. Microcolonies are clusters of microbial cells that begin to gather and adhere to the surface or each other. These are essentially the early stages of biofilm formation (37).

In this study, FISH provided additional diagnostic insights in 5 cases (41%), including detecting biofilms not identified by culture. It confirmed culture results in seven cases, including one match with E. faecalis. However, discrepancies were noted in four cases with questionable or negative culture results and one case where S. epidermidis biofilms were detected instead of E. faecalis.

Imaging study

Biofilm formation

One study used an imaging technique to identify biofilm formation. Elgharably et al. (9) used scanning electron microscopy (SEM) to examine biofilms attached to the sternal wire and debrided sternal tissue. All six DSWI patients had biofilms in their sternal wounds and sternal metal wires, whereas all non-DSWI patients had no biofilms.

Discussion

This scoping review analyzed 71 DSWI studies regarding their definition of DSWI, location, method of specimen acquisition, and techniques of microbial identification. Most of the included studies used the CDC diagnostic criteria for defining DSWI. Only a few of the studies specified the specimen location and acquisition method, which is disappointing given the importance of these details. An accurate description of the wound specimen location is important because it helps identify which part of the wound is involved in the infection. Additionally, a clear description of how the wound specimen was obtained is critical, as each collection method carries different potential biases. These biases include the types of microorganisms collected, the tissue origin (e.g., skin or wound bed) of those microorganisms, and errors introduced to the analysis results (38).

A swab was the most common acquisition method since it is simple, non-invasive, and cost-effective, whereas debridement and biopsy are invasive techniques that cause pain and incur greater costs (38). However, swab culture using the Z-technique may identify microorganisms on the wound surface only, excluding microorganisms present within the wound tissue (38,39). Swab culture using the Levine technique has shown high accuracy in capturing microorganisms within wound tissue (39). Unfortunately, none of the included studies reported how swabs were collected. This lack of information prevents the assessment of the validity of the findings of these studies. Future research should ensure detailed reporting of both the location and method of wound specimen collection to enhance the reliability and validity of the results.

The majority of studies used wound cultures, whereas molecular analysis techniques were used in a few studies to identify wound microorganisms associated with DSWI. Culture techniques identify only one or a few pathogens from multiple microorganisms present because they use selective media and drugs (40,41). Microbial growth in the culture media can be limited due to the antimicrobial treatment and the presence of microorganisms that are difficult to grow or slow-growing (40,41). This limited information is clinically relevant but, by design, it excludes the remaining microorganisms potentially associated with pathological importance (42). Therefore, the body of literature on the microbiology of DSWI is incomplete because it only describes a fraction of the phenomena. It is remarkable that culture still has been a standard for microbiological analysis in DSWI, although advanced molecular techniques have been developed. This could indicate that the challenges of advanced molecular techniques, such as high costs and large databases, may delay the application of molecular analysis to clinical practice.

Furthermore, this scoping review synthesized the microbial findings in DSWI based on the four dimensions of the wound microbiome. None of the studies included in this scoping review examined microbial load, although it has historically provided the threshold for transition from colonization to infection (14). Due to this lack of research on microbial load, it is difficult to determine whether microbial load is important in DSWI. Further studies examining microbial load are required to elucidate its role in DSWI.

Increasing evidence suggests that microbial diversity in wounds plays a critical role in wound healing (10,12). Some studies suggest that higher microbial diversity is associated with negative wound outcomes, such as longer wound duration and recurrent wounds (43-45), while others indicate that reduced microbial diversity is harmful for wound health (46,47). Thus, the role of microbial diversity in wound healing is complex. However, it is difficult to determine the true degree of microbial diversity and its role in DSWI because all the studies that measured microbial diversity used culture techniques only. These culture studies defined microbial diversity as more than one microorganism present in a wound. This definition results in only two levels: one or fewer microorganisms and two or more microorganisms. This indicates that DSWI caused by two microorganisms is considered the same polymicrobial infection as one caused by 10 microorganisms.

To solve this problem, advanced molecular techniques have been developed to understand the complex role of microbial diversity and the interplay between different microbial species and their host interactions using microbial genetic footprint (42,48). Molecular analysis techniques have been found to detect a much greater diversity within a wound compared to culture techniques (40,49,50). This means that molecular analysis can capture more complexity of microbial composition in the wound microbiome than culture techniques. Thus, using 16S ribosomal RNA (rRNA) gene sequencing or metagenomic shotgun sequencing allows us to better understand microbial diversity in DSWI.

Of the four dimensions of the wound microbiome, the presence/abundance of common wound microorganisms was the most frequently examined dimension in DSWI. Most studies that examined the presence/abundance of common wound microorganisms used culture techniques, and SA was the most common microorganism present in the deep sternal wounds. However, these results can be questioned because they used media that select SA, potentially leaving out other pathogens.

The molecular studies that measured the presence/abundance of common wound microorganisms examined the antibiotic resistance genes associated with SA, S. epidermidis, and CRE, including blaZ, aac(6’)-aph(2’’), mecA, and bla_KPC. These studies excluded other virulence genes of potential pathogens that are critical in wound infection. For example, the accessory gene regulator (agr) system regulates the production of a diverse range of genes involved in Staphylococcus pathogenesis, resistance, and biofilm formation (51). There are also virulence genes known as microbial surface components recognizing adhesive matrix molecules (MSCRAMMs). MSCRAMM genes play a key role in colonizing and forming biofilms on the wound surface (52). The agr and MSCRAMM genes were commonly identified in SA strains from deep surgical incisions after orthopedic surgery (53). Unlike cultures and other molecular techniques, metagenomic shotgun sequencing can identify any potential pathogens present in the wound and their virulence factors (e.g., toxins, adhesins, and immune evasion) in addition to the antimicrobial resistance genes. Therefore, using metagenomic shotgun sequencing will provide new insights into the presence of potential pathogens and their functions in DSWI.

Biofilm formation was measured using FISH and SEM in two studies. SEM is an excellent method for detecting, preserving, and characterizing bacterial biofilm structure, yet it is unsuitable for identifying the microbial composition. To comprehensively understand biofilm formation, advanced molecular analysis methods, such as 16S rRNA sequencing, could be used alongside SEM.

One of the limitations of this scoping review is the inability to accurately assess the quality and reliability of findings, as most included studies did not specify the location and method of wound specimen acquisition. The lack of detail may stem from the absence of standardized protocols for specimen collection in DSWI, leading to inconsistencies in acquisition and reporting across studies. However, accurate and comprehensive reporting of specimen acquisition is critical for understanding the context and validity of the microbiome data. Its absence limits the interpretability and comparability of the study results.

Another major limitation of this scoping review is that most studies on DSWI have focused on only one dimension of the wound microbiome, specifically the presence/abundance of common wound microorganisms, as many studies prioritize infection diagnosis over microbiome characterization. This narrow focus overlooks other critical dimensions of the wound microbiome, such as microbial load, microbial diversity, and biofilm formation, which can be more influential in developing wound infections and poor healing outcomes. Consequently, the existing studies fail to provide a comprehensive assessment of all dimensions of the wound microbiome, limiting the scope and depth of the findings.

The last limitation is the almost complete reliance on culture techniques to identify wound microorganisms in DSWI. Reliance on culture-based techniques persists due to historical clinical practice, cost constraints, and limited access to molecular methods. This reliance limits the understanding of the wound microbiome’s complexity and diversity. To enhance the efficiency and accuracy of wound microbiome research, utilizing molecular techniques strategically is essential. Different molecular techniques should be selected depending on the study aims. For hypothesis generation or the discovery of new microbiome components, metagenomic shotgun sequencing is ideal due to its ability to provide a broad and detailed view of the microbial community. However, this technique is expensive (54) and requires significant effort to differentiate between human and bacterial DNA (41,55-57). For hypothesis testing, more cost-effective methods like PCR or 16S rRNA gene sequencing can be employed, as they offer better insights than traditional culture techniques while being more feasible in terms of cost and labor (58-61). The standardization to more sophisticated methods will contribute to the identification of significant microbiome dimensions associated with DSWI outcomes and to more effective, targeted interventions that can modify the impact of the microbiome on wound pathogenesis and healing, potentially reducing the incidence and severity of DSWIs.

Conclusions

In conclusion, this scoping review identified several methodological gaps, including inadequate reporting of specimen location and a reliance on simple swab collection techniques that may fail to capture microorganisms from deeper tissue layers. Most studies used culture methods using selective culture media, which might overlook other pathogens significant to DSWI pathogenesis and healing, and may not fully represent the microbial diversity within wounds. The majority of these studies focused on only one dimension of the wound microbiome: the presence/abundance of common wound microorganisms, and the presence of SA can be problematic for wound healing after CV surgery. The review also highlighted the underreported significance of other dimensions of the wound microbiome, such as microbial load and biofilms. Addressing these limitations will contribute to a better understanding of the wound microbiome’s role in DSWI, leading to more effective prevention and treatment strategies.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the PRISMA-ScR reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1648/rc

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1648/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1648/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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