Abstract
Purpose: Cutaneous infection in epidermolysis bullosa (EB) can cause significant morbidity, mortality, and dangerous sequelae. This review article aims to delve into the known epidemiology of EB, highlight the disease’s primary causative agents and their antimicrobial resistance spectrum.Materials and methods: A thorough literature search was conducted using Medline, EMBASE, JBI and PubMed to gather data on the microbial landscape of EB wounds. The focus was on identifying the most common bacteria associated with EB infections and assessing their antimicrobial resistance profiles.Results: The analysis revealed that Staphylococcus aureus is the most frequently identified bacterium in EB wounds, with a notable prevalence of methicillin-resistant strains (MRSA). Specific studies on mupirocin resistance further indicated rising rates of mupirocin-resistant Staphylococcus aureus, with one study reporting rates as high as 16.07%. Additionally, high resistance to other antibiotics, such as levofloxacin and trimethoprim/sulfamethoxazole, was observed in MRSA isolates.Conclusions: The findings highlight the critical need for regular resistance surveillance and the prudent use of mupirocin to manage infections effectively in EB. The multi-drug resistant nature of pathogens in EB presents a significant challenge in treatment, highlighting the importance of antimicrobial stewardship. Ultimately, given the sparse literature and the rarity of large-scale studies, further longitudinal research on the antimicrobial resistance profile of bacteria isolated from EB wounds is essential.
Keywords:
1. Introduction
Epidermolysis bullosa (EB) describes a group of rare heterogeneous congenital conditions characterized by defective epithelial adhesion causing mucocutaneous fragility and blister formation, often induced by minor mechanical trauma (Citation1–3). EB can be segmented into four major types: EB simplex (EBS), junctional EB (JEB), dystrophic EB (DEB) and the rarer Kindler syndrome (KS), and more than 35 subtypes (Citation3). The diagnosis is formulated based on symptoms and confirmed through genetic testing and/or skin biopsy (Citation2). EB presentation can vary from mild to severe, and no cure is yet available. Thus, a multi-disciplinary approach with patient management from birth is important to ensure early diagnosis, appropriate clinical care and improved quality of life (Citation4).
Management of EB in the absence of curative care involves intensive daily wound care and individualized treatment plans which minimize the risk of blister formation and prevent significant sequelae such as failure to thrive, serious systemic infection and cancer (Citation5). Chronic wounds are frequently colonized with bacteria, a subset of which have been linked to risk for squamous cell carcinoma (SCC) (Citation6, Citation7). Hence, understanding antimicrobial resistance patterns in bacteria isolated from EB wounds is critical in optimizing treatment recommendations (Citation5). Numerous meta-analyses contest the causative agents involved, with cultures most frequently identifying Staphylococcus aureus (S. aureus) (methicillin-sensitive S. aureus [MSSA] and methicillin-resistant S. aureus [MRSA]), Pseudomonas aeruginosa (P. aeruginosa) and Streptococcus species (Citation5–7). Furthermore, the alarming emerging incidence of MRSA colonizing EB patients, emphasizes concern about the indiscriminate manner of antibiotic prescription and poorer patient outcomes (Citation8). Hence, the purpose of this literature review is to explore and critique the current knowledge on the spectrum of causative bacteria of clinical infection in EB wounds and the antimicrobial resistance patterns.
2. Epidemiology of EB
The most comprehensive epidemiological data available regarding EB originates from a prospective cross-sectional and longitudinal study conducted in the US, where data was obtained from 3271 patients enrolled in the National Epidermolysis Bullosa Registry from 1986 to 2002. Overall, data showed a prevalence of 11.1 per one million live population and an incidence of 19.6 per one million live births for all major EB types combined (Citation1, Citation9). The registry also showed specific prevalence and incidence values for the major types, shown in . However, mild EB cases were not included in this study (Citation9), and infants who died from EB without diagnostic confirmation were also excluded, indicating that the prevalence and incidence rates may underestimate the true values. This selection bias highlights potential critical gaps in our epidemiological understanding, suggesting that the true burden of EB may be greater than current data indicates. Further research should aim to include a broader spectrum of cases, especially those fatal cases having clinical features, but lacking diagnostic confirmation.
Table 1. Comparison of the prevalence and incidence rates of EB types in the USA and Australia. Taken from (Citation9,Citation10).
An observational study by Kho et al. (Citation10) (cross-sectional and longitudinal) examining data from the Australasian EB Registry (AEBR) from 2006 to 2008, concurred similar epidemiology to the USA with an overall prevalence of 10.3 per one million population. also reflects the Australian prevalence rates of registered EB types. The prevalence of EBS in Australia is notably lower than the rates observed in other countries (Citation10). This discrepancy may be attributed to an underrepresentation within the recruited cohorts of more severe EBS variants and of mild EB not requiring regular care. These discrepancies are further exacerbated by the nascent stage of the AEBR at the time of this study (Citation11) and the limited access to specialized care centers in Australia, which pose a significant barrier to comprehensive case identification and registration.
3. Infection in EB
One of the major sequelae of EB is the tendency to develop chronic wounds that become colonized by bacteria (Citation6). These wounds cause considerable morbidity, including pain, odor, and exudate, and may require long hours of dressing changes (Citation12, Citation13). Cutaneous infections which are not treated effectively could progress into systemic infections and sepsis (Citation13). Sepsis is in fact, a leading cause of infant mortality across many EB subtypes and up to 24% of patients with JEB die from sepsis by the age of 156. Thus, it is vital that wounds and infections in EB patients are treated promptly and effectively.
3.1. Role of biofilms
Biofilms are a leading cause of persistent, non-healing wounds due to their complex aggregations of bacteria encased in a self-produced matrix of polysaccharides, proteins and DNA (Citation14). This protective layer complicates infection management as bacteria in biofilm display characteristics distinct from planktonic bacteria. Within biofilms, bacteria can cluster into microcolonies which not only enhance resistance to antimicrobials but contribute to delayed wound healing and sustained ulceration (Citation14–17). These bacteria can exhibit a 100-to-1,000-fold increase in antibiotic resistance compared to their planktonic counterparts. Furthermore, antibiotic susceptibility testing may provide deceptive results as traditional culture techniques only reveal the properties of planktonically growing bacteria (Citation14, Citation18). Studies show that different bacteria also form unique biofilm architectures, affecting their resistance profiles. For instance, a study found that Salmonella enterica forms small clusters, P. aeruginosa develops mushroom-shaped biofilms and S. aureus creates varied structures (Citation19). These structures integrate persister cells, capable of surviving under high levels of antibiotic treatment and evading the host’s immune system, which greatly restricts the penetration of antibiotics into the biofilm (Citation16).
Although no literature exists on the specific role of biofilms in EB, they are thought to contribute to the chronic nature of EB wounds as well as antimicrobial resistance patterns (Citation15). Biofilm formation is especially prevalent among S. aureus (particularly MRSA (Citation20, Citation21)) and P. aeruginosa (Citation22, Citation23). This is concurred by an Israeli study which analyzed the biofilm formations among MSSA and MRSA wound isolates, revealing a statistically significant positive association between methicillin resistance and biofilm production (Citation24). This is critically relevant in the context of EB given that S. aureus (including MRSA) and P. aeruginosa are among the primary agents responsible for infections.
Thus, when treating active EB infections, strategies to combat biofilm must be incorporated. This includes targeting premature biofilms with combinatorial antimicrobial therapy to avert the biofilm from growing (Citation17). Cephalosporins, aminoglycosides, monobactams, tetracyclines and glycylglycines have been proven to be effective against biofilms through topical administration in higher doses (Citation25). However, premature biofilms are difficult to detect and are likely to mature by the time of diagnosis. Ultimately, there is a significant need for research into the effects of biofilms on EB-specific wounds. Such research could provide valuable insights into addressing antimicrobial resistance challenges and refining treatment strategies for better outcomes.
3.2. Causative agents
Given the rarity of EB, literature on microbiological colonization is sparse, as evidenced by , which compares the various studies found on causative organisms. There are three studies to date which comprehensively analyze a wide scope of causative agents (Citation5–7), whilst five others focus predominantly on the prevalence of S. aureus in particular (Citation8, Citation13, Citation26–28).
Table 2. Comparison of studiesa on causative organisms of infection in EB.
The current largest study conducted on causative agents is a multicenter retrospective analysis of 739 EB wound cultures from 158 patients from 2001 to 2008. From 152 positive cultures, 86% of patients were positive for S. aureus, 37% for P. aeruginosa, 34% for Streptococcus pyogenes (GAS), 20% for Corynebacterium spp. and 11% for Proteus spp (Citation7). Nearly half of the patients with S. aureus-positive cultures had MRSA. However, the variability in data collection methods across multiple centers might introduce sampling bias. If some centers have more stringent criteria for which wounds to culture or have variations in wound culture techniques and the medium used, it can lead to an overestimation or underestimation of certain bacteria’s prevalence in the overall study.
S. aureus being the most common bacteria is consistent with another retrospective review of 30 EB patients and 192 positive wound cultures, with 78.6% of positive cultures presenting with Staphylococcus spp. Converse to the previous study, only 1.6% presented with MRSA while the majority (59.4%) of Staphylococcus spp. isolates were MSSA (Citation6). Furthermore, this study replicated a similar prevalence order for other causative agents with P. aeruginosa being the second-common species at 18.8% and Streptococcus spp. following at 12.5%. However, like the previous study, the retrospective nature of this review highlights a critical methodological limitation: the lack of a systematic approach to sample collection. As such, it is unclear if only clinically infected wounds were swabbed or all wound subtypes including chronic wounds without active infection. This distinction is particularly important in the context of EB, as wound colonization does not necessarily correlate with active infection but can still influence the choice of antibiotics. Hence, this could lead to overtreatment or inappropriate antimicrobial management.
4. Antimicrobial resistance patterns
Research on the antimicrobial resistance spectrum in bacteria isolated from patients with EB is limited, but evidence, including data from , indicates a growing prevalence of MRSA. This trend highlights concerns over the potential overuse of antibiotics and the subsequent escalation of antibiotic resistance. Given MRSA’s multidrug-resistant nature, its increasing presence poses significant challenges in EB management, where antimicrobials are a key defence against infection. Moreover, with the possible complication of sepsis, significantly higher mortality is associated amongst patients with multi-drug resistant pathogens than those without (Citation29, Citation30).
Various studies reported the prevalence of MRSA (as seen in ) from 6.7% of 30 EB patients in the study by Brandling-Bennet and Morel (Citation6) to as high as 47% and 57.1% in studies by Levin et al. (Citation7) and Graber et al. (Citation27) respectively. This considerable variation in results likely stems from the small sample sizes of these studies, presenting a limitation in making reliable comparisons. Furthermore, although supported by limited evidence, the prevalence of other causative agents such as vancomycin-resistant enterococcus (VRE) in the study by Singer et al. (Citation5) points to more issues with potential antimicrobial resistance.
4.1. Mupirocin resistance
Some of the literature on antimicrobial resistance in bacteria isolated from patients with EB has a particular focus on mupirocin. Mupirocin, a widely used topical antibiotic, prevents bacterial protein synthesis and is active against staphylococcus (especially MRSA), streptococci and certain gram-negative bacteria (Citation7). However, since its introduction into clinical practice in 1985, mupirocin-resistant (mupR) S. aureus has quickly followed.
An EB sub-analysis of a retrospective pediatric study analyzing mupirocin resistance in 358 S. aureus isolates, revealed that out of the 28 EB isolates, 10 were mupirocin-sensitive (mupS) and 18 were mupR S. aureus (Citation31). The study concluded that S. aureus isolates in patients with EB had a higher likelihood of mupirocin resistance compared to those in patients with more common pathologies like atopic dermatitis. However, the study exclusively sourced data from a tertiary dermatology center, which introduces a selection bias, likely reflecting a population with more severe and chronic infections. This could potentially inflate the observed prevalence of mupR S. aureus. Despite this limitation, study findings are underscored by a multivariate analysis p-value of 0.039, indicating a statistically significant association between EB isolates and the occurrence of mupR S. aureus (Citation31). This is particularly compelling as it remains significant even after adjusting for confounders, lending robust support to the study’s validity. Moreover, during the follow-up of 20 pediatric patients in the observational cohort study by Singer et al. (Citation5), 13 (65%) patients had a documented mupR S. aureus isolate, with ten having mupR MSSA and three having mupR MRSA. Both these pediatric studies reflect considerably high mupR S. aureus rates. Hence, conducting surveillance cultures and regularly testing for mupirocin resistance could support the management of antibiotic use and provide direction for patient advice.
Mupirocin resistance is considered rare in adult populations, leading to infrequent mupirocin testing, which subsequently complicates efforts to investigate patterns of resistance. In the study conducted by Levin et al. (Citation7), cultures from only 15 patients (out of 158) underwent mupirocin susceptibility testing, revealing that 9 (60.0%) patients had mupS S. aureus, 4 (26.7%) had mupR S. aureus and 2 (13.3%) had both mupS and mupR isolates in their wound cultures. Although this study represents only a small subset of the cohort and its retrospective design is merely a snapshot in time, it forms an important foundation for future research. It highlights the need for larger, longitudinal studies on mupirocin resistance patterns.
Furthermore, studies have correlated mupirocin resistance with mupirocin use (Citation31, Citation32) and Singer et al. (Citation5) revealed that more than half of their patients reported current mupirocin use and all but one had documented prior mupirocin use. Mupirocin resistance was found to be highly prevalent in MRSA isolates in particular (Citation5) and MRSA is considered a strong risk factor for resistance to mupirocin. This suggests that mupirocin resistance is likely to remain a significant issue moving forward. Therefore, despite the scarcity of relevant literature, existing studies highlight a significant presence of mupirocin-resistant organisms in EB, which is of particular concern given the extensive use of mupirocin in its management.
4.2. Other antimicrobials
Although the literature is sparse, three key studies (Citation5, Citation8, Citation26) reveal that concerns for the antimicrobial resistance profile of MRSA and other causative agents extend beyond merely topical mupirocin. Antonov et al. (Citation31) also examined resistance in S. aureus isolates, yet the scope extends beyond EB and omits a sub-analysis. This limitation complicates drawing significant conclusions about the spectrum of antimicrobial resistance within EB infections.
Santin et al. (Citation8) conducted a multicenter cross-sectional study involving 89 patients with EB, of which 26 were analyzed for S. aureus infections. The study uncovered statistically significant (p < 0.001) resistance rates of MRSA to levofloxacin (36.8%) and trimethoprim/sulfamethoxazole (52.6%). MRSA isolates exhibited significantly higher resistance to these antibiotics than MSSA, which is concerning since these medications are important for the treatment of MRSA infections. Additionally, although not statistically significant, high resistance rates to erythromycin and clindamycin were also observed. The cross-sectional design means that despite showing prevalence, the study fails to identify changing resistance patterns, further reflected by its temporal constraints with its data collected from only 2015 - 2017. Hence, the study’s findings might not reflect current antimicrobial resistance trends due to the evolving nature of bacterial resistance mechanisms.
Furthermore, a retrospective analysis examining bloodstream infections among 126 pediatric patients with EB, of whom 15 experienced infectious episodes, identified that out of 12 P. aeruginosa isolates, five exhibited resistance to ceftazidime (42%). Notably, four of these ceftazidime-resistant isolates also demonstrated resistance to meropenem and quinolones (33%) (Citation26). As for S. aureus, four out of 11 (36%) isolates were methicillin-resistant and three (27%) were clindamycin-resistant. Although the study provides useful insights into the resistance patterns, the single-center nature of the study may limit the applicability of the results to other settings.
Finally, Singer et al. (Citation5) also reported S. aureus susceptibilities from the wounds of 19 EB patients, identifying erythromycin (53%), oxacillin (32%) and levofloxacin (21%) to induce the highest rates of intermediate and high levels of resistance. Unfortunately, the results are presented without a detailed statistical analysis, making it difficult to assess significance.
Small sample sizes are a feature of all three studies, which indicates large effect sizes due to their mostly statistically significant findings. However, this also makes them privy to generalizability concerns about how well these findings can be applied to the broader EB population. Furthermore, other studies are required with rigorous statistical analyses to verify whether these results are reproducible. Ultimately, they provide crucial evidence for the multi-drug resistant nature of S. aureus and other infective agents, as well as highlight the importance of understanding their profiles.
5. Effects on treatment
In the absence of curative treatment, the management of EB stems largely from managing wound infections (Citation33). Currently, bacterial load reduction can be achieved by using diluted bleach baths, topical antiseptics, and antibiotics (Citation34). Hence, understanding antibiotic resistance patterns is important in shaping the treatment of actively infected wounds.
Given the urgent issue of antibiotic resistance, treatment should start with broad-spectrum antibiotics, followed by targeted therapy as per sensitivity tests (Citation35). Topical antibiotics ought to be short-term, while systemic antibiotics, guided by antibiogram results, are advised for acute needs. For persistent wounds, low-dose, long-term antibiotics can be suggested for their anti-inflammatory benefits (Citation36). Despite limited research on the effectiveness of antimicrobial treatments for active EB infections, presents a few studies examining long-course antimicrobials on wound healing.
Table 3. Comparison of literature analyzing effects of antimicrobials on EB patients.
The systematic review by Langan and Williams (Citation37) found "no reliable trial evidence" supporting antimicrobial interventions for EB. Its analysis on two randomized control trials (RCTs), specifically tetracycline versus placebo, showed no significant effects. The credibility of these findings is weakened by small sample sizes, incomplete trials, and high dropout rates. Moreover, the review’s outdated status since 2009 fails to account for recent advancements in treatment strategies.
In the study by Lara Corrales et al. (Citation38), patients on trimethoprim (TMP) showed improved wound healing, with six out of seven completing the study experiencing over 50% reduction in chronic wound size, despite no statistical significance over placebo. No resistant bacteria emerged during the study. Gentamicin also demonstrated effectiveness as a short-term EB therapy in studies by Hammersen et al. (Citation39) and Mosallaei et al. (Citation40). Observationally, Singer et al. and another study with 202 EB patients found mupirocin and bacitracin to be the most common topical antimicrobials (Citation5, Citation41). This highlights the significant role of antimicrobials in EB treatment and the urgent need for research regarding resistance patterns for the efficient use of such antibiotics.
6. Conclusion
In summarizing the exploration of antimicrobial resistance within the context of EB, this review has shed light on several pivotal areas. Primarily, it identified S. aureus as the predominant causative agent of infection in EB patients, a finding consistent across various studies. MSSA is the most common accompanied by a high prevalence of MRSA. Despite the acknowledged significance of biofilms in the persistence and resistance of infections, the specific impact on EB-related wounds remains unexplored, revealing a notable gap in current research. Furthermore, the observed antimicrobial resistance patterns, particularly the rising prevalence of MRSA and mupirocin resistance, highlights key information in the choice of first line antibiotics in EB patient while awaiting swab results and the need for ongoing antimicrobial stewardship. The significant prevalence of mupR also draws important attention to this issue in EB patients and the need to optimize antimicrobials and limit topical antibiotics. Ultimately, there is a notably low volume of literature analyzing the antimicrobial resistance profiles of bacteria isolated from patients with EB wounds. Given the critical role of antimicrobials in treating cutaneous infections, and sepsis and preventing serious sequelae, this review reveals a necessity for greater longitudinal studies to detail insights into the microbiological landscape of the EB population.
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