The Global Prevalence of Methicillin-Resistant Staphylococcus Aureus in Patients with Diabetic Foot Ulcers: A Systematic Review and Meta-Analysis

Introduction

Diabetes mellitus represents a critical global health concern, with its incidence rising annually. It is projected that by 2035, approximately 592 million individuals will be affected.¹ DFUs constitute a frequent complication of diabetes, affecting about 15% of individuals with this condition during their lifetime.^2,3 Diabetic foot infection (DFI) is clinically characterized by signs of inflammation in any tissue below the malleoli in individuals with diabetes mellitus. It ranks among the most severe complications of diabetes, significantly contributing to diminished quality of life for patients and substantial economic losses.⁴ Patients with DFU exhibit a dismal prognosis, as evidenced by a comprehensive prospective study. One year following diagnosis, a mere 46% of patients achieved ulcer healing, with a subsequent 10% experiencing recurrence. Additionally, a noteworthy 15% of patients succumbed to the condition, underscoring its life-threatening nature. Furthermore, a substantial 17% of patients necessitated lower limb amputation.⁵ Presently, the therapeutic approach for DFU encompasses a multifaceted strategy, which comprises the following key principles: Treatment of foot infections, Restoration of tissue perfusion, Pressure offloading and ulcer protection, Local ulcer care, and Person-centered care. These core principles constitute the fundamental pillars of DFU management, reflecting a holistic and patient-centric approach to address the complex challenges associated with this condition.⁶ Following the aforementioned therapeutic principles, the majority of patients with DFU experience successful wound healing. However, a subset of patients may encounter severe complications, some of which pose life-threatening risks. Furthermore, the financial burden associated with DFUs is substantial, with annual costs estimated at nearly £1 billion in the United Kingdom, amounting to approximately 1% of the National Health Service (NHS) budget.⁷ In contrast, the proportion of healthcare resources dedicated to DFUs is considerably higher in developing countries, underscoring the urgent need for targeted interventions and resource allocation to address this pressing issue.⁸

Staphylococcus aureus, a bacterium, is the predominant microorganism found in diabetic foot infections. These infections can be further classified into two main categories: MRSA and methicillin-sensitive Staphylococcus aureus (MSSA).⁹ A study conducted in the United Kingdom revealed that DFUs testing positive for MRSA exhibit a prolonged time to ulcer healing compared to DFUs testing positive for MSSA.¹⁰ In addition, there has been an increase in the requirement for amputation and surgical wound debridement among patients infected with MRSA.⁶ The occurrence of MRSA infection in wounds imposes a substantial economic and clinical burden, characterized by elevated hospitalization expenses and an augmented likelihood of patient mortality.^11,12 Factors such as diabetes mellitus, previous exposure to antimicrobial agents, recent hospitalization within the preceding 12 months, the presence of skin or soft tissue infections upon admission, and HIV infection have all been identified as significant contributors to an increased susceptibility to MRSA infection.¹³

Presently, the incidence of diabetes mellitus continues to escalate annually, while the worldwide prevalence of antimicrobial drug resistance exhibits a corresponding upward trajectory. Consequently, it becomes imperative to comprehend the prevalence and epidemiological patterns of drug-resistant pathogens, such as MRSA, within the context of DFU. Despite numerous antecedent investigations documenting MRSA prevalence in DFU, a comprehensive global assessment of MRSA prevalence and its epidemiological trends within this specific clinical context remains conspicuously absent. To address this critical knowledge gap, we conducted a systematic review and meta-analysis aimed at elucidating the global prevalence of MRSA in DFU and its temporal prevalence trends.

Methods

Registration

The research endeavor adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for its execution and subsequent reporting. Additionally, it was duly registered with PROSPERO under the registration identifier CRD42023444360.¹⁴

Search Strategy and Selection Criteria

Two authors conducted independent searches across four databases (PubMed, Embase, Scopus, Ovid) from their inception to July 2023, without imposing any language restrictions. In the aforementioned databases, the following search terms were employed: [(“diabetic foot” OR “Diabetic Feet” OR “Diabetic foot infection” OR “diabetic foot ulcer”) AND (“Methicillin-Resistant Staphylococcus aureus” OR “MRSA”) AND (“Prevalence” OR “incidence” OR “epidemiology” OR “occurrence” OR “rate”)] (See Appendix 1).

The articles incorporated in our analysis were observational and focused on documenting the prevalence of MRSA in patients with DFUs in the absence of specific interventions. The studies included in our analysis required minimum recruitment of 30 participants and the utilization of established diagnostic techniques for assessing exudates from ulcer surfaces. In the case of clinical trials, we exclusively extracted baseline data. Articles that could not be accessed in full text and those that exhibited redundancy with the datasets already included, as well as systematic reviews, editorials, case reports, and case series, were excluded from our study.

Data Extraction and Quality Assessment

Data extraction was performed by a single author utilizing a standardized template within an Excel spreadsheet. This extraction was subsequently cross-verified by another author, with any ambiguities or discrepancies resolved through collaborative discussion. The extracted information encompassed details such as the publication year, primary author, publication country, geographical setting, study design, sample size, study duration, source of the study sample, and the reported prevalence.

Our analysis was stratified based on the regions defined by the World Health Organization (WHO), which include Africa, the Eastern Mediterranean, Europe, Southeast Asia, the Americas, and the Western Pacific, as well as the income categories designated by the World Bank. We employed the Joanna Briggs Institute (JBI) Prevalence Essential Assessment Tool to evaluate the quality of the studies included in our analysis.¹⁵ The checklist was divided into three categories of risk of bias, depending on the number of met criteria: high (0–3 items), moderate (4–7 items), and low (8–10 items). The process of data extraction and quality assessment was executed meticulously, with any discrepancies resolved through consensus.

Statistical Analyses

We conducted a meta-analysis of the compiled data employing STATA 16.0 software. To assess inter-study heterogeneity, Cochran’s Q test and the I2 index were utilized.¹⁶ When P > 0.10 and I2 ≤ 50%, it indicated a lack of statistical heterogeneity among study results, and a fixed-effects model was employed for analysis. Conversely, if P ≤ 0.1 and I2 > 50%, a random-effects model was utilized for the meta-analysis.¹⁷ Additionally, subgroup analyses were performed based on publication year, patient origin, World Health Organization (WHO)-defined region, income level, and diagnostic method type. Prevalence rates were calculated for each subgroup, followed by comparisons of prevalence rates among subgroups using the χ² test. It is noteworthy that publication bias was not assessed in this study, as it was deemed unrelated to prevalence.¹⁸

Results

Study Characteristics

A total of 860 records were retrieved from the four databases. Following the removal of 314 duplicates, the initial screening encompassed 546 documents. Subsequently, after a meticulous evaluation of titles and abstracts, a comprehensive review was conducted on 164 documents, culminating in the inclusion of 40 original articles for analysis (Figure 1).^9,10,19–56 These selected studies involved a collective cohort of 12,924 patients with Diabetic Foot Ulcers (DFU) spanning the years 1999 through 2021 (refer to Table 1). Among the 40 studies, 26 (65%) were conducted on inpatients, six focused on outpatients (15%), and eight did not differentiate between outpatient and inpatient populations (20%). All studies uniformly utilized samples of exudates from ulcer surfaces for bacterial culture. Geographically, the distribution of these studies was as follows: 13 (32.5%) from Europe, 12 (30%) from Asia, 10 (25%) from North America, 4 (10%) from Africa, and 1 (2.5%) from South America, collectively representing 20 different countries in the study design.

Figure 1 Study selection.

Table 1 Basic Information

Meta-Analysis Results

We conducted a comprehensive meta-analysis utilizing data extracted from 40 studies that met the stipulated inclusion criteria. The analysis estimated the global prevalence of MRSA among patients with DFU to be 17.0% (95% CI 0.14–0.27) (Figure 2). Interestingly, the risk of MRSA contraction from DFUs has exhibited a declining trend over the past two decades. Before 2010, the prevalence was 25% (95% CI 0.13–0.37), whereas it reduced to 9% (95% CI 0.05–0.13) after the year 2021 (Figure 3). The prevalence of MRSA in DFUs exhibited geographical variations, with South America recording the highest prevalence at 61% (95% CI 0.46–0.76), followed by North America (20%, 95% CI 0.12–0.27), Europe (19%, 95% CI 0.14–0.25), Africa (13%, 95% CI 0.06–0.20), and the lowest prevalence observed in the subgroup (11%, 95% CI 0.08–0.15) (Figure 4). Furthermore, we categorized our analysis according to the latest World Bank classification (https://datahelpdesk.worldbank.org/knowledgebase/articles/906519-world-bank-country-and-lending-groups), which segregated countries into low-income, middle-income, and high-income groups. This revealed that the prevalence of MRSA in diabetic foot ulcers was 19% (95% CI 0.15–0.23) in high-income countries, 13% (95% CI 0.09–0.17) in middle-income countries, and 20% (95% CI 0.13–0.27) in low-income countries (Figure 5). Importantly, it is worth noting that all 40 studies included in our analysis were assessed as low-risk based on the JBI assessment tool.

Figure 2 Global prevalence of MRSA in patients with diabetic foot ulcers.

Figure 3 Global prevalence of MRSA in diabetic foot ulcers, by time of study publication.

Figure 4 Global prevalence of diabetic foot ulcer MRSA, by geographic location.

Figure 5 Global prevalence of MRSA in diaxbetic foot ulcers, by income.

Discussion

This marks the inaugural systematic review and meta-analysis to delineate the global prevalence of MRSA in DFU. Within the scope of this investigation, we have furnished a comprehensive meta-analysis, encompassing diverse geographical regions, to ascertain the prevalence of MRSA in DFU. Our findings indicate a worldwide MRSA prevalence of 17%, a figure in alignment with previous reports (18%), thus reinforcing the high incidence of MRSA in this context.⁹ However, our study further contributes by offering a detailed breakdown of MRSA prevalence across various geographical locations, encompassing a spectrum of economic strata, while also affording insight into the temporal trends of MRSA prevalence.

Furthermore, we identified a paucity of relevant evidence in numerous regions across the globe, with only approximately 20 countries furnishing robust data. This observation underscores the pronounced regional disparities in MRSA prevalence, potentially associated with the respective countries’ economic status and healthcare infrastructure. Notably, our analysis revealed a relatively diminished MRSA prevalence in low-income regions, a trend likely attributed to factors such as delayed access to healthcare services for individuals with Diabetic Foot Ulcers (DFU) or limited availability of antibiotic treatment. These discrepancies are reflected in the limited data contributions from countries characterized by lower economic income. Moreover, our findings indicate a discernible decrease in the prevalence of MRSA in Diabetic Foot Infections (DFI) over time, aligning with the observations made by Moore et al.⁸ The plausible rationale behind this declining trend could be the implementation of standardized antibiotic protocols.

Long-term DFU and prolonged antibiotic use are associated with MRSA infections.¹⁰ Chronic ulcers represent the most significant risk factor for MRSA infection. Additionally, chronic kidney disease presents another risk factor for MRSA isolation.⁶ One study has indicated an association between MRSA isolated from DFU and nasal MRSA carriage.⁵⁷ Long-term or inappropriate antibiotic use and previous hospitalizations are contributing factors to MRSA infections. It is crucial to note that MRSA infections not only prolong wound healing times but also elevate the risk of amputation in cases of DFI.^10,58 Moreover, MRSA escalates the likelihood of osteomyelitis development in DFUs.⁵² Consequently, understanding the prevalence and temporal trends of MRSA in DFU is paramount for clinical practice. Firstly, it serves as a reminder to healthcare providers to exercise restraint in antibiotic utilization. Secondly, it underscores the importance of healthcare practitioners and policymakers focusing on preventive measures, timely detection, and appropriate management of DFIs, thus providing valuable insights for policy decisions.

Several limitations must be acknowledged in this study. It is crucial to recognize that significant heterogeneity existed among the studies, likely attributed to population diversity and variations in hygienic environments. While certain studies exclusively included patients hospitalized for their initial episode, others might have encompassed recurrent hospitalizations. Such substantial heterogeneity among these studies may potentially limit the interpretability of pooled estimates.

Furthermore, subanalyses conducted by geographical regions, although beneficial for assessing overall trends, may offer relatively lower resolution due to the intricate factors underlying MRSA prevalence. Additionally, the lack of standardized criteria for classifying the degree of ulceration in patients with diabetic foot ulcers, coupled with the varying degrees of ulceration observed across the included studies, introduces an additional layer of complexity.

To address these limitations, further research is warranted, particularly investigations specifically focused on MRSA in patients with diabetic foot ulcers. Such endeavors would bolster the evidence base and facilitate more refined stratification of data in future analyses.

Conclusions

In summary, the findings of this study reveal that while there is a declining trend in MRSA prevalence among patients with DFU, it remains at a relatively elevated level. Our comprehensive assessment has quantified these global trends in MRSA prevalence within the context of DFU, providing essential foundational data for future research and clinical endeavors. These insights can also inform healthcare policymakers in devising programs and interventions aimed at improving hygiene practices and mitigating adverse outcomes. There is a pressing need for concerted efforts within the healthcare sector to educate both clinical personnel and patients afflicted with DFUs about preventive measures, thus reducing the risk of unfavorable prognoses in this patient population. Furthermore, considering the rising levels of antibiotic resistance, it is imperative to prioritize research into alternative therapies, alongside continued efforts in infection prevention.⁵⁹