DIABETIC FOOT ULCER
Diabetes is one of the worst global health crises of the century and the ninth major cause of death worldwide, claiming 1.6 million fatalities in 2019.[1–4] Diabetes has several adverse metabolic consequences, which further develop pathophysiological complications including foot ulcers, neuropathy, and atherosclerosis. Nearly 12–25% of individuals with diabetes are prone to developing diabetic foot ulcers (DFUs).[6,7] DFU is a complex cellulitis or osteomyelitis situation caused by interaction between the host immune system and colonizing bacteria, which has devastating consequences on health, economy and psychology. Once DFUs are infected with external agents, mainly bacteria, the situation gets worse, and finally, patients are advised to get hospitalized. It is estimated that approximately 44–68% of patients admitted to hospitals develop osteomyelitis, which eventually leads to amputation of the infected part.[9,10] To avoid further complications, inclusive therapies comprising the use of antibiotics, neuropathic drugs, growth factors and inflammatory modulators have been suggested.[11,12] However, one of the major obstacles to treating DFU is bacterial colonization and antibiotic resistance.
Microbiology of DFU
Recent studies reported that bacterial infection plays a central role in the chronicity of DFU. DFU generally gets infected by skin surface bacteria and further establishes colonies with complex bacterial polycultures. Although the skin surface is a common source for bacterial introduction in DFU, the environment created by early invaders eventually accommodates obligatory non-native bacteria.[14,15] Bacteria inhibiting DFU sometimes secrete toxins. The toxins secreted by bacteria increase the severity of wounds and hamper the healing process.[16,17]
In addition, the isolation of pathogenic bacteria or bacterial strains is another hindrance to DFU treatments. It is difficult to determine the role of individual bacteria or a combination of different bacterial species in DFU infections. Bacteria that may not be harmful can provide a platform for other pathogenic bacteria.[18,19] A combination of collaborating bacteria synchronizes and forms functional pathogenic groups, which are essentially responsible for the maintenance of chronic DFU. The symbiotic association of various co-aggregated bacteria acts synergistically to form the biofilm. Such bacterial infections are resistant to anti-microbial treatments, interfere with the host’s immune system, increase the chronicity of DFU and delay healing. In more than 70% of DFU cases, bacterial infections are found to be multidrug resistant.[21,22] Therefore, it is necessary to identify bacterial diversity, biofilm existence and multidrug resistance while treating chronic DFU. The microbiology of DFU has been studied and fairly discussed in the literature; however, the Indian scenario has never been discussed.[7,14,23]
India is one of the leading countries, with more than 77 million individuals with diabetes, and that number is estimated to rise to 35.7 million by 2045. Diabetes is prevalent in 8.9% of the Indian population, with an estimated 1 million diabetes-related deaths each year.[1,24] Singh and Shankhdhar et al. estimated that nearly 25% of individuals with diabetes patients in India will develop DFU. This situation may degrade further owing to lack of general awareness, medical infrastructure and economic limitations.[26,27] The Indian population comprises diverse ethnic and genetic groups, which may have a considerable influence on the aetiology of diabetes, physiological consequences and responses to diabetic treatments.[24,28,29] India harbours a diverse cultural population in different geographical regions with variations in cultural beliefs and sanitary practices. Therefore, there may be aetiological and epidemiological differences in diabetes-related complications (including DFU), which need to be investigated. Currently, DFU-related problems are rising in India and are associated with the prevalence of diabetes.[31,32] Several factors, including socioeconomics and lifestyle, contribute to the occurrence of DFU in India. Moreover, the aetiological trends and the demography of DFU have never been discussed from the Indian perspective.[15,30,31]
In this article, we reviewed studies on the microbiology of diabetic foot infections in India. We summarized demographic trends in aetiology and bacterial diversity in DFU.
We searched for articles related to the current topic in four databases, Web of Science, PubMed, Google Scholar and Science Direct, using key words ‘diabetic foot ulcer’, ‘diabetic foot infection’, ‘microbiology’, ‘bacteria’, and ‘India’ with ‘and’ and ‘or’ Boolean operators. We selected articles indexed in PubMed, Web of Science and the journals indexed in Scopus. We searched for articles published from January 1980 to July 2022. In addition, separately for each year, we searched for articles related to the present topic in Google Scholar using the combinations of phrases and words mentioned above. In Google Scholar searches, we screened the first hundred articles published in each year. Among the total number of articles searched, we screened for research articles on the microbiology of DFU in India. We included a total of 56 studies for further analysis. From the selected articles, we extracted information on the study location, number of patients analysed in the study, pathophysiological complications, number of DFU positive for bacterial infection, age of the patients, sex of the patients, type of bacterial species (mono or polymicrobial), type of predominant bacteria (Gram-positive or Gram-negative), predominant isolates and multiple drug resistance (tested or not). We presented the extracted data in table and graphical formats.
The first microbiological study of DFU was reported in 2005 by Sivanmaliappan and Sevanan. Since then, an increasing trend in the number of studies has been observed, with the highest number of studies carried out in 2018 [Figure 1]. Among the 56 studies, the highest number of studies was carried out in South India, followed by North India [Figure 2]. Surprisingly, there are no reports of microbial infection in DFU from central India. DFU microbiological studies are reported from 12 states, among which the highest number of studies are reported from Karnataka, followed by Uttar Pradesh and Tamil Nadu [Figure 3]. All 56 studies were reported from urban cities.
Our analysis revealed that neuropathy and peripheral vascular disease (PVD) were the most common pathological complications in the patients reported with DFU, followed by nephropathy, retinopathy, hypertension and osteomyelitis [Table 1]. Among 56 studies, 6 studies reported the position of the DFU in patients [Table 2]. The heel and toe were the most common sites of DFU in Indian patients [Table 2]. Fifty-three studies reported sampling methods employed to isolate the bacteria [Figure 4]. Most of the studies used tissue samples (58.49% of them) for bacterial isolation, followed by pus samples (47.16%). A percentage of 58.49 of the studies collected samples using swabs [Figure 4].
Overall, male patients were predominantly reported with a bacterial infection in DFU (71.59% males and 28.39% females; SE = 1.41; n = 43). The highest proportion of male patients was reported to be 92.6%, and the lowest proportion of male patients was reported at 54%. The average age of the patients with DFU in India is 56.39 (n = 23 studies). The median age of DFU patients with bacterial infections was 55.4 (n = 20 studies).
Among the patients reported with DFU, 85.01% (SE = 2.34; n = 23) of patients were positive for bacterial infection. The highest proportion of patients positive for microbial infection (100%) was reported by Appapalam et al 2021., Haldar et al., 2017. and Raghu et al., 2016, while the lowest proportion of patients positive for microbial infection (55.38%) was reported by Seth et al., 2019 [Figure 5]. Generally, the number of bacteria isolated in a particular study exceeded the number of patients in the respective study, with an average of 1.66 isolates per patient (SE = 0.16; n = 31). Exceptionally, three studies by Ishwarya et al 2019, Noor et al. and Insan et al. 2013 reported fewer isolates than the number of patients studied for bacterial infection in DFU. Further, DFUs were found to be infected by single or multiple bacteria [Figure 5]. Overall, 49.74% (SE = 3.7; n = 33) DFUs were infected by a single bacterium, while 42.99% (SE = 3.65; n = 38) DFUs were infected by multiple bacteria [Figure 5].
Among the bacterial isolates, Gram-negative bacteria (64.06%; SE = 1.29; n = 42) were predominant as compared to Gram-positive bacteria [36.51%; SE = 1.2; n = 41; Figure 5]. The lowest proportion of Gram-negative isolates (45.5%) was reported by Chitra et al. 2016 and the highest proportion of Gram-negative isolates (86.95%) was reported by Shahi et al 2013. Among the studies included in this article, 12 studies isolated both aerobic and anaerobic bacteria. Aerobic isolates (85.6%; SE = 2.8) were predominant as compared to anaerobic (15.11%; SE = 2.8) isolates [Figure 5]. The highest proportion (95.9%) of aerobic isolates was reported by Rastogi et al. 2017, while the highest (31.4%) proportion of anaerobic isolates was reported by Zubair et al. 2011. Among 56 studies, 6 studies used molecular methods to identify isolates from DFU. A total of three studies used 16S rRNA meta-genomic methods for the identification of the total inhabitants in DFU.[36,42,46] Among the Gram-negative bacteria, E. coli was predominantly isolated in 79.62% of studies, followed by P. aeruginosa (59.25%), Klebsiella sp. (37.03%), Proteus sp. (35.18%) and so on [Figure 6]. S. aureus (75.92%) and Enterococcus sp. (31.48%) were the predominant Gram-positive bacteria isolated in different studies [Figure 6]. There is no chronological trend in the reporting of different isolates in different studies [Table 3].
In this article, we summarized the aetiology and microbiology of DFIs and presented their trends. In the Indian population, DFU was reported in 4.5% of patients with newly diagnosed diabetes. The proportion of DFU patients among diabetic patients is much lower in India than that in the Western world.[30,31,68,69] The possible occurrence of low DFU patients could be due to under-reporting, the lack of awareness, younger age or as shorter duration of diabetes.[58,70] Microbiological studies of DFU were reported from urban cities, irrespective of the prevalence of individuals with diabetes patients in those regions. In India, diabetes is more prevalent in urban areas of the states of Tripura, Chandigarh, Tamil Nadu, Jharkhand and Andhra Pradesh. Contrastingly, DFU microbiology studies were predominantly reported from Karnataka, Uttar Pradesh and Tamil Nadu. Previously, Vishwanathan et al., 2005, Rastogi and Bhansali 2016 and Jayaprakash et al., 2009. reported that neuropathy and PVD were the most common pathophysiological complications in the patients reported with DFU. Following these previous studies, neuropathy and PVD seem to be the most common pathophysiological complications in patients with DFU.
Conventional culture-based methods combined with molecular methods for bacterial identification are important for the proper identification of isolates, their metabolic characterization and the study of their drug resistance.[71–73] Moreover, advanced genomic methods provide detailed information on the diversity of culturable and non-culturable bacteria, which has implications for understanding the complexity of infection, bacterial co-aggregation and biofilm formation. We identified only 6 studies (of the total of 56 studies included in the present review) in which molecular methods were used to identify bacterial isolates. Among the total number of studies included in this study, a few studies investigated biofilm formation by bacteria inhabiting DFU.[48,50,74–76] Biofilm formation in DFU and its nature are independent of the type and diversity of bacteria, and possibly the result of metabolic cooperation, horizontal gene transfer and so on. Biofilm formation is an important aspect that needs to be further explored extensively to counter the problem of antibacterial drug resistance in the bacteria residing in the DFU. Bacteria inhabiting DFU have shown to be resistant to antibacterial treatment.[12,22,77,78] Among the studies considered for the present review, 45 studies tested multidrug resistance in isolates. Antibiotic resistance in bacteria is a potential cause of chronic DFU.[21,79] Few studies reported the patterns of bacterial diversity in the samples obtained from different tissues[22,56,66,57] and wound properties.[42,60,66,80] Further studies need to consider these important aspects of DFU infection as they provide valuable etiological information necessary for understanding the complexity of infection.
The present review highlights that Gram-negative bacteria were more prevalent in DFU in Indian patients than Gram-positive. Macdonald et al., 2021 reported that the prevalence of Gram-positive and Gram-negative bacteria is associated with income status of people. Patients from middle-income and lower middle-income countries were reported to predominantly Gram-negative bacteria. The difference in the prevalence of Gram-positive and Gram-negative bacteria can be further associated with the sanitation and hygiene of the people in their respective countries.[23,51,69]
The bacterial species reported in DFU in various studies differ considerably. E. coli, P. aeruginosa and S. aureus were reported to be the most predominant bacteria in different studies. The aetiological causes of the diversity reported in DFU are diverse and may have links with hygiene practices, cultural diversity, geographical variations, awareness, antibacterial treatment and so on.[69,81,82] Sampling methods are also reported to influence bacterial diversity.[8,83,84] Since the abundance of aerobic/anaerobic and Gram-positive/Gram-negative bacteria reside at different sites of DFU, the sampling methods also contribute to bacterial diversity patterns.[71,57,85] Most of the studies included in the present analysis employed swabs and tissues for bacterial sampling [Figure 4].
This article provides a comprehensive review of an important and neglected diabetes-related complication, diabetic foot infections. We believe that this article has the potential to serve as collective baseline data and trends on the microbiology of DFU, which could help in designing further strategic studies focusing on DFU and anti-microbial therapies. Antibiotic drug resistance and biofilm formation seem to be the most thriving future research areas in DFU in India.
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Conflicts of interest
There are no conflicts of interest.
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