Biomedical and Biotechnology Research Journal (BBRJ)

REVIEW ARTICLE
Year
: 2021  |  Volume : 5  |  Issue : 3  |  Page : 235--244

Microbiological profile, antibiogram, and risk factors of patients with diabetic foot infections: A systemic metaanalysis


Fatima H Kadhim, Suhad Hadi Mohammed 
 Department of Clinical Laboratories, College of Applied Medical Sciences, Kerbala University, Karbala, Iraq

Correspondence Address:
Prof. Suhad Hadi Mohammed
Department of Clinical Laboratories, College of Applied Medical Sciences, University of Kerbala, University Street 11252, Kerbala
Iraq

Abstract

Background: Diabetic foot ulcer (DFU) is considered a major social and economic problem, and it is also known as a leading cause of morbidity and mortality. Patients with DFUs frequently require amputation of the lower limbs, and in more than half of the cases, infection is the predominant factor. The aim of this systemic review is to highlight the risk factors such as age and gender associated with DFU infections, whether the infection is caused by single bacteria or polymicrobial infection and what is the most prevalent bacteria and their susceptibility pattern to currently used antibiotics. Methods: Three databases were searched from December 2020 to February 2021 including PubMed, Hinari, and Google Scholar. A total of 12 articles were included in the current meta-analysis. Results: Higher frequency of DFU in males than in females and maximum number of DFU mostly occur within the age group 40–60 years was reported. Monomicrobial infections in DFU were higher than monomicrobial infection. Escherichia coli, Pseudomonas, and Staphylococcus aureus were the most prominent microorganism. The higher grades of the DFUs were infected with more than one organism. High resistance rates of the isolated bacteria to the most commonly used antibiotics were documented and there were alarming growing resistance rate to Carbapenems which were considered the most effective Antibiotics nowadays. Conclusions: DFU infections are one of the major social and economic problems. There is an urgent need for continuous antibiotic sensitivity testing for the isolated bacteria to choose the appropriate antibiotics during the management and limit the spreading of multidrug-resistant bacteria and reduce the burden of health-care cost.



How to cite this article:
Kadhim FH, Mohammed SH. Microbiological profile, antibiogram, and risk factors of patients with diabetic foot infections: A systemic metaanalysis.Biomed Biotechnol Res J 2021;5:235-244


How to cite this URL:
Kadhim FH, Mohammed SH. Microbiological profile, antibiogram, and risk factors of patients with diabetic foot infections: A systemic metaanalysis. Biomed Biotechnol Res J [serial online] 2021 [cited 2021 Nov 26 ];5:235-244
Available from: https://www.bmbtrj.org/text.asp?2021/5/3/235/325616


Full Text



 Introduction



Diabetes mellitus (DM) is a metabolic disease, characterized by elevated blood glucose levels (hyperglycemia) resulting from defects in insulin secretion, insulin action, or both. Insulin is a hormone manufactured by the beta cells of the pancreas, which is required to utilize glucose from digested food as an energy source.[1] Diabetes is classified into two major classes: Type 1 DM (T1DM) and Type 2 DM (T2DM).[1] About 5%–10% of people with diabetes have T1DM and it is mostly diagnosed during childhood,[1] whereas T2DM accounting for 90%–94% of all diabetes and it is usually develops after the age of 40 years, but it may occur at any age.[2]

Approximately 150–170 million of the world's population is suffering from DM and its prevalence will most likely multiply by two folds by 2025.[3] Previous studies estimated that at least 20% increase in diabetes patients occur in low- and middle-income countries between 2010 and 2030.[4]

Patients with uncontrolled diabetes are at high risk for developing complications such as diabetic foot ulcer (DFU), diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy.[5],[6] Among all complications of diabetes patients, DFU is considered as a major social and economic problem, and it is also known as a leading cause of morbidity and mortality among developing countries[4] and represent one of the most common causes of hospitalization of diabetic patients.[7] It is estimated that DFU is responsible for more than 20% of diabetes-related hospital admissions.[4]

DFUs are an injury to all layers of the skin that usually occur on the soles of the feet which including ulcerations.[8] Once the protective layer of a skin is broken, deep tissues are exposed to a bacterial infection that progresses rapidly.[7] The progression of infection occurs as a result of suppressed immune status, delayed diagnosis, underestimation of extent of infection, and suboptimal antimicrobial therapy. This may lead to lower extremity amputations if not treated timely and properly.[9]

Patients with DFUs frequently require amputation of the lower limbs, and in more than half of the cases, infection is the predominant factor. It has been reported that around 25% of people with diabetes will develop a DFU during their life time. In addition, it has been estimated that every 20s a lower limb is amputated due to diabetic complications.[7] Within the diabetic population, annually, foot ulcers develop in 9.1 million to 26.1 million people worldwide.[10]

Risk factors of DFU include age,[11] male gender,[12],[13] duration of diabetes,[11],[12] poor glycemic control[14] peripheral vascular disease,[13],[15] diabetic retinopathy,[12],[13] and nephropathy.[16],[17]

In diabetic foot infections, the patterns of microbial infection are not consistent.[9] Single organisms, such as Staphylococcus aureus, are usually isolated from mild infections, whereas polymicrobial organisms, including Gram-positive cocci (such as S. aureus, Staphylococcus epidermis, and Enterococci), Gram-negative bacilli (such as Pseudomonas spp., Escherichia coli, and Enterobacter spp), and aerobes (such as Bacteroides spp), are isolated from severe infections.[18] Hence, repeated evaluation of causative organisms and their antibiotic susceptibility is required for the selection of appropriate empirical therapy.[9]

The aim of this systemic review is to highlight the risk factors such as age and gender associated with DFU infections, whether the infection is caused by single bacteria or polymicrobial infection and what is the most prevalent bacteria and their susceptibility pattern to the antibiotics that used as empirical treatment (according to the latest guidelines) during management.

 Methods



To collect the most relative studies, three databases were searched from December 2020 to February 2021 including PubMed, Hinari, and Google Scholar. The research articles published within the period (January 2017 to December 2020) were retrieved. The key words which we used for searching databases were (DFU, bacterial infection, and risk factors). Every study does not meet the inclusion criterion was excluded from this study. Observational prospective cross-sectional were included, whereas retrospective studies were excluded. Types of participants included in the selected studies include patients with type 1 and T2DM with DFU. The age of participants was more than 18 years old from both gender. PRISMA flow diagram was generated using PRISMA flow diagram generator website: http://prisma.thetacollaborative.ca, [Figure 1].{Figure 1}

 Results



The data searching strategy revealed 222 articles which were published between the period 2017–2020. After evaluation of the tittles and abstracts of the recognized articles, a total of 12 articles were included in the current meta-analysis. Three studies were conducted in Iraq, three in India, three in Pakistan, one in Malaysia, Nigeria, and Guyana, [Table 1]. A narrative reviewing was drawn through this study. The total number of patients within the included articles were (1871) from both gender. The study design of the included studies was observational, prospective, and cross-sectional.{Table 1}

Association of diabetic foot ulcer with gender and age

Almost all of the included studies were reported a higher frequency of DFU in males than in females, but the included studies did not document the presence of statistically difference between them. The highest male-to-female ratio was reported by Datta et al., (2.84:1). Eight from 12 included studies documented that maximum number of DFU mostly occur within age group 40–60 years, as shown in [Table 2].{Table 2}

Polymicrobial versus monomicrobial infection of the diabetic foot ulcer

Higher proportion of monomicrobial infections in DFU was documented in six included studies, whereas higher proportion of polymicrobial infections was documented in three of them. Type of microbial infection whether its monomicrobial or polymicrobial was not mentioned in another three, [Table 3].{Table 3}

Type of microorganism associated with diabetic foot ulcer

Nine included studies documented that Gram-negative bacteria were more predominant than Gram-positive bacteria. E coli, Pseudomonas, Proteus, and Klebsiella being the most prominent microorganism. S. aureus is the most prominent Gram-positive bacteria [Table 4].{Table 4}

Country and type of predominating bacteria

The three studies that carried out in Iraq documented higher proportion of monomicrobial infection. Two of them documented the predominance of Gram-negative bacteria, especially, E. coli and Pseudomonas. In India, two out of three included studies were documented the presence of monomirobial infection and Gram-negative bacteria were predominating strains. In Pakistan, two of three documented the predominance of Gram-negative bacteria and only one study (Kaim et al.) had mentioned the presence of polymicrobial infections of DFU. In Nigeria and Malaysia, higher proportion of polymicrobial infections were reported, and the predominating bacteria were Gram-positive and Gram-negative bacteria, respectively, [Table 3] and [Table 4].

Distribution and type of microorganism with wound grade

As shown in [Table 3] and [Table 5], 5 out of 12 of the included studies have analyzed the type and distribution of the microorganism isolated from DFU [Table 5]. Otta et al. had documented that 45% and 50% of the grade 4 wounds were infected with one organism and more than two organisms, respectively, whereas, approximately 70% of the Grades 2 and 3 wound were infected with single organism. On the other hand, 13% and 30% of Grades 2 and 3 wound were infected with more than two organisms, respectively.{Table 5}

Goh et al. documented that 85% of patients with mild, moderate, and severe wound grade were infected with two or more organisms, respectively. Datta et al. documented that 13, 26, and 17 out of 56 patients with Grades 1, 2, and 3 were infected with MDRO, whereas, 20, 11, and 13 out of 44 patients were infected with Non-MDRO.

Kurup et al. documented that mild, moderate, and severe infection among MDR and NMDR patients was recorded as 45.3% (95% confidence interval [CI] 32.8–58.3), 26.5% (95% CI 16.3–39.1), 28.1% (95% CI 17.6–40.8) and 51.3% (95% CI 41.9–60.5), 32.8% (95% CI 24.4–42.0), 16.0% (95% CI 9.9–23.8), respectively. Qadir et al. documented the presence of highly significant association between the isolated Gram-negative microorganisms and higher grades of DFUs.

Antibiotic sensitivity testing

Because antibiotic resistant bacteria have become the major public health problem, antibiotic susceptibility pattern for the most prevalent bacteria must be monitored continuously especially for antibiotics that currently used as empiric treatment. In the current systemic review, the results of antibiotic susceptibility testing which were done for the most prevalent bacteria reported in 11 of the included studies were highlighted [Table 6]. All the included studies were tested the antimicrobial susceptibility testing using the disc-diffusion method in accordance with the guidelines of the Clinical and Laboratory Standards Institute. S. aureus represent the commonly isolated Gram-positive bacteria, whereas E. coli and Pseudomonas represent the most prevalent Gram-negative bacteria isolated from DFU.{Table 6}

Antibiotics used as empiric treatment for DFU management include Flucloxacin, Metronidazole, Amoxicillin-Clavulanic acid, Pipracillin-Tazobactam, Cefalexin, Cefazolin, Cefepime, Clindamycin, Ciprofloxacin.[19],[20]

Glycopeptide – vancomycin

Seven studies tested the sensitivity of S. aureus to vancomycin, susceptibility rates were ranged between 85% and 100%. The lowest susceptibility rates were documented by Singh et al., whereas the highest rates were documented by Ullah et al., Goh et al., and Kurup et al. Comparable sensitivity rates were documented by Neama et al., Otta et al., and Amjad et al. For E. coli and Pseudomonas, the only study that analyzed the sensitivity of these bacteria against Vancomycin was Amjad et al., who reported high resistance rates (59.4% and 57.1%, respectively).

Lincosamide – clindamycin, erythromycin, and azithromycin

Eight studies were analyzed the sensitivity rates to Clindamycin and/or Erythromycin, Azithromycin for S. aureus and two studies for E. coli and Pseudomonas. Lowest resistance rates were reported by Kurup et al., (12.2% and 10.3%) for MRSA and MSSA, respectively, whereas, higher resistance rates were reported by Neama et al., (53.7%) followed by Anyim et al., (45.5%). Comparable resistance rates were reported by Singh et al., (30%) and Amjad et al., (32.7%). For E. coli and Pseudomonas, high resistance rates were documented by Amjad et al., (68.8% and 71.4%, respectively).

Metronidazole

Susceptibility testing was analyzed by Kaimlhani et al., Pseudomonas isolates were showed higher resistance rates (37.8%) than E. coli (28.6%) and S. aureus (27.6%).

Pipracillin-tazobactam

Resistance rates were documented by two studies, Otta et al., and Kaimlhani et al., for S. aureus, E. coli, and Pseudomonas. Higher resistance rates were reported by Kaimlhani et al., in comparison to Otta et al., for the three types of bacteria. Goh et al. reported 18% resistance rate for Pseudomonas isolates.

Cephalosporins

For S. aureus isolates, high resistance rates were documented in eight studies, Neama et al., (92.6%), Amjad et al., (84.6%), Otta et al., (82%–86%), Ullah et al., (76.77%), Anyim et al., (45%–72%), Kaimlhani et al., (65%–70%), Saleh et al., (25%–40%), and Kurup et al., (0 and 33.33 for MRSA and MSSA). For E. coli, high resistance rate was documented by Otta et al., whereas high sensitivity rates were documented by Kurup et al., followed by Singh et al., Datta et al., and Amjad et al., for Pseudomonas, higher sensitivity rates were documented by Singh et al., then by Datta et al., and the least sensitivity was reported by Amjad et al.,

Amoxicillin-clavulanic acid

Almost all of the tested S. aureus, E. coli, Pseudomonas isolates in 9 of the included studies were reported high resistance rates to this antibiotic.

Quinolones: Ciprofloxacin, levofloxacin

High resistance rates were documented to quinolones that includes, Ciprofloxacin and or Levofloxacin were documented by Ullah et al., Amjad et al., Singh et al., Kurup et al., and Kaimlhani et al., Otta et al.

Carbapenems: Imipenem, meropenem, and ertapenem

High susceptibility rates were documented in the included studies and the authors considered it as the most effective antibiotic. However, the highest resistance rates for Pseudomonas was documented by Ullah et al., (31%) and followed by Amjad et al., (28.6%). For E coli, Kurup et al., documented the highest resistance rates (23.1%).

 Discussion



The lifetime prevalence of DFU in diabetic patients has been estimated to be 15%, with DFU responsible for about 20% of diabetes-related hospital admissions.[21] If not treated properly, DFU can lead to limb amputation.

The purpose of this systematic review was to obtain a wider piece of work and highlight the presence of certain risk factor in DFU development, the most common type of isolated bacteria and their susceptibility pattern. A total of 12 articles were included in the current meta-analysis.

Age and gender

Almost all of the included studies were reported a higher frequency of DFU in males than in females. Eight from 12 included studies documented that maximum number of DFU mostly occur within the age group of 40–60 years. Both male gender and age were considered as risk factor for DFU. Male predominance was explained in several previous studies due to outdoor activity of males, hard physical activity, being at higher risk for trauma, higher alcohol consumption, higher smoking behavior, better access to health-care settings, less compliance to foot care practice. The elderly patients have spent longer time with diabetic mellitus will have decreased immunity, nutritional deficiencies, and were at risk for the development of certain complications such as peripheral neuropathy and vascular diseases which might results in foot ulceration that characterized by poor healing over a long period of time.[2],[7],[9],[22],[23],[24]

Region and type of predominating bacteria

The three included studies that carried out in Iraq documented the higher proportion of Monomicrobial infection. Two of them documented the predominance of Gram-negative bacteria especially, E. coli and Pseudomonas. In India, two out of three included studies were documented the presence of monomicrobial infection and Gram-negative bacteria were predominating strains. In Pakistan, two of three documented the predominance of Gram-negative bacteria and only one study (Kaim et al.,) had mentioned the presence of polymicrobial infections of DFU.

These differences could be partly due to changes in the causative organisms occurring over time, geographical variations, or the types and severity of infection. Differences could further result from use of a relatively small number of specimens, and inadequate specimen collection techniques (which would fail to exclude superficial or colonizing organisms), poor handling techniques and poor preservation methods for anaerobic organism.[25]

Grade monomicrobial versus polymicrobial infections

There are several classification systems to define the presence and severity of infection in the feet of people with diabetes. Most of the included studies documented that the higher grades of the DFUs were infected with more than one organism and these bacteria were MDR. Otta et al., had documented that 50% of the grade 4 wounds were infected with more than two organisms, whereas, 70% of the wound with grade 2 and 3 wound were infected with single organism. Goh et al., documented that 85% of patients with all wound grade were infected with two or more organisms.

It is important to distinguish between microbial colonization and infection. Although ulcers may be colonized with microorganisms, infections that require treatment are characterized by bacterial invasion of skin, other soft tissues, or bone.

Initially, DFU typically are colonized by gram-positive bacteria like S aureus, S pyogenes, S agalactiae and when an ulcer becomes chronic become colonized with gram-negative bacteria. So, that's why we can see polymicrobial infection in high grade wounds. With hospitalization and treatment, ulcer flora might possibly change to MDR bacteria like methicillin resistant S. aureus, Vancomycin resistant Enterococcus, and Extended spectrum β-lactamase resistant bacteria.[26]

Some studies suggest that the presence of more than one organisms within these polymicrobial mixtures might lead to the production of some virulence factors, like hemolysins, proteases, and collagenases, as well as short-chain fatty acids, that cause inflammation, and contribute to the chronicity of the infection.[27],[28]

Antibiotic susceptibility testing

DFU infections must be treated with empiric antimicrobial therapy because culture results of the specimen taken from the infected ulcer are not yet available at time of treatment. However, culture results aid to identify the causative pathogens, allowing for any necessary modification to optimize antimicrobial therapy because The antibacterial effect of antibiotic used in treatment for patients with DFU is highly correlated with the resistance pattern of pathogenic bacteria.

The results of the included studies showed high resistance rates of the isolated bacteria to the most commonly used antibiotics like Amoxicillin, different generations of Cephalosporins, Ciprofloxacin, Levofloxacin, Clindamycin and there were alarming growing resistance rate to Carbapenems which considered the most effective Antibiotics nowadays.

 Conclusions



DFU infections are one of the major social and economic problem. S. aureus, E. coli and Pseudomonas were found to be the most prevalent bacteria isolated from diabetic foot infections. Gram negative bacteria were found to be predominating in Iraq, India, Pakistan, and Malyasia. Male gender and age over 40 years were considered risk factor for DFU development. The bacteriological profile of the isolated organism from DFU are mainly monomicrobial with high resistance rates to common antibiotics and increasing percentage of multidrug resistance organisms associated with these ulcers. Unfortunately, there were growing resistance rates to carabapenemes which were considered the most effective antibiotic nowadays. Thus, there is an urgent need for continuous antibiotic sensitivity testing for the isolated bacteria to choose the appropriate antibiotics during management and limit the spreading of MDR bacteria and reduce the burden of health care cost.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1Ubeid MH. Prevalence of leukocytes in type 2 diabetic patients in Erbil City. Med J Babylon 2020;17:19.
2Saleh RH, Hadi B. Bacterial profile in patients with diabetic foot infections and its association with TNF-α. Plant Archives Vol. 19, Supplement 1, 2019 pp. 222-228.
3Goh TC, Bajuri MY, C Nadarajah S, Abdul Rashid AH, Baharuddin S, Zamri KS. Clinical and bacteriological profile of diabetic foot infections in a tertiary care. J Foot Ankle Res 2020;13:1-8.
4Kurup R, Ansari AA, Singh J. A review on diabetic foot challenges in Guyanese perspective. Diabetes Metab Syndr 2019;13:905-12.
5Johani K, Fritz BG, Bjarnsholt T, Lipsky BA, Jensen SO, Yang M, et al. Understanding the microbiome of diabetic foot osteomyelitis: Insights from molecular and microscopic approaches. Clin Microbiol Infect 2019;25:332-9.
6Anvarinejad M, Pouladfar G, Japoni A, Bolandparvaz S, Satiary Z, Abbasi P, et al. Isolation and antibiotic susceptibility of the microorganisms isolated from diabetic foot infections in Nemazee hospital, Southern Iran. J Pathog 2015;2015:328796.
7Marzoq, Abdulhussein, Shiaa, Nadeem, Zaboon, Raghda, et al. Assessment of the outcome of diabetic foot ulcers in Basrah, Southern Iraq: A cohort study. Int J Diabetes Metab 2019;25:33-8.
8Alavi A, Sibbald RG, Mayer D, Goodman L, Botros M, Armstrong DG, et al. Diabetic foot ulcers: Part I. Pathophysiology and prevention. J Am Acad Dermatol 2014;70:1.e1-8.
9Amjad SS, Zafar J, Shams N. bacteriology of diabetic foot in tertiary care hospital; frequency, antibiotic susceptibility and risk factors. J Ayub Med Coll Abbottabad 2017;29:234-40.
10Armstrong DG, Boulton AJ, Bus SA. Diabetic foot ulcers and their recurrence. N Engl J Med 2017;376:2367-75.
11Al-Rubeaan K, Al Derwish M, Ouizi S, Youssef AM, Subhani SN, Ibrahim HM, et al. Diabetic foot complications and their risk factors from a large retrospective cohort study. PLoS One 2015;10:e0124446.
12Almobarak AO, Awadalla H, Osman M, Ahmed MH. Prevalence of diabetic foot ulceration and associated risk factors: An old and still major public health problem in Khartoum, Sudan? Ann Transl Med 2017;5:340.
13Jupiter DC, Thorud JC, Buckley CJ, Shibuya N. The impact of foot ulceration and amputation on mortality in diabetic patients. I: From ulceration to death, a systematic review. Int Wound J 2016;13:892-903.
14Porselvi A, Uma Shankar MS, Lakshmi KS, Sankar V. A retrospective qualitative study on current diabetic foot ulcer management and discussion on extended role of clinical pharmacist. Marmara Pharmaceutical Journal Vol 21 issue 2: pages 412-418, 2017.
15Smith-Strøm H, Iversen MM, Igland J, Østbye T, Graue M, Skeie S, et al. Severity and duration of diabetic foot ulcer (DFU) before seeking care as predictors of healing time: A retrospective cohort study. PLoS One 2017;12:e0177176.
16Spichler B, Hurwitz D, Armstrong DG, Lipsky BA. Microbiology of diabetic foot infections: From Louis Pasteur to 'crime scene investigation. BMC Medicine (2015) 13:2 page 1-13. DOI 10.1186/s12916-014-0232-0.
17Meloni M, Giurato L, Izzo V, Stefanini M, Gandini R, Uccioli L. Risk of contrast induced nephropathy in diabetic patients affected by critical limb ischemia and diabetic foot ulcers treated by percutaneous transluminal angioplasty of lower limbs. Diabetes Metab Res Rev 2017;33:e2866.
18Akhi MT, Ghotaslou R, Asgharzadeh M, Varshochi M, Pirzadeh T, Memar MY, et al. Bacterial etiology and antibiotic susceptibility pattern of diabetic foot infections in Tabriz, Iran. GMS Hyg Infect Control 2015;10:Doc02.
19Australia, G.o.S. Diabetic Foot Infections: Antibiotic Management Clinical Guideline. Vol. 1.1. Government of South Australia: SA Health; 2019. p. 13.
20Team, N.F.A.M. Diabetic Foot Infection – Empirical Antibiotic Management. Vol. 382. NHS Fife Antimicrobial Management Team: NHS Fife; 2017. p. 2.
21Kurup R, Ansari AA. A study to identify bacteriological profile and other risk factors among diabetic and non-diabetic foot ulcer patients in a Guyanese hospital setting. Diabetes Metab Syndr 2019;13:1871-6.
22Neama NA, Darweesh MF, Al-Obiadi AB. Prevalence and antibiotic susceptibility pattern in diabetic foot ulcer infection with evaluation the role of biomarker il-12 in disease. Biochem. Cell. Arch year of publication 2018 Vol 18 Issue 2 Pages 2321-2328.
23Qadir, Aso Nasih, Mahmoud, Bakhtiar Mohamed, Mahwi, Taha Othman, Al-Attar, Delman Mohammed Raoof Arif, Mahmood, Safeen Othman. Prevalence of microorganisms and antibiotic sensitivity among patients with diabetic foot ulcer in Sulaimani City, Iraq. Hosp Pract Res 2020;5:56-63.
24Ullah I, Ali SS, Ahmed I, Khan MN, Rehman MU, Malik SA. Bacteriological profile and antibiotic susceptibility patterns in diabetic foot infections, at lady reading hospital, Peshawar. J Ayub Med Coll Abbottabad 2020;32:382-8.
25Orji F, Nwachukwu N, Udora E. Bacteriological evaluation of diabetic ulcers in Nigeria. Afr J Diabetes Med 2009;15:19-21.
26Andrew JM. Boulton, David G Armstrong, Matthew J Hardman, Matthew Malone, John M Embil, Christopher E Attinger, et al. Diabetic Foot Infections. American Diabetes Association; 2020.
27Wall IB, Davies CE, Hill KE, Wilson MJ, Stephens P, Harding KG, et al. Potential role of anaerobic cocci in impaired human wound healing. Wound Repair Regen 2002;10:346-53.
28Yao Y, Sturdevant DE, Villaruz A, Xu L, Gao Q, Otto M. Factors characterizing Staphylococcus epidermidis invasiveness determined by comparative genomics. Infect Immun 2005;73:1856-60.