The Significant Association between

Original Article
Polymicrobial Diabetic Foot Infection
and Its Severity and Outcomes
Sharifah Aisyah Syed Hitam1,2, Siti Asma’ Hassan1,2,
Nurahan Maning3

Submitted: 07 Jan 2018 1

Department of Medical Microbiology and Parasitology, School of Medical
Accepted: 17 Oct 2018 Sciences, Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan,
Online:  28 Feb 2019 Malaysia
2
Hospital USM, Health Campus, Universiti Sains Malaysia,
16150 Kubang Kerian, Kelantan, Malaysia
3
Pathology Department, Hospital Raja Perempuan Zainab 2,
15586 Kota Bharu, Kelantan, Malaysia

To cite this article: Sharifah Aisyah SH, Siti Asma’ H, Nurahan M. The significant association between polymicrobial
diabetic foot infection and its severity and outcomes. Malays J Med Sci. 2019;26(1):107–114. https://doi.org/10.21315/
mjms2019.26.1.10

To link to this article: https://doi.org/10.21315/mjms2019.26.1.10

Abstract
Background: Foot infection is a major complication of diabetes mellitus (DM) and
its agents are usually polymicrobial. This study aims to describe the agent and determine the
association between polymicrobial infections and the severity of diabetic foot infections (DFI) and
their outcomes.
Methods: This retrospective cohort study was conducted during one year and it involved
104 patients. Their records were reviewed and assessed. The causative agents and its sensitivity
pattern were noted. The results were presented as descriptive statistic and analysed.
Results: A total of 133 microorganisms were isolated with 1.28 microorganisms per lesion.
The microorganism isolated were 62% (n = 83) GN (Gram-negative) and 38% (n = 50) GP (Gram-
positive). GN microorganisms include Pseudomonas spp (28%), Proteus spp (11%), Klebsiella spp
(8%) and E. coli (4%). Staphylococcus aureus (54%) was predominant among GP, followed by
Group B Streptococci (26%) and Enterococcus spp (6%). Thirty patients (28.8%) had polymicrobial
infections. The association between the quantity of microorganisms and severity of DFI was
significant. Among severe DFI cases, 77.8% with polymicrobial microorganisms underwent
amputation compared to 33.3% with monomicrobial infection.
Conclusion: GN microorganisms were predominantly isolated from DFIs and remained
sensitive to widely used agents. Polymicrobial infections were associated with DFI severity.

Keywords: diabetic foot infection, diabetes mellitus, microorganisms, polymicrobial infection, severity of
infection

Introduction this endocrine disorder are also mounting and

diabetic foot infections (DFIs) is an important
Foot infections are among the most cause of morbidity and mortality in patients
common lower extremity complications in the with DM. DFI affect one in 10 patients with DM
diabetic population (excluding neuropathy), during their lifetime (2). They have increased
second only to foot ulcers in frequency (1). risk of lower extremity amputations and the
As the incidence of diabetes mellitus (DM) is main cause is diabetic peripheral arterial
increasing globally, complications related to disease accelerated by the direct damage to the

Malays J Med Sci. Jan–Feb 2019; 26(1): 107–114

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This work is licensed under the terms of the Creative Commons Attribution (CC BY) 107
(http://creativecommons.org/licenses/by/4.0/).
Malays J Med Sci. Jan–Feb 2019; 26(1): 107–114

nerves and blood vessels by high blood glucose severity of infections and its outcome in term of
levels. Smokers, older patients with a longer amputation and discharge from hospital.
history of uncontrolled diabetes, and those with
gangrenous infections and large ulcers have Materials and Methods
poorer outcomes with amputations (3).
It is well documented that diabetic foot
This was a retrospective study that was
infections are frequently polymicrobial in nature
carried out for a duration of one year from June
(4, 5, 6). Hyperglycemia, impaired immunologic
2014 to June 2015. All patients diagnosed as type
responses, neuropathy, and peripheral arterial
1 or type 2 DM in the ward and clinic of Hospital
disease are the major predisposing factors
Universiti Sains Malaysia who were suspected
leading to limb-threatening DFI (4).
of having DFI with or without bone infection
Foot infections in persons with DM are
based on clinical signs and symptoms using
often initially treated empirically. The empirical
Infectious Disease Society of America (IDSA)
antibiotics used are usually meant for broad-
(2) were included in this study. Patients who
spectrums organisms coverage or according to
suffered from trauma or had incomplete details
local antibiogram study. Hence, therapy directed
and more than 10% incomplete data records for
at known causative organisms may improve the
the main variables of interest were excluded.
outcome. Many studies have reported on the
Repeat patients with same diagnosis were also
bacteriology of DFIs over the past 25 years, but
excluded. The data were collected from medical
the results have varied, and they have often been
record obtained from the hospital record office.
contradictory (7). Therefore, study on the local
Relevant information on diabetic patients also
causative organisms and antibiograms of DFI
has been explored. This information included
is an essential tool for better management of
patient demographic data like age and gender;
diabetic foot patients.
comorbid illness like hypertension, ischaemic
A number of studies have found that
heart disease, bronchial asthma and chronic
Staphylococcus aureus is the main causative
obstructive lung diseases (COAD); severity of
pathogen (8, 9), but more recent investigations
the illness, diagnosis during admission; and
have reported a predominance of Gram-negative
laboratory result parameters (red blood cell
(GN) (10, 11). The role of anaerobes is especially
count, haemoglobin level, total white cell counts
unclear, because in many studies, specimens
and HbA1c). The sampling method applied
were not collected or cultured properly to recover
in this study was a simple random sampling.
these organisms. Among those that did use
During the data collection, the registration
appropriate methods, some have reported that
number of all patients that were admitted to
anaerobes play a minimal role and Bacteroides
the ward and clinic of Hospital Universiti Sains
fragilis is the predominant anaerobe isolated (12,
Malaysia were coded and kept separately with
13). These discrepancies of aetiological agents
a confidential safe guard. Sample size for the
could be partly due to differences in the causative
association between polymicrobial infections
organisms occurring over time, geographical
and severity of DFI was calculated using a two
variations or the types and severity of infection
proportion formula and the sample size was 104.
included in the studies.
Regarding the selection of microorganisms,
Optimal management requires aggressive
the data were extracted from the USM WHONET
surgical debridement and wound management,
system. The quantity of microorganism was
effective antibiotic therapy, and correction of
recorded. Monomicrobial infection was
metabolic abnormalities mainly hyperglycaemia
defined as a single infectious agent, whereas
and arterial insufficiency. In current practice,
polymicrobial infections is a multiple infectious
little attention is paid to the possible
agents (14). All of the microorganism types
pathogen that causing the DFI although some
including Gram-positive (GP), Gram-negative
pathogens have different types of virulence,
(GN) and anaerobes were recorded and analysed.
as well as responding to different antibiotics.
The data from patients’ medical records
Polymicrobial infection of DFI also contributes
was extracted and recorded in Microsoft Office
to the severity of disease; therefore, it can be
Excel 2013. After reviewing the data, all the
one of the prognostic factors and more vigilant
relevant information was entered into IBM SPSS
management should be taken. This study
Statistics Version 22. The statistical analysis
describes the microorganisms involved in DFI,
that was used in this study was descriptive and
the association of polymicrobial infection with
categorical data analysis (Fisher’s Exact test

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 Original Article | Severity of polymicrobial diabetic foot infections

or Pearson Chi-square test). The descriptive Results

analyses were performed for both numerical
and categorical independent variables. A total of 104 DFI patients who fulfilled the
The measurements used for the numerical inclusion criteria were successfully recruited. The
independent variable were the mean and gender distribution among the patients with DFI
standard deviation (SD). The statistic could also was almost equal at 44% (n = 46) male and 56%
be reported as the median and inter-quartile (n = 58) female. Most of the DFI patients were
range (IQR) when the normality distribution aged 41–60 years old. There were two younger
was skewed. Meanwhile, the frequency and patients with DFI at the ages of 25 and 27 years
percentage were examined for the categorical old. Both of them had type 1 DM.
independent variable. A P-value with less than A total of 133 microorganisms were
0.05 indicated statistically significant. The isolated. Among them, the commonest were
approval from Research Ethics Committee Pseudomonas spp, followed by Staphylococcus
(Human) USM (JEPeM) were obtained (Ref. aureus (Table 1). The antibiotic sensitivity
No.:15010011). patterns of the GP and GN organisms are shown
in Table 2 and Table 3.

Table 1.  Distribution of aetiologic agent in DFI participants (n = 133)

Pathogen n (%)
Gram positive
• Staphylococcus aureus 27 (20.3)
• Streptococcus agalactiae 13 (9.8)
• Enterococcus spp 4 (3.0)
Other Gram positive organisms 6 (4.5)
Gram negative
• Klebsiella spp 11 (8.3)
• Escherichia. coli 5 (3.8)
• Proteus spp 14 (10.5)
• Enterobacter spp 8 (6.0)
• Pseudomonas spp 37 (27.8)
• Acinetobacter spp 6 (4.5)
Anaerobes 2 (1.5)

Table 2.  Antibiotic sensitivity pattern of Gram-positive pathogen (n = 50)

Staphylococcus Streptococcus Enterococcus *Other
Antibiotic aureus agalactiae spp organism
n (%) n (%) n (%) n (%)
Oxacillin 26 (96.3) - - -
Penicillin 5 (18.5) 13 (100.0) 4 (100.0) 6 (100.0)
Gentamicin 27 (100.0) 13 (100.0) 4 (100.0) 6 (100.0)
Rifampicin 27 (100.0) - - -
Vancomycin 27 (100.0) - 4 (100.0) -
Trimethoprim sulfamethoxazole 27 (100.0) - - 6 (100.0)
Clindamycin 27 (100.0) - - -
Fusidic acid 24 (88.9) - - -
Erythromycin 27 (100.0) 12 (92.3) 4 (100.0) 6 (100.0)
*Streptococcus pyogenes, Streptococcus group C, Streptococcus group G, Streptococcus mitis and coagulase-negative
Staphylococcus aureus

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Malays J Med Sci. Jan–Feb 2019; 26(1): 107–114

Table 3.  Antibiotic sensitivity pattern of Gram-negative microorganisms (n = 83)

Klebsiella Proteus Enterobacter Pseudomonas Acinetobacter
E. coli Anaerobes*
Antibiotic spp spp spp spp spp
n (%) n (%)
n (%) n (%) n (%) n (%) n (%)
Ampicillin 0 (0) 2 (40) 8 (57) 1 (17) - - -
Gentamicin 11 (100) 5 (100) 12 (86) 8 (100) - 0 (0) -
Amikacin 11 (100) 5 (100) 14 (100) 8 (100) - 0 (0) -
Cefuroxime 8 (73) 3 (60) 12 (86) 8 (100) - - -
Cefotaxime 8 (73) 3 (60) 14 (100) 8 (100) - 0 (0) -
Ceftazidime 8 (73) 3 (60) 14 (100) 8 (100) 36 (97) 0 (0) -
Cefepime 8 (73) 3 (60) 14 (100) 8 (100) 35 (95) 0 (0) -
Amoxycillin- 8 (73) 5 (100) 7 (50) 2 (33) - - -
clavulanate
Trimethoprim 8 (73) 5 (100) 12 (86) 4 (67) - 0 (0) -
sulfamethoxazole
Ciprofloxacin 10 (91) 5 (100) 13 (93) 8 (100) 34 (92) 0 (0) -
Piperacillin- 11 (100) 5 (100) 14 (100) 8 (100) 34 (92) 0 (0) -
tazobactam
Ertapenem 11 (100) 5 (100) 14 (100) 8 (100) - - -
Meropenem 11 (100) 5 (100) 14 (100) 8 (100) 36 (97) 0 (0) -
Imipenem 11 (100) 5 (100) 13 (93) 8 (100) 37 (100) 0 (0) -
Metronidazole - - - - - - 2 (100)
Polymyxin b - - - - - 6 (100) -
Colistin - - - - - 6 (100) -

*Bacteroides fragilis

Thirty patients (28.8%) had polymicrobial In contrast, studies from developed countries
infections and 74 (71.2%) patients had like those in North American and Europe found
monomicrobial infections. There were that GP aerobes especially Staphylococcus
statistically significant between two interested aureus, are the predominant pathogens in DFI
variables of interest with a P-value less than (7, 16). A large multicentre study from United
0.05. Fisher’s Exact test (P = 0.003), as shown States from 2008 revealed that 77% of DFI,
in Table 4. Patients with polymicrobial DFI had were caused by GP aerobes, while 21.2% were
higher glucose levels and total white cells. In caused by GN aerobes (17). Another study done
contrast, the haemoglobin was found to be lower in Turkey by Hatipoglu et al. (18) in 2014 found
(Table 5). that both aerobic GP and aerobic GN organisms
were isolated with almost equal frequency from
Discussion DFIs, throughout period of 1989–2011 (48.4%
versus 48.4%) (18).
Among GN bacteria isolated in this study,
DFI is often inadequately managed due
the most common were Pseudomonas spp
to a lack of understanding of the microbial
(27.8%), followed by Proteus spp (10.5%) and
prevalence, antibiotic sensitivity and therapeutic
Klebsiella spp (8.3%). Similar results were
approaches. This will lead to increased infection-
recorded by Ramakant et al. in 2011, Hatipoglu
related morbidity, increased duration of hospital
et al. in 2014 and Hobizal et  al. in 2012 (15, 18,
stay and the incidence of major limb amputation.
19). On the other hand, another study showed
The etiological agents of DFI are mostly
E. coli (20.3%) and K. pneumoniae (17.4%)
due to GN bacteria. In this study, we found that
were the leading cause of DFI (20). Among GP
GN bacteria are the predominant aetiological
bacteria, S. aureus is the commonest isolate.
agents representing a percentage of 62.4% of the
The result is similar to those recent studies either
total isolates. Similar results have been found
from eastern or western region. (11, 15, 18, 20,
in many other studies worldwide (9, 10, 15).
21).

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Table 4.  Associated factors between quantity of microorganisms among patients and severity of DFI
(n = 104)
Severity of diabetic foot infection
Quantity of Organisms Mild Moderate Severe P-value
n (%) n (%) n (%)
Monomicrobial 14 (17.7) 59 (74.7) 6 (7.6) 0.003a
Polymicrobial 2 (8.0) 14 (56.0) 9 (36.0)
Fisher’s Exact test was applied
a

Table 5.  Other parameters for polymicrobial DFI (n = 30)

Polymicrobial DFI
Variable
Mean (SD)
HbA1c 11.8 (2.1)
RBS 16.3 (5.2)
TW 16.6 (2.4)
Haemoglobin 9.0 (1.3)

It is well documented in the literature isolated from wounds. Of all Pseudomonas spp,
that DFIs are polymicrobial in nature (5, 7, 22). P. aeruginosa was isolated in less than 10%
Our study observed that moderate to severe DFI of wounds (27, 28). The suggested empirical
comprised infection by polymicrobial organisms antibiotic regimens for treatment of DFI for
whereas mild DFI are mostly monomicrobial. patients with risk factors for polymicrobial
The findings are similar to studies done by infection include ampicillin/sulbactam (unasyn),
many other researches (4, 15, 23, 24). We found ceftriaxone plus clindamycin or metronidazole,
about 28.8% (n = 30) of DFI patients had levofloxacin plus clindamycin, moxifloxacin and
polymicrobial infections which is represented ertapenem (29).
a lower level than those found in other studies. Clinicians must also consider covering
The reason for this maybe because, in this study, other resistant organisms, including extended
the isolate was more towards aerobic culture, spectrum beta lactamase producing Gram
with the fact that polymicrobial infections in DFI negative isolates and methicillin resistant
contain anaerobic organisms. This study gained Staphylococcus aureus especially in countries
only two anaerobic organisms, which were both in which they are relatively common (30).
Bacteroides fragilis. Bacteroides fragilis is the Other laboratory parameters are also important
commonest species of anaerobic organisms in diagnosing and managing DFI. Another
found in DFI (4, 9, 10, 25). study found that, severe DFI patients with
The microorganisms isolated in this polymicrobial infections had higher glucose
study were sensitive to a number of agents. levels and total white cell counts. In contrast,
The carbapenem group including ertapenem, the haemoglobin was found to be lower. In
meropenem and imipenem, showed good activity physiological terms, a higher blood hemoglobin
toward GN bacteria except for Acinetobacter spp, level indicated that more oxygen molecules
which are usually multidrug resistant and only were carried to local tissue, and consequently,
sensitive to polymixin B and colistin. Oxacillin anabolism and catabolism occurred more
had very good coverage for sensitive strains of effectively. Blood haemoglobin is also a good
Staphylococcus aureus and vancomycin was indicator of nutritional status. The above two
found to be the most effective drug overall factors were probably the reason why low blood
against GP organisms. These findings were in haemoglobin levels are found in DFI (31). An
accordance with previous studies (9, 26). elevated white blood cell (WBC) count might
As stated above, Pseudomonas was the reflect responses to both inflammation and
most common organism found in this study. infection, and it could be an important risk factor
Although isolated in many patients, it is often for amputation in DFI (32).
considered a non-pathogenic coloniser when

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Malays J Med Sci. Jan–Feb 2019; 26(1): 107–114

In general, there were many outcomes of Authors’ Contributions

polymicrobial infection. However, this study
only focused on amputation and discharge in Conception and design: SASH, SAH
individual patients. Our study showed that the Analysis and interpretation of the data: SASH, SAH
outcomes exhibited no statistically significant Drafting of the article: SASH, SAH
different between amputation and discharge Critical revision of the article for important intellectual
of patients with severe polymicrobial DFI. In content: SAH, NM
a few studies, the authors described individual Provision of study materials or patients: SASH
Collection and assembly of data: SASH
pathogens to assess predictive factors for limb
loss rather than comparing polymicrobial and
monomicrobial infections; for example, they Correspondence
found that DFI infected with Staphylococcus
aureus (P = 0.042) was predictive factor for limb Dr Siti Asma’ Hassan
loss (33). Severity of DFI can be confounded by Associate Professor, Senior Lecturer
other factors such as age of patients, duration of MPath (Microbiology) (USM)
DM, control of DM and so on. Interactions with Department of Medical Microbiology and Parasitology,
all these factors may be present. Therefore, all School of Medical Sciences, Universiti Sains Malaysia,
16150 Kubang Kerian, Kelantan, Malaysia.
these factors must also be considered apart from
Phone: +609 7676826
polymicrobial infections for the determination of Fax: +609 7676964
severe DFI. E-mail: [email protected]
In conclusion, GN bacteria are dominant
in DFI patients. Pseudomonas ssp. and
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