Technical Note 2

Antibiotic resistance in diabetic ulcer

Domain: Antibiotic, Resistance, Diabetic Ulcer
Domain 1: Antibiotic
Definition
The definition of “antibiotic,” as first proposed by Selman
Waksman, the discoverer of streptomycin and a pioneer in
screening of soils for the presence of biologicals; it is simply a
description of a use, a laboratory effect, or an activity of a
chemical compound. The generic term “antibiotic” is used here to
denote any class of organic molecule that inhibits or kills microbes
by specific interactions with bacterial targets, without any
consideration of the source of the particular compound or class
(Davies, 2010).

Antibiotics are derived from three sources: moulds or fungi;

bacteria; or synthetic or semi-synthetic compounds. They can be
used either internally or topically, and their function is to either
inhibit the growth of pathogens or to kill them (Zhang, 2007).

Antibiotic classification Antibiotics can thus be divided into Bacteriostatic drugs, which
merely inhibit the growth of the pathogen, and Bacteriocidal drugs,
which actually kill the bacteria. Antibiotics can also be divided into
broad-spectrum and narrow-spectrum antibiotics (Zhang, 2007).

Mechanism antibiotic Antibiotics fight against bacteria by inhibiting certain vital

processes of bacterial cells or metabolism. Based on these
processes, can divide antibiotics into five major classes :
Cell wall inhibitors, Inhibitors of nucleic acid synthesis which
inhibits DNA/RNA synthesis, Protein synthesis inhibitors, Anti-
metabolites, such as the sulfa drugs, Antibiotics that can damage the
membrane of the cell (Zhang, 2007).
Domain 2: Resistance
Definition of antibiotic Antibiotic resistance is defined as acquired or inherent resistance to
resistance at least one antibiotic (Chatterjee et al, 2018)

Antibiotic resistance does not mean the body is becoming resistant

to antibiotics; it is that bacteria have become resistant to the
antibiotics designed to kill them. Antibiotic resistance happens
when germs like bacteria and fungi develop the ability to defeat the
drugs designed to kill them. That means the germs are not killed and
continue to grow (CDC).

Classically, antibiotic resistance has been defined from an

operational viewpoint that classifies bacteria as resistant or
susceptible on the basis of the possibility of treating the infections
they can produce (Martinez, 2014).

Antibiotic resistance in bacterial pathogens is an adaptive trait

acquired after challenge with therapeutic antibiotics (Martinez,
2014).

History of resistance The first sign of antibiotic resistance became apparent soon after the
discovery of penicillin in 1928 by Alexander Fleming, In 1940,
Abraham and Chain reported that an E. coli strain was able to
inactivate penicillin by producing penicillinase (Lobanovska &
Pilla, 2017).

The first effective antimicrobial agent, sulfonamide, was introduced

in 1937. Within 2 years, sulfonamide resistance was reported and
the same AR mechanisms are still clinically present more than 70
years later (Watkins, 2016).

Since antibiotics came into widespread use some 70 years ago, the
evolution spread of antibiotic-resistant pathogens have been fueled
by the extensive use and and overuse antibiotic in human and
animals (Knöppel, 2017)

Mechanism of antibiotic Three major mechanisms of antibiotic resistance reveal a few

resistance common themes used by bacteria to fend off antibiotics. One
mechanism is destruction of the antibiotic by bacterial enzymes, A
second mechanism is bacterial reprogramming of the antibiotic
 target to lowered susceptibility, The third major route , is to pump
out antibiotics via transmembrane efflux pumps, keeping antibiotic
concentration within the bacterial cell below toxic threshold
concentrations (Walsh & Wright, 2005).

From a biochemical point of view, these can be grouped into

mechanisms that modify either the target of an antibiotic, or that
modify the concentration of its ligand (the antibiotic itself).
Target modification can be achieved by target mutation (e.g.
quinolone resistance is caused by mutations in bacterial
topoisomerases), target replacement (beta-lactam resistance
sometimes due to the acquisition of chimeric penicillin binding
proteins [PBPs]), enzymatic modification of the target (e.g.
resistance to vancomycin occurs through the reorganization of the
cell wall), or target protection (Martinez, 2014).
Reductions in antibiotic concentrations can be achieved either by
impeding the entry of the antibiotic. Or by extruding the antibiotic
through efflux pumps. These mechanism do not change the structure
of the antibiotic itself. Mechanisms exist that do cause such change,
for example, mutations in the enzyme that activate a pre-antibiotic
(as required for isoniazid in Mycobacterium tuberculosis) or the
presence of antibiotic-inactivating enzymes (Martinez, 2014).

When the antibiotic target is not a single gene product it is thought

to be more difficult to evolve resistance. Examples of this include
antibiotics that function by interacting with or disrupting the cell
membrane itself, or antibiotics that target the precursors of cell
structures like the building blocks of cell wall polymers
(Waglechner, 2017).
In some cases, the antibiotic producers’ own self-resistance genes
have been argued to be the ancestors of the resistance determinants
found in non-producing organisms (Waglechner, 2017)

Prevalence antibiotic In western countries, community-associated meticillin-resistant

resistance Staphylococcus aureus (MRSA), vancomycin-resistant enterococci
(VRE), extended-spectrum b-lactamase (ESBL)-producing
Escherichia coli and Klebsiella pneumoniae, and carbapenem
resistant Enterobacteriaceae (CRE) have become more prevalent
than before (Lai et al, 2014).
 The epidemiology of antibiotic-resistant bacteria in Asia may be
different to other regions, and clinical condition may be worse than
in western countries. Antibiotic-resistant bacteria, including
community-acquired and hospital-acquired meticillin-resistant
Staphylococcus aureus (MRSA), vancomycin-intermediate S.
aureus (VISA), vancomycin-resistant enterococci, macrolide- and
penicillin resistant Streptococcus pneumoniae, extend-spectrum b-
lactamase (ESBL)-producing Escherichia coli and Klebsiella
pneumoniae, carbapenem-resistant Enterobacteriaceae, and
multidrug-resistant Pseudomonas aeruginosa, and Acinetobacter
spp., are becoming prevalent in many countries in Asia (Lai et al,
2014).

Three classes of antibiotic-resistant pathogens are emerging as

major threats to public health. First, methicillin-resistant
Staphylococcus aureus (MRSA). Pathogens from the second class,
multi drug resistant (MDR) and pandrug-resistant (PDR) Gram
negative bacteria. The third class comprises MDR and extensively
drug-resistant (XDR) strains of Mycobacterium tuberculosis
(MDR-TB and XDR-TB), which are a rising threat in the
developing world (Fischbach, 2009).

Antibiotic resistance in With an estimated population of 258 million people, Indonesia is

indonesia the fourth most populous country in the world and is categorised as
a lower middle income country Data on AMR in Indonesia have
been patchy, sporadic, and selective, commonly generated by a few
laboratories from large universities, which are not connected in a
national network (Parathon et al, 2017).

In Semarang, Indonesia, prevalence of S pneumoniae in 2010 was

43% in children aged 6-60 months and 11% in adults aged 45-75
years, of which isolates 24% were penicillin non-susceptible and
45% were resistant to cotrimoxazole (Parathon et al, 2017).
In 2001, E coli from rectal samples showed remarkably high
resistance to ampicillin (73%), trimethoprim-sulfamethoxazole
(56%) and ciprofloxacin (22%), especially at the time of hospital
discharge (Parathon et al, 2017).

From 2001 to 2012, resistance to imipenem rates reached 30% in

some epidemic areas of the Middle East, while the top two Asian
 countries with the highest resistance rates to imipenem were
Indonesia (6%) and the Philippines (4%) (Parathon et al, 2017).

Strategy to prevent Antibiotic stewardship programmes include heterogeneous

spread of antibiotic interventions, such as auditing, restriction of specific antibiotics,
resistance restriction of treatment duration, and antibiotic cycling or mixing
The implementation of these measures has been shown to
significantly reduce hospital costs and use of antibiotics (Baur et al,
2017)

Antimicrobial stewardship programs (ASPs) are coordinated

programs aimed at promoting the appropriate use of antimicrobials,
improving patient outcomes, reducing the emergence of
antimicrobial resistance, and decreasing the spread of infections
caused by multidrug-resistant organisms. ASPs include a wide
variety of strategies: multidisciplinary groups, medical education
on antimicrobial prescription, antibiotic cycling, restriction of
antibiotic use, combining therapies, dose optimization, and
conversion of parenteral administration to oral administration are
among the main elements considered (Bertollo, 2018)

In May 2017. WHO supported the Indonesian Ministry of Health to

develop a national action plan, first by conducting a review of
current activities. The review focused on a situation analysis of
challenges to tackling AMR. The South East Asia Regional Office
(SEARO) of WHO has proposed a stepwise, incremental approach
to implementing GAP-AMR, consisting of five phases (Parathon et
al, 2017).

In Indonesia, the Ministry of Health has made a general guideline

for use antibiotics and promulgated in the regulation of the minister
of health of the Republic of Indonesia number 2406 / MENKES /
PER / XII / 2011. This guide aims to provide a reference for health
workers in using antibiotics in health services, facilities health
services and government policies to optimize use antibiotics can be
wisely achieved (Desrini, 2015).
Domain 3 : Diabetic ulcer
Definition Diabetic foot ulcer is an outcome of complicated amalgam of
various risk factors such as peripheral neuropathy, peripheral
vascular disease, foot deformities, arterial insufficiency, trauma
and impaired resistance to infection (Noor, 2015)

Diabetic ulcer One of the most often used classification system is Wagner-
classification Meggit system. It is a six grade classification system which takes
into consideration the depth of ulcer, presence of gangrene and
level of tissue necrosis. The University of Texas Antonio
classification system (UTSA) assess diabetic foot lesion according
to depth, wound infection and presence of lower limb ischemia.
UTSA system is now widely used in various clinical trials and
diabetic centers. International working group classification The
risk assessment instrument developed by the International
Working Group on the Diabetic Foot (IWGDF) has been
beneficial in assuring diabetic foot complications (Noor, 2015)

Diagnosis for diabetic There was no evidence that single items on a clinical examination
ulcer infection checklist were reliable in identifying infection in DFUs. Wound
swabs performed poorly against wound biopsies. Semi-quantitative
analysis of wound swabs may be a useful alternative to quantitative
analysis (Nelson et al, 2006).

The wound should be sampled after proper debridement of callus

and necrotic tissue. Superficial cultures obtained with cotton swabs
are easily collected, but less reliable than tissue biopsies or
curettings. Most studies have found that swab specimens have more
isolates (likely contaminating or colonizing flora) than aseptically
obtained deep tissue specimens (Peters, 2013).

The Consensus Development Conference on Diabetic Foot Wound

Care agreed that a DFU should be considered infected when there
are purulent secretions or the presence of two or more signs of
inflammation (erythema, warmth, tenderness, heat, induration)
(Howell et al, 2005).

The mostly antibiotic More recently, extended-spectrum b-lactamase (ESBL)–producing

resistance to diabetic Enterobacteriaceae are an emerging international problem,
ulcer including in diabetic foot infections. The likelihood of isolating
 MRSA from a diabetic foot infection has increased over the past
decade, but seems to be decreasing more recently (Peters, 2013).

Bacteria in diabetic ulcer Potential causative organisms of the DFUs are believed to include
Staphylococcus, Streptococcus, Proteobacteria, Pseudomonas
aeruginosa and coliform bacteria (Noor, 2015).

Diabetic foot infections are often caused by a number of infecting

microorganisms. Staphylococcus aureus, Streptococcus pyogenes,
Staphylococcus epidermidis, E. coli, Pseudomonas aeruginosa,
Klebsiella pneumoniae, Acinetobacter spp, Proteus spp., and
Enterococcus spp are some of the frequent pathogens contribute to
progressive tissue damage (Radji, 2014).

Most mild infections in patients who have not recently been treated
with antibiotics are caused only by aerobic gram-positive cocci,
predominantly Staphylococcus aureus and/or, to a lesser degree, b-
hemolytic streptococci. Recent studies from developing countries
have noted that isolation of Staphylococcus aureus in diabetic foot
infections is less common than in developed countries (30% vs
75%). Cultures of deep wounds with moderate to severe infections,
especially in previously treated patients, are usually polymicrobial
with mixed gram-positive cocci, gram negative rods (eg,
Escherichia coli, Proteus, Klebsiella), sometimes nonfermentative
gram-negative rods (eg, Pseudomonas), and obligate anaerobes (eg,
Peptostrepto- coccus, Finegoldia, Bacteroides (Peters, 2013).

The reported data on skin and soft-tissue infection confirmed earlier

observations suggesting that Gram-positive microorganisms play
the leading role in DFI. There is, however, emerging observational
evidence that Gram-negative species (especially Pseudomonas
aeruginosa) are frequent pathogens in some populations, especially
those in warm climates and developing countries (Peters et al, 2012)
Antibiotic therapy in The International Working Group on the Diabetic Foot
ulcer recommends a complex antibiotic strategy which involves
intravenous and/or possibly oral use of empirical broad-spectrum
antibiotics in the presence of deep foot infections. The list of
regimens suggested includes ampicillin/sulbactam,
ticarcillin/clavulanate, co-amoxiclav, clindamycin and a quinolone,
 second or third generation cephalosporin and a quinolone, and
metronidazole with a quinolone (Howell et al, 2005).

It is possible to treat selected patients with a DFI in an outpatient

setting with an oral antibiotic regimen, either initially or after a
switch from parenteral therapy (Peters, 2013).

References
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Stewardship on the Incidence of Infection and Colonisation with Antibiotic-Resistant Bacteria and
Clostridium Difficile Infection: A Systematic Review and Meta-Analysis. The Lancet Infectious
Diseases 17, 990–1001.

Bertollo L.G, Lutkemeyer D.S, Levin A.S. (2018). Are Antimicrobial Stewardship Programs Effective
Strategies for Preventing Antibiotic Resistance? A Systematic Review. American Journal of
Infection Control 46, no. 7, 824–36.

Chatterjee A, Modarai M, Naylor RN, Boyd ES, Atun R, Barlow J, Holmes HA, Johnson A, Robotham VJ.
(2018). Quantifying Drivers of Antibiotic Resistance in Humans: A Systematic Review. ” The Lancet
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Davies, J., and Davies, D. (2010). Origins and Evolution of Antibiotic Resistance. Microbiology and
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Desrini, S. (2015). Resistensi Antibiotik, Akankah Dapat Dikendalikan ? Jurnal kedokteran dan kesehatan
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Nelson, E, S O’Meara, D Craig, C Iglesias, S Golder, J Dalton, K Claxton, et al. (2006). A Series of Systematic
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PADANAN KATA
Domain Antibiotic: Antimicrobial, antibacterial
Domain Resistance: Resist, Resistant, drug resistant, multi drug resistance
Domain Diabetic Ulcer: Diabetic foot ulcer, diabetic foot infection, diabetic foot, wound
infection, foot infection, chronic wound, complex wound, hard-to-heal ulcer