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European Journal of Applied Sciences – Vol. 10, No. 3
Publication Date: June 25, 2022
DOI:10.14738/aivp.103.12338. Arama, D. P., Somboro, A. M., & Dackouo, B. (2022). Fluoroquinolone Resistance: An Overview. European Journal of Applied
Sciences, 10(3). 539-549.
Services for Science and Education – United Kingdom
Fluoroquinolone Resistance: An Overview
Dominique Patomo ARAMA
Faculty of Pharmacy (FAPH)/University of Bamako (USTTB)
P. O. Box: 1805, Bamako, Mali
Anou Moise SOMBORO
Faculty of Pharmacy (FAPH)/University of Bamako (USTTB)
P. O. Box: 1805, Bamako, Mali
Blaise DACKOUO
Faculty of Pharmacy (FAPH)/University of Bamako (USTTB)
P. O. Box: 1805, Bamako, Mali
ABSTRACT
In this review, we addressed different types and mechanisms of resistance to
fluoroquinolones. Strategies to overcome resistance to these antimicrobials were
discussed. The study showed that resistance by efflux was the reported type of
mechanism of resistance varied with bacteria stains. For Enterobacteriaceas,
plasmid mediated genese were responsible of the resistance but In Shigella, the
resistance was due to chromosomal mutation. Helicobacter, Pseudomonas,
Enterobacteria, Mycobacteria were found to be the most resistant microorganisms.
To face the situation many strategies are usable such as rational antibiotic
prescription, new compound discovery, antimicrobial and stewardships. The
AWaRe concept is recently developed by the WHO as powerful tool to overcome
antibiotic resistance.
INTRODUCTION
Infections are more and more difficult to treat as antimicrobial resistance is increasing in
frequency [6]. Million people are dying from antimicrobial resistance because of a lack in global
public awareness campaign, inadequate prescriptions, and unnecessary use of antimicrobials
in agriculture [13]. In Sub-Saharan Africa, the phenomenon is worsened by poor hygiene, water
supply deficiencies, civil conflicts and HIV [14]. For Theuretzbacher in Journal of Global
Antimicrobial Resistance (June 2013); the worldwide antibacterial resistance is: “The never
ending story” [17].
Researchers point gram-negative infections to be the most resistant strands to bacterial
resistance to many antibacterial agents including Fluoroquinolones [15]. According to the WHO
guidance, Quinolones and Fluoroquinolones are classified as critically important antimicrobials
for human medicine and must be prescribed rationally [18]. These antibiotics are known to
select for Salmonella and E. coli that are quinolones-resistant in animals but are also of the few
available treatments for serious infections of Salmonella and E. coli [18]. Little is known about
fluoroquinolones resistance patterns, prevalence and predictors despite their importance in
therapy and the high burden of multidrug resistance to this category of antibiotics that are
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backbone in the treatment of infectious diseases [24]. The adoption restrictive prescription
policies and a rational use of Fluoroquinolones are needed draw back the threat [24]. In 2017
the WHO recommended researches for new drugs to fight the high alarming resistance to
Fluoroquinolones in Campylobacters [33]. Tuberculosis that is still they major cause of Global
mortality and morbidity with 6.4 million new cases in 2017 is unfortunately affected by
antimicrobial resistance including resistance to Fluoroquionolones determined by regions
mutations in gyrA and gyrB [36]. Some scientists point poor treatment of multi-grug resistance
to anti-tuberculosis drugs to be the origin of Fluoroquinolone resistance [36]. The phenomenon
is mostly due to the frequent use of fluoroquinolones [38]. There is a need to monitor the
adequate use of these antibiotics for the detection of antimicrobial resistance (AMR)[38]. Some
studies tried to understand the impact and different types of antimicrobial resistance in order
to elaborate strategies and guidelines for reducing AMR spread [41]. Bacteria involved in the
resistance to fluoroquinolones need to be explored [51].
TYPES OF RESISTANCES (1, 15, 26, 29, 35, 43, 44, 45, 48, 51)
GyrAE89K substitution of gyrase/topoisomerase IV is one type of mutation that leads to
quinolone-resistance in B. anthracis Species by substitution of C8 hydrogen with a methoxyl
group [1]. Gram-Negative are bacterial sterns usually known to display antibacterial resistance
[15]. A resistant bacterium modifies structures of Fluoroquinolones in order to make them
inactive [Rosana Rosa]. The high-level resistance to fluoroquinolones for Mycoplasma hominis
seems to be associated to DNA gyrase and the ParC of topoisomerase IV mutations [26]. In
Salmonella enterica serovar Pullorum, the MLST genotype and the type ST-92 that is correlated
to Asp87Gly substitution are incriminated [29]. Streptococcus pneumoniae is also reported to
develop resistance to Fluoroquinolones [35]. A study performed in Brazil from 2021 to 2015
found 13.5 % of resistance to Fluoroquinolones, and a D91N mutation and a N87K mutation in
DNA are responsible of rate [43]. A Cochran review explored the resistance development and
the mutagenesis using a minimal inhibitory concentration (MIC) of fluoroquinolones [44]. A
study of 562 samples from patients with lung tuberculosis found 102 DNA gyrA mutations, 2
DNA gyrB mutations pointing that Fluoroquinolone resistance diagnosis should be performed
before treatment in to control drug resistance [45]. Stenotrophomonas maltophilia trains
belong to bacteria that develop Fluoroquinolone resistance. A university Hospital study
detected as possible mechanisms: the expression of efflux pump smeD and smeF genes [48].
Fluoroquinolone resistant Corynebacteria tend to be susceptible to CMX [51].
RESISTANCE MECHANISMS
It seems like Gyrase is targeted by quinolones in Bacillus anthracis infectious diseases. It is then
essential to understand this mechanism of action and characterize interactions between
Quinolones and Bacillus anthracis gyrase [1]. Bacteria resist to antimicrobial by inactivating
them, modifying their structures, avoiding them penetrate cells or inhibiting their metabolism
[2]. Neisseria meningitides and Haemophilus influenza are also part of microbial agents that
display resistance to Fluoroquinolones [6]. Several resistance mechanisms are displayed by
infection agents to survive to antimicrobial agent effects: genetic mutation, latent gene
resistance expression and acquisition, biochemical ways of resisting antimicrobial agents [7].
In quinolone resistant bacteria, there is a target modification leading to alterations in DNA
topoisomerase [7]. There can also be a decreased drug uptake by alteration in outer-membrane
proteins [7]. The mechanisms of resistance of Topoisomerase Inhibitors include mutational
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URL: http://dx.doi.org/10.14738/aivp.103.12338
alterations in drug target affinity and efflux pump expression and acquisition of the resistance
gene [9]. There are two mechanisms of resistances to quinolones: mutation and resistance
conferring-gene acquisition targeting both two drug target enzymes (DNA gyrase and DNA
topoisomerase IV)[10]. These two enzymes tend to be targeted by gram-negative bacteria [20].
For Alekshun et al, the main mechanism of resistance of bacteria to antibiotics is associated to
efflux pumps that exclude chemicals form the cell of the pathogen [21]. The phenomenon can
also be due to mutations in bacteria strains precisely in Helicobacter pylori species [23]. In
Enterobacteriaceae, Plasmid-mediated genes and mutations are sometimes responsible of
resistance to quinolones [25]. In Pathogenic Enterobacteriaceae, the resistance mechanism
tends to genetic by encoding a DNA gyrase protection protein that inhibits dihydropteroate
synthases of folate pathway [26]. In Mycoplasma hominis, the resistance is associated with
mutations in Par C sub-unit of the Topoisomerase IV and DNA gyrase [27]. In Romania, a genetic
resistance study found that the type of resistance responsible for Fluoroquinolone resistance
in Helicobacter pillory was more frequent in women [28]. Salmonella enterica serovar Pullorum
that resistant to Fluoroquinolones is able produce biofilm which is capable to prevent
fluoroquinolones from penetrating bacteria cell walls [29]. Molecular studies of gastric biopsies
detected that Helicobacter pylori resisted to Fluoroquinolones by expressing resistance genes
[30]. In Shigella flexneri strains the drug resistance is conferred by mdfA mutations in
chromosomal genes [31].This mdfa gene mutation encodes efflux pump resistance of
fluoroquinolones [39]. Litle is known about the antimicrobial susceptibility of Campylobacter
concisus multidrug resistance mechanism to fluoroquinolones [42]. There is still need to classify
Fluoraoquinolones resistance mechanism of actions [44]. The fluoroquinolone resistance
mechanism can be determined by the detection of PMQR genes and mutations in quinolone
resistance determining region (QRDR) [45]. The molecular detection of Mycobacterium
tuberculosis infection resistance to Fluoroquinolones is associated to a mutation in DNA gyrase
subunit A (gyrA) and B (gyrB) [46]. It is important to know the prevalence rate of
Fluoroquinolone resistance in order to define the best treatment to recommend [47]. The efflux
pump can be specific to an antibiotic [7]. The expression of efflux pump genes has correlation
with fluoroquinolone resistance [48]. Fluoroquinolones are classified in the groupe A of
tuberculosis drugs [50]. Signal detected by microbial agents are influenced by factors such as
temperature, pH, or nutrient availability and cues from the hos and surrounding infection [53].
The contribution of efflux pumps in Fluoroquinolone resistance occurring is not negligible [54].
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Figure. 1: Biochemical mechanisms of resistance to Fluoroquinolones inspired from
Giedraitienė et al 2011 [2]
Figure 2: Genetical mechanisms of resistance to Fluoroquinolones inspired from Liwa et al
2015 [7]
CURRENT STRATEGIES TO FIGHT ANTIBIOTIC RESISTANCES
To face antimicrobial resistance, it is necessary to discover novel antimicrobial agents and use
derivative preparation by semisynthetic methods, which are not affected by existing resistance
mechanisms. To do so is essential to understand current antimicrobial mode of actions and how
pathogens become resistant them [7]. Fluoroquinolones are antibiotics that kill bacteria by an
interference with their nucleic acid synthesis leading to the inhibition of the DNA synthesis [7].
It is possible to reduce antimicrobial resistance by reducing the transmission of resistant
microbial agents or their resistant genes by appropriate prescriptions, by an adequate
environmental hygiene policies and the identification of resistant microbial trends [7].
Structure modification of old antibiotics and combination of antibacterial drugs are some
strategies actually used as solutions to cross antimicrobial resistance [22]. Adjustments of
treatments can also be a way to face the situation [32]. The treatment root change cans also a
solution [34].
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URL: http://dx.doi.org/10.14738/aivp.103.12338
RATIONAL PRESCRIPTION
Point prescription surveys (PPS) is method used to enter data from 226 hospitals in 41
countries of Europe, Africa, Asia, Australia, Latin America and North America in term antibiotic
prescription showed that it was possible to use antibacterial drugs to set benchmarks and
monitor interventions of hospitalized neonates and children [5]. It is important to diagnosis
accurately infection before prescribing antimicrobials, to detect when narrow-spectrum can be
used, to choose cheapest and shortest treatment, and to understand and use anti-microbial
stewardship for the benefit of this guidance [16].
New compound discovery
New quinolone synthesis is one way to face the resistance phenomenon; it can include green
chemistry and microwave –assisted synthesis [4]. Clinical studies recommend short use of
Fluoroquinolones in therapeutic for mild to moderate illness patients [8]. The WHO urges for
action to be taken [19].
Antimicrobial stewardships
Antimicrobial stewardship is one key approach to face resistance to fluoroquinolones [5]. It
reduces the use of fluoroquinolones and increases the susceptibility of pathogens to this group
of antibiotics [40].
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Fugure. 3: Stratégies to fighting antimicrobial resistance inspired from [56]
DISCUSSIONS
A wide range of activities have been reported for quinolones including anti-cancer and anti- microbial activities [4]. [12]. A study undertaken in Uganda showed that Fluoroquinolones
resistance in increasing. As an example it was found that quinolone-resistance to Nesseiria
gonorrhea increased from 9.5% in 2007 to 50 % in 2009 in Western Kenya [14]. WHO has
developed the Access, Watch, Reserve (AWaRe) classification of antibiotics in 2019 where
Strategies
Hospitals
Regulation
authorities
Industry:
control of
advertisments
Patients and
community
• Implementation of
therapeutic commities
• Quality ensurance of
diagnostic tests
• Registration of lab data
• Rapport of monitoring
• Rational use of medicines
• Update of
treatment
guidelines
• Update of
essential drug list
• Education
• And
Sensibilisation on
the control of
bacterial
resistance
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many quinolones are part of Watch group [55]. In this group we have antibiotics with higher
resistance potential and include must of the highest priority agents among the critically
important antimicrobials for human medicine [18]. It is recommended to adopt restrictive
policies to control the prescription and the delivery of this antibiotic group to prevent resistant
bacteria strains [24]. The problem is significant and needs to be solved by surveillance
programs of the use of these antibiotics in health care centers [33]. The frequency is high in dog
ophthalmic diseases [38]. Some scientists suggest that establishing antimicrobial resistance
surveillance and research network is a well suited tool to obtain data of antimicrobial
resistances [41]. It is essential to understanding these data in order to better taking decisions
about future approaches in therapy [52].
CONCLUSION
For this review more than 50 papers published this last decade were collected. The most
reported resistance mechanisms, they different types of mechanisms and current strategies to
overcome Fluoroquinolone resistances were addressed in this work. Microorganisms that most
frequently resisted to Fluoroquinolones were also discussed. The mechanism of resistance by
efflux was the most reported for fluoroquinolones. The most of the resistance occurred through
DNA mutation. The rational use of Fluoroquinolones is advised to prevent antimicrobial
resistance to these antibiotics. Besides, in countries with low-income where 60 % of infections
are resistant to antibiotics, the AWaRe tool could be useful to reduce the risk of resistance
emergence.
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