#### **8. Conclusion**

Antimicrobial stewardship plays a crucial role in managing multidrug-resistant bacterial infections. De-escalation therapy, combination therapy, dose optimization, and prophylactic antibiotic use are key strategies. Guidelines on antibiotic prescribing, a multidisciplinary team approach, education and training, surveillance and monitoring, close collaboration between clinicians and microbiologists, and benchmarking and quality improvement all contribute to the uptake and performance evaluation of antimicrobial stewardship.

#### **Conflict of interest**

The authors declare that there is no conflict of interest.

*Antimicrobial Stewardship in the Management of Multidrug-Resistant Gram-Negative... DOI: http://dx.doi.org/10.5772/intechopen.112848*

#### **Author details**

Temitope Oyedemi1 \*, Tolulope Fadeyi2 and Kolapo Fasina3

1 Department of Microbiology, Adeleke University, Ede, Osun State, Nigeria

2 Department of Pharmaceutical Microbiology, University of Ibadan, Ibadan, Oyo State, Nigeria

3 Biotechnology Division, Rubber Research Institute of Nigeria, Benin, Edo State, Nigeria

\*Address all correspondence to<EMAIL_ADDRESS>
© 2024 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **References**

[1] Perez KK, Olsen RJ, Musick WL, Cernoch PL, Davis JR, Land GA, et al. Integrating rapid pathogen identification and antimicrobial stewardship significantly decreases hospital costs. Archives of Pathology and Laboratory Medicine. 2013;**137**(9):1247-1254

[2] Cerceo E, Deitelzweig SB, Sherman BM, Amin AN. Multidrugresistant Gram-negative bacterial infections in the hospital setting: Overview, implications for clinical practice, and emerging treatment options. Microbial Drug Resistance. 2016;**22**(5):412-431

[3] Zagaliotis P, Michalik-Provasek J, Gill JJ, Walsh TJ. Therapeutic bacteriophages for Gram-negative bacterial infections in animals and humans. Pathogens and Immunity. 2022;**7**(2):1

[4] Razzaque MS. Implementation of antimicrobial stewardship to reduce antimicrobial drug resistance. Expert Review of Anti-infective Therapy. 2021;**19**(5):559-562

[5] Ruiz-Ramos J, Ramírez P. Antimicrobial stewardship programs in the Intensive Care Unit in patients with infections caused by multidrugresistant Gram-negative bacilli. Medicina Intensiva (English Edition). 2022;**47**(2):99-107

[6] World Health Organization. Antimicrobial stewardship programmes in health-care facilities in low-and middle-income countries. A Practical Toolkit. 2019;**1**:1-71

[7] Al-Omari A, Al Mutair A, Alhumaid S, Salih S, Alanazi A, Albarsan H, et al. The impact of antimicrobial stewardship program implementation at four tertiary private hospitals: Results of a five-years pre-post analysis. Antimicrobial Resistance & Infection Control. 2020;**9**(1):1-9

[8] File TM Jr, Srinivasan A, Bartlett JG. Antimicrobial stewardship: Importance for patient and public health. Clinical Infectious Diseases. 2014;**59** (Suppl. 3):S93-S96

[9] Nathwani D, Varghese D, Stephens J, Ansari W, Martin S, Charbonneau C. Value of hospital antimicrobial stewardship programs [ASPs]: A systematic review. Antimicrobial Resistance & Infection Control. 2019;**8**:1-3

[10] Aiesh BM, Nazzal MA, Abdelhaq AI, Abutaha SA, Zyoud SE, Sabateen A. Impact of an antibiotic stewardship program on antibiotic utilization, bacterial susceptibilities, and cost of antibiotics. Scientific Reports. 2023;**13**(1):5040

[11] Majumder MA, Rahman S, Cohall D, Bharatha A, Singh K, Haque M, et al. Antimicrobial stewardship: Fighting antimicrobial resistance and protecting global public health. Infection and Drug Resistance. 2020;**13**:4713-4738

[12] Hayes JF. Fighting back against antimicrobial resistance with comprehensive policy and education: A narrative review. Antibiotics. 2022;**11**(5):644

[13] Knobloch MJ, McKinley L, Keating J, Safdar N. Integrating antibiotic stewardship and infection prevention and control programs using a team science approach. American Journal of Infection Control. 2021;**49**(8):1072-1074

[14] Sheikh F, Zarowitz BJ, Sheikh F, Naqvi FA, Heil E, Brandt N.

*Antimicrobial Stewardship in the Management of Multidrug-Resistant Gram-Negative... DOI: http://dx.doi.org/10.5772/intechopen.112848*

Interprofessional collaboration improves antibiotic stewardship. Journal of the American Medical Directors Association. 2019;**20**(3):B22

[15] Exner M, Bhattacharya S, Christiansen B, Gebel J, Goroncy-Bermes P, Hartemann P, et al. Antibiotic resistance: What is so special about multidrug-resistant Gram-negative bacteria? GMS Hygiene and Infection Control. 2017;**12**:1-24

[16] Bassetti M, Kanj SS, Kiratisin P, Rodrigues C, Van Duin D, Villegas MV, et al. Early appropriate diagnostics and treatment of MDR Gram-negative infections. JAC-Antimicrobial Resistance. 2022;**4**(5):dlac089

[17] Breijyeh Z, Jubeh B, Karaman R. Resistance of Gram-negative bacteria to current antibacterial agents and approaches to resolve it. Molecules. 2020;**25**(6):1340

[18] Reygaert WC. An overview of the antimicrobial resistance mechanisms of bacteria. AIMS Microbiology. 2018;**4**(3):482

[19] Uddin TM, Chakraborty AJ, Khusro A, Zidan BR, Mitra S, Emran TB, et al. Antibiotic resistance in microbes: History, mechanisms, therapeutic strategies and future prospects. Journal of Infection and Public Health. 2021;**14**(12):1750-1766

[20] Fadeyi TE, Oyedemi OT, Awe OO, Ayeni F. Antibiotic use in infants within the first year of life is associated with the appearance of antibiotic-resistant genes in their feces. PeerJ. 2023;**11**:1-16

[21] Wenzler E, Maximos M, Asempa TE, Biehle L, Schuetz AN, Hirsch EB. Antimicrobial susceptibility testing: An updated primer for clinicians in the era of antimicrobial

resistance: Insights from the Society of Infectious Diseases Pharmacists. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy. 2023;**43**(4):264-278

[22] Ohl CA, Luther VP. Antimicrobial stewardship for inpatient facilities. Journal of Hospital Medicine. 2011;**6**(S1):S4-S15

[23] Barlam TF, Cosgrove SE, Abbo LM, MacDougall C, Schuetz AN, Septimus EJ, et al. Implementing an antibiotic stewardship program: Guidelines by the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America. Clinical Infectious Diseases. 2016;**62**(10):e51-e77

[24] Lipsky BA, Dryden M, Gottrup F, Nathwani D, Seaton RA, Stryja J. Antimicrobial stewardship in wound care: A position paper from the British Society for Antimicrobial Chemotherapy and European Wound Management Association. Journal of Antimicrobial Chemotherapy. 2016;**71**(11):3026-3035

[25] Taplitz RA, Ritter ML, Torriani FJ. Infection prevention and control, and antimicrobial stewardship. Infectious Diseases. 2017:54

[26] Bassetti M, Peghin M, Vena A, Giacobbe DR. Treatment of infections due to MDR Gram-negative bacteria. Frontiers in Medicine. 2019;**6**:74

[27] Lin TL, Chang PH, Chen IL, Lai WH, Chen YJ, Li WF, et al. Risk factors and mortality associated with multi-drugresistant Gram-negative bacterial infection in adult patients following abdominal surgery. Journal of Hospital Infection. 2022;**119**:22-32

[28] Li XZ, Plésiat P, Nikaido H. The challenge of efflux-mediated antibiotic resistance in Gram-negative bacteria. Clinical Microbiology Reviews. 2015;**28**(2):337-418

[29] Darby EM, Trampari E, Siasat P, Gaya MS, Alav I, Webber MA, et al. Molecular mechanisms of antibiotic resistance revisited. Nature Reviews Microbiology. 2023;**21**(5):280-295

[30] Munita JM, Arias CA. Mechanisms of antibiotic resistance. Virulence Mechanisms of Bacterial Pathogens. 2016;**4**(2):481-511

[31] Jian Z, Zeng L, Xu T, Sun S, Yan S, Yang L, et al. Antibiotic resistance genes in bacteria: Occurrence, spread, and control. Journal of Basic Microbiology. 2021;**61**(12):1049-1070

[32] Serwecińska L. Antimicrobials and antibiotic-resistant bacteria: A risk to the environment and to public health. Water. 2020;**12**(12):3313

[33] Ventola CL. The antibiotic resistance crisis: Part 1: Causes and threats. Pharmacy and Therapeutics. 2015;**40**(4):277

[34] Chia PY, Sengupta S, Kukreja A, Ponnampalavanar SSL, Ng OT, Marimuthu K. The role of hospital environment in transmissions of multidrug-resistant Gram-negative organisms. Antimicrobial Resistance & Infection Control. 2020;**9**(29):1-11

[35] Tacconelli EC, Cataldo MA, Dancer SJ, De Angelis G, Falcone M, Frank U, et al. ESCMID guidelines for the management of the infection control measures to reduce transmission of multidrug‐resistant Gram‐negative bacteria in hospitalized patients. Clinical Microbiology and Infection. 2014;**20**:1-55

[36] Morris S, Cerceo E. Trends, epidemiology, and management of multi-drug resistant Gram-negative bacterial infections in the hospitalized setting. Antibiotics. 2020;**9**(4):196

[37] Suleyman G, Alangaden G, Bardossy AC. The role of environmental contamination in the transmission of nosocomial pathogens and healthcareassociated infections. Current Infectious Disease Reports. 2018;**20**(12):1-11

[38] Moolchandani K, Sastry AS, Deepashree R, Sistla S, Harish BN, Mandal J. Antimicrobial resistance surveillance among intensive care units of a tertiary care hospital in southern India. Journal of Clinical and Diagnostic Research: JCDR. 2017;**11**(2):DC01

[39] Shime N, Kosaka T, Fujita N. De-escalation of antimicrobial therapy for bacteraemia due to difficult-totreat Gram-negative bacilli. Infection. 2013;**41**:203-210

[40] Lanckohr C, Bracht H. Antimicrobial stewardship. Current Opinion in Critical Care. 2022;**28**(5):551-556

[41] Bassetti S, Tschudin-Sutter S, Egli A, Osthoff M. Optimizing antibiotic therapies to reduce the risk of bacterial resistance. European Journal of Internal Medicine. 2022;**99**:7-12

[42] Mathieu C, Pastene B, Cassir N, Martin-Loeches I, Leone M. Efficacy and safety of antimicrobial de-escalation as a clinical strategy. Expert Review of Anti-Infective Therapy. 2019;**17**(2):79-88

[43] Al Salman J, Al Dabal L, Bassetti M, Alfouzan WA, Al Maslamani M, Alraddadi B, et al. Management of infections caused by WHO critical priority Gram-negative pathogens in Arab countries of the middle east: A consensus paper.

*Antimicrobial Stewardship in the Management of Multidrug-Resistant Gram-Negative... DOI: http://dx.doi.org/10.5772/intechopen.112848*

International Journal of Antimicrobial Agents. 2020;**56**(4):106104

[44] Ahmed A, Azim A, Gurjar M, Baronia AK. Current concepts in combination antibiotic therapy for critically ill patients. Indian Journal of Critical Care Medicine: Peer-Reviewed, Official Publication of Indian Society of Critical Care Medicine. 2014;**18**(5):310

[45] Fischbach MA. Combination therapies for combating antimicrobial resistance. Current Opinion in Microbiology. 2011;**14**(5):519-523

[46] Tamma PD, Cosgrove SE, Maragakis LL. Combination therapy for treatment of infections with Gramnegative bacteria. Clinical Microbiology Reviews. 2012;**25**(3):450-470

[47] Póvoa P, Moniz P, Pereira JG, Coelho L. Optimizing antimicrobial drug dosing in critically ill patients. Microorganisms. 2021;**9**(7):1401

[48] Phe K, Heil EL, Tam VH. Optimizing pharmacokinetics-pharmacodynamics of antimicrobial management in patients with sepsis: A review. The Journal of Infectious Diseases. 2020;**222**(Suppl. 2):S132-S141

[49] Drusano GL. Antimicrobial pharmacodynamics: Critical interactions of 'bug and drug'. Nature Reviews Microbiology. 2004;**2**(4):289-300

[50] Aguado JM, Silva JT, Fernández-Ruiz M, Cordero E, Fortún J, Gudiol C, et al. Management of multidrug resistant Gram-negative bacilli infections in solid organ transplant recipients: SET/GESITRA-SEIMC/REIPI recommendations. Transplantation Reviews. 2018;**32**(1):36-57

[51] Buchan CA, Kotton CN, AST Infectious Diseases Community of Practice. Travel medicine, transplant tourism, and the solid organ transplant recipient—guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clinical Transplantation. 2019;**33**(9):e13529

[52] De With K, Allerberger F, Amann S, Apfalter P, Brodt HR, Eckmanns T, et al. Strategies to enhance rational use of antibiotics in hospital: A guideline by the German Society for Infectious Diseases. Infection. 2016;**44**:395-439

[53] Lim CJ, Kong DC, Stuart RL. Reducing inappropriate antibiotic prescribing in the residential care setting: Current perspectives. Clinical Interventions in Aging. 2014;**9**:165-177

[54] Slama TG, Amin A, Brunton SA, File TM Jr, Milkovich G, Rodvold KA, et al. A clinician's guide to the appropriate and accurate use of antibiotics: The Council for Appropriate and Rational Antibiotic Therapy (CARAT) criteria. The American Journal of Medicine. 2005;**118**(7):1-6

[55] MacDougall C, Polk RE. Antimicrobial stewardship programs in health care systems. Clinical Microbiology Reviews. 2005;**18**(4):638-656

[56] Wong D, Spellberg B. Leveraging antimicrobial stewardship into improving rates of carbapenemresistant Enterobacteriaceae. Virulence. 2017;**8**(4):383-390

[57] Rahman MM, Alam Tumpa MA, Zehravi M, Sarker MT, Yamin MD, Islam MR, et al. An overview of antimicrobial stewardship optimization: the use of antibiotics in humans and animals to prevent resistance. Antibiotics. 2022;**11**(5):667

[58] Sarwar MR, Saqib A, Iftikhar S, Sadiq T. Knowledge of community

pharmacists about antibiotics, and their perceptions and practices regarding antimicrobial stewardship: A crosssectional study in Punjab, Pakistan. Infection and Drug Resistance. 2018;**11**:133-145

[59] Foral PA, Anthone JM, Destache CJ, Vivekanandan R, Preheim LC, Gorby GL, et al. Education and communication in an interprofessional antimicrobial stewardship program. Journal of Osteopathic Medicine. 2016;**116**(9): 588-593

[60] Yau JW, Thor SM, Tsai D, Speare T, Rissel C. Antimicrobial stewardship in rural and remote primary health care: A narrative review. Antimicrobial Resistance & Infection Control. 2021;**10**:1-33

[61] West LM, Cordina M. Educational intervention to enhance adherence to short-term use of antibiotics. Research in Social and Administrative Pharmacy. 2019;**15**(2):193-201

[62] Pearson M, Chandler C. Knowing antimicrobial resistance in practice: A multi-country qualitative study with human and animal healthcare professionals. Global Health Action. 2019;**12**(Supp 1):1599560

[63] Váradi L, Luo JL, Hibbs DE, Perry JD, Anderson RJ, Orenga S, et al. Methods for the detection and identification of pathogenic bacteria: Past, present, and future. Chemical Society Reviews. 2017;**46**(16):4818-4832

[64] Rittmann B, Stevens MP. Clinical decision support systems and their role in antibiotic stewardship: A systematic review. Current Infectious Disease Reports. 2019;**21**:1-2

[65] Taheri Moghadam S, Sadoughi F, Velayati F, Ehsanzadeh SJ, Poursharif S. The effects of clinical decision support

system for prescribing medication on patient outcomes and physician practice performance: A systematic review and meta-analysis. BMC Medical Informatics and Decision Making. 2021;**21**(1):1-26

[66] Righi E, Mutters NT, Guirao X, Del Toro MD, Eckmann C, Friedrich AW, et al. ESCMID/EUCIC clinical practice guidelines on perioperative antibiotic prophylaxis in patients colonized by multidrug-resistant Gramnegative bacteria before surgery. Clinical Microbiology and Infection. 2023;**29**(4):463-479

[67] Hawkey PM, Warren RE, Livermore DM, McNulty CA, Enoch DA, Otter JA, et al. Treatment of infections caused by multidrug-resistant Gramnegative bacteria: Report of the British society for antimicrobial chemotherapy/ healthcare infection society/british infection association joint working party. Journal of Antimicrobial Chemotherapy. 2018;**73**(Suppl. 3):iii2-iii78

[68] Tacconelli E, Sifakis F, Harbarth S, Schrijver R, van Mourik M, Voss A, et al. Surveillance for control of antimicrobial resistance. The Lancet Infectious Diseases. 2018;**18**(3):e99-e106

[69] Morel CM, De Kraker ME, Harbarth S. Enhanced Surveillance Expert Consensus Group (CANSORT-SCI). Surveillance of resistance to new antibiotics in an era of limited treatment options. Frontiers in Medicine. 2021;**8**:652638

[70] World Health Organization. Global Antimicrobial Resistance Surveillance System (GLASS) Report: Early Implementation 2016-2017. WHO. 2018. ISBN:<PHONE_NUMBER>449

[71] Perez F, Villegas MV. The role of surveillance systems in confronting the global crisis of antibiotic-resistant *Antimicrobial Stewardship in the Management of Multidrug-Resistant Gram-Negative... DOI: http://dx.doi.org/10.5772/intechopen.112848*

bacteria. Current Opinion in Infectious Diseases. 2015;**28**(4):375

[72] Tiseo G, Brigante G, Giacobbe DR, Maraolo AE, Gona F, Falcone M, et al. Diagnosis and management of infections caused by multidrug-resistant bacteria: Guideline endorsed by the Italian Society of Infection and Tropical Diseases (SIMIT), the Italian Society of Anti-Infective Therapy (SITA), the Italian Group for Antimicrobial Stewardship (GISA), the Italian Association of Clinical Microbiologists (AMCLI) and the Italian Society of Microbiology (SIM). International Journal of Antimicrobial Agents. 2022;**60**(2):106611

[73] Paul M, Carrara E, Retamar P, Tängdén T, Bitterman R, Bonomo RA, et al. European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guidelines for the treatment of infections caused by multidrugresistant Gram-negative bacilli (endorsed by European society of intensive care medicine). Clinical Microbiology and Infection. 2022;**28**(4):521-547

[74] Patel SV, Vergnano S. The impact of paediatric antimicrobial stewardship programmes on patient outcomes. Current Opinion in Infectious Diseases. 2018;**31**(3):216-223

[75] Jamaluddin NA, Periyasamy P, Lau CL, Ponnampalavanar S, Lai PS, Ramli R, et al. Point prevalence survey of antimicrobial use in a Malaysian tertiary care university hospital. Antibiotics. 2021;**10**(5):531

#### **Chapter 11**

## Dispatching Biocompatible Polymers toward Antimicrobial Applications

*Ruogu Tang*

#### **Abstract**

Antimicrobial materials have become an essential part of various fields. In the past decades, various types of antimicrobial materials were developed and practically used. Based on the feedback from the clinical usage and market, the biocompatible materials have been very welcomed due to less side effects. This chapter provides a small and general review of biocompatible polymer materials and their applications in antimicrobial fields. This chapter could be divided into several parts: starting from the background introduction of microbial threats, the first section discusses the demands of biocompatible polymers for antimicrobial applications, then, the following sections would describe the basic knowledge of biocompatible polymers, including the definition, advantages, and typical examples, the next section reviewed and discussed some approaches to apply biocompatible polymers into antimicrobial applications.

**Keywords:** antimicrobial, biocompatibility, biocompatible polymer natural environment, functional modification, functional group

#### **1. Introduction**

Microbial invasions and infections have been accompanying human beings for thousands of years, and have caused countless causalities [1, 2]. The battle against microbial threats had already begun before people acquired the understanding of microorganisms [3]. During this long-lasting fighting, though the concept was not initially established, people had invented and developed antimicrobial materials, which contain contents that have the functions of preventing microbial invasion and/or sterilizing the microbes [4, 5]. Up to date, various types of antimicrobial materials have been developed and many of them have been successfully applied to real usages [6–9].

One major concern regarding the usage of antimicrobial materials is the side effects [10, 11]. For example, it was reported that some antimicrobial materials might cause damage to human bodies while killing the microbes [11]. Also, some antimicrobial materials, once abandoned or released, could lead to environmental and ecological issues [12]. Therefore, it has become a consensus that antimicrobial materials, no matter how potent they are, should be less collateral damaging. Under this demand, biocompatible polymers-based antimicrobial materials (i.e., biocompatible

antimicrobial polymers) have become more favorable among customers and markets, and this type of material has become a new area for research [12].

This chapter provides a mini-review of biocompatible antimicrobial polymers, including the description of typical polymer materials, their usage in antimicrobial fields, the current challenges, and future perspectives.

### **2. Understanding the biocompatible polymers**

#### **2.1 Definition of biocompatible polymers**

Admittedly, the terminology of biocompatible polymers is not well defined yet, and researchers prefer to create their own descriptions in the publications. However, so far, some consensuses regarding the definition of biocompatible polymers have been built and recognized among different researchers, which at least include the following:

#### **2.2 Advantages of biocompatible polymers**

It is easy to recognize that biocompatible polymers are attractive, but much more than the common opinions, biocompatible polymers have various advantages in different aspects. The following briefly describes some significant points:

Availability: unlike traditional polymers obtained from the synthesis of monomers, most biocompatible polymers (in the form of raw materials) could be obtained or extracted from natural products. For example, cellulose was rich in cotton, flax, and straw [14]; chitosan and chitin could be extracted in arthropod animals [15]; alginate could be obtained as a major product of brown algae [16]. The easy accessibility of biocompatible polymers reduces the costs, especially exempting the processing of monomer preparations and polymerizations.

#### *Dispatching Biocompatible Polymers toward Antimicrobial Applications DOI: http://dx.doi.org/10.5772/intechopen.114250*

Low hazard: as mentioned above, biocompatible polymers could leave fewer side effects; this was considered one of the most significant advantages. Within the antimicrobial application, the biocompatible polymers could be comfortably applied on humans without considering the toxicities or body exclusions, and there will be fewer concerns about byproducts during usage.

Biodegradability: for most traditional polymers, one critical shortage is collateral environmental pollution, as they are hard to decompose in the natural environment. However, many biocompatible polymers are biodegradable to microorganisms or medium, simplifying depolymerization's artificial processing after usage [17]. In addition, the degraded components are also generally biocompatible and could be further decomposed and absorbed by the microorganisms [17]. Therefore, the applications of biocompatible polymers could reduce environmental concerns.

#### **2.3 Representative examples of biocompatible polymers**

After years of development, certain biocompatible polymers have been commercially used, and more candidates are being investigated in the research labs. Among various products, they could be divided into natural and synthetic biocompatible polymers. This part listed some typical examples.

Cellulose: Cellulose is a linear polysaccharide that consists of 1,4-D-glucose units (**Figure 1**) [14]. It is one of the earliest used biocompatible polymers, even before people established the concept of polymer materials. Cellulose exists abundantly in nature and serves as a major component of the cell walls of plants and wood. As a natural product, cellulose is nontoxic, non-polluting, and fully biodegradable, making itself popular nowadays [18]. Within the antimicrobial applications, cellulose is more likely to be considered and used either as raw materials or substrate for further modification.

Chitin and chitosan: chitin and chitosan share a highly similar structure. Chitin is a linear polysaccharide that contains repeated N-acetyl-D-glucosamine units (**Figure 2**), and chitosan is a linear polysaccharide (**Figure 3**) composed of randomly distributed D-glucosamine (deacetylated unit) and N-acetyl-D-glucosamine (acetylated unit) [15]. Chitin and chitosan are also rich in nature, but unlike cellulose, chitin and chitosan are more likely to be found in arthropod animals such as crabs, shrimps, and some insects [15]. It is interesting to notice that chitin and some sorts of chitosan could be fully or partially digested by certain types of enzymes and decomposed into monosaccharides and ammonia [19]. The digestibility of chitosan and chitin has become a huge advantage for antimicrobial applications, as they have great potential for *in vivo* usage [19].

Alginic acid: alginic acid is a welcomed edible polysaccharide. Alginic acid has a copolymer structure of β-D-mannuronate block and α-L-guluronate block (**Figure 4**). In the natural environment, it often exists in the form of sodium salt (referred to as

**Figure 1.** *Structure of cellulose.*

**Figure 2.** *Structure of chitin.*

#### **Figure 3.**

*Structure of chitosan.*

#### **Figure 4.** *Structure of alginic acid.*

alginate) [16]. Thanks to its edibility, alginic acid is favorable in the food and drug industry and is becoming promising for antimicrobial applications.

Polyvinyl alcohol: polyvinyl alcohol (PVA) is a synthetic biocompatible polymer with the formula of [CH2CH(OH)]n. Though not invented as a biocompatible material, its biocompatibility was soon proved, and then, it started being investigated in biomedical engineering fields [20]. Unlike most polymers, PVA is water soluble, which could be fully carried forward in the case of antimicrobial application in aqueous conditions.

Of course, there are many more candidates than those listed above. To date, there is an increasing trend of research addressing biocompatible polymers [21], including obtaining novel materials, modifying current products, developing processing techniques, and exploring the markets.

#### **3. Practicing biocompatible polymers in antimicrobial applications**

#### **3.1 Approaches toward antimicrobial applications**

The intrinsic advantages of biocompatible polymers do not guarantee the feasibility of applications. Instead, the applications are largely associated with proper approaches. The following are some typical approaches developed for antimicrobial applications.

Direct processing: In terms of some biocompatible polymers, the raw materials could be extracted from natural products, and the raw materials could be directly manufactured to produce designed products without losing structure integrity, functionality, and biocompatibility. For example, chitosan with a high content of amino groups could be manufactured into thin films with antimicrobial functions due to the positively charged amino groups [22]. However, most biocompatible polymers in the form of raw materials do not have antimicrobial functions. Therefore, other approaches are needed.

Functional modification: For most biocompatible polymers, functional modification is the best approach to equip materials with antimicrobial abilities. A traditional and simple method is to physically blend polymers with antimicrobial moieties to obtain the antimicrobial mixtures, on which polymers could serve as the substrate materials to enhance the antimicrobial effects [23]. However, recent research has been more focused on the modifications of the polymer's own structures, as these kinds of materials are more chemically stable. Notably, many biocompatible polymers have functional groups on their backbones or side chains. These groups are chemically reactive and could be transferred into an antimicrobial moiety. For example, alginic acid and cyclodextrin could be oxidized, and the hydroxyl groups were transferred into aldehyde groups, which present some practical antimicrobial effects [24, 25]. Another method is to use crosslinkers, such as chitosan or other amino-containing polymers; the amino groups could be linked with crosslinkers containing aldehyde groups [26], acyl chloride [27], or other groups so the antimicrobial moieties could be covalently bound onto the polymers.

Transformation: It was found that materials in different forms would present different characteristics. This clue could be useful for biocompatible polymers. Many researches indicated that the raw polymers could be made into some "new" forms, such as nanoparticles [28], hydrogels [29], and colloids [30]. With a different size scale, shape, and morphology, the material might present antimicrobial functions or become a good candidate for antimicrobial modifications.

#### **3.2 Representative antimicrobial applications of biocompatible polymers**

A general recognition of biocompatible polymers for antimicrobial applications is the low and controllable side effects on targeted recipients while eliminating microorganisms. But when it comes to different specific fields, biocompatible polymers could present unique advantages in various ways; the following are some leading examples.

Medical and clinical usages: medical products made of biocompatible polymers have been top-rated in the market. Biocompatible polymer-based products, such as bandages, blood bags, and gauze, could be smoothly applied to humans. While eliminating and inhibiting microorganisms, the products could cause less toxic or

hazardous chemicals and leave less hurtful or uncomfortable sensing. There would be fewer concerns about the residues from the products after usage.

Food industry: traditional polymer materials have always been used in the food industry (such as food containers, food packages, and food processing instruments), but in recent years, biocompatible polymers have become more favored. One major advantage of biocompatible polymers is less generating and releasing poisons onto food, enhancing food safety [31]. In addition, biocompatible polymers with antimicrobial functions could protect the food from microbe-induced spoilage and improve the food quality [32].

Environment engineering: in this field, biocompatible polymers were adequately used to produce biocides while killing microorganisms; they would not cause pollution or collateral damage to the surrounding environment. In addition, biodegradable products could be processed by natural decomposers, leaving fewer problems in the after-usage stage [33].

#### **4. Conclusion**

As a novel class of polymeric materials, biocompatible polymers have various unique and irreplaceable advantages for antimicrobial applications. However, the basic information of biocompatible polymers was not well recognized yet. This chapter provided a brief summary about biocompatible polymers and usages in antimicrobial applications, including a comprehensible and understandable definition, a list of advantages and some typical examples. Based on these, the achieved and potential approaches for antimicrobial applications were discussed. This chapter could serve as a "getting started" brochure to introduce the concept of using biocompatible polymers for antimicrobial applications to the public.

#### **Conflict of interest**

The author declared no conflict of interest.

#### **Author details**

Ruogu Tang University of Massachusetts, Lowell, Massachusetts, USA

\*Address all correspondence to<EMAIL_ADDRESS>
© 2024 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Dispatching Biocompatible Polymers toward Antimicrobial Applications DOI: http://dx.doi.org/10.5772/intechopen.114250*

#### **References**

[1] Duan S, Wu R, Xiong YH, Ren HM, Lei C, Zhao Y, et al. Multifunctional antimicrobial materials: From rational design to biomedical applications. Progress in Materials Science. 2022;**125**:100887. DOI: 10.1016/j. pmatsci.2021.100887

[2] Yudaev P, Chuev V, Klyukin B, Kuskov A, Mezhuev Y, Chistyakov E. Polymeric dental nanomaterials: Antimicrobial action. Polymers. 2022;**14**(5):864. DOI: 10.3390/polym14050864

[3] Jurenas D, Fraikin N, Goormaghtigh F, Melderen LV. Biology and evolution of bacterial toxin–antitoxin systems. Nature Reviews Microbiology. 2022;**20**:335-350. DOI: 10.1038/s41579-021-00661-1

[4] Lanckohr C, Bracht H. Antimicrobial stewardship. Current Opinion in Critical Care. 2022;**28**(5):551-556. DOI: 10.1097/ MCC.0000000000000967

[5] Siachalinga L, Mufwambi W, Lee IH. Impact of antimicrobial stewardship interventions to improve antibiotic prescribing for hospital inpatients in Africa: A systematic review and metaanalysis. Journal of Hospital Infection. 2022;**129**:124-143. DOI: 10.1016/j. jhin.2022.07.031

[6] Ahmed S, Sameen DE, Lu R, Li R, Dai J, Qin W, et al. Research progress on antimicrobial materials for food packaging. Critical Reviews in Food Science and Nutrition. 2022;**62**(11):3088-3102. DOI: 10.1080/10408398.2020.1863327

[7] Yang F, Wang A. Recent researches on antimicrobial nanocomposite and hybrid materials based on sepiolite and palygorskite. Applied Clay Science. 2022;**219**:106454. DOI: 10.1016/j. clay.2022.106454

[8] Sheridan M, Winters C, Zamboni F, Collins MN. Biomaterials: Antimicrobial surfaces in biomedical engineering and healthcare. Current Opinion in Biomedical Engineering. 2022;**22**:100373. DOI: 10.1016/j.cobme.2022.100373

[9] Haktaniyan M, Bradley M. Polymers showing intrinsic antimicrobial activity. Chemical Society Reviews. 2022;**51**:8584- 8611. DOI: 10.1039/D2CS00558A

[10] Coombs K, Rodriguez-Quijada C, Clevenger J, Sauer-Budge A. Current understanding of potential linkages between biocide tolerance and antibiotic cross-resistance. Microorganisms. 2023;**11**(8):2000. DOI: 10.3390/ microorganisms11082000

[11] Arzani F, dos Santos JHZ. Biocides and techniques for their encapsulation: A review. Soft Matter. 2022;**18**:5340-5358. DOI: 10.1039/D1SM01114F

[12] Weber F, Esmaeili N. Marine biofouling and the role of biocidal coatings in balancing environmental impacts. The Journal of Bioadhesion and Biofilm Research. 2023;**39**:661-681. DOI: 10.1080/08927014.2023.2246906

[13] Baranwal J, Barse B, Fais DGL, Kumar A. Biopolymer: A sustainable material for food and medical applications. Polymers. 2022;**4**(5):983. DOI: 10.3390/polym14050983

[14] Etale A, Onyianta AJ, Tuner SR, Eichhorn SJ. Cellulose: A review of water interactions, applications in composites, and water treatment. Chemical Reviews. 2023;**123**(5):2016-2048. DOI: 10.1021/acs. chemrev.2c00477

[15] Riseh RS, Vatankhah M, Hassanisaadi M, Kennedy JF. Chitosanbased nanocomposites as coatings and

packaging materials for the postharvest improvement of agricultural product: A review. Carbohydrate Polymers. 2023;**309**:120666. DOI: 10.1016/j. carbpol.2023.120666

[16] Saji S, Hebden A, Goswami P, Du C. A brief review on the development of alginate extraction orocess and its sustainability. Sustainability. 2022;**14**(9):5181. DOI: 10.3390/ su14095181

[17] Samir A, Ashour FH, Hakim AAA, Bassyouni M. Recent advances in biodegradable polymers for sustainable applications. npj Materials Degradation. 2022;**6**:68. DOI: 10.1038/ s41529-022-00277-7

[18] Tanpichai S, Boonmahitthisud A, Soykeabkaew N, Ongthip L. Review of the recent developments in all-cellulose nanocomposites: Properties and applications. Carbohydrate Polymers. 2022;**286**:119192. DOI: 10.1016/j. carbpol.2022.119192

[19] Zhou X, Zhang W, Zhao L, Gao S, Liu T, Yu D. Immobilization of lipase in chitosan-mesoporous silica material and pore size adjustment. International Journal of Biological Macromolecules. 2023;**235**:123789. DOI: 10.1016/j. ijbiomac.2023.123789

[20] Liu B, Zhang J, Guo H. Research progress of polyvinyl alcohol waterresistant film materials. Membranes. 2022;**12**(3):347. DOI: 10.3390/ membranes12030347

[21] Das A, Ringu T, Ghosh S, Pramanik N. A comprehensive review on recent advances in preparation, physicochemical characterization, and bioengineering applications of biopolymers. Polymer Bulletin. 2022;**80**:7247-7312. DOI: 10.1007/ s00289-022-04443-4

[22] Li D, Liu P, Hao F, Lv Y, Xiong W, Yan C, et al. Preparation and application of silver/chitosan-sepiolite materials with antimicrobial activities and low cytotoxicity. International Journal of Biological Macromolecules. 2022;**210**:337-349. DOI: 10.1016/j. ijbiomac.2022.05.015

[23] Lemke P, Junemann L, Moerschbacher BM. Synergistic antimicrobial activities of chitosan mixtures and chitosan-copper combinations. International Journal of Molecular Sciences. 2022;**23**(6):3345. DOI: 10.3390/ijms23063345

[24] Kusmono HP, Wildan MW. Oxidized cellulose nanocrystals from durian peel waste by ammonium persulfate oxidation. ACS Omega. 2023;**8**(33):30262-30272. DOI: 10.1021/ acsomega.3c03117

[25] Varaprasad K, Karthikeyan C, Yallapu MM, Sadiku R. The significance of biomacromolecule alginate for the 3D printing of hydrogels for biomedical applications. International Journal of Biological Macromolecules. 2022;**212**:561-578. DOI: 10.1016/j. ijbiomac.2022.05.157

[26] Pawariya V, De S, Dutta J. Chitosan-based Schiff bases: Promising materials for biomedical and industrial applications. Carbohydrate Polymers. 2024;**323**:121395. DOI: 10.1016/j. carbpol.2023.121395

[27] Li B, Han L, Ma J, Zhao M, Yang B, Xu M, et al. Synthesis of acylated derivatives of chitosan oligosaccharide and evaluation of their potential antifungal agents on *Fusarium oxysporum*. Carbohydrate Polymers. 2023;**314**:120955. DOI: 10.1016/j.carbpol.2023.120955

[28] Ahmady AR, Solouk A, Saber-Samandari SS, Akbari S, *Dispatching Biocompatible Polymers toward Antimicrobial Applications DOI: http://dx.doi.org/10.5772/intechopen.114250*

Ghanbari H, Brycki B. Capsaicin-loaded alginate nanoparticles embedded polycaprolactone-chitosan nanofibers as a controlled drug delivery nanoplatform for anticancer activity. Journal of Colloid and Interface Science. 2023;**638**:616-628. DOI: 10.1016/j.jcis.2023.01.139

[29] Liu W, Madry H, Cucchiarini. Application of alginate hydrogels for next-generation articular cartilage regeneration. International Journal of Biological Macromolecules. 2022;**23**(3):1147. DOI: 10.3390/ ijms23031147

[30] Peers S, Montembault A, Ladaviere C. Chitosan hydrogels incorporating colloids for sustained drug delivery. Carbohydrate Polymers. 2022;**275**:118689. DOI: 10.1016/j. carbpol.2021.118689

[31] Zhang M, Biesold G, Choi W, Yu J, Deng Y, Silvestre C, et al. Recent advances in polymers and polymer composites for food packaging. Materials Today. 2022;**5**:134-161. DOI: 10.1016/j. mattod.2022.01.022

[32] Min T, Zhou L, Sun X, Du H, Zhu, Z, Wen Y. Electrospun functional polymeric nanofibers for active food packaging: A review. Food Chemistry. 2022;**391**:133239. DOI: 10.1016/j. foodchem.2022.133239

[33] Dalton B, Bhagabati P, De Micco J, Padamati RB, O'Connor K. A review on biological synthesis of the biodegradable polymers polyhydroxyalkanoates and the development of multiple applications. Catalysts. 2022;**12**(3):319. DOI: 10.3390/ catal12030319

#### **Chapter 12**

## Antimicrobial Resistance and Virulence of *Escherichia coli* in the Purview of Public Health Monitoring

*Pankti Dhumal, Srashti Bajpai, Nachiket Garge, Agrima Bhatt, Fatema Rampurwala, Nishat Sulaimani, Shikha Gaikwad, Utpal Roy, Manasi Mishra and Rehan Deshmukh*

#### **Abstract**

Antimicrobial resistance (AMR) has emerged as a major threat to human, animal, and environment health in the developed as well as the developing nations. The usage of antibiotics outside of the prescribed parameters in both the healthcare and livestock sectors is directly tied to this resistance event. Additionally, several *Escherichia coli* strains harbor the AMR genes, which can be transferred to humans leading to public health problems. Depending on the type of antibiotics used, *E. coli* has evolved to prowess several resistance mechanisms.  Different resistance genes for each class of antibiotics are encoded by resistant *E. coli*. In conclusion, the current chapter ushers light on the molecular evolution of resistance and the regulatory genes contributing to the development of MDR in *E. coli.* Moreover, we have also discussed about the inappropriate practices of prescribing the antibiotics leading to intensifying the MDR in bacteria envisaging the implementation of rigorous guidelines for proper use of antibiotics in human beings.

**Keywords:** *E. coli*, antimicrobial resistance, genes, pathogenicity, virulence

#### **1. Introduction**

The primary concern that impacts public health in the twenty-first century is the resistance of pathogenic microorganisms to antibiotics [1]. This resistance is posing a more significant threat to public health worldwide [2]. Numerous classes of antibiotics can simultaneously render microorganisms resistant. The usage of antibiotics outside the prescribed parameters is linked to the emergence of antimicrobial resistance (AMR) [3]. The primary reasons fueling the egression of AMR in bacteria are its inappropriate use in agriculture, retail sectors like pharmacies, industries, and inefficacious prevention and control of infections in health care systems [4, 5].

The gastrointestinal tract of humans and animals is a reservoir of *Escherichia coli* which is a facultative anaerobe and usually, a harmless organism [6]. However, a few strains of *E. coli* have been known to cause infections in the gastrointestinal, urinary, and central nervous systems [7, 8]. Continuous exposure to antibiotics has shown to confer AMR in *E. coli* [9, 10]. Extended-spectrum β-lactamases (ESBLs) are plasmidmediated enzymes that hydrolyze β-lactam antibiotics, including penicillin, cephalosporin, and the monobactam aztreonam, resulting in multidrug-resistant (MDR) organisms. Bacteria exhibiting ESBLs have been linked with unsatisfactory treatment outcomes [11]. MDR *E. coli* produces ESBLs is an example of antibiotic resistance linked to the infections that can be fatal [12]. Such AMR strains of *E. coli* present in animals are significant in developing infections in humans [6, 13–19]. Studies showed that through the consumption of contaminated food and water, AMR strains of *E. coli* can be transmitted from the environment to humans [9]. Therefore, evaluating the widespread of such MDR *E. coli* in various habitats becomes very necessary for setting guidelines in animal and human health care domains [17–19].

To this end, we conducted a systematic review and meta-analysis to investigate the prevalence, molecular evolution and the regulatory genes contributing to AMR in *E. coli*. We have also discussed the factors contributing to the development of AMR and possible ways to tackle and mitigate multidrug resistant in *E. coli*.

#### **2. An overview of** *E. coli*

*E. coli* is a Gram-negative facultative anaerobe which belongs to *Enterobacteriaceae* family of the Gammaproteobacteria class [20]. It is commonly found as normal microflora in human and animal gut [21]. Sequence analysis of the *E. coli* genome was first reported in 1997. Since then, more than 4800 *E. coli* genomes have been sequenced [22, 23]. *E. coli* has been widely used to monitor AMR in livestock and food of animal origin. This is because *E. coli* can be found in the digestive tracts of warm-blooded animals [24]. Furthermore, various strains of *E. coli* are probable sources of the AMR gene, which can be transmitted to humans through various means [21, 25]. *E. coli* carried through feces or treatment of wastewater disposed of in waterways can pollute the environment [26]. The concentration of *E. coli* per gram of feces differs over the host species, usually reaching 107 –109 in humans and 104 –106 in domestic animals [27]. Shiga toxin-producing *E. coli* (STEC), entero-toxigenic *E. coli* (ETEC), enteropathogenic *E. coli* (EPEC), diffusely adherent *E. coli*, and entero-invasive *E. coli* are among the six intestinal pathotypes of *E. coli*. These bacteria are categorized according to their pathogenicity mechanisms and virulence traits [28–31]. *E. coli* is a major cause of enteric foodborne illness, bloodstream infections, intra-abdominal infections, and urinary tract infections (UTIs) in animals and humans [30, 31]. UTIs can also be caused by *Proteus* spp., *Staphylococcus saprophyticus*, *Klebsiella* spp., and other *Enterobacteriaceae* in addition to *E. coli*. However, *E. coli* is regarded as the most prevalent source of nosocomial and community-acquired UTI among bacteria that cause UTIs. Additionally, patients' history of UTI raises their risk of infection [22]. Antibiotics such as cotrimoxazole (trimethoprim/sulfamethoxazole), nitrofurantoin, ciprofloxacin, and ampicillin are used as therapeutic methods for treating UTIs [32, 33]. However, research on antibiotic resistance in *E. coli* isolates from the urinary tract have revealed a rise in resistance to several antibiotics, such as ampicillin and cotrimoxazole [32]. Bloodstream infections brought on by *E. coli* can result in morbidity, death, and other health issues [34]. These infections may raise hospital mortality rates and result in antibiotic resistance, which

*Antimicrobial Resistance and Virulence of* Escherichia coli *in the Purview of Public Health… DOI: http://dx.doi.org/10.5772/intechopen.108299*

lengthens hospital stays [35]. There have been reports of nosocomial bloodstream infections brought on by resistant bacteria, particularly in fragile and high-risk environments like critical care units and pediatric departments [36–38].

#### **3. Molecular evolution of AMR in** *E. coli*

AMR has been found to stem from human activities and indiscriminate or irrational uses of antibiotics. Various studies at genomic level pertaining to bacterial commensals and environmental bacteria revealed the presence of significant numbers of resistance determinants already embedded within their genomes not generated from any horizontal transmission and prior to the clinical introduction of antibiotics [39]. The molecular mechanism of emergence of antibiotic resistance and its spread, and persistence in bacterial population may be influenced by the interplay of several factors, such as (*a*) the mutation supply rate, (*b*) the level of resistance conferred by the resistance mechanism, (*c*) the fitness of the antibiotic-resistant mutant bacteria as a function of drug concentration, and (*d*) the strength of selective pressures [40]. Mutation supply rate is said to be determined by population sizes and mutation rates and horizontal gene transfer (HGT). Besides, in human hosts, the extent of genetic heterogeneity in a bacterial population is largely influenced by the mutation supply rate and the host-pathogen interaction [41]. The genetic perspective of AMR remains incomplete and impedes progress towards better patient outcomes and new therapeutics for resistant bacteria [42]. AMR surveillance drive indicated that drug-resistance to all the important antibiotics is in circulation among *E. coli* strains [43], including extended-spectrum β-lactams (ESBL), carbapenems, and more recently, plasmidmediated colistin resistance (mcr-1), particularly in food animals from Asian countries [44–46]. As inter- and intraspecies HGT and mobile genetic elements are factors for AMR [47], close genomic surveillance of AMR cargo within *E. coli* populations is need of the hour. The mobilization of cargo genes from a donor to a recipient site essentially provides a contribution to HGT [48]. Transposon7 (Tn7)-carrying cargo and as many as 50 Tn7-like transposons identified integrons with antibiotic resistance gene cassettes and heavy metal resistance genes [49].

Mutations are also responsible for the acquisition of amino acid substitutions leading to change of properties of protein structures to provide an altered function and a selective thriving advantage [50]. The newer introduction of more potent antibiotics into clinical settings could potentially trigger the evolution of antibiotic-ring hydrolyzing enzymes rendering powerful drug resistance. These enzymes achieve the ability towards drastically decimating the prowess of antibiotics by acquiring point mutations near or at their active sites that augment catalytic activity of β-lactamases [51]. Since enzymes are endowed with a limited capacity of taking fewer destabilizing mutations before unfolding or loosing activity, newer gain-of-function mutations at active sites often comes at the cost of stability of the enzymes [52, 53]. The alanine to valine (A77V) substitution is such a stabilizing (point) mutation that demonstrates the compensation for a loss in stability associated with substitutions that alter catalytic prowess. This compensation mechanism enables the enzymes to continuum of evolution, resulting in elevated resistance [54].

The unresolved teething problem here is to predict the probability of HGT leading to antibiotic resistance. In this regard, various related factors might play the roles in influencing the probability where particular gene would transfer into a relevant human pathogen have not been very well understood [55]. The global microbiome

might act as a potential source of resistance genes and genes for most classes of antibiotics have been found out in the human gut microbiome [ 56 ], and the soil microbiome [ 57 ].

 Quiet interestingly, it has been hypothesized that within the human microbiota, there has been frequent exchanges between bacteria of antibiotic resistance genes (ARGs), where the intestinal *E. coli* community acts as a melting pot for the HGT [ 58 , 59 ]. Antibiotic-sensitive bacterial populations developed drug-resistance either through HGTs or mutations and expression of resistance genes from other strains, either distantly or closely related ( **Figure 1** ). Detection of multiple mutational events can be selected in a step wisely to "train" resistance in a bacterium with successive mutations imparting additive effects [ 60 ]. As mentioned before, the human or animal gastrointestinal tract provides an ideal milieu where factors responsible for the upheaval of antibiotic resistance genes and spreading across resident bacterial populations are present [ 61 ]. The presence of high cell density is certainly one of the major factors. Additionally, spread of resistant infections is encouraged by selection followed by the innate ability for gene transfer through a variety of different mechanisms [ 62 ]. As bacterial cells get exposed to an anti-bacterial drug at sub minimum inhibitory concentrations (MIC), bacteria can thrive to gain resistance under selective pressure [ 63 ]. Recent work in this line demonstrated that there may be different resistance mechanisms induced by sub-inhibitory antibiotic exposure compared to lethal selection [ 64 ]. In *Salmonella enterica* , sub-inhibitory concentrations of streptomycin selected for high-level resistance through multiple-negligible-effect resistance

#### **Figure 1.**

 *E. coli virulence factors can be encoded by plasmids (e.g., heat-labile enterotoxin (LT) of ETEC and invasion factors of EIEC), several mobile genetic elements, including transposons (Tn) (e.g., heat stable enterotoxin (ST) of ETEC), pathogenicity islands (PAIs)- e.g., the locus of enterocyte effacement (LEE) of EPEC/EHEC and PAIs I and II of UPEC and bacteriophage (e.g., Shiga toxin of EHEC). Deletions, additions, and other genetic rearrangements may result in evolution of wild type to pathogenic E. coli strains responsible for causing dysentery (EIEC), diarrhea (EPEC, EAEC, EHEC, DAEC), urinary tract infections (UPEC) and hemolytic uremic syndrome (EHEC). UTI, urinary tract infection; HUS, hemolytic uremic syndrome. The figure was created using www.BioRender.com .*

*Antimicrobial Resistance and Virulence of* Escherichia coli *in the Purview of Public Health… DOI: http://dx.doi.org/10.5772/intechopen.108299*

mutations, whereas lethal selection led to specific target mutations [65]. However, resistant mutants derived from sub-inhibitory fluoroquinolone exposure may not always induce causative changes in the target quinolone resistance determining region (QRDR) [65]. Experimental demonstrations also suggest that alterations in drug efflux systems are a major mechanism under pressure from sub-lethal ciprofloxacin exposure in case of *E. coli* [66]. Concentration-dependent responses are also mooted as anthropic drivers of resistance. These phenomena go beyond changes in resistance genes since different drug concentrations may alter the community behavior in response to drugs [67]. Reports are rife to indicate that for the manifestations of virulence and AMR, *E. coli* are armed with mobile genetic elements such as plasmids, genomic islands (PAIs and resistance islands [REIs]), or transposons [68]. The ability of mobile genetic elements is acquired at a higher rate [69] rendering *E. coli* ST131 an ideal subject to examine the co-evolution of AMR and virulence [70]. In such *E. coli* ST131 population, chromosomal mutations in quinolone-resistance determining regions (QRDR) of gyrA and parC, conferring high-level fluoroquinolone resistance were reported in the phylogenetic subclades, C1, and C2 [71, 72].

#### **4. Regulatory genes in MDR** *E. coli*

The emerging MDR of *E. coli* to several antibiotics is a significant problem leading to the development of pan resistant species and is the major bottleneck in the treatment of diseases. Development of resistance in bacterial pathogens is an adaptive trait and is acquired mainly either by HGT of mobile genetic elements carrying resistance or de novo mutations. *E. coli* strains producing ESBL enzymes like Cefotaximase-Munich (CTX-M) β-lactamases are emerging with higher frequency in hospital and healthcare-associated setups leading to community-onset urinary tract and bloodstream infections [73]. In many Gram-negative bacteria, chromosomal loci specifying global regulatory proteins that control MDR have been characterized in bacteria including *E. coli, Klebsiella pneumoniae,* and other *Enterobacteriaceae*, and *Neisseria gonorrhoeae*, *Bacillus subtilis,* and *S. aureus* [74]. In most instances, the regulatory proteins function as activators or repressors of transcription and contain either a single DNA-binding domain or two separate regions responsible for DNA binding and interacting with small-molecule substrates [75]. The potential genes responsible for encoding MDR in *E. coli* are listed in **Table 1**.

ESBLs hydrolyze and cause resistance to oxyimino-cephalosporins (e.g., cefotaxime, ceftazidime, ceftriaxone, cefuroxime and cefepime), monobactams (e.g., aztreonam), aminoglycosides and co-trimoxazole. ESBLs have evolved due to point mutations around the active site of β-lactamase [90]. Reports have described *ampC* genes present on the plasmid can be potentially transferred among *E. coli*, *Klebsiella* spp., and *Salmonella* spp. [76]. The ESBL/*ampC* genes are often surrounded by mobile genetic elements (e.g., transposons, IS elements or class 1 integrons), that mediate transmission, and involved in the expression of the genes IS*Ecp1* and IS*CR1* [77]. Gene encoding for CTX-M β-lactamases, *bla*CTX-M is encoded by narrow hostrange incompatibility type plasmids (i.e.IncFI, IncFII, IncHI2 and IncI) or the broad host-range incompatibility type plasmids (i.e. IncN, IncP-1-a, IncL/M and IncA/C) and is associated with highly efficient mobile genetic element IS*Ecp1* [78–80]. Insertion sequence IS*Ecp1* belongs to the chromosomes of the environmental bacteria called *Kluyvera spp*. [91]. Plasmids encoding for CTX-M-15 also carry additional antibiotic resistance genes—*bla*OXA-1, *bla*TEM-1, *tetA*, *aac(6*′*)-Ib-cr* and *aac(3)-II*, often

*Antimicrobial Resistance and Virulence of* Escherichia coli *in the Purview of Public Health… DOI: http://dx.doi.org/10.5772/intechopen.108299*

#### **Table 1.**

*List of genes encoding multiple drug resistance in E. coli.*

contained within class 1 integrons [79, 85]. ESBL-producing Enterobacteriaceae are now significantly emerging in the community. The prototype *cat* genes (*cat I*, *cat II*, *cat III*, *cat A*, *cat B*, etc.) encode for chloramphenicol acetyltransferases (CAT) which can inactivate chloramphenicol as well as thiamphenicol, azidamfenicol, and florfenicol [86]. CATs are detected in a wide variety of bacteria including *E. coli*. *cat I* was originally identified as part of transposon Tn9 in *E. coli* and has been detected in several resistance plasmids of Gram-negative bacteria [92]. Various groups of *cat* genes are often located on small multicopy plasmids also carrying streptomycin resistance or macrolide resistance gene [93]. Export of chloramphenicol and florfenicol out of the bacterial cell via specific membrane transporters or multidrug transporters is another mechanism of resistance shown by microorganisms. Genes encoding for such transporters/efflux proteins (E-1 to E-8) are found in several clinically relevant and environmental bacteria [94]. A number of genes [*pp-flo*, *cmlA*-like, *floSt*, *flo*, or *floR*] grouped in E-3 mediate combined resistance to chloramphenicol and florfenicol. These genes show high homology [96–100%] and their protein products also show 88–100% identity. Often these genes coding for CATs and specific transporters are located on conjugative plasmids, gene cassettes and associated with transposon elements. This facilitates their fast and efficient dissemination among bacteria of same or different species and genera.

Sulphonamide resistance genes *sul1* and *sul2* encoding for dihydropteroate synthase enzymes have been known since decades [83]. A third sulphonamide resistance gene, *sul3*, was identified from porcine *E. coli* [95]. *Mef* (B) gene encoding for macrolide-efflux pump which mediates resistance to macrolides was found located in the vicinity of *sul3* in porcine *E. coli* [84]. In previous reports, mef (A), a homolog of mef (B) was found to be present only in Gram positive bacteria being encoded on a transposable element. However, the emergence of new resistance genes is *E. coli* isolates reflects on the positive selection pressure for sulphonamide and macrolide resistance despite its restricted use is many countries.

In *E. coli*, the MarA is the protein that regulates the expression of many chromosomal genes (the Mar regulon), including those specifying an MDR efflux pump and other proteins (e.g., porins) that mediate antibiotic susceptibility [96]. In *E. coli*, over expression of this MarA leads to reduced expression of the OmpF porin [97] as well as increased expression of the multidrug efflux pump AcrAB [88], thereby conferring resistance to a large number of antimicrobial agents. Resistance-nodulation-division (RND) pumps in *E. coli*, TolC plays the roles of proton antiporters and confer resistance to many important antibiotics, tetracyclines, chloramphenicol, some β-lactams, vancomycin, and fluoroquinolones [98, 99].

The most common ESBL gene in *E. coli* isolates of human origin is *blaCTX-M-15* and ST-131 clone and are implicated in AMR dissemination [81]. The increase in carbapenems (CPE) is mainly associated with the extensive dissemination of acquired CPE. CPE encoding genes are usually located in mobile genetic elements (MGEs), implying in the emergence of MDR and XDR strains [100]. Extraintestinal pathogenic *E. coli* (ExPEC) bacteria are the group of pathogenic strains that have the uncanny ability to cause severe ailments, such as urinary tract infections (UTIs) and bacteremia [101]. The emergence of MDR in *E. coli* has already become a global concern, with particular emphasis on *E. coli* sequence type (ST) 131 reported in UTIs. *CTX*-*M* Drug resistance phenomenon is mediated by extended-spectrum β-lactamases (ESBLs), mainly of the CTX-M family, particularly CTX-M-15 and 14, and less frequently of the SHV and OXA families [102]. CTX-M-15 first detected in *E. coli* isolates from India has become one of the most widely spread CTX-M β-lactamase worldwide. Association of *bla*CTX-M-15 with the insertion element IS*Ecp1* plays an important role in its expression and mobilization [89]. From UTI patients, *E. coli* and *K. pneumoniae* with CTX-M type ESBLs were isolated. These enzymes are carried by *E. coli* with multidrug resistance phenotype [103]. MDR expressed by CTX-M-producing isolates from the community is often associated with the presence of multiple ESBLs genes, as well as aminoglycoside and quinolone resistance genes, thereby limiting the choice of effective antimicrobial drugs [104]. As mentioned earlier, that evolution in antibiotic resistance enzymes could rely on the acquisition of stabilizing mutations. A77V substitution is one such mutation that was detected in CTX-M extended-spectrum β-lactamases (ESBLs) from a good number of clinical isolates, pointing towards the significance of the β-lactamase evolution in antibiotic resistance in gram-negative bacteria [105].

Resistance to polypeptide antimicrobials like Colistin (CST) have also been reported in *E. coli* isolated from diseased pigs [106]. Most of such isolates also show resistance to sulfonamides, trimethoprim, tetracycline, ampicillin, or chloramphenicol. Acquired resistance to CST is known to be because of lipopolysaccharide (LPS) modifications—the addition of 2-aminoethanol, 4-amino-4-deoxy-L-arabinose (L-Ara4N) or phosphoethanolamine (PetN), or other strategies such as efflux pump and capsule formation. Mutations in chromosomal genes *mgrB*, *mgrR*, *etk* play a

*Antimicrobial Resistance and Virulence of* Escherichia coli *in the Purview of Public Health… DOI: http://dx.doi.org/10.5772/intechopen.108299*

role in resistance to CST in *E. coli* [ 87 ]. Resistance to colistin could also be due to mutations in chromosomal genes or it may be acquired. *Colistin-resistance in E. coli* is plasmid-mediated colistin resistance via the acquisition of the *MCR-1* gene that can propagate efficiently and imparts resistance to other bacteria [ 107 ]. *MCR-1* protein enables the addition of a phosphor-ethanolamine group to lipid A. This modification imparts a charge alteration on LPS, which in turn reduces the binding affinity of colistin towards LPS [ 82 ].

#### **5. AMR in** *E. coli* **: contributory factors and its mitigation**

MDR *E. coli* spreads over time and stop responding to the drugs which makes it difficult to control the infections caused by them. This increases the risk of spreading diseases, developing major illnesses, and their transmission from one person to other. Hence, uttermost attention is required to mitigate MDR as it plays a significant role in the accomplishment of the sustainable development goals (SDGs). There are numerous factors ( **Figure 2** ) which contribute to AMR in *E. coli* listed below.

#### **5.1 Overuse, misuse, and inappropriate prescribing of antibiotic or antimicrobials (AM)**

 It has been established that the main factors contributing to medication fatalities include taking antibiotics or AM specifically when not needed or ingesting it more than approved doses and concentrations. For example, any antibiotic used to treat a bacterial infection will kill susceptible bacteria; if appropriately targeted, the pathogenic microorganism will also be eradicated; nevertheless, the antibiotic will also

kill any sensitive microbiota in the patient along with the infecting bacteria [108]. If the anatomical region has robust bacteria, whether they come from the healthy microbiota or the pathogenic germs that are being treated, they will proliferate and finally take control. As a result, bacteria are evolving quickly in response to selective antibiotic pressure, which is a significant feature in the growth of multidrugresistant strains [108]. According to Balbina et al. [109], kanamycin, gentamicin, ciprofloxacin, fluoroquinolones, rifampicin, sulfisoxazole, cefoxitin, ampicillin, and fosfomycin are the most frequently prescribed antibiotics for treating *E. coli* related infections. However, ciprofloxacin is one of the drugs that are most likely to be prescribed incorrectly [109, 110]. Globally, the percentage of human antibiotic use was 65 percent between 2000 and 2015, however, if current trends are not changed, it is predicted that animal antibiotic use will increase by 11.5 percent by 2030, which will contribute to the emergence of additional MDR *E. coli* strains [111]. In the year 2021, Browne and his coworkers [112] reported that the global consumption rate of antibiotics was 14.3 well-defined daily doses (DDD) per thousand people per day in 2018 (40.2 [372–437] billion DDD), up 46% from 9.8 (92–105) DDD per 1000 per day in 2000 [112]. *E. coli* and other strains of the *Enterobacteriaceae* family are becoming gradually resistant to antibiotics due to an intensification in the appearance of membrane proteins that impel the drugs out of the cell, especially in topoisomerases, alterations in the target enzymes, and the presence of mobile genetic elements (plasmids, transposons, and integrons) that support in the lateral transmission of resistance genes in prokaryotes [113–115].

#### **5.2 Use of non-antibiotic antimicrobials (NAAM)**

Compared to antibiotics, a lot more non-antibiotic antimicrobial (NAAM) compounds are utilized as biocidal agents. As a result, the environment has significant residual levels of NAAM compounds in the soil, water, and air. One typical biocidal agent, triclosan (TCS), is utilized in more than 2000 different items, including hand washing liquids and toothpaste [116]. According to reports, triclosan causes *E. coli* to develop heritable multi-drug resistance [116]. 1.1 × 105 to 4.2 × 105 kg of TCS is released annually by wastewater treatment plants (WWTPs) in the US alone [117].

#### **5.3 Lack of sanitary facilities and clean water**

Water is a vital resource for all living things. All species, including humans, have microbes living inside and on them. According to Collignon et al. [118], environmental variable quantity such as advanced deficient technologies in waste management, availability of non-potable drinking water, overcrowded housing, and poor cleanliness may stimulate the growth and expansion of resistant bacteria globally. The unique capability of *E. coli* in colonization of the animal gut has given additional evolutionary benefit in acquiring resistance attributes from other bacteria in its environment [118]. Antibiotics are frequently used in livestock or food animals to combat and prevent diseases as well as to promote growth, which causes AMR to develop and raises the possibility of antibiotic-resistant bacterial colonization [118]. These bacteria may be spread while handling the animals, slaughtering them, or processing the meat. Additionally, fruits and vegetables can be infected with fecal material directly from the animals or through irrigation water that has been contaminated with animal or human waste [116, 118]. More than 1000 unique antibiotic-resistant genes have been identified in the human gut microbiota, and the transfer of these features between gut

*Antimicrobial Resistance and Virulence of* Escherichia coli *in the Purview of Public Health… DOI: http://dx.doi.org/10.5772/intechopen.108299*

commensals is prevalent, according to one study done by Hu et al. [119]. In underdeveloped regions of the world, antibiotic-resistant strains of *E. coli* are detected at the time of birth, at the highest rates in human feces. Studies in China [114] have stated that ESBL genes in *E. coli* are transmitted by conjugation that enters in food chain directly or indirectly which facilitates explaining why ESBL-producing *E. coli* are so prevalent in feces around the world.

#### **5.4 Insufficient infection prevention and control promote the spread of microbes**

Since many sick individuals congregate in hospitals and healthcare centers and antibiotic consumption is prevalent, resistant strains of bacteria are selected for and disseminated throughout these settings, making them important hotspots for most bugs [120]. Additionally, inadequate hygiene habits may make it easier for resistant microbes to transmit from patients or visitors to doctors, nurses, and other healthcare professionals through their hands or clothing [121]. Other risk factors include inadequate sanitation, inappropriate cleaning of the facilities, and dirty equipment. Few isolation rooms and crowded wards further encourage spread [120, 121]. Poor approaches towards reasonably priced medicines, vaccines, and diagnostics are the most defined factors for showing the resistance to antimicrobial treatment case of *E. coli*, which is understudied in many underdeveloped nations [122]. Patients face substantial health risks when doctors attempt to treat infections about which they are ignorant. Medical facilities should set up systems to guarantee the identification and management of a range of bacterial diseases without prescribing incorrect medications [122]. Over time, incorrect medicine prescriptions have led to several patients' deaths and even more severe health issues [120–122] With the right diagnosis and care, patients can reduce their risk of developing medication resistance-related issues. In addition, the ongoing development of strategies for the cultivation of bacteria using a variety of culture media and conditions a process known as culturomics is crucial for the identification of antibiotic resistance genes (ARGs) and the comprehension of the cellular mechanisms underlying the association between ARGs and resistance phenotypes in various bacteria [123]. One of the major issues with building a consolidated database is establishing a clear strategy and making it into a regular practice of environmental-quality monitoring [124].

#### **5.5 Lack of enforcement of legislation**

By 2050, it is predicted that antibiotic resistance will have killed more people than cancer today. According to Naghavi's analysis in the published report in the year 2022, there would be 12.7 million deaths caused by bacterial AMR in 2022, out of an expected 495 million deaths linked to bacterial AMR in 2019 [125]. Death by thirdgeneration cephalosporin-resistant *E. coli* was found to be the most prevalent [125]. Therefore, the lawmakers must keep an eye on how often antibiotics or other biocidal chemicals are used. The sum of all the efforts, including legislation, studies of community attitudes and knowledge regarding antibiotics, educational initiatives, and follow-up policies, will undoubtedly contribute not only to reducing antibiotic misuse in the short term but also to fostering appropriate knowledge among society members regarding the advantages of using antibiotics properly. These actions will be crucial to lowering patient demand for antibiotics and preventing detrimental effects on public health and the economy. Although the creation of stringent legislation like "Schedule H1" is crucial, it might only be one component of the solution. Delaying these reforms emphasizes the risky game we are playing with the health of people and animals, which might have terrible repercussions**.**

#### **5.6 The absence of new antibiotic discoveries**

It can be crucial in treating a variety of bacterial illnesses. Some bacterial strains are still evolving and developing medication resistance. Although few new antibiotics are being introduced to the market, they could be useful in attempting to close the gap.

#### **6. Conclusions and future horizons**

A persistent global concern in the field of medicine is microbial resistance to antibiotics. One among numerous bacteria is *E. coli*, which is frequently found in humans and animals. Finding novel antibiotic substitutes that are more potent in treating pathogenic infections, particularly the ones caused due to *E. coli* is required since there are less options for antibiotics that are sensitive to this bacterium. *E. coli* and other Gram-negative bacteria have evolved to develop different mechanism to encounter any antimicrobials. Moreover, different studies have showed higher prevalence of ESBL antibiotic resistance and MDR *E. coli* strains in animals than in humans. Besides, the stability and spread of colistin resistance in multiple reservoirs are an emerging public health threat worldwide. Dissemination of antibiotic resistance genes via transmissible plasmids, integrons and transposons to several environmental reservoirs like wastewater treatment plants (WWTPs), agriculture fields, animal manure, and hospital-associated setups is an emerging threat to environmental and public health safety. Our meta-analysis suggests that comprehensive surveilling of hospitalassociated diseases, careful monitoring of hospital waste management procedures, supervising antibiotic use in animals, tracking and evaluating antibiotics susceptibility trends, and the development of trustworthy antibiotic strategies may facilitate more corrective actions for the inhibition and control of *E. coli* infections in various parts of the world and practical guidelines can be put in place for proper prescription of antibiotics in humans to ensure better public health monitoring.

#### **Acknowledgements**

RD would like to thank Dr. Vishwanath Karad MIT-World Peace University for providing Students' Innovation Seed Fund to PD, SB, NG, AB, FR and NS. SG and MM are grateful to the institute for providing the facilities and infrastructure.

#### **Conflict of interest**

The authors declare no conflict of interest. All authors have contributed to the chapter and agreed for its publication.

*Antimicrobial Resistance and Virulence of* Escherichia coli *in the Purview of Public Health… DOI: http://dx.doi.org/10.5772/intechopen.108299*

#### **Author details**

Pankti Dhumal1 , Srashti Bajpai1 , Nachiket Garge1 , Agrima Bhatt1 , Fatema Rampurwala1 , Nishat Sulaimani1 , Shikha Gaikwad1 , Utpal Roy2 , Manasi Mishra1 and Rehan Deshmukh1 \*

1 Faculty of Science, School of Biology, Dr. Vishwanath Karad MIT World Peace University, Pune, India

2 Department of Biological Sciences, Birla Institute of Technology and Science-K.K. Birla Goa Campus, Goa, India

\*Address all correspondence to<EMAIL_ADDRESS>
© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **References**

[1] Irrgang A, Hammerl JA, Falgenhauer L, Guiral E, Schmoger S, Imirzalioglu C, et al. Diversity of CTX-M-1- producing *E. coli* from German food samples and genetic diversity of the blaCTX-M-1 region on IncI1 ST3 plasmids. Veterinary Microbiology. 2018;**221**:98-104

[2] World Health Organization. Antimicrobial Resistance: Global Report on Surveillance. Geneva, Switzerland: WHO.int; 2014. https://doi. org/9789241564748

[3] Ramírez-Castillo FY, Moreno-Flores AC, Avelar-González FJ, Márquez-Díaz F, Harel J, Guerrero-Barrera AL. An evaluation of multidrug-resistant *Escherichia coli* isolates in urinary tract infections from Aguascalientes, Mexico: Cross- sectional study. Annals of Clinical Microbiology and Antimicrobials. 2018;**17**(1):1-3

[4] Alonso CA, Zarazaga M, Ben Sallem R, Jouini A, Ben Slama K, Torres C. Antibiotic resistance in *Escherichia coli* in husbandry animals: The African perspective. Letters in Applied Microbiology. 2017;**64**(5):318-334

[5] Van Boeckel TP, Brower C, Gilbert M, Grenfell BT, Levin SA, Robinson TP, et al. Global trends in antimicrobial use in food animals. Proceedings of the National Academy of Sciences. 2015;**112**(18):5649-5654

[6] Agunos A, Léger D, Carson C. Review of antimicrobial therapy of selected bacterial diseases in broiler chickens in Canada. The Canadian Veterinary Journal. 2012;**53**(12):1289

[7] Landoni MF, Albarellos G. The use of antimicrobial agents in broiler chickens. The Veterinary Journal. 2015;**205**(1):21-27

[8] Page SW, Gautier P. Use of antimicrobial agents in livestock. Revue Scientifique et Technique-OIE. 2012;**31**(1):145

[9] Chen Y, Liu Z, Zhang Y, Zhang Z, Lei L, Xia Z. Increasing prevalence of ESBL-producing multidrug resistance *Escherichia coli* from diseased pets in Beijing, China from 2012 to 2017. Frontiers in Microbiology. 2019;**10**:2852

[10] Effendi MH, Cicilia R, Rahmahani J, Tyasningsih W. Public awareness for antimicrobial resistance from *Escherichia coli* isolated from beef sold on several wet market in Surabaya, Indonesia. Indian Journal of Public Health Research and Development. 2020;**11**(9):295-300

[11] Baron S, Jouy E, Larvor E, Eono F, Bougeard S, Kempf I. Impact of thirdgeneration-cephalosporin administration in hatcheries on fecal *Escherichia coli* antimicrobial resistance in broilers and layers. Antimicrobial Agents and Chemotherapy. 2014;**58**(9):5428-5434

[12] Chantziaras I, Boyen F, Callens B, Dewulf J. Correlation between veterinary antimicrobial use and antimicrobial resistance in food-producing animals: A report on seven countries. Journal of Antimicrobial Chemotherapy. 2014;**69**(3):827-834

[13] Peralta-Sánchez JM, Martín-Platero AM, Ariza-Romero JJ, Rabelo-Ruiz M, Zurita-González MJ, Baños A, et al. Egg production in poultry farming is improved by probiotic bacteria. Frontiers in Microbiology. 2019;**10**:1042

[14] Nhung NT, Chansiripornchai N, Carrique-Mas JJ. Antimicrobial resistance in bacterial poultry pathogens: *Antimicrobial Resistance and Virulence of* Escherichia coli *in the Purview of Public Health… DOI: http://dx.doi.org/10.5772/intechopen.108299*

A review. Frontiers in Veterinary Science. 2017;**4**:126

[15] Chah KF, Ugwu IC, Okpala A, Adamu KY, Alonso CA, Ceballos S, et al. Detection and molecular characterisation of extended-spectrum β- lactamaseproducing enteric bacteria from pigs and chickens in Nsukka, Nigeria. Journal of Global Antimicrobial Resistance. 2018;**15**:36-40

[16] Falgenhauer L, Imirzalioglu C, Oppong K, Akenten CW, Hogan B, Krumkamp R, et al. Detection and characterization of ESBL-producing *Escherichia coli* from humans and poultry in Ghana. Frontiers in Microbiology. 2019;**9**:3358

[17] Martínez-Vázquez AV, Rivera-Sánchez G, Lira-Méndez K, Reyes-López MÁ, Bocanegra-García V. Prevalence, antimicrobial resistance and virulence genes of *Escherichia coli* isolated from retail meat in Tamaulipas, Mexico. Journal of Global Antimicrobial Resistance. 2018;**14**:266-272

[18] Rahman SU, Ahmad S, Khan I. Incidence of ESBL-producing-*Escherichia coli* in poultry farm environment and retail poultry meat. Pakistan Veterinary Journal. 2018;**39**:116-120

[19] Casella T, Nogueira MC, Saras E, Haenni M, Madec JY. High prevalence of ESBLs in retail chicken meat despite reduced use of antimicrobials in chicken production, France. International Journal of Food Microbiology. 2017;**257**:271-275

[20] Jang J, Hur HG, Sadowsky MJ, Byappanahalli MN, Yan T, Ishii S. Environmental *Escherichia coli*: Ecology and public health implications—A review. Journal of Applied Microbiology. 2017;**123**(3):570-581

[21] Kheiri R, Akhtari L. Antimicrobial resistance and integron gene cassette

arrays in commensal *Escherichia coli* from human and animal sources in IRI. Gut Pathogens. 2016;**8**(1):1-0

[22] Jan NA, Meshram SU, Kulkarni A. Plasmid profile analysis of multidrug resistant *E. coli* isolated from UTI patients of Nagpur City, India. Romanian. Biotechnological Letters. 2009;**14**(5):4635-4640

[23] Tenaillon O, Barrick JE, Ribeck N, Deatherage DE, Blanchard JL, Dasgupta A, et al. Tempo and mode of genome evolution in a 50,000-generation experiment. Nature. 2016;**536**(7615): 165-170

[24] Nhung NT, Cuong NV, Thwaites G, Carrique-Mas J. Antimicrobial usage and antimicrobial resistance in animal production in Southeast Asia: A review. Antibiotics. 2016;**5**(4):37

[25] Overdevest I, Willemsen I, Rijnsburger M, Eustace A, Xu L, Hawkey P, et al. Extended-spectrum β-lactamase genes of *Escherichia coli* in chicken meat and humans, The Netherlands. Emerging Infectious Diseases. 2011;**17**(7):1216

[26] Berthe T, Ratajczak M, Clermont O, Denamur E, Petit F. Evidence for coexistence of distinct *Escherichia coli* populations in various aquatic environments and their survival in estuary water. Applied and Environmental Microbiology. 2013;**79**(15):4684-4693

[27] Tenaillon O, Skurnik D, Picard B, Denamur E. The population genetics of commensal *Escherichia coli*. Nature Reviews Microbiology. 2010;**8**(3): 207-217

[28] Issa AH, Almayah AA. New virulence factor of Normal Flora *E. coli*. Systematic Reviews in Pharmacy. 2020;**11**(2): 71-76

[29] Kai A, Konishi N, Obata H. Diarrheagenic *Escherichia coli.* Nihon rinsho. Japanese Journal of Clinical Medicine. 2010;**68**:203-207

[30] Kaper JB, Nataro JP, Mobley HLT. Pathogenic E. coli. Nature Reviews/ Microbiology. 2004;**2**:123-140

[31] Alanazi MQ, Alqahtani FY, Aleanizy FS. An evaluation of *E. coli* in urinary tract infection in emergency department at KAMC in Riyadh, Saudi Arabia: Retrospective study. Annals of Clinical Microbiology and Antimicrobials. 2018;**17**(1):1-7

[32] Foxman B. The epidemiology of urinary tract infection. Nature Reviews Urology. 2010;**7**(12):653-660

[33] Poolman JT, Wacker M. Extraintestinal pathogenic Escherichia coli, a common human pathogen: challenges for vaccine development and progress in the field. The Journal of Infectious Diseases. 1 Jan 2016;**213**(6):6-13

[34] Naylor NR, Pouwels KB, Hope R, Green N, Henderson KL, Knight GM, et al. The health and cost burden of antibiotic resistant and susceptible *Escherichia coli* bacteraemia in the English hospital setting: A national retrospective cohort study. PLoS One. 2019;**14**(9):e0221944

[35] Saied T, Elkholy A, Hafez SF, Basim H, Wasfy MO, El-Shoubary W, et al. Antimicrobial resistance in pathogens causing nosocomial bloodstream infections in university hospitals in Egypt. American Journal of Infection Control. 2011;**39**(9): e61-e65

[36] Tansarli GS, Poulikakos P, Kapaskelis A, Falagas ME. Proportion of extended- spectrum β-lactamase

(ESBL)-producing isolates among Enterobacteriaceae in Africa: Evaluation of the evidence—Systematic review. Journal of Antimicrobial Chemotherapy. 2014;**69**(5):1177-1184

[37] Ma F, Xu S, Tang Z, Li Z, Zhang L. Use of antimicrobials in food animals and impact of transmission of antimicrobial resistance on humans. Biosafety and Health. 2021;**3**(01):32-38

[38] Petrillo F, Folliero V, Santella B, Franci G, Foglia F, Trotta MC, et al. Prevalence and antibiotic resistance patterns of ocular bacterial strains isolated from pediatric patients in University Hospital Of Campania "Luigi Vanvitelli," Naples, Italy. International Journal of Microbiology. 2020:6

[39] Cafini F, Romero VM, Morikawa K. Mechanisms of horizontal gene transfer. The Rise of Virulence and Antibiotic Resistance in Staphylococcus Aureus. 2017;**61**:61-79

[40] Dunny GA, Yuhasz MI, Ehrenfeld EL. Genetic and physiological analysis of conjugation in *Streptococcus faecalis*. Journal of Bacteriology. 1982;**151**(2):855-859

[41] Worby CJ, Lipsitch M, Hanage WP. Within-host bacterial diversity hinders accurate reconstruction of transmission networks from genomic distance data. PLoS Computational Biology. 2014;**10**(3):e1003549

[42] Munita JM, Arias CA. Mechanisms of antibiotic resistance. Microbiology Spectrum. 2016;**4**(2):4-2

[43] Paitan Y. Current trends in antimicrobial resistance of *Escherichia coli*. *Escherichia coli*, a Versatile Pathogen. 2018;**416**:181-211

*Antimicrobial Resistance and Virulence of* Escherichia coli *in the Purview of Public Health… DOI: http://dx.doi.org/10.5772/intechopen.108299*

[44] Zhao Q, Li Y, Tian Y, Shen Y, Wang S, Zhang Y. Clinical impact of colistin banning in food animal on mcr-1-Positive enterobacteriaceae in patients from Beijing, China, 2009-2019: A long-term longitudinal observational study. Frontiers in Microbiology. 2022;**13**:826624

[45] Newton-Foot M, Snyman Y, Maloba MR, Whitelaw AC. Plasmidmediated mcr-1 colistin resistance in Escherichia coli and Klebsiella spp. clinical isolates from the Western Cape region of South Africa. Antimicrobial Resistance & Infection Control. Dec 2017;**6**(1):1-7

[46] Sun J, Zeng X, Li XP, Liao XP, Liu YH, Lin J. Plasmid-mediated colistin resistance in animals: Current status and future directions. Animal Health Research Reviews. 2017;**18**(2):136-152

[47] Partridge SR, Kwong SM, Firth N, Jensen SO. Mobile genetic elements associated with antimicrobial resistance. Clinical Microbiology Reviews. 2018;**31**(4):e00088-e00017

[48] Peters JE, Fricker AD, Kapili BJ, Petassi MT. Heteromeric transposase elements: Generators of genomic islands across diverse bacteria. Molecular Microbiology. 2014;**93**(6):1084-1092

[49] Parks AR, Peters JE. Transposon Tn 7 is widespread in diverse bacteria and forms genomic islands. Journal of Bacteriology. 2007;**189**(5):2170-2173

[50] Romero PA, Arnold FH. Exploring protein fitness landscapes by directed evolution. Nature Reviews Molecular Cell Biology. 2009;**10**(12):866-876

[51] Bush K. Proliferation and significance of clinically relevant β-lactamases. Annals of the New York Academy of Sciences. 2013;**1277**(1):84-90

[52] Bloom JD, Labthavikul ST, Otey CR, Arnold FH. Protein stability promotes evolvability. Proceedings of the National Academy of Sciences. 2006;**103**(15):5869-5874

[53] Orencia MC, Yoon JS, Ness JE, Stemmer WP, Stevens RC. Predicting the emergence of antibiotic resistance by directed evolution and structural analysis. Nature Structural Biology. 2001;**8**(3):238-242

[54] Patel MP, Fryszczyn BG, Palzkill T. Characterization of the global stabilizing substitution A77V and its role in the evolution of CTX-M β-lactamases. Antimicrobial Agents and Chemotherapy. 2015;**59**(11):6741-6748

[55] Hughes D, Andersson DI. Environmental and genetic modulation of the phenotypic expression of antibiotic resistance. FEMS Microbiology Reviews. 2017;**41**(3):374-391

[56] Sommer MO, Dantas G, Church GM. Functional characterization of the antibiotic resistance reservoir in the human microflora. Science. 2009;**325**(5944):1128-1131

[57] D'Costa VM, McGrann KM, Hughes DW, Wright GD. Sampling the antibiotic resistome. Science. 2006;**311**:374-377. Google Scholar There is no corresponding record for this reference

[58] Trobos M, Lester CH, Olsen JE, Frimodt-Møller N, Hammerum AM. Natural transfer of sulphonamide and ampicillin resistance between *Escherichia coli* residing in the human intestine. Journal of Antimicrobial Chemotherapy. 2009;**63**(1):80-86

[59] Porse A, Gumpert H, Kubicek-Sutherland JZ, Karami N, Adlerberth I, Wold AE, et al. Genome dynamics

of *Escherichia coli* during antibiotic treatment: Transfer, loss, and persistence of genetic elements in situ of the infant gut. Frontiers in Cellular and Infection Microbiology. 2017;**7**:126

[60] Alekshun MN, Levy SB. Molecular mechanisms of antibacterial multidrug resistance. Cell. 2007;**128**(6):1037-1050

[61] Huddleston JR. Horizontal gene transfer in the human gastrointestinal tract: Potential spread of antibiotic resistance genes. Infection and Drug Resistance. 2014;**7**:167

[62] Bennett PM. Plasmid encoded antibiotic resistance: Acquisition and transfer of antibiotic resistance genes in bacteria. British Journal of Pharmacology. 2008;**153**(S1):S347-S357

[63] Andersson DI, Hughes D. Microbiological effects of sublethal levels of antibiotics. Nature Reviews Microbiology. 2014;**12**(7):465-478

[64] Ramsay KA, McTavish SM, Wardell SJ, Lamont IL. The effects of sub-inhibitory antibiotic concentrations on *Pseudomonas aeruginosa*: Reduced susceptibility due to mutations. Frontiers in Microbiology. 2021;**20**(12):789550

[65] Wistrand-Yuen E, Knopp M, Hjort K, Koskiniemi S, Berg OG, Andersson DI. Evolution of high-level resistance during low-level antibiotic exposure. Nature Communications. 2018;**9**(1):1-2

[66] Li XZ, Plésiat P, Nikaido H. The challenge of efflux-mediated antibiotic resistance in gram-negative bacteria. Clinical Microbiology Reviews. 2015;**28**(2):337-418

[67] Wang Q, Sun FJ, Liu Y, Xiong LR, Xie LL, Xia PY. Enhancement of biofilm formation by subinhibitory concentrations of macrolides in

icaADBC-positive and-negative clinical isolates of *Staphylococcus epidermidis*. Antimicrobial Agents and Chemotherapy. 2010;**54**(6):2707-2711

[68] Kaper JB, Nataro JP, Mobley HL. Pathogenic *Escherichia coli*. Nature Reviews Microbiology. 2004;**2**(2):123-140

[69] Decano AG, Downing T. An *Escherichia coli* ST131 pangenome atlas reveals population structure and evolution across 4,071 isolates. Scientific Reports. 2019;**9**(1):1-3

[70] Totsika M, Beatson SA, Sarkar S, Phan MD, Petty NK, Bachmann N, et al. Insights into a multidrug resistant Escherichia coli pathogen of the globally disseminated ST131 lineage: Genome analysis and virulence mechanisms. PLoS One. 2011;**6**(10):e26578

[71] Biggel M, Moons P, Nguyen MN, Goossens H, Van Puyvelde S. Convergence of virulence and antimicrobial resistance in increasingly prevalent *Escherichia coli* ST131 papGII+ sub lineages. Communications Biology. 2022;**5**(1):1-0

[72] Piddock LJ, Hall MC, Walters RN. Phenotypic characterization of quinolone-resistant mutants of Enterobacteriaceae selected from wild type, gyrA type and multiplyresistant (marA) type strains. Journal of Antimicrobial Chemotherapy. 1991;**28**(2):185-198

[73] Nicolas-Chanoine MH, Blanco J, Leflon-Guibout V, Demarty R, Alonso MP, Caniça MM, et al. Intercontinental emergence of *Escherichia coli* clone O25: H4-ST131 producing CTX-M-15. Journal of Antimicrobial Chemotherapy. 2008;**61**(2):273-281

[74] Grkovic S, Brown MH, Skurray RA. Regulation of bacterial drug export

*Antimicrobial Resistance and Virulence of* Escherichia coli *in the Purview of Public Health… DOI: http://dx.doi.org/10.5772/intechopen.108299*

systems. Microbiology and Molecular Biology Reviews. 2002;**66**(4):671-701

[75] Schumacher MA, Brennan RG. Structural mechanisms of multidrug recognition and regulation by bacterial multidrug transcription factors. Molecular Microbiology. 2002;**45**(4):885-893

[76] Jacoby GA, Munoz-Price LS. The new β-lactamases. New England Journal of Medicine. 2005;**352**(4):380-391

[77] Poirel L, Naas T, Nordmann P. Genetic support of extended-spectrum β-lactamases. Clinical Microbiology and Infection. 2008;**14**:75-81

[78] Poirel L, Menuteau O, Agoli N, Cattoen C, Nordmann P. Outbreak of extended-spectrum β-lactamase VEB-1-producing isolates of *Acinetobacter baumannii* in a French hospital. Journal of Clinical Microbiology. 2003;**41**(8):3542-3547

[79] Carattoli A. Resistance plasmid families in *Enterobacteriaceae*. Antimicrobial Agents and Chemotherapy. 2009;**53**(6):2227-2238

[80] Peirano G, Mulvey GL, Armstrong GD, Pitout JD. Virulence potential and adherence properties of *Escherichia coli* that produce CTX-M and NDM β-lactamases. Journal of Medical Microbiology. 2013;**62**(4):525-530

[81] Xia J, Sun J, Li L, Fang LX, Deng H, Yang RS, et al. First report of the IncI1/ ST898 conjugative plasmid carrying rmtE2 16S rRNA methyltransferase gene in *Escherichia coli*. Antimicrobial Agents and Chemotherapy. 2015;**59**(12):7921-7922

[82] Aghapour Z, Gholizadeh P, Ganbarov K, Bialvaei AZ, Mahmood SS, Tanomand A, et al. Molecular mechanisms related to colistin resistance in Enterobacteriaceae. Infection and Drug Resistance. 2019;**12**:965

[83] Sköld O. Resistance to trimethoprim and sulfonamides. Veterinary Research. 2001;**32**(3-4):261-273

[84] Liu J, Keelan P, Bennett PM, Enne VI. Characterization of a novel macrolide efflux gene, mef (B), found linked to sul3 in porcine *Escherichia coli*. Journal of Antimicrobial Chemotherapy. 2009;**63**(3):423-426

[85] Boyd DA, Tyler S, Christianson S, McGeer A, Muller MP, Willey BM, et al. Complete nucleotide sequence of a 92-kilobase plasmid harboring the CTX-M-15 extended-spectrum betalactamase involved in an outbreak in long-term-care facilities in Toronto. Canada. Antimicrobial Agents and Chemotherapy. 2004;**48**(10):3758-3764

[86] Van Hoek AH, Mevius D, Guerra B, Mullany P, Roberts AP, Aarts HJ. Acquired antibiotic resistance genes: An overview. Frontiers in Microbiology. 2011;**2**:203

[87] Olaitan AO, Morand S, Rolain JM. Mechanisms of polymyxin resistance: Acquired and intrinsic resistance in bacteria. Frontiers in Microbiology. 2014;**5**:643

[88] Okusu H, Ma D, Nikaido H. AcrAB efflux pump plays a major role in the antibiotic resistance phenotype of *Escherichia coli* multiple-antibioticresistance (Mar) mutants. Journal of Bacteriology. 1996;**178**(1):306-308

[89] Karim A, Poirel L, Nagarajan S, Nordmann P. Plasmid-mediated extended-spectrum β-lactamase (CTX-M-3 like) from India and gene association with insertion sequence

IS Ecp1. FEMS Microbiology Letters. 2001;**201**(2):237-241

[90] Paterson DL, Bonomo RA. Extended-spectrum β-lactamases: A clinical update. Clinical Microbiology Reviews. 2005;**18**(4):657-686

[91] Lartigue MF, Poirel L, Aubert D, Nordmann P. In vitro analysis of IS Ecp1B-mediated mobilization of naturally occurring β-lactamase gene Bla CTX-M of Kluyvera ascorbata. Antimicrobial Agents and Chemotherapy. 2006;**50**(4):1282-1286

[92] Alton NK, Vapnek D. Transcription and translation of R-plasmid 538-1 DNA: Effects of mercury induction and analysis of polypeptides coded for by the r-determinant region. Plasmid. 1979;**2**(3):366-376

[93] Schwarz S, Kehrenberg C, Doublet B, Cloeckaert A. Molecular basis of bacterial resistance to chloramphenicol and florfenicol. FEMS Microbiology Reviews. 2004;**28**(5):519-542

[94] Butaye P, Devriese LA, Haesebrouck F. Antimicrobial growth promoters used in animal feed: Effects of less well-known antibiotics on grampositive bacteria. Clinical Microbiology Reviews. 2003;**16**(2):175-188

[95] Perreten V, Boerlin P. A new sulphonamide resistance gene (sul3) in *Escherichia coli* is widespread in the pig population of Switzerland. Antimicrobial Agents and Chemotherapy. 2003;**47**(3):1169-1172

[96] Barbosa TM, Levy SB. Differential expression of over 60 chromosomal genes in *Escherichia coli* by constitutive expression of MarA. Journal of Bacteriology. 2000;**182**(12):3467-3474

[97] Cohen SP, McMurry LM, Levy SB. marA locus causes decreased expression of OmpF porin in multipleantibiotic-resistant (mar) mutants of *Escherichia coli*. Journal of Bacteriology. 1988;**170**(12):5416-5422

[98] Fajardo A, Martinez-Martin N, Mercadillo M, Galán JC, Ghysels B, Matthijs S, et al. The neglected intrinsic resistome of bacterial pathogens. PLoS One. 2008;**3**(2):e1619

[99] Cox G, Wright GD. Intrinsic antibiotic resistance: Mechanisms, origins, challenges and solutions. International Journal of Medical Microbiology. 2013;**303**(6-7):287-292

[100] Ramsamy Y, Mlisana KP, Amoako DG, Abia AL, Ismail A, Allam M, et al. Mobile genetic elementsmediated Enterobacterales-associated carbapenemase antibiotic resistance genes propagation between the environment and humans: A One Health South African study. Science of the Total Environment. 2022;**806**:150641

[101] Poolman JT, Wacker M. Extraintestinal pathogenic Escherichia coli, a common human pathogen: challenges for vaccine development and progress in the field. The Journal of Infectious Diseases. 2016;**213**(1):6-13

[102] Knox JR. Extended-spectrum and inhibitor-resistant TEMtype beta-lactamases: Mutations, specificity, and three-dimensional structure. Antimicrobial Agents and Chemotherapy. 1995;**39**(12):2593-2601

[103] Martinez P, Garzón D, Mattar S. CTX-M-producing *Escherichia coli* and *Klebsiella pneumoniae* isolated from community-acquired urinary tract infections in Valledupar, Colombia. The Brazilian Journal of Infectious Diseases. 2012;**16**(5):420-425

[104] Saidani M, Messadi L, Mefteh J, Chaouechi A, Soudani A, Selmi R, et al. *Antimicrobial Resistance and Virulence of* Escherichia coli *in the Purview of Public Health… DOI: http://dx.doi.org/10.5772/intechopen.108299*

Various Inc-type plasmids and lineages of *Escherichia coli* and *Klebsiella pneumoniae* spreading blaCTX-M-15, blaCTX-M-1 and mcr-1 genes in camels in Tunisia. Journal of Global Antimicrobial Resistance. 2019;**19**:280-283

[105] Novais Â, Cantón R, Coque TM, Moya A, Baquero F, Galán JC. Mutational events in cefotaximase extendedspectrum β-lactamases of the CTX-M-1 cluster involved in ceftazidime resistance. Antimicrobial Agents and Chemotherapy. 2008;**52**(7):2377-2382

[106] Delannoy S, Le Devendec L, Jouy E, Fach P, Drider D, Kempf I. Characterization of colistin-resistant *Escherichia coli* isolated from diseased pigs in France. Frontiers in Microbiology. 2017;**8**:2278

[107] Newton-Foot M, Snyman Y, Maloba MR, Whitelaw AC. Plasmidmediated mcr-1 colistin resistance in Escherichia coli and Klebsiella spp. clinical isolates from the Western Cape region of South Africa. Antimicrobial Resistance & Infection Control. 2017;**6**(1):1-7

[108] Kolář M, Urbanek K, Látal T. Antibiotic selective pressure and development of bacterial resistance. International Journal of Antimicrobial Agents. 2001;**17**(5):357-363

[109] Balbin MM, Hull D, Guest C, Nichols L, Dunn R, Thakur S. Antimicrobial resistance and virulence factors profile of salmonella spp. and *Escherichia coli* isolated from different environments exposed to anthropogenic activity. Journal of Global Antimicrobial Resistance. 2020;**22**:578-583

[110] Shively NR, Buehrle DJ, Clancy CJ, Decker BK. Prevalence of inappropriate antibiotic prescribing in primary care clinics within a veterans affairs health care system. Antimicrobial

Agents and Chemotherapy. 2018;**62**(8):e00337-e00318

[111] Tiseo K, Huber L, Gilbert M, Robinson TP, Van Boeckel TP. Global trends in antimicrobial use in food animals from 2017 to 2030. Antibiotics. 2020;**9**(12):918

[112] Browne AJ, Chipeta MG, Haines-Woodhouse G, Kumaran EP, Hamadani BH, Zaraa S, et al. Global antibiotic consumption and usage in humans, 2000-18: A spatial modelling study. The Lancet Planetary Health. 2021;**5**(12):e893-e904

[113] Schneiders T, Amyes SG, Levy SB. Role of AcrR and RamA in fluoroquinolone resistance in clinical *Klebsiella pneumoniae* isolates from Singapore. Antimicrobial Agents and Chemotherapy. 2003;**47**(9):2831-2837

[114] Wang H, Dzink-Fox JL, Chen M, Levy SB. Genetic characterization of highly fluoroquinolone-resistant clinical *Escherichia coli* strains from China: Role of acrR mutations. Antimicrobial Agents and Chemotherapy. 2001;**45**(5):1515-1521

[115] Piddock LJ. Mechanisms of fluoroquinolone resistance: An update 1994-1998. Drugs. 1999;**58**(2):11-18

[116] Lu J, Wang Y, Li J, Mao L, Nguyen SH, Duarte T, et al. Triclosan at environmentally relevant concentrations promotes horizontal transfer of multidrug resistance genes within and across bacterial genera. Environment International. 2018;**121**:1217-1226

[117] Dann AB, Hontela A. Triclosan: Environmental exposure, toxicity and mechanisms of action. Journal of Applied Toxicology. 2011;**31**(4):285-311

[118] Collignon P, Beggs JJ, Walsh TR, Gandra S, Laxminarayan R.

Anthropological and socioeconomic factors contributing to global antimicrobial resistance: A univariate and multivariable analysis. The Lancet Planetary Health. 2018;**2**(9):e398-e405

[119] Hu Y, Yang X, Lu N, Zhu B. The abundance of antibiotic resistance genes in human guts has correlation to the consumption of antibiotics in animal. Gut Microbes. 2014;**5**(2):245-249

[120] Clements A, Halton K, Graves N, Pettitt A, Morton A, Looke D, et al. Overcrowding and understaffing in modern health-care systems: Key determinants in meticillin-resistant *Staphylococcus aureus* transmission. The Lancet Infectious Diseases. 2008;**8**(7):427-434

[121] Kumarasamy KK, Toleman MA, Walsh TR, Bagaria J, Butt F, Balakrishnan R, et al. Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: A molecular, biological, and epidemiological study. The Lancet Infectious Diseases. 2010;**10**(9):597-602

[122] Singh BR. ESKAPE pathogens in animals and their antimicrobial drug resistance pattern. Journal of Dairy, Veterinary & Animal Research. 2018;7(3):1-0

[123] Lagier JC, Armougom F, Million M, Hugon P, Pagnier I, Robert C, et al. Microbial culturomics: Paradigm shift in the human gut microbiome study. Clinical Microbiology and Infection. 2012;**18**(12):1185-1193

[124] Berendonk TU, Manaia CM, Merlin C, Fatta-Kassinos D, Cytryn E, Walsh F, et al. Tackling antibiotic resistance: The environmental framework. Nature Reviews Microbiology. 2015;**13**(5):310-317

[125] Naghavi M, Murray CJ, Ikuta KS, Mestrovic T, Swetschinski L, Sartorius B. Global burden of antimicrobial resistance: Essential pieces of a global puzzle–Authors' reply. The Lancet. 2022;**399**(10344):2349-2350

#### **Chapter 13**

## Phylotypes and Pathotypes of Diarrheagenic *Escherichia coli* of Gastroenteritis

*Hadi Sajid Abdulabbas, Noor Al-Khafaji, Suhad Y. Abed, Hussein Al-Dahmoshi and Huda Najh Al-Baroody*

#### **Abstract**

*Escherichia coli* responsible for wide range of common bacterial infections, the frequent one is gastroenteritis. Bacterial gastroenteritis mainly attributed to diarrheagenic *E. coli* and accompanied by diarrhea and vomiting. Actually pathogenic *E. coli* can be classified according to the site of infection whether it be within intestine (called intestinal *pathogenic E. coli* InPEC) or cause infection outside intestine (called extraintestinal pathogenic *E. coli* ExPEC*)*. They are assigned to 4 main phylogenetic groups: InPEC include A and B1 while ExPEC have B2 and D groups. Seven Pathotypes have been assigned: Enteropathogenic *E. coli* (EPEC), enterotoxigenic *E. coli* (ETEC), enterohemorrhagic (Shiga-toxin producing *E. coli* (EHEC/STEC), enteroaggregative *E. coli* (EAEC), diffusely adherent *E. coli* (DAEC), enteroinvasive *E. coli* (EIEC) and adherent invasive *E. coli* (AIEC). The patho-phylotyping of diarrheagenic *E. coli* interaction along with antibiotic resistance and biofilm formation capacity may be valuable insight to know real threat of this pathogen and this is tried to be covered with this chapter. The results revealed that the among DEC, EPEC and ETEC were assigned in high rate to B1 followed by A, B2, D, E, C and F while EAEC show different assignment: D followed by B2, A, B1, C, E and F. The other DEC pathotypes showed different styles.

**Keywords:** Pathotypes, phylotypes, *E. coli*, antibiotic resistance, biofilm, InPEC, ExPEC

#### **1. Introduction**

*Escherichia coli* is commensal enterobacteial member emerging as opportunistic pathogen causing numerous of intestinal and extraintestinal infections. Concern Pathotypes of *E. coli*, they divided in to two main groups: Extraintestinal pathogenic *E. coli* (ExPEC) and intestinal pathogenic *E. coli* (InPEC). ExPEC cause range of infections for Human being outside intestine like meningitides as in neonatal meningitis *E. coli* (NMEC), urinary tract infection as in uropathogenic *E. coli* (UPEC) and sepsis-associated *E. coli* (SEPEC) [1–3]. InPEC includes 8 Pathotypes of diarrheagenic *E. coli* (DEC) including: enteropathogenic *E. coli* (EPEC), enterotoxigenic

#### **Table 1.**

*Genotypic profile for 6 phylogenetic groups and 5 clades of* E. coli.

*E. coli* (ETEC), enteroaggregative *E. coli* (EAEC), diffusely adherent *E. coli* (DAEC), enteroinvasive *E. coli* (EIEC), enterohemorrhagic *E. coli* (EHEC) (also known as Shiga-toxin-producing *E. coli* (STEC) or, verotoxin-producing *E. coli* (VTEC), necrotoxic *E. coli* (NTEC) and adherent-invasive *E. coli* (AIEC) [4–6]. Two systems named as Clermont triplex and quadruplex PCR were used to assign the *E. coli* isolates to seven phylogroups (A, B1, B2, C, D, E and F) and five clades (clade I, II, III, IV and V) according to presence/absence of six genes: chuA, yjaA, TspE4.C2, arpA, *arpAgpEh and trpA(*trpAgpC) as mentioned in **Table 1** [7–9].

#### **2. Diarrheagenic** *E. coli* **(DEC) phylotypes**

Diarrheagenic *E. coli* (DEC) is a term referring to 8 or 9 pathotypes of *E. coli* causing diarrhea in travelers. It accounting for up to 40% of infantile and children diarrhea worldwide [10] and responsible for most of diarrheal outbreaks globally [11]. All DEC Pathotypes categorized according to molecular contents of some virulence genes: *eae* and *bfpA* for EPEC [12]; *st1a*, *st1b* and *ltb1* for ETEC; *aggR* for EAEC; *stx1* and *stx2* for EHEC/STEC; *ipaH* for EIEC; *daaD* for DAEC [13]. Many studies revealed that, the most prevalent diarrheagenic *E. coli* were ETEC, EPEC, EAEC, AIEC, EHEC/STEC and DAEC [14–17]. Concern phylogroups of EPEC, the results gathered from 18 studies for 433 EPEC isolates revealed that: B1 compile (39.3%), A(23.3%), B2(18.2%), D(8.5%), (6.2%, 3.5% and 0.9%) for E, C and F phylogroups respectively (**Table 2**) [18–35]. ETEC phylogroups includes: B1(43.3%), A(28.2%), D(14%), B2(13.4%), C(0.6%), E(0.6%) and F(0.0%) (**Table 3**) [18, 23–25, 27, 28, 30, 31, 33, 35–37]. Concern EAEC phylogroups the results showed that, among 399 EAEC isolates they assigned for D(32.8%), B2(30.5%)A(19.2), B1(16.2%), C(0.8%), E(0.5%) and F(0.0%) (**Table 4**) [18, 24, 25, 27, 28, 30–32, 35, 37–40]. **Table 5** showed the phylogroups of EIEC, EHEC/STEC, AIEC and DAEC pathotypes. EIEC phylogroups were A, B1, E, D, B2 and C compile (37.6%, 21.2%, 17.7%, 12.9%, 8.2% and 2.4% respectively). EHEC/STEC phylogroups were C, B1, B2, A, E, D and Fcompile (21.5%, 20.1, 18.7%, 16.2%, 13.4%, 7.7% and 2.4% respectively). AIEC phylogroups were B2, D, A and B1 compile (51.3%, 25.2%, 18.3% and 5.2%

#### *Phylotypes and Pathotypes of Diarrheagenic* Escherichia coli *of Gastroenteritis DOI: http://dx.doi.org/10.5772/intechopen.109860*

#### **Table 2.**

*ExPEC and InPEC phylogroups of EPEC isolates.*

#### **Table 3.**

*ExPEC and InPEC phylogroups of ETEC isolates.*

#### **Table 4.**

*ExPEC and InPEC phylogroups of EAEC isolates.*

*Phylotypes and Pathotypes of Diarrheagenic* Escherichia coli *of Gastroenteritis DOI: http://dx.doi.org/10.5772/intechopen.109860*

**Table 5.**

*ExPEC and InPEC phylogroups of EIEC, EHEC/STEC AIEC and DAEC isolates.*

respectively) while DAEC phylogroups were A (5/11), B2(3/11) and B1(3/11) [18, 24–28, 33, 36, 37, 39–41, 43–47].

#### **3. Uropathogenic** *E. coli* **(UPEC) phylotypes**

Uropathogenic *E. coli* (UPEC) is the most common ExPEC causing UTI, one of the most frequent bacterial infections with significant morbidity worldwide, which

#### **Table 6.**

*Distribution of phylogenetic groups among UPEC isolates in Iraq.*

may convey a sets of virulence factors and belonging to diverse phylogenetic groups [48]. UPEC as ExPEC must be belong to either B2 or D phylogroups. The B2 include 2 phylosubgroups: B22 (*chuA+, yjaA+, TspE4.C2-, arpA-, arpAgpE-, TrpAgpC-*) and B23 (*chuA+, yjaA+, TspE4.C2+, arpA-, arpAgpE-, TrpAgpC-*) while D have 2 phylosubgroups: D1 (*chuA+, yjaA-, TspE4.C2-, arpA+, arpAgpE-, TrpAgpC-*) and D2 (*chuA+, yjaA-, TspE4.C2-, arpA+, arpAgpE-, TrpAgpC+*) [49, 50].

Many Iraqi studies studied the assignment of UPEC to phylogroups. Since 2017–2022 only 11 Iraqi studies with valuable no. of UPEC isolates analyze 1119 isolates and assigning them to 7 phylogroups and they are found that: 566(50.6%) for B2, 241(21.5%) for D, 208(18.6%) for A, 60(5.4%) for B1, 23(2.1%) for C, 11(1%) for E and 10(0.8%) for F (**Table 6**) [51–61]. Concern Iranian studies, 19 study were conducted including 2313 UPEC isolates assigned to phylogroups as follow: 1190(51.4%) for B2, 481(20.8%) for D, 399(17.3%) for A, 190(8.2%) for B1, 26(1.1%) for C, 23(1%) for E and 4(0.2%) for F (**Table 7**) [25, 62–79]. Ten studies from Egypt deal with 892 UPEC isolates stated that, B2 compile (38.1%), D (15.2%), A (23.2%), B1 (14.3%), C (3.4%), E (2.8%) and F (2.9%) as mentioned in **Table 8** [25, 42, 49, 54, 76, 80–84]. Nine Turkish studies showed that, among 901 isolated of UPEC, (39.3%) were B2,

#### **Table 7.**

*Distribution of phylogenetic groups among UPEC isolates in Iran.*

#### *Phylotypes and Pathotypes of Diarrheagenic* Escherichia coli *of Gastroenteritis DOI: http://dx.doi.org/10.5772/intechopen.109860*

#### **Table 8.**

*Distribution of phylogenetic groups among UPEC isolates in Egypt.*

#### **Table 9.**

*Distribution of phylogenetic groups among UPEC isolates in Turkey.*

(31.5%) for D, (2.4%) for A, (6.4%) for B1, (0.1%) for C, (2.1%) for E and (0.1%) for F phylogroups (**Table 9**) [85–93].

#### **4. Conclusion**

Data analysis of current study revealed that the among DEC, EPEC and ETEC were assigned in high rate to B1 followed by A, B2, D, E, C and F while EAEC show different assignment: D followed by B2, A, B1, C, E and F. The other DEC pathotypes showed different styles.

### **Conflict of interest**

There is no 'conflict of interest' for this work.

### **Author details**

Hadi Sajid Abdulabbas1 , Noor Al-Khafaji2 , Suhad Y. Abed3 , Hussein Al-Dahmoshi2 \* and Huda Najh Al-Baroody4

1 Faculty of Dentistry, University of Al-Ameed, Karbala, Iraq

2 Biology Department, College of Science, University of Babylon, Hilla, Iraq

3 Department of Biology, College of Science, Mustansiriyah University, Baghdad, Iraq

4 Department of Microbiology, College of Medicine, University of Al-Ameed, Karbala, Iraq

\*Address all correspondence to<EMAIL_ADDRESS>
© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Phylotypes and Pathotypes of Diarrheagenic* Escherichia coli *of Gastroenteritis DOI: http://dx.doi.org/10.5772/intechopen.109860*

#### **References**

[1] Denamur E, Clermont O, Bonacorsi S, Gordon D. The population genetics of pathogenic *Escherichia coli*. Nature Reviews. Microbiology. 2021;**19**(1):37-54. DOI: 10.1038/s41579-020-0416-x

[2] Connolly JPR, Turner NCA, Hallam JC, Rimbi PT, Flett T, McCormack MJ, et al. d-serine induces distinct transcriptomes in diverse Escherichia coli pathotypes. Microbiology (Reading). 2021;**167**(10):1-13. DOI: 10.1099/mic.0.001093

[3] Becker S, Saidenberg A, AHM v V, Stegger M, Johannesen TB, Semmler T, et al. Genomic analysis of the zoonotic ST73 lineage containing avian and human extraintestinal pathogenic *Escherichia coli* (ExPEC). Veterinary Microbiology. 2022;**267**:109372. DOI: 10.1016/j.vetmic.2022.109372

[4] Martinez-Medina M. Special issue: Pathogenic Escherichia coli: Infections and therapies. Antibiotics. 2021;**10**(2):112. DOI: 10.3390/ antibiotics10020112

[5] Angulo-Zamudio UA, Gutiérrez-Jiménez J, Monroy-Higuera L, Flores-Villaseñor H, Leon-Sicairos N, Velazquez-Roman J, et al. Nondiarrheagenic and diarrheagenic E. coli carrying supplementary virulence genes (SVG) are associated with diarrhea in children from Mexico. Microbial Pathogenesis. 2021;**157**:104994. DOI: 10.1016/j.micpath.2021.104994

[6] Suleiman K, Kolo I, Mohammed SSD, Magaji YG. Bacterial diarrhea among infants in developing countries: An overview of diarrheagenic Escherichia coli (DEC). Gadau Journal of Pure and Allied Science. 2022;**1**(1):73-81. DOI: 10.54117/gjpas.v1i1.10

[7] Clermont O, Christenson JK, Denamur E, Gordon DM. The Clermont Escherichia coli phylo-typing method revisited: Improvement of specificity and detection of new phylo-groups. Environmental Microbiology Reports. 2013;**5**(1):58-65. DOI: 10.1111/1758-2229.12019

[8] Clermont O, Gordon D, Denamur E. Guide to the various phylogenetic classification schemes for Escherichia coli and the correspondence among schemes. Microbiology (Reading). 2015;**161**(5):980-988. DOI: 10.1099/mic.0.000063

[9] Bujňáková D, Karahutová L, Kmeť V. Escherichia coli specific virulence-gene markers analysis for quality control of ovine cheese in Slovakia. Microorganisms. 2021;**9**(9):1808. DOI: 10.3390/microorganisms9091808

[10] Miliwebsky E, Schelotto F, Varela G, Luz D, Chinen I, Piazza RM. Human diarrheal infections: Diagnosis of diarrheagenic *Escherichia coli* pathotypes. In: *Escherichia coli* in the Americas. Berlin: Springer; 2016. pp. 343-369

[11] Croxen MA, Law RJ, Scholz R, Keeney KM, Wlodarska M, Finlay BB. Recent advances in understanding enteric pathogenic Escherichia coli. Clinical Microbiology Reviews. 2013;**26**(4):822- 880. DOI: 10.1128/CMR.00022-13

[12] Kotloff KL, Nataro JP, Blackwelder WC, Nasrin D, Farag TH, Panchalingam S, et al. Burden and aetiology of diarrhoeal disease in infants and young children in developing countries (the global enteric multicenter study, GEMS): A prospective, case-control study. Lancet. 2013;**382**(9888):209-222. DOI: 10.1016/ S0140-6736(13)60844-2

[13] Guion CE, Ochoa TJ, Walker CM, Barletta F, Cleary TG. Detection of diarrheagenic Escherichia coli by use of melting-curve analysis and real-time multiplex PCR. Journal of Clinical Microbiology. 2008;**46**(5):1752-1757

[14] Asadi Z, Ghanbarpour R, Kalantar-Neyestanaki D, Alizade H. Determination of extended-spectrum β-lactamase producing and hybrid pathotypes of Escherichia coli isolates from diarrheic samples. Gene Reports. 2022;**27**:101583. DOI: 10.1016/j. genrep.2022.101583

[15] Moyo SJ, Maselle SY, Matee MI, Langeland N, Mylvaganam H. Identification of diarrheagenic Escherichia coli isolated from infants and children in Dar es Salaam, Tanzania. BMC Infectious Diseases. 2007;**7**(1):92. DOI: 10.1186/1471-2334-7-92

[16] Franzolin MR, Alves RC, Keller R, Gomes TA, Beutin L, Barreto ML, et al. Prevalence of diarrheagenic Escherichia coli in children with diarrhea in Salvador, Bahia, Brazil. Memórias do Instituto Oswaldo Cruz. 2005;**100**(4):359-363. DOI: 10.1590/ s0074-02762005000400004

[17] Abdlla YA, Al-Sanjary RA. The molecular identification of diarrheagenic Escherichia coli (DEC) isolated from meat and meat products. Iraqi Journal of Veterinary Sciences. 2022;**37**(1):9-15. DOI: 10.33899/ijvs.2022.133244.2192

[18] Alfinete NW, Bolukaoto JY, Heine L, Potgieter N, Barnard TG. Virulence and phylogenetic analysis of enteric pathogenic Escherichia coli isolated from children with diarrhoea in South Africa. International Journal of Infectious Diseases. 2022;**114**:226-232. DOI: 10.1016/j.ijid.2021.11.017

[19] Otero-García A, Pérez-Vargas AK, Eslava-Campos C, Licona-Moreno D,

León LA, Pérez-Soto G, et al. Molecular genotyping of Escherichia coli o111 isolated from children with diarrhea in rural and urban areas. Europub Journal of Health Research. 2022;**3**(3):421-435. DOI: 10.54747/ejhrv3n3-009

[20] Singh T, Das S, Ramachandran VG, Wani S, Shah D, Maroof KA, et al. Distribution of Integrons and phylogenetic groups among Enteropathogenic Escherichia coli isolates from children <5 years of age in Delhi, India. Frontiers in Microbiology. 2017;**8**:561. DOI: 10.3389/ fmicb.2017.00561

[21] Jafari E, Mostaan S, Bouzari S. Characterization of antimicrobial susceptibility, extended-spectrum β-lactamase genes and phylogenetic groups of enteropathogenic Escherichia coli isolated from patients with diarrhea. Osong Public Health and Research Perspectives. 2020;**11**(5):327-333. DOI: 10.24171/j.phrp.2<IP_ADDRESS>

[22] Memariani M, Najar-Peerayeh S, Zahraei Salehi TZ. Multi locus vntR (MLVA) typing and detection of the OI-122 pathogenicity island in typical and atypical enteropathogenic Escherichia coli isolated from children with acute diarrhea. Archives of Clinical Infectious Diseases. 2019;**14**(3):1-7. DOI: 10.5812/archcid.65855

[23] Taghadosi R, Shakibaie MR, Hosseini-Nave H. Antibiotic resistance, ESBL genes, integrons, phylogenetic groups and MLVA profiles of Escherichia coli pathotypes isolated from patients with diarrhea and farm animals in southeast of Iran. Comparative Immunology, Microbiology and Infectious Diseases. 2019;**63**:117-126. DOI: 10.1016/j. cimid.2019.01.004

[24] Mahdavi Broujerdi S, Roayaei Ardakani M, Rezatofighi SE. Characterization of diarrheagenic *Phylotypes and Pathotypes of Diarrheagenic* Escherichia coli *of Gastroenteritis DOI: http://dx.doi.org/10.5772/intechopen.109860*

Escherichia coli strains associated with diarrhea in children, Khouzestan, Iran. Journal of Infectious Development Ctries. 2018;**12**(8):649-656. DOI: 10.3855/ jidc.9538

[25] Salmani H, Azarnezhad A, Fayazi MR, Hosseini A. Pathotypic and phylogenetic study of diarrheagenic Escherichia coli and uropathogenic E. coli using multiplex polymerase chain reaction. Jundishapur. Journal of Microbiology. 2016;**9**(2):e28331. DOI: 10.5812/jjm.28331

[26] Staji H, Badagliacca P, Salehi TZ, Lopes F, Iorio M, Tonelli A, et al. Pathotyping of diarrhoeagenic cattle Escherichia coli strains isolated in the province of Tehran, Iran. Veterinaria Italiana. 2017;**53**(4):345-356

[27] Alizade H, Ghanbarpour R, Aflatoonian MR. Molecular study on diarrheagenic Escherichia coli pathotypes isolated from under 5 years old children in southeast of Iran. Asian Pacific Journal of Tropical Disease. 2014;**4**:S813-S817. DOI: 10.1016/S2222-1808(14)60733-7

[28] Ferdous J, Rashid RB, Sultana R, Saima S, Jahan Prima M, Begum A, et al. Is it human or animal? The origin of pathogenic E. coli in the drinking water of a low-income Urban Community in Bangladesh. Trop med. Infectious Diseases. 2021;**6**(4):181. DOI: 10.3390/ tropicalmed6040181

[29] Martins FH, Nepomuceno R, Piazza RMF, Elias WP. Phylogenetic distribution of tir-cytoskeleton coupling protein (tccP and tccP2) genes in atypical enteropathogenic Escherichia coli. FEMS Microbiology Letters. 2017;**364**(11):1-7. DOI: 10.1093/femsle/fnx101

[30] Coelho CVL, Gomes TAT, Vieira MAM, Rosa ACP, Marinho DP, Söhsten BLV, et al. Brazilian indigenous children as carriers of Diarrheagenic *Escherichia coli* Pathotypes. Advances in Infectious Disease. 2018;**08**(4):200-216. DOI: 10.4236/aid.2018.84017

[31] Regua-Mangia AH, Irino K, da Silva PR, Pimentel Bezerra RM, Santos Périssé AR, Teixeira LM. Molecular characterization of uropathogenic and diarrheagenic *Escherichia coli* pathotypes. Journal of Basic Microbiology. 2010;**50**(Suppl 1):S107-S115. DOI: 10.1002/jobm.200900364

[32] Khairy RMM, Fathy ZA, Mahrous DM, Mohamed ES, Abdelrahim SS. Prevalence, phylogeny, and antimicrobial resistance of Escherichia coli pathotypes isolated from children less than 5years old with community acquireddiarrhea in upper Egypt. BMC Infectious Diseases. 2020;**20**(1):908. DOI: 10.1186/ s12879-020-05664-6

[33] El-Shaer S, Abdel-Rhman SH, Barwa R, Hassan R. Virulence characteristics, serotyping and phylogenetic typing of clinical and environmental Escherichia coli isolates. Jundishapur Journal of Microbiology. 2018;**11**(12):1-12. DOI: 10.5812/jjm.82835

[34] Badagliacca P, Agnoletti F, Drigo I, Merildi V, Lopes F, Pompilii C, et al. Virulence gene profiles of rabbit enteropathogenic *Escherichia coli* strains isolated in northern Italy. Veterinaria Italiana. 2018;**54**(3):189-196. DOI: 10.12834/VetIt.859.4260.2

[35] Müller A, Stephan R, Nüesch-Inderbinen M. Distribution of virulence factors in ESBL-producing Escherichia coli isolated from the environment, livestock, food and humans. Science of the Total Environment. 2016;**541**:667- 672. DOI: 10.1016/j.scitotenv.2015.09.135

[36] Hoseinzadeh T, Ghanbarpour R, Rokhbakhsh-Zamin F. Phylogenetic

background of enterotoxigenic and enteroinvasive Escherichia coli from patients with diarrhea in Sirjan, Iran. Iran Journal of Microbiology. 2016;**8**(3):187-192

[37] Bautista-Trujillo GU, Gutiérrez-Miceli FA, Mandujano-García L, Oliva-Llaven MA, Ibarra-Martínez C, Mendoza-Nazar P, et al. Captive green iguana carries diarrheagenic Escherichia coli pathotypes. Frontiers in Veterinary Science. 2020;**7**:99. DOI: 10.3389/ fvets.2020.00099

[38] AMARAL MSMG. Genes relacionados à virulência, resistência aos antimicrobianos, filogrupos genéticos e resposta imunoinflamatória associadas com cepas de Escherichia coli enteroagregativa isoladas de crianças nutridas e desnutridas em Fortaleza-Ce, Brasil [dissertação] (Mestrado em Microbiologia Médica) - Faculdade de Medicina. Fortaleza: Universidade Federal do Ceará; 2018. p. 98 f

[39] Kilani H, Abbassi MS, Ferjani S, Ben Salem R, Mansouri R, Ben Chehida N, et al. Diverse Escherichia coli pathovars of phylogroups B2 and D isolated from animals in Tunisia. Journal of Infection in Developing Countries. 2017;**11**(7):549- 556. DOI: 10.3855/jidc.8579

[40] Modgil V, Mahindroo J, Narayan C, Kalia M, Yousuf M, Shahi V, et al. Comparative analysis of virulence determinants, phylogroups, and antibiotic susceptibility patterns of typical versus atypical enteroaggregative E. coli in India. PLoS Neglected Tropical Diseases. 2020;**14**(11):e0008769. DOI: 10.1371/journal.pntd.0008769

[41] da Silva LC, de Mello Santos AC, Silva RM. Uropathogenic Escherichia coli pathogenicity islands and other ExPEC virulence genes may contribute to the genome variability of enteroinvasive E.

coli. BMC Microbiology. 2017;**17**(1):68. DOI: 10.1186/s12866-017-0979-5

[42] El-Baz R, Said HS, Abdelmegeed ES, Barwa R. Characterization of virulence determinants and phylogenetic background of multiple and extensively drug resistant Escherichia coli isolated from different clinical sources in Egypt. Applied Microbiology and Biotechnology. 2022;**106**(3):1279-1298. DOI: 10.1007/s00253-021-11740-x

[43] Jafari E, Oloomi M, Bouzari S. Characterization of antimicrobial susceptibility, extended-spectrum β-lactamase genes and phylogenetic groups of shigatoxin producing Escherichia coli isolated from patients with diarrhea in Iran. Annals of Clinical Microbiology and Antimicrobials. 2021;**20**(1):24. DOI: 10.1186/ s12941-021-00430-1

[44] Rebello RC, Regua-Mangia AH. Potential enterovirulence and antimicrobial resistance in Escherichia coli isolates from aquatic environments in Rio de Janeiro, Brazil. Science of the Total Environment. 2014;**490**:19-27. DOI: 10.1016/j.scitotenv.2014.04.040

[45] Céspedes S, Saitz W, Del Canto F, De la Fuente M, Quera R, Hermoso M, et al. Genetic diversity and virulence determinants of Escherichia coli strains isolated from patients with Crohn's disease in Spain and Chile. Frontiers in Microbiology. 2017;**8**:639. DOI: 10.3389/ fmicb.2017.00639

[46] Camprubí-Font C, Lopez-Siles M, Ferrer-Guixeras M, Niubó-Carulla L, Abellà-Ametller C, Garcia-Gil LJ, et al. Comparative genomics reveals new single-nucleotide polymorphisms that can assist in identification of adherentinvasive Escherichia coli. Scientific Reports. 2018;**8**(1):2695. DOI: 10.1038/ s41598-018-20843-x

*Phylotypes and Pathotypes of Diarrheagenic* Escherichia coli *of Gastroenteritis DOI: http://dx.doi.org/10.5772/intechopen.109860*

[47] Lee JG, Han DS, Jo SV, Lee AR, Park CH, Eun CS, et al. Characteristics and pathogenic role of adherent-invasive Escherichia coli in inflammatory bowel disease: Potential impact on clinical outcomes. PLoS One. 2019;**14**(4):e0216165. DOI: 10.1371/ journal.pone.0216165

[48] Rezatofighi SE, Mirzarazi M, Salehi M. Virulence genes and phylogenetic groups of uropathogenic Escherichia coli isolates from patients with urinary tract infection and uninfected control subjects: A case-control study. BMC Infectious Diseases. 2021;**21**(1):361. DOI: 10.1186/ s12879-021-06036-4

[49] Hassuna NA, Khairalla AS, Farahat EM, Hammad AM, Abdel-Fattah M. Molecular characterization of extendedspectrum β lactamase- producing E. coli recovered from community-acquired urinary tract infections in upper Egypt. Scientific Reports. 2020;**10**(1):2772. DOI: 10.1038/s41598-020-59772-z

[50] Haghighatpanah M, Zeighami H, Mozaffari Nejad AS, Hajipour N. Phylogenetic groups and antimicrobial resistance characteristics of Escherichia coli strains isolated from clinical samples in North Iran. Arab J Gastroenterology. 2022;**23**(2):102-107. DOI: 10.1016/j. ajg.2022.02.003

[51] Al-Guranie DR, Al-Mayahie SM. Prevalence of E. coli ST131 among uropathogenic E. coli isolates from Iraqi patients in Wasit Province, Iraq. International Journal of Microbiology. 2020;**2020**:8840561. DOI: 10.1155/2020/8840561

[52] Allami M, Bahreini M, Sharifmoghadam MR. Antibiotic resistance, phylogenetic typing, and virulence genes profile analysis of uropathogenic Escherichia coli isolated from patients in southern Iraq. Journal of Applied Genetics. 2022;**63**(2):401-412. DOI: 10.1007/s13353-022-00683-2

[53] Ahmed NA, Mahmood SS, Abbas AH. A comparative study of some virulence factors and phylogenetic characterization of Escherichia coli isolates causing urinary tract infection and the commensal gut. Iraqi Journal of Agriculture Science. 2019;**50**(3):1193-1198

[54] Mahmoud AT, Salim MT, Ibrahem RA, Gabr A, Halby HM. Multiple drug resistance patterns in various phylogenetic groups of hospitalacquired uropathogenic E. coli isolated from cancer patients. Antibiotics (Basel). 2020;**9**(3):108. DOI: 10.3390/ antibiotics9030108

[55] Hama-Soor TA, Salih SS, Muhamad SJ. The β-lactamase profile of Escherichia coli isolates from patients with urinary tract infections in teaching Hospital in Sulaimani, Iraq. Annals Parasitology. 2021;**67**(4):659-670. DOI: 10.17420/ap6704.382

[56] Pirko EY, Ali MRN. The relationship between phylogenic typing and antimicrobial susceptibility patterns for Escherichia coli isolated from UTIs atMany hospitals in Baghdad city. Nursing National Iraqi Specialties. 2017;**30**(2):1-2

[57] Gatya Al-Mayahie SM, Al-Guranie DRT, Hussein AA, Bachai ZA. Prevalence of common carbapenemase genes and multidrug resistance among uropathogenic Escherichia coli phylogroup B2 isolates from outpatients in Wasit Province/ Iraq. PLoS One. 2022;**17**(1):e0262984. DOI: 10.1371/ journal.pone.0262984

[58] Hussein FA, Alwash MS. Molecular detection of extended spectrum

β-lactamase genes in Escherichia coli isolates from urinary tract infected patients. Journal of Applied National Sciences. 2022;**14**(4):1485-1492

[59] Al-Zuhairy AM, Al-Dahmoshi HO. CTX-M genotyping among cystitis associated cefotaxime-resistant uropathogenic Escherichia coli (CRUPEC). Journal of Pure and Applied Microbiology. 2018;**12**(3):1515-1523. DOI: 10.22207/JPAM.12.3.56

[60] Bachai ZA, Al-Mayahie SM. Molecular comparison of adhesins of uropathogenic Escherichia coli isolates from patients with first episode and recurrent urinary tract infections. Indian Journal of National Science. 2019;**9**(52):16529-16535

[61] Merza NS. Prevalence and molecular characterization of Fim H gene in Escherichia coli isolates recovered from patients with utis. Medicine Journal of Babylon. 2017;**14**(3):470-477