Antibiotics - Therapeutic Spectrum and Limitations

Antibiotics: Therapeutic Spectrum and Limitations provides up-to-date information on managing microbial infections, the development and types of antibiotics, the rationale for utilizing antibiotics, toxicity considerations, and the control of antibiotic resistance in one single resource. This book also aims to provide comprehensive insights and current trends on antibiotic therapies to treat microbial infections, their mechanisms of action, and the role of modern drug delivery in improving their efficacy. Written by leading experts from around the globe, the chapters in the book covers important aspects of microbial infections including hospital acquired infections and community acquired infections and adult sepsis, examines the various types of antibiotics with different mechanisms and therapeutic uses, the global challenge of antibiotic resistance, and clinical trials, regulatory considerations, and market overview of antibiotics. Furthermore, the chapters include updated literature reviews of the relevant key topics, high-quality illustrations, chemical structures, flowcharts, and well-organized tables, all of which enable better understanding by the readers.

• Provides in-depth and updated information and analyses on microbial infections, antibiotics and therapeutics, the consequences of antibiotic resistance, and the role of modern drug delivery in improving efficacy
• Discusses different types of antibiotics and their mechanisms as well as traditional medicine, herbal drugs, and postbiotics in the treatment and prevention of microbial infections and management of antibiotic resistance
• Contributed by global leaders and experts from academia, industry, research institutes, and regulatory agencies

• Language: English
• Publisher: Academic Press
• Release date: Jul 13, 2023
• ISBN: 9780323957861

Book preview

Section I

Introduction

Chapter 1: Introduction to antibiotic therapy

Amal Kumar Dharaa; Amit Kumar Nayakb    a Department of Pharmacy, Contai Polytechnic, Government of West Bengal, Contai, Purba Medinipur, West Bengal, India

b Department of Pharmaceutics, School of Pharmaceutical Sciences, Siksha ‘O’ Anusandhan (Deemed to be University), Bhubaneswar, Odisha, India

Abstract

Spectrum of microbial infections is highly wide with complicated pathophysiology of microorganisms. There is limited availability of antibiotics as compared with the variation in microbial pathogens and their infections. During the past few decades, the discovery of new antibiotic molecules is insufficient to combat the known, reemerging, and emerging infections. The emergence of antibiotic resistance is a serious concern of the clinicians as well as the biomedical scientists. Management of microbial infections by antibiotics, their rational uses, improvement of efficacy, as well as controlling of resistance by using combination therapy, modern drug delivery, phytomedicines, probiotics, etc., are the most important aspects of antibiotics.

Keywords

Antibiotic; Bacterial infections; Therapeutic spectrum; Antimicrobial resistance

1: Introduction

Before the discovery of antibiotics, people used various agents to cure microbial infections in different ways. More than 2000 years ago in China, Greece, and Egypt, antibiotic-producing microbes were used to treat wounds and other infections [1]. In the literature survey, a list of remedies was mentioned, which includes medicinal soil and moldy bread (1550 BC) [2]. It has been recently observed that about 1000 years ago, an Anglo-Saxon recipe exhibited bactericidal effect against methicillin-resistant Staphylococcal aureus (MRSA) [3].

2: Bacterial infection

Varieties of microorganisms including bacteria, fungi, protozoa, viruses, etc., are responsible for different infections and diseases in human beings. The mode of transmission of the microorganisms to humans through various means includes soil, air, water, food, direct contact, inhalation, or contact with the fecal matter, insect bite, etc. [4,5]. Different types of bacterial infections including upper and lower respiratory tract infection, upper and lower urinary tract infection, skin infection, eye infection, otitis media (inflammation of the middle ear and tympanic membrane), pneumonia, meningitis, intra-abdominal infections, gastritis, sexually transmitted diseases (syphilis, gonorrhea, Chlamydia, chanchroid, etc.), septicemia, etc., are usually observed in humans [5,6]. Different methods are being employed to prevent the infections caused by pathogenic organisms. With the advancement of medical sciences, different antibiotics are being discovered and also are being used to treat the infectious diseases either alone or in combinations with antibiotics.

3: Antibiotic era

In 1910, Salvarsan, the first systemic antibiotic, was developed by Paul Ehrlich, synthesized from clothes dye, and was found to be effective against Treponema pallidum[7]. Another synthetic compound sulfonamide was discovered by Gerhard Domagk [8]. Sir Alexander Fleming discovered Penicillin by chance for the first time in the history of antibiotics. The penicillin was obtained from a fungus called Penicillium notatum, grown on soil [9]. Later penicillin was purified by three famous scientists, Howard Florey, Norman Heatley, and Ernst Chain [10]. The β-lactam structure of penicillin was an important breakthrough from which the idea of the development of semisynthetic penicillin came, which helped to overcome the microbial resistance to penicillin. The source of penicillin was a microorganism, this fact influenced Selman Waksman (1930) for the investigation of antimicrobials from microbes, and he gave the definition of antibiotic as a compound made by a microbe to destroy other microbes [11,12]. Based on this concept, many antimicrobials have already been isolated from soil-dwelling actinomycetes including streptomycin, the first drug effective against tuberculosis [13]. This was discovered by Waksman, who also observed that the secondary metabolite produced by streptomyces is highly effective against bacteria, viruses, fungi, and also having immunosuppressant and anticancer activities [12]. From 1940 to 1960, it was considered as Golden age of discovery of antibiotics, as many antimicrobials developed during this period and are still in clinical use. Studies revealed that more than 55% of total antibiotics were obtained from streptomyces and its precursors [14]. A substantial number of antibiotics were developed in between 1943 and 1960. And this period is called as Golden age of antibiotics. The chronological development of antimicrobial agents is shown in Table 1.

Table 1

4: Challenges in the development of antibiotics

The recent pandemic situation opened our eyes and warned that the world is far behind to combat against the threat of different pathogenic organisms. The incidence of antimicrobial resistance is one of the most important challenges. Emergence of new infectious organisms, bioterrorism, etc., is great concern to the researcher. To overcome these hurdles, newer approaches are required. During the golden age of antibiotics (1940–60), the rate of death due to infectious disease declined by a factor of 20 (797 per 1000,000 to 36 per 1000,000) [15]. Unfortunately, the rate of death was doubled due to human immunodeficiency virus (HIV) infection (1980–2000) and also, due to emergence of MRSA. Antibiotic resistance caused illness of about 2 million North Americans, resulting in death of more than 23000 people [16,17]. Each year, in the European Union and in the United States, about 25,000 and 36,000 patients, respectively, die from an infection of multidrug-resistant bacteria and hospital-acquired infections [18].

The need for new antimicrobial agents is very much important to overcome situations such as emergence of resistance and also the new type of infections. Discovery of fourth-generation β-lactam antibiotic as well as some macrolide antibiotics (third generation) helped to overcome the situation, but the development of a number of new antibiotics is much lesser than the need. To meet the demand, the current antibiotic discovery platforms (ADPs) are developing suitable molecules for treating untreatable microbial infections. The FDA has already approved antimicrobial agents every year, and many more are in the pipeline [19].

5: Classes of antibiotics and their therapeutic spectrum

Since the inception of penicillin, many antibiotics have already been developed as well as clinically used for the treatment of varieties of infections [5,12]. Different classes of antibiotics, their sources, years of clinical applications, and mechanism of actions are mentioned in Table 2.

Table 2

6: β-Lactam antibiotics

Since the discovery of penicillin (1928) by Sir Alexander Fleming, β-lactam antibiotics are still one of the most widely used antibiotics for the treatment of varieties variety of diseased conditions [20,21]. Due to the presence of β-lactam ring in their structure, they have been named β-lactam and also confer the antimicrobial activity [22]. β-Lactam antibiotics are again subdivided into five classes: (i) penicillins, (ii) cephalosporins, (iii) carbapenems, (iv) monobactams, and (v) β-lactamase inhibitors.

Different types of penicillins are produced, such as natural penicillins (e.g., benzyl penicillin, phenoxymethyl penicillin), penicillinase-resistant penicillins (e.g., cloxacillin, dicloxacillin, flucloxacillin, oxacillin, nafcillin, methicillin), aminopenicillin (e.g., ampicillin, amoxicillin, etc.), extended-spectrum penicillin (e.g., carboxypenicillin-ticarcillin, carbenicillin, etc., and ureidopenicillin-piperacillin, mezlocillin, etc.) [23–25]. β-Lactam antibiotics inhibit the bacterial cell wall synthesis by binding with penicillin-binding protein (PBP).

From Cephalosporium strains, cephalosporin was first (1945) isolated [26]. Based on the time of discovery and activity against Gram (+)ve and/or Gram (−)ve bacteria, they are subclassified into five categories, including first-generation cephalosporins (e.g., cephalexin, cephalothin and cefadroxil), second-generation cephalosporins (e.g., cefaclor, cefoxitin, and cefuroxime), third-generation cephalosporins (e.g., cefixime, cefpodoxime, ceftibuten, and cefdinir), fourth-generation cephalosporins (e.g., cefepime and cefpirome), and fifth-generation cephalosporins (e.g., ceftaroline and ceftobiprole) [27,28]. Carbapenems are highly effective, broad spectrum, resistant to degradation by most of the β-lactamases-producing organisms. They are also effective against hospital-acquired as well as community-acquired infections and also against MRSA [28–31].

Monobactams are also effective Gram (−)ve and β-lactamases-producing organisms. These are monocyclic; hence, β-lactam ring is not found with other rings. The protype example of this group is aztreonam, which is an example of a highly effective antibiotic [32,33]. Some β-lactamase inhibitors including clavulanic acid, sulbactam, tazobactam, etc., have β-lactam ring, and they inactivate β-lactamase by binding (reversibly or irreversibly) with β-lactamase [34]. They have little or no antibacterial activity, and thus, they are used in combination with other suitable antibiotics.

7: Aminoglycoside antibiotics

Aminoglycosides are a category of broad-spectrum potent inhibitors of bacterial protein synthesis [35]. These are water-soluble oligosaccharides typically functionalized by three to six ammonium groups. Aminoglycoside antibiotics exhibit bactericidal activity against most of the Gram (−)ve aerobic and also, against some anaerobic bacilli. Due to their toxicity (more specifically, the shared toxicities such as ototoxicity, nephrotoxicity, and neuromuscular blockade) and loss of efficacy owing to the development of resistance, the uses of aminoglycoside antibiotics have been limited. In spite of those limitations, some drugs of this group are still used widely and effectively. In the year 1943, streptomycin was first discovered from Streptomyces griseus and had been using as first-line antitubercular drug since 1954 [36,37]. The important members having significant activity and used clinically include tobramycin, gentamycin, neomycin (topical preparation for skin infection), paromomycin, amikacin, etc. Aminoglycoside antibiotics are used clinically in a variety of disease conditions including Gram (−)ve bacillary infections, pelvic and abdominal sepsis, septicemia, streptococcal and staphylococcal infections of heart valves, tuberculosis, pneumonias, plague, brucellosis, etc. [35]. Topical uses of aminoglycosides include infection of external ear, conjunctiva, etc. [38]. The aminoglycoside antibiotics should be avoided during pregnancy (risk of fetal toxicity), and concurrent use of other nephrotoxic (vancomycin, amphotericin B, cephalexin, cyclosporine, etc.) and ototoxic drugs (minocycline, high ceiling diuretic, etc.) [38,39] should be avoided.

8: Chloramphenicol and tetracyclines

In 1947, chloramphenicol was first isolated from a soil sample (collected in Venezuela), produced by Streptomyces venezuela[40]. In 1949, the chemical structure of chloramphenicol was established, which leads to their synthesis in the laboratory [41]. It is broad-spectrum antibiotic and acts by binding reversibly to the 50S ribosomal subunit and thus inhibits the protein synthesis in bacteria [42]. Chloramphenicol is primarily bacteriostatic but exhibits the bactericidal effect in higher concentration against Haemophilus influenza, Streptococcus pneumonia, Neisseria meningitis, etc. [43]. It is active against both aerobic and anaerobic Gram (+)ve and Gram (−)ve bacteria, mycoplasma, rickettsiae, etc. [44,45]. Chloramphenicol produces some severe toxicities including aplastic anemia, dose-related reversible bone marrow depression, gray baby syndrome, etc. [46–48].

Tetracyclines are a group of broad-spectrum antibiotics. This group includes tetracycline, oxytetracycline, demeclocycline, methacycline, doxycycline, and minocycline [49,50]. They inhibit the protein synthesis in bacteria by binding to 30S subunit of ribosome and thus, prevent aminoacyl tRNA binding to the mRNA ribosome complex [51]. Antimicrobial spectrum of tetracyclines includes all Gram (+)ve and Gram (−)ve cocci, sensitive Gram (+)ve and Gram (−)ve bacilli (except mycobacteria and Haemophilus influenza), all rickettsiae and chlamydiae, mycoplasma, Entamoeba histolytica, plasmodia, etc. [50]. Tetracyclines cause some important toxicity particularly in pregnant women (teratogenicity), in children owing to their chelating property that affects the teeth and bones [52,53].

9: Macrolide antibiotics

The macrolides are the broad-spectrum antibiotics with a macrocyclic lactone ring (usually having 14 or 16 atoms), where deoxysugars are attached [54]. An important member of this group, erythromycin, was first isolated in 1952 from Streptomyces erythraeus[55]. There are six important drugs in this group including erythromycin, roxithromycin, clarithromycin, azithromycin, fidaxomicin, and telithromycin (ketolides). These drugs are popular because of their relative safety and spectrum of activity. Macrolides are effectively used in the respiratory tract infections caused by both Gram (+)ve and Gram (−)ve pathogens [56,57]. Macrolide antibiotics inhibit the protein synthesis as they attach to 50S subunit of bacterial ribosome, which leads to suppression of RNA-dependent protein synthesis [58]. They are bacteriostatic and show the antibacterial activities against clostridia, listeria, corynebacteria, haemophilus sp., various strains of streptococci and staphylococci, Neisseria meningitis, pneumonia, Helicobacter pylori, cryptosporidia, etc. [56,57].

10: Lincosamide and glycopeptide antibiotics

There are two naturally occurring lincosamides including cilastatin and lincomycin. Lincomycin is obtained naturally from different species, namely Streptomyces lincolnensis, Streptomyces caelestis, etc. [59]. In the structure of lincosamides, pyrrolidine ring attaches to the pyranose moiety through amide bond [60,61]. Clindamycin is a derivative of lincomycin that is clinically significant and is used in a variety of bacterial infections including inflammatory diseases of pelvis, infections of the bones or joints, pneumonia, infection of the middle ear, and some cases of MRSA [62,63]. Lincosamide antibiotics cause inhibition of bacterial protein synthesis by binding with 50S subunit of ribosome [60]. Lincosamides are highly effective against many Gram (+)ve organisms (Streptococcus pyogenes, pneumonia, viridian streptococci, and MRSA) [60,61].

Vancomycin is an example of naturally occurring glycopeptide antibiotics isolated from soil bacterium, Amycolatopsis orientalis[64]. Another glycopeptide antibiotic, teicoplanin, was first synthesized in 1980s, which is still being clinically used for the treatment of a variety of bacterial infections [64,65]. Its antibacterial action is due to the inhibition of cell wall synthesis. It is used clinically in treating infection caused by Gram (+)ve microorganisms and also MRSA and Enterococcus faecalis[64,65].

11: Polypeptide antibiotics

Polypeptide antibiotics exhibited antiinfective as well as antitumor activities [66,67]. Polymyxin belonging to this group was first discovered in 1947 and obtained naturally from Paenibacillus polymyxa[68,69]. Colistin is a member of polymyxin family used clinically for the first time in 1959 [70]. Detergent-like effect of polymyxin disrupts the integrity of cell membrane that causes the leakage of cellular components, and finally, cell death occurs [71,72]. The different members of polypeptide antibiotics including bacitracin, colistin, polymyxin B, and colistin are in clinical use [66,67]. Polymyxin B sulfate along with other drugs is used in cases of eye, ear, and skin infections [73]. Bacitracin produced by the bacterium Bacillus subtilis causes the inhibition of cell wall synthesis [74]. The spectrum of activity of bacitracin includes Gram (+)ve cocci and bacilli, Haemophilus influenza, neisseria, etc. [75,76]. It is recommended for topical applications in cases of eye and skin infections [75].

12: Antifungal antibiotics

Fungi can exist in almost all environments and can be seen with the naked eye (e.g., mushrooms) as well as microscope (e.g., yeast, molds, etc.). Many fungi cause fungal infections, and some may cause life-threatening, e.g., cryptococcal meningitis. Antifungal drugs (antimycotic drugs) are either fungistatic or fungicidal and are used to prevent and treat a variety of fungal infections (mycosis) including ringworm, candidiasis, athlete's foot, and serious systemic infections such as cryptococcal meningitis [77,78]. In 1958, Amphotericin B (a polyene group of antibiotic) was used for the first time for the treatment of systemic fungal infections [79]. In 1959, 1971, and 1973, griseofulvin, flucytosine, and clotrimazole (azole group), respectively, were introduced [80–82]. Table 3 lists the causative organism(s) and associated fungal infections. Table 4 lists different classes of antifungal drugs with examples and modes of actions.

Table 3

Table 4

Some serious adverse effects of antifungal antibiotics with common side effects are as follows: amphotericin B causes renal insufficiency, hypokalemia, hypotension, hypomagnesaemia, anemia, etc. [79,83]; azoles are relatively safe but produce hepatotoxicity; griseofulvin causes granulocytopenia, hepatotoxicity, skin photosensitivity, erythema, etc.; echinocandins also produce hepatotoxicity [82,84,85].

13: Antitubercular antibiotics

Tuberculosis (TB) caused by Mycobacterium tuberculosis is a major health problem across the globe [86]. TB is one of the oldest recognized diseases (9000 years ago) of mankind [87]. Death due to TB is increasing every year. The symptoms of TB include fever, cough with bloody sputum, weight loss, night sweat, etc. Many drugs have been discovered for the effective management of TB [88–90]. However, the development of resistance is a great concern in the treatment of TB [90]. In Table 5, the year of discovery/development of different anti-TB drugs is mentioned.

Table 5

Due to the emergence of drug resistance, treatment of TB becomes complicated day by day. Different drug-resistance TBs include MDR TB (multidrug resistance TB), XDR TB (extensive drug resistance TB), and TDR TB (Total drug resistance TB). Discovery of newer ant-TB drug such as bedaquiline helps to overcome this drug-resistance situation.

14: Toxicity of antibiotics

There are no antibiotics without toxicity. Because almost all antibiotics interfere with the physiological process of microorganisms, side by side they also cause toxicity to a lesser extent to the host cell as an extension of their mechanism of action [91]. The adverse effects caused by various antibiotics can be grossly categorized into five types [83,91–93]: (i) hypersensitivity reaction—the use of antibiotics may cause immediate or delayed hypersensitivity reactions. Penicillins, sulfonamides, streptomycin, etc., exhibit different hypersensitivity reactions; (ii) Direct adverse effect—some important organs are affected by the direct toxicity of antibiotics, e.g., ototoxicity caused by aminoglycoside antibiotics and bone marrow depression by chloramphenicol; (iii) change in microbial flora—antibiotics cause alteration in normal gut flora, which may result in either overgrowth of some harmful strains or decrease of some species diversity; and (iv) microbial lysis—clinical condition of patients sometimes deteriorated due to toxicity caused by toxin released after lysis of microorganisms, e.g., erythema nodosum leprosum caused by antileprotic drug dapsone.

15: Antimicrobial resistance

In the 21st century, antimicrobial resistance is one of the serious and major public health problems. Due to development of resistance, the prevention and treatment of infections caused by pathogenic microorganisms such as bacteria, parasites, fungi, and viruses have become difficult or sometimes not possible by using common antimicrobial agents. The World Health Organization (WHO) has taken this issue seriously. In 2001, the WHO had framed strategies to prevent or reduce the spread of antimicrobial resistance globally [94].

The widespread use, more specifically, irrational use of antibiotics everywhere, i.e., humans, animal farming, agriculture, etc., is the principal cause of development antimicrobial resistance. Between 2000 and 2010, the consumption of antibiotics sharply increased by about 70% globally [95]. About 2 tons of antibiotics are consumed across the globe every 10 min, and that too without any prescription or supervision [96]. In 2012, WHO had taken different actions to improve the health system by controlling the uses of antibiotics in hospitals as well as in the community, development of new drugs and vaccines, and increase awareness among the common people. In the United States, over 2 million people affected with antimicrobial-resistance infections every year and about 23,000 deaths occur as a result of such infections [97].

Antimicrobial resistance is a natural phenomenon, which happens when microorganisms are exposed to antimicrobial agents. Overuses as well as inappropriate uses, i.e., inappropriate selections, inadequate dose, lack of adherence to guideline of antibiotic treatment, etc., contribute significantly to the emergence of antimicrobial resistance. The antimicrobial resistance may be acquired where the sensitive organism acquires a resistance mechanism due to either mutation or acquisition of new genetic material [98]. The different resistances include: (i) intrinsic resistance, (ii) acquired resistance, and (iii) adaptive resistance (mutational and horizontal gene transfer). The mechanisms by which antimicrobial resistance is developed are: (i) limiting uptake of drugs, (ii) inactivating of drugs, (iii) modifying a drug targets, (iv) active drug efflux, and (v) metabolic bypass.

In this planet, microorganisms are versatile and adaptive. Every organism wants to survive. Bacteria that can infect are also able to modify against antibiotics. To control this rapid development of resistance, a global and multidisciplinary approach is very much essential. Increased awareness, development of novel antibiotics, ecological and environmental aspects analysis, development of new diagnostic tools, providing updated information to physicians, pharmacists, and other healthcare professionals can be the effective ways to overcome the issue of antimicrobial resistance.

16: Prospect of probiotics and natural products

Antibiotics are the most widely and efficiently used agents against a variety of bacterial infections. The life expectancy increased from 47 to 78.8 years by using antibiotics that prevent millions of death caused by microbial infections [99]. With the increasing use of antimicrobial agents, the antimicrobial resistance is also enhanced proportionately, and about 1.27 million deaths occurred in 2019, globally [100]. To overcome the impact of MDR infections on human health, researchers studied the role of probiotics [101]. The combination of probiotics with antibiotics exhibited higher antibacterial activities against a wide variety of microorganisms [102]. It has also been studied that probiotics decrease the incidence of adverse effects caused by the use of antimicrobial agents [103]. Probiotics play a significant role to combat the problem associated with antimicrobial resistance, probably by preventing the expansion of resistome and the spread of antibiotic resistance genes [104]. The probable mechanism, by which probiotics reduce the incidence of bacterial resistance, is that the probiotics caused the colonization of gut microbiota to boost the disruption due to bacterial infections [105].

From the very beginning of human civilization, plants are playing a significant role in the prevention and treatment of a variety of disease conditions. Phytoconstituents exhibited the potential health benefits such as anticancer, antihypertensive, antidiabetic, antimicrobial, etc., activities. Due to the emergence of multidrug resistance by using antibiotics, phytochemists explore different phytochemicals that are showing significant antimicrobial activity against a variety of bacterial infections [106,107]. In traditional medicinal system, a variety of herbs possess potent antimicrobial activities including cloves, garlic, cinnamon, etc. In Table 6, herbal plants, active constituents, and their uses are mentioned.

Table 6

As there is increased incidence of antimicrobial resistance, the researchers are trying to find out new molecules, and at the same time, clinical trial and regulatory factors are also very important. The USFDA (Unite States Food and Drug Administration) is one of the most important regulators, responsible for providing approval of new drugs for human and veterinary usage. The drug manufacturer submits Investigational New Drug Application (INDA) to USFDA before marketing the drug. The USFDA reviews various aspects of applications and allows for sale in the market.

17: Conclusion

Spectrum of microbial infections is highly wide, with complicated pathophysiology of microorganisms. Incidence of emerging microbial infections is increasing day by day. However, there is limited availability of antibiotics as compared with the variation in microbial pathogens and their infections. Discovery of new antibiotic molecules during the last few decades are insufficient to combat the known, reemerging, and emerging infections. Most of the antibiotics act by inhibiting cell wall synthesis, membrane damage, protein synthesis, interfering with DNA synthesis and DNA functions, etc., and are used for the treatment of a variety of diseased conditions including TB and cancers. Emergence of antibiotic resistance is a serious concern of the clinicians as well as the biomedical scientists around the globe. Thus, the management of microbial infections by antibiotics, their rational uses, and improvement of efficacy as well as control of resistance by using combination therapy and modern drug delivery are the most important aspects of antibiotics. Uses of phytomedicines and probiotics are also the prospective alternatives to overcome the drawback of semisynthetic and synthetic antibiotics.

References

[1] Ventola C.L. The antibiotic resistance crisis: part 1: causes and threats. P T. 2015;40(4):277–283.

[2] Haas L.F. Papyrus of Ebers and Smith. J Neurol Neurosurg Psychiatry. 1999;67:572–578.

[3] Harrison F., Roberts A.E., Gabrilska R., Rumbaugh K.P., Lee C., Diggle S.P. A 1,000-year-old antimicrobial remedy with antistaphylococcal activity. MBio. 2015;6(4):e01129.

[4] van Seventer J.M., Hochberg N.S. Principles of infectious diseases: transmission, diagnosis, prevention, and control. Int Encyclop Public Health. 2017;22–39.

[5] Doron S., Gorbach S.L. Bacterial infections: Overview. Int Encyclop Public Health. 2008;273–282.

[6] Deusenbery C., Wang Y., Shukla A. Recent innovations in bacterial infection detection and treatment. ACS Infect Dis. 2021;7(4):695–720.

[7] Gelpi A., Gilbertson A., Tucker J.D. Magic bullet: Paul Ehrlich, Salvarsan and the birth of venereology. Sex Transm Infect. 2015;91(1):68–69.

[8] Aminov R.I. A brief history of the antibiotic era: lessons learned and challenges for the future. Front Microbiol. 2010;1:134.

[9] Fleming A. On the antibacterial action of cultures of a penicillium, with special reference to their use in the isolation of B. influenzae. Br J Exp Pathol. 1929;10:226–236.

[10] Abraham E.P., Chain E., Fletcher C.M., Gardner A.D., Heatley N.G., Jennings M.A., Florey H.W. Further observations on penicillin. Lancet. 1941;238:177–189.

[11] Iqbal Z., Sun J., Yang H., Ji J., He L., Zhai L., Ji J., Zhou P., Tang D., Mu Y., Wang L., Yang Z. Recent developments to cope the antibacterial resistance via β-lactamase inhibition. Molecules. 2022;27(12):3832.

[12] Hutchings M.I., Truman A.W., Wilkinson B. Antibiotics: past, present and future. Curr Opin Microbiol. 2019;51:72–80.

[13] Waksman S.A., Schatz A., Reynolds D.M. Production of antibiotic substances by actinomycetes. Ann N Y Acad Sci. 2010;1213:112–124.

[14] Newman D.J., Cragg G.M. Natural products as sources of new drugs from 1981 to 2014. J Nat Prod. 2016;79(3):629–661.

[15] Armstrong G.L., Conn L.A., Pinner R.W. Trends in infectious disease mortality in the United States during the 20th century. JAMA. 1999;281(1):61–66.

[16] Dadgostar P. Antimicrobial resistance: Implications and costs. Infect Drug Resist. 2019;12:3903–3910.

[17] Antimicrobial Resistance Collaborators. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet. 2022;399(10325):629–655.

[18] Lim C., Takahashi E., Hongsuwan M., Wuthiekanun V., Thamlikitkul V., Hinjoy S., Day N.P., Peacock S.J., Limmathurotsakul D. Epidemiology and burden of multidrug-resistant bacterial infection in a developing country. Elife. 2016;5:e18082.

[19] Al-Tawfiq J.A., Momattin H., Al-Ali A.Y., Eljaaly K., Tirupathi R., Haradwala M.B., Areti S., Alhumaid S., Rabaan A.A., Al Mutair A., Schlagenhauf P. Antibiotics in the pipeline: a literature review (2017-2020). Infection. 2022;50(3):553–564.

[20] Ligon B.L. Penicillin: its discovery and early development. Semin Pediatr Infect Dis. 2004;15(1):52–57.

[21] Sternbach G., Varon J. Alexander Fleming: the spectrum of penicillin. J Emerg Med. 1992;10(1):89–91.

[22] Pandey N., Cascella M. Beta lactam antibiotics. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022.

[23] Wright A.J. The penicillins. Mayo Clin Proc. 1999;74(3):290–307.

[24] NIH (National library of medicine). Penicillins (4th Generation). 2012.

[25] Wright A.J., Wilkowske C.J. The penicillins. Mayo Clin Proc. 1991;66(10):1047–1063.

[26] Abraham E.P., Loder P.B. Cephalosporin C. In: Cephalosporins and Penicillins. USA: Elsevier; 1972:1–26.

[27] Bui T., Preuss C.V. Cephalosporins. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022.

[28] Christensen S.B. Drugs that changed society: History and current status of the early antibiotics: Salvarsan, sulfonamides, and β-Lactams. Molecules. 2021;26(19):6057.

[29] Yoon Y.K., Yang K.S., Lee S.E., Kim H.J., Sohn J.W., Kim M.J. Effects of group 1 versus group 2 carbapenems on the susceptibility of Acinetobacter baumannii to carbapenems: A before and after intervention study of carbapenem-use stewardship. PloS One. 2014;9(6):e99101.

[30] Sugihara K., Sugihara C., Matsushita Y., Yamamura N., Uemori M., Tokumitsu A., et al. In vivo pharmacodynamic activity of tomopenem (formerly CS-023) against Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus in a murine thigh infection model. Antimicrob Agents Chemother. 2010;54(12):5298–5302.

[31] El-Gamal M.I., Brahim I., Hisham N., Aladdin R., Mohammed H., Bahaaeldin A. Recent updates of carbapenem antibiotics. Eur J Med Chem. 2017;131:185–195.

[32] Carreira E.M., Yamamoto H., Cossi J.R. Biological significance—pharmacology, pharmaceutical, agrochemical. In: Comprehensive chirality. Amsterdam: Elsevier; 2012.

[33] Bush K., Bradford P.A. β-Lactams and β-lactamase inhibitors: an overview. Cold Spring Harb Perspect Med. 2016;6(8):a025247.

[34] Drawz S.M., Bonomo R.A. Three decades of β-lactamase inhibitors. Clin Microbiol Rev. 2010;23(1):160–201.

[35] Krause K.M., Serio A.W., Kane T.R., Connolly L.E. Aminoglycosides: an overview. Cold Spring Harb Perspect Med. 2016;6(6):a027029.

[36] Daniel T.M. Selman Abraham Waksman and the discovery of streptomycin. Int J Tuberc Lung Dis. 2005;9(2):120–122.

[37] Woodruff H.B., Selman A. Waksman, winner of the 1952 Nobel Prize for physiology or medicine. Appl Environ Microbiol. 2014;80(1):2–8.

[38] Gopinath S., Lu P., Iwasaki A. Cutting Edge: The use of topical aminoglycosides as an effective pull in Prime and Pull vaccine strategy. J Immunol. 2020;204(7):1703–1707.

[39] Oliveira J.F., Silva C.A., Barbieri C.D., Oliveira G.M., Zanetta D.M., Burdmann E.A. Prevalence and risk factors for aminoglycoside nephrotoxicity in intensive care units. Antimicrob Agents Chemother. 2009;53(7):2887–2891.

[40] Ehrlich J., Gottlieb D., Burkholder P.R., Anderson L.E., Pridham T.G. Streptomyces venezuelae , n. sp., the source of chloromycetin. J Bacteriol. 1948;56(4):467–477.

[41] Rebstock M.C., Crooks H.M., Controulis Jr. J., Bartz Q.R. Chloramphenicol (chloromycetin). IV. Chemical studies. J Am Chem Soc. 1949;71:2458–2462.

[42] Louzoun Zada S., Green K.D., Shrestha S.K., Herzog I.M., Garneau-Tsodikova S., Fridman M. Derivatives of ribosome-inhibiting antibiotic chloramphenicol inhibit the biosynthesis of bacterial cell wall. ACS Infect Dis. 2018;4(7):1121–1129.

[43] Guggenbichler J.P. Bakterizidie von Chloramphenikol und Synergismus mit beta-Lactam-Antibiotika [Bactericidal action of chloramphenicol and synergism with beta-lactam antibiotics]. Padiatr Padol. 1983;18(1):11–20 [German].

[44] Pacifici G.M. Management of typhoid fever and bacterial meningitis by chloramphenicol in infants and children. Int J Pediatr. 2018;6:6783–6808.

[45] Sood S. Chloramphenicol—A potent armament against multi-drug resistant (MDR) Gram Negative Bacilli?. J Clin Diagn Res. 2016;10(2):DC01-3.

[46] Hanekamp J.C., Bast A. Antibiotics exposure and health risks: chloramphenicol. Environ Toxicol Pharmacol. 2015;39(1):213–220.

[47] Mulhall A., Louvois J., Hurley R. Chloramphenicol toxicity in neonates: its incidence and prevention. BMJ. 1983;12(6403):1424–1427.

[48] Wiest D.B., Cochran J.B., Tecklenburg F.W. Chloramphenicol toxicity revisited: a 12-year-old patient with a brain abscess. J Pediatr Pharmacol Ther. 2012;17(2):182–188.

[49] Jesus K., Moita L.F. Tetracyclines: four rings to rule infections through resistance and disease tolerance. J Clin Invest. 2022;132(17):e162331.

[50] Chukwudi C.U. rRNA Binding sites and the molecular mechanism of action of the tetracyclines. Antimicrob Agents Chemother. 2016;60(8):4433–4441.

[51] Chopra I., Roberts M. Tetracycline antibiotics: mode of action, applications, molecular biology, and epidemiology of bacterial resistance. Microbiol Mol Biol Rev. 2001;65(2):232–260.

[52] Sobkowiak E.M., Radtke G. Zur Frage der teratogenen Wirkung von Tetrazylklinen unter besonderer Berücksichtigung von Otesolut und Terramyzin im Tierexperiment [Teratogenic action of tetracyclines with special reference to otesolut and terramycin in animal experiments]. Zahn Mund Kieferheilkd Zentralbl. 1977;65(2):163–167 [German].

[53] Kashyap A.S., Sharma H.S. Discolouration of permanent teeth and enamel hypoplasia due to tetracycline. Postgrad Med J. 1999;75(890):772.

[54] Dinos G.P. The macrolide antibiotic renaissance. Br J Pharmacol. 2017;174(18):2967–2983.

[55] Jelić D., Antolović R. From erythromycin to azithromycin and new potential ribosome-binding antimicrobials. Antibiotics (Basel). 2016;5(3):29.

[56] Farrington E. Macrolide antibiotics. Pediatr Nurs 1998;24(5):433-4, 437-46.

[57] Arsic B., Barber J., Čikoš A., Mladenovic M., Stankovic N., Novak P. 16-Membered macrolide antibiotics: a review. Int J Antimicrob Agents. 2018;51(3):283–298.

[58] Vázquez-Laslop N., Mankin A.S. How macrolide antibiotics work. Trends Biochem Sci. 2018;43(9):668–684.

[59] Spízek J., Rezanka T. Lincomycin, clindamycin and their applications. Appl Microbiol Biotechnol. 2004;64(4):455–464.

[60] Spížek J., Řezanka T. Lincosamides: Chemical structure, biosynthesis, mechanism of action, resistance, and applications. Biochem Pharmacol. 2017;133:20–28.

[61] Matzov D., Eyal Z., Benhamou R.I., Shalev-Benami M., Halfon Y., Krupkin M., Zimmerman E., Rozenberg H., Bashan A., Fridman M., Yonath A. Structural insights of lincosamides targeting the ribosome of Staphylococcus aureus. Nucleic Acids Res. 2017;45(17):10284–10292.

[62] Smieja M. Current indications for the use of clindamycin: a critical review. Can J Infect Dis. 1998;9(1):22–28.

[63] Guay D. Update on clindamycin in the management of bacterial, fungal and protozoal infections. Expert Opin Pharmacother. 2007;8(14):2401–2444.

[64] Butler M.S., Hansford K.A., Blaskovich M.A., Halai R., Cooper M.A. Glycopeptide antibiotics: back to the future. J Antibiot (Tokyo). 2014;67(9):631–644.

[65] Binda E., Marinelli F., Marcone G.L. Old and new glycopeptide antibiotics: action and resistance. Antibiotics (Basel). 2014;3(4):572–594.

[66] Deslouches B., Di Y.P. Antimicrobial peptides with selective antitumor mechanisms: prospect for anticancer applications. Oncotarget. 2017;8(28):46635–46651.

[67] Bian X., Qu X., Zhang J., Nang S.C., Bergen P.J., Tony Zhou Q., Chan H.K., Feng M., Li J. Pharmacokinetics and pharmacodynamics of peptide antibiotics. Adv Drug Deliv Rev. 2022;183:114171.

[68] Poirel L., Jayol A., Nordmann P. Polymyxins: antibacterial activity, susceptibility testing, and resistance mechanisms encoded by plasmids or chromosomes. Clin Microbiol Rev. 2017;30(2):557–596.

[69] Nang S.C., Azad M.A.K., Velkov T., Zhou Q.T., Li J. Rescuing the last-line polymyxins: achievements and challenges. Pharmacol Rev. 2021;73(2):679–728.

[70] El-Sayed Ahmed M.A.E., Zhong L.L., Shen C., Yang Y., Doi Y., Tian G.B. Colistin and its role in the Era of antibiotic resistance: an extended review (2000–2019). Emerg. Microbes Infect. 2020;9(1):868–885.

[71] Trimble M.J., Mlynárčik P., Kolář M., Hancock R.E. Polymyxin: alternative mechanisms of action and resistance. Cold Spring Harb Perspect Med. 2016;6(10):a025288.

[72] Mohapatra S.S., Dwibedy S.K., Padhy I. Polymyxins, the last-resort antibiotics: mode of action, resistance emergence, and potential solutions. J Biosci. 2021;46(3):85.

[73] Zavascki A.P., Goldani L.Z., Li J., Nation R.L. Polymyxin B for the treatment of multidrug-resistant pathogens: a critical review. J Antimicrob Chemother. 2007;60(6):1206–1215.

[74] Kingston A.W., Zhao H., Cook G.M., Helmann J.D. Accumulation of heptaprenyl diphosphate sensitizes Bacillus subtilis to bacitracin: implications for the mechanism of resistance mediated by the BceAB transporter. Mol Microbiol. 2014;93(1):37–49.

[75] Nguyen R., Khanna N.R., Safadi A.O., Sun Y. Bacitracin topical. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022.

[76] Storm D.R., Toscano W.A. Bacitracin. In: Hahn F.E., ed. Mechanism of action of antibacterial agents, antibiotics. Berlin, Heidelberg: Springer; . 1979;vol. 5/1.

[77] Vallabhaneni S., Chiller T.M. Fungal infections and new biologic therapies. Curr Rheumatol Rep. 2016;18(5):29.

[78] Vandeputte P., Ferrari S., Coste A.T. Antifungal resistance and new strategies to control fungal infections. Int J Microbiol. 2012;2012:713687.

[79] Carolus H., Pierson S., Lagrou K., Van Dijck P. Amphotericin B and other polyenes-discovery, clinical use, mode of action and drug resistance. J Fungi (Basel). 2020;6(4):321.

[80] Williams D.I., Marten R.H., Sarkany I. Griseofulvin. Br J Dermatol. 1959;71:434–443.

[81] Utz J.P. Flucytosine. N Engl J Med. 1972;286(14):777–778.

[82] Crowley P.D., Gallagher H.C. Clotrimazole as a pharmaceutical: past, present and future. J Appl Microbiol. 2014;117(3):611–617.

[83] Laniado-Laborín R., Cabrales-Vargas M.N. Amphotericin B: side effects and toxicity. Rev Iberoam Micol. 2009;26(4):223–227.

[84] Castagnola E., Machetti M., Bucci B., Viscoli C. Antifungal prophylaxis with azole derivatives. Clin Microbiol Infect. 2004;10(Suppl 1):86–95.

[85] Peng X.M., Cai G.X., Zhou C.H. Recent developments in azole compounds as antibacterial and antifungal agents. Curr Top Med Chem. 2013;13(16):1963–2010.

[86] Zaman K. Tuberculosis: a global health problem. J Health Popul Nutr. 2010;28(2):111–113.

[87] Hershkovitz I., Donoghue H.D., Minnikin D.E., Besra G.S., Lee O.Y., Gernaey A.M., Galili E., Eshed V., Greenblatt C.L., Lemma E., Bar-Gal G.K., Spigelman M. Detection and molecular characterization of 9,000-year-old Mycobacterium tuberculosis from a neolithic settlement in the eastern Mediterranean. PloS One. 2008;3(10):e3426.

[88] Tiberi S., du Plessis N., Walzl G., Vjecha M.J., Rao M., Ntoumi F., Mfinanga S., Kapata N., Mwaba P., McHugh T.D., Ippolito G., Migliori G.B., Maeurer M.J., Zumla A. Tuberculosis: progress and advances in development of new drugs, treatment regimens, and host-directed therapies. Lancet Infect Dis. 2018;18(7):e183–e198.

[89] Peloquin C.A., Davies G.R. The treatment of tuberculosis. Clin Pharmacol Ther. 2021;110(6):1455–1466.

[90] Al-Humadi H.W., Al-Saigh R.J., Al-Humadi A.W. Addressing the challenges of tuberculosis: a brief historical account. Front Pharmacol. 2017;8:689.

[91] Eyler R.F., Shvets K. Clinical pharmacology of antibiotics. Clin J Am Soc Nephrol. 2019;14(7):1080–1090.

[92] Cunha B.A. Antibiotic side effects. Med Clin North Am. 2001;85(1):149–185.

[93] Maymone M.P., Venkatesh S., Stryjewska B.M., Dunnick C.A., Dellavalle R.P. Leprosy: Treatment and management of complications. J Am Acad Dermatol. 2020;83:17–30.

[94] World Health Organization. WHO global strategy for containment of antimicrobial resistance. Geneva: WHO; 2001.

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

[96] Van Boeckel T.P., Gandra S., Ashok A., Caudron Q., Grenfell B.T., Levin S.A., et al. Global antibiotic consumption 2000 to 2010: an analysis of national pharmaceutical sales data. Lancet Infect Dis. 2014;14(8):742–750.

[97] Centres for Disease Control and Prevention, US Department of Health and Human Services. Antibiotic resistance threats in the United States. Atlanta: CDC; 2013. Available from: http://www.cdc.gov/drugresistance/pdf/ar-threats-2013-508.pdf

[98] Munita J.M., Arias C.A. Mechanisms of Antibiotic Resistance.. 2016;25.

[99] CDC. 2022 [Internet]. Life expectancy. [updated 2022; cited 2022 April 20]. Available from: https://www.cdc.gov/nchs/fastats/life-expectancy.htm.

[100] Murray C.J.L., Ikuta K.S., Sharara F., Swetschinski L., Robles Aguilar G., Gray A., et al. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. The Lancet. 2022;399(10325):629–655.

[101] Newman A.M., Arshad M. The role of probiotics, prebiotics and synbiotics in combating multidrug-resistant organisms. Clin Ther. 2020;42(9):1637–1648.

[102] Ji J., Yang H. Using probiotics as supplementation for Helicobacter pylori antibiotic therapy. Int J Mol Sci. 2020;21(3):1136.

[103] Ouwehand A.C., Forssten S., Hibberd A.A., Lyra A., Stahl B. Probiotic approach to prevent antibiotic resistance. Ann Med. 2016;48(4):246–255.

[104] Montassier E., Valdés-Mas R., Batard E., Zmora N., Dori-Bachash M., Suez J., et al. Probiotics impact the antibiotic resistance gene reservoir along the human GI tract in a person-specific and antibiotic-dependent manner. Nat Microbiol. 2021;6(8):1043–1054.

[105] Farache J., Koren I., Milo I., Gurevich I., Kim K.W., Zigmond E., et al. Luminal bacteria recruit CD103+ dendritic cells into the intestinal epithelium to sample bacterial antigens for presentation. Immunity. 2013;38(3):581–595.

[106] Khameneh B., Eskin N.A.M., Iranshahy M., Fazly Bazzaz B.S. Phytochemicals: A promising weapon in the arsenal against antibiotic-resistant bacteria. Antibiotics (Basel). 2021;10(9):1044.

[107] Khare T., Anand U., Dey A., Assaraf Y.G., Chen Z.S., Liu Z., Kumar V. Exploring phytochemicals for combating antibiotic resistance in microbial pathogens. Front Pharmacol. 2021;12:720726.

Section II

Microbial infection and antibiotics development

Chapter 2: Bacterial infections: Types and pathophysiology

V.T. Anjua; Siddhardha Busib; Mahima S. Mohanb; Madhu Dyavaiaha    a Department of Biochemistry and Molecular Biology, School of Life Sciences, Pondicherry University, Pondicherry, India

b Department of Microbiology, School of Life Sciences, Pondicherry University, Pondicherry, India

Abstract

Microorganisms play a vital role in maintaining human health and involve in different infections and diseases. The infections caused by various microbes including bacteria, fungi, and viruses are the greatest challenge to the world. Among all infections, bacteria can be eliminated and treated easily but with the advent of antibiotic resistance, management of bacterial infections is very difficult. The process of bacterial infections starts with the initial colonization of bacteria to the host system, adhesion, invasion, and replication inside the host leading to the damage of host system. The major modes of transmission are contact, air, water, food, living vectors, fomites, and soil. The virulence factors of pathogens including their toxins, polysaccharide capsules, and surface proteins are involved in the pathogenesis of bacteria to the host. The different bacterial infections of host include infections of the skin, eye, meninges, middle ear, respiratory tract, abdomen, gastric glands, reproductive organs, and implant-associated infections. The pathogenesis and associated symptoms of infections are provided in this chapter along with the preventive measures.

Keywords

Infections; Host; Transmission; Etiologic agent; Bacteria; Pathogenesis

1: Infection: An overview

Infection is the term used to describe the invasion of foreign cells into the host, which tend to replicate inside the host cells. The causative agents of infection are predominantly bacteria, then fungus, virus, etc. The signs and symptoms caused by the infection vary according to the pathogen. The pathophysiology of the infection involves a chain of reactions from infectious agent, reservoir, colonization into the host, exit, and transmission to a new host. For the entry of pathogens into the host, there are different modes of transmission. In some infections, the living host and nonliving objects act as the reservoirs for the disease progression. Proper diagnosis of the infection is necessary for the better treatment of diseases, but some infections are asymptomatic in nature. Prevention is the better way to avoid the infection because of the generation of antibiotic-resistant strains.

2: Bacterial infections and mechanism of pathogenesis

Bacterial infection refers to the invasion of bacteria into the body, which multiply and cause harm to the host. Pathogenicity is the ability of an organism to cause a disease. Pathogens are of three types based on their pathogenicity. Opportunistic pathogen causes infection when the host is an immunocompromised individual. Primary pathogens are the prime cause for the diseases, and the other group is nonpathogenic in nature but becomes pathogenic due to some external factors [1]. The modes of transmission of the pathogen to the humans are through air, water, food, or living vectors. Humans, animals, and arthropods serve as reservoirs, whereas nonliving reservoirs include food, water, soil, fomites, and air (Fig. 1). Infections transmitted through animals are called zoonoses, which can be spread through direct contact, bite, contact with the secretion, inhalation, or contact with the fecal particles. The arthropods that serve as vectors especially are mosquito, flies, fleas, lice, etc. [2].

Fig. 1

Fig. 1 Different modes of transmission of bacterial pathogen to the host [2] .

Host susceptibility to infection is determined by the condition of the host especially physiological and immunologic conditions as well as the bacterial virulence. Host body defends the invading pathogen via the innate immune response while the adaptive immune response is activated after several days. Host resistance can be affected based on the health condition of the host, and for example, it will be disrupted when there is any trauma in the skin surface. Virulence factors in the pathogens are encoded in the plasmid and/or chromosomal DNA, due to the transfer of genetic material via gene transfer mechanism contributing to the development of antimicrobial resistance pathogens, which are hard to treat.

Virulence factors secreted by the pathogens help in the cellular colonization of the host. Adherence factors such as adhesins are essential for the binding to the host mucosa, epithelial cells, attachment to the matrix components of the host cells, and also help in biofilm formation. Adhesin binding to the host cell receptors induces the signaling pathways and leads to the activation of morphological changes, immune system, and also apoptosis. The secretory pathways possessed by the bacterial pathogen can deliver various proteins as well as the toxins. In Gram-negative bacteria, there are six secretory systems to deliver the toxins and proteins into the host cells. Type 1 secretion system is an ATP-dependent pathway, and the substrates involved in the secretion are exotoxin, adhesin, and proteases. Type 2 secretion system is a two-step process, which delivers the toxins such as cholera toxin, staphylolysin, protease, and exotoxin. Types 3 and 6 are single-step processes where the toxins are directly injected into the host cells [3].

Bacterial toxins are polypeptides produced by the pathogenic bacteria, cause damage to the cells, and help in the proliferation of pathogen. Exotoxin is the most virulence factor that affects the host via disrupting the membrane structures and intracellular signaling pathways. Exotoxins are of three different types based on the effect: enterotoxin, neurotoxin, and cytotoxin. Neurotoxin produced by Clostridium botulinum affects the motor neurons and prevents the release of acetylcholine at the neuromuscular junction and causes flaccid paralysis. Enterotoxin, which stimulates the increase in the secretion of water and electrolytes, results in the formation of watery diarrhea. Cytotoxin produced by the Corynebacterium diphtheriae inhibits the protein biosynthesis [1]. The host cell activates the immune system, but sometimes the overactivation of immune cells such as leukocytes secretes the toxic factors that damage the host tissues. This type of host-mediated pathogenicity was reported in the case of Gram-negative bacterial sepsis, tuberculosis, and leprosy [1].

Prevention of bacterial infection is one of the major ways to avoid the antimicrobial resistance. The major principles in the control of bacterial infections are: elimination of the source of infection, disruption of transmission process, and protection of the host. The spread of disease from one to another can be prevented by self-restriction/isolation. The use of hand wash or sanitizer after contact with the body secretions, contaminated objects, and hygienic practices can prevent the spreading of infection. Antibiotic prophylactic measures and also the lifestyle changes can prevent the bacterial infections. Using microscopy, the causative agents can be visualized after staining. Commercially available antigen detection kits are useful for the immediate determination of bacterial infections. Nucleic acid probe and polymerase chain reaction are useful for the detection of pathogens. Culturing the samples or bacteria in selective or differential media can understand the growth morphology of the bacteria. Antigen–antibody interaction helps in the determination of disease-associated antigen or antibody in the serum of the host [2]. Treatment of the bacterial infections includes the use of antimicrobial agents. Due to the emergence of antimicrobial resistance, the use of conventional antibiotics is ineffective. There are three main resistance mechanisms involved in the bacterial cells to prevent the attack from the antibiotics: (1) target site alteration, (2) membrane permeability, and (3) enzyme inactivation. In order to avoid the antibiotic resistance, better treatment strategies are necessary to combat the progression of disease and hence mortality.

3: Types of bacterial infections and pathophysiology

3.1: Skin infections

Skin is the largest physical barrier that separates the internal parts from the external environment. It acts as a protective layer against injuries and hazardous materials and also helps to retain the moisture. The surface of the skin is colonized by various commensals and prevents the entry of pathogenic microorganisms. This is achieved by occupying the spaces, nutrients, toxic metabolite production, and also enhancing the immune system of the host system.

Necrotizing fasciitis (NF) is an acute, infectious disease that affects the superficial skin and also the necrosis of fascia, subcutaneous tissues, which leads to sepsis, shock, and death [4]. Studies reported that the NF are classified into four types [5]. Type I is the most common type of infection known as polymicrobial type, which accounts for 70%–90% of the infections. Type II infection or monomicrobial type is affected by Streptococcus pyogenes. In some cases, about 10%–30% of infections are caused by Staphylococcus aureus toxins, leads to necrosis and WBC destruction. Type III infections are mainly due to Clostridium species or by Gram-negative species, which can enter through the external injuries. Vibrio spp. and Aeromonas are able to cause type III infections. Type IV infections are formed due to the fungal species such as Candida spp. and Zygomycetes, and higher cases were observed in immunocompromised individuals. The portal of entry of pathogen is through the skin via injuries, insect bites, catheter insertions, etc. [4]. The symptoms started to appear within 48 h such as erythema, pain, edema, and necrosis of the tissues [6].

Impetigo is a type of epidermal, highly contagious infection affecting the children. The main causative agents are S. aureus and S. pyogenes. The main portal of entry is through direct skin invasion or wounds. There are two forms of impetigo: nonbullous, characterized by itchy yellow crusting lesion, and mainly affected parts are face. Bullous impetigo characterized by a bullae, which forms a brown crust, mainly caused by S. aureus[7].

Ecthyma is a form of impetigo having ulcerations with erythematous border, affects all age groups and genders. The pathogenic lesions appear in the axillary as well as anus and genital regions, but the other parts such as the legs, face, and trunk can also be affected. Pseudomonas aeruginosa is the prominent organism affecting almost 74% of the cases. The other organisms that can cause ecthyma are methicillin-resistant S. aureus (MRSA), S. pyogenes, Citrobacter freundii, Escherichia coli, Aeromonas hydrophila, Klebsiella pneumoniae, Serratia marcescens, Xanthomonas maltophilia, Morganella morganii, Corynebacterium diphtheriae, Neisseria gonorrhoeae, Yersinia pestis, Candida species, and herpes virus [8]. Erysipelas is an acute infection caused by beta-hemolytic streptococci, S. pyogenes, commonly affecting the lymphatic system. The lesions occur as sharp demarcation of the skin especially on the face.

3.2: Eye infections

Eye is one of the sensory organs, which helps in vision. Eye infection is common in healthcare settings. Several bacterial species can cause eye infection such as S. aureus, Streptococcus spp., Haemophilus influenza, P. aeruginosa, N. gonorrhoeae, and Chlamydia trachomatis. Conjunctivitis, keratitis, and endophthalmitis are the important eye infections caused by the bacterial species. Conjunctivitis is a common eye infection due to the dilation of the conjunctival blood vessels as a result of viral or bacterial infection, chemical exposure to the eyes, and allergens [9]. The eyes of the person infected with viral or bacterial conjunctivitis appear as red in color, which is more common among children. Bacterial conjunctivitis can be transmitted from one person to another through objects, hand-to-eye contact and also the droplets. H. influenza, Streptococcus pneumoniae, Moraxella catarrhalis, and S. aureus are the important bacteria causing conjunctivitis. Gonococcal conjunctivitis is a bacterial eye infection caused by N. gonorrhoeae, which affects the neonates and sexually active adults. Chlamydial conjunctivitis caused by C. trachomatis consists of symptoms such as mucopurulent discharge from the eyes, swollen eyes, redness, photophobia, itching, and swollen lymph nodes around the eyes [10,11].

Keratitis is an acute or chronic corneal tissues infection, caused due to the invasion of virus, fungi, protozoa, and bacteria. The causative agents of bacterial keratitis are S. aureus, coagulase-negative Staphylococci, S. pneumoniae, and P. aeruginosa. One of the major reasons for the occurrence of bacterial infection is the use of contact lens. Lack of hygiene, sharing, contact with tap water, overnight use, improper cleaning of lens, contamination, etc. are the possible causes for the infection. N. gonorrhoeae, C. diphtheriae, Hemophilus aegyptius, and Listeria monocytogenes can penetrate the corneal epithelial cells. The common signs and symptoms of keratitis are pain, photophobia, discharge, blurred vision, redness, and ulcers [10,12].

Endophthalmitis is an ocular infection that mainly affects the posterior portion of the eye, and the causative agents are bacteria and fungi. The exogenous portal of entry of bacteria into the ocular globe of the eye is through trauma or surgery, and the bacteria are seeded into the eye exogenously. One of the major problems of endophthalmitis is the damage to the photoreceptor cells of the retina [13], which leads to blurred vision. The sign and symptoms are pain, redness, decreased vision. Coagulase-negative Staphylococci, Bacillus, and fungi are the predominant etiological agents, Streptococcus pneumonia, Enterococci, or Haemophilus influenzae is involved in the bleb-related endophthalmitis. P. aeruginosa secretes toxins and virulence factors that cause the rapid tissue necrosis, leads to endophthalmitis [10,14].

3.3: Bacterial meningitis

Meninges is the protective coat that covers the brain and the spinal cord. Meningitis is the acute inflammation of the meninges layer especially the pia mater and the arachnoid by the bacteria. Besides bacteria, fungi and virus are the main causative agents reported in meningitis; they replicate and cause inflammation. In neonates, group B Streptococcus agalactiae, Escherichia coli, and L. monocytogenes are the causative agents, while in adults and children, S. pneumoniae and Neisseria meningitidis are responsible for meningitis [15]. Previously, the causative agent was H. influenzae, which was successfully eliminated via vaccination. Pneumococci are other important bacteria that cause meningitis in adults and children, but the use of conjugate vaccines declined the infection rate [16]. Pneumococcus secretes the cytotoxin called pneumolysin, which causes neuronal damage and also produces hydrogen peroxide, which causes DNA damage and cell death [17]. N. meningitidis is one of the leading pathogens in the developing countries. One of the indications of bacterial meningitis is the accumulation of leukocytes in the cerebrospinal fluid. Early signs and symptoms include fever, malaise, headache, in the late-phase meningismus, photophobia, phonophobia, vomiting, etc., develop. The bacteria present in the systemic circulation penetrate the blood–brain barrier, infect the brain, and further lead to inflammation. In the cerebrospinal fluid (CSF), elevated number of leukocyte counts and also the elevated protein content indicate the blood–CSF barrier disruption [16].

3.4: Otitis media

The inflammation of the middle ear and tympanic membrane is called otitis media. The infections exhibit a spectrum of infections such as acute otitis media, effusion, and chronic suppurative otitis media [18,19]. Acute otitis media exhibits symptoms such as fever, irritability, and otalgia. Asymptomatic infections with accumulated fluid in the middle ear are observed in otitis media with effusion [20]. Otitis media can also become a secondary infection to upper respiratory tract infections. Even, allergy infections, anatomical or functional changes in the middle ear and Eustachian tube may cause otitis media. Otitis media is graded as the fifth most global burden and second most cause of hearing loss affecting approximately 1.23 billion people globally. Otitis media is commonly observed in children [21]. Chronic and recurrent otitis media is associated with hearing loss, declined learning capability, and low education. It is reported that around thousands of people including children of 5 years or below die due to the complications related to otitis media every year [22,23].

Microbiology of otitis media includes bacteria, fungi, and viruses. The bacterial pathogens are S. pneumoniae, P. aeruginosa, S. aureus, P. mirabilis, E. coli, S. pyogenes, M. catarrhalis, and H. influenzae. The pathogenesis initiates with the colonization of pathogen in the nasopharynx followed by the disruption of mucociliary system. The adhesion and invasion of octopathogens leading to biofilm formation and persistent infection cause acute inflammation of the middle ear and eventually chronic ear disease, thus interrupting the host immune system defense and permitting the attachment and invasion of the pathogen leading to otitis media [24,25].

Long-term prophylactic measures including antibiotic therapy may reduce the risk associated with otitis media [20]. Oral paracetamol and ibuprofen are provided to relieve the symptoms of acute otitis media, ear pain, and fever. For the effective treatment of otitis media complications, patients with penicillin allergy are suggested to use amoxicillin, macrolides, cefdinir, cefuroxime, or clarithromycin [25].

3.5: Upper and lower respiratory tract infections

The bacterial respiratory tract infections are observed in the sinuses, throat, lungs, and airways. Bacteria cause infections to both the upper and lower respiratory tracts. The lower and upper respiratory tract infections include common cold, sinusitis, pharyngitis, epiglottitis, laryngotracheitis, otitis media, bronchitis, and pneumonia [26]. Reports says that lower respiratory tract infections account for around 2.6 million deaths in the year 2013, and it continues to increase by years