Antibiotic

Antimicrobial Agents

Antimicrobial agents are substances produced by microorganisms that selectively suppress the growth of or kill other microorganisms at very low concentrations. This definition excludes natural substances that also inhibit microorganisms but are produced by higher forms (e.g., antibodies) or those produced by microbes but are needed in high concentrations (such as ethanol, lactic acid, and H2O2).

Initially, the term "chemotherapeutic agent" was restricted to synthetic compounds. However, since many antibiotics and their analogues have been synthesized, this criterion has become irrelevant. Both synthetic and microbiologically produced drugs need to be included together. The term Antimicrobial agent (AMA) is used to designate synthetic as well as naturally obtained drugs that attenuate microorganisms.

History

The history of chemotherapy may be divided into three phases:

Phase 1: The Period of Empirical Use

This phase includes the use of:

• "Mouldy curd" by the Chinese on boils
• Chaulmoogra oil by the Hindus in leprosy
• Chenopodium by the Aztecs for intestinal worms
• Mercury by Paracelsus (16th century) for syphilis
• Cinchona bark (17th century) for fevers

Phase 2: Ehrlich's Phase of Dyes and Organometallic Compounds (1890–1935)

With the discovery of microbes in the latter half of the 19th century and their role in causing many diseases, Paul Ehrlich proposed that if certain dyes could selectively stain microbes, they could also be selectively toxic to these organisms. He experimented with methylene blue, trypan red, and others. Ehrlich developed the arsenicals—atoxyl for sleeping sickness, arsphenamine in 1906, and neoarsphenamine in 1909 for syphilis. He coined the term "chemotherapy" because he used drugs of known chemical structure (unlike most other drugs in use at that time) and demonstrated that selective attenuation of infecting parasites was possible.

Phase 3: The Modern Era of Chemotherapy

This phase began in 1935 when Gerhard Domagk demonstrated the therapeutic effect of Prontosil, a sulfonamide dye, in pyogenic infection. It was soon realized that the active moiety was paraamino benzene sulfonamide, and the dye part was not essential. Sulfapyridine (M & B 693) was the first sulfonamide to be marketed in 1938.

Louis Pasteur demonstrated the phenomenon of antibiosis in 1877: growth of anthrax bacilli in urine was inhibited by air-borne bacteria. In 1929, Alexander Fleming discovered that a diffusible substance was elaborated by Penicillium mould, which could destroy Staphylococcus on the culture plate. He named this substance penicillin but could not purify it. Howard Florey and Ernst Chain followed up this observation in 1939, culminating in the clinical use of penicillin in 1941. Due to its great potential for treating war wounds, commercial manufacture of penicillin soon began.

In the 1940s, Selman Waksman and his colleagues undertook a systematic search for Actinomycetes as a source of antibiotics and discovered streptomycin in 1944. This group of soil microbes proved to be a treasure trove of antibiotics, and soon tetracyclines, chloramphenicol, erythromycin, and many others followed. All three groups of scientists—Domagk, Fleming-Chain-Florey, and Waksman—received the Nobel Prize for their discoveries.

Semisynthetic Antibiotics

In the past 40 years, the emphasis has shifted from searching for new antibiotic-producing organisms to developing semisynthetic derivatives of older antibiotics with more desirable properties or differing spectrum of activity. A few novel synthetic AMAs, such as fluoroquinolones and oxazolidinones, have also been produced.

Staphylococcus Aureus Susceptibility

Main article: Staphylococcus aureus susceptibility

Staphylococcus aureus susceptibility refers to the ability of this bacterium to be affected by certain antimicrobial agents. The susceptibility of a particular strain of Staphylococcus aureus to different antibiotics can vary, making it essential to choose the appropriate antimicrobial agent for treatment.

Staphylococcus aureus susceptibility

(c) The modern era of chemotherapy was ushered by Domagk in 1935 by demonstrating the therapeutic effect of Prontosil, a sulfonamide dye, in pyogenic infection. It was soon realized that the active moiety was paraamino benzene sulfonamide, and the dye part was not essential. Sulfapyridine (M & B 693) was the first sulfonamide to be marketed in 1938.

Pasteur

The phenomenon of antibiosis was demonstrated by Pasteur in 1877: growth of anthrax bacilli in urine was inhibited by air-borne bacteria. Fleming (1929) found that a diffusible substance was elaborated by Penicillium mould which could destroy Staphylococcus on the culture plate. He named this substance penicillin but could not purify it. Chain and Florey followed up this observation in 1939 which culminated in the clinical use of penicillin in 1941. Because of the great potential of this discovery in treating war wounds, commercial manufacture of penicillin soon started.

Waksman

In the 1940s, Waksman and his colleagues undertook a systematic search of Actinomycetes as source of antibiotics and discovered streptomycin in 1944. This group of soil microbes proved to be a treasure-house of antibiotics and soon tetracyclines, chloramphenicol, erythromycin and many others followed. All three groups of scientists, Domagk, Fleming-Chain-Florey and Waksman received the Nobel Prize for their discoveries.

Semisynthetic antibiotics

In the past 40 years emphasis has shifted from searching new antibiotic producing organisms to developing semisynthetic derivatives of older antibiotics with more desirable properties or differing spectrum of activity. Few novel synthetic AMAs, e.g. fluoroquinolones, oxazolidinones have also been produced.

CLASSIFICATION

Antimicrobial drugs can be classified in many ways:

• Chemical structure

1. Sulfonamides and related drugs: Sulfadiazine and others, Sulfones—Dapsone (DDS), Para aminosalicylic acid (PAS).
2. Diaminopyrimidines: Trimethoprim, Pyrimethamine.
3. Quinolones: Nalidixic acid, Norfloxacin, Ciprofloxacin, Gatifloxacin, etc.
4. β-Lactam antibiotics: Penicillins, Cephalosporins, Monobactams, Carbapenems.
5. Tetracyclines: Oxytetracycline, Doxycycline, etc.
6. Nitrobenzene derivative: Chloramphenicol.
7. Aminoglycosides: Streptomycin, Gentamicin, Amikacin, Neomycin, etc.
8. Macrolide antibiotics: Erythromycin, Clarithromycin, Azithromycin, etc.
9. Lincosamide antibiotics: Lincomycin, Clindamycin.
10. Glycopeptide antibiotics: Vancomycin, Teicoplanin.
11. Oxazolidinone: Linezolid.
12. Polypeptide antibiotics: Polymyxin-B, Colistin, Bacitracin, Tyrothricin.
13. Nitrofuran derivatives: Nitrofurantoin, Furazolidone.
14. Nitroimidazoles: Metronidazole, Tinidazole, etc.
15. Nicotinic acid derivatives: Isoniazid, Pyrazinamide, Ethionamide.
16. Polyene antibiotics: Nystatin, Amphotericin-B, Hamycin.
17. Azole derivatives: Miconazole, Clotrimazole, Ketoconazole, Fluconazole.
18. Others: Rifampin, Spectinomycin, Sod. fusidate, Cycloserine, Viomycin, Ethambutol, Thiacetazone, Clofazimine, Griseofulvin.

1. Inhibit cell wall synthesis: Penicillins, Cephalosporins, Cycloserine, Vancomycin, Bacitracin.
2. Cause leakage from cell membranes: Polypeptides—Polymyxins, Colistin, Bacitracin. Polyenes—Amphotericin B]], Nystatin, Hamycin.
3. Inhibit protein synthesis: Tetracyclines, Chloramphenicol, Erythromycin, Clindamycin, Linezolid.
4. Cause misreading of m-RNA code and affect permeability: Aminoglycosides—Streptomycin, Gentamicin, etc.
5. Inhibit DNA gyrase: Fluoroquinolones— Ciprofloxacin and others.
6. Interfere with DNA function: Rifampin, Metronidazole.
7. Interfere with DNA synthesis: Acyclovir, Zidovudine.
8. Interfere with intermediary metabolism: Sulfonamides, Sulfones, PAS, Trimethoprim, Pyrimethamine, Ethambutol.

• Type of organisms against which primarily active

1. Antibacterial: Penicillins, Aminoglycosides, Erythromycin, etc.
2. Antifungal: Griseofulvin, Amphotericin B, Ketoconazole, etc.
3. Antiviral: Acyclovir, Amantadine, Zidovudine, etc.
4. Antiprotozoal: Chloroquine, Pyrimethamine, Metronidazole, Diloxanide, etc.
5. Anthelmintic: Mebendazole, Pyrantel, Niclosamide, Diethyl carbamazine, etc.

• Spectrum of activity

1. Narrow-spectrum: Penicillin G, Streptomycin, Erythromycin.
2. Broad-spectrum: Tetracyclines, Chloramphenicol.

• Type of action

1. Primarily bacteriostatic: Sulfonamides, Erythromycin, Tetracyclines, Ethambutol, Chloramphenicol, Clindamycin, Linezolid.
2. Primarily bactericidal: Penicillins, Cephalosporins, Aminoglycosides, Vancomycin, Polypeptides, Nalidixic acid, Rifampin, Ciprofloxacin, Isoniazid, Metronidazole, Pyrazinamide, Cotrimoxazole.

• Antibiotics are obtained from

1. Fungi: Penicillin, Griseofulvin, Cephalosporin.
2. Bacteria: Polymyxin B, Tyrothricin, Colistin, Aztreonam, Bacitracin.
3. Actinomycetes: Aminoglycosides, Macrolides, Tetracyclines, Polyenes, Chloramphenicol.

Overuse of antibiotics

Antibiotics save lives, but any time antibiotics are used, they can cause side effects and lead to antibiotic resistance. In U.S. doctors’ offices and emergency departments, at least 47 million antibiotic prescriptions each year are unnecessary, which makes improving antibiotic prescribing and use a national priority, according to the CDC.

Antibiotic resistance

Antibiotic resistance is one of the biggest public health challenges of our time. Each year in the U.S., at least 2.8 million people get an antibiotic-resistant infection, and more than 35,000 people die, according to the CDC.

History of antibiotic resistance

Penicillin, the first commercialized antibiotic, was discovered in 1928 by Alexander Fleming. Ever since, there has been discovery and acknowledgement of resistance alongside the discovery of new antibiotics. In fact, germs will always look for ways to survive and resist new drugs. More and more, germs are sharing their resistance with one another, making it harder for us to keep up.

Select Germs Showing Resistance Over Time

Select Germs Showing Resistance Over Time

Antibiotic Approved or Released	Year Released	Resistant Germ Identified	Year Identified
Penicillin	1941	Penicillin-resistant Staphylococcus aureus Penicillin-resistant Streptococcus pneumoniae Penicillinase-producing Neisseria gonorrhoeae	1942 1967 1976
Vancomycin	1958	Plasmid-mediated vancomycin-resistant Enterococcus faecium Vancomycin-resistant Staphylococcus aureus	1988 2002
Amphotericin B	1959	Amphotericin B-resistant Candida auris	2016
Methicillin	1960	Methicillin-resistant Staphylococcus aureus	1960
Extended-spectrum cephalosporins	1980 (Cefotaxime)	Extended-spectrum beta-lactamase- producing Escherichia coli	1983
Azithromycin	1980	Azithromycin-resistant Neisseria gonorrhoeae	2011
Imipenem	1985	Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae	1996
Ciprofloxacin	1987	Ciprofloxacin-resistant Neisseria gonorrhoeae	2007
Fluconazole	1990 (FDA approved)	Fluconazole-resistant Candida	1988
Caspofungin	2001	Caspofungin-resistant Candida	2004
Daptomycin	2003	Daptomycin-resistant methicillin-resistant Staphylococcus aureus	2004
Ceftazidime-avibactam	2015	Ceftazidime-avibactam-resistant KPC-producing Klebsiella pneumoniae	2015

Antibiotic stewardship

Antibiotic stewardship is the effort to measure antibiotic prescribing; to improve antibiotic prescribing by clinicians and use by patients so that antibiotics are only prescribed and used when needed; to minimize misdiagnoses or delayed diagnoses leading to underuse of antibiotics; and to ensure that the right drug, dose, and duration are selected when an antibiotic is needed.

Benefits of antibiotic stewardship

Antibiotic stewardship can be used in all health care settings in which antibiotics are prescribed and remains a cornerstone of efforts aimed at improving antibiotic-related patient safety and slowing the spread of antibiotic resistance.

Goal of antibiotic stewardship

The goal of antibiotic stewardship is to maximize the benefit of antibiotic treatment while minimizing harm both to individual persons and to communities.

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