Antibiotics

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Antibiotics

Introduction

Different drugs have been developed over the past centuries to combat various disease processes that occur in living organisms. Several of these drugs prove lifesaving in many instances.

Antibiotics are drugs that work against bacteria. They either kill bacteria or stop their growth within the bodies of other living organisms. They are used worldwide to treat bacterial infections. Today, we have a wide range of antibiotics that are used in different infectious diseases.

Most of these antibiotics are derived from the bodies of living organisms. However, some are being synthesized in the labs by microbiologists. Different chemical substances are also added to antibiotics to enhance their effect.

Antibiotics provide some of the most dramatic examples of the advancement in modern science. There are a number of infectious diseases that were once considered incurable can now be treated with a few pills of antibiotics. The powerful and specific action of antibiotics is due to their selectivity of the targets. Different antibiotics are used against different strains of bacteria. Each category of antibiotics has its own mechanism of action.

In this article, we will talk about a brief history of antibiotics, various classes of antibiotics, their mechanism of action, uses, and side effects.

History

In 1909, Paul Ehrlich, a German physician, discovered the chemical arsphenamine that was able to treat Syphilis. This chemical could kill the bacteria responsible for Syphilis. Thus, arsphenamine technically became the first antibiotic in history. However, Ehrlich used the term chemotherapy for his discovery.

The first antibiotic to be discovered was penicillin. It was accidentally discovered by Sir Alexander Fleming in 1928. He found that a fungus called Penicillium notatum stunted the growth of bacteria on a culture plate. The fungus accidentally got into the culture plate and created freeze zones around the bacterial growths on the culture plate.

Fleming later continued experimentation and proved that P. notatum could stop bacterial growth at very low concentrations and was less toxic than the disinfectants that were used at that time.

Later, various pharmaceutical companies started making penicillin at mass levels, and it was made available in the market worldwide. Since then, hundreds of antibiotics have been made and are available in the market for the treatment of infectious diseases.

Mechanism of Action

Antibiotics are divided into multiple classes on the basis of their mechanism of action. Most antibiotics kill bacteria or stop their growth by one of the following mechanisms. Classes of antibiotic are also mentioned, along with each mode of action.

  • Inhibition of bacterial cell wall synthesis

This method is used by penicillins, cephalosporins, imipenem, aztreonam, vancomycin.

  • Inhibition of bacterial protein synthesis

This is the mechanism of action of macrolides, aminoglycosides, chloramphenicol, tetracyclines, streptogramins.

  • Inhibition of nucleic acid synthesis

Fluroquinolones and rifampin use this method.

  • Inhibition of folic acid synthesis

It is used by sulfonamides, trimethoprim and pyrimethamine.

Further detail of each of these classes is discussed below.

Penicillins

As mentioned earlier, penicillins were the first antibiotics to be discovered. They are divided into multiple classes based on their antimicrobial activity. Details about this class of antibiotics is as follows.

Mechanism of Action

A bacterial cell wall is a cross-linked polymer of polysaccharides and pentapeptides. Penicillins inhibit the synthesis of the bacterial cell wall by inhibiting the transpeptidation reaction. This reaction is involved in cross-linking the final steps in the synthesis of the bacterial cell wall. Penicillins do so by binding to cytoplasmic membrane-binding proteins called penicillin-binding proteins (PBPs).

Subgroups

Penicillins are divided into the following subgroups based on the cover provided against various strains of bacteria.

Narrow Spectrum

These are beta-lactamase sensitive and thus are not effective against bacteria having beta-lactamase enzyme. These include penicillin G and penicillin V. They provide cover against streptococci, pneumococci, meningococci, and Treponema pallidum.

Very Narrow Spectrum

They are beta-lactamase resistant and include nafcillin, methicillin, and oxacillin. Their spectrum is very narrow and provides cover against staphylococci only. It does not include methicillin-resistant staphylococci (MRSA).

Broad Spectrum

These include beta-lactamase sensitive aminopenicillins such as ampicillin and amoxicillin. They provide cover against gram-positive cocci, E. coli, H. influenzae, Listeria monocytogenes, Borrelia and H. pylori.

Extended Spectrum

These are beta-lactamase sensitive anti-pseudomonal penicillins. These include ticarcillin and piperacillin. They provide cover against gram-negative rods, including Pseudomonas aeruginosa.

Mechanism of Resistance

Bacteria can develop resistance against penicillins by the following three mechanisms.

  • Penicillins have a beta-lactam ring in their structure. Some bacteria have a beta-lactamase enzyme, also called penicillinase, that breaks down the beta-lactam ring. It is present in staphylococci.
  • Some bacteria can introduce some changes in the penicillin-binding proteins (PBPs), as seen in methicillin-resistant staphylococcus aureus.
  • Bacteria can also develop penicillin-resistant by changing the porin structure, as seen in the case of Pseudomonas.

Side Effects

Following are the common side effects that can develop in a person taking penicillins.

  • Hypersensitivity: Its incidence is 5-7% with multiple ranges of hypersensitivity reactions. The most common is an urticarial skin rash. Severe reactions, including anaphylaxis, are also possible in some individuals.
  • GI distress, including vomiting and diarrhoea is seen especially with ampicillin.
  • Jarisch-Herxheimer reaction is seen in the treatment of Syphilis.

Cephalosporins

Cephalosporins are another important group of antibiotics. They are widely used in the infections of the upper respiratory system, urinary system, etc. They also act by inhibiting the bacterial cell wall synthesis, thus limiting the growth of bacteria.

Mechanism of Action

Cephalosporins are also beta-lactam drugs and act in the same way as penicillins. They inhibit cell wall synthesis by preventing the cross-linking.

Generations

Cephalosporins are divided into four generations based on the antibiotic cover provided by them. The four generations are mentioned below.

First Generation

  • These include cefazolin and cephalexin.
  • These antibiotics provide cover against gram-positive cocci, E. coli, Klebsiella pneumonia, and Proteus species.
  • They found common use in surgical prophylaxis worldwide.
  • One important feature of cephalosporins is that they do not enter the CNS.

Second Generation

  • These include cefotetan, cefaclor, and cefuroxime.
  • These cephalosporins have increased gram-negative cover along with some anaerobes.
  • Only cefuroxime can enter the CNS.

Third Generation

  • These include ceftriaxone that is given IM, cefotaxime that is given parenteral, and cefdinir and cefixime that are given orally.
  • The third-generation cephalosporins provide increased coverage against gram-positive and gram-negative cocci as well as some gram-negative rods.
  • As most of these drugs can enter the CNS, they are more important in the management of bacterial meningitis and sepsis.

Fourth Generation

  • It includes only one drug, cefepime. It is always given IV.
  • It has the widest coverage among the cephalosporins.
  • It is resistant to beta-lactamase enzyme and can enter CNS.

Mechanism of Resistance

The mechanism of resistance of cephalosporins is also similar to that of penicillins.

Side Effects

These drugs have quite a number of side effects. Some important ones are listed below.

  • Hypersensitivity reaction is seen in 2% of the people taking cephalosporins. The symptoms have a wide range, but rashes and drug fever are the most common.
  • The patient taking cephalosporins have a positive Coombs test. However, it does not always mean hemolysis. Hemolysis is seen only in rare cases.

It should be kept in mind that if a person is allergic to one class of cephalosporins, complete cross allergenicity should be assumed. Also, if a person is allergic to cephalosporins, penicillins cannot be used in such patients.

Imipenem and Meropenem

These are the beta-lactam drugs, having a beta-lactam ring in their structure similar to the antibiotics discussed earlier. They have a very broad spectrum and are resistant to the beta-lactamase enzyme found in some bacteria.

These drugs provide cover against gram-positive cocci, gram-negative rods and a number of anaerobes.

They are widely used in terminally ill patient to treat severe life-threatening infections.

Both these drugs undergo renal clearance. Thus, their dose is decreased in patients having renal dysfunction.

Side Effects

These include:

  • GI distress like nausea, vomiting, diarrhoea
  • Drugs fever
  • CNS symptoms such as seizures in case of high dose. Seizures can also occur in renal dysfunction patients who are given imipenem.

Vancomycin

Vancomycin is another widely used antibiotic that performs its action by inhibiting bacterial cell wall synthesis. Brief details about this drug are discussed below.

Mechanism of Action

It acts by binding to the terminal muramyl peptide in the synthesis of proteoglycan. In this way, it creates a steric hindrance and prevents transglycosylation reactions. This, in turn, prevents the elongation of peptidoglycan chains.

It does not interact with penicillin-binding proteins, unlike the antibiotics discussed above.

Vancomycin is used orally in most patients. However, in case of colitis, it is given in IV. It cannot enter the CNS tissues. As vancomycin is also removed via renal clearance, its dose must be decreased in patients with renal dysfunction.

Spectrum

Although then the spectrum of vancomycin is narrow, it is important as it provides cover against bacteria that are resistant to other antibiotics.

Vancomycin is used in case of infection caused by methicillin-resistant Streptococcus aureus (MRSA), enterococci and in Clostridium difficile.

Mechanism of Resistance

The vancomycin-resistant strain of bacteria is also emerging. They develop resistance against this drug by changing the muramyl peptide target as we know that vancomycin binds to terminal D-ala. Bacteria develop resistance by replacing D-ala with D-lactate.

Side Effects

Following are the important side effects of vancomycin.

  • Rapid infusion of vancomycin can cause the release of histamine, resulting in increased local blood flow and flushing. This is known as “Redman syndrome”.
  • It is harmful to the ears. Ototoxicity caused by vancomycin is permanent.
  • Vancomycin is also toxic to kidney tissue. Its nephrotoxicity is mild but is markedly enhanced if other nephrotoxic drugs are also being used.

Aminoglycosides

These are antibiotics that kill bacteria by inhibiting the synthesis of proteins. A continuous supply of proteins is necessary for the survival and growth of bacteria. Inhibiting protein synthesis can cause the death of bacteria. Some details about this class of antibiotics are discussed below.

Mechanism of Action

Aminoglycosides inhibit the formation of the initiation complex. They do so in the following ways:

  • By interfering with the function of initiation codon function
  • By blocking the association of bacterial 50S rRNA with 30S rRNA
  • By causing misreading of codons
  • By causing the incorporation of a wrong amino acid in the polypeptide chain

Aminoglycoside is taken up by bacteria via an oxygen-dependent pathway. Thus, they do not work with anaerobic bacteria.

All the above-mentioned processes result in either the inhibition of protein synthesis or synthesis of abnormal proteins. Both these ultimately result in the death of bacteria.

These drugs cannot be absorbed if given orally. So, they are always given via IM or IV injections. They are eliminated from the body via renal clearance.

Spectrum

Aminoglycosides provide cover against gram-negative rods. They are often used in combinations such as gentamycin with tobramycin and amikacin.

They also have synergistic action with other antibiotics in the treatment of some infections like:

  • Aminoglycosides are used with penicillin G or ampicillin in the treatment of enterococcal infections
  • They are used synergistically with third-generation cephalosporins to treat Pseudomonas infection

Streptomycin is an important aminoglycoside that is used as the drug of choice in the treatment of tuberculosis and bubonic plague.

Mechanism of Resistance

Bacteria develop resistance to aminoglycoside by developing certain conjugating enzymes. These enzymes render the drug inactive by conjugating them with certain groups like acetyl, phosphoryl or adenyl groups.

Side Effects

Aminoglycosides are antibiotics that have some major side effects. The most important ones are discussed below.

  • Nephrotoxicity is the most common side effect that is seen in 6-7% of individuals. It can cause proteinuria (plasma proteins lost in urine), hypokalemia (decreased potassium level), acidosis and acute necrosis of the kidney tubule. All these side effects are reversible if the drug is stopped. However, they are further enhanced if other nephrotoxic drugs are used like vancomycin, etc.
  • Ototoxicity is seen in 2% of the individuals. They affect the hearing process by damaging the hair cells in the cochlea and vestibule. Deafness is irreversible, while vestibular dysfunction is reversible. The symptoms can be enhanced by other ototoxic drugs.
  • They can also cause contact dermatitis and skin infections.

Macrolides

Macrolides are also bacteriostatic in nature. They inhibit bacterial growth by inhibiting protein synthesis. These drugs are widely used to treat a number of bacterial infections. A brief detail is mentioned below.

Mechanism of Action

Macrolides inhibit protein synthesis by interfering with the translocation process. They inhibit the translocation of peptidyl-tRNA from the acceptor site to the donor site. Thus, the peptide synthesis is inhibited.

Spectrum

Macrolides include three drugs, i.e., erythromycin, azithromycin, and clarithromycin. They are wide spectrum antibiotics that provide cover against gram-positive cocci, atypical organisms, Legionella pneumophila, Campylobacter jejuni, H. pylori and MAC. They are drug of choice in the treatment of community-acquired pneumonia.

Mechanism of Resistance

Bacteria develop resistance against macrolides by the formation of methyltransferase enzymes. These enzymes can alter drug binding site on the surface of bacterial ribosomes. In this way, the drugs cannot perform their action.

Another method by which bacteria can develop resistance against macrolides is the active transport of drugs out of the cell.

Side Effects

Following are the important side effects of macrolides.

  • Macrolides can cause gastrointestinal distress as they stimulate motilin receptors
  • They can cause reversible deafness at higher doses
  • Increased QT interval can also be seen in some patients

Inhibitors of Folic Acid Synthesis

Folic acid is an important requirement for the survival and growth of bacteria. Unlike humans, bacteria can synthesize folic acid within their cells using pteridine and PABA as precursors. Some antibiotics can inhibit folic acid synthesis at multiple steps, thus inhibiting bacterial growth or killing them.

Mechanism of Action

This class includes sulfonamides, trimethoprim, and pyrimethamine.

Sulfonamides inhibit the first step in folic acid synthesis. They do so by inhibiting the dihydropteroate synthetase enzyme.

Trimethoprim and pyrimethamine inhibit the last step in folic acid synthesis. They are the inhibitors of the dihydrofolate reductase enzyme.

Clinical Uses

Sulfonamide alone is not that useful due to multiple resistance.

Along with certain combinations, they are used in ulcerative colitis and rheumatoid arthritis. In combination with silver, they are used in the treatment of burns.

The combination of sulfonamides with dihydrofolate reductase inhibitors decrease their resistance.

The combination regimen issued as the drug of choice against Nocardia and a backup drug for Listeria. It is also used in the treatment of certain gram-positive and gram-negative infections.

Side Effects

These drugs can cause the following side effects.

  • Sulfonamide can cause hypersensitivity reaction, hemolysis in G6PD deficiency as well as phototoxicity.
  • Dihydrofolate reductase inhibitors can cause bone marrow suppression.

Fluoroquinolones

These drugs inhibit the synthesis of nucleic acids in bacteria. Nucleic acids are needed for the replication of bacteria. Inhibition of nucleic acid synthesis prevents replication of bacteria within the human body, thus limiting their ability to invade tissues further.

Mechanism of Action

These are bactericidal in nature as they interfere with the process of DNA synthesis and replication. These antibiotics inhibit topoisomerase II and topoisomerase IV enzymes. These enzymes are responsible for the separation of replicated DNA during cell division.

Generations

Fluoroquinolones are divided into three generations based on their spectrum and clinical uses.

First Generation

These include norfloxacin. This drug is used in urinary tract infections. It is a narrow spectrum fluoroquinolone.

Second Generation

These include ciprofloxacin and ofloxacin. These provide increased cover against gram-negative bacteria, mycobacteria, and pneumonia. They are used in infections of the urogenital and gastrointestinal tracts.

Third Generation

These include levofloxacin and moxifloxacin. These drugs provide increased cover against gram-positive bacteria. They are also used against MRSA. These are most commonly used in the case of respiratory tract infections.

Mechanism of Resistance

Bacteria develop resistance against fluoroquinolones by changing the sensitivity of the target enzyme. Once the sensitivity is changed, the target enzyme cannot be inhibited. The resistance also increased by using transport mechanisms that promote the efflux of drug out of the bacterial cell cytoplasm.

Side Effects

Some important side effects of fluoroquinolones are as follows.

  • They can cause tendinitis and tendon rupture
  • They increase phototoxicity
  • Rashes can also appear on different areas of skin
  • They can cause CNS effects like insomnia, dizziness, and headache
  • GI upset is also an important side effect
  • They can cause prolongation of QT segment

Fluoroquinolones are contraindicated in pregnant women and in children.

Summary

  • Antibiotics are the drugs used to treat and prevent bacterial infections. They are either derived from the bodies of living organism or are made in the laboratory.
  • The first antibiotic was accidentally discovered by Sir Alexander Fleming while he was growing some bacteria on a culture plate. Some years before Fleming, a German physician discovered a compound that could effectively kill the bacteria responsible for Syphilis and treat the patients. However, he used the term chemotherapy instead of antibiotic for his discovery.
  • Antibiotics can either stop bacterial growth or kill the bacterial cells by employing one of the four mechanisms.
  • They can inhibit bacterial cell wall synthesis and thus stop their growth and replication. It is seen in the case of penicillins, cephalosporins, imipenem and meropenem. Vancomycin also inhibits bacterial cell wall synthesis. However, it employs a mechanism different from the ones discussed earlier.
  • Antibiotics can also inhibit protein synthesis, and either can kill bacteria or stop their growth. This method is used by aminoglycosides and macrolides.
  • Some antibiotics perform their action by inhibiting the synthesis of folic acid and thus are bactericidal. These include sulfonamides, trimethoprim and pyrimethamine.
  • Fluoroquinolones are the antibiotics that cause the death of bacteria by directly inhibiting the synthesis of nucleic acids.
  • Bacteria can develop resistance against these antibiotics by different methods that have been discussed in the chapter under subsequent headings.
  • Antibiotics can also produce some serious side effects that have also been mentioned.

References

  1. Gould, K (2016). “Antibiotics: From prehistory to the present day”. Journal of Antimicrobial Chemotherapy. 71 (3): 572–575. doi:10.1093/jac/dkv484. PMID 26851273.
  2. Gualerzi CO, Brandi L, Fabbretti A, Pon CL (4 December 2013). Antibiotics: Targets, Mechanisms and Resistance. John Wiley & Sons. p. 1. ISBN 978-3-527-33305-9.
  3. Antimicrobial resistance: global report on surveillance (PDF). The World Health Organization. April 2014. ISBN 978-92-4-156474-8. Retrieved 13 June 2016.
  4. Antibiotics Simplified. Jones & Bartlett Publishers. 2011. pp. 15–17. ISBN 978-1-4496-1459-1.