Antimicrobials : Classification, MOA, Uses, And Side Effects
Antimicrobials differ from all others in that they are designed to inhibit/kill the infecting organism and to have minimal or no effect on the recipient. This type of therapy is called chemotherapy; which means treatment of systemic infections with specific drugs that selectively suppress the infecting micro-organism without significantly affecting the host.
Antibiotics are substances produced by microorganisms, which selectively suppress the growth of or kill other microorganisms at very low concentrations. This definition excludes other natural substances that also inhibit microorganisms but are produced by higher forms, (e.g. antibodies).
Antimicrobials designate synthetic as well as naturally obtained drugs that attenuate microorganisms.
Classification of Antimicrobials
Antimicrobials can be classified according to some factors in different classes. For example:
Classification according to Chemical structure:
- Sulfonamides and related drugs eg sulfadiazine and others, Sulfones such as dapsone.
- Quinolones like Ciprofloxacin, Norfloxacin...
- β Lactum antibiotics – Penicillins, Cephalosporins, monobactums, carbapenems...
- Tetracyclines - doxycycline
- Aminoglycosides –streptomycin, gentamycin, etc
- Macrolides - erythromycin...
- Azole derivatives – Miconazole, clotrimazole, Ketoconazole.
Classification according to the Mechanism of action
- Inhibit cell wall synthesis ie penicillins, cephalosporins...
- Inhibit protein synthesis including, tetracyclines, chloramphenicol, erythromycin...
- Cause leakage from cell membranes - polypeptides like Amphotericin B, nystatin...
- Inhibit DNA gyrase – Fluoroquinolones - Ciprofloxacin...
- Interfere with DNA synthesis such as Zidovudine, acyclovir...
Classification based on Type of organism against which primarily active
- Antibacterial - penicillins, aminoglycosides...
- Antifungal - Ketoconazole, Amphotericin B...
- Antiviral - Zidovudine, acyclovir...
- Antiprotozoal - chloroquine, metronidazole...
- Antihelmintic - mebendazole, albendazole...
According to Spectrum of activity
- Narrow spectrum antimicrobials like penicillin G, erythromycin, streptomycin...
- Broad-spectrum antimicrobials ie tetracyclines, chloramphenicol...
According to the type of action
- Primarily bacteriostatic - sulfonamides, tetracyclines, chloramphenicol, erythromycin...
- Primarily bactericidal - penicillins, aminoglycosides, rifampicin, cephalosporins...
Classification according to Source of antibiotics
- Fungi -penicillin, cephalosporins
- Bacteria -colistin, bacitracin
How do antibacterial substances work?
- Bactericidal agents - Kill bacteria rapidly (e.g. aminoglycosides, polymyxin)
- Bacteriostatic agents Prevent bacteria from replicating; but do not kill them (e.g. sulphonamides, tetracyclines, chloramphenicol).
When a drug is given at high doses to highly susceptible organisms; a normally bacteriostatic agent such as penicillin may become bactericidal.
Antibiotics and Bacterial cell wall
Many antibiotics exert their effects directly on the bacterial cell wall or must pass through it before disrupting bacterial metabolism at the intracellular level.
The cell walls of all bacteria are composed of layers of protein molecules bound together by cross-linkages, resulting in the large, complex chemical aggregate, but their fine structure depends on whether they are Gram-positive or Gram-Negative.
The fine structure of the cell wall influences susceptibility to the different groups of antibiotics; e.g. erythromycin is able to penetrate the cell wall of Gram-positive bacteria and is effective in the treatment of some staphylococcal or streptococcal infections, but it has no effect on Gram-Negative bacteria.
Gram-positive and gram-negative bacteria
With a few exceptions, bacteria may be classified as Gram Positive and Gram Negative, according to the staining technique used in laboratory identification.
Gram-negative species multiply rapidly in the presence of moisture even when provided with minimal nourishment.
Here are examples of Gram-positive and Gram-negative organisms in hospitals
|Staphylococcus aureus||Haemophilus influenza|
|Streptococcus pyogenes||Neisseria gonorrhea|
|Streptococcus viridians||Neisseria meningitides|
|Streptococcus pneumonia||Escherichia coli, proteus, pseudomonas, klebsiella|
- Anaerobic bacteria can live and multiply in the absence of free oxygen.
- In the laboratory, they require special conditions before they will grow in culture, but they are able to cause severe infections given the correct circumstances.
What are the problems that arise with the use of antimicrobials
- Local irritancy. This is exerted at the site of drug administration. Pain, abscess formation at the site of IM injection.
- Systemic toxicity. Almost all antimicrobials produce dose-related and predictable organ toxicities.
- Chloramphenicol .Bone marrow depression.
- Tetracyclines. Liver and Kidney damage.
- Hypersensitivity reactions Practically all antimicrobials are capable of causing hypersensitivity reactions. They are unpredictable and unrelated to dose. The whole range of reactions from rashes to anaphylactic shock can be produced. Examples penicillins, cephalosporins, sulfonamides, fluoroquinolones.
- Drug resistance Refers to the unresponsiveness of a microorganism to antimicrobials.
- Natural resistance Some microbes have always been resistant to certain antimicrobials. They lack the metabolic process or the target site which is affected by a particular drug. This is generally a group or species characteristic.
- Acquired resistance The development of resistance by an organism (which was sensitive before) due to the use of antimicrobials over a period of time. This can happen with any microbe and is a major clinical problem.
- Superinfection (Suprainfection) This refers to the appearance of a new infection as a result of antimicrobial therapy.
The use of antimicrobials causes some alterations in the normal microbial flora of the body. The normal flora contributes to host defense by elaborating substances called bacteriocins, which inhibit pathogenic organisms.
Also, ordinarily, the pathogen has to compete with the normal flora for nutrients, etc. to establish itself.
Lack of competition may allow even a normally non-pathogenic component of flora, which is not inhibited by the drug to establish itself and predominates e.g. candida.
It is commonly associated with the use of broad-spectrum antibiotics e.g. tetracyclines, chloramphenicol, newer cephalosporins.
Sites involved in superinfection are those that normally harbor commensals, i.e. intestines, respiratory and genitourinary tracts.
How to minimize superinfection
Use specific (narrow spectrum) antimicrobials whenever possible.
Do not use antimicrobials to treat trivial, self-limiting or untreatable (viral) infections.
Do not unnecessarily prolong antimicrobial therapy.
- Nutritional deficiencies. Some of the B complex vitamins and Vitamin K synthesized by the intestinal flora are utilized by man. Prolonged use of antimicrobials that alter this flora may result in vitamin deficiencies.
- Masking of an infection - a short course of antimicrobials may be sufficient to treat one infection but only briefly suppress another one contacted concurrently.
The other infection will be masked initially, only to manifest later in severe form; e.g. syphilis masked by the use of a single dose of penicillin which is sufficient for gonorrhea. TB masked by a short course of streptomycin given for trivial respiratory infection.
Sulfonamides are one of the oldest groups of antibacterial agents. They differ to some extent in the range of organisms they attack, but most of their pharmacological properties are similar.
They are primarily bacteriostatic against many Gram-positive and Gram-Negative and they have been largely replaced because of the development of bacterial resistance and adverse side effects.
Mechanism of action
Many bacteria synthesize their own folic acid (FA) of which Para-aminobenzoic acid (PABA) is a constituent, and is taken up from the medium. Sulfonamides being structural analogs of PABA, inhibit bacterial folate synthetase; therefore, FA is not formed and a number of essential metabolic processes suffer.
Human beings also require FA, but they utilize preformed FA supplied in the diet and are unaffected by sulfonamides.
Available sulphonamide examples
- Sulfadimidine. This drug is well absorbed orally and indicated for Urinary tract infections.
- Sulfasalazine is indicated for ulcerative colitis & Crohns disease, rheumatoid arthritis
- Silver sulfadiazine is used in severe burns.
They are well absorbed from the intestinal tract; they circulate widely in the body fluids and cross the meningeal barrier to enter the cerebrospinal fluid (CSF).
After absorption, the liver begins to acetylate the sulphonamides. The acetylated drugs together with the unaltered sulphonamides are excreted in the urine. The acetylated sulphonamides are very poorly soluble and therefore there is a danger that they will precipitate in the urine unless an adequate flow is maintained.
Precipitation of urinary tract causing obstruction; the patient should be given 2-3 liters of fluid daily to maintain good urinary flow.
Rashes of various types sometimes fever.
Nausea can be troublesome and sulfasalazine may be relieved by giving small and more frequent doses.
Sperm count is reduced by sulfasalazine but recovers on stopping the drug.
Kernicterus may be precipitated in newborns, especially premature, by displacement of bilirubin from plasma protein binding sites and a more permeable blood-brain barrier.
Co-Trimoxazole (Trimethoprim and Sulfamethoxazole)
Mechanism of action
Sulphonamides affect bacteria by interfering with their use of para-aminobenzoic acid (PABA), a precursor of folic acid, which is ultimately essential in cell division.
Trimethoprim interferes with folic acid metabolism, at the phase when folic acid is changed to folinic acid to build up the cell nucleus. This requires the action of an enzyme, and by combining with that enzyme, trimethoprim stops the reaction and the cell dies.
Para Amino Benzoic Acid (PABA)
The combination is particularly effective in preventing bacterial cell division and is also bactericidal.
Most acute uncomplicated infections respond rapidly.
Respiratory tract infections
Both upper and lower respiratory tract infections.
Bacterial diarrhea and dysentery.
- These are largely similar to those of sulphonamides. More serious is the occasional development of the Stevens-Johnson syndrome with a bullous rash, mouth ulceration, and fever, which can be fatal.
- Folate deficiency (megaloblastic anaemia).
It can also be used alone for the treatment of urinary tract infections.
Quinolones comprise of;
- Nalidixic acid
Mechanism of action
They interfere with the enzyme necessary for cell division of bacteria. They are active primarily against Gram-negative bacteria; also some also inhibit Gram-positive bacteria.
Acts against a wide range of organisms, but is not very effective against some Gram-positive organisms particularly pneumococci.
- Gastrointestinal upsets and rashes
- It should be avoided in patients with epilepsy, it has the potential to cause seizures.
- In children, it may cause damage to developing weight-bearing joints.
- Ciprofloxacin and other quinolones are contraindicated during pregnancy.
Ciprofloxacin raises the blood levels of theophylline, caffeine, warfarin. The action of warfarin is increased.
Ciprofloxacin is effective in a broad range of infections including some difficult to treat ones. Because of wide spectrum bactericidal activity, oral efficacy and good tolerability, it is being extensively used for blind therapy.
Similar to ciprofloxacin. Ofloxacin works by inhibiting Mycobacterium tuberculosis.
More active against S. pneumonia and can be used in community-acquired pneumonia but offers no real advantage over the usual antibiotics.
Norfloxacin & nalidixic acid
Are effective in uncomplicated urinary tract infections and are used when the infecting organism is resistant to the older antibacterial drugs. They should be avoided in children and pregnancy, in case of renal failure.
Another important class of antimicrobials is beta-lactam antibiotics
Can be divided into:
The penicillins were the first antibiotics to be isolated and used clinically in 1941. Over the years, their structure has been repeatedly modified to deal with the problem of resistance to penicillin and to extend their antibacterial range.
Mechanism of action
All β lactam antibiotics interfere with the synthesis of the bacterial cell wall. Rapid cell wall synthesis occurs when the organisms are actively multiplying. β - lactam antibiotics are more lethal in this phase.
1.Penicillin G (Benzyl Penicillin) PnG
- Penicillin G is destroyed by gastric acid; less than a third of the dose is absorbed inactive form. Absorption from the intramuscular site is rapid and complete.
- It undergoes very rapid renal excretion. When treating an infection it is ideal to maintain the blood level of penicillin continually at bactericidal levels, and this requires injections every 4 hours.
Learn more about the Procaine and Benzathine penicillins here.
PnG is a narrow-spectrum antibiotic; activity is limited primarily to gram-positive bacteria and a few others.
- Many bacteria are inherently insensitive to PnG. The primary mechanism of acquired resistance is the production of penicillinase.
- Local irritancy & direct toxicity, Pain at the IM site, nausea on oral ingestion
- Hypersensitivity or allergic reactions (rash, itching, and fever) are the major problems in the use of penicillins.
Range of activity
Benzylpenicillin is effective against a fairly wide range of the organism. Penicillins are bacteriostatic and in higher doses are bactericidal.
Penicillin resistance: penicillinase and the β lactam ring
Certain organisms develop resistance to the action of penicillin. Organisms that were originally sensitive appear to adapt themselves to the penicillin by producing an enzyme called penicillinase, which inactivates penicillin by attacking part of the penicillin molecule known as β lactam ring.
This structure is an essential part of penicillins and cephalosporins, and the family of enzymes involved is sometimes known as β lactamases.
These penicillins comprise of:
- Broad-spectrum penicillins
- Extended-spectrum penicillins
- Adequate absorption with a satisfactory therapeutic response usually occurs with oral penicillin but it is important that it is taken 30 minutes before a meal.
- The patient must be examined in case the drug is ineffective due to vomiting or inadequate absorption.
Penicillinase resistant and are therefore effective against the organism, particularly staphylococci, which have become resistant to benzylpenicillin.
Almost used exclusively for treating staphylococcal infections.
Strains of staphylococci have emerged which are resistant even to flucloxacillin. They are called Methicillin-resistant staphylococcus aureus (MRSA); they respond only to Vancomycin or teicoplanin.
Broad-spectrum penicillins (includes Ampicillin, amoxicillin)
- Effective against a number of bacteria, including salmonellae, E.coli, shigella, and H.influenzae.
- It can be given orally or injection.
- Very similar to ampicillin, but better absorbed so a smaller dose is required.
Co-amoxiclav (amoxicillin / clavulanic acid)
- Some bacteria produce β lactamases capable of breaking down both ampicillin and amoxicillin together with other antibiotics.
- Antibiotics are combined with a substance called clavulanate, which prevents this breakdown and thus enables it to destroy β lactamases producing bacteria.
Extended-spectrum penicillins (Ureido penicillins)
- Includes azlocillin, piperacillin and ticarcillin.
- They have almost the same activity as ampicillin but they are also effective against pseudomonas aeruginosa and proteus morganii.
- They are inactivated by some β lactamases and are not active against penicillin-resistant staphylococci.
- They are not very effective against Gram-positive organisms.
- They are not absorbed from the gut and must be given as an injection.
- They are reserved for serious infections with pseudomonas or when the causative organism is not known.
Adverse effects of penicillins
Considering the wide use of penicillin, it is remarkably free from toxic effects.
- Sensitization rashes either as a result of contact with the drug or after systemic administration.
- Pain and rarely abscess formation may be seen at the site of injection.
- Acute anaphylactic reaction rarely occurs; it can be fatal.
Always ask about previous drug reactions before giving patient penicillin, cephalosporin or any other drug. It is advisable to observe a patient with suggestive drug history for at least half an hour after administering penicillin injection.
This is a large group of antibiotics that are structurally similar to penicillins in that they have β lactam ring.
They have a wide range of antibacterial activity, although there are differences in this respect between the older cephalosporins and the newer introductions.
Most of them can only be given by injection.
Although they are efficient antibiotics they are rarely the drugs of the first choice, as for many infections there are cheaper, effective substitutes.
They can be divided into:
Cefuroxime Cefuroxime axetil
The 1st Generation cephalosporins
Have high activity against gram-positive but weaker against Gram-negative bacteria. Cefazolin is used in surgical prophylaxis while Cefadroxil is fairly β lactamase stable.
The 2nd generation cephalosporins
These are an improvement on the 1st generation members of the group. They are more β lactamase resistant and are therefore effective against some resistant strains.
Are more active against gram-negative organisms with some members active against anaerobes.
3rd generation cephalosporins
Have highly augmented activity against gram-negative Enterobacteriaceae, some inhibit Pseudomonas as well. All are highly resistant to the β lactamases from gram-negative bacteria.
They are less active against anaerobes and gram-positive organisms.
4th generation cephalosporins
Have similar activity like 3rd generation, but are highly resistant to β lactamases, hence active against many bacteria resistant to other drugs.
Cross sensitivity to penicillin
Approximately 10% of patients who are allergic to penicillin will also be allergic to a cephalosporin.
This excludes the use of cephalosporins in penicillin-sensitive patients, although exceptions can be made in special circumstances.
- Are generally well tolerated but more toxic than penicillins.
- Hypersensitivity reactions mainly rashes
- Diarrhea due to alteration of gut ecology.
- Used as alternatives to penicillin G, particularly allergic patients.
- Surgical prophylaxis 1st generation
- Respiratory / urinary / soft tissue infections
a) Systemic aminoglycosides
b) Topical aminoglycosides
Common properties of aminoglycosides.
- All are bactericidal and more active at alkaline Ph
- All are not absorbed orally and do not penetrate the brain (BBB) and CSF.
- Act primarily against aerobic gram-negative bacilli and do not inhibit anaerobes.
- They have a relatively narrow margin of safety.
- All exhibit ototoxicity/nephrotoxicity.
Mechanism of action
Interferes with the protein synthesis in bacteria and are bactericidal.
They have a fairly wide range of antibacterial range and one of them streptomycin is effective against Mycobacterium tuberculosis.
Effectiveness of aminoglycosides
- All are given by injection if a systemic action is desired.
- The kidneys excrete them all and accumulation occurs with impaired renal function. in these circumstances, a lower dosage is required and information is available which relates the dose necessary to the degree of impairment of the renal function.
- Reduced doses are also given to elderly patients.
- They are all and to a lesser degree, ototoxic (they impair hearing/balance) and also nephrotoxic.
It is widely used especially in treating severe infection by staphylococci and by various Gram Negative organisms.
It is given IV /IM. Excretion is via kidney, is fairly rapid therefore administered three times a day.
Toxicity not only depends on the blood level but also on the length of treatment. Increasing interest has been shown on the once-daily administration of aminoglycosides. The blood levels can be measured once or twice daily and adjusted accordingly.
Gentamicin reacts with many drugs; therefore it should not be mixed in the same syringe with other drugs.
Adverse drug effects
- Renal damage - may occur if gentamicin is given along with Frusemide.
- Ototoxic causing disorders of balance/hearing.
- Should be avoided in pregnancy because it is ototoxic.
Tobramycin, amikacin, netilmicin
They are very similar to gentamicin, however, they are sometimes effective against Gram-negative organisms that are resistant to gentamicin.
Side effects are similar except netilmicin which is less toxic.
Used in the treatment of gonorrheal infection due to organisms that have become resistant to penicillin.
It has a wide range of antibacterial activity, against both Gram-positive and Gram-negative bacteria and against Mycobacterium tuberculosis.
It is very poorly absorbed from the intestinal tract and because of toxicity, it is not given systemically.
It is used to sterilize the gut before surgery.
Also applied locally as ear/eye drops.
Usually given as IM injection.
It is not absorbed after oral administration, so this route is not used except for treating gut infections.
It is mainly used in the treatment of drug-resistant TB.
Avoid aminoglycosides during pregnancy due to the risk of fetal ototoxicity.
Avoid concurrent use of other ototoxic drugs such as minocycline
Avoid concurrent use of other nephrotoxic drugs e.g. Amphotericin B, Vancomycin.
Cautious use in patients past middle age especially those with renal failure.
Should not be mixed in the same syringe with other drugs.
Mechanism of action
Tetracyclines inhibit protein synthesis.
They are very similar in chemical structure and toxic effects and are effective against a wide range of organisms.
The properties of these drugs are so similar that they can be considered together.
- Are usually given orally, are quite well absorbed from the GIT and 6 hourly dosage is satisfactory.
- Tetracycline HCL may be given IV. However, it is very irritating to the veins and best given as continuous Infusion.
- Absorption of tetracyclines in the Gut is delayed or reduced by antacids, milk and various salts e.g. calcium, aluminum, iron, and magnesium.
Distribution / excretion
- After absorption, tetracyclines spread widely through the body.
- Most of these drugs are excreted in the urine.
- They are broad-spectrum antibiotics.
- With some bacteria, resistant strains have emerged which limit their use.
- Used over a long time in the treatment of acne.
- Similar to the older tetracycline, but is excreted slowly so that one dose can be given daily.
- It can be used when the renal function is impaired.
- Used in malaria prevention.
Adverse effects of tetracyclines
- Teeth & bones Weaken, damage and discolor the developing teeth; therefore, they are contraindicated in pregnancy until the child is 12 years old.
- Tetracyclines can cause epigastric pain, nausea, vomiting, and diarrhea.
- Liver damage.
- Kidney damage. It is prominent in the presence of existing kidney disease.
- Phototoxicity a sunburn and other severe skin reactions. a higher incidence with demeclocycline and doxycycline.
- Superinfection. Tetracyclines are the most common antibiotics responsible for superinfection. Candida albicans is the most prominent, Higher doses suppress the flora more completely - the higher the chance of superinfection.
- Tetracyclines should not be used in pregnancy, lactation and in children.
- They should be used cautiously in renal/hepatic insufficiency.
- Preparations should not be used beyond their expiry dates.
- Do not mix injectables tetracycline with penicillin because inactivation occurs.
Chloramphenicol is a broad-spectrum antibiotic closely related in its action to the tetracyclines.
It is primarily bacteriostatic. It has serious but rare toxic side effects of bone marrow suppression; this limits its use to patients who can not obtain benefit from any other form of treatment.
- Is given by mouth and rapidly absorbed from the intestines.
- It diffuses widely and crosses the meningeal barrier into the CSF.
- It is excreted via the kidney.
- Used in meningitis
- Also used in typhoid
- Used in solution as ear/eye drops.
- Bone marrow toxicity. Although rare, they are nearly always fatal when they occur. The most common is aplastic anemia. Toxic effects are more common after prolonged or repeated chloramphenicol therapy. Their appearance may be delayed to 2 months after receiving therapy.
- Hypersensitivity Rashes, fever.
- Superinfections Similar to tetracyclines, but less common.
- Gray baby syndrome occurs due to the inability of the newborn to adequately metalize and excrete chloramphenicol.
- Never use chloramphenicol for minor infection or those of undefined etiology.
- Do not use chloramphenicol for infections treatable by other safer antimicrobials.
- Avoid repeated courses
- Daily dose not to exceed 2-3g; duration of therapy to be < 2 weeks; total dose in a course < 28g.
- Regular blood counts may detect dose-related bone marrow toxicity.
It is absorbed rather erratically after oral administration and diffuses widely, but does not enter CSF. It is bacteriostatic and is a narrow-spectrum antibiotic; it includes mostly Gram-positive and a few Gram-negative organisms.
It has a similar range of activity to penicillin and is used instead of penicillin in those who are allergic to penicillin.
It is used for various respiratory diseases including mycoplasma pneumonia and legionnaires disease. To reduce nausea, best given with food.
Rare and include diarrhea, vomiting and rarely jaundice.
It has similar antimicrobial spectrum as erythromycin, but higher concentrations are found in tissues. Has a greater effect against Haemophilus influenza.
- Also used in the eradication of Helicobacter pylori.
- Less common gastric upsets.
- Once-daily dosing.
- It has a long half-life.