Listen to Audio Summary of Chapter 12
Antimicrobial drugs are chemicals used to prevent and treat microbial infections. Antimicrobial drugs can be classified as antibacterial, antifungal, antiviral, or antiparasitic depending on the type of microbe the drug targets. The development of antimicrobial drugs began in the late 1800's with Paul Erlich, a German scientist, who discovered that arsenic compounds were an effective treatment for syphilis. Unfortunately, these compounds were also highly toxic to the patients they were being used to treat. In 1928 Sir Alexander Fleming accidentally stumbled upon the discovery of the wonder drug, penicillin. As he was inspecting a plate of Staphylococcus aureus contaminated with the mold Penicillium, Fleming noticed that the mold had inhibited the growth of the bacterial colonies. He later isolated the compound responsible for this inhibition and named it penicillin. The first sulfa drug, sulfanilamide, was discovered in 1932 by the German chemist, Gerhard Domagk.
Watch this Video about the Discovery of Penicillin
Antimicrobial drugs can also be classified based upon how they are made. Antimicrobial drugs can be naturally-derived, semi-synthetic or synthetic. Bacteria and fungi produce and release natural antibiotics, such as penicillin, in order to kill or eliminate competition from neighboring microbes. Penicillin, which was the first naturally produced antibiotic discovered, is derived from the fungus Penicillium and the drug cephalosporin comes from the fungus Cephalosporium. Examples of bacterial-derived drugs include bacitracin and polymyxin (both found in the topical antibiotic ointment, neosporin), which are produced by the soil bacteria, Bacillus licheniformis and Bacillus polymyxa. More than half of all natural antibiotics and semi-synthetic drugs are derived from different species of the soil bacteria, Streptomyces. Streptomyces produces: streptomycin, neomycin, tetracycline,vancomycin, erythromycin, chloramphenicol, rifampin, and amphotericin B.
Semi-synthetic drugs are isolated from natural sources, but then chemically modified in a laboratory to make the drugs more effective, longer lasting, easier to administer, and less toxic to the patient. For example,ampicillin and methicillin are semi-synthetic drugs derived from penicillin. Synthetic drugs are compounds that are completely artificial and are synthesized in a laboratory. Synthetic drugs tend to have high toxicity to both the microbe and the human host.
Antimicrobial drugs can be classified as narrow or broad spectrum based upon their spectrum or range of effectiveness. Broad-spectrum drugs are effective against many types of microbes and tend to have higher toxicity to the host. Narrow-spectrum drugs are effective against a limited group of microbes and exhibit lower toxicity to the host.
Can you match each term with its correct definition?
When selecting an appropriate treatment for a patient, 3 factors should be considered:
1) the type of microbe causing the infection (bacterial, fungal, protozoan, parasitic or viral);
2) the sensitivity or susceptibility of the microbe to various drugs; and
3) the overall medical condition of the patient being treated.
An ideal antimicrobial medication should be: 1) highly toxic to the microbe; 2) non-toxic to the host; 3) not interfere with the ability of the host to fight other diseases; and 4) not lead to the development of drug resistance.
The therapeutic index (TI) is a ratio or comparison of the drug dose that is toxic to the patient versus the minimum drug dose required to kill the microbe. Ideally, the larger the therapeutic index or ratio, the less likely it is that the drug will be toxic to the patient. Antibacterial medications have low toxicity to humans because they interfere with prokaryotic, but not eukaryotic, structures and processes. In contrast, antifungal medications have a higher level of toxicity to the human host because both fungi and the host cells are eukaryotic and share similar structures. Antiviral medications are the most toxic to humans because in order to inactivate the virus, they must also kill or damage the host cell.
The Kirby-Bauer antibiotic susceptibility test is used to determine whether an antibiotic is effective against a particular microbe. The efficacy of the drug is determined by the zone of inhibition, which is a region surrounding the antibiotic where microbial growth is inhibited. A large zone of inhibition indicates that the antibiotic is effective and the microbe is sensitive to the drug. A small zone of inhibition indicates that the antibiotic is less effective or that the microbe is resistant to the drug.
The Minimum Inhibitory Concentration (MIC) Test is used to determine the lowest concentration (dose) of the drug able to kill or inhibit growth of the microbe. This test can be performed by adding varying concentrations of the drug to test tubes that contain a set amount of the bacteria or by placing small disks of paper that have been soaked in varying concentrations of the drug onto a bacterial lawn culture.
Drug toxicity to the patient should always be considered when selecting an antimicrobial drug for treatment. Toxicity is especially important to consider when treating a pregnant woman, because many drugs that are safe for adults can have adverse effects on the fetus. In addition, special care must be taken when treating immuno-compromised patients who have HIV or cancer or who have undergone a transplant surgery, as some antimicrobial drugs interfere with normal immune function.
Adverse side effects associated with the use of antimicrobial drugs include: 1) damage to the patient's cells or organs; 2) allergic reactions to the drug which can lead to anaphylatic shock; and 3) disruption of the normal, protective bioflora of the body or immune function, which make the patient more susceptible to secondary infections, such as thrush or vaginal yeast infections. Shown below are side effects associated with the use of: 1) tetracycline which causes discoloration of the teeth and interferes with normal bone development in the developing fetus; and 2) the antiprotozoan drug metronidazole (Flagyl), which causes black "hairy" tongue.
Most of our body surfaces, such as the skin, large intestine, and mucosal openings are populated with beneficial bacterial and fungal residents called bioflora or biota. When the number of these organisms is maintained at a constant level, they help prevent outside pathogens from establishing infections within our body. However, during treatment with broad-spectrum antibiotics, such as tetracycline or cephalosporin, some of the beneficial bacteria are destroyed along with the bacteria causing the infection. This disrupts the balance of microorganisms growing in the body and allows certain pathogens to grow unchecked. This can lead to a superinfection (see below).
For example, when the drug cephalosporin is used to treat urinary tract infections in women, it also kills off beneficial bacteria, such as lactobacillus, which reside in the vagina. No longer having to compete with lactobacillus for space and nutrients, Candida albicans is allowed to grow unchecked, causing a vaginal yeast infection. Antibiotic-associated colitis (pseudomembranous colitis) is a potentially fatal superinfection of the bowel caused by the overgrowth of Clostridium difficile.
Antimicrobial drugs are grouped based upon their primary site of action. Antibacterial drugs regulate microbial growth and division by: 1) inhibiting cell wall synthesis; 2) disrupting the plasma membrane; 3) blocking protein synthesis; 4) disrupting metabolic pathways; and 5) inhibiting nucleic acid (DNA and RNA) synthesis. Cell wall inhibitors block the synthesis and repair of the bacterial cell wall and include drugs such as penicillin, cephalosporin, vancomycin, bacitracin, and cycloserine. Polymyxin is a drug that disrupts the bacterial plasma membrane. Protein synthesis inhibitors include those that target the 50S ribosomal subunit (chloramphenicol, erythromycin, and clindamycin) and those that target the 30 ribosomal subunit (aminoglycosides, tetracyclines, and streptomycin). Nucleic acid inhibitors block replication and transcription and include drugs such as ciprofloxacin (DNA) and rifampin (RNA). Metabolic inhibitors prevent folic acid synthesis and include sulfa drugs and trimethoprim.
Watch this Video about Antibacterial Drug Targets
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Click Here to See Recommended Doses for Commonly Prescribed Antibiotics
The most common antibacterial drugs are those that inhibit cell wall synthesis and repair. The penicillins (end in -cillin) are fungal-derived, narrow spectrum antibiotics used primarily to treat Gram-positive infections. The natural form of the drug is penicillin G, which is a narrow-spectrum drug with limited action against Gram-negative bacteria. The semi-synthetic forms (ampicillin and amoxicillin) derived from penicillin G, are broad-spectrum drugs that target both Gram-positive and Gram-negative bacteria. Penicillin and penicillin-derived drugs have a characteristic beta-lactam ring structure that is used to disrupt bacterial cell wall synthesis, by blocking the formation of peptide links between adjacent strands of peptidoglycan.
The "-cillin" family of drugs have relatively low toxicity to humans because they target the bacterial cell wall, which humans lack. However, there are a few drawbacks to their use, including drug allergies and microbial resistance. Many bacteria produce enzymes, called beta-lactamases or penicillinases, that can destroy the beta-lactam ring structure. To prevent the breakdown of the drug by bacterial enzymes, clavulanic acid is often added to semi-synthetic penicillins. For example, clavamox is a combination of amoxicillin and clavulanate marketed under the trade name Augmentin.
Other cell wall inhibitors include cycloserine, cephalosporin, bacitracin, vancomycin, imipenem, and aztreonam. Bacitracin is a narrow-spectrum antibiotic produced by Bacillus subtilis. Bacitracin is a major ingredient in the triple antibiotic ointment, Neosporin, and is used to treat Gram-positive skin infections. Vancomycin is a narrow-spectrum drug used to treat penicillin and methicillin-resistant Staphylococcus infections. Cephalosporins (cephalothin, cephalexin, cefotaxime, cefepime) are broad-spectrum cell wall inhibitors that are resistant to most pencillinases and cause fewer allergic reactions than penicillin.
Watch this Video about Cell Wall Inhibitors
Disruption of cell wall synthesis and repair, weaken the bacterial cell wall making the bacteria more susceptible to lysis.
Drugs such as isoniazid and ethambutol inhibit synthesis of mycolic acid, which is found in the waxy cell walls of acid-fast bacteria such as Mycobacterium tuberculosis (TB). These drugs are used in the treatment of tuberculosis and leprosy.
Some antimicrobial drugs bind to and disrupt the plasma membrane of the cell, causing the cell to undergo lysis. Polymyxin B is highly effective against Gram-negative bacteria (Pseudomonas aeruginosa) due to its interaction with LPS on the surface of the Gram-negative cell. Due to its toxicity to the kidneys, polymyxin B is used only as a topical drug. Along with bacitracin and neomycin, polymyxin B is found in the triple antibiotic ointment, Neosporin. Gramicidin and daptomycin target the plasma membrane of Gram-positive bacteria.
Protein synthesis inhibitors include drugs that target the 50S ribosomal subunit (chloramphenicol, erythromycin, and clindamycin) and those that target the 30 ribosomal subunit (aminoglycosides, tetracyclines, and streptomycin).
Watch this Video about Protein Synthesis Inhibitors
Aminoglycosides (streptomycin, gentamicin, neomycin) are broad spectrum drugs that block the initiation of translation and cause the misreading of mRNA. These drugs are effective against Gram-positive and aerobic Gram-negative bacteria. Streptomycin is used to treat bubonic plague, tularemia and tuberculosis. Gentamicin is less toxic and is used to treat infections caused by Gram-negative rods (E.coli, Pseudomonas, Salmonella, and Shigella).
Tetracyclines are toxic, broad spectrum drugs that block the attachment of tRNA to the ribosome. These drugs are used to treat Gram-positive and Gram-negative rods and cocci, aerobes and anaerobes, Rocky Mountain spotted fever, Lyme disease, cholera, acne and some protozoan infections. Tetracycline has several side effects, which limit its use including GI tract disruption and delay in bone growth and discoloration of tooth enamel.
Chloramphenicol is a toxic, broad-spectrum, synthetically produced antibiotic that blocks peptide bond formation and protein synthesis. Due to its high toxicity, its use is limited to treating typhoid fever and brain abscesses. Side effects of this drug include bone marrow damage and aplastic anemia.
Erythromycin is a broad-spectrum protein synthesis inhibitor with relative low toxicity. It is used to treat Chlamydia, diphtheria, syphilis, acne, and penicillin-resistant streptococci.
Antimetabolic drugs target differences in the metabolic processes of a pathogen and its host. The sulfonamides are broad spectrum (Gram + and some Gram -)synthetic drugs produced in the laboratory. Examples include the Sulfonamide drugs (sulfamethoxazole) and trimethoprim (Septra and Bactrim). These drugs disrupt bacterial metabolism by acting as competitive inhibitors to PABA, a precursor molecule used to synthesize folic acid, which bacteria need for nucleic acid synthesis.
Click Here to Watch a Video about the Discovery of Sulfa Drugs
Nucleic acid inhibitors are highly toxic, broad spectrum (Gram +, Gram-, Acid fast, fungi, viruses), synthetic drugs that block the replication of DNA or prevent its transcription into RNA. Nucleotide analogs (compounds that have a structure similar to the bases adenine, thymine, cytosine and guanine) are incorporated into the DNA or RNA of microbes, where they alter the structure of the nucleic acids and block replication, transcription, or translation. These drugs are commonly used to treat virally-infected cells and rapidly dividing cancerous cells.
The synthetic fluoroquinolones (ciprofloxacin) inhibit DNA gyrase, an enzyme needed for bacterial DNA replication. Ciprofloxacin is a fluoroquinolone drug commonly prescribed for cases of anthrax, sexually transmitted diseases, respiratory infections, and urinary tract infections. Rifamycin (rifampin) is an RNA synthesis inhibitor used to treat tuberculosis and leprosy.
Microbes develop drug resistance due to genetic mutations and by acquiring genes from other microbes via processes like conjugation, transformation, and transduction.
Watch this Video about the Transfer of Drug Resistance
Antibiotic resistance genes found on the Resistance or "R" plasmid enable the microbe to counteract the effects of antibiotics by: 1) using enzymes (beta-lactamase or penicillinase) to break down or inactivate the drug; 2) using porins to block uptake of the drug or using drug pumps to remove the drug; 3) altering the structure of the drug or its receptor; or 4) altering the metabolic pathways.
Watch this Video about the Mechanisms of Drug Resistance
Humans contribute to the development and spread of drug resistance by: 1) not using the appropriate drug for a particular type of infection; 2) not finishing medication or not taking it properly; or 3) using antimicrobial drugs when they are not needed. When an antimicrobial drug is present and the majority of drug-sensitive cells die, the drug-resistant cells left behind will be allowed to grow unchecked until they outnumber the drug-sensitive cells.
When a patient does not finish their medication or does not take it properly, drug-resistant strains can arise as shown below.
Some types of bacteria have developed multiple-drug resistant forms. For example, Staphylococcus aureus has developed resistance to penicillin, methicillin (MRSA: Methicillin-resistant Staphylococcus aureus), and vancomycin (VRSA: Vancomycin-resistant Staphylococcus aureus).
Antifungal drugs can be organized into 4 main groups: polyenes, synthetic azoles, flucytosine and griseofulvin. Amphotericin B, nystatin and the azoles (fluconazole, ketoconazole, miconazole, clotrimazole) target ergosterol, a lipid found in fungal cell membranes. The azoles (fluconazole, ketoconazole, miconazole, clotrimazole) are broad-spectrum antifungal drugs which are used to treat fungal infections of the skin, mouth and vagina. Griseofulvin is an antifungal drug used to treat athlete's foot. Flucytosine is an analog of cytosine that inhibits DNA synthesis and is used to treat cutaneous fungal infections.
Quinine and the related compounds chloraquine, primaquine, and mefloquine are used to treat infections caused by the malarial parasite, Plasmodium.
Other drugs used to treat protozoan infections include metronidazole, suramin, melarsopral, and nitrifurimox.
Antibiotics are NOT effective against viral infections, because viruses are non-living, intracellular parasites that hijack host cell machinery in order to replicate. Antiviral medications are highly toxic to humans because in order to damage the virus, they must also kill or damage the host cell. Antiviral medications have 3 targets: 1) inhibition of attachment or entry; 2) inhibition of DNA or RNA synthesis; and 3) inhibition of protein assembly and viral release.
Examples include: 1) fuzeon which prevents HIV from fusing to its host cell receptor, thereby blocking viral entry; 2) Amantadine, which prevents uncoating of the influenza A virus; 3)acyclovir, valacyclovir, famciclovir and ribavirin, which inhibit viral DNA replication; 4) Azidothymidine (AZT), which inhibits reverse transcription of viral RNA into DNA; and 5) protease inhibitors, such as indinavir, which block viral protein assembly.
Watch this Video about Antiviral Drugs
Listen to Audio Summary of Chapter 12
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