Chapter 14 - Antimicrobial Drugs

Selective toxicity

killing harmful microbes without damaging the host

Chemotherapy

the use of chemical drugs to treat a disease

Antibiotic

A chemical secreted by a living organism that kills or reduces the reproduction rate of other organisms

Antimicrobial drug

a chemical that inhibits the growth of or kills microorganisms; the term encompasses antibiotics and chemically synthesized drugs

Alexander Fleming (1928)

Discovered the first antibiotic, penicillin, produced by the fungus Penicillium

Prontosil red dye

Antimicrobial drug discovered in 1932 used for streptococcal infections

1940 - Penicillin

First clinical trials of penicillin

Narrow spectrum antibiotics

Effective for narrow group of bacteria

Broad spectrum antibiotics

Affect a broad range of gram-positive or gram-negative bacteria

Superinfection

overgrowth of normal microbiota that is resistant to antibiotics

Bactericidal

kill microbes directly

Bacteriostatic

inhibits growth of bacteria

Action of antimicrobial drugs

1. Inhibition of cell wall synthesis

2. Inhibition of protein synthesis

3. Inhibition of nucleic acid replication and transcription

4. Injury to plasma membrane

5. Inhibition of synthesis of essential metabolites

Penicillins

Contain β-lactam ring and prevent cross-linking of peptidoglycan

Natural penicillins

Extracted from Penicillium cultures

Penicillin G (injected) and Penicillin V (oral)

Narrow spectrum of activity

Susceptible to penicillinases (β-lactamases)

Semisynthetic penicillins

Contain chemically added side chains, making them resistant to penicillinases

Penicillinase-resistant penicillins

Methicillin and oxacillin

Extended spectrum penicillins

Amoxicillin and ampicillin; effective against gram-negatives and gram-positives

Clavulanic acid

Noncompetitive inhibitor of penicillinases/β-lactamases; often combined with penicillin treatment

Carbapenems

Substitute a C for an S and add a double bond to the penicillin nucleus; broad spectrum; Primaxin, doripenem

Monobactam

Synthetic; single ring instead of the β-lactam double ring; Low toxicity but effective only against certain gram-negatives; Aztreonam

Aztreonam

Broad spectrum monobactam penicillin that is less susceptible to β-lactamases and is effective against Gram-negative rods only

Cephalosporins

Work similar to penicillins but have different β-lactam ring; grouped according to their generation of development

Polypeptide antibiotics

Bacitracin, vancomycin, teixobactin

Bacitracin

A topical antibiotic that affects cell wall synthesis and is effective against gram-positive bacteria

Vancomycin

Glycopeptide inhibitor of cell wall synthesis; last line of defense against MRSA

Teixobactin

A new antibiotic that kills gram-positive pathogens without detectable resistance; inhibits peptidoglycan and teichoic acid synthesis

Inhibit cell wall synthesis of gram-positives

Natural penicillins (penicillin G and V), methicllin, oxacillin, ampicillin, amoxicillin, primaxin, dorpenem, cephalosporins, bacitracin, vancomycin, teixobactin

Inhibit cell wall synthesis of gram-negatives

Amoxicillin, ampicillin, aztreonam, some cephalosporins

Inhibit cell wall synthesis of mycobacteria

Isoniazid, Ethambutol

Isoniazid (INH)

Inhibits the mycolic acid synthesis in mycobacteria

Ethambutol

Inhibits incorporation of mycolic acid into the cell wall

Nitrofurantoin

Synthetic antimicrobial used for urinary bladder infections; attack bacterial ribosomal proteins

Chloramphenicol

Broat spectrum synthetic antimicrobial that blocks peptidyltransferase at 50S ribosomal subunit; bacteriostatic; can suppress bone marrow function and inhibit blood cell formation

Aminoglycosides

Antimicrobial that consists of amino sugars linked by glycoside bonds; change the shape of the 30S subunit of the 70S ribosome; can cause auditory damage

Aminoglycoside examples

Streptomycin, neomycin, gentamicin

Tetracyclines

Broad spectrum antibiotic produced by Streptomyces that interferes with tRNA attachment; penetrative and effective against obligate intracellular parasites like rickettsias and chlamydias; can suppress normal intestinal microbiota

Glycylcyclines

Broad spectrum, bacteriostatic antimicrobial that binds to the 30S ribosomal subunit; inhibits rapid efflux; administered intravenously; useful against MRSA

Macrolides

Narrow spectrum antimicrobials that contain a macrocyclic lactone ring; effective against gram-positives

Macrolide examples

Erythromycin, azithromycin

Streptogramins

Antimicrobials that attach to the 50S subunit; effective against gram-positives that are resistant to other antibiotics

Oxazolidinones

Synthetic antimicrobials that bind to the 50S/30S subunit interface; effective against MRSA

Linezolid

Oxazolidinone that is effective against antibiotic-resistant strains such as MRS and VRE

Pleuromutilins

Retapamulin: topical and effective against gram-positives

Inhibitors of protein synthesis

Nitrofurantoin, chloramphenicol, streptomycin, neomycin, gentamycin, tetracyclines, glycylcyclines, erythromycin, azithromycin, streptogramins, oxazolidinones, retapamulin

Daptomycin

Lipopeptide antibiotic produced by streptomycetes that disrupts cell membranes of gram-positives; used for skin infections (especially MRSA)

Polymyxin B

Topical, bacteriocidal lipopeptide antimicrobial; effective against gram-negatives; combined with bacitracin and neomycin in nonprescription ointments

Polymyxin E

Colistin; lipopeptide antimicobial that disrupts membrane integrity

Rifamycin

Antimicrobial that inhibits mRNA synthesis; penetrates tissues; antitubercular activity

Quinolones and fluoroquinolones

Synthetic antimicrobials that nucleic acid synthesis; nalidixic acid, norfloxacin, ciprofloxacin

Nalidixic acid

Quinolone; inhibits DNA gyrase

Norfloxacin and ciprofloxacin

Fluoroquinolone antibiotic that inhibits nucleic acid synthesis; broad spectrum; relatively nontoxic

Nucleic acid synthesis inhibitors

Rifamycin, Quinolone (nalidixic acid) and fluoroquinolones (norfloxacin and ciprofloxacin)

Sulfonamides

inhibit folic acid synthesis by competitively binding to enzyme for PABA production

TMP-SMZ

Combination of trimethoprim and sulfamethoxazole

Polyenes

Amphotericin B

Nystatin

Amphotericin B

Antifungal produced by Streptomyces; highly toxic to kidneys

Nystatin

Most commonly used antifungal

Azoles

Imidazoles and triazoles

Imidazoles

Topical antifungal used in treatment of cutaneous mycoses

Triazole

Antifungal drug used to treat systemic fungal infections

Allylamines

Antifungal used for azole-resistant infections

Agents affecting fungal sterols

Interrupt the synthesis of ergosterol, making the membrane excessively permeable; polyenes, azoles, allylamines

Echinocandins

Inhibit the synthesis of β-glucan in fungal cell walls

Flucytosine

Antifungal cytosine analog that inhibits DNA synthesis.

Griseofulvin

Antifungal produced by Penicillium that inhibits microtubule formation; active against superficial dermatophytes

Tolnaftate

Antifungal used to treat athlete's foot

Pentamidine

Anti-Pneumocystis; may bind DNA

Antiviral drugs

Entry and fusion inhibitors

Uncoating, genome integration, and nucleic acid synthesis inhibitors

Exit inhibitors

Interferons

Entry and fusion inhibitors

Antivirals that block the receptors on the host cell that bind to the virus thereby blocking fusion of virus to host cell

Uncoating Inhibitors

Antivirals that prevent viral uncoating

Genome integration inhibitors

Antivirals that inhibit viral DNA integration into the host genome

Viral nucleic acid synthesis inhibitors

Antiviral nucleoside analogs (or non-nucleoside inhibitors) that inhibit DNA or RNA synthesis

Protease inhibitors

Antivirals that inhibit the processing of large viral proteins into individual components

Exit inhibitors

Antivirals that inhibit neuraminidase, an enzyme required for some viruses to bud from the host cell

Antiretrovirals

Prevent replication of retroviruses within host cells; used for HIV infections

Antiprotozoan drugs

Quinine, chloroquine, artemisinin, metronidazole, miltefosine

Quinine and chloroquine

Antiprotozoan that treats malaria

Artemisinin

Antiprotozoan drug that kills the sporozoites of Plasmodium spp in the blood

Metronidazole

Antibacterial/Antiprotozoal that treats Trichomonas, giardiasis, amebic dysentery, and anaerobic bacteria infections

Miltefosine

Antiprotozoal that inhibits cytochrome oxidase; treats amebic encephalitis and leishmaniasis

Antihelminthic

Niclosaminde, praziquantel, mebendazole, albendazole, ivermectin

Niclosamide

Antihelminthic drug that prevents ATP generation; treats tapeworms

Praziquantel

Antihelminthic drug that alters membrane permeability; treats tapeworms and flukes

Mebendazole, albendazole

Antihelminthic drugs that interfere with nutrient absorption; treat intestinal roundworms

Ivermectin

Antihelminthic drug that causes paralysis in helminths; treats roundworms and mites

Disk-diffusion method

(Kirby-bauer test); Tests the effectiveness of chemotherapeutic agents; paper disks impregnated with chemotherapeutic placed on agar; zone of inhibition compared to standards to determine resistance/susceptibility

Zone of inhibition

Region around a chemical saturated disc, where bacteria are unable to grow due to adverse effects of the compound in the disc.

E test

Uses strips instead of disks to determine effectiveness of chemotherapeutic agent; intersection of elliptical zone of inhibition with strip indicates MIC

Minimal inhibitory concentration (MIC)

The lowest concentration of the drug that will prevent the growth of an organism

Broth dilution test

A method of determining the minimal inhibitory concentration and minimal bactericidal concentration by using serial dilutions of an antimicrobial drug

Minimal bactericidal concentration (MBC)

The lowest concentration of chemotherapeutic agent that will kill test microorganisms

Antibiograms

Reports that record the susceptibility of organisms encountered clinically

Persister cells

Microbes with genetic characteristics allowing for their survival when exposed to an antibiotic

Superbugs

Bacteria that are resistant to large numbers of antibiotics

Resistance genes

Confer resistance to antimicrobial drugs, often spread horizontally among bacteria on plasmids or transposons via conjugation or transduction

Mechanisms of resistance

Enzymatic destruction or inactivation of the drug

Prevention of penetration to the target site within the microbe

Alteration of the drug's target site

Rapid efflux (ejection) of the antibiotic

Variations of mechanisms of resistance

Antibiotic misuse

Using outdated or weakened antibiotics

Using antibiotics for the common cold and other inappropriate conditions

Using antibiotics in animal feed

Failing to complete the prescribed regimen

Using someone else's leftover prescription

Antibiotic safety

Therapeutic index: risk versus benefit

Reactions of antibiotics with other drugs

Damage to organs

Risk to the fetus

Synergism

the effect of two drugs together is greater than the effect of either alone