Drugs, Microbes, Host-The Elements of Chemotherapy

Chapter 12

Drugs, Microbes, Host-The Elements of Chemotherapy

Chapter Outline

12.1. Principles of Antimicrobial Therapy

A. Goal of antimicrobial chemotherapy:

1. Administer a drug to an infected person which destroys the infective agent without harming the host’s cells.

B. The origins of antimicrobial drugs

1. Bacteria:

a. Streptomyces

b. Bacillus

2. Mold:

a. Penicillium

b. Cephalosporium

12.2. Interactions Between Drug and Microbe

A. Introduction

1. Selectively toxic

2. Chemotherapy: not just cancer treatment

B. Mechanisms of drug action

1. Antimicrobial drugs that affect the bacterial cell wall

a. Penicillins and cephalosporins

b. Most of these antibiotics are active only when cells are growing

c. Cell wall is weakened, leading to lysis of the cell

2. Antimicrobial drugs that affect nucleic acid synthesis

a. Chloroquine (antimalaria drug)

b. AZT and acyclovir (antiviral drugs)

3. Antimicrobial drugs that block protein synthesis

a. Most inhibitors of protein synthesis react with the ribosome-mRNA complex

b. Aminoglycosides

c. Erythromycin

d. Tetracycline

e. Chloramphenicol

4. Antimicrobial drugs that disrupt cell membrane function

a. Polymyxin

b. Amphotericin B

5. Antimicrobial drugs that inhibit folic acid synthesis

a. Sulfonamides and trimethoprim

i. Competitive inhibition

ii. Metabolic analogs in folic acid synthesis pathway

iii. Synergism

12.3. Survey of Major Antimicrobial Drug Groups

A. Antibacterial drugs targeting the cell wall

1. Penicillin and its relatives

a. Made by Penicillium chysogenum

b. Contain beta-lactam ring

c. Subgroups and uses of penicillins

i. Penicillin G and V

ii. Some bacteria produce enzymes to break down penicillin:

1. Penicillinase (beta-lactamases) destroy beta-lactam ring of penicillins

2. Methicillin and nafcillin are penicillins resistant to penicillinases

iii. Primary problems in therapy include allergic reactions and resistance in strains of bacteria

2. The cephalosporin group of drugs:

a. Made by the mold Cephalosporium acremonium

b. Subgroups and uses of cephalosporins

i. Many are administered parenterally

ii. Second generation cefaclor and cefonacid for Enterobacter, Proteus,

and Haemophilus infections

iii. Third generation Keflex for beta-lactamase producers

3. Other beta-lactam antibiotics

a. Imipenem

b. Aztreonam

4. Other drugs targeting the cell wall

a. Bacitracin

b. Isoniazid (Mycobacterium tuberculosis)

c. Vancomycin

d. Fosfomycin trimethamine

B. Antibacterial drugs targeting protein synthesis

1. The aminoglycoside drugs

a. Made by Streptomyces and Micromonospora

b. Subgroups and uses of aminoglycosides

i. Gentamicin for Escherichia coli, Pseudomonas, and Salmonella and

Shigella infections

ii. Tobramycin and amikacin

2. Tetracycline antibiotics

a. Made by Streptomyces

b. Subgroups and uses of tetracyclines

i. Mycoplasma pneumonia and cholera

3. Chloramphenicol

a. Made by Streptomyces venezuelae

b. Toxic properties limit use

4. Erythromycin and clindamycin

a. Made by Streptomyces

b. Erythromycin: used to treat Mycoplasma pneumoniae, legionellosis, Chlamydia, and Mycobacterium MAC

c. Clindamycin: used to treat penicillin-resistant Staphylococcus and anaerobic infections

5. Synercid and oxazolidinones

a. Synercid: resistant strains of Streptococcus

b. Linezolid: resistant strains of Staphylococcus aureus (MRSA) and Enterococcus (VRE)

C. Antibacterial drugs targeting folic acid synthesis

1. The sulfonamides, trimethoprim, and sulfones

a. Trimethoprim-sulfamethoxazole

i. Used to treat Pneumocystis (carinii) jirovecii pneumonia

b. Dapsone: a sulfone

i. Used to treat Hansen’s disease (leprosy)

D. Antibacterial drugs targeting DNA or RNA

1. Fluoroquinolones

2. Rifamycin (rifampin)

E. Antibacterial drugs targeting cell membranes

1. Polymixins (made by Bacillus polymyxa)

2. Daptomycin (made by Streptomyces)

F. Agents to treat fungal infections

1. Macrolide polyenes

a. Amphotericin B

b. Nystatin

2. Griseofulvin

3. Azoles

4. Flucytosine

G. Antiparasitic chemotherapy

1. Antimalarial drugs: Quinine and its relatives

a.Quinine from bark of cinchona tree

b. Synthesized quinolines (chloroquine, primaquine, mefloquine)

i. Used to treat malaria (Plasmodium)

2. Chemotherapy for other protozoan infections

a. Metronidazole (Flagyl)

i. Used to treat Entamoeba histolytica infections

ii. Also used for Giardia lamblia and Trichomonas vaginalis infections

3. Antihelminthic drug therapy

a. Mebendazole and thiabendazole

b. Pyantel

c. Praziquantel and ivermectin

H. Antiviral chemotherapeutic agents

1. Three major modes of action

a. Preventing the virus from penetrating into the host cell

i. Fuzeon, Amantidine, Tamiflu

b. Blocking transcription and translation of viral molecules

i. Acyclovir, AZT, Nevirapine

c. Preventing the maturation of viral particles

i. Protease inhibitors: saquinavir

2. Interferons

a. Glycoprotein produced by human cells

b. Has antiviral and anticancer properties

c. Now made using recombinant DNA technology

I. Interactions between microbes and drugs: The acquisition of drug resistance

1. How does drug resistance develop?

a. Microbes become resistant to a drug after either:

i. Spontaneous mutation occurs in critical chromosomes

ii. New genes or sets of genes are acquired through transfer from another species

2. Specific mechanisms of drug resistance

a. Drug inactivation mechanisms

i. Beta-lactamases destroy penicillins and cephalosporins

ii. Staphylococcus aureus

iii. Neisseria gonorrhoeae and PPNG (penicillinase producing NG)

b. Decreased drug permeability or increased drug elimination

i. Multidrug resistant pumps

ii. Staphylococcus, Streptococcus, Pseudomonas, Escherichia coli

c. Change of drug receptors

i. Erythromycin: alteration on the 50S ribosomal binding site

ii. Penillin: alteration in the binding proteins in the cell wall

d. Changes in metabolic patterns

3. Natural selection and drug resistance

a. Any large population of microbes will have a few members who are already drug resistant, due to mutations or transfer of plasmids

b. If the population is exposed to the drug, resistant members survive and flourish, while sensitive members are killed

c. Leads to a new population that is resistant overall

J. New approaches to antimicrobial therapy

1. Iron-scavenging capabilities

2. Riboswitches

3. Probiotics and prebiotics

4. Lantibiotics

12.4. Interaction Between Drug and Host

A. Toxicity to organs

B. Allergic responses to drugs

C. Suppression and alteration of the microbiota by antimicrobials

1. Biota

2. Superinfection

a. Candida albicans

b. Clostridium difficile

12.5. Considerations in Selecting an Antimicrobial Drug

A. Identifying the agent

B. Testing for the drug susceptibility of microorganisms

1. Kirby-Bauer method

2. Minimum inhibitory concentration (MIC)

C. The MIC and therapeutic index

1. Ratio of dose toxic to humans as compared to its mimimum effective dose

2. The art and science of choosing an antimicrobial drug

D. An antimicrobial drug dilemma

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