Prescott's Microbiology,4/e

		Microbiology, 4/e Prescott, Harley, Klein
		Instructor Resources

33 Antimicrobial Chemotherapy

CHAPTER OVERVIEW

The control or the destruction of microorganisms that reside within the bodies of humans and other animals is of tremendous importance. This chapter introduces the principles of chemotherapy, and discusses the ideal characteristics for successful chemotherapeutic agents (including the concept of selectively damaging the target microorganism while minimizing damage to the host). The chapter also presents characteristics of some commonly used antibacterial, antifungal, and antiviral drugs.

CHAPTER OBJECTIVES

After reading this chapter you should be able to:

! discuss the various ways in which antimicrobial agents can damage pathogens while causing minimal damage to the host

! discuss the various factors that influence the effectiveness of a chemotherapeutic agent

! discuss the increasingly serious problem of drug-resistant pathogens

! discuss the increasing demand for and availability of antifungal and antiviral agents

CHAPTER OUTLINE

I. The Development of Chemotherapy

A. Ancient herbal remedies were actually primitive forms of chemotherapy

B. Paul Ehrlich (1904-1909)Caniline dyes and arsenic compounds

C. Gerhard Domagk, and Jacques and Therese Trefouel (1939)Csulfanilamide

D. Ernest Duchesne (1896) discovered penicillin; however, this discovery was not followed up and was lost for 50 years until rediscovered by a librarian

E. Alexander Fleming (1928) accidentally discovered the antimicrobial activity of penicillin on a contaminated plate; however, follow-up studies convinced him that penicillin would not remain active in the body long enough to be effective

F. Howard Florey and Ernst Chain (1939) aided by the biochemist, Norman Heatley, worked from Fleming=s published observations, obtained a culture from him, and demonstrated the effectiveness of penicillin

G. Selman Waksman (1944)Cstreptomycin; this success led to a worldwide search for additional antibiotics, and the field has progressed rapidly since then

II. General Characteristics of Antimicrobial Drugs

A. Selective toxicity with minimal side effects

1. Therapeutic doseCthe drug level required for clinical treatment of a particular infection

2. Toxic doseCthe drug level at which the agent becomes too toxic for the host (produces undesirable side effects)

3. Therapeutic indexCthe ratio of toxic dose to therapeutic dose: the larger the better, all other things being equal

B. Broad spectrum activity (activity against a wide variety of pathogens) is more desirable than narrow spectrum activity, but this is not crucial

C. Drug can be cidal (able to kill) or static (able to reversibly inhibit growth)

D. Chemotherapeutic agents can occur naturally or be synthetic or semisynthetic (chemical modifications of naturally occurring antibiotics)

III. Determining the Level of Antimicrobial Activity

A. Dilution susceptibility tests

1. The lowest concentration of the antibiotic resulting in no microbial growth is the minimal inhibitory concentration (MIC)

2. Tubes showing no growth are subcultured into tubes of fresh medium that contain no antibiotic to determine the lowest concentration of the drug from which the organism does not recoverCthe minimal lethal concentration (MLC)

B. Disk diffusion testsCdisks impregnated with specific drugs are placed on agar plates inoculated with the test organism; clear zones (no growth) will be observed if the organism is sensitive to the drug; the size of the clear zone is used to determine the relative sensitivity according to tables prepared for the various available drugs; zone width is a function of initial concentration, solubility and diffusion rate of the antibiotic

C. Measurement of drug concentrations in the blood can be done using microbiological, chemical, immunological, enzymatic, and/or chromatographic assays

IV. Mechanism of Action of Antimicrobial Agents

A. Inhibition of cell wall synthesis

B. Inhibition of protein synthesis

C. Inhibition of nucleic acid synthesis

D. Disruption of cell membranes

E. Inhibition of metabolic activities (antimetabolites)

V. Factors Influencing the Effectiveness of Antimicrobial Drugs

A. Factors influencing a drug=s ability to reach the site of infection

1. Mode of administration

a. Oral

b. Topical

c. Parenteral (injection)

2. Susceptibility to various bodily defense mechanisms (e.g., penicillin is rapidly degraded in the stomach, but the penicillin derivative ampicillin is more acid stable)

B. Factors influencing drug concentration in the body, which must exceed the pathogen=s MIC for the drug to be effective; this will depend on

1. Amount of drug administered

2. Route of administration

3. Speed of uptake

4. Rate of clearance (elimination) from the body

C. The nature of the pathogen, including its inherent susceptibility and the presence of its active growth, may have a profound effect on susceptibility to particular drugs

D. Drug resistance has become an increasing problem

VI. Antibacterial Drugs

A. Sulfonamides, or sulfa drugs, are structural analogues of metabolic intermediates (also called antimetabolites); they inhibit folic acid synthesis

B. Quinolones inhibit bacterial DNA gyrase, thereby disrupting replication, repair, and other processes involving DNA

C. Penicillins inhibit cell wall synthesis

D. Cephalosporins also inhibit cell wall synthesis, but have a broader spectrum of activity; they can be given to some patients with penicillin allergies

E. Tetracyclines inhibit protein synthesis

F. Aminoglycosides (streptomycin, kanamycin, neomycin, tobramycin, gentamicin) inhibit protein synthesis

G. Erythromycin and other macrolides inhibit protein synthesis

H. Chloramphenicol inhibits protein synthesis; it has a broad spectrum but is toxic

VII. Drug Resistance

A. Mechanisms of drug resistance

1. Exclusion of drug from cellCchanges in ability of drug to bind to and/or penetrate the cell or the ability to pump the drug out of the cell once it has entered

2. Enzymatic inactivation of the drugCchemical modification of the drug by cellular enzymes can render it inactive before it has a chance to damage the cell

3. Alteration of target enzyme or organelleCmodification of the target so that it is no longer susceptible to the action of the drug

4. Use of alternative pathways and increased production of the target metabolite have been used by some organisms to minimize the effects of the drug

B. The origin and transmission of drug resistance involve chromosomal or plasmid genes for drug resistance

1. Drug resistance has become an increasing problem

2. Superinfection by drug-resistant pathogens may result because of the lack of competition from drug-sensitive strains

VIII. Antifungal DrugsCfungal infections are more difficult to treat than bacterial infections, because the greater similarity between fungi and host limits the ability of a drug to have a selective point of attack

A. Superficial mycoses are infections of superficial tissues and can often be treated by topical application of antifungal drugs such as miconazole, nystatin, and griseofulvin, thereby minimizing toxic systemic side effects

B. Systemic mycoses are more difficult to treat and can be fatal; however, amphotericin B and flucytosine have been used with limited success; amphotericin B is highly toxic and must be used with care; flucytosine must be converted by the fungus to an active form, and animal cells are incapable of this; some selectivity is possible, but severe side effects have been observed with both drugs

C. Drug resistant fungal strains are also beginning to emerge

IX. Antiviral DrugsCselectivity has been a problem because viruses use the metabolic machinery of the host; recently, however, drugs that inhibit virus-specific enzymes (such as amantadine, vidarabine, acyclovir, and azidothymidine [AZT]) have been found and offer hope for this area in the future, another promising area is the possibility of using human interferon (a naturally produced antiviral substance) as an effective treatment; develoment of drug resistance is minimized by the use of a cocktail of several drugs at high doses

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