Chapter 28: Antimicrobial Chemotherapy

INTRODUCTION

Drugs have been used for the treatment of infectious diseases since the 17th century (eg, quinine for malaria and emetine for amebiasis); however, chemotherapy as a science began in the first decade of the 20th century with understanding of the principles of selective toxicity, the specific chemical relationships between microbial pathogens and drugs, the development of drug resistance, and the role of combined therapy. Experiments by the German physician and scientist Paul Erlich led to the arsphenamines for syphilis, the first planned chemotherapeutic regimen.

The current era of antimicrobial chemotherapy began in 1935 with the discovery of the sulfonamides by German physician and scientist Gerhard Domagk. In 1940, it was demonstrated that penicillin, discovered in 1929 by Scottish physician and scientist Sir Alexander Fleming, could be an effective therapeutic substance. During the next 25 years, research on chemotherapeutic agents focused largely on substances of microbial origin called antibiotics. The isolation, concentration, purification, and mass production of penicillin were followed by the development of streptomycin, tetracyclines, chloramphenicol, and many other agents. These substances were originally isolated from filtrates of media in which their respective molds and filamentous bacteria had grown. Synthetic modification of previously described drugs has been prominent in the development of new antimicrobial agents.

Antimicrobial agents commonly used in the treatment of patients with bacterial infections are presented in this chapter. The chemotherapy of viruses, fungi, and parasites is discussed in Chapters 30, 45, and 46, respectively. Additional comments on antimicrobial susceptibility testing for bacteria are found in Chapter 47.

MECHANISMS OF ACTION OF ANTIMICROBIAL DRUGS

Antimicrobial drugs act in one of several ways: by selective toxicity, by inhibition of cell membrane synthesis and function, by inhibition of protein synthesis, or by inhibition of nucleic acid synthesis.

SELECTIVE TOXICITY

An ideal antimicrobial agent exhibits selective toxicity, which means that the drug is harmful to a pathogen without being harmful to the host. Often, selective toxicity is relative rather than absolute; this implies that a drug in a concentration tolerated by the host may damage an infecting microorganism.

Selective toxicity may be a function of a specific receptor required for drug attachment, or it may depend on the inhibition of biochemical events essential to the pathogen but not to the host. The mechanisms of action of antimicrobial drugs can be discussed under four headings:

1. Inhibition of cell wall synthesis

2. Inhibition of cell membrane function

3. Inhibition of protein synthesis (ie, inhibition of translation and transcription of genetic material)

4. Inhibition of nucleic acid synthesis

INHIBITION OF CELL WALL SYNTHESIS

Bacteria have a rigid outer layer, the cell wall. The cell wall maintains the shape and size of the microorganism, which has a high internal osmotic pressure. Injury to the cell wall (eg, by ...