Antibiotics and Chemotherapy

The antimicrobial drugs can be subclassified as antibacterial, antifungal, and antiviral agents. These agents include natural compounds, called antibiotics, as well as synthetic compounds. An antibiotic is a substance produced by one microbe that can inhibit the growth or viability of another microbe. The earliest use of antibiotics was probably in the treatment of skin infections with moldy bean curd by the ancient Chinese. The development of modern antibiotics can be traced to the work of Louis Pasteur, who observed that the in vitro growth of one microbe was inhibited when another microbe was added to the culture. Pasteur called this phenomenon antibiosis and predicted that substances derived from microbes would someday be used to treat infectious diseases.

Several decades later, Alexander Fleming observed that the growth of his staphylococcal cultures was inhibited by a Penicillium contaminant. Fleming postulated that the fungus produced a substance, which he called penicillin, and that this substance inhibited the growth of staphylococci. His observations eventually led to the isolation and use of penicillin for treating bacterial infections. The discovery of penicillin stimulated the discovery and development of many other antibiotics and revolutionized the treatment of infectious diseases.

Synthetic drugs have also provided major advances in the treatment of infectious diseases and cancer. During the Renaissance, Paracelsus used mercury compounds for the treatment of syphilis. In the late 19th and early 20th centuries, Paul Ehrlich pioneered the search for selectively toxic compounds. After many failed attempts, he discovered arsphenamine (SALVARSAN), an arsenical compound for the treatment of syphilis. Ehrlich, who became known as the father of chemotherapy, also studied bacterial stains as potential antimicrobial agents. He reasoned that a stain’s selective affinity for bacteria could be coupled with an inhibitory action to halt microbial metabolism and destroy invading organisms. This concept led to the discovery of sulfonamides, drugs that were originally derived from a bacterial stain called PRONTOSIL. The sulfonamides were the first effective drugs for the treatment of systemic bacterial infections, and their development accelerated the search for other antimicrobial agents.

Bactericidal or Bacteriostatic Effect

A bactericidal drug kills sensitive organisms so that the number of viable organisms falls rapidly after exposure to the drug (Fig. 37-2). In contrast, a bacteriostatic drug inhibits the growth of bacteria but does not kill them. For this reason, the number of bacteria remains relatively constant in the presence of a bacteriostatic drug, and immunologic mechanisms are required to eliminate organisms during treatment of an infection with this type of drug. (The same principle applies to a drug that kills or inhibits the growth of fungi and is referred to as a fungicidal drug or a fungistatic drug, respectively.)

A bactericidal drug is usually preferable to a bacteriostatic drug for the treatment of most bacterial infections. This is because bactericidal drugs typically produce a more rapid microbiologic response and more clinical improvement and are less likely to elicit microbial resistance. Bactericidal drugs have actions that induce lethal changes in microbial metabolism or block activities that are essential for microbial viability. For example, drugs that inhibit the synthesis of the bacterial cell wall (e.g., penicillins) prevent the formation of a structure that is required for the survival of bacteria. In contrast, bacteriostatic drugs usually inhibit a metabolic reaction that is needed for bacterial growth but is not necessary for survival. For example, sulfonamides block the synthesis of folic acid, which is a cofactor for enzymes that synthesize DNA components and amino acids.

Drugs that reversibly inhibit bacterial protein synthesis (e.g., tetracyclines) are also bacteriostatic, whereas drugs that irreversibly inhibit protein synthesis (e.g., streptomycin) are usually bactericidal.

Some drugs can be either bactericidal or bacteriostatic, depending on their concentration and the bacterial species against which they are used.

Antimicrobial Spectrum

The spectrum of antimicrobial activity of a drug is the primary determinant of its clinical use. Antimicrobial agents that are active against a single species or a limited group of pathogens (e.g., gram-positive bacteria) are called narrow-spectrum drugs, whereas agents that are active against a wide range of pathogens are called broad-spectrum drugs. Agents that have an intermediate range of activity are sometimes called extended-spectrum drugs. Narrow-spectrum drugs are sometimes preferred because they target a specific pathogen without disturbing the normal flora of the gut or respiratory tract. Broad-spectrum drugs are sometimes preferred for the initial treatment of an infection when the causative pathogen is not yet identified.

Concentration- and Time-Dependent Effects

Antimicrobial drugs exhibit various concentration- and time-dependent effects that influence their clinical efficacy, dosage, and frequency of administration. Examples of these effects are the minimal inhibitory concentration (MIC), the concentration-dependent killing rate (CDKR), and the postantibiotic effect (PAE).

The MIC is the lowest concentration of a drug that inhibits bacterial growth. Based on the MIC, a particular strain of bacteria can be classified as susceptible or resistant to a particular drug (see later).

An example of a CDKR is shown in Figure 37-3A. Some aminoglycosides (e.g., tobramycin) and some fluoroquinolones (e.g., ciprofloxacin) exhibit a CDKR against a large group of gram-negative bacteria, including Pseudomonas aeruginosa and members of the family Enterobacteriaceae. In contrast, penicillins and other β-lactam antibiotics usually do not exhibit a CDKR.

After an antibacterial drug is removed from a bacterial culture, evidence of a persistent effect on bacterial growth may exist. This effect (see Fig. 37-3B) is the PAE. Most bactericidal antibiotics exhibit a PAE against susceptible pathogens. For example, penicillins show a PAE against gram-positive cocci, and aminoglycosides show a PAE against gram-negative bacilli. Because aminoglycosides exhibit both a CDKR and a PAE, treatment regimens have been developed in which the entire daily dose of an aminoglycoside is given at one time. Theoretically, the high rate of bacterial killing produced by these regimens would more rapidly eliminate bacteria, and the PAE would prevent any remaining bacteria from replicating for several hours after the drug has been eliminated from the body.

Resistance can be innate or acquired. Acquired drug resistance arises from mutation and selection or from the transfer of plasmids that confer drug resistance.

Mutation and Selection.

Microbes can spontaneously mutate to a form that is resistant to a particular antimicrobial drug. These mutations occur at a relatively constant rate, such as in 1 in 10¹² organisms per unit of time. If the organisms are exposed to an antimicrobial drug during this time period, the sensitive organisms may be eradicated, enabling the resistant mutant to multiply and become the dominant strain (Fig. 37-4A).

The probability that mutation and selection of a resistant mutant will occur is increased during the exposure of an organism to suboptimal concentrations of an antibiotic, and it is also increased during prolonged exposure to an antibiotic. This observation has obvious implications for antimicrobial therapy. Laboratory tests should be used to guide the selection of an antimicrobial drug, and the dosage and duration of therapy should be adequate for the type of infection being treated. Whenever possible, the bacteriologic response to drug therapy should be verified by culturing samples of appropriate body fluids.