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Antimicrobial Drug Action and Interaction: An Introduction

John F. Prescott

Antimicrobial drugs exploit differences in structure or biochemical function between host and parasite. Modern chemotherapy is traced to Paul Ehrlich, a pupil of Robert Koch, who devoted his career to discovering agents that possessed selective toxicity so that they might act as so-called "magic bullets" in the fight against infectious diseases. The remarkable efficacy of modern antimicrobial drugs still retains the sense of the miraculous. Sulfonamides, the first clinically successful broad-spectrum antibacterial agents, were produced in Germany in 1935.

However, it was the discovery of the antimicrobial penicillin, a fungal metabolite, by Fleming in 1929 and its subsequent development by Chain and Florey during World War II that led to the "antibiotic revolution." Within a few years of the introduction of penicillin, many other antimicrobials were described. This was followed by the development of semisynthetic and synthetic antimicrobial agents which has resulted in an increasingly powerful and effective array of compounds used to treat infectious diseases.

The term antibiotic has been defined as a low molecular weight substance produced by a microorganism that at low concentrations inhibits or kills other microorganisms. In contrast, the word antimicrobial has a broader definition than antibiotic and includes any substance of natural, semisynthetic, or synthetic origin that kills or inhibits the growth of a microorganism but causes little or no damage to the host. Antimicrobial agent and antibiotic are commonly used synonymously. The term antimicrobial is preferentially used in this book as the more encompassing term.

The marked structural and biochemical differences between prokaryotic and eukaryotic cells give antimicrobial agents greater opportunities for selective toxicity against bacteria than against other microorganisms such as fungi, which are nucleated like mammalian cells, or viruses, which require their host's genetic material for replication. Nevertheless, in recent years increasingly effective antifungal and antiviral drugs have been introduced into clinical practice.

Important milestones in the development of antibacterial drugs are shown in Figure 1.1. Because of the enormous costs of development, the therapeutic use of these agents in veterinary medicine has usually followed their use in human medicine. However, some antimicrobials have been developed specifically for animal health and production (e.g., tylosin, tiamulin, tilmicosin, ceftiofur, tulathromycin, gamithromycin, tildipirosin), although all these are related to drug classes used in human medicine. A few classes not used because of toxicity for humans, such as the orthosomycins, have been relegated to oral use in animals for treatment of enteric infections. Figure 1.1 highlights the relationship between antimicrobial use and the development of resistance in many target microorganisms.

Figure 1.1 Milestones in human infectious disease and their relationship to development of antimicrobial drugs, 1930-2010, illustrating the relationship between the introduction of an antibacterial drug and the emergence of resistance.

Source: Modified and reproduced with permission from Kammer (1982).

Spectrum of Activity of Antimicrobial Drugs

Antimicrobial drugs may be classified in a variety of ways, based on four basic features.

Class of Microorganism

Antiviral and antifungal drugs generally are active only against viruses and fungi, respectively. However, some imidazole antifungal agents have activity against staphylococci and nocardioform bacteria. Antibacterial agents can be described as narrow spectrum if they inhibit only Gram-positive and Gram-negative bacteria or broad spectrum if they also inhibit a wider range of bacteria such as chlamydia, mycoplasma, and rickettsia (Table 1.1).

Table 1.1 Spectrum of activity of common antibacterial drugs.

Drug Class of Microorganism Bacteria Fungi Mycoplasma Rickettsia Chlamydia Protozoa Aminoglycosides + - + - - - Beta-lactams + - - - - - Chloramphenicol + - + + + - Fluoroquinolones + - + + + - Glycylcyclines + + + + +/- Lincosamides + - + - - +/- Macrolides + - + - + +/- Oxazolidinones + - + - - - Pleuromutilins + - + - + - Tetracyclines + - + + + +/- Streptogramins + - + - + +/- Sulfonamides + - + - + + Trimethoprim + - - - - +

+/-, activity against some protozoa.

Antibacterial Activity

Within the class description of antibacterial drug activity, antimicrobial drugs can further also be described as narrow spectrum if they inhibit only either Gram-positive or Gram-negative bacteria and as broad-spectrum drugs if they inhibit both Gram-positive and Gram-negative bacteria. This distinction is often not absolute since, although some agents may be primarily active against Gram-positive bacteria, they may also inhibit some Gram negatives (Table 1.2). It seems likely that some antimicrobial drugs developed in the future may be narrow spectrum and targeted to particular pathogens, avoiding the considerable "bystander" effect of broad-spectrum antimicrobials on the nonpathogenic microflora.

Bacteriostatic or Bactericidal Activity

The minimum inhibitory concentration (MIC) is the lowest concentration of an antimicrobial agent required to prevent the growth of the pathogen. In contrast, the minimum bactericidal concentration (MBC) is the lowest concentration of an antimicrobial agent required to kill the pathogen. Antimicrobials are usually regarded as bactericidal if the MBC is no more than four times the MIC. This distinction is rarely important for treatment of clinical conditions. Some drugs are routinely bactericidal (e.g., beta-lactams, aminoglycosides) whereas others are usually bacteriostatic (e.g., chloramphenicol, tetracyclines), but this distinction depends on both the drug concentration at the site of infection and the microorganism involved. For example, benzyl penicillin is bactericidal at usual therapeutic concentrations but bacteriostatic at lower concentrations.

Table 1.2 Antibacterial activity of selected antibiotics.

Spectrum Aerobic Bacteria Anaerobic Bacteria Examples Gram + Gram - Gram + Gram - Very broad + + + + Carbapenems; chloramphenicol; third-generation fluoroquinolones; glycylcyclines Intermediately broad + + + (+) Third- and fourth-generation cephalosporins + (+) + (+) Second-generation cephalosporins (+) (+) (+) (+) Tetracyclines Narrow + +/- + (+) Ampicillin; amoxicillin; first-generation cephalosporins + - + (+) Penicillin; lincosamides; glycopeptides; streptogramins; oxazolidinones + +/- + (+) Macrolides +/- + - - Monobactams; aminoglycosides ... (+) + - - Second-generation fluoroquinolones