7       Antibacterial agents

 

Antibiotics are low-molecular-weight microbial metabolites which can kill or inhibit the growth of susceptible bacteria. The term ‘antimicrobial agent’ is sometimes used to include both antibiotics and synthetic compounds with antimicrobial activity. The therapeutic use of antibiotics depends on their selective toxicity: these drugs kill or inhibit bacterial pathogens without direct toxicity for animals receiving treatment. Individual antibacterial agents are not effective against all pathogenic bacteria. Some are active against a narrow range of bacterial species, while broad-spectrum antibiotics such as tetracyclines and chloramphenicol are active against many species.

The modes and sites of action of antibacterial drugs range from interference with DNA synthesis to inhibition of cell wall synthesis. The major classes of antimicrobial drugs and their modes of action are listed in Table 7.1. Because peptidoglycan is a unique component of bacterial cell walls, antibacterial agents which prevent cross-linking of peptidoglycan chains inhibit cell wall synthesis and are selectively toxic for bacteria. The penicillins and cephalosporins comprise the largest and most important class of antibacterial drugs which inhibit cell wall synthesis. A number of classes of antibacterial agents inhibit protein synthesis. Aminoglycosides bind to 30S ribosomal subunits and affect a number of different steps in protein synthesis. Macrolide antibiotics inhibit protein synthesis by blocking 50S subunit activity. Many antibacterial agents including quinolones, novobiocin, rifampin, nitroimidazoles and sulphonamides inhibit nucleic acid synthesis. The activity of antibacterial drugs is influenced in vivo by the site and rate of absorption, the site of excretion and the tissue distribution and metabolism of a particular agent. In addition, antibacterial activity can be affected by interactions between pathogen and drug and between host and pathogen.

Table 7.1 Major classes of antibacterial drugs and their modes of action.

Antibacterial drug	Mode of action	Effect	Comments
β-Lactam antibiotics  Penicillins  Cephalosporins	Inhibition of cell wall synthesis	Bactericidal	Low toxicity. Many are inactivated by β-lactamases
Glycopeptides  Vancomycin	Inhibition of cell wall synthesis	Bactericidal	Used against methicillin-resistant Staphylococcus aureus
Polypeptides  Polymyxin  Colistin	Inhibition of cell membrane function	Bactericidal	Resistance slow to develop. Potentially nephrotoxic and neurotoxic
Nitrofurans  Nitrofurantoin	Inhibition of protein synthesis	Bacteriostatic	Synthetic agents with broad-spectrum activity. Relatively toxic
Aminoglycosides  Streptomycin  Neomycin	Inhibition of protein synthesis Block 30S ribosomal activity	Bactericidal	Active mainly against Gram-negative bacteria. Ototoxic and nephrotoxic
Tetracyclines  Oxytetracycline  Doxycycline	Inhibition of protein synthesis Block 30S ribosomal activity	Bacteriostatic	Formerly used in feed for prophylactic medication. Development of resistance common
Chloramphenicol Florfenicol	Inhibition of protein synthesis Block 50S ribosomal activity	Bacteriostatic	Use prohibited in food-producing animals in some countries. Potentially toxic
Lincosamides  Clindamycin  Lincomycin	Inhibition of protein synthesis Block 50S ribosomal activity	Bactericidal or bacteriostatic	May be toxic in many species. Contraindicated in horses and neonatal animals. Oral administration is hazardous in ruminants
Macrolides  Erythromycin  Tylosin	Inhibition of protein synthesis Block 50S ribosomal activity	Bacteriostatic	Active against Gram-positive bacteria. Some macrolides active against mycoplasmal pathogens
Quinolones  Nalidixic acid  Enrofloxacin	Inhibition of nucleic acid synthesis by blocking DNA gyrase	Bactericidal	Synthetic agents used for treating enteric infections and for intracellular pathogens
Novobiocin	Inhibition of nucleic acid synthesis by blocking DNA gyrase	Bactericidal or bacteriostatic	Often used along with other compatible drugs for treatment of mastitis
Rifampin	Inhibition of nucleic acid synthesis by blocking DNA-dependent RNA polymerase	Bacteriostatic	Antimycobacterial activity; used with erythromycin for treating Rhodococcus equi infections
Sulphonamides  Sulphamezathine  Sulphamethoxazole	Inhibition of nucleic acid synthesis by competitive blocking of para-aminobenzoic acid (PABA) incorporation into folic acid	Bacteriostatic	Synthetic structural analogues of PABA active against rapidly growing bacteria
Trimethoprim	Inhibition of nucleic acid synthesis by combining with the enzyme dihydrofolate reductase	Bacteriostatic	Usually administered with sulphamethoxazole. This combination, referred to as a potentiated sulphonamide, is bactericidal
Nitroimidazoles  Metronidazole	Disruption of DNA structure and inhibition of DNA repair	Bactericidal	Particularly active against anaerobic bacteria; also active against some protozoa

When antibacterial drugs are combined for treatment of disease, the outcome is influenced by the particular combinations employed. If a bacteriostatic drug is combined with a bactericidal drug, antagonism may occur. Bactericidal drugs, particularly the β-lactam antibiotics, are effective against actively dividing cells. If they are combined with a bacteriostatic drug which inhibits bacterial growth, their bactericidal activity may be abolished. Drugs which act synergistically include sulphonamides and trimethoprim, which act at two different sites in the folic acid pathway, and clavulanic acid and penicillin combinations, in which clavulanic acid inhibits β-lactamase activity, preventing inactivation of penicillin.

Antimicrobial drugs can alter the host's immune response and may change the normal flora, particularly on the skin and in the intestinal tract. Disturbance of the normal intestinal flora following therapy for enteric pathogens, such as Salmonella species, may allow the development of an extended carrier state and prolonged therapy may predispose the recipient to fungal infections.