9       Bacterial resistance to antimicrobial drugs

 

Resistance to antibacterial drugs is an important problem in both animals and humans. The widespread and sometimes indiscriminate use of these drugs results in the selection of bacteria which are inherently resistant. Not only may these resistant bacteria become the predominant species in a population, but they may also transfer genetic material to other bacterial species which confers resistance on recipients. In broad terms, resistance of an organism can be defined as either innate (intrinsic) or acquired (extrinsic). Innate resistance is chromosomally encoded and relates to the general physiology of an organism arising from its existing properties such as cell wall complexity, efflux mechanisms or enzymatic inactivation of an antibiotic. In contrast, acquired resistance can arise from a mutation in a resident gene or the transfer of genetic material encoding resistance genes via plasmids, bacteriophages carrying resistance genes or transposons containing integron sequences (Table 9.1 and Chapter 3). Resistance to an antibacterial agent often results in cross-resistance to other agents in the same class. Carriage of several resistance genes by plasmids and transposable elements often enable bacteria to become resistant to a number of drugs of different classes. This type of resistance can be transferred rapidly between different bacterial genera and species, creating multi-drug resistant isolates such as Salmonella Typhimurium DT104. This strain is characterized by a penta-resistant phenotype ACSSuT (conferring resistance to ampicillin, chloramphenicol, streptomycin, sulphonamide and tetracycline). The resistance genes corresponding to the ACSSuT phenotype are encoded on the Salmonella Genomic Island 1 which is located on the chromosome but can be transferred between organisms within this bacterial genus. A monophasic variant of Salmonella Typhimurium, Salmonella 4,[5],12:i:-, is increasing in prevalence worldwide and exhibits an ASSuT resistance phenotype; the genes encoding resistance in these isolates are located on a chromosomal genomic island also. Multiple drug resistance is of particular concern in zoonotic pathogens and in nosocomial pathogens. The latter cause disease in hospitalized humans and animals where the selection pressure is high. These nosocomial pathogens are sometimes referred to as ‘superbugs’ and generally fall into one of two categories: widely recognized pathogens such as methicillin-resistant Staphylococcus aureus which have acquired resistance to multiple antimicrobial agents, and environmental organisms such as Pseudomonas aeruginosa which are intrinsically resistant to many agents and cause opportunistic infections.

Table 9.1 Antibacterial drug resistance.

Drug	Target	Examples of resistant bacteria / Genetic basis	Comments
Fluoroquinolones	DNA gyrase Topoisomerase	Gram-positive, Gram-negative / Chromosomally-based	Mutation results in structurally altered enzyme
	Cell membrane	Enterobacteriaceae / Chromosomally-based	Decreased permeability
Rifampin	DNA-dependent RNA polymerase	Enterobacteriaceae / Chromosomally-based	Mutation results in structurally altered enzyme
Erythromycin	Ribosomal protein	Staphylococcus aureus / Chromosomally-based	Due to structural change, ribosomes unaffected by drug action
Streptomycin	Ribosomal protein	Enterobacteriaceae / Chromosomally-based	Mutation results in altered ribosome
Tetracycline	Ribosomal protein	Enterobacteriaceae / Plasmid-mediated	Ribosome protection proteins produced
	Transport mechanisms	Enterobacteriaceae / Plasmid-mediated	Decreased absorption or development of energy-dependent efflux mechanism
Chloramphenicol	Peptidyltransferase	Staphylococcus species, streptococci / Plasmid- or chromosomally-based	Inactivation of drug by a specific acetyltransferase
Sulphonamides	Dihydropteroate synthetase	Enterobacteriaceae / Plasmid- or chromosomally-based	New folic acid synthetic pathway employing sulphonamide-resistant enzyme
β-Lactam antibiotics	Penicillin-binding proteins (PBP)	Staphylococcus aureus / Chromosomally-based	Decreased affinity of PBP for drug
	Penicillin-binding proteins	Enterobacteriaceae / Chromosomally-based	Outer membrane of most Gram-negative bacteria inherently impermeable to drug
	Penicillin-binding proteins	Staphylococcus aureus, Enterobacteriaceae / Plasmid- or chromosomally-based	Enzymatic degradation of drug by β-lactamases

In general terms, resistance to antibiotics occurs as a result of drug inactivation, drug-target modification and decreased intracellular accumulation associated with reduced membrane permeability or increased drug efflux. Mechanisms producing resistance to antibacterial drugs include production of enzymes by bacteria which destroy or inactivate the drug. Production of β-lactamases renders bacteria resistant to β-lactam antibiotics. The mode of action of these antibiotics involves interacting with penicillin-binding proteins which interfere with transpeptidation. β-Lactamases cleave the β-lactam ring, rendering the antibiotic ineffective. These enzymes may be plasmid-mediated, as in staphylococci, or they may be chromosomally encoded, as in Gram-negative bacteria. Sulphonamides interfere with the formation of folic acid, an essential precursor for nucleic acid synthesis. Their action relates to their structural similarity to para-aminobenzoic acid. When present at sufficient concentrations, sulphonamides are utilized by the enzyme dihydropteroate synthetase instead of para-aminobenzoic acid, forming non-functional analogues of folic acid.

Bacteria may also develop alternative metabolic pathways to those inhibited by the drug. An antibiotic may be eliminated from the cell through the action of a range of membrane-bound efflux pumps or the target site of the drug may be structurally altered (Table 9.1).

Antibacterial resistance is widespread in many regions of the world and control measures in a particular country may not be effective if resistant bacteria in food or in the normal flora of animals or humans are imported from countries with less stringent controls. Effective surveillance systems for collecting data on resistant organisms should be established at local, national and international levels. The supply and use of antibacterial drugs should be closely monitored to facilitate evaluation of the risks and benefits of therapy and there should be strict adherence to the recommended therapeutic dose for the prescribed period of time. Adherence to drug withdrawal periods following treatment of food-producing animals should be strictly enforced. Antimicrobial agents should not be used for growth promotion and greater reliance should be placed on improved hygiene measures, disinfection and vaccination for the prevention and control of infectious diseases in animals.