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P A R T 2  Chemotherapeutic agents

mediators, leucocytes, lymphocytes, antibodies and locally released enzymes and chemicals. When this response is completely functional and all of the neces- sary proteins, cells and chemicals are being produced by the body, it can isolate and eliminate foreign proteins, including bacteria, fungi and viruses. However, if a person is immunocompromised for any reason (e.g. mal- nutrition, age, acquired immune deficiency syndrome [AIDS], use of immunosuppressant drugs), the immune system may be incapable of dealing effectively with the invading organisms. It is difficult to treat any infections in such people for two reasons: (1) anti-infective drugs cannot totally eliminate the pathogen without causing severe toxicity in the host; and (2) these people do not have the immune response in place to deal with even a few invading organisms. Immunocompromised people present a significant challenge to healthcare providers. In helping these people cope with infections, prevention of infection and proper nutrition are often as important as drug therapy. Resistance Resistance can be natural or acquired, and refers to the ability over time to adapt to an antibiotic and produce cells that are no longer affected by a particular drug. Because anti-infectives act on specific enzyme systems or biological processes, many microorganisms that do not use that system or process are not affected by a par- ticular anti-infective drug and are said to have a natural or intrinsic resistance. When prescribing a drug for treatment of an infection, this innate resistance should be anticipated. The selected drug should be one that is known to affect the specific microorganism causing the infection. Since the advent of anti-infective drugs, micro­ organisms that were once very sensitive to the effects of particular drugs have begun to develop acquired resist- ance to the agents (see Box 8.3). This can result in a serious clinical problem. The emergence of resistant strains of bacteria and other organisms poses a threat. Anti-infective drugs may no longer control potentially life-threatening diseases and uncontrollable epidemics may occur. Acquiring resistance Microorganisms develop resistance in a number of ways, including the following: • Producing an enzyme that deactivates the antimicrobial drug. For example, some strains of bacteria that were once controlled by penicillin now produce an enzyme called penicillinase, which inactivates penicillin before it can affect the bacteria. This occurrence led to the development of new drugs that are resistant to penicillinase. • Changing cellular permeability to prevent the drug from entering the cell or altering transport systems

to exclude the drug from active transport into the cell. • Altering binding sites on the membranes or ribosomes, which then no longer accept the drug. • Producing a chemical that acts as an antagonist to the drug. Most commonly, the development of resistance depends on the degree to which the drug acts to elimi- nate the invading microorganisms that are most sensitive to its effects. The cells that remain may be somewhat resistant to the effects of the drug, and, with time, these cells form the majority in the population. These cells differ from the general population of the species because of slight variations in their biochemical processes or biochemicals. The drug does not cause a mutation of these cells; it simply allows the somewhat different cells to become the majority or dominant group after elimination of the sensitive cells. Other microbes may develop resistance through actual genetic mutation. A mutant cell survives the effects of an antibiotic and divides, forming a new colony of resistant microbes with a genetic composition that provides resistance to the anti-infective agent. Vancomycin ( Vancocin ) is an antibiotic that interferes with cell wall synthesis in susceptible bacteria. It was developed as a result of a need for a drug that could be used both in people who are intolerant to or allergic to penicillin and/or cephalosporins and in the treatment of people with staphylococcal infections that no longer respond to penicillin or cephalosporins. This anti- infective drug can be used orally or intravenously to treat life-threatening infections when less toxic drugs cannot be used. It is used orally as prophylaxis against bacterial endocarditis in people who cannot take penicillins or cephalosporins and to treat staphylococcal infections in people who cannot take these groups of drugs. Because vancomycin may be highly toxic, its use is reserved for very special situations. It can cause renal failure, ototoxicity, superinfections and a condition known as “red man syndrome”, which is characterised by sudden and severe hypotension, fever, chills, paraesthesias and erythema or redness of the neck and back. When it is the only antibiotic that is effective against a specific bacterium, however, the benefits outweigh the risks. Usual dosage Adult: 500 mg to 1 g PO or IV q 6 hours for 7–10 days. Paediatric: 40 mg/kg/day PO or IV in four divided doses; do not exceed 2 g/day. ■■ BOX 8.3  Bacterial resistance to an anti-infective drug